LSF Magazine Winter 2013

FACTOR VIIIThe Race to Clone

Winter 2013

LSF MagazineTelling the Story of Biotechnology

Two pioneering biotech companies race to manufacture a recombinant version of the vital clotting factor

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Departments02 LSF News

Updates on the Foundation and affiliates + a look at Rare Disease Day

06 LSF Oral History ProgramJames Blair

08 Advisory Board SpotlightJames Greenwood

10 Gems from the ArchivesBiogen’s Ambitious Plan

12 Biotech BookshelfBiopunk

Features14 The Polymerase Chain Reaction

Thirty Years On

26 Archetypal BioentrepreneurAlejandro Zaffaroni, Part II

42 The Race to Clone Factor VIIIGenetics Institute vs. Genentech

58 A Hard Man with a Soft SpotArlen Specter, in memoriam

Editor Mark Jones

Staff Writers Brian Dick Gavin Rynne

Contributor Josh Roberts

Production Manager Donna Lock

Design/Layout Zachary Rais-Nor-man

Thanks to David Gelfand Gabe Schmergel Ana Leech Matilda Nieri Dan Adams for historical documents/photos42

Mark Jones

Heather Erickson

This year marks a number of noteworthy anniversaries in the life sciences and biotechnology. Sixty years ago, James D. Watson and Francis Crick deciphered the molecular structure of DNA. Forty years ago, Herbert Boyer and Stanley N. Cohen invented recombinant DNA technology. Thirty years ago, Kary Mullis con-ceived the polymerase chain reaction (PCR).

Over the course of the year, LSF Magazine will look back on these fundamental discoveries, review the conditions and actions that gave rise to them, identify the factors that determined their evolutionary paths, and consider the practical impacts they have had in science, medicine, agriculture, energy, and other areas of modern life.

In this issue, we commemorate the invention and refinement of PCR at Cetus Corporation in the mid-1980s, and take note of subsequent enhancements and improvements devised at Perki-nElmer, Roche Molecular, and numerous other R&D organiza-tions.

PCR has transformed the life sciences and biomedicine. It has facilitated exponential increases in the efficiency, speed, and throughput of myriad laboratory procedures requiring the manipu-lation of DNA. It has enabled momentous advances in biological understanding and vastly expanded the technical capacities of life scientists to make interventions in biological processes. PCR will be identified rightly as one of the leading scientific and technologi-cal breakthroughs of the 20th century.

The cover story in this issue revisits efforts at two early biotech-nology companies, Genentech and Genetics Institute, to clone the

gene that codes for Factor VIII. Factor VIII is a blood protein that plays a crucial role in the complex biochemistry of blood clotting. For hemophiliacs who lack it, purified Factor VIII is a life-saving therapy. The isolation and sequencing of the Factor VIII gene posed a formidable technical challenge that was over-come only by extraordinary ingenuity, skill, and persistence.

Many of the obstacles that confronted cloners at Genentech and Genetics Institute have since been elimi-nated by PCR. Comparing the conditions of ‘gene work’ before and after the introduction of PCR highlights both the magnifi-cence of Mullis’ invention and the remarkable efforts of molecular biologists who achieved great things without it.

There are other anniversaries to note. Thirty-five years ago, an early and influential biotech startup got underway in Ge-neva, Switzerland – Biogen (see p. 10). Thirty years ago, the U.S. Congress passed the Orphan Drug Act, a piece of legislation that engendered sweeping changes in science, medicine, industry, and the nation’s health. Our brief on the recent February observance of ‘Rare Disease Day’ (p. 4) reviews the history of the law and its reverberating impacts.

Finally, the Biotechnology Industry Organization (BIO) cel-ebrates its twentieth this year. LSF Magazine is pleased to include in this issue contributions from BIO’s founding President, Carl Feld-baum (p. 58), and current President James C. Greenwood (p. 8).

Diving into 2013, LSF is excited by the significant progress we are making on our major projects – a definitive history of the industry’s early years and a robust oral history program to capture the stories of biotech’s founders. Both projects will reach mile-stones later this year. The “Big Book”, a comprehensive publication on the history of biotechnology, will move onto publication at year-end and, later this fall, we are poised to complete our 100th oral history interview.

But LSF is not just about collecting primary source materials and writing a book. We endeavor to provide accessible snippets of the history in our magazine and through our web and social media presences – constantly expanding our materials for scholars and lay audiences alike. In the coming year, LSF’s team will be looking for additional outlets to share these inspiring stories. We are exploring opportunities with documentary film, curriculum

supplements, and self-directed learning. We are also reaching out to research institutions across the country in an effort to develop a sustained and coordinated archival strategy for our industry.

As is the case in this issue and in our broader activities, LSF welcomes contribu-tions, criticisms and input to all our work. Know of a story you’d like to help us tell? Have corrections or additional insight to share in a letter to the editor? Let us know. And, we are always on the lookout for great new archival materials and anecdotes that help bring biotech’s history to life. I invite you to contact me at any time with thoughts on how we can better serve the life sciences community at [email protected].

From the president and CEO

From the editor

LSF News

Foundation & Event Updates

2 LSF Magazine Winter 2013

LSF Welcomes Michael Hammerschmidt Michael Hammerschmidt has joined the LSF staff to lead the Foundation’s development effort. He brings thirty years of fund-raising experience in both established and startup academ-ic and non-profit healthcare organizations. Most recently, Michael served as Senior Advi-sor to the National Institute for Psychobiology at Hebrew University in Tel Aviv, Israel. He will be based in Boston.

LSF Board Member RecognitionGeorge Scangos, CEO of Biogen Idec, was recognized on Fortune’s 2012 Businessperson of the Year list. He also received a Lifetime Achievement Award from the East West CEO Conference. On November 28, Dennis Gillings of Quintiles received the prestigious SCRIP Lifetime Achievement Award in London and Art Levinson was awarded the Cold Spring Har-bor Laboratory Double Helix Medal in New York.

Biotech Documentary Film ProjectLSF is collaborating with Radi-ant Features to produce a one-hour documentary film on the beginnings of biotechnology for public broadcast. The film will add another dimension to LSF’s program for capturing the history, preserving the heritage, and sharing the stories of the biotech industry. The project is currently in preliminary plan-ning stages. For more infor-mation contact Donna Lock, Director of Communications at [email protected]

Book UpdateLSF is making great progress on writing a book on the origins of the commercial biotech industry scheduled for completion in 2014. The book follows the careers and exploits of the enterprising scientists, financiers, and businesspeople who established the world’s first biotechnology companies in the period from 1971 through 1982.

Event Recaps

What’s Past is Prologue in San DiegoOn November 7, The Life Sciences Foundation and

UC San Diego Library presented a first of its kind event, What’s Past is Prologue: Creating the Life Sciences Indus-try in San Diego featuring legendary venture capitalists (left to right) Kevin Kinsella, Tim Wollaeger, and Jim Blair and moderated by Ivor Royston. View photos and video at lifesciencesfoundation.org/sandiego.html

Winter 2013 LSF Magazine 3

April 15 in San Francisco: The Centaur and the Whale: Cetus, Chiron, and the Emergence of Bio-technology. Please join us to hear the founders and leaders of Cetus and Chiron discuss the origins of the life sciences industry in the San Francisco Bay Area during the 1970s and 1980s. Ed Penhoet, for-mer CEO of Chiron, will moderate. Chiron co-founders Bill Rutter and Pablo Valenzuela will be on hand as panelists, along with former President of Cetus, Hollings Renton, and former Vice-President Frank McCormick.

Through March 10 in Seattle: The Seattle Repertory Theater presents Photograph 51 - an intriguing portrait of British x-ray crystallographer Rosa-lind Franklin and the crucial contributions she made to the discovery of the double helix.

March 14 – 15 in Boston: Registration is now open for the MassBio Annual Meeting. Events on the agenda include the Henri Termeer Innovative Leadership Award Luncheon, and presentation of the Lead-ing Impact Award and the Joshua Boger Innovative School of the Year Award. massbio.org

March 21 in San Diego: CONNECT’s Entrepreneur Hall of Fame Awards. Each year CONNECT honors individu-als who have achieved distinc-tion in founding or advancing a San Diego technology-based or life sciences business or or-ganization. This year’s honoree is Ron Taylor, co-founder, Chairman and Chief Executive Officer of Cardinal Health 301. connect.org

April 22 – 25 in Chicago: The Biotechnology Industry Organization (BIO) celebrates its 20th anniversary this year, at the annual BIO International Convention in the Windy City. bio.org

Other Upcoming Events

Save the Date for Upcoming LSF EventsJune 4 in Boston: The Origins of Biotech in Boston. 4:30 – 6:30 p.m. at the Hotel Marlowe in Cambridge

25th Annual CONNECT Most Innovative New Product AwardsCongratulations to Life Technologies and Amylin Pharmaceu-

ticals! Both companies were recognized with Most Innovative New Product Awards at CONNECT’s annual luncheon on December 7. Life Technologies was honored for the ION Proton Sequencer, and Amylin for its new diabetes compound, Bydureon®. Greg Lucier, Chairman & CEO of Life Technologies received the Dis-tinguished Contribution Award in Life Science Innovation.

The Evolution of HIV/AIDS Therapies in Palo AltoOn December 4, LSF and the Chemical Heritage Founda-

tion co-presented a special event at the Gordon and Betty Moore Foundation. Moderator Jeffrey Sturchio sat with four leaders in HIV/AIDS research, policy, and practice – Gregg Alton and Norbert Bischofberger of Gilead Sciences, and Sir Richard Feachem and Paul Volberding of the University of California, San Francisco – to discuss both the remarkable progress that has been made in the treat-ment of HIV infection, and challenges still to be met.

The Rare Disease Day logo


Rare Disease Day

February 28th was Rare Disease Day in the United States and over forty countries worldwide. Hundreds of organizations repre-senting patients, families, and caregivers held events to raise public awareness and focus the attention of legislators on healthcare chal-lenges posed by rare illnesses. Rare Disease Day was first observed in Europe in 2008. The event was promoted by EURORDIS, the leading European rare disease advocacy organization. Five years of networking and cooperative action have turned the event into a global phenomenon.

In the United States, a rare disease is defined as one that af-fects fewer than 200,000 people. There are approximately 7,000 such illnesses that affect some 30 million Americans. For the vast majority, there is no treatment. These rare disorders are also known as orphan diseases because, prior to legislation designed to rectify what had become a dire situation in a nation that prided itself on having the world’s premier healthcare system, pharmaceutical corporations lacked economic incentives to develop drugs for them. The potential markets were insufficient in size to justify investments in expen-sive and risky R&D programs. The economic and medical realities combined to produce a mas-sive public health dilemma.

The problem was not addressed until the late 1970s and early 1980s when a coalition of patient groups recognized that biomedical research – a sizable portion of which was funded by the advocacy organizations themselves – was not leading to progress in drug development. The coalition partners soon came together formally as the National Organization for Rare Disorders (NORD). They lobbied for legis-lative action and embarked on an effective campaign to raise public awareness. Responding to a groundswell of support for compas-sionate aid to patients and families battling rare diseases, the 98th US Congress ratified the Orphan Drug Act (ODA) with strong bipartisan approval. President Ronald Reagan signed the Act into law on January 4, 1983.

To academic institutions and pharmaceutical companies ad-dressing the needs of small patient populations, the ODA afforded drug development grants, tax credits for research expenditures, fast-track regulatory approvals, and seven-year market exclusivity.

A subsequent amendment exempted orphan drug developers from FDA user fees charged under the Prescription Drug User Fee Act (PDUFA) of 1997.

The ODA incentives facilitated the early growth of two of the biotech industry’s largest and most successful drug makers, Genen-tech in South San Francisco, California and Amgen in Thou-sand Oaks, California. Genentech’s recombinant human growth hormone, Protropin®, was granted orphan drug status in 1985. In 1989, Amgen received the designation for Epogen®, a recombinant form of erythropoietin, a red blood cell growth factor used to treat anemia in kidney dialysis patients. Another industry giant-in-the-making, Genzyme, headquartered in Cambridge, Massachusetts, made unmet medical needs the principal focus of its research and development operations. By producing a string of enzyme

replacement therapies accorded orphan status (the first was introduced in 1992), Genzyme demonstrated the

viability of rare disease niche marketing as a pharmaceutical business growth model.

A flock of drug companies both large and small have since fol-

lowed Genzyme’s lead. As a result, more than 350

new orphan drugs have been introduced in the United States, and hun-dreds of other therapies are moving through the laboratory and clinical testing pipeline. The global market for

orphans has also expanded rapidly. Total annual sales

have surpassed $50 billion. Biopharmaceutical makers cur-

rently working on drugs for rare diseases include Actelion, Aegerion, Alexion, Amicus, Biomarin, Celgene, Isis, Protalix, Raptor, Santhera, Sarepta, Shire, Synageva, and Viro-Pharma. Lately, large pharmaceutical corporations have also begun dedicating substantial resources to research on orphans, with Novartis, Pfizer, and GlaxoSmithKline leading the way. The trend is a striking indication of how effectively NORD, the ODA, and small biopharmaceutical firms have responded to the rare disease challenge over the past three decades.

Pricing remains a difficult and controversial issue. Consumers and taxpayers are making great sacrifices to underwrite therapies for patients with rare diseases. The financial burden is growing. At

LSF News

A portion of the photos uploaded to the Rare Disease Day gallery

“Nature is nowhere accustomed more openly to display her secret

mysteries than in cases where she shows tracings of her workings

apart from the beaten paths; nor is there any better way

to advance the proper practice of medicine than to give our minds to the discovery of the

usual law of nature, by careful investigation of cases

of rarer forms of disease.”

William Harvey (1578-1657) English physician


over $400,000 per patient, per year, Alexion’s Soliris® is the most expensive drug in the world, but it is the sole treatment available for a life-threatening blood disease, paroxysymal nocturnal hemoglobinuria (PNH). There are fewer than 6,000 PNH patients in the United States. The sustainability of such pricing structures is an open question. As drug prices escalate amidst calls for fiscal austerity and health-care reform and cost containment, loads of stress increase on every beam, joint, seam, and suture in the healthcare system. The pressures are felt simultaneously by patients, families, physicians, government agencies, academic researchers, insurance companies, and pharmaceutical developers.

In this environment, plenty of work re-mains for rare disease advocacy groups. They continue to educate patients, healthcare providers, and the general public, and to work cooperatively with governments and the pharmaceutical industry to promote and sustain commitments to

biomedical and pharmacological research on rare diseases – in-quiries that may not only transform the lives of patients

and families but create healthier, more productive, and more humane societies. The international

observance of Rare Disease Day has become the focal point of their efforts.


James C. BlairLSF Oral History Program

By any measure, Jim Blair has had a stellar career. Domain Associates, the investment firm he founded in 1985, has supported the formation and maturation of over 250 biotech and biomedical companies. Blair served as a director on the boards of more than forty of them. His oral history consists of reflections on forty-three years of professional experience in finance and technology develop-ment. Here we present a few excerpts, some of Blair’s observations regarding mentors and colleagues – major figures in the history of the venture capital industry.

After making a start as an engineering manager at RCA (while simultaneously earning a PhD at the University of Pennsylvania) young Jim Blair made a move to Wall Street in 1969. He worked first as an investment analyst at F.S. Smithers & Company. He was mentored there by Charlie Lea, who evaluated high tech deals for Smithers’ wealthy clients. Blair assisted and learned about venture investing. After two-and-a-half years, Lea left to join New Court Securities, the venture arm of N.M. Rothschild & Sons. Blair moved on to investment banking at White, Weld & Co. In 1978, he was recruited by Lea to New Court, just as opportunities in bio-technology were beginning to appear.

At New Court, Blair met and worked closely with Lord Victor Rothschild, a scientist by training and a close friend of famed molecular biologist Sydney Brenner. The British peer kept a watch-ful eye on the early development of biotech-related research, and soon decided to establish a dedicated life science investment fund, Biotechnology Investments Limited (BIL). Rothschild appointed David Leathers to serve as the fund’s chief operative in England. Blair became the principal US agent. Like many early participants in the venture capital industry, Blair lacked formal training in the life sciences, and had to learn quickly. He was tutored by Brenner, who traveled frequently to the United States to make rounds with scientific contacts.

In 1980, promising investment opportunities in California – startup projects that turned into Amgen and Applied Biosystems – brought Blair into contact with West Coast venture capitalists. The venture capital business was first professionalized in the United States after World War II, in two different locales – on the East Coast, principally in New York City and in Boston, Massachusetts, in close proximity to the efflorescence of electronics and computing firms along Route 128, and on the West Coast in the San Francisco Bay Area, in and around the flourishing entrepreneurial hotbed of Silicon Valley. Blair came from New York, was introduced to West Coast peers by Charlie Lea, and observed stylistic differences:

I started to understand that western VCs didn’t think the same way as eastern VCs about deal structures. In the West, there was more interpersonal involvement with en-

trepreneurs. There was a certain formality to relationships in the East, probably because the people in the East were working for wealthy families – the Rockefellers, Whitneys, Phipps, and so on. They were agents of well-to-do people, and in many cases, weren’t authorized to make decisions without going back to get approval. So, there tended to be more stiffness in their relationships.

Pitch Johnson was one of the West Coast VCs with whom Blair worked closely, first on the board of directors at Amgen, and on several later deals. Blair studied Johnson’s methods and came to appreciate his understated approach. He was particularly impressed by the friendly but incisive questions that Johnson put to prospec-tive entrepreneurs. Blair explains that Johnson possessed a knack for eliciting full disclosures and uncovering weaknesses in business plans without appearing critical or invasive:

When Pitch heard something that he found incredible, he wouldn’t say, ‘I don’t believe that.’ He would probe a little deeper. He would say, ‘That’s a very interesting state-ment, let’s explore that ….’ He remained a total gentle-man throughout the whole process. At the end of the day, the individual was undressed, but didn’t realize it. The

Oral histories are narrative accounts of events and historical processes as told from the point of view of eyewitnesses and participants. They preserve the experiences, recollections, and testimonies of history-makers. The latest addition to LSF’s digital archive of oral histories is a conversation with life science venture capitalist James C. Blair.


impression was that we remained extremely interested, and that as soon X, Y, and Z were provided, we would move forward aggressively. The individual would leave the room with a sense of eagerness on our part to proceed, but the truth might have been quite the contrary. Pitch had established some deliverables. If they weren’t delivered, we wouldn’t move forward. So the individual was in control of his or her own destiny, but sometimes there were things that Pitch knew would never be delivered. Stylistically, I came away with a phenomenal admiration for him. He is a very bright guy who never wore his intelligence on his sleeve. He never tried to ‘one up’ anyone in conversation. He got where he needed to go as effectively as the smartest man in the room. I always felt that Pitch was the smartest man in the room.

Blair was also influenced significantly by the example and coun-sel of Tommy Davis, with whom he served as a director at Applied Biosystems. Davis was one of the original Silicon Valley money men. In 1961, he co-founded the firm of Davis & Rock with ven-ture capital legend Arthur Rock. The pair invested in Teledyne, a seminal California electronics firm, and Scientific Data Systems, an early computer maker. In 1969, Davis founded the Mayfield Fund in Menlo Park. Blair visited the firm regularly on western trips, to see close family friend and Mayfield partner, Grant Heidrich. While on the premises, he says, “I would often find a way to go to Tommy’s office and spend some time talking to him.” He credits Davis with shaping his approach to doing business at Domain:

Tommy was a straight shooter. He had some very simple tenets regarding how to treat limited partners fairly, how to run a firm, how to pay your people, how to treat them. When I decided to set up Domain, a lot of the philosophy I brought to it came from conversations with Tommy. At that stage in my life, he was the right person at the right time. I learned a heck of a lot from him. I think all of the people who worked with him felt the same way about him. There weren’t a lot of people that didn’t like Tommy.

After more than thirty years in venture capital, Blair has many friends in the business, too. He especially enjoys the company of a good-humored fellowship formed in 1996 when investors in Athena Neurosciences gathered to celebrate the sale of the com-pany to the Élan Corporation, a drug maker headquartered in Ath-lone, Ireland. Athena was founded in 1989 to develop treatments for Alzheimer’s Disease (AD). Scientists at the firm developed a transgenic mouse carrying a human gene associated with AD. The mouse provided a unique model for studying the progression of the disease. It was exciting, promising science, but it was becoming harder and harder in the mid-1990s for investors to generate mar-ket value and realize returns on the basis of encouraging research.

“Everybody,” Blair recalls, “was excited about dot.coms and the in-ternet boom. We were getting trashed by high-tech investors who wondered why we were even bothering with the biotech stuff.”

While Wall Street became transfixed by the emerging dot.com boom, the biotech sector remained mired in red ink. Life science venture capitalists felt beleaguered. When Athena was sold, and the science was saved, and obligations to limited partners were discharged, the original investors met to toast their hard-earned success. To set the tone, Brook Byers played a video clip of Sir Laurence Olivier’s stirring ‘band of brothers’ speech from the 1944 film version of Shakespeare’s Henry V. As the story goes, the mon-arch addressed his troops on October 25 – St. Crispin’s Day – in 1415 to inspire them to victory against the French in the Battle of Agincourt. The band of biotech brothers continues to meet every year in order to boost morale, celebrate accomplishments, and commiserate over tough times and disappointments. “We call it the St. Crispin Society,” says Blair. “Even if we’re sitting in a good restaurant or club in San Francisco, we always play that video as the preamble.”

From this day to the ending of the world,But we in it shall be remembered-

We few, we happy few, we band of brothers;For he today that sheds his blood with me

Shall be my brother; be he ne’er so vile,This day shall gentle his condition;

And gentlemen in England now-a-bedShall think themselves accurs’d they were not here,And hold their manhoods cheap whiles any speaks

That fought with us upon Saint Crispin’s day.

—William Shakespeare, Henry V

To read more about Jim Blair’s distinguished career in life science venture capital, please visit www.biotechhistory.org/oralhistories


Advisory Board Spotlight

James Greenwood

In July 2004, James C. Greenwood, US Representative for Pennsylvania’s Eighth Congressional District, announced unex-pectedly that he would not seek re-election for a seventh term in office. Greenwood was a popular moderate Republican. He had already secured his party’s nomination with a victory in the spring primary election, but had subsequently received an invitation to become President & CEO of the Biotechnology Industry Organi-zation (BIO).

Greenwood explained to his constituents that the opportunity and the mission were too important and too exciting to ignore. BIO is the world’s largest biotechnology trade association. Head-quartered in Washington, D.C., it represents and assists more than 1,200 biotechnology companies, research centers, and universities in the United States and thirty other countries – institutions and organizations that strive to improve the health and material well-being of people all around the world.

At the time of his announcement, Greenwood had held politi-cal office for twenty-four consecutive years – six in the Pennsyl-vania General Assembly, six in the State Senate, and twelve in Washington, D.C., in the House of Representatives. As a senior member of the House Energy and Commerce Committee, he was widely recognized as a leader on health care and environmental policy issues. From 2001 to 2004, he served as Chairman of the Subcommittee on Oversight and Investigation and led hard-hitting investigations into corporate misconduct at Enron, Global Cross-ing and WorldCom, terrorist threats to the nation’s infrastructure, and waste and fraud in federal government agencies.

Greenwood’s path into public service began shortly after he graduated from Dickinson College in Carlisle, Pennsylvania in 1973, with a degree in sociology. He was deeply committed to conservation and environmental protection. He calls himself “a typical baby-boomer hippie.” With youthful enthusiasm, he resolved to ‘get back to nature’ and to live off the land, as simply as possible. He went to the Parks & Recreation Department of Bucks County, Pennsylvania, inquired about residences, and volunteered to serve as a caretaker. He learned that the county owned a Nature Center and intended to hire a live-in curator.

The position entailed service as a part-time naturalist and a weekend park ranger. Part of the job was learning the local flora and fauna – wildflowers, trees, insects, birds, and so on. To Green-wood, it sounded ideal. He applied for the job and was hired: “I ran to the bookstore, bought field manuals and a pair of binocu-lars, and started to find birds. I started working on the Audubon Bird Census, which takes place twice a year. There is a Christmas count and another in the spring during the migratory season.”

The nature work led Greenwood to the next phase of his career.

The county needed a caretaker because local kids were vandal-izing the Nature Center. “They wanted me to chase them away,” he recalls. “What I did instead was invite them to come into the Nature Center. I created a nature club for local kids. A lot of them came from broken homes in tough places and tough circum-stances. Because of that experience, I decided to start working with kids.” Greenwood became a house parent at the Woods Schools, a Pennsylvania institution dedicated to serving the needs of develop-mentally delayed and emotionally troubled children. From there, he went into social work. He joined the Bucks County Children and Youth Social Service Agency, and worked with abused and neglected children until making his first run for elected office in 1980.

Greenwood never gave up birding: “I continued to work on the Audubon counts. Birding has become a lifelong hobby and pas-sion. When I travel I take my binoculars and my bird guides.” He has logged sightings of over three hundred North American birds. He was recently inspired to work seriously on his photographic skills. After joining a Bucks Country nature group called Bucks Birders, and subscribing to the group’s blog, he took notice of pho-tographs posted regularly by Howard Eskin, a well-known birder, now seventy-seven years old and making nature photography the principal occupation of his retirement. “I was so impressed,” says Greenwood, “that I sent an email. I said, ‘I really admire your photographs. I’d love to learn at the master’s knee. Can I tag along with you?’ We go out almost every weekend, if weather permits, to regional sites such as the Brigantine National Wildlife Refuge and the Barnegat Light Jetty in New Jersey, and Bombay Hook National Wildlife Refuge in Delaware. I’m learning as I go.”

Please enjoy Jim Greenwood’s photographic work…


Left to right, top to bottom: Goldfinch;Yellow-rumped Warbler;Red-winged Blackbird;Dickcissel;Common Yellowthroat;Allen’s Hummingbird;Great Egret;Black-crowned Night Heron


Gems from the Archives

Biogen’s Ambitious Plan

Thirty-five years ago, on March 1, 1978, venture capitalists Dan Adams, Moshe Alafi, Kevin Landry, and Ray Schaefer con-vened a meeting with some of the world’s top molecular biologists at the Hotel Le Richemond in Geneva, Switzerland. On hand were Walter Gilbert of Harvard University, Brian Hartley (Imperial College London), Peter-Hans Hofschneider (Max Plank Institute, Munich), Phillipe Kourilsky (Institut Pasteur, Paris), Bernard Mach (University of Geneva), Kenneth Murray (University of Ed-inburgh), Heinz Schaller (University of Heidelberg), Phillip Sharp (MIT), and Charles Weissmann (University of Zurich).

The financiers explained their interest in starting a recombinant DNA (rDNA) company. They were believers. They were certain that the technology could generate useful products in medicine, agriculture, and industrial processing. They proposed a startup and invited the scientists to participate, but failed to secure commit-ments. At a second meeting in Paris three weeks later, however, the biologists huddled and agreed to sign on. They had been reassured that they would retain control of the company’s research programs.

The firm, called Biogen, was formally incorporated in Luxem-bourg. Adams opened an office in Geneva, and drew up a business plan dated May 19, 1978. The document introduced the intended purpose of the company, staff, finances, and so on, and then reviewed the fundamentals of recombinant DNA. The next section outlined projects that the scientists had identified as commercially promising and technically feasible. Interferon was first on the list. The interferon work was performed in the Zurich laboratory of Charles Weissmann, who wrote about the episode in a famous scientific memoir entitled “The Cloning Interferon and Other Mistakes.”

Further down the list of proposed projects, on pages twenty-two and twenty-three, sandwiched between discussions of ethanol and antineoplastic enzymes, was a précis on the opportunity to develop a vaccine against the hepatitis B virus, often the cause of chronic and damaging infections of the liver. A plan was formu-lated to clone a non-infectious viral coat protein called HBsAg.

Most of the work was performed in Britain, since Ken Mur-ray of the University of Edinburgh led the project (along with Peter Hans Hofschneider, who traveled from Germany to perform cloning procedures in a P4 containment facility at Porton Down, outside of Salisbury in Wiltshire. In the late 1970s and 1980s, there were still concerns about possible rDNA biohazard risks).

Murray came originally from the English Midlands. He left school at the age of sixteen to work as a lab technician at Boots, the English pharmacy company that invented ibuprofen. He eventually returned to academics, at first taking classes on a part-time basis, and then carrying on until he was awarded a PhD in

microbiology from Birmingham University.Murray accepted a faculty position at Edinburgh and took up

the study of restriction enzymes shortly after Werner Arber, Daniel Nathans, and Hamilton Smith reported the first isolations in 1970. That work prepared him to take part in the biotech revolution when Adams, Alafi, Landry, and Schaefer appeared on the scene.

Murray obtained HBsAg-positive plasma samples from medical colleagues in Edinburgh, and managed to clone the protein in 1981. Biogen subsequently developed a therapy, but was not first to market with a recombinant vaccine against hepatitis. On July 23, 1986, Merck & Company received approval from the US Food and Drug Administration (FDA) to sell Recombivax HB®, the world’s first genetically-engineered vaccine. The product had been developed by the Chiron Corporation of Emeryville, California.

The Biogen vaccine, licensed to SmithKline Beckman and called Engerix-B®, was not approved until January 1988 when the FDA endorsed its use in the United States, but when released, it quickly dominated the market. It was more effective and priced considerably lower than the Merck product.

As the sole inventor on the patent, Murray was in line to re-ceive substantial royalties from sales of the therapy, but he declined them and instead established the Darwin Trust to support educa-tion and research in the natural sciences. He was later knighted for a extraordinary career in science, medicine, and industry, and for excellent service to the realm.


left: From pages 22 and 23 of the 1978 Biogen business planopposite:A portrait of Sir Kenneth Murray and Lady Noreen Murray, by Fionna Carlisle, University of Edinburgh Fine Art Collection


Biotech Bookshelf

Biopunk

Some are professionals, some are students, some are self-taught amateurs. All are ‘biopunks,’ participants in the DIY (Do-It-Yourself ) biology movement. They are ‘citizen scientists’ keen to challenge widespread assumptions about the character and preconditions of biological research.

DIY biology refers to low-budget and sometimes low-tech biological research carried out individually or collectively, not in properly outfitted laboratory facilities, but in mostly private and rarely well-equipped spaces – kitchens, garages, or rented space in strip malls or old warehouses, for example. The phenom-enon is growing, and the methods and varieties of inquiry are multiplying. Like a robust culture in a petri dish, DIY biology is spreading rapidly many directions. Marcus Wohlsen’s Biopunk offers a wide-ranging overview.

SMALL SCIENCEDIY biology is not new. Contemporary biopunks carry

on a long tradition of small-scale, self-sufficient independent research in the biological sciences. Many important life science discoveries of the twentieth century were made in ‘legitimate’ laboratories not much better-equipped than the average modern kitchen. In 1952, for example, Hershey and Chase’s famous ‘blender’ experiment confirmed that viral replication in bacteria is accomplished by DNA and not proteins. The experimen-tal apparatus was an ordinary household appliance, a Waring Osterizer.

Biopunks believe that access to laboratory hardware should not limit inquiry in the life sciences. Many are finding low-cost ‘work arounds’ for their experiments. They often make what they cannot afford to buy. Some have turned the manufacture and sale of low-end laboratory equipment into small businesses. ‘Open source’ PCR kits are available online for $600. According to Wohlsen, it is now possible to assemble a fairly sophisticated wet lab for the price of a small used car.

Community wet labs are springing up in urban centers. New York’s Genspace and the San Francisco Bay Area’s BioCuri-ous, for example, offer laboratory space and access to supplies, equipment, and instrumentation for low monthly membership

fees. Genspace opened the country’s first ever community-based Biosafety Level One laboratory space in Brooklyn in 2010.

MULTIPLE RESEARCH ETHICSThe motivations of DIY scientists are varied. For some,

biological research is simply fun – a diversion, a hobby. For others, it is a serious avocation – the point is to make important discoveries and to advance the boundaries of knowledge in the life sciences. Some use DIY biology to educate. They set up teaching laboratories in order to share a passion for science and to train the next generation of experimentalists.

A significant biopunk minority is driven by commercial ambitions. Inspired by the early computer industry, some DIY scientists hope to build the next Genentech from humble begin-nings in their garages. Others conduct biomedical research,

Marcus Wohlsen, Biopunk: Solving Biotech’s Biggest Prob-lems in Kitchens and Garages (New York: Penguin, 2012).


often with a sense of great urgency, to learn about a medical condition affecting themselves, a family member, or a larger patient community.

Another biopunk constituency takes its inspira-tion from techie and cybercultures that originated in the Bay Area in the 1970s and 1980s and have now spread all around the world. Self-proclaimed ‘biogeeks’ are importing the subversive attitudes of computer hackers to the life sciences. They are on a mission to democratize knowledge and reclaim biol-ogy from firmly ensconced, well-heeled institutional experts. In this register, DIYbio becomes overtly po-litical, a movement that poses libertarian challenges to regulation, whether corporate or governmental.

But the leveling of elites and masses may not require a revolution. Digital technologies are rapidly bringing ‘big data’ within reach of the common biopunk, and the scientific mainstream does not oppose the DIYbio movement. In the main, the pros applaud efforts to improve scientific literacy. They encourage positive contributions from ‘citizen scientists.’

BIOSECURITY At the same time, lurking in the shadows of

Wohlsen’s story is the fact that DIY biology makes many people uneasy. In the public mind, the life sci-ences have become associated with risk and danger – with ‘Frankenfoods,’ bioterrorism, viral pandemics loosed by H5N1 research, the creation of transgenic monstrosities, etc. Sensationalizing media repre-sentations often induce anxieties. Consequently, homebrew genetics and microbiology can be socially awkward pastimes.

Late sections in the book deal with post-9/11 biosecurity. On the one hand, the FBI has enrolled DIYbio research communities as sentinels on the

lookout for suspicious movements of equipment and materials. On the other, many DIY investigators are reluctant to tell neighbors about experiments conducted in garages and lofts. Whether ‘citizen scientists’ can avoid greater regulatory oversight remains to be seen. Wohlsen concludes his informa-tive survey of the DIYbio phenomenon by noting that more biopunk science entails greater biopunk responsibility.

We reject the popular perception that science is only done in million-dollar university, government, or corporate labs; we assert that the right of freedom of inquiry, to do research and pursue understanding under one's own direction, is as fundamental a right as that of free speech or freedom of religion.

— From A Biopunk Manifesto by Meredith Patterson

Scenes from DIY bio labs


THE POLYMERASE CHAIN REACTION THIRTY YEARS ONThe idea of the polymerase chain reaction (PCR) – a laboratory protocol that copies specific genetic sequences in virtually unlimited amounts – came to biochemist Kary Mullis thirty years ago, late on a Friday night in the spring of 1983, as he drove north on Highway 128 in Mendocino County, California. PCR radically transformed the material conditions of molecular biology and genetics. It was one of the most important scientific advances of the twentieth century. Where did it come from?

Kary Mullis


AN ANTHROPOLOGICAL VIEWThe history of science is replete with discovery legends: Ar-

chimedes realized the principle of buoyancy as he stepped into a bath. The idea of universal gravitation visited Sir Isaac Newton when he observed an apple falling from a tree. German chemist August Kekulé visualized the ring-shaped structure of benzene after dreaming of a snake chasing its tail. There are many such tales.

Whether authentic or apocryphal, these stories are incomplete. When Archimedes, Newton, and Kekulé made their discoveries, they were immersed in efforts to solve practical problems. Archi-medes had been charged by King Hieron II of Syracuse to develop a method for determining the purity of gold. Newton was seeking a unified explanation for the motions of physical bodies, terrestrial and celestial. Kekulé had been attempting to work out the funda-mental chemistry of carbon-based compounds. Their insights did not appear out of the blue.

Further, intuitions must be confirmed empirically before they qualify as genuine discoveries. To test the density hypothesis, Archimedes submerged golden crowns of identical weight and compared measurements of displaced water. To account for heav-enly and earthly observations in the same manner, according to the same general laws, Newton had to work out the integral calculus. Kekulé’s proposed chemical structure was not established with certainty for more than thirty years after his death. In 1929, an x-ray diffraction image of a benzene crystal showed that the molecule was, in fact, circular. ‘Eureka!’ moments are neither beginnings nor endings.

In the case of PCR, the periods before and after the discovery are well-documented. Mullis’ own account is historical. By now retold multiple times in a Nobel Prize essay, magazine articles, a book chapter, public lectures, and courtroom proceedings, it describes how Mullis reconfigured existing methods of nucleic acid chemistry to facilitate the exponential amplification of DNA.

If, as some of Mullis’ colleagues contend, this version slights experimental work that subsequently reduced the invention to practice, the score was balanced in the early 1990s by Dr. Ramunas Kondratas, curator of the Smithsonian Institution’s National Muse-um of American History. Kondratas conducted in-depth interviews with Mullis and thirty other participants in the development and commercialization of PCR at the Cetus Corporation, and later at

Perkin Elmer and Roche Molecular Systems.In 1996, anthropologist Paul Rabinow of the University of

California, Berkeley re-examined the life and times of the inven-tion in a book called Making PCR. The narrative depicted late twentieth century molecular biology as a culture with its own distinctive practices, conventions, and values, and the introduction of PCR as a transformative episode in the history and experience of the tribe. Mullis ran through the implications of his discovery in a matter of minutes as he drove down a dark country road, but only gradually over the course of months and years did researchers at Cetus, and later far beyond, come to realize that their way of life had been irrevocably altered.

These sources treat scientific discovery as a collective rather than individual phenomenon. They also portray organizations and cul-tures as inherently conservative and resistant to change, even those that revere progress. Cetus’ molecular biologists nurtured PCR, but the company struggled simultaneously with conflicts and dis-ruptions that it engendered. For his part, Mullis was eager to push development of the new tool, but displayed slight regard for the established traditions, hierarchies, and standards of the company and the scientific community. The realization and incorporation of PCR was at once glorious and painful for all involved.

To commemorate the thirtieth anniversary of the invention, we retell the story. We review once more how Kary Mullis’ sublime idea was turned into a material procedure that revolutionized biol-ogy, medicine, and a host of other fields.

Highway 128, Mendocino County, California


DNA CHEMISTRYIn October 1979, the Cetus Corporation of Emeryville, Cali-

fornia advertised an open position for a chemist with knowledge of nucleic acids. The company needed an able manufacturer of oliogonucleotides – short, single-stranded DNA molecules that have numerous uses in genetic research as reagents and probes.

Tom White, a senior scientist at the firm, learned of the open-ing, and signaled Kary Mullis, a friend from graduate school in the Department of Chemistry at the University of California, Berkeley. Mullis was searching for interesting work. He had scant experience with nucleic acids, but he had developed an interest in the area.

Mullis thought that DNA was messy – “hard to isolate, big, long, and stringy” – but he had been impressed when Genentech synthesized and cloned a human gene in 1977. The work was

clean and artful. Mullis remembers thinking: “’Wow, somebody took a chemically made piece of DNA, stuck it into a plasmid, and reproduced it in a bacterium.’” He became interested in DNA syn-thesis. On the tip from White, he interviewed

at Cetus and was hired.At the time, making oligonucleotides was a tedious chore. Mul-

lis describes the process:

We were using the block condensation method. You had to do a lot of little reactions to make one oligonucleotide. Each of those reactions took a lot more than one proce-dure. Every condensation required many procedures. It was drudgery after a while because, although the reactions weren’t identical, they were similar enough that you became really bored. It was clearly something that needed to be au-tomated.”

Mullis began exploring the latest methods of synthesis, and searched constantly for ways to streamline production and improve quality. He was adept at computer programming and automated many of the lab’s routine functions. By early 1981, he was ap-pointed head of Cetus’ DNA synthesis operation.

Mullis’ talents were recognized and appreciated by his su-periors, including White, who had been appointed director of molecular and biological research, but it was also evident that Mullis was not a diplomat or politician. He became involved in regular scrapes with colleagues. White tells the illustrative story of a debate surrounding methods for testing the identity and purity of oligonucleotides that Mullis’ team supplied to various company laboratories:

Kary worked out a method called compositional analysis to save time in showing that his technicians had, in fact, produced the oligonucleotides that had been ordered. Since it was a new method, it took a while for it to be accepted by other scientists in the company. That was a source of conflict. The other scientists felt the products hadn’t been validated.

Mullis insisted that his technique was sound. He had little pa-tience with others telling him how to manage his scientific affairs. When experiments in other laboratories didn’t work, researchers occasionally pinned the blame on Mullis’ oligonucleotides. Trouble ensued. Finally, says White:

It was clearly something that

needed to be automated


We asked Kary to do a series of experiments to show that the compositional analysis gave the same result as accepted techniques. He thought the exercise was a waste of time. He didn’t see the need for validation, and particularly the need for him to do it. We insisted. In fact, he was correct. The methods were concordant.

The episode was a portent. Mullis established a reputation as an innovator and a reliable manufacturer of oligonucleotides, but also as a difficult, volatile collaborator. He carried on trying to advance and improve the work of his laboratory.

When word of automated DNA synthesizers began to circulate in the scientific community, Mullis ordered the instruments to try them out. The first never worked properly, but in the second instance, Mullis received a call from Ron Cook, a friend from the University of California, San Francisco who had designed a pro-toype synthesizer and was seeking to place it for trials. Mullis in-stalled it at Cetus, and after some tinkering, found that it worked. Cook’s device accomplished in a single day what had previously taken the lab an entire week.

THE DISCOVERYMullis was soon directing a largely computerized and auto-

mated operation. He had significantly improved the laboratory’s output and efficiency. With time on his hands “to think and putter,” he began considering ways in which methods of DNA synthesis could be applied to solve technical problems in other

laboratories. For example, one of the company’s molecular biology groups was attempting to develop a diagnostic assay for sickle cell anemia. Mullis thought about the project on a Friday night in the spring of 1983 as he packed his car for a weekend out of town in Mendocino County.

Sickle cell anemia is caused by a single point mutation in the beta globin gene. Mullis believed that it might be possible to modi-fy established methods of DNA sequencing to identify the pair of nucleotide bases that resides at the critical point and thereby distinguish normal and mutant versions of the gene. As he drove north on Highway 128, he worked through a series of thought experiments, considering potential problems and solutions.

Mullis knew that applying heat to a DNA molecule would cause it to unwind and separate into two single strands. He imagined that he could then fuse an oligonucleotide primer to one of the strands in a position adjacent to the point in question, preparing it for enzymatic re-hybridization with a deoxynucleoside triphosphate containing a complimentary nucleotide base (either adenine, thymine, guanine, or cytosine, the information-bearing constituents of the genetic code).

If the necessary enzyme, DNA polymerase, was added to the solution, it would incorporate a complementary base and reassem-ble the molecule. The fluorescent label would light up and reveal the identity of the nucleotide. The procedure would show whether the sample beta globin gene was normal or a mutant.

Mullis immediately recognized that if this could be accom-plished with one of the single strands, then it could also be done simultaneously with the other. The signal strength of the test would be doubled. He thought further about the implications. It occurred to him that it was not necessary to terminate hybridiza-tion after the reconstruction of a single point. Mullis saw that longer sequences could be bracketed by primers and reproduced. He realized that the protocol was not only a diagnostic assay; it was also a means of copying genes.

He considered copying possibilities, and became progressively astonished by where his thoughts were leading. If both strands of a sample gene were utilized as templates and resynthesized, the result was two copies. If the process was repeated, four would be

The polymerase chain reaction (PCR) is an efficient means of copy-ing pieces of DNA in high volumes. Reagents for the reaction include 1) the DNA sequence to be copied; 2) short single-stranded pieces of DNA called primers; 3) batches of deoxynucleoside triphosphates, the building block mol-ecules of DNA, each containing one of four nucleotide bases – adenine (A), thymine (T), cytosine (C), or guanine (G); and 4) enzymes called polymerases that ordinarily synthesize and repair DNA by adding nucleotides to existing strands and sealing them in place.

The first cycle of process begins when the piece of DNA to be copied is heated to 95 degrees Celsius. At that temperature, the double-helical structure of the molecule unwinds leaving two single-stranded pieces. The solution is then cooled to 55 degrees Celsius. At this temperature, the prim-ers bind selectively to the two strands at either the beginning or end of the target sequence and prepare it to be re-synthesized by the polymerases. The polymerases select proper complemen-tary nucleotides and add them to the primed target strands. The final result is

two copies of the desired piece of DNA where there was previously only one. The next cycle repeats the process start-ing with two molecules and concluding with four. The heating and cooling process can be repeated continuously. Copies of the original piece of DNA are reconstructed at an exponential rate.

After thirty cycles, more than a billion copies have been manufactured. The ability to make virtually unlimited amounts of specific DNA sequences has vastly extended the capacities of biological laboratories.

A PCR Primer


produced. Mullis was used to thinking about iterative loops in computer programming, where the output of an operation be-comes the input for a successive round. He quickly realized that he was looking at the potential for exponential growth.

Mullis had discovered a method for the in vitro production of unlimited supplies of specific DNA sequences. Previously, research-ers in the molecular life sciences had trouble isolating specific sequences in sufficient quantities. In the early 1980s, genes could be chemically synthesized or clipped out of DNA molecules with restriction enzymes, isolated, purified, patched into plasmids or viral DNA and inserted into cells for cloning, but these were not particularly efficient means of manufacturing genes for experi-mentation. The scarcity of genes was a limiting factor in molecular biological research.

Mullis’ thought experiment presented a possible solution. He thought, “I’ll be able to make discrete pieces of DNA. I’ll be able to do it without restriction enzymes, and I’ll be able to make as many as I want.” He was amazed, but then, in an instant, wracked by doubts. It seemed too simple: “I said, ‘My God, there’s got to be something wrong here. I’m just a little old nucleotide chemist rid-

ing down the road, heading for Mendocino. I’ve got to be missing something.’ It didn’t make sense to me that I hadn’t heard about somebody doing this.”

REDUCTION TO PRACTICEWhen Mullis returned to work on Monday morning, he asked

the Cetus librarian to conduct a literature search. Nothing turned up. He then shared the idea with all who would listen. He talked to David Gelfand, Cetus’ vice-president of scientific affairs. Mullis asked, “Has anyone done this before? Is there anything you know about DNA that says it won’t work?” Gelfand was encouraging: “It should work. It could be really important. It could create a new field of molecular diagnostics. It’s a great idea, go do it.”

Others were less impressed. Cetus lab technician Randy Saiki remembers Mullis talking about a scheme to make “obscene amounts of DNA.” He thought the idea clever, but remained doubtful about its practicality: “My molecular biology prejudices led me to think that it wouldn’t work, because of problems with the complexity of DNA.”

Some senior scientists were skeptical as well. Tom White


discussed the idea with Henry Erlich and Norman Arnheim of the company’s Human Genetics Department: “We had reasons to suspect that the method wouldn’t work. It might work on a very small sample, but in the complex milieu of total genomic DNA, the primers might not bind specifically to targeted genes.” If oligonucleotide primers bound promiscuously, the procedure would create only a mess. DNA would be amplified, but a mix of heterogeneous sequence fragments would result, not a pure supply of the desired gene.

There were a host of additional variables to consider – buffer and reagent concentrations, the timing and temperature of steps in the reaction, and so on. Facilitating conditions for the proce-dure were unknown. It had never been done before. On hearing of repeated heating and cooling steps, biochemists and molecular biologists concluded that the procedure would be complicated and cumbersome. That tended to dampen their interest.

Mullis had expected an enthusiastic response. He was antici-pating a technical revolution in molecular biology, but no one, it seemed, shared his vision: “I think the reason they thought it wouldn’t work was that the result it gave was so preposterous.” Mullis was a believer, but, as John Sninsky, the head of the com-pany’s diagnostic research explains, “Kary hadn’t been trained long enough in biology to know that things wouldn’t work.”

Mullis didn’t attempt the first experiment on PCR until September. He and assistant Fred Faloona threw the necessary ingredients into a test tube – a pBR322 plasmid (a small circular piece of bacterial DNA widely employed as a cloning vector), cus-tomized oligonucleotide primers, deoxynucleoside triphosphates in four varieties, and a commercially available segment of a DNA polymerase purified from E. coli cells called the Klenow fragment.

Reasoning that there might be enough DNA molecules separat-ing naturally into single strands even without heat cycling, Mullis and Faloona set the reaction temperature at 37 degrees Celsius, the ideal temperature for E. coli polymerase activity. They went away hoping that plasmid DNA would be amplified. It wasn’t.

The pair began to experiment with heat cycling. By December, they succeeded in amplifying a twenty-five base pair fragment of plasmid DNA well enough to convince Mullis that the invention worked, even though others at the company maintained that they would accept only copies of a single gene embedded in genomic DNA – all of the DNA contained in a cell – as a satisfactory demonstration.

Mullis and Faloona continued to refine the process. They collected data on the amplification of a fifty-eight base pair seg-ment of the pBR322 plasmid and presented it on a poster at the company’s annual scientific retreat held in Monterey in June 1984. It was mostly ignored. The protocol had not yet made a practical difference in any of Cetus’ ongoing projects.

By this time, Mullis was frustrated and deeply unhappy with what he perceived as a lack of confidence in his scientific judgment and a lack of support in the organization for the development of PCR. He was, in addition, experiencing a great deal of stress due to problems in his personal life. His relationships with colleagues deteriorated, shifting in some cases from bad to worse. White recalls that he became “belligerent and combative.” At the retreat, Mullis got into a fight with a fellow scientist and harangued White about demanding experimental proof for PCR. Some at Cetus wanted him fired.

White wasn’t convinced that PCR would work on clinical samples, but he understood the revolutionary nature of Mullis’

idea. Seeking simultaneously to defuse workplace tensions, help his friend, and smooth the way forward for the development of the technology, he relieved Mullis of duties in the oligonucleotide synthesis lab and gave him a year to focus exclusively on the devel-opment of PCR.

By November 1984, Mullis and Faloona had generated promis-ing experimental results. Technician Stephen Scharf was instructed to help with optimization of the technique. He was tasked with validating results: “Fred Faloona ran the first few reactions and brought the material down to me. I ran the assay to identify the products of the reaction. I remember the ethanol precipitating the DNA in the tube. I looked at it and thought, ‘My God, there’s an awful lot of DNA in this tube.’”

In January, Randy Saiki joined the project as well. Data indicating reduction to practice was accumulating. “By Febru-ary or March of ’85,” says White, “we all began to think that it actually worked.” Mullis had already disclosed the invention to the company’s intellectual property attorney, Al Halluin. A patent application was drawn up and filed on March 28, 1985. Mullis was the sole inventor. Commercial rights were assigned to the Cetus Corporation.

Several research groups began working in earnest to incorporate PCR into diagnostic tests for genetic diseases, including sickle cell anemia and beta thalassemia, and infectious diseases such as HIV/AIDS and chlamydia. Henry Erlich’s lab applied it to investigate the highly polymorphic genes that code for the major histocom-

My God, there’s an awful lot of DNA in this tube

Mr. Cycle

Randy Saiki


patibility complex, a set of immune cell surface mol-ecules critical in medical tissue typing. Cetus engineers began designing a device – called Mr. Cycle – that automated the process.

PUBLICATION AND CREDITWhite, Erlich, Arnheim, and Mullis met to dis-

cuss a timetable for putting PCR into the scientific literature. The plan was to publish two papers, one by Mullis, an exposition of fundamental theory and method backed up the experimental data that he and Faloona had amassed on plasmid DNA, and a second, to be submitted after Mullis’ article, reporting on PCR amplification of the beta globin gene for the diagnosis of sickle cell anemia. October was the target date for submissions.

Mullis took a long time. He believed that PCR could produce signals so strong and clean that the use of radioactivity would no longer be necessary in many standard laboratory protocols. His aim was to generate compelling data for the fundamentals paper without having to rely on radioactive labels in auxiliary valida-tions.

August came and went. In September, White told

Mullis: “You must write this thing or you’re going to be superseded by work done by other people.” Saiki, Erlich, and Arnheim were ready to publish. White suggested that Mullis incorporate a radioactive South-ern blot analysis to strengthen his data. By this time thoroughly disaffected, Mullis refused to compromise his objective.

White allowed the diagnostics group to submit their paper to Science. It was accepted but reviewers and editors insisted that the authors account for the data generated by PCR, for there was no prior account of the method in literature. A detailed description of the PCR protocol was added, the first of its kind. The article was published in December 1985.

Mullis was incensed that the paper had been revised but authorship credit had not. Randy Saiki had performed most of the hands-on lab work with the beta globin gene, and took pride of place as first author. Erlich and Arnheim appeared in the final spots reserved for laboratory directors. Mullis was buried in the middle, the fourth of seven authors. It was impos-sible from this placement to discern his contribution as the inventor of the polymerase chain reaction.

Mullis finished the fundamentals paper and submit-ted it to Nature without a cover letter explaining the significance of the invention. It was rejected. Evidently, the reviewers and editors did not comprehend the implications of the technology. Mullis then sent the paper to Science along with a cover letter that White

Taq polymerase

In the late summer of 1966, Thomas D. Brock, a microbial ecolo-gist and Professor of Microbiology at Indiana University, undertook a study of ‘extremophiles’ residing in Yellow-stone National Park. Extremophiles are microorganisms that thrive under conditions that lesser forms of life can-not endure.

On September 5, with help from graduate student Hudson Freeze, he collected a bacterial sample from a pool called Mushroom Spring, a hot spring in the Great Fountain area of Lower Geyser Basin. In October, Brock and Freeze isolated and cultured an unusual organism from the sample. Brock proposed to place it in a new genus. The culture was labeled YT-1. Brock named the microbe Thermus aquaticus. Freeze established that enzymes from the organism retained ac-tivity even in boiling water, at tempera-tures above 100 degrees Celsius.

Brock later found that T. aquati-

cus is widely distributed in hot water environments. He established and char-acterized cultures with strains collected from sites all over the world, including one that originated in the hot water system of a building on the campus of Indiana University. All of Brock’s cultures were deposited in the Ameri-

can Type Culture Collection, which made them available to any researcher. David Gelfand obtained them for Ce-tus in order to isolate and analyze Taq polymerases. The enzyme with the best properties for use in PCR was derived from the original Yellowstone strain in culture YT-1.

The Discovery of Thermus aquaticus


helped to craft. It too was rejected – the editors argued that since the applications paper had already disclosed the technique, the more detailed fundamentals paper belonged in a methodological journal.

Mullis and Faloona’s “Specific syn-thesis of DNA in vitro via a poly-merase-catalyzed chain reaction,” did not appear in print until late 1987, in an issue of Methods in Enzymology edited by Cetus advisor Ray Wu. Mullis felt betrayed by his collabo-rators: “Those bastards screwed me to the wall.” Randy Saiki later com-mented, “We probably should have argued more with Science or Nature that, truly, Kary was the inventor.” White concedes that the outcome was unfortunate, but believes that Mullis shared responsibility for it, and

failed to acknowledge help that he received in reducing the concept to practice. The episode further strained the

friendship between the two.In early 1986, Cetus cancer researcher Frank McCormick called James Watson at Cold Spring Harbor Laboratory and asked whether Mullis could speak at the Symposium on Quantitative Biology scheduled for June. Watson sent an invi-tation, Mullis spoke, hundreds of leading molecular biologists learned about PCR, and then gave the wayward biochemist a standing ovation.

TAQ POLYMERASEThe arrival of PCR was celebrated

three years after Mullis’ midnight ride, but the procedure was hardly refined.

Even the automated version was grueling

He said, ‘I order you to stop Gelfand from cloning it.’

I told Gelfand, ‘Pay no attention. Continue making the stuff, just don’t

say anything about it.’

Thermocycler evolution


for technicians: “You were literally chained to the bench for three to four hours,” Stephen Scharf explains. “Every two minutes you had to add enzyme or put the tube in the denaturing bath.” The polymerizing enzyme was the biggest problem. Heat destroyed it. The supply had to be replenished before each cycle. As long as PCR was dependent on the heat-labile Klenow fragment, it remained, according to Saiki, “a method of last resort.”

Since the earliest PCR experiments in September 1983, Mullis had considered incorporating a thermophilic polymerase to obvi-ate the addition of fresh reagents between cycles. He found a few papers describing heat-tolerant enzymes, but did not obtain or

purify them himself. The PCR group eventually asked enzymolo-gist David Gelfand to look into it. Gelfand ordered several strains of thermophilic bacteria from the American Type Culture Collec-tion (ATCC), grew them up, made crude extracts, and tested for polymerase activity.

An enzyme from a bacterium called Thermus aquaticus (called Taq, for short) yielded the best results. Taq had been discovered in hot springs at Yellowstone National Park. Gelfand found two papers that described partial purification of a Taq polymerase, which gave him a place to start. With Susanne Stoffel, he purified the enzyme in the first quarter of 1986.

Tom White remembers encountering resistance from senior management. The top brass were focused on biopharmaceutical projects. They considered PCR a distracting sideline and were loath to dedicate resources to the development of an odd reagent. White disobeyed direct orders: “We had purified the enzyme. I asked Gelfand to clone it. Then, in a memorable senior manage-ment meeting, [Cetus CEO] Bob Fildes said, ‘It’s a waste of time. You’re already making enough of the other stuff [the Klenow fragment].’ I said, ‘Yeah, but we can increase the productivity by a factor of one hundred.’ He said, ‘I order you to stop Gelfand from cloning it.’ I told Gelfand, ’Pay no attention. Continue making the stuff, just don’t say anything about it.’”

In early 1986, Gelfand handed a vial of Taq polymerase to Randy Saiki. Saiki ran the reaction without refreshing the enzyme: “My first impression was that it didn’t work, because there was

Bob Fildes and David Gelfand


only a single band. We normally saw a smear of DNA.” In fact, the reaction conditions required for the use of Taq polymerase had significantly reduced non-specific binding of the primers. “That’s when the real revolution took place,” says Saiki, “in my mind at least.”

Henry Erlich announced the incorporation of Taq polymerase at a scientific meeting in September 1986, just as Kary Mullis was leaving Cetus to search for a more congenial scientific home. In early 1988, Saiki was again the first author on a paper published in Science: “Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase.” For several years, it was the most cited paper in the life sciences. A special place was reserved for Mullis in the list of authors.

PCRTaq polymerase permitted the full automation of PCR, and

significantly improved the specificity of the reaction. The enzyme transformed the discovery from a notable scientific advance into an indispensable practical tool for biological laboratories, a viable commercial product for vast and expanding markets in clinical and basic research.

In 1987, Cetus and Perkin Elmer expanded a joint instrumen-tation and reagents development venture known as Perkin Elmer/Cetus Instruments to encompass the design and manufacture of automated PCR equipment and supplies. Engineers worked fever-ishly to turn out market-ready laboratory devices. On November

What PCR Can Do


PCR makes copious amounts of DNA. Genes were once scarce and difficult to manufacture. Now, thanks to PCR, customized DNA is readily available for many different purposes in biological research and human and veterinary medicine. The first clinical applications were in the diagnosis of genetic and infectious diseases and the improvement of tissue typing for trans-plantation. Extensions of the technol-ogy soon catalyzed the acceleration of DNA sequencing that occurred in the late 1980s and the subsequent revolu-tion in genomics. Whole genome sequencing, personalized medicine, and synthetic biology would not have emerged and advanced without it.

Exponential gene amplification significantly expanded the utility of genetics in pharmaceutical discovery and development, industrial chemi-cal processing, agriculture, bioenergy production, oceanography, climate science, and environmental protection. It revolutionized forensic procedures

in medicine, civil and criminal law, anthropology, linguistics, ecology, archaeology, and paleontology. PCR is now used routinely to determine personal identify, paternity, and family lineage. It opened up new paths of research in evolutionary biology and historical population genetics. The resolving power of the technique per-mitted the analysis of degraded DNA, which enabled researchers to work with samples from ancient ancestors and extinct species such as Neanderthals and wooly mammoths.

Important advances in PCR tech-nology included inventions generated by David Gelfand and colleagues at Cetus, and refined and commercialized at Roche Molecular Sytems – real-time quantitative PCR and thermostable reverse transcriptase PCR. Real-time quantitative PCR (qRT-PCR) employs fluorescent probes and optical moni-toring systems to measure reaction kinetics and the accumulation of am-plified DNA as reactions are cycling.

Real-time instruments have eliminated the need to run time-consuming end-point analyses on electrophoresis gels in order to collect quantitative data.

Reverse transcriptase PCR (RT-PCR) was adapted to detect and quantify levels of RNA in samples. The procedure involves two steps (which may be prepared simultaneously). The first employs reverse transcriptase to synthesize complementary DNA (cDNA) from RNA templates. In the second, cDNA is amplified by specific primer extension with Taq polymerase. The procedure enables gene expression analyses and quantitative monitoring of viral load in cases of retroviral infec-tions such as HIV. RT-PCR can also be monitored in real time.

Thirty years have passed since Kary Mullis first envisioned the process of DNA amplification. Today, highly re-fined versions of the technique shaped by thousands of hands are employed in biological and medical laboratories all over the world.


19, the two companies issued a joint press release introducing the first ‘Thermocycler,’ a fully automated gene amplification system, along with AmpliTaq DNA polymerase.

Initial projections for US sales of thermocyclers were modest – perhaps 100-150 instruments per year. By 1991, 13,000 instru-ments had been sold. The first machines were bulky and slow, and plagued by uneven distributions of heat. They required a layer of oil on top of the reaction to prevent evaporation. A second genera-tion soon followed on. The improved machines cycled rapidly, distributed heat evenly, accommodated 96-well plates, and featured a heated lid to prevent evaporation.

In 1989, Cetus entered an agreement with Hoffmann-La Roche to develop diagnostic applications of PCR. On December 10, 1991, just before Cetus was purchased by the Chiron Corporation, Roche acquired full rights to PCR – control of the Mullis patent and the Taq patent – for $330 million. Many from Cetus’ PCR de-velopment teams migrated to the Swiss company to continue refin-

ing and extending the invention (although most remained in Cali-fornia, at a new diagnostics subsidiary, Roche Molecular Systems, established in Alameda). PCR went on to become an incredibly productive research tool, and, for Roche, the source of enormous revenues. The $330 million investment returned billions.

In December 1989, Science named Taq polymerase its “Mol-ecule of the Year.” In 1993, Kary Mullis was awarded the Japan Prize and a share of the Nobel Prize in Chemistry for the discovery the polymerase chain reaction. Today, Tom White, who spent most of his professional career exploring novel applications of PCR at Cetus and Roche Molecular Systems, laments the fact that he can’t reflect on participation in the development of the epoch-making technology with his former comrade: “Kary and I had a wide group of mutual friends who were both scientists and artists. We have had little or no contact with him since 1995, a couple of years after the Nobel Prize. We always enjoyed his eccentric personality and ways.” Ø

Building M (now demolished) at Cetus Corporation in Emeryville, California. Mullis’ DNA chemistry lab was on the fourth floor,

on the left hand side of the building

In Part I, we told the tale of a biochemist from Uruguay, trained in the United States., who spurned offers of employment from top academic institutions and stately pharmaceutical corporations to join a startup chemical company in Mex-ico. He soon found himself digging up yams in the jungle of Veracruz for use as raw materials in the synthesis of steroid hormones. The work was far from glamorous, but it suited Alejandro Zaffaroni. The science was stimulating, his colleagues were brilliant, and Syntex, as the company was called, was ready to establish itself as a leader in industrial biochemistry.

When Syntex decided to move into pharmaceutical development in 1962, Presi-dent George Rosenkranz called on Zaffaroni to set up a research division in Palo Alto, California. After successfully establishing the company in the United States, Zaffaroni began looking for other exciting startup opportunities. In 1968, he founded the innovative drug delivery company, ALZA, in the Stanford Indus-trial Park. The firm was technically superb, but its first commercial projects were ill-fated. By the mid-1970s, ALZA faced serious financial difficulties. Ciba-Geigy put in funds to keep the firm afloat, but Zaffaroni was forced to surrender control. Part II picks up Zaffaroni’s story at this critical juncture.

ALEJANDROZAFFARONI

The Archetypal Bioentrepreneur

Part II


A COMPANY LIKE NO OTHERAlex Zaffaroni founded ALZA in 1968 to develop novel drug

delivery technologies. He was convinced that many drugs failed or produced harmful side effects because doses were too large, too small, poorly timed, poorly absorbed, not directed to appropri-ate tissues, or degraded by the body’s natural defenses. He wanted to provide solutions and improve the tools used by physicians to combat disease.

From the beginning, he surrounded himself with the best avail-able talent – the best scientists, engineers, and business people. His first hire (after bringing his secretary, Ana Leech, his cook, Matilda Nieri, and his driver, Joseph Jussen, from Syntex) was a young man named Martin Gerstel, a top MBA student in the class of 1968 at the Stanford Graduate School of Business.

In the late 1960s, business school enrollments were rapidly ex-panding. The buzz in industry was that MBAs would soon rule the world. Gerstel had been featured in a profile of top business school graduates in Business Week. His picture graced the cover. He was heavily recruited by leading corporations and consulting firms. He was wined and dined in major cities on both coasts. He was served caviar and champagne on yachts in Europe. McKinsey and Boston Consulting made lucrative offers. The Ford Motor Company of-fered to make him an assistant controller.

Then the young man was called to Syntex. Gerstel remembers meeting the master: “We sat, had tea, and talked about the world. We discussed nothing about business – zero. He asked me about

my philosophy of life. I remember thinking, “What in the world is going on? Why am I here?” Finally, Zaffaroni explained that he was starting ALZA. He invited Gerstel to join. Gerstel knew nothing about the pharmaceutical industry, but sensed something special in the works: “Instantly, I said, ‘Yes, I’d love to.’ There was just something about him.”

Zaffaroni allowed Gerstel to select his own position and title. He chose vice-president of finance. As he began to discern Zaffaro-ni’s vision of ALZA, he came to understand that the entrepreneur did not want simply to establish a profitable business. He wanted to build an organization that would do extraordinary things. He wanted extraordinary science and extraordinary pharmaceuti-cal products. He intended to revolutionize the formulation and administration of drugs. He wanted ALZA to become a company like no other.

Martin Gerstel

If you wanted Alex to do something, the best thing to do was to say, ‘This hasn’t been done before.’ He would immediately want to do it.


In order to make it happen, Zaffaroni sought to create an environment conducive to innovation, one in which risks would be embraced rather than avoided. He brought in scientists and engineers who were not only talented, but also passionate, enthusiastic, and not afraid to fail. Most came from universities rather than industry, and most were young. He recruited an advisory board of leading academic experts. Zaffaroni wanted individuals and teams that would relish the toughest challenges. ALZA was to be driven by techni-cal achievements, not profits.

Naturally, the company’s business and finance professionals also had to understand the founder’s commitment to excellence in science and technology. “The company was his dream,” Gerstel explains, “so it was an absolute requirement for new employees to be ‘believers.’”

GOING PUBLICALZA became thoroughly innovative in practice,

just as Zaffaroni had envisioned it. “I learned,” says Gerstel, “that the biggest mistake you could make at ALZA was to ask what the rules were, or what other people had done. If you wanted Alex to do something, the best thing to do was to say, ‘This hasn’t been done before.’ He would immediately want to do it.”

Very little that ALZA did was accomplished by conventional means, and many of its experiments were broadly influential – in pharmaceutical science, in business, and in finance. The company’s unorthodox approach to raising money, for example, left a lasting imprint.

To get started, Zaffaroni raised $3 million from friends and professional contacts. Allstate Insurance invested, and Zaffaroni made a sizable personal contribution. The sum was sufficient to set up labs, commence research, and file patents, but not enough to

sustain product development efforts. The firm needed to raise a lot of money.

In late 1969, Zaffaroni and Gerstel took the problem to ALZA’s legal counsel, Julian Stern, a partner at the esteemed San Francisco

law firm, Heller Ehrman. With assistance from George Blackstone, a securities specialist at Heller Ehrman and a former associate director of the US Securities Exchange Commission (SEC), Stern de-vised a plan for accessing public capital markets.

In those days, regulators did not permit compa-nies without earnings to issue stock to the public. Stern saw a way around the restriction. In negotiat-ing an exit from Syntex, Zaffaroni had promised the pharmaceutical maker a 25 percent stake in the new startup. Stern recommended that ALZA offer

additional stock to Syntex on the condition that it would be dis-tributed to the corporation’s 20,000 shareholders. The distribution would instantly make ALZA a public company.

ALZA was obliged to register the offering with the SEC. The

525 University Ave. in downtown Palo Alto.

ALZA's first offices were on the 14th floor

photo: Stefan Armijo

ALZA headquarters at 950 Page Mill Road in the Stanford Industrial Park


accompanying disclosure statement prominently displayed the frank truth: the company had little money, nowhere near enough to support its implausibly ambitious technological and commercial plans. It had no products, no revenues, and not a prayer of turning a profit for years.

According to Gerstel, the SEC was perplexed: “They said, ‘We can’t approve this. You have to show how this offering will enable you to become a self-sustaining company. We can’t allow you to become a public company if you’re going out of business in six months. We’re the SEC. We protect the public from this kind of thing.’ So we said, ‘What are you protecting them against? We’re not asking for any money.’”

The agency tried to prevent Syntex from making the distribu-tion. It identified a tax issue – the shares were dividends, in effect, in the form of stock rather than cash. The dividends, however, had no value. There was no price and no market. The offering was allowed. ALZA didn’t list the stock, but the struggling Pacific Stock Exchange picked it up and set a price: $1 per share. Trading ensued, and the value of shares ascended to more than $30. For a brief period, the company’s market capitalization exceeded $100 million.

Gerstel was amazed: “There was nothing there, just a few of us in an office building in downtown Palo Alto.” As the company had clearly stated in its prospectus, it had little going for it, only some vague ideas, a handful of patents, and the man who had helped George Rosenkranz turn Syntex into a huge international success. ALZA’s market value resided almost entirely in the person of Alex Zaffaroni. The bubble soon burst and the market settled on a rea-sonable valuation, but over the next two years, ALZA was able to raise $19 million in private placements during 1970, and another $12 million in a 1971 offering made to existing shareholders.

“Once we became public in this manner,” says Gerstel, “the SEC was never able to stop anybody else. Today, companies can

raise huge sums without showing how they will be profitable. After ALZA, venture capitalists could put money into startup biotech firms and be followed by public investments.” The biotechnology industry may have followed a very different developmental course had not ALZA changed attitudes and policies at the SEC.

ALZA remained financially inventive throughout its history as an independent organization. It was the first company in the pharmaceutical industry to establish itself through technology out-licensing. Scores of biotechnology firms would later adopt the model. And in the 1980s and 1990s, under Gerstel’s leadership, ALZA was among the first companies to make use of R&D limited partnerships and similarly structured off-balance sheet financing vehicles. These arrangements offered tax breaks to investors and permitted the company to spend on research without incurring losses that would damage its stock on Wall Street.

HOPES DASHEDALZA was a great technical success. The company’s scientists

and engineers did fine work. In 1974, the US Food and Drug Administration (FDA) approved the company’s first product, an ocular insert that accomplished, for the first time, the continu-ous release of a medication to relieve eye pressure associated with

ALZA TECHNOLOGY PLATFORMS:

AN OVERVIEWALZA’s innovative drug delivery technologies have im-proved the lives of countless patients taking prescribed medications. These technologies have been employed

in over 30 commercial products, marketed in over 70 countries. Over 1,000 US patents have

been issued to ALZA inventors. The company commercialized seven

technology platforms:

D - T R A N S ® and MACROFLUX® (transdermal delivery)

Patches that release drugs formulated for transmis-

sion through the skin.

STEALTH® (liposome delivery)

Tiny bubbles filled with aqueous drugs and encased by a lipid bilayer, the same mate-rial as a cell membrane, that

enable the drugs to dif-fuse into the blood-

stream.

E - T R A N S ®

(electrotransport sys-tem delivery)

A device that generates an electrical charge to pro-

pel drugs through the skin.

ALZAMER® Depot (biodegrad-

able polymer delivery)A drug-dispensing implant

that doesn’t need to be removed after the drug is

depleted – it erodes naturally.

OROS®

(oral osmosis delivery)A pill with a semi-perme-able lipid membrane that

slowly releases medications into the bloodstream at

controlled rates.

DUROS® (implant delivery)A miniature drug-dispensing pump placed under the

skin.


glaucoma. In 1976, the agency gave the company a green light to market a second product called Progestasert®, an intrauterine contraceptive device that controlled the release of an ovulation-regulating hormone.

The products were safe and effective. They demonstrated the practical utility of controlled release drug delivery, but they were also unfamiliar to physicians and patients, and somewhat more expensive than available alternatives. Customers did not intui-tively grasp the advantages of continuous dosing, but they readily expressed discomfort with insertions in the eye and uterus. Neither product became a commercial success.

Many elderly glaucoma patients continued to use eye drops rather than switch to Ocusert®, especially after Merck introduced a new class of beta blockers in drop form that eliminated side effects and reduced dosing frequencies. Progestasert was a reliable birth control device, medically and pharmacologically superior to oral contraceptives, and simple to use, but most women who opted for hormone treatments continued to take daily pills.

These were not technology failures. They were marketing failures. ALZA had not been well-served, in these two instances, at

least, by its myopic fo-cus on technical excellence.

Of Ocusert and Progestasert, Gerstel says, “They were probably the best drug-delivery products ever made. I doubt that anyone will ever make better ones. But they were made to win Nobel Prizes, not to make money.” The outcomes were instructional. Stanford biochemist, Nobel laure-ate, and ALZA advisor Arthur Kornberg later said, “I learned how important marketing is for the proper testing and ultimate utility of a drug.”

With slack sales of its lead products, and research, manufactur-ing, and marketing costs all on the rise, ALZA piled up losses and encountered serious financial shortfalls. The value of the company’s stock began to slide, which effectively foreclosed the possibility of

ALZA scientists and advisors (left to right): John Shell, Arthur Kornberg, Hans Selye, Alejandro Zaffaroni, and Takeru Higuchi

They were the best drug-delivery products ever made. I doubt that anyone will ever make better ones. But they were made to win Nobel Prizes, not to make money.


another public offering. Bankruptcy loomed. It was a harrowing period. According to Gerstel, “Alex began putting more and more of his personal money into the company. I knew—no one else did—that he even borrowed against his house. He put in every penny. He was in very, very deep.”

The executives made the painful decision to cut the sales force and administrative infrastructure in order to buy some time. The hope was to preserve the research operation, the heart of the orga-nization, long enough to find corporate partners willing to help the firm regain its footing in exchange for technology rights. Zaffaroni was forced to concede that “my idea of creating a full-fledged pharmaceutical company with its own sales force had failed.” Gerstel remembers a rueful admission: “It hasn’t worked out the way I thought it would.”

Through 1977, ALZA held meetings with more than fifty potential partners. Zaffaroni even led a group to Tehran to discuss an investment with the Shah. There were no takers to be found – the pharmaceutical industry had not yet recognized the medical and commercial potential of drug delivery technologies. Just as the company was nearing the end of its rope, Ciba-Geigy expressed interest in making a deal. The Swiss corporation spied an opportunity to try out ALZA’s delivery systems, but was even more intrigued by tax benefits that the California firm’s accumulated net operating losses

and research credits might afford.In December, ALZA shareholders approved a complicated

agreement. Ciba-Geigy’s US subsidiary, Ciba-Geigy Corp., located in Summit, New Jersey, would purchase $30 million of preferred stock in ALZA. The Swiss agreed to sponsor $15 million in con-tract research at ALZA over the next five years. In return, Ciba-Geigy acquired control of the board of directors – 80 percent of voting rights, and eight of eleven seats (but only 50 percent of total equity). The company also received rights to exclusive licenses on ALZA technologies. Ciba-Geigy would pay royalties of 5-10 per-

cent on technologies developed in California. ALZA could license technologies independently, but only if approved by Ciba-Geigy AG in Basel.

Top: Portrait of JR Geigy and family Bottom: Ciba facilities in Basel, Switzerland, 1880


The big corporation allowed ALZA to maintain its name, and did not interfere, for the most part, with its research operation. There was little collaboration be-tween scientists at the companies, and few substantial technology transfers. Problems arose in the partnership when ALZA researchers sought to advise develop-ment specialists in Switzerland (frequently ignoring established hierarchies of authority in the process) and when the small company complained about the neglect of ALZA technologies and products by Ciba-Geigy’s marketing department. The California group also bemoaned a lack of responsiveness from Basel when it sought to negotiate licensing deals with other pharma-ceutical corporations.

Ciba-Geigy was a venerable Swiss chemical corpora-tion that traced its roots back to 1758 when Johann Rudolf Geigy-Gemuseus of Basel first began trading in chemicals and dyes. Over two hundred years later, its organizational structure was stolid. Its operations were governed by numerous committees and coordinating boards. New ideas had to make slow, arduous treks through multiple levels of red tape. Throughout the organization, autonomy was limited and risks were avoided. Innovations were rarities. The big corpora-tion could survive and prosper without taking chances and without running hot. For ALZA, the opposite was true. In retrospect, the mismatch is apparent; at the time, the incompatibilities had to be discovered in practice.

ALZA was now a contract research organization, and its work was subject to review by Ciba-Geigy’s de-cision-making apparatus. Zaffaroni couldn’t tolerate it. He thrived on opportunities to create, on independent action, progress, mobility, and change. He found large bureaucracies dispiriting, suffocating. “When we had to cede control to Ciba-Geigy,” says Gerstel, “he had to find other ways to channel his inventive energies.”

Zaffaroni largely withdrew from ALZA’s day-to-day business, and transferred most of his operating respon-sibilities to Gerstel. He carried on as chairman of the board, and remained involved in high-level delibera-tions on business strategy and technological direction, but he had little interest in or aptitude for routine bargaining with Ciba-Geigy managers in Summit or Basel. He naturally gravitated away from corporate encumbrances toward stimulating entrepreneurial op-portunities.

Under Gerstel’s determined leadership, ALZA

made good progress on its innovative drug delivery products, including the first transdermal patch, the Transderm Scop®, approved by the FDA and marketed by Ciba-Geigy in 1981. The patch regulated the topical administration of scopolamine, a drug prescribed for the prevention of motion sickness. ALZA was slowly converting drug delivery skeptics into believers, but its climb to profitability was long and steep – the cost of the company’s research efforts continued to exceed its meager revenues from royalty payments.

DNAXIn his time away from

ALZA, Zaffaroni continued to work with Dynapol, a company that he had spun out of ALZA in 1972 to in-vestigate biochemical means of improving food product safety. Steve Goldby, ALZA’s original patent attorney, had been installed as CEO. The idea was to attach large poly-mer molecules to potentially toxic or carcinogenic food additives such as artificial sweeteners, flavors, colors, and preservatives in order to inhibit absorption in the gut.

Zaffaroni also sought new creative outlets. In 1980, he founded a molecular biology company called DNAX. “DNAX,” he later wrote, “was started as a kind of insurance policy. I wanted to be able to continue an independent life in a field that held great attraction for me with friends for whom I had great respect, such as Arthur Kornberg.” Kornberg was a professor of biochemistry at Stanford University and a Nobel laureate. He and Zaffaroni first met when Korn-berg was invited to talk at Syntex in 1961. Impressed by Zaffaroni’s scientific talent and leadership, Kornberg became a technical advisor to ALZA and served for twelve years until DNAX was founded.

In 1979, Kornberg had entered into discussions with Stanford chemical engineering professor Chan-ning Robertson about starting a company to develop

Arthur Kornberg

Had it not been Alex Zaffaroni, I would have said no.


large scale bioprocessing systems. Robertson was convinced that recombinant proteins would soon become important raw materials in the chemical industry. He had already lined up venture capital. Kornberg was interested in the idea, and had asked departmental colleagues Paul Berg (who was soon to receive the 1980 Nobel Prize in Chemistry) and Charles Yanofsky (a Lasker award winner) to consider joining in, but he was dubious about the proposed equity terms.

The trio contacted Zaffaroni for advice. According to Berg, Zaf-faroni said, “’If you’re serious about getting involved in a biotech company, I’ll form one and you can join me.’” Berg says, “I didn’t know him well, but Arthur had the highest regard for him. He was clearly an innovator and a creative entrepreneur. He wanted us to provide the scientific energy behind this company.”

Berg and Yanofsky had previously spurned all offers to become involved in for-profit enterprises. Both had expressed reservations about the commercialization of academic research in biology. The DNAX opportunity prompted them to change their minds. “Had it not been in collaboration with Arthur and Charlie Yanofsky,” says Berg, “and had it not been Alex Zaffaroni, I would have said no. These were colleagues I respected and worked well with, and the person who was going to handle the business for us I admired in many ways. DNAX was the first time I conceded that my stand-offish attitude toward industry was probably outlived.”

“The three of us felt comfortable with Alex,” Kornberg later wrote, “because of his extensive experience in business and science and his deep understanding of the pace and vagaries of labora-tory progress. Above all, he was someone we trusted.” In October,

1980, the group agreed to work together. Zaffaroni secured $4 million from private investors in Europe, and the Stanford profes-sors began recruiting a scientific staff that would enable DNAX to compete head-to-head with other emerging biotech firms associ-ated with leading molecular biologists: Amgen, Biogen, Cetus, Genentech, Genetics Institute, and Immunex. News of the DNAX startup made the others nervous.

DNAX planned initially to engineer antibodies, but soon shifted gears and focused on cloning cytokines – interleukins, interferons colony-stimulating factors, for example – small signal-ing proteins responsible for intercellular communication in the immune system. In the spring of 1982, Schering-Plough purchased the company for $29 million – $1 million for each of the PhDs employed at the firm. DNAX was allowed to operate for more than a decade without interference from Schering’s main R&D organization. The unit produced many important discoveries and inventions in molecular immunology, although not a pharmaceuti-cal product.

RECLAIMING ALZAIn the second half of 1981, ALZA’s five-year deal with Ciba-

Geigy was nearing its point of termination. Ciba-Geigy had put more than $100 million into the company, a sum that had enabled ALZA to maintain its momentum in drug delivery research, but the company was still posting losses. Its stock price remained de-

pressed, and it hadn’t had an opportunity to amass a war chest for indepen-dent operations. The firm remained undercapitalized.

For two years, Gerstel had pressed Ciba-Geigy’s representatives on the board to attend to long-

term funding issues. The responses were consistently evasive. Even-tually, the big corporation came to the table to negotiate. “They were not nice,” says Julian Stern. “It was just before Thanksgiving in 1981. They called Alex and Martin to say, ‘We’re not going to continue.’” Ciba-Geigy proposed to surrender control, to exchange its preferred stock and voting rights for common stock amounting to half of the company and non-exclusive, royalty-free licenses to

Martin Gerstel and Alex Zaffaroni at the

ALZA 20th anniversary celebration

They thought ALZA would go belly-up, they would end up with the

technology, and that would be the end.


all of ALZA’s technologies.Such an arrangement would have left ALZA in extremely poor

shape. Ciba-Geigy had paid for the company’s technical progress, but ALZA had not been enriched by it. Of the corporation’s late bargaining ploy, Stern says, “They thought ALZA would go belly-up, they would end up with the technology, and that would be the end.” He advised Zaffaroni and Gerstel to inform Summit and Basel that ALZA would file suit if the offer wasn’t amended – in his opinion, a strong case could be made that the Ciba-Geigy ma-jority on the ALZA board of directors had not fulfilled its fiduciary responsibilities to ALZA shareholders.

The ALZA team was not caught entirely off-guard by Ciba-Geigy’s hardball tactics. They had been exploring the possibility of funding research independently through R&D limited partner-ships underwritten by Merrill Lynch, and Zaffaroni was reasonably confident that he could secure a research contract with Pfizer.

ALZA had suggested the development of a time-release version of Procardia®, one of Pfizer’s best-selling medicines for the treat-ment of angina and high blood pressure. The three times per day dosage form was coming off patent. Buying a new formulation from ALZA would permit Pfizer to retain its franchise. Zaffaroni felt that if ALZA could negotiate a better divorce settlement from Ciba-Geigy and secure revenue-gener-ating R&D con-tracts, it would have a fighting chance for survival.

At the next meet-ing held to discuss parting terms, the small firm insisted that it needed cash to stay afloat – a mini-mum of $10 million. The big company agreed to a convoluted stock swap that would free up the sum, and also committed to a modicum of contract research funding through 1984.

In return, ALZA granted Ciba-Geigy’s wish for non-exclusive royalty-free licenses on all co-developed products – except Trans-derm Nitro®, a patch that delivers nitroglycerine continuously for

the treatment of angina and high blood pressure. The final accord stipulated that ALZA would receive a 5 percent royalty on sales of the patch (which eventually reached $1 billion annually).

When the agreement was ratified and signed, ALZA had regained its independence. It was once again free to establish cor-porate partnerships and negotiate licenses without restriction.

In 1983, ALZA licensed drug delivery technologies to numer-ous pharmaceutical corporations, including Eli Lilly, Glaxo, and Schering Plough. The deal with Pfizer was made. ALZA began developing Procardia XL®, a controlled-release, once-a-day form of the heart drug (which became Pfizer’s first billion dollar prod-uct when approved for sale by the FDA in 1991). R&D limited partnerships brokered by Merrill Lynch funded the development of two additional delivery technologies. The company’s recovery was gradual but steady: “We never again had a loss quarter,” says Stern.

The same year, as part of ALZA’s recapitalization, Gerstel took a portion of the stock returned by Ciba-Geigy, converted it to second-class non-tradable shares, and distributed it to employees – including secretaries, lab technicians, and maintenance person-nel – in a show of appreciation for loyalty to the firm through its darkest days. When the company showed a profit of $5 million in 1984, the second class stock was converted to tradable common shares, and more than 100 ALZA employees became instant paper millionaires.

In 1985, the company was strong enough to make another public offering of stock. $93 million was raised, and the company’s scientists had the resources they needed to push products through the development pipeline. By 1992, ALZA had clawed its way

John Diekman


completely out of the abyss – it had attained a market value of $3 billion. At that point, Zaffaroni had achieved his original goal. His ideas for new drug delivery technologies had revolutionized the formulation and administration of pharmaceuticals.

Zaffaroni stayed on as chairman of the board until 1998. By 2000, ALZA’s annual sales were approaching $1 billion. In 2001, Johnson & Johnson made an offer that shareholders could not refuse – the company was acquired in a transaction worth $13.7 billion.

COMBINATORIAL CHEMISTRYIn 1987, after helping ALZA regain its momentum, Zaffaroni

asked Gerstel to take over as CEO. He then embarked, at the age of sixty-four, on a remarkable technological odyssey that spanned twenty years and resulted in the formation of ten new companies.

The journey began when Zaffaroni struck up a conversation with Leighton Read of the Harvard School of Public Health about the possibility of improving established methods of drug discovery. The two discussed the feasibility of applying recently developed techniques in combinatorial chemistry to increase the productivity of pharmaceutical screening assays.

The following year, Zaffaroni and Read joined forces with chemists Lubert Stryer of Stanford University and Peter Schultz of the University of California (UC), Berkeley to found Affymax in Palo Alto, in 1988. The founding group drew together an all-star

team of scientific advisors: Paul Berg, Mark Davis, Carl Djerassi, Avram Goldstein, Michael Pirrung from Stanford, Murray Good-man from the University of California, San Diego, and Joshua Lederberg at Rockefeller University.

The name of the company was derived from ‘affinity matrix,’ Zaffaroni’s inchoate notion of a black box of assays into which compounds and molecular targets would enter and new drug candidates would be spit out: “We knew what we wanted to do,” says Zaffaroni, “but we weren’t sure how to do it. I didn’t feel that we needed a clear technology in the beginning because I knew this talented group of people would come up with something.”

Zaffaroni raised $22 million in private investments, and Stryer took a one-year leave to plan the company’s R&D efforts. Zaf-faroni soon recruited Djerassi’s former student, John Diekman, to serve as president and chief operating officer. Diekman had previ-ous experience in both roles at Zoecon, Djerassi’s biological pest control company, which was spun out of Syntex at the same time ALZA was founded.

Affymax scientists developed three complimentary platforms for the generation and efficient screening of potential drug candidates: 1) ‘very large scale immobilized polymer synthesis’ (VLSIPS); 2) ‘encoded Synthetic Libraries (ESL); and 3) ‘recombinant peptide diversity’ (RPD). Each involved the creation of vast protein librar-ies, the first on semiconductor chips, the second on microscopic beads, and the last on bacteriophage (viruses) or plasmids (circular bacterial DNA molecules) in bacterial cultures.

The company tested proteins in the libraries for activity with cellular receptors known to be involved in processes of disease, re-corded information indicating the potential efficacy and toxicity of each molecule, and culled promising drug leads, as Zaffaroni later explained, “with much higher throughput and substantially lower costs than conventional testing.” The goal of Affymax’s technical teams was to increase the density and capacity of synthesized pep-tide libraries – to miniaturize, in other words – while accelerating synthesis, screening, and analysis.

In the early 1990s, Zaffaroni saw that the maturation of competing technologies would soon turn combinatorial chemistry into a commodity business, and that the full value of the approach would be realized downstream in the development of pharmaceu-ticals. Affymax was not equipped to take on development projects, so Zaffaroni judged it time to shop the company to prospective buyers. His fellow directors were reluctant but eventually swayed to Zaffaroni’s point of view. In 1995, Affymax was sold to Glaxo

THE GENE CHIP®The GeneChip® consists of a precise ar-rangement of tens of thousands distinct single-stranded DNA probes (oligonucle-otides) on a microscopic grid etched into a thumbnail-sized glass or silica surface. Clinical and research uses vary. Microarray analyses are conducted by dousing chips with samples containing DNA from genes of interest labeled with fluorescent or chemiluminescent dyes. The sample DNA will naturally hybridize with complemen-tary probes fastened to the chips. The chips are then washed, leaving only hy-bridized probes and targets with labels that can be excited, detected, measured, and recorded by laser scanners. The intensity of the signal is a quantitative measure of lev-els of hybridization and gene expression. A survey of all reaction sites on a chip can produce a broad gene expression profile.

left: Leighton Readright: Michael Pirrung


for $533 million. Zaffaroni called the acquisition “a tremendous affirmation of what we had accomplished.”

DNA MICROARRAYSWhen Affymax got started in 1988, the notion

came to Leighton Read and Michael Pirrung to employ photolithographic techniques borrowed from the semiconductor industry for the random generation of vast peptide libraries fixed on the surfaces of silicon chips where they could be assayed, en masse and in parallel, in miniaturized, automated systems. That was the beginning of VLSIPS technology. There was some skepticism among the company’s scientific advisors regarding the practicality of the novel approach, but the line of inquiry was pursued.

In February of 1991, the Affymax group published a seminal paper in Science entitled “Light-directed, spatially addressable parallel chemical synthesis.” It de-scribed the first combination of photolithography and solid-phase organic chemistry for peptide synthesis on silicon. The research fed directly into the development of DNA microarrays for use in genomics research.

The first author of the Science paper was Stephen Fodor, a young biochemist who came to Affymax from a postdoc at UC Berkeley. He saw that nucleic acids

were well suited to the microarray format, and that screening DNA libraries with hybridizing oligonucle-otide probes would have important applications – not directly in pharmaceutical discovery, Affymax’s stock in trade, but in genomics and medical diagnostics. He brought the idea to Zaffaroni, who was supportive.

By 1993, Zaffaroni had spun out a new company provisionally called Affygene. The name was soon changed to Affymetrix, Inc. Fodor was the principal scientist. Affymax provided seed funding. Zaffaroni then rounded up $60 million from private investors over the next three years, while grants from the federal government added another $30 million. The compa-ny’s IPO in 1996 yielded proceeds of $90 million.

With these ample resources and input from Zaf-faroni’s group of brilliant scientific advisors, Affymetrix invented, manufactured, and marketed the GeneChip®, a small glass microchip chemically prepared to host a DNA microarray. Each chip contained 64,000 sites at which purified, single-stranded DNA probes were fixed to the surface, awaiting samples for testing and

analysis.The technology has vastly accelerated clinical and

laboratory work in genetics and molecular biology. DNA microarrays are used to identify genes and gene mutations, compare genomes, or produce gene expression profiles. In medicine and pharmaceutical applications, they are used to identify gene expression patterns associated with diseases, determine individual

A 1990 fax from Stephen Fodor (left) to Lubert

Stryer: “The results from the first 1024 grid!”

Peter Schultz


predispositions to cancer and other genetic diseases, and to assess the likelihood that a patient will respond to a drug or suffer side-effects.

Affymetrix was a major success, technologically and commercially. It was the first company to market a DNA microarray, and arguably the best. It captured a lion’s share of the market for gene identification and expression profiling systems and services, and held it for many years. Recently, the company has been pressed by competition from Agilent and Illumina, among others.

MATERIALS DISCOVERYZaffaroni’s next company, Symyx, was another

Affymax off-shoot, first conceived in 1994, although it took the better part of two years to get up and running in earnest. Symyx employed combinatorial chemistry to discover new, industrially useful inorganic materials

– high-temperature superconductors, supermagnetic alloys, metal oxide catalysts, and luminescent materials, for example.

Like Affymetrix, Symyx’s fundamental technology represented an important advance in the discipline

of chemistry, and an early report graced the pages of Science. With academic colleagues at UC Berkeley, Affymax co-founder and the company’s scientific lead, Peter Schultz, published an article with academic col-leagues in the June 1995 issue, called “A Combinatorial Approach to Materials Discovery.”

Zaffaroni provided seed money and organized the venture. To get started, he sent Isy Goldwasser, a twenty-four-year-old PhD student in Stanford’s chemi-cal engineering program to visit Schultz. The young man from Colombia had been recommended by John Diekman. Goldwasser was appointed vice-president of corporate development. W. Henry Weinberg, a professor in chemical engineering at the University of California, Santa Barbara was recruited to serve as chief technical officer. Some months later, Steve Goldby, former ALZA attorney and Dynapol CEO was tabbed to lead the company as chief executive.

The technology appealed to chemical companies under pressure to lower R&D costs. Symyx adopted a service-based business model, and even as a slew of large and small competitors took up combinatorial chemistry, solidified its position as the leader of the pack with a robust patent portfolio. Bill Down, direc-tor of biotechnology R&D at Dow Chemical, surveyed the field and commented: “Either you make the com-mitment Symyx has, or you ought to stay home.”

By 2007, Symyx had entered into more than twenty multi-year research collaborations with a roster of partners that included some of the world’s largest chemical corporations: Agfa, BASF, Bayer, Celanese, Dow Chemical, Exxon Mobil, Novartis, and Unilever. The company also had thirteen proprietary materials of its own in development.

The same year, Symyx made a diversifying move into chemoinformatics (while remaining focused on throughput improvement). The company acquired

Gordon Ringold


MDL Systems, an R&D informatics outfit, and became custodian of the Centers for Disease Control and Prevention-National Insti-tute of Occupational Safety and Health Registry of Toxic Effects of Chemical Substances, a database of basic toxicity information on household chemicals, food additives, drugs, solvents, biocides, and industrial wastes.

In 2010, the company merged with San Diego-based Accelrys, a firm that specializes in informatics, modeling and simulation, data management and work flow automation software and services. The combined entity goes by the Accelrys name.

TECHNOLOGICAL IMPRESARIOIn 1997, Zaffaroni decided to raise a private investment fund

for the creation of new biotech companies. He had previously ap-proached investors on a deal-by-deal basis, and only after putting his own money into a venture, but he felt that the time was right to implement a new approach: “As we were starting companies more and more frequently, I thought I should simplify the funding process.” He was able to enroll limited partners from within his extensive network of faithful friends and associates.

Technogen was established to provide to discovery stage start-ups an alternative to venture capital. Zaffaroni resolved to fund only companies that he would assemble and technologies that he was personally committed to seeing through to commercial suc-cess. At Technogen, Zaffaroni continued to work with investors, entrepreneurs, scientists, engineers, and new firms as a startup art-ist, business advisor, technical consultant, and formally as a board member.

Many of Technogen’s investments had roots in Zaffaroni’s previ-ously established enterprises. SurroMed was a medical fluidics company started by pharmacologist and former Affymax CEO Gordon Ringold, the son of Syntex chemist Howard Ringold, and Zaffaroni’s first lieutenant at Technogen. Surromed’s charge was to advance the discovery and utilization of disease biomarkers.

Maxygen was spun out of Affymax when senior scientist Pim Stemmer devised a method for the artificial acceleration of genetic diversity, a process of ‘directed evolution’ or ‘molecular breeding’ used to identify genes coding for useful proteins. Durect was cre-ated to refine and extend ALZA’s implant delivery technologies. It was taken out of the parent and set up independently in 1998.

XenoPort, founded in 1999, was yet another Affymax offshoot that melded combinatorial chemistry with non-oral drug delivery technologies. In 2000, Zaffaroni established Genospectra to im-prove the manufacture of DNA chips. At the same time, Stephen Fodor started Perlegen as a subsidiary of Affymetrix to adapt mi-

croarray technologies to tasks in whole genome sequence analysis. He and Zaffaroni set the company up on its own the following year. Verdia, Codexis, and Avidia were spin-offs from Maxygen, in agricultural genetics, industrial bioprocessing, and pharmaceutical development, respectively. The list goes on.

ALEXZAAlex Zaffaroni started his last company, Alexza, in 2000. His

finale brought him back to his entrepreneurial origins in drug de-livery systems. The idea for the project came from his observation that cigarettes are superb delivery instruments. They permit the efficient and rapid transmission of nicotine through the lungs and into the blood, and then the brain via inhalation. Zaffaroni knew that many drugs prescribed for central nervous system disorders would be more effective if delivered directly to the brain.

Alexza’s mission was to invent rapid onset-of-action delivery technologies targeting pulmonary tissues in order to facilitate the speedy absorption of drugs into the bloodstream and across the blood/brain barrier. Zaffaroni saw many opportunities to reformu-late existing and well-understood drugs for administration with a unique aerosol inhalation device.

Zaffaroni financed the operation with his own money. Gordon Ringold was conscripted as head of research, and Josh Rabinowitz, a young MD/PhD (in chemistry) from Stanford, was recruited as the hands-on laboratory operator. Zaffaroni saw that through his broad training, Rabinowitz had acquired an ideal mix of physi-ological, medical, clinical, and scientific skills and understandings.

To his surprise, Zaffaroni soon discovered that another Silicon

Zaffaroni receives the National Medal of Technology from Al Gore and Bill Clinton


Valley company, Molecular Delivery Corporation (MDC), was working on a similar project. MDC had done good preliminary engineering work in the area, but was short on cash. Zaffaroni and Ringold met with the founder, Steve Schneider, and proposed to merge the two companies.

Zaffaroni was hesitant about pursuing MDC’s chosen drug candidate – medical marijuana: “We didn’t think that marijuana was the drug of choice to present to the FDA as an initial product. Although it could very well carry a therapeutic indication, it was controversial. But we felt that the two groups could work together synergistically.”

The deal was consummated; the marijuana project was side-lined. In 2002, the company raised $45 million from top venture capital firms – Frazier Healthcare and Versant Ventures led the syndicate; Alloy Ventures, CMEA Ventures, New Enterprise As-sociates, and Zesiger Capital Group also participated. Tom King, a manager with experience in both large and small pharmaceutical companies, was brought in to serve as the company’s chief execu-tive.

Alexza filed its first investigational new drug (IND) application in 2004, that first of several that it would submit the FDA over the next five years. The company intended to test therapies for condi-tions ranging from insomnia and migraine headaches to panic attacks and schizophrenia. Alexza registered for an IPO in 2006.

Zaffaroni was eighty-three years old.In 2012, the FDA approved Alexza’s first

product, Adasuve® (loxapine) an, inhalation powder for the treatment of schizophrenia and bipolar I disorder, administered with Alexza’s proprietary Staccato® delivery system, a hand-held inhaler designed to deliver aerosol drugs deep into the lungs.

LEGACYAlejandro Zaffaroni established himself

as mover and shaker in pharmaceuticals in the 1950s and 1960s when he helped Syntex become one of just a handful of new entrants to the industry after the turn of the twentieth century. He then struck out on his own and by force of will invented an entirely new industrial sector. ALZA was the first drug delivery technology company. Today, there are dozens of companies in the field, marketing hundreds of products. Total revenues from sales exceed $100 billion annually.

ALZA pioneered many of the practices that defined the bio-technology industry in its early days. It was a Silicon Valley startup adapted to the peculiar conditions and demands of pharmaceuti-cal development. It mixed science and business in novel ways, relied on a distinguished board of scientific advisors, and attracted public investors long before it had tangible goods and revenues to advertise. Its first products were ideas. Its most valuable assets were knowledge and skill embodied in people. In many ways, ALZA was a model for biotech startups that followed a decade later.

After ALZA, Zaffaroni continued to work in spaces where chemistry and biology intersect with other scientific and indus-trial fields – genetics, medicine, pharmacology, agriculture, food science, chemical engineering, and materials science, for example. Many of the scientific platforms developed at Zaffaroni’s compa-nies became mainsprings in the evolution of the biotech industry and the expansion of molecular biology into new domains of

ALEJANDRO ZAFFARONI’S ACCOLADES AND HONORS

By the end of his career, Alejandro Zaffaroni’s accomplishments were widely recognized, admired, and appreciated. The biochemist from Uru-guay had become an American national treasure.

Fellow (American Academy of Arts and Sciences; 1973)Fellow (Academy of Pharmaceutical Research and Science; 1973)Barren Medal Award (Barren Foundation, Chicago; 1974)Member (National Academy of Sciences’ Institute of Medicine; 1977)The President’s Award (Weizmann Institute of Science; 1978)Chemical Pioneer Award (The American Institute of Chemists; 1979)National Medal of Technology (The President of the United States; 1995) Lifetime Achievement Award (University of California, Berkeley, Haas

School of Business; 1998)Fellow (American Association for the Advancement of Science; 1998)The UCSF Medal (University of California, San Francisco; 2002)Winthrop-Sears Award (The Chemists’ Club; 2004)Bower Award for Business Leadership (Franklin Institute; 2005)Gregory Pincus Award (Worcester Foundation; 2005)Biotechnology Heritage Award (The Chemical Heritage Foundation;

2006)Woodrow Wilson Award for Public Service (Woodrow Wilson

International Center for Scholars, Smithsonian Institution; 2008)National Inventors Hall of Fame (2012)

Zaffaroni meets world leaders.top: With Mexican President Miguel Alemanbottom: With Indian Prime Minister Jawaharlal Nehru


research, development, and material production.Zaffaroni’s influence on science, industry, and

medicine continues in the present. Individuals in-volved in his companies have gone on to found or di-rect a slew of biotechnology and biomedical startups. Scattered around Silicon Valley and other industrial precincts in the San Francisco Bay Area (and further afield as well) are hundreds of executives and scientists schooled in Zaffaroni’s philosophy of technological enterprise, and particularly its central tenet: building big companies with great economic value is com-mendable, but the best way to achieve the goal is to nurture innovation and growth in small ones.

Those who have known and worked with Zaffaroni remark freely on his creativity in science, daring in entrepreneurship, integrity in business, and wisdom in management. They also note his special genius for relationships – Zaffaroni displayed an uncommon knack for collaboration, mentoring, and friendship. He possessed a singular ability to inspire talented people, and to imbue collective projects with his own unique enthusiasm and spirit. Most remarkable was the rare combination of all these attributes embodied in the same person.

The loyalty and affection that Zaffaroni elicited from employees and business associates is well-known and easy to understand – his companies were good places for people. They were steeped in the decency and compassion of their founder and leader. Martin Gerstel tells a story to illustrate how Zaffaroni influ-enced those around him:

In the mid-1970s, ALZA was working on Proges-tasert. The product was in clinical trials at sites all over the country. The company had few revenues, and the trials were enormously expensive. ALZA was hemor-rhaging money. The firm was in dire financial straits, and desperately needed a clinical success to ensure its continued survival.

The Progestasert program was run by a young PhD, a first-class pharmacologist named Bruce Phar-riss. Pharriss was personable and engaging, well-liked by everyone in the company. One day, he went to Gerstel’s office and closed the door. He had a grim look on his face. Gerstel braced himself for bad news regarding the clinical trials, but the topic never came up: “Bruce said to me, ‘Martin, I’ve been diagnosed with cancer and I’ll be going through radiation. It’s pretty advanced. You need to understand that I may not be available for some meetings. I may not be here all the time.”

Gerstel was shocked. Pharriss was a personal friend, in his thirties, exuberant, full of vitality. “I went to Alex. We talked about Bruce, and then I asked, ‘Who will run this program?’ Alex said, ‘What are you talking about?’ I said, ‘Well, who’s going to run the program? What are we going to do?’ He said, “Bruce is going to run the program.” I couldn’t see how. I said, “But Bruce is going to be getting radia-tion and he’s not going to be here a lot. We have a

responsibility.” Alex said, “Bruce has a disease that may very well kill him in a short period of time. He’s going to fight it. Neither you nor I, nor anyone else in this company is going to tell him that we’re giving up on him.”

“When I think about this now,” says Gerstel, “I realize that I changed at that moment. I became a dif-ferent person. Alex had put his name on the company, put in all of his resources, borrowed money against his house. Everything was riding on this product – his company, his livelihood, his reputation, his future, all of it – and it didn’t bother him one bit. He didn’t take any of that into consideration. It simply wasn’t an is-sue. For me, that was an amazing experience.” Ø

The Race to Clone

FACTOR VIII


HEMOPHILIAHemophilia is an inherited blood disorder that impairs the

body’s ability to coagulate blood. The primary danger is internal bleeding, which can result in swelling, joint damage, disfigure-ment, and death. Symptoms range from mild to severe.

For centuries, the cause of the disease remained a medical mystery. Scottish physician Thomas Addis established the basis for modern understandings in 1911. He reasoned that since blood transfusions were therapeutic, the condition stemmed from a

deficiency, the lack of a ‘factor’ that he called anti-hemophilic factor (AHF).

Two types of hemo-philia are now known, A and B. Both result from the absence of a specific clotting factor in the blood. Hemophilia A, a deficiency of func-tional Factor VIII, occurs in about one in every

10,000 male births. Hemophilia B is due to a lack of Factor IX, present in around one in every 25,000 male births. An estimated 500,000 people suffer from hemophilia. Approximately 20,000 reside in the United States.

Hemophilias A and B are X-linked recessive genetic disorders caused by mutations in the genes that code for Factors VIII and IX. Both genes are located on the X chromosome. Hemophilia

Hemophiliacs lack a necessary blood clotting factor called Factor VIII. In the first half of the twentieth century, whole blood transfusions were the only treatment for the disease. In the 1950s, blood plasma products containing Factor VIII became available. When the AIDS epidemic began in 1981, the blood supply became contaminated with HIV. Thousands of hemophiliacs were infected. Two early biotechnology companies, Genentech and Genetics Institute, Inc. raced to manufacture a safe recombinant version of the vital clotting factor.

Dr. Thomas Addis


generally occurs in males because males possess only one X chromosome. If a male child inherits a defective gene, the disease manifests. It is possible but rare for hemophilia to be passed down

to females (when the father is a hemophiliac and the mother is a carrier), or to occur as the result of a spontaneous mutation.

In the first half of the 20th century, hemophilia was treated with whole blood transfusions. The life expectancy of patients was about twenty-seven years. In the 1950s, doctors began treating the condition with fresh frozen plasma (FFP). Concentrations of clot-ting factors remained low, so FFP was also administered intrave-nously in hospitals, in high volume transfusions.

In the 1960s, Stanford scientist Judith Pool discovered a

method for making FFP concentrates. When FFP is thawed in cold rooms, a blood factor-enriched cryoprecipitate forms. By the early 1970s, scientists had developed methods to calibrate doses, which were then packaged and sold in labeled bottles. Hemophili-acs were able for the first time to manage the condition themselves with injections. Life expectancy was extended to forty years of age. By 1980, the figure reached sixty years, but this string of spectacu-lar improvements in the life chances of hemophiliacs was about to be erased.

TAINTED BLOODThe first cases of the infectious disease that came to be known

as AIDS were identified in 1981, in New York and Los Angeles. Public health officials soon recognized that homosexuals and intra-venous drug users in these cities and others were presenting with multiple devastating and unexplained infections, and that diagno-ses were accumulating at an alarming rate. The following year, the US Centers for Disease Control (CDC) counted thousands who were affected. Hundreds had already died.

The cause and mode of transmission were mysterious. The uncertainty fueled public fears. If the pathogen was airborne, then all were at risk. Some healthcare workers refused to attend to victims of the disease. The initial reaction of many groups and

X- linked Recessive, Carrier MotherSons who receive an X-linked recessive gene from a carrier mother are afflicted;daughters who receive an X-linked recessive gene become carriers.


individuals was to blame and shun victims. The malady was widely stigmatized as a ‘gay disease’ and a ‘drug-users disease,’ the result of lifestyle choices for which patients were responsible. The scientific community suspected a virus. A broad search was undertaken by epidemiologists and virologists.

In July 1982, the CDC reported the first diagnosed cases in hemophiliacs. Mounting evidence suggested that the pathogen was transmitted by blood. In January 1983, the American Red Cross, the American Association of Blood Banks, and the Council of Community Blood Banks issued a joint statement that acknowl-edged the hazard and advised member organizations against ac-cepting donations from individuals belonging to high-risk groups.

Mandatory screening of donated blood for the presence of hepatitis B had been instituted in 1971, but patients remained at high risk of contracting a ‘non-A, non-B’ hepatitis (known today as type C). Since transfusions are life-saving measures and there was uncertainty in the 1970s and early 1980s about the course and severity of non-A, non-B infections, doctors generally judged the risk acceptable. With the emergence of the AIDS epidemic, however, this risk-benefit calculus was radically altered.

The immediate response of the gay community to disease, death, and discrimination was to organize. The first advocacy groups – Gay Men’s Health Crisis, People Living with AIDS, and the National Association of People with AIDS – appeared in 1982 and 1983. They staged highly visible protests against ‘the biomedi-

cal establishment’ – public health officials, the scientific commu-nity, pharmaceutical companies, and the FDA.

The activists complained that responses to the epidemic were slow and inadequate. They demanded increased federal sup-port for AIDS research, broad access to experimental therapies,

Hemophilia was known through much of the nineteenth and twentieth centuries as the ‘Royal Disease’ because of its prevalence in the ruling houses of Europe. The type was hemophilia B, a deficiency of Factor IX. Geneticists suspect that the original carrier was Queen Victoria, the monarch of Great Britain for sixty-three years, from 1837 to 1901, likely due to a spontaneous mutation. The disorder is apparently extinct in contemporary royal bloodlines.

Hemophilia - The Royal Disease

below: Queen Victoria below left: The most famous hemophiliac of his time, Prince Alexi Romanov (second from right) with his family in 1912. Alexi was the son of Tsar Nicholas II, the great-grandson of Queen Victoria, and heir to the Russian throne


accelerated regulatory approvals, reduced drug prices, and opportunities to participate directly in health policy decision-making. They challenged the conflation of medical and moral agendas in public discourse, and railed against figures such as Christian evangelist Dr. Jerry Falwell who expressed the opinion that AIDS represented “the wrath of a just God against homo-sexuals.”

In contrast, most hemophiliacs with AIDS suffered in silence. To avoid the stigma associated with the disease, many attempted to conceal the diagnosis, but as the pathogen and its mode of transmission became known, their predicament became appar-ent. Due to their dependence on the blood supply, hemophiliacs were hit harder by HIV/AIDS than any other group. In addi-tion, spouses of hemophiliacs were exposed to HIV through sexual intercourse, and the virus was passed on to many infants of infected parents. Alan Brownstein, director of the American Hemophilia Foundation, called the tragedy “staggering in its magnitude.”

A RECOMBINANT SOLUTION?The AIDS epidemic was an important backdrop for the emer-

gence of the commercial biotechnology industry. In the late 1970s and early 1980s, new recombinant DNA companies surveyed the commercial landscape in pharmaceuticals and drew similar conclu-sions regarding prospects and opportunities – the technology could revolutionize the production of therapeutic proteins. Two firms, Genentech of South San Francisco, California, and Genetics Insti-tute, Inc. (GI) of Cambridge, Massachusetts, selected Factor VIII as a target since the plasma concentration process was crude and expensive, clotting factors were in short supply, and hemophiliacs were contracting hepatitis (and would soon be beset by HIV).

Genentech and Genetics Institute had assembled some of the world’s best gene cloners, along with top protein and nucleic acid chemists. Many of the scientists knew each other personally. Most had been recruited from the higher circles of molecular biology – a relatively closed guild of gene workers with affiliations at a limited number of leading academic institutions, places such as Cold Spring Harbor Laboratory, Caltech, Harvard, MIT, Stanford, the University of California, San Francisco, the University of Washing-ton, and a handful of others.

Genetics Institute, Inc. was founded in 1980 by Harvard molecular biologists Mark Ptashne and Tom Maniatis. With help from investor Henry McCance of the venture capital firm Greylock Partners, they recruited Gabe Schmergel, an experienced general manager in the healthcare industry, to direct the organiza-tion as CEO. Schmergel came from Baxter International, a fifty

AIDS activism–speaking out of desperation


year-old public corporation headquartered in the Chicago suburbs that specialized in blood products, including plasma concentrates. He knew the market well and saw that recombinant Factor VIII (rFVIII) would transform it.

Schmergel also knew that Genentech was interested in Factor VIII. Genentech was the original recombinant DNA company, founded in 1976. Its first commercial project was the manufacture of recombinant human insulin. That work was underwritten by Eli Lilly & Company. Sometime after, the California clon-ers approached Baxter to propose a partner-ship for the development and marketing of a genetically engineered version of Factor VIII. Schmergel was not involved in the talks, but knew of the big company’s response: “Baxter said it was blue sky and would never work.” Genentech set the project temporarily aside.

Eventually, Genentech’s grand success changed perceptions of the technology and its practical import. In 1979, the company an-nounced that it had cloned the gene for human

growth hormone. In the fall of 1980, the firm made a hugely success-ful public offering of stock. In 1982, as Lilly was preparing to intro-duce Genentech’s human insulin to the marketplace as the world’s first recombinant biotherapeutic product, Schmergel was able to

Hemophiliac Ryan White contracted AIDS as a child from a blood transfusion. When his condition became known in his hometown of Kokomo, Indiana in 1985, concerned parents and teachers objected to his presence at school. Public health officials insisted that the risk of transmis-sion was virtually non-existent, but the local school board voted to bar White from attending classes.

A legal battle ensued. The case received widespread publicity. Celebrities flocked to Indiana to support White and champion AIDS awareness. The Indiana Department of Education intervened and permitted White to return to school. Opponents

secured a temporary restraining order, but a Federal Circuit Court judge overturned the ban and the Court of Appeals refused to hear further arguments.

The case moved the plight of hemo-philiacs into the national spotlight. White became a symbol of the universality of AIDS, the personification of efforts to combat ignorance and fear and promote decency and compassion.

Ryan White passed away in April 1990 at the age of eighteen. In August, Congress enacted the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, which provided federal funds for the care and treatment of people living with AIDS.

Ryan White

Ryan White (left) with Elton John (right)

(left to right) Gabe Schmergel, Mark Ptashne, and Tom Maniatis


persuade former colleagues at Baxter that the Factor VIII project wasn’t impossible after all. He traded mar-keting rights on an initial product to Baxter’s Hyland Laboratories Division in exchange for R&D support, royalties, and a contract to manufacture the protein.

When GI elected to pursue Factor VIII, Genentech quickly followed suit. David Goed-del, Genentech’s chief scientist, remembers that Bob Swanson, the company’s co-founder and CEO, was determined not to surrender the commercial prize to a competi-tor: “There were rumors that Genetics Institute had something on Factor VIII, so Swanson wanted me to work on it.”

As research at the two companies got underway, the AIDS crisis exploded, public health officials realized that contaminated blood products posed a grave threat to hemophiliacs, and the urgency of efforts to clone the Factor VIII gene became even more pro-nounced – recombinant DNA technology represented a means of producing a pure, pathogen-free version of the life-saving protein.

THE DIMENSIONS OF THE PROBLEMIn the early 1980s, Factor VIII was still not fully understood

at the molecular level. Researchers remained uncertain about the identity, size, and source of the protein. Factor VIII is ordinarily bound to a molecule called von Willebrand factor (vWF) that sta-bilizes and protects it from degradation in the bloodstream. Only on initiation of the clotting process is Factor VIII cleaved from von

When a blood vessel is injured, platelets circulating in the blood come into contact with fibrous tissues containing col-lagen. Collagen stimulates platelets to release assorted proteins and organic compounds that trigger a complex series of reactions known as the blood coagulation cascade. The coagulation cascade leads to the formation of a fibrin-reinforced platelet plug that stops bleeding. It proceeds through the stepwise activation of a series of zymogens (enzyme precursors) that cleave and mobilize proteins downstream, and through the synthesis or release of molecules that perform regulatory functions – inhibiting, stabilizing, degrading, and so on.

Factor VIII is activated about halfway through the coagulation cascade when it is proteolytically cleaved from von Willebrand factor. In the presence of calcium ions and phospholipids, Factor VIII acts as a cofactor with Factor IX in the activation of Factor X, which is responsible for production of a thrombin ‘burst.’ Throm-bin is a serine protease that converts fibrinogen into its insoluble form, fibrin. Fibrin binds to platelets accumulating at the site of damage, forming a stable plug that stems blood flow.

The Blood Coagulation Cascade

(left to right) David Goeddel, Bob Swanson, and lab tech

Elizabeth Macleod


Willebrand factor.Clear evidence that Factor VIII and vWF are distinct proteins

did not appear until 1979 when Edward (‘Ted’) Tuddenham, a British hematologist working in the lab of Leon Hoyer at the University of Connecticut, devised a method for separating them by immunoadsorbent chromatography, and showed that von Wil-lebrand factor was not directly implicated in coagulation.

Researchers at Genentech and GI (and elsewhere) anticipated that cloning the Factor VIII gene would be extraordinarily difficult due to its immense size. It is now known that the gene spans 186 kilobases (kb) of DNA, with twenty-six exons (coding regions) containing instructions for the manufacture of 2,351 amino acids. By comparison, the first human gene cloned by Genentech coded for somatostatin, a peptide hormone composed of a mere fourteen amino acid residues. Genentech’s other recombinant proteins, human insulin and growth hormone, contained fifty-one and 191 amino acids, respectively. Factor VIII was gargantuan.

Genentech had used chemical methods to synthesize the

somatostatin and insulin genes. Human growth hormone was produced with a ‘semi-synthetic’ method that married chemically-fabricated bits of DNA with biologically-derived complimentary DNA (cDNA) sequences. Neither ap-proach was suitable for Factor VIII. The gene was too big. The task exceeded the capabilities of the then current state-of-the-art in DNA chemistry.

The cloners saw that it would be necessary to replicate the gene al-most entirely by biological means, by isolating messenger RNA transcripts (mRNA) from cells and using an

enzyme, reverse transcriptase, to synthesize new cDNA copies of the original gene. They knew how to make genes in this way, but they weren’t sure they could produce a cDNA molecule as large as Factor VIII. It had never been done.

There was another complication – the researchers could not proceed directly to this step because Factor VIII’s tissues of origin had not been identified. The protein circulates in the blood, but the whereabouts of cells that produce it were unknown. No one knew where to look for the mRNA that indicates gene expres-sion and serves as a template for cDNA synthesis. The biology of clotting factors was only partially understood, and Factor VIII is extremely scarce, expressed at very low levels. If ever a gene was a needle in a haystack, it was this one.

Despite the degrees of difficulty, both Genentech and GI judged that the potential rewards of success outweighed the risks of failure. Steve Clark, GI’s first scientific employee, remembers deliberations: “I looked at the current literature, evaluated it, and said, ‘I don’t think we can do this. It looks too hard.’ I passed it on

Jay Toole (left) with Gabe Schmergel


to others, and Jay Toole said, ‘I think we can do it.’” Ptashne was skeptical, but approved the project. Maniatis called Factor VIII “scary,” but also gave assent.

At Genentech, David Goeddel was busy trying to clone inter-feron. He assigned Factor VIII to Dick Lawn, and sent his best postdoc, Dan Capon, to Lawn’s lab to assist. The race was on. The commercial stakes were high, the work was demanding, and the outstanding problems were enormously complex. It was also dawn-ing on the scientists that the outcome of the race could have life or death implications. At the end of 1982, biomedical researchers and public health officials had not yet determined the cause of AIDS, but they had recognized that blood transfusions were placing hemophiliacs in jeopardy.

WORKING BACKWARDSThe two companies adopted similar technical strategies. The

first step was to find a source of purified protein that would en-able ‘reverse genetics’ – working backwards from the amino acid sequences of protein chains to deduce the codons that compose DNA sequences. It wasn’t easy. Purified Factor VIII was a scarce commodity. Only very small amounts of the protein are produced in the body, and when isolated, the molecule is highly unstable, fragile, and easily degraded.

Toole began making inquiries to protein chemistry labs. He was eventually put in touch with David Fass of the Mayo Clinic in Rochester, Minnesota, who had recently used monoclonal antibod-ies to purify Factor VIII from the blood of hogs. Toole considered porcine Factor VIII a viable substitute for the human protein. It was widely assumed that the gene was highly conserved in both species. The molecules were likely to be very similar.

Fass agreed to provide the protein, but it was in short supply. Bob Kamen, GI’s director of research, recalls wondering “how politely to ask the Mayo to work a little faster.” The company sent John Knopf to Minnesota to assist. Knopf visited hog farms, took buckets of blood from pigs, and ran them through the purification process. GI was able to secure an adequate

quantity of porcine Factor VIII with which to work.Rod Hewick, GI’s chief protein chemist, was responsible for

determining the amino acid structure of the molecule. He had worked at Caltech with Leroy Hood, Mike Hunkapiller, and Bill Dreyer to develop the first automated gas-liquid phase protein sequencer. Applied Biosystems, Inc. shipped the first commercial units in August 1982. GI purchased one, and set out to identify the more than 2,300 amino acids that compose porcine Factor VIII.

Protein chemistry work at Genentech was directed by Gordon Vehar. Vehar had reported the first purification of bovine Factor VIII – in miniscule amounts – in 1980 while working as a postdoc in the lab of biochemist Earl Davie at the University of Washing-ton. He was unable reproduce the feat with the human protein at Genentech, and turned to Ted Tuddenham for help.

Tuddenham had moved to the Royal Free Hospital in Lon-don and devised means for purifying human Factor VIII. It took Genentech nine months to negotiate a deal with the hospital, which had already entered into a contract with a British company, Speywood, for certain rights to the molecule. Once an agreement was reached, production was meager. Tuddenham’s lab shipped pu-rified protein at the rate of one milligram every three weeks. In all, twenty milligrams were sent from London to South San Francisco. That quantity was derived from 2,000 liters of blood collected and roughly 10,000 individual donations.

When Hewick and Vehar had partial protein sequences in hand, they designed oligonucleotide probes (relatively short pieces of single-stranded DNA) with which to screen a genomic DNA li-brary – a permanent collection of total genomic DNA maintained in culture. The probes were configured to hybridize with comple-

Dick Lawn, second from the right, with Genentech’s original cloners (from left):Dennis Kleid, David Goeddel, Art Levinson, Herb Heyneker, Peter Seeberg, and Axel Ullrich


mentary portions of the Factor VIII gene. They carried radioactive labels, so hybridization events could be monitored.

Because the library contained all DNA in the human genome, it was virtually guaranteed to contain the gene (albeit as a vanish-ingly small fraction of the total DNA). The approach was novel – for good reason. In the cloning business, combing through the entire human genome for a scarcely-expressed gene was a method of last resort. Factor VIII was a special case.

Both companies used a human genomic library that Ge-nentech’s Dick Lawn and GI’s Ed Fritsch had established while working as postdocs in Tom Maniatis’ laboratory at Caltech in the late 1970s. Lawn and Fritsch had chopped up human DNA with restriction enzymes, separated the pieces by gel electrophoresis, and packaged them into lambda phage particles. Lambda phage is a virus that infects E. coli bacteria. The library consisted of millions

of viral particles multiplying in a bacterial culture, each propagat-ing a bit of dissected human DNA. The companies looked through it to find partial clones of the Factor VIII gene, which would then be used as probes in complementary DNA (cDNA) libraries.

cDNA libraries contain, not total genomic DNA extracted from cell nuclei, but DNA synthesized from mRNA gene transcripts recovered from cytoplasm. mRNA molecules convey instructions for protein synthesis to ribosomes, the cellular organ-elles on which proteins are manufactured. The presence of mRNA in a cell is evidence of gene expression – it indicates that genes are being replicated, transcribed, and translated into amino acid chains, the structural components of proteins. By the early 1970s, molecular biologists had acquired enzymatic tools that enabled them to reverse the transcription process and create cDNA replicas of genes from mRNA templates. A cDNA library is a collection of such replicas.

Obtaining a cDNA clone was necessary because the DNA in human genomic libraries is composed of interspersed exons and introns – coding and non-coding regions of genes. In 1983, neither company held out hope that bacterial or mammalian cells would modify RNA transcribed from a genomic clone in a manner permitting the expression of a functional recombinant protein (even if a full-length sequence of genomic DNA could somehow be cobbled together – that in itself would be a monumental ac-complishment). cDNA clones, in contrast, are synthesized from mRNA templates and contain only uninterrupted exons. mRNA molecules are formed in enzymatic processes that cut out introns and re-splice exons into concise coding sequences.

The gene hunters in Boston and San Francisco planned to screen the big genomic library to identify bits of the Factor VIII gene sequence. Probes that hybridized portions of the gene would then be used to screen cDNA libraries. Libraries containing traces of the Factor VIII sequence would be re-screened once more with the same probes in order to uncover either a full-length clone or a series of partial clones that would together encompass the entire gene. With a full-length cDNA clone in hand, the cloners could move on to expression, to the manufacture of the recombinant protein.

Due to the complexities of DNA transcription and translation,

The process of deriving a cDNA clone of the Factor VIII gene from genomic and cDNA libraries

diagram: Lawn and Vehar, Scientific American

Deriving a Clone


and the scarcity and size of Factor VIII, the search for the gene was inefficient and subject to error. Missteps were numerous and prog-ress slow. Toole worked with Fritsch, Knopf, and John Wozney to search for Factor VIII sequences in the genomic library. “We had failure after failure after failure,” he says. “We kept getting false positives. We would take a hybridized probe, clone it out, and it would turn out to be junk.” In Lawn’s lab at Genentech, Dan Ca-pon, Jane Gitschier, and Bill Wood encountered similar difficulties.

Small probes lacked specificity. They hybridized with DNA sequences repeated throughout the genome, and not unique to the Factor VIII gene. Longer probes were more selective, but the ge-netic code contains redundancies. Protein sequences can be coded in a variety of ways. The longer the targeted sequence, the larger was the battery of probes that had to be tested. Finding the right oligonucleotides was a frustrating slog. Endurance was as impor-tant as biological knowledge and analytical skill.

The teams persevered. By mid-1983, both Genentech and GI had obtained short segments of the gene. To confirm that they were X-linked, positive probes were deployed a second time to screen a library containing DNA from a rare XXXXY cell line. The line came from the cells of an individual with four X chromo-somes. When Southern blot comparisons of results from Lawn and Fritsch’s library and the XXXXY library displayed expected hybrid-ization frequency ratios (1:4), the researchers knew the sequence was X-linked and could belong to the Factor VIII gene.

From these starting points and preliminary validations, the teams laboriously assembled progressively longer genomic clones, piece by piece, and used them to probe cDNA libraries. As in-cremental advances accumulated, the companies began devoting greater resources to the projects. Both eventually assigned more than thirty scientists to Factor VIII cloning duties. Lawn says: “We pillaged other Genentech labs for a couple of years while the project was hot.”

KEEPING SECRETS AND MAKING DISCLOSURESAt both companies, there was intense interest in what the other

side was doing, and much internal speculation. The competi-tors looked over their shoulders constantly. Jay Toole recalls that “rumors were rampant.” Dick Lawn remembers being “nervous the entire time.” On business trips that brought him from London to California, Ted Tuddenham observed what he calls “almost para-noid secrecy” at Genentech.

Lines of communication remained open nevertheless. Molecu-lar biologists Chris Simonsen at Genentech and Randy Kaufman at GI had worked together in Bob Schimke’s laboratory at Stan-ford, and had remained friends. They didn’t divulge trade secrets or report on progress, but, Kaufman says, “We talked. They were cloning Factor VIII, we were cloning Factor VIII. We generally knew what was going on.”

Lawn’s experience was similar – he went to GI to visit his for-mer Caltech boss, Maniatis, and former benchmate, Fritsch: “We never discovered directly where we stood. It was like baseball play-ers on opposing teams before the game—you could shake hands or chat around the batting cage, but once the game started, it was very competitive.”

Kaufman concedes that it was sometimes difficult to avoid unintended disclosures while maintaining collegial relations in the scientific community: “We had invited [Genentech scientist and later CEO] Art Levinson to give a talk at GI. It was the day that Rod Hewick’s chemistry group figured out an important amino-terminal sequence of Factor VIII. I was showing Art around. Rod saw me and shouted, ‘We got it!’ I said, ‘Rod, this is Art Levin-son.’”

According to Toole, the urgency and gravity of the undertaking generated high levels of stress: “John Knopf and I would some-times see the company’s CFO in the elevator, and he would ask

cDNA libraries are assembled in the following steps: 1) single-stranded mRNA is extracted from cells and purified for in vitro pro-cessing; 2) reverse transcriptase is added to synthesize complimentary DNA strands; 3) RNase is employed to degrade the RNA; 4) DNA polymerase is used to replace degraded RNA with newly-synthesized DNA, creating double-stranded cDNA copies of the genes from which the original mRNA molecules were transcribed; 5) the cDNA copies are spliced into viral or plasmid vectors; 6) the vectors are deployed to transfect or transform bacteria; 7) bacterial colonies are grown up in culture, and as they multiply, the recombinant cDNA is reproduced.

When cDNA libraries are constituted, and portions of gene se-quences are known, specific genes can be targeted with labeled nucleic acid probes and isolated for full sequencing or further cloning.

The Formation of cDNA Libraries

He had no concept of how the science worked. He would

say things like, ‘If you guys don’t succeed, the whole company is going to fail.’


‘Have you cloned it yet?’ He had no concept of how the science worked. If we said no, he would say things like, ‘If you guys don’t succeed, the whole company is going to fail.’ John Knopf wanted to strangle him. The pressure was enormous.”

The work at the lab bench inched forward. At Genentech, Jane Gitschier developed a boot-strapping sequencing technique called ‘genome-walking,’ the fundamentals of which are still widely-employed. She worked from established sequence data to configure extended probes that would overlap and generate data on adjacent regions. The GI group devised similar techniques.

On October 28, 1983, GI filed a patent application on “prepa-rations of recombinant DNA which code for cellular production of human and porcine Factor VIII and methods of obtaining such DNA and expression thereof in bacteria and eukaryotic cells.” The application was based on a partial clone and specified steps for

deriving a full human sequence. The inventors, Jay Toole and Ed Fritsch, later amended sequence data – in a ‘continuation-in-part’ filing – in order to strengthen the claim to the gene. The original application was filed quietly in order to establish priority. On De-cember 1, however, the company issued a press release on further developments.

Dick Lawn remembers hearing about it the next day: “Some-body called me and said, ‘There’s a New York Times article about Genetics Institute and their Factor VIII project.’ I went down to Irving Street in San Francisco, bought the paper, and started reading.” Lawn was afraid that researchers at GI had obtained the full sequence and expressed human Factor VIII. They hadn’t. They were reporting a cDNA clone that represented “a significant por-tion” of the human gene. “I was so relieved,” Lawn says. “GI was announcing in public that they were behind us.”

Dan Capon’s reaction was very different. He was working with genomic clones produced by Jane Gitschier and Bill Wood to screen cDNA libraries for Factor VIII mRNA. “My heart sank,” he says. “They were so far ahead of us.” Capon had constructed over fifty cDNA libraries from various cell lines, each containing an average of seven million clones. He recalls having worked out just 10 percent of the sequence, while GI had started with liver and

spleen tissues and found enough Factor VIII mRNA to synthesize a larger partial clone.

Capon redoubled his efforts: “Instead of working 16 hours a day, I started working 20 hours a day.” On December 26th, he was finished – the cDNA sequence was complete. Dan Eaton, Art Levinson, Chris Simonsen, and Bill Wood pressed ahead to express the gene in mammalian cells. Genentech had used E. coli cells to produce recombinant somatostatin, insulin, and growth hormone, but the group did not expect the simple bacterial system to manu-facture a functional protein as complex as Factor VIII. They tried it and found that they were right.

After a second failed attempt with Chinese hamster ovary (CHO) cells, the company achieved expression in baby ham-ster kidney (BHK) cells. “On 10 April 1984,” Gitschier reports, “Gordon came by Dick’s lab and left a note on Bill Wood’s desk: ‘See me. They had activity!’” Tests had shown that the recombinant protein was a viable substitute for native Factor VIII. A patent application was hastily written up and filed ten days later (setting the stage for a legal contest). The submission covered cloning, ex-pression, and the full sequence of the human Factor VIII gene. The inventors were Dan Capon, Dick Lawn, Art Levinson, Gordon Vehar, and Bill Wood. Genentech was ahead, by a nose.

Sometime shortly after – precisely when isn’t clear – GI ben-efitted from a chance occurrence that eliminated a great deal of monotonous bench work in a single lucky stroke. “One night,” Toole says, “we were able to get two clones that overlapped to cre-ate a full length clone. It was pretty remarkable.” Toole checked the human clone against the known porcine sequence. It corresponded closely. “The ultimate test,” he says, “was performed in Randy Kaufman’s lab. Randy put the full-length cDNA into a monkey kidney cell line using an SV 40 vector, took out the supernatant, and showed that it had coagulation activity. It was Factor VIII. We had it. We started celebrating.”

The race to clone Factor VIII had ended in a virtual dead heat. David Goeddel says, “I’m not sure it was ever resolved who got the clone first or who got it expressed first.” Progress reports were part of a cat and mouse game for the control of intellectual properties. Genentech was first to announce a complete cDNA clone, and first to achieve expression, but by mid-1984, both companies had rFVIII, and both had patents pending. It was a photo finish.

INTERSECTIONS AND TURNING POINTSIn June 1984, Professor Luc Montagnier of the Pasteur Institute

in Paris, France and Dr. Robert Gallo of the US National Institutes of Health (NIH) held a joint press conference to announce that the retroviruses they had associated with AIDS – Montagnier’s lymphadenopathy associated virus (LAV) and Gallo’s human T-lymphotropic virus (HTLV-III) – were probably the same, and likely the cause of the spreading epidemic. The pathogen was later renamed the human immunodeficiency virus (HIV). Virologists


and public health officials had a target at which to aim.In mid-August, Genentech submitted three papers to Nature

– one each on Factor VIII protein structure, cloning, and gene sequence. Deputy editor Peter Newmark contacted GI and offered to publish a report on the sum of its work, too – if it could be written up within a week. “Later,” Lawn recalls, “Jay told me they stayed up night and day writing it. I think he said someone flew to London with the manuscript, I’m not sure.”

In the first week of September, Lawn and Toole attended International Congress XVI of the World Federation of Hemo-philia in Rio de Janeiro. They were the main speakers on the first night of the meeting. “Sure enough,” says Toole, “we presented the same data back-to-back, on the expression of full-length Fac-tor VIII.” The implications for the AIDS crisis were obvious, but the researchers prefaced talk about recombinant blood factors as substitutes for plasma concentrates with a disclaimer: ‘It could take years.’

B.L. Evatt of the CDC’s Division of Hematology also attended the Congress. He presented the results of experiments to deactivate LAV (HIV) in blood: the virus was readily destroyed by brief expo-sures to temperatures in excess of 70 degrees Celsius (158 degrees Fahrenheit).

In the second week of September, Genentech signed a clini-cal testing, manufacturing, and marketing agreement with Cutter Biological, a division of Bayer’s US subsidiary, Miles Laboratories, located in Berkeley, California. In exchange for cash and down-stream royalties, Genentech surrendered worldwide marketing rights to rFVIII (save for certain United States and Canadian rights that would be restored to Genentech two years after the introduc-tion of a product).

In October, the American Hemophilia Foundation’s Medical

and Scientific Advisory Committee strongly recommended that physicians and hemophiliacs rely on heat-treated blood and plasma products exclusively.

On November 22, 1984, Nature ran four papers on Factor VIII – three by Genentech, and one by GI – as lead articles. Edi-tor John Maddox hailed the cloning of the protein as “a technical triumph without parallel.”

By the end of the year, the CDC reported 7,699 confirmed cases of AIDS in the United States, and 3,665 deaths. Epidemiolo-gists reckoned that tens of thousands more had been infected by HIV.

On March 20, 1985, the US Food and Drug Administration (FDA) licensed Abbott Laboratories to sell the first antibody test to detect HIV in serum. Blood banks began screening donated blood. By this time, heat-treatment had been broadly implemented. The AIDS epidemic raged on, but HIV transmission to hemophiliacs through blood transfusions or the use of plasma products was halted abruptly. The blood supply and blood products became virtually HIV-free.

Recombinant Factor VIII didn’t rescue hemophiliacs from exposure to HIV after all. The cavalry didn’t charge over the hill in the movie’s climactic scene. The real-life solution was prosaic and low-tech. It was also tragically belated. According to the National Heart, Blood, and Lung Institute of the NIH, half of all hemo-philiacs in the United States had contracted HIV by 1985; among patients with severe forms of the disease requiring frequent blood transfusions, the figure was 90 percent.

COMMERCIALIZATIONRecombinant Factor VIII was no longer desperately needed

to rescue hemophiliacs from exposure to HIV, but the AIDS epidemic had made medical professionals, the scientific commu-nity, the healthcare industry, and the government acutely aware of the vulnerability of the blood supply to unknown threats. It was

Infusion for the first clinical trial of rFVIII

Poster announcing a regulatory approval celebration for Recombinate, Genetics Institute's recombinant Factor VIII therapy


widely understood that the availability of recombinant blood fac-tors could avert similar tragedies in the future.

Nevertheless, without the urgency and demand generated by contamination of the blood supply, subsequent decisions regard-ing the development of rFVIII became at once more mundane and more complex. GI, Genentech, and their corporate partners believed that the recombinant product would be superior, but safety and efficacy in human beings hadn’t been demonstrated. There were concerns that recombinant proteins secreted from non-human mammalian cells – and especially proteins as large and complex as Factor VIII – would not be properly glycosylated (decorated with carbohydrates) and folded, and rendered ineffec-tive or immunogenic as a result.

There were financial, commercial, and legal issues to sort out as well. Screening and heating made blood and plasma products more expensive to produce, but it was unclear whether recombinant methods afforded economic advantage. Making market projections was impossible. Recombinant production could help to alleviate chronic clotting factor shortages, and perhaps generate surpluses that would permit prophylactic treatments, but by the time new products had passed through clinical trials, the patient population could be wiped out by AIDS. Intellectual property positions were also difficult to assess. For the involved parties – Baxter and GI and Bayer and Genentech – the only sure thing was that litigation would be expensive.

Given the prevailing uncertainties, GI diverted resources from rFVIII to R&D on erythropoietin (EPO), a red blood cell growth-

stimulating hormone used to treat anemia. According to Randy Kaufman, “The company couldn’t afford to go all out on both at the same time. It had to focus on one. EPO was chosen because the market was bigger.” GI remained committed to delivering recombinant Factor VIII to Baxter and to hemophiliacs in need, but CEO Schmergel needed to allocate materials and personnel to both projects contingently. In the shuffle, the development of Factor VIII was slowed for nearly two years.

On the West Coast, Genentech was developing two important recombinant therapeutic proteins simultaneously: Factor VIII and tissue plasminogen activator (tPA), a molecule that dissolves blood clots. Genentech needed cash, and could not afford to manufac-ture and market both products on its own. tPA was expected to be the greater revenue generator as a treatment to unblock coronary arteries after heart attacks and cranial arteries after strokes. The company sold the rights to rFVIII and turned its technology over to Cutter Biological. Cutter made conventional plasma concen-trates and lacked expertise in the manufacture of recombinant proteins in mammalian cell cultures. The company had trouble producing a stable protein. The Genentech molecule languished for a time in pre-clinical development.

GI solved stability problems by co-expressing recombinant von Willebrand factor (VWF) with Factor VIII in CHO cells. VWF, which naturally binds to Factor VIII and protects it from disinte-gration, was cloned at Harvard in 1986. GI licensed and incorpo-rated the technology. According to Randy Kaufman, who led the expression effort, the uniquely adaptable and scalable CHO cells were indispensable for high volume production of rFVIII: “We had these cells that made a boatload of Von Willebrand factor in order to make just a little usable Factor VIII, but we were able to scale it up.”

When clinical testing of the GI product got underway in March of 1987, the immunogenicity of CHO cell-derived proteins remained a worrisome possibility. Dr. Gilbert C. White conducted the first human trial at the Center for Thrombosis and Hemosta-sis at the University of North Carolina. He tells the story of an enrolled subject, G.M., a forty-three-year-old male: “I infused the material and noticed that G.M.’s eyes were closed and his chin was resting on his chest. I asked if he was OK, but he didn’t answer. I asked again, but no answer. Louder, I said, ‘Speak to me.’ He looked up and started making hamster noises.”

Baxter held a dinner to celebrate the first clinical trial. Toole was invited, along with patient #1, the first person to receive a therapeutic dose of rFVIII. There was an emergency. The patient, Toole explains, “felt his mouth filling up with blood. He injected himself with rFVIII and the bleeding stopped immediately. Every-


body breathed a sigh of relief.”GI’s Factor VIII patent issued in 1989. The

interference between the companies’ claims remained unresolved, and the Californians had a strong argu-ment to test – GI had described a method for produc-ing the Factor VIII gene, but Genentech had specified the complete gene sequence. Neither party was eager to enter into risky and potentially damaging litigation, so

a royalty-free cross-licensing agreement was negoti-ated. The terms gave GI and Baxter and Genentech and Bayer clear paths to the marketplace, so long as the FDA approved their products.

GI’s Recombinate® was approved for sale in Decem-ber 1992. Cutter Biological had moved the Genentech molecule into clinical trials in June of 1988. Its prod-uct, Kogenate®, made in BHK cells, came to market in early 1993. The race to clone the Factor VIII gene had been a sprint; the race to bring the product to market became – as is the norm in the pharmaceutical industry – a test of endurance.

REFINEMENTSResearch at Genetics Institute led eventually to

a ‘second generation’ Factor VIII product. In 1986, Toole’s group compared the gene sequences cod-ing for three principal structural domains of Factor VIII molecules – A, B, and C – in hogs and human

beings. The A and C portions were nearly identi-cal, but the B sections differed considerably. “We saw,” says Toole, “a huge middle region in which the homology between the two factors was completely lost.”

The lack of conservation between species suggested that the B domain did not play a functional role in blood coagulation. Toole discovered that the entire

middle region (38 percent of the molecule) could be removed without diminishing therapeutic efficacy: “It was just filler protein. I made a clone that got rid of the B domain, and it retained activity, which was a remarkable thing.” Genet-ics Institute published the finding in Proceedings of the National Academy of Sciences in August 1986. The modification increased the efficiency of expression and significantly reduced costs of producing the protein.

A Genentech group led by Dan Eaton and Bill Wood reported the same alteration in Bio-chemistry in December, but according to Dennis Kleid, one of Genentech’s senior scientists: “Bayer didn’t want to work on the B-domain deleted product even though we had given them an exclusive license to make and sell it. They never developed it.” In March 2000, the FDA approved Genetics Institute’s product under the

trade name Refacto®. It was marketed by Pharmacia and Wyeth (which wholly acquired Genetics Institute in 1996).

A ‘third generation’ product followed eight years later. Serum albumin (human or bovine) was added to CHO and BHK cell culture media in the production of Recombinate, Kogenate, and Refacto, and mono-clonal antibodies of murine origin were employed in immunoaffinity purification processes. In the manufac-ture of the third generation product, all contact with human or animal-derived proteins was eliminated. In addition, a virus-retaining filtration step was incorpo-rated.

These measures make the latest version of recom-binant Factor VIII as pure, safe, and protected against blood-borne pathogens as is possible given the current state-of-the-art in pharmaceutical technologies. The FDA approved Wyeth’s Xyntha/ReFacto AF® for sale in February of 2008.

Commercial rFVIII, Recombinate

Never again was a project as difficult as Factor VIII was in its time.


CONCLUSIONThe AIDS epidemic was a public health watershed. Blood

banks, government officials, and scientists joined forces to solve the problem of HIV contamination, and, as a result, the blood supply and blood-based medical products have never been safer. Today, physicians and hemophiliacs rely on clotting factor-enriched plasma concentrates without anxiety or fear. The transmission of disease through transfusions is rare.

However, risks of contamination from known and unknown pathogens can never be eliminated entirely. For this reason, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation endorses recombinant clotting factors as first-line therapies, and most physicians prescribe them for newly-diagnosed hemophiliacs.

Approximately 40 percent of the Factor VIII used to treat hemophilia A patients is genetically-engineered. Recombinant products are more expensive, but guaranteed to be safe, and they have done much to alleviate chronic shortages of the life-saving protein. Prophylactic treatment of hemophilia A is now possible and common – rFVIII has helped thousands of patients lead nor-mal lives. Memories of the AIDS tragedy linger, but the outlook for hemophiliacs in the US has never been brighter. Patients and their families now await the next great scientific advance – a gene therapy that can cure the disease.

The cloning of Factor VIII was a triumph for genetic engineer-ing. It was one of the signal events that established molecular biology as a legitimate technological platform in the pharmaceuti-cal industry. Looking back, Tom Maniatis says: “It was a huge challenge to characterize the protein, and to isolate, clone, and ex-press this enormous gene. Making that happen was a tremendous accomplishment.” David Goeddel calls Factor VIII “the last great cloning project.” “Never again,” he says, “was a project as difficult as Factor VIII was in its time.”

All of the main participants went on to fashion distinguished careers in science and industry. Jay Toole’s experience with Factor VIII left him fascinated with human physiology. He left GI in 1987 to train in medicine at Stanford. He subsequently returned to industry as Gilead Sciences’ Senior vice-president of clinical research. After Factor VIII was shuttled off to Cutter, Dick Lawn went on to direct atherosclerosis R&D projects at Genentech. In 1993, he moved to CV Therapeutics in Palo Alto, California to manage projects in genomics and cardiovascular disease.

When Jane Gitschier’s postdoctoral stint came to an end, she moved to a faculty position at the University of California, San Francisco and carried on with investigations into the genetics of

hemophilia. Bill Wood stayed at Genentech until 2008. He led a string of cloning projects, and after 1997 began working in bioinformatics. Dan Capon became involved in Genentech’s efforts to develop an HIV vaccine. In 1991, he joined newly-founded Ab-genix to work on the transgenic production of human antibodies, and in 1995, started his own company, Monogram Biosciences, in South San Francisco. Gordon Vehar remained at Genentech until 2000 when he left to join Raven Biotechnologies as vice-president of research & development.

John Knopf stayed with Genetics Institute through its acqui-sition by American Home Products (later Wyeth), until 2002. The following year, he founded Acceleron Pharma, a biothera-peutics company, in Cambridge, MA. Knopf was appointed the firm’s CEO in 2007. Randy Kaufman eventually returned to academic science as a professor and Howard Hughes Medical Re-

search Institute investigator at the University of Michigan Medi-cal School. He is now a faculty member at the Sanford Burn-ham Medical Research Insti-tute in La Jolla, California.

After Factor VIII, John Wozney worked on the development of GI’s success-ful bone morphogenetic proteins and various other projects. In 2000, he became director of basic research and pre-clinical R&D at Pfizer. Ed Fritsch spent nineteen years at GI, contributing to numerous research programs until 2000. He subsequently became a senior vice-president of research & development at Phylos in Lexington, Massachusetts. Rod Hewick continued to work in protein chemistry at GI and Wyeth for more than twenty years.

The scientific competition between Genentech and Genetics Institute for Factor VIII was relatively brief – about two years – but intense. Genentech’s Jane Gitschier has written about it: “We knew what those at Genetics Institute had been through. We felt a kindred spirit.” Dan Capon tells of running into Jay Toole many years later, in a parking lot in Foster City, California. He says he was pleased to meet “one of the few people in the world who understood what it was all about.” Ø

Carl Feldbaum (center), with father, Maurice (right), and

Senator Arlen Specter (left)


LSF director Carl Feldbaum became the founding president of the Biotechnology Industry Organization (BIO) in 1993. His prior life of public service began in 1973. As a new graduate of the University of Pennsylvania Law School, he was hired by Special Prosecutor Archibald Cox to assist in the investigation of the Watergate scandal. Feldbaum later became Inspector General for Defense Intelligence in the Pentagon, special assistant to the Secretary of Energy, and founding director of the Palomar Corporation, a national security think tank. He also worked closely for many years with Arlen Specter, the late Senator from Pennsylvania. Specter was first elected to the Senate in 1980. He remained there for thirty years, a staunch supporter of legislation promoting the life sciences and biomedical research. Feldbaum was an assistant district attorney to Specter in Philadelphia in the 1970s, and, in Washington in the 1980s, the Senator’s Chief-of-Staff for four years. Here, he reflects on the legacy of his former boss.

by Carl Feldbaum

A HARD MAN WITH A SOFT SPOT

ARLEN SPECTER

~

Former Senator Arlen Specter was the hardest man I ever knew, even harder than my Dad or Henri Termeer. Arlen took the cake. On the occasion of his sixtieth birthday, when I was Arlen’s Senate Chief-of-Staff, a gracious staff

member baked him a cake, but was too terrified to take it to him, as were other staff members. So, it fell to me, and as I approached, candles lit, he actually snarled.

Arlen was not a back-slapping collegial senator. He was commonly known behind his back as “Snarlin’ Arlen.” But his colleagues knew him as the Senate’s best lawyer, and as a fierce advocate. Many fellow senators avoided at all costs getting into an elevator with him, lest he accost them in a confined space with the implications of their legislation, which he had analyzed deeper than they.

He was tough on his staff as well. I wiped the tears of many and gently dismissed those who could not stand up to him or meet his standards. One Labor Day, The Washington Post published an article, “The Worst People in Washington to Work For.” Specter came in seventh. I promptly wrote a letter of protest to The Post, saying in effect “We’re not 7th in anything! We’re No. 1!” I noted the governors, federal judges and state senators who had graduated successfully from Arlen Specter’s “intellectual Parris Island” (which was every bit as tough as the US Marine Corp’s South Carolina boot camp). The Post sort of recanted and published a wonderful

Left: Arlen Specter at 16; Right: The Russell, Kansas American Legion baseball team; Specter, front, second from right.


photo of Arlen and his wife Joan over my letter with the headline “They’re No. 1!”

As I write in November 2012, two weeks have passed since Arlen’s death, following multiple bouts with brain tumors, heart bypasses and both Hodgkin’s and Non-Hodgkin’s lymphoma. How could you not love this guy? I did, because, first and foremost, as demanding as he was, he held himself to even higher, more exact-ing standards than he held others.

Arlen Specter came to be a hard case honestly. His parents were

Jewish immigrants from the Ukraine who had grown up on dirt floors without electricity. His father was a veteran, wounded in World War I, who moved to Russell, Kansas, where he owned the local junkyard. During summers, Arlen and his father peddled canteloupes door-to-door. During the rest of the year, Arlen was handed an oxyacetylene torch and sent to nearby oil fields to cut up derricks toppled by tornadoes. His father sold the remnants as scrap metal. I won’t belabor this part, you get the point. Arlen went on to the University of Pennsylvania and Yale Law School,

then he became District Attorney of Philadelphia and later (after three electoral defeats) the longest serving senator in Pennsylvania history.

I was more than privileged to have him as a men-tor and friend. After being his law student, his Assistant District Attorney, and fifteen years later, his Senate Chief-of-Staff, he was kind enough to inscribe in his memoir “To Carl, my only three-time loser.” Of course, he was kidding. At least I think he was. With Arlen, you could never tell.

Early in his thirty-year Senate career, Arlen revealed a soft spot: a deep commitment to medical research and

Left: Specter in 1977, failing a third time to win a Senate seat in Pennsylvania;

Right: campaigning with Ronald Reagan in 1980


the National Institutes of Health (NIH). This passion preceded his own medical problems. It resulted from his experience with beloved family and friends who had died of heart disease and various cancers. It also derived from a more general sense of compassion that he had tried, and largely succeeded, to keep concealed.

Once Arlen made up his mind to champion a cause, you did well to just get out of his way. Noth-ing and no one could stop him. In 1998, he decided he wanted the NIH budget doubled in five years. By 2003, he had made it happen. It’s a Washington cliché that, like sausage, you don’t want to see how laws (and especially appropriations) are made, but in the Appropriations Subcommittee for Labor, Health and Human Services, Arlen crossed the partisan aisle to work cooperatively for years with Senator Tom Harkin (the Democrat from Iowa). The two traded places as chairman and vice-chair of that Subcommittee whenever the Senate leadership changed hands, but their partner-ship was steady and their bipartisan goals were largely achieved. Suffice it to say that Specter and Harkin ‘convinced’ their fellow legislators and three presidents (Bush, Clinton, and Bush) that NIH was, as Arlen put it, the “Crown Jewel of the Federal Government.” With his typical exactitude, Arlen seemed to know every disease that his fellow Senators suffered from or were concerned about because of family members, friends, or constitu-ents. He buttonholed, cajoled and occasionally slammed his fist on the table, but his approach was intellec-tual, rational and compelling. When

asked by a reporter why he had made medical research a priority, he answered with characteristic bluntness: “Health is our nation’s number one asset. Without your health you can’t do anything!”

Arlen Specter was a visionary leader for the life sciences. Seated in front of me at his funeral were past and present NIH Direc-tors Harold Varmus and Francis Collins. They sat in quiet respect for an extraordinary, unquiet man. In a statement to the press, Dr. Collins called Specter a “towering champion for biomedical research and the National Institutes of Health.” He cited Arlen’s recognition of the potential of stem cells, and praised him for “holding hearing after hearing to bring to the forefront the impor-

tance of federal funding to support research.”

For the record, Arlen Specter also brought his iron will, intellect, and occasional fist down in support of telemedicine for underserved areas, the alleviation of our nursing shortage, prescriptions for our poor-est seniors, and the establishment of a childhood cancer database.

I hope we see his like again soon, but don’t hold your breath.

G. Steven Burrill, Chair Burrill & Company

Brook Byers Kleiner Perkins Caufield & Byers

Carl Feldbaum Biotechnology Industry Organization

Frederick Frank Burrill & Company

Dennis Gillings Quintiles Transnational

John Lechleiter Eli Lilly and Company

Heather Erickson Life Sciences Foundation

Ivor Royston Forward Ventures

Phillip Sharp MIT (Academic Advisor)

Henri Termeer Genzyme Corporation

Board of Directors

Daniel Adams Protein Sciences

Sol Barer Celgene

James Blair Domain Associates

William Bowes U.S. Venture Partners

Robert Carpenter Hydra Biosciences

Marc Casper Thermo Fisher Scientific

Nancy Chang Orbimed

Jay Flatley Illumina

Martin Gerstel Compugen

Joseph Goldstein UT Southwestern

James Greenwood Biotechnology Industry

Organization

Harry Gruber Tocagen

David Hale Hale BioPharma Ventures

William Haseltine Access Health International

Paul Hastings OncoMed Pharmaceuticals

Susan Desmond-Hellmann

University of California, San Francisco

Perry Karsen Celgene

Rachel King Glycomimetics

Arthur Levinson Genentech

Greg Lucier Life Technologies

Joel Marcus Alexandria Real Estate

Equities

Alan Mendelson Latham & Watkins

Fred Middleton Sanderling Ventures

Tina Nova Genoptix

Stelios Papadopoulos Exelixis

Richard Pops Alkermes

George Poste Arizona State University

William Rastetter Receptos

Roberto Rosenkranz Roxro Pharma

William Rutter Synergenics

George Scangos Biogen Idec

Steven Shapin Harvard University

Stephen Sherwin Ceregene

Jay Siegel Johnson & Johnson

Vincent Simmon Genex Corporation

Mark Skaletsky Fenway Pharmaceuticals

Sally Smith Hughes University of California,

Berkeley

Thomas Turi Covance

J. Craig Venter J. Craig Venter Institute

Board of Advisors

*One affiliation past or present


the C e n t a u r+the W h a l e

the

Chiron, Cetus and the Emergence of Biotech

Date: Monday, April 15

Time: 5:30 – 6:30 p.m. talk 6:30 – 7:30 p.m. reception

Location: UCSF Mission Bay Fisher Banquet Room 1675 Owens Street Parking available off 16th Street at 1625 Owens

During this one-hour talk, you will hear from the founders and leaders of Cetus and Chiron, two of the pioneering and most successful biotechnology companies of the 1970s and early 1980s. The discussion will focus on their first 10 – 15 years of operation, before these two great Bay Area companies merged. Hear about their successes, mistakes, and lessons that have helped inform how we define biotech success today. Moderated by Ed Penhoet, former CEO of Chiron.

More info: lifesciencesfoundation.org/cetuschiron

Life Sciences FoundationOne Embarcadero Center, 27th FloorSan Franciosco, CA 94111

Telling the Story of Biotechnology

LSF Magazine Winter 2013

Documents

Transcript of LSF Magazine Winter 2013