LSF Magazine Winter 2014

Winter 2014LSF Magazine

Telling the Story of Biotechnology

Double Helix The Supporting Cast

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Departments04 LSF News

Updates on the Foundation and affiliates

08 Biotech BookshelfAffordable Excellence, by William Haseltine

Frankensteins Cat, by Emily Anthes Spillover, by David Quammen

10 LSF Oral History ProgramWilliam K. Bowes, Jr., native history maker

14 Gems from the ArchivesThe GeneCo business plan

16 Twenty Years AgoMedImmunes Wayne Hockmeyer bets the farm

20 ObituariesLen Herzenberg Fred Sanger Jim Vincent

Features26 Restriction Enzymes

The Cold Spring Harbor Laboratory

history conference

28 The Double HelixInspired by Jim Watsons book

32 The Supporting CastSixty years after the discovery of the molecular structure of DNA

44 The World Food PrizeMary-Dell Chilton, Robert T. Fraley, and Marc

Van Montagu

46 Back to the FutureA brief history of biofuels14

Mark Jones

Editor Mark Jones

Associate Editors Brian Dick Brianna Rego Lind

Production Manager Donna Lock

Design/Layout Zachary Rais-Norman

Contributors John Anderson Brian Dick Mark Jones Brianna Rego Lind Gavin Rynne Sarah C.P. Williams

Copyright 2014 Life Sciences Foundation All rights reserved

On the cover: photoillustration by Garrett Miller

From top to bottom: James D. Watson

Francis Crick Lawrence Bragg

Jerry Donohue Linus Pauling

Rosalind Franklin Maurice Wilkins

Sixty years have passed since Jim Watson and Francis Crick figured out the molec-ular structure of DNA. At that time, only biochemists, molecular biologists, and geneticists took notice (and many were not yet convinced that DNA was the essential stuff of genetic inheritance). Virtually no one else had heard of DNA. There were no press conferences or newspaper headlines.

Times have changed. Although the gen-eral public remains poorly informed about molecular genetics (for example, 71 percent of respondents to a 2010 survey conducted by the US National Institutes of Health agreed that there are different types of genes in different parts of the body), DNA has entered the vernacular. People of all ages are continually reminded of its significancein biology classes at school, at the doctors office, in newspapers, on the Internet, at the movies, and so on.

Over the past sixty years, the masses have come to understand that DNA carries genetic information, plays a central role in inheritance, can be used to identify individ-uals and establish kinship relationships, and is implicated in certain kinds of disease. In 2003, a Harris poll found that when asked What does DNA stand for, two-thirds of respondents were able to recognize deoxy-ribonucleic acid as the correct answer. The details may be fuzzy, but the importance and

value of DNA is widely recognized.

In the United States, popular support is strong for federal funding of genomics research. The results of a survey published last month by investigators from Yale University and New York Universi-ty show that, even amidst broad calls for fiscal austerity, 57 percent of Americans believe that the government should spend more on genomics. Millions have been persuaded that greater knowledge of DNA will be beneficial and should be prioritized.

A comparative measure of perceived value: in November 2012, the Nobel Prize medal awarded to physicist Niels Bohr was put on the auction block in Denmark. Bohr received the medal in 1922 for describing the struc-ture of the atoman advance in knowledge that led eventually to the atomic bomb, nuclear energy, the integrated circuit, and the big screen TV. The high bidder paid the kro-ner equivalent of $48,000 US. In April of last year, the Crick family trust auctioned Francis Cricks 1962 Nobel Prize medal in New York City. The bidding passed the $1 million mark in less than a minute. The final sale price, paid by Chinese-American businessman Jack Wang, was $2.2 million.

From the editor

Winter 2014LSF Magazine

Telling the Story of Biotechnology

Double Helix The Supporting Cast

2 LSF Magazine Winter 2014

Dear Friends,

As Chairman of the Board of the Life Sciences Foundation, I want to express my personal gratitude, along with the rest of the Board, to all the individuals and corporations who have made financial contributions to LSF since our founding just three years ago. Without your investment, the Foundations important work of capturing the history, preserving the heritage, and sharing the stories of biotechnology could not happen.

With your support, LSF is quickly becoming the definitive source for complete and credible information about the history of biotechnology. To start bringing this story to even more people in the coming months, the Foundation will be launching a series of education pilots in partnership with leading formal and informal education providers throughout the country. LSF is also rede-signing its website and increasing its multimedia and social media activities to enable all of us to participate directly in sharing our stories with future generations of scientists and entrepreneurs.

The following listing of cumulative gifts represents the many generous gifts and pledge commitments received by LSF from its inception in 2010 through the end of December 2013. The listing of annual gifts reflects gifts and pledge payments received during our 2013 Fiscal Year, from July 1, 2012 through June 30, 2013.

We look forward to adding additional names to this dis-tinguished list of supporters and to increasing the number of those who have given so generously to help us launch LSF in its important mission. We have received generous three-year, $100,000 per year, commitments from two Board members who are challenging others to join them in supporting LSF. I join them in asking you to consider such a multi-year commitment at whatever level you can. Your ongoing support is critical as we work to become an impactful and sustained force for under-standing the life sciences. We are grateful for your interest and involvement.

G. Steven Burrill

Donor Recognition ProgramThe Life Sciences Foundation has devel-

oped a new donor recognition program to enhance its relationship building, fundrais-ing, and stewardship efforts. We want to express our gratitude and recognize donors publicly for their generosity and good will. We will of course honor the wishes of those who wish to remain anonymous.

The program recognizes both annual gifts and cumulative giving. The Founders Club recognizes cumulative commitments of $100,000 or more by any individual, family, corporation, or foundation. It contains four levels.

LSF also recognizes annual donors with membership in the Presidents Club. Indi-viduals and families are recognized for gifts of $5,000 or more; corporations or foundations for gifts of $25,000 or more. The Presidents Club has five levels.

$1,000,000+ The Darwin Circle for Charles Darwin, who conceptualized the fundamental dynamic of life in his theory of evolution.

$500,000+ The Mendel Circle for Gregor Mendel, whose empirical research on patterns of inheritance laid the foundations of modern genetics.

$250,000+ The Watson & Crick Circle for James D. Watson and Francis Crick who discovered the molecular structure of DNA.

$100,000+ The McClintock Circle for Barbara McClintock whose studies of genes illuminated mechanisms of genetic change and regulation.

Founders Club

$100,000+ The Pasteur Circle for Louis Pasteur, the father of microbiology, who established the germ theory of disease.

$50,000+ The Koch Circle for Robert Koch whose research postulates defined methods of inquiry in modern bacteriology and biomedicine.

$25,000+ The Fleming Circle for Alexander Fleming who discovered penicillin and ushered in the age of antibiotics.

$10,000+ The Crowfoot Hodgkin Circle for Dorothy Crowfoot Hodgkin who pioneered the analysis of biomolecular structures.

$5,000+ The Salk Circle for Jonas Salk who championed the polio vaccine.

Presidents Club

Winter 2014 LSF Magazine 3

Donor RecognitionFounders Club

Darwin CircleEli Lilly and Company

Mendel CircleDaniel D. Adams

Celgene Corporation

Genentech, Inc.

Johnson & Johnson

Watson & Crick Circle William K. Bowes, Jr.

Amgen Inc.

Burrill & Company

Merck & Co.

Pfizer Inc.

Quintiles Corporation

Sigma-Aldrich Co.

Thermo Fisher Scientific Inc.

McClintock CircleJoshua Boger

Brook Byers Family

Frederick Frank

The Franklin & Catherine Johnson Foundation

Mark Levin

Fred Middleton

Ivor Royston

Alejandro Zaffaroni and the Zaffaroni Family

Genzyme Corporation

Millennium, The Takeda Oncology Company

Presidents Club FY 2013

Pasteur CircleDaniel D. Adams

Alejandro Zaffaroni and the Zaffaroni Family

Burrill & Company

Johnson & Johnson

Merck & Co.

Millennium, The Takeda Oncology Company

Quintiles Corporation

Sigma-Aldrich Co.

Thermo Fisher Scientific Inc.

Koch CircleCarl Feldbaum

Dennis B. Gillings

John C. Lechleiter

Mark Levin

Edward E. Penhoet

Henri A. Termeer

Genzyme Corporation

MedImmune, LLC

Ivor Royston

Gabriel Schmergel

Allergan Inc.

BioMarin Pharmaceuticals, Inc.

MassBIO

Jim C. Blair

Martin S. Gerstel

William J. Rutter

Salk CircleAnthony B. Evnin

Frederick Frank

Alan C. Mendelson

Hollings C. Renton, III

Dennis L. Winger

Fleming Circle

Crowfoot Hodgkin Circle


Foundation & Event UpdatesLSF News

LSF research associates Brian Dick and Brianna Rego Lind presented papers at two aca-demic conferences held in the fall. Dick presented Contract Pharmaceutical Research in situ at the annual meeting of the Society for Social Studies of Science (4S) in San Diego in October, and Atomic Gardens: Radiation-Induced Mutagenesis and Agricultural Improvement at the annual meeting of the History of Science Society (HSS) in Boston in November. Rego Lind presented Behind a Veil of Smoke: R&D at Philip Morris at 4S, and A Post-Antibiotic World? Biotech Approaches to Antibiotic Resis-tance at HSS.

LSF Researchers Present Work at Scholarly Conferences

LSF Associate Wins Research Award

Congratulations to Ramya Rajagopalan, the 2013 recipient of the prestigious David Edge Prize awarded annually by the Society for the Social Studies of Science (4S) for the best article in the field of science & technology studies. Rajagopalan was honored with co-author Joan Fujimura of the University of Wisconsin-Madison. The paper, Different differences: The use of genetic ancestry versus race in biomedical human genetic research, was published in the leading journal Social Studies of Science in February 2011.

Dennis Purcell Joins LSF Board of Advisors

Dennis Purcell, senior managing director of Aisling Capital, has joined the Life Sciences Foundation board of advisors.

Prior to joining Aisling in 2000, Mr. Purcell served as managing director of the Life Sciences Investment Banking Group at Chase H&Q (formerly Hambrecht & Quist, H&Q) for over five years. He previously served as a member of the Advisory Council at Harvard Medical School, and as a director at the Biotechnology Industry Organization (BIO), the New York Biotechnology Association, and the Irvington Institute.

Ian Signer Named LSF Director of Education and Partnerships

Ian Signer joined LSF as the director of education and part-nerships in October. Signer will help LSF develop programs that effectively introduce the story of biotechnology to diverse, national audiences through ed-ucation partnerships, outreach efforts, and virtual engagement opportunities.

He brings over ten years of education experience to LSF. He has worked with such organizations as the Wildlife Conservation Society, the World Wildlife Fund, the National Geographic Society, Conservation International and Californias Education and the Environment Initiative, to develop, lead, and implement interactive education programs and curricula.


Jay Flatley Recognized by PMWC International

LSF Welcomes Alan Gold as an Advisor

LSF, BayBio partner for CEO Roundtable

Susan Desmond-Hellmann joins the Gates Foundation

Jay Flatley, CEO of Illumina and a member of LSFs board of advisors, will be recognized as the Personalized Medicine World Conference (PMWC) Luminary Award recipient on January 26 in Mountain View, California. PMWC Interna-tional is dedicated to trans-forming healthcare through the global adoption of personalized medicine. LSF is proud to be a partner of the January 27 28 conference, which features over one hundred speakers, includ-ing LSF director Brook Byers, Kim Popovits, Lee Hood, Mike Hunkapiller and Randy Scott. For more information, visit 2014sv.pmwcintl.com

Alan Gold, chairman and chief executive officer of BioMed Realty, has joined LSFs Board of Advisors. A life-long resident of San Diego County, Gold has been involved in the develop-ment of commercial life science properties for nearly thirty years. In 1998, he established Bernardo Property Advisors, Inc., the privately held prede-cessor to BioMed Realty, with partner Gary Kreitzer. Before that, he served as president and as a director of Alexandria Real Estate Equities, Inc. BioMed Realty is currently active in all of the leading US life science markets.

On November 5, LSF and BayBio collaborated to present a LSF/BayBio CEO round-table: Is Bioscience Fundable Today? The event brought together BayBio fellows, early stage life science entrepreneurs, and respected industry leaders to discuss the challenges of financing innovative bioscience companies. Financiers and for-mer executives John Diekman, Larry Lasky, Fred Middleton, and Steve Sherwin participated in the roundtable on behalf of LSF. The meeting was held at BayBios offices in South San Francisco.

Susan Desmond-Hellmann, chancellor of the University of California, San Francisco (UCSF), and an LSF advi-sor, has been named the next CEO of the Bill and Melinda Gates Foundation, the worlds largest private philanthropic institution. The foundation is committed to improving educa-tion and solving global health problems. Desmond-Hellmann has led UCSF since 2009. She has experience as an epide-miologist, oncologist, clinical researcher, and pharmaceutical executive. According to Melin-da Gates, Desmond-Hellman was selected because of her scientific knowledge and deep technical expertise on the foun-dations issues.

Herb Boyer, Reg Kelly, and Kathy Ku

Keith Yamamoto Stan Cohen

David Ewing Duncan, Keith Yamamoto, and Stan Cohen

Niels Reimers Tom White visits with a student

View more photos and video at lifesciencesfoundation.org/techtransfer


Event RecapsLSF News

On November 18, LSF hosted Campus to Commerce: Trailblazers of Biotechnology Transfer, a panel discussion on the evolution of university-industry relations, at the Mission Bay campus of the University of California, San Francisco. Distinguished speakers included Herb Boyer and Stan Cohen, the co-inventors of recombinant DNA technology; UCSF Vice Chancellor of Research Keith Yamamoto; Regis Kelly, Director of the QB3 Institute; and Kathy Ku, Director, and Niels Reimers, former Director, of the Stanford University Office of Technology Licensing. David Ewing Duncan served as moderator. The event was sponsored by BioMed Realty with promotional support from community partners BayBio, QB3, UCSF and the Entrepreneurship Center at UCSF.

Campus to Commerce: Trailblazers of Biotechnology Transfer

Check the LSF website for information on coming events

Spring in San Diego: Industry Pioneers Discuss NextGen Sequencing: How Did We Get Here? Where Are We Going?

Spring in Cambridge: Patient AdvocacyLessons from History

View more photos and video at lifesciencesfoundation.org/bostonbiotech

Phil Sharp, Josh Boger, Eric Lander, Bob Coughlin, Mark Levin, and Henri Termeer

Henri Termeer Carl Feldbaum

Josh Boger, Eric Lander, and Bob Coughlin

Phil Sharp and Bob Carpenter Liz Kong Dan Adams


In June, LSF hosted Courage to Innovate: Early Lessons from Bostons Biotech Founders in Cambridge, Massachusetts. The sold-out event featured conversations with Joshua Boger, Bob Coughlin, Eric Lander, Mark Levin, Phil Sharp, and Henri Termeer, eminent scientists and industrialists who helped to create the citys thriving cluster of life science enterprises.

Courage to Innovate: Early Lessons from Bostons Biotech Founders

William Haseltine

William A. Haseltine, Affordable Excellence: The Singapore Healthcare Story (Washington D.C.: Brookings Institute Press, 2013).


Winter ReadingBiotech Bookshelf

The United States spends more on healthcare (both per capita and as a percentage of GDP) than any other country in the world. Yet quality of life indicatorssuch as average life expectancy, infant mortality rates, and the prevalence of chronic disease morbidityplace it well below most advanced industrialized nations. The

contradiction of high spending and poor outcomes in the United States makes the comparative analysis of diverse healthcare systems indispensable to domestic policy debates.

In Affordable Excellence, William Haseltine carefully examines Singapores healthcare system and draws lessons from its success that may be applicable to ongoing healthcare reform efforts in both developing and industrialized nations. Haseltine is a former Professor at the Harvard Medical School, current Chairman of Access Health International, and founder of numerous biotechnology companies including Human Genome Sciences.

Singapore is a city-state made up of sixty-three islands located off the southern tip of Malaysia. It is home to over five million people. A British colony since 1826, Singapore became partially self-governing after 1955, and in 1959 began moving toward full independence from the crown. It merged with the Republic of Malaysia in 1963, but withdrew less than two years later to become a sovereign democratic state. It has been governed ever since by the Peoples Action Party (PAP).

As Singapores economy expanded during the late 1970s, the party leadership resolved to improve the nations health. The city-states first National Health Plan was implemented in 1983. Hygienic conditions were improved through the construction of government housing and responsibilities for healthcare costs were reapportioned through the establishment of an individualized medical savings program (Medisave). The hospital system was restructured to encourage competition between public and private facilities. When market forces failed to improve efficiency, the government intervened to exert greater influence on the supply side. Haseltine calls the result a form of highly calibrated capitalism.

Today, Singapore spends less than 4 percent of its GDP on health-care (compared to 18 percent in the United States), but has an infant mortality rate lower than all other high-income countries except Japan, life expectancies two to three years longer than in the US and the UK, and high levels of patient satisfaction.

Haseltine asserts that the Singapore case provides proof of prin-ciple that systems can be designed to provide affordable healthcare to all citizens in a developed economy, and that medical costs can be controlled without compromising quality. He believes that Singapores success is due in large measure to the governments long-term political unity and constancy of purpose, the national acceptance of public health improvement as a collective goal, and a culture that embraces social harmony, communal well-being, and individual responsibility as civic values.

Haseltines presentation is polished, accessible, and adorned with full-color charts of cross-national health comparisons. Each of the books eight chapters concludes with a section summarizing key points.

Although Affordable Excellence admirably details the organization of the Singapore healthcare system and the reasons behind its success, the books central claimthat Singapore can serve as a working example for other countriesremains hypothetical. It is unclear whether the Singapore result can be replicated in larger, less unified nations. It may be unique to the peculiar political history and culture of the Asian city-state. Still, Haseltines extrapolations provide food for thought for policymakers in other countries, including the United States, who are seeking to control rising health care costs.

Emily Anthes, Frankensteins Cat: Cuddling Up to Biotechs Brave New Beasts (New York: Scientific American / Farrar, Straus and Giroux, 2013).

David Quammen, Spillover: Animal Infections and the Next Human Pandemic (New York: W.W. Norton and Co., 2012).


Animal husbandry is an ancient practice. People first began living symbiotically with wolves more than 30,000 years ago. Since then, they have tamed, selectively bred, and domesticated wild creatures for utilitarian purposes, including food, labor, protection, sport, and compan-

ionship. For thousands of years, breeding techniques remained mostly unchanged. In the past four decades, however, the tools of modern biotechnology have dramatically extended the capabilities of human beings to modify the characteristics of other species.

In Frankensteins Cat, journalist Emily Anthes surveys the various ways in which biotechnologies are used to transform the animal kingdom. She resists the temptation to moralize. Instead, she provides an even-handed overview of controversial issues and allows readers to form their own opinions. Frequently, she reflects on her experienes with her own petsnot to make arguments, but to incorporate em-pathy into discussions of relationships between animals and human beings.

Anthes considers the potential implications of a range of animal engineering projects that have been accomplished, contemplated, and imagined, from manufacturing fluorescent Glofish to cloning beloved pets, resurrecting extinct species, and creating Noahs Ark gene banks. Some technological advances are intended to benefit animalsthe implantation of tracking devices to inform wildlife conservation efforts, for example, or the design of artificial limbs like the prosthetic tail made for Winter, a dolphin who lost her posterior appendage in a crab trap. Others, such as hijacking beetle brains to control insect flight patterns or reconstructing neuticles to substitute for losses suffered by neutered dogs (and to quell the insecurities of male owners), deliver exclusively human benefits.

Although Anthess book is shaped by a certain technological optimism, she emphasizes that there are no easy answers to the ethical dilemmas that arise when animals are treated instrumentally as tools and commodities. Following the philosopher Harold Herzog, she adopts the contradictory standpoint of the troubled middle. We can, says Anthes, love and care about animals and endeavor to minimize their suffering, while still recognizing the necessity and legitimacy of using them as sources of food and subjects of medical experimentation.

Humans are a force of naturewe are, in some senses, the force of natureand we influence animals whether we intend to or not, Anthes concludes. So the real question, going forward, is not wheth-er we should shape animals bodies and lives, but how we should do sowith what tools, under what circumstances and to what end.

Frankensteins Cat provides a sensible and humane guide for ad-dressing these issues.

Science and nature writer David Quammens latest book, Spillover: Animal Infections and the Next Human Pandemic, is a part-history, part-travelogue, and part-medical mystery story. Its about zoonotic diseases that have spilled over from animals to human beings (unlike

polio and smallpox, for example, that exist only in humans). Quammen stresses the importance of environmental relationships between humans and animals in the spread of disease. As human populations increase, people wander further into the wild. Shake a tree, Quammen explains, and things fall out.

Several chapters consider virusesEbola, Hendra, influenza, Marburg, Nipah, and SARS. Quammen accompanied virologists, ecologists, veterinarians, and physicians into the field to track movements of these pathogens across species. Tales of his adventures speckle the book with self-deprecating asides, lightening an other-wise alarming read. In Bangladesh, for example, he was warned to keep his mouth shut when looking up, as bat urine falling from the night sky might infect him with Nipah.

The case studies are fascinating, but how do they matter if only a handful of individuals die from most of these diseases? Quammen reminds readers that AIDS is a zoonotic disease. The riveting chapters on the origins of HIV include the fictional biography of a man who could have brought HIV out of the forest and into the city, perhaps during the 1910s. Before it spread around the world, the epidemiological profile of AIDS mirrored many of the other illnesses discussed in the book. It is imperative, Quammen argues, to monitor emerging zoonotic diseases. The next crossover could unleash another pandemic.

The book contains chapters on influenza and SARS, which are timely in light of recent avian flu (H7N9) and MERS outbreaks in East and Southeast Asia. Scientists are currently tracing the causal agents back to their original animal hosts, in order to determine when and how they made the jump to humans.

But despite the potentially grave threats posed by emerging zoo-notic diseases, Quammen does not overdramatizethe health risks that should provoke immediate anxiety, he says, are more mundane than a new virus lately emerged from a duck or a chimpanzee or a bat.

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 LSFs digital archive of oral histories is a conversation with venture capitalist William K. Bowes, Jr.


Bill BowesLSF Oral History Program

Bill Bowes is a native San Franciscan. His father came to the Bay Area from Chicago after World War I to study at Stanford. He stayed on afterwards, settled in San Francisco, and worked in finance and real estate. Bowess mother grew up in Southern Californias Ojai Valley, where her family grew oranges. She, too, went to Stanford, and was one of only two women to earn a degree from the universitys School of Medicine in 1925. She met her husband in San Francisco, and prac-ticed medicine in the city for a few years before retiring to raise the couples two sons, Bill and John.

The family lived in a small brown-shingled house on Laguna Street in Pacific Heights (it still stands, now surrounded by high rises). Bowes describes his parents as kind, gentle people who worked hard to provide opportunities for their children. His father struggled financially through the Depression, but survived and recovered. He eventually became a hotelier, the owner of numerous upscale properties in the East Bay.

Bowes attended Lowell High, a public school near the panhandle of Golden Gate Park. It had been his parents ambition for him to prepare for college in the east at the Lawrenceville School and then go on to

Princeton, but, he says, The Depression put an end to that idea. Instead, he took summer jobs to save money for tuition. He worked as a camp counselor in the Sierra Nevada, and as a laborer in the Mendocino County timber industry and the construction business in Alaska. On graduating in 1943, he chose to enroll, like both of his parents and many of his friends from Lowell, at Stanford. He majored in chemical engineer-ing.

After a year, World War II interrupted his academ-ic career. As soon as he turned eighteen, Bowes was drafted into the army, trained in haste to serve in the infantry, and shipped off to the Pacific theater. But the war was almost over. Bowes was sent first to the Phil-ippines, and subsequently spent over a year in Japan, as part of the military occupation and reconstruction effort under the general command of Douglas MacAr-thur. When he returned to the States, he took full advantage of the GI Bill:

I wont say I enjoyed the army but I appreciat-ed the experience I was given. I lived through it and it gave me five years on the GI Bill, which completely paid my tuition for the next three years at Stanford. I was very proud of myself when, on my twenty-first birthday, I was able to tell my father I wouldnt need money from him. Im not sure he appreciated it, but it felt good to say it.

Native History MakerRecently, the San Mateo County Historical Association held a banquet to

recognize the achievements of four San Francisco Bay Area history makers: venture capitalists Franklin Pitch Johnson, Reid Dennis, William Draper III, and Wil-liam K. Bowes, Jr. Each participated, during the 1960s and 1970s, in the creation of Silicon Valley and the entrepreneurial culture that continues to propel the regions innovative high tech economy. They all knew each other well, and sometimes worked together. All remain active as philanthropists.

LSF is preparing to publish an oral history with Bowes, the member of this dis-tinguished group best known for being taciturn and tight-lipped. On learning once that Bowes had spoken to a journalist, his longtime friend Bill Edwards, another Bay Area venture trailblazer, commented: That must have been an interesting interview because Bill doesnt talk a lot. Draper puts it this way: Bill Bowes is really good at listening.

Bowes may be frugal with words, but he shared enough in his oral history to provide a fascinating first-hand account of the formation of venture capital and high technologies in the San Francisco Bay Area. When he began working in corporate finance in San Franciscos financial district in the early 1950s, banking, shipping, agriculture, light manufacturing, and food, oil, and chemical processing were the main staples of the regions diversified economy. The story of Bill Bowess career is the story of how all were eclipsed by new technologies and new ways of doing business.


Once back in Palo Alto, Bowes decided to change his major: After three years in the army, I was out of it, scholastically. My brain was mush. I figured I couldnt do chemistry, so I majored in something I thought was easy: economics. He graduated in 1950, and then completed his education at the Harvard Business School. The quality of the school was ap-pealing, and he also wanted to spend time on the East Coast. He doesnt recall taking specific lessons from the training, but feels that he benefited from Harvards emphasis on producing well-rounded, ethical business-people: I came out feeling good about myself.

With MBA in hand, Bowes returned to San Francisco and began working in corporate finance on Montgomery Street in the citys financial district. He landed a job with Blyth & Companya terrific firm. Blyth was a small but distinguished investment bank, highly regarded on the West Coast, from Seattle to San Diego. Bowes provided financial services to major West Coast corporations, including Bank of America, Chevron, and Pacific Gas & Electric.

After a few years, he found himself spending time in the Santa Clara Valley (now better known as Silicon Valley) south of San Francisco: Things were starting to happen down there. Bowes surveyed the area to identify emerging electronics firms that needed expert assistance with financial transactions. He called on Hewlett-Packard (HP), met the founders, and asked for their business:

Hewlett-Packard was already a great compa-ny. They were doing $60 million worth of business, which was a lot back then. Dave [Packard] and Bill [Hewlett] were terrific guys. Dave said, Ill tell you what. If you can get Charlie Blyth to go on our board of directors, youve got it.

Bowes suggested that Blyth and Packard spend some time together. They did, he says, and they fell in love. They were soul mates that hadnt met yet. Bowes worked on HPs 1957 IPO:

The company didnt need any money; the real purpose of the offering was to create a public market for the stock. I told them any price between $16 and $18 a share would work because thats where the demand was. They immediately agreed to $16. They were good people to do business with.

During this period, Bowes made friends among Sili-con Valleys earliest venture capitalistsPitch Johnson

(whom he had known at Harvard Business School), Tommy Davis, Bill Draper, Joe McMicking, Arthur Rock, and Ed Heller.

Bowes started dabbling in venture capital, too. He and friends from San Franciscos financial community, John Bryan, Reid Dennis, Bill Edwards, and Dan Mc-Ganneyall of whom went on to play important roles in the formation and growth of Silicon Valleypooled money for small investments and advised entrepreneurs on fundraising strategies.

They became known as The Group. From 1955 through the late 1960s, The Group met regularly at Sams Grill on Bush Street in downtown San Francis-co. They often invited prospective entrepreneurs to lunch, to tell their stories. After lunch, as Reid Dennis remembers, Wed say, Go stand outside on the sidewalk for ten minutes, and let us talk this over. Well

Powell Street in San Francisco, 1940s


come out and tell you what our decision is. And wed talk around the table: Did you like it? Do you have questions? Whos going to be on the board? and so on. According to Bowes:

Some of the investments worked, some didnt. We were rank amateurs. We were smart, but we didnt know anything about building com-panies. We did it for fun. We all had day jobs.

Bowes enjoyed a couple of outstanding successes with Raychem, a Menlo Park company founded in 1957 that made industrial electronic components (and invented shrink wrap), and Dymo Industries, an Emeryville company that began in 1958 with a manual label maker, a gun for printing and attaching adhesive-backed plastic strips. Today, Raychem is a massive global corporation with dozens of internation-al subsidiaries. Dymo continues as a unit of Newell Rubbermaid.

In 1970, Blyth & Company was sold to the Insurance Corporation of North America. When that happened, says Bowes, it wasnt as much fun any-more. Two years later, Blyth was auctioned off again, this time to New York merchant bank Eastman Dillon Union Securities. The locus of power within the new entity, Blyth, Eastman, Dillon & Co., was on the East Coast. In 1978, Blyth began negotiating another merg-er, this time with Paine Webber. Bowes knew he didnt want to be part of it.

He left and took up venture capital full-time, as a lone operator working out of a small office on Montgomery Street. He approached the founders of promising young companies, and offered to help them raise them money. It wasnt very competitive, he says, against guys who had checkbooks. Still, he enjoyed remarkable success. He started three new companies in two years, and two became big hitsApplied Micro Circuits and Applied Molecular Genetics.

Applied Micro Circuits made processing chips for computers. It remains a leader in the field. Applied Molecular Genetics (Amgen) was a biotechnology company. In 1972, Bowes had gotten involved with a Berkeley-based genetic engineering company called Cetus. A.E.Ponting, a Blyth colleague, invited him to join the board. At that time, biotech was just a glimmer, but it was a useful introduction to biologi-cal and biomedical projects. Primed by his experience at Cetus, Bowes was attuned to opportunities in the field. Amgen was a good choice: it became arguably the greatest commercial success in the history of the

biopharmaceutical industry.By 1981, Bowes decided that he needed to raise

money from institutional investors in order to remain competitive in the venture capital game. He also felt that his San Francisco office was too far from the heart of the action in Silicon Valley. He established a new investment firm on Sand Hill Road, in the thick of things, with partners that he had known for yearsStuart Moldaw, a retail apparel entrepreneur, and Bob Sackman, a principal executive at Ampex, an early and influential Silicon Valley electronics company.

The trio called their firm US Venture Partners (USVP). They pulled together $3 million to get started, and raised an initial institutional fund of $50 million in less than a year. It was an enormous success. Moldaw investigated retail opportunities, Sackman covered electronics, computing, and software, and Bowes reviewed plans for biomedical startups. On the strength of investments in Ross Dress-for-Less stores, Callaway Golf, Sun Microsystems, and Applied Biosys-tems, the fund generated a tenfold return in four years. That performance made subsequent fundraising efforts much easier.

Over the years, USVP has raised ten funds and invested more than $2.7 billion in hundreds of com-panies across a broad spectrum of industrial sectors, including semiconductors, software, IT systems, data storage, wireless communications, the Internet, social media, cleantech, medical devices, and pharmaceuti-cals.

Bowes is especially proud of companies that have delivered important scientific and medical advanc-esApplied Biosystems, for example, which made instruments that enabled the sequencing of the human genome, and Advanced Cardiovascular Systems, which commercialized the first implantable defibrillator and the first angioplasty balloon catheter. He says that by virtue of his professional exposure to inventors and innovative technologies, he has become a science connoisseur, or, he jokes, a gourmand, but he believes his greatest assets in the investing business are his people skills:

Im trustworthy. I think I convey that. People like to do business with me. I dont over-reachits not my nature. I work well with people. I think Ive proven that over the years. Ive always gotten along with venture capital-ists and executives, and Ive been able to pull off some interesting financial transactions.


Bowes continues at USVP as a senior advisor, but spends most of his time on philanthropic efforts in education and the sciences. In the mid-1990s, the University of California, San Francisco was running out of space at its Parnassus Heights location and resolved to build a new campus at Mission Bay. Bowes was chairman of the capital campaign for the first building projects.

He has since endowed a number of professorial chairs at UCSF, including one in memory of his younger brother John, who also made a career in company-building as an entrepreneur. He had three different companies, says Bowes, each of which was very successful. The first, the Kransco Group Com-panies, was in the toy business. As it grew, Krans-co acquired Wham-O, the maker of Frisbees and Hula-Hoops, and the firms that introduced boogie boards, hacky sack, and Big Wheels. John sold the company to Mattel in 1994. His second company was Yakima, a car rack maker, and then, Bowes says:

He started a company called Camelbak, which made water bags for bicyclists. You put the water bag on your bike, and you have a tube to drink from. The timing was right for that product because the importance of hy-dration during exercise was being recognized

and publicized. Even construction workers were beginning to use these things. The US Army was a customer during the war in Iraq. Actually, the army didnt issue them; GIs had to buy them, which they did.

Bowes has also contributed time and money to advance San Franciscos Exploratorium, the Cali-fornia Institute for Regenerative Medicine (CIRM), and Seattles Institute for Systems Biology. In 2004, he was honored with the National Venture Capital Associations American Spirit Award for his generosity and assistance to deserving institutions and commu-nity-enhancing arts and education projects in the San Francisco Bay Area. He has served on the boards of the Asian Art Museum, Grace Cathedral, the Hoover Institution, the Environmental Defense Fund, and the San Francisco Conservatory of Music.

In 2012, Bowes received a lifetime achievement award from BayBio, Northern Californias leading biotech trade association. He rose to speak, and explained, in his characteristically laconic way, that while he was heartened and humbled by the recog-nition, the recipient of a lifetime achievement award cannot help but perceive in the accolade a gentle nudge into oblivion. In good humor, he concluded, Not quite yet!

The University of California, San Francisco, Mission Bay campus.


The GeneCo business planGems from the Archives

GeneCo was founded in 1981 to manufacture and sell reagents, fine chemicals, and instruments for use in biological laboratories. The company set up shop in Foster City, California and before the decade was out, had sparked revolutions in genetics and molecular biology, enabled vaulting advances in pharmaceutical discovery and development, and provided the instrumental means for sequencing the human genome.

The company originated with Silicon Valley venture capitalist William K. Bowes. Bowess search for high-tech investment oppor-tunities had led him to Pasadena, to examine an automated protein sequencer invented by Leroy Hood and Mike Hunkapiller at the California Institute of Technology.

After securing a license to the invention (following a difficult round of negotiations with the school administration), Bowes brought in two Hewlett Packard engineers with research manage-ment experience. Sam Eletr became president of the new firm; Andr Marion became vice president and chief operating officer. Marion remembers meeting Bowes: He was not interested in numbers, not at all. He was interested in character, and people, and excitement, so with Sam, I decided to join.

In May of 1981, Eletr and Marion drew up a seventy-page business plan that outlined a strategy for refining, manufacturing, and marketing three devices on Hoods Caltech drawing boardthe protein sequencer, a peptide synthesizer, and an oligonucleotide synthesizer incorporating a new DNA chemistry developed by Marv Caruthers at the University of Colorado. The plan also disclosed GeneCos intent to license a device that Hood and Hunkapiller were designing with the help of computer scientist Tim Hunkapiller and laser expert Lloyd Smiththe

worlds first automated DNA sequencer.The company dropped the GeneCo name early in its startup

phase, and became known as Applied Biosystems (ABI). ABIs first product, the Model 470A gas-phase protein sequencer, was shipped in August 1982. The 380A DNA synthesizer was released in 1983, and the 430A peptide synthesizer in 1984. ABI became a publicly traded company in 1983, and in 1986, introduced the 370A DNA sequencing system. ABI had been profitable for four straight years, revenues had soared, the number of employees at the firm had grown to nearly 800, and research in the life sciences and biomedicine was being conducted at high velocity. The GeneCo plan had been executed to perfection.

ABI was acquired by Perkin-Elmer in 1993, and continued to grow. The companys Foster City campus eventually filled nine buildings in an area bounded by the San Francisco Bay to the north and east, California State Route 92 to the south, and the Foster City Lagoon to the west. After running out of space (again) in 1999, ABI acquired a facility on the opposite side of the lagoon and received permission from the city to build a bridge. It was called the Bridge to Success.

A plaque on the Bridge to Success salutes Andr Marions contributions to

Applied Biosystems.

Wayne Hockmeyer


In 1966, Wayne Hockmeyer was a senior biology major at Purdue University with an abiding interest in parasitic diseases. When he learned from a professor that the military was seeking medical entomologists, he was sufficiently intrigued to enlist in the US Army. He served in Vietnam and East Africa and studied insect-borne pathogens, including the protozoa that cause malaria and African sleeping sickness.

When reassigned to the United States, he took a doctorate in entomology from the University of Florida, and then accepted a post at the Walter Reed Army Institute of Research (WRAIR) in Silver Spring,

Maryland, where he continued to perform research on malaria for the Army.

In 1986, Lieutenant Colonel Hockmeyers twen-tieth year in the service, he had a choicesign up for another ten years, or get out. If I was going to start a second career, he recalls thinking, I might as well start at forty-one rather than fifty-one. So I took a leap and did it.

Hockmeyer accepted a position as vice presi-dent of research at Praxis Biologics, a publicly owned vaccine developer in Rochester, New York. He knew nothing about business, but immediately received a crash course. He also assembled a valuable network of professional contacts that included Wallace Steinberg, co-chairman of the Healthcare Investment Corpora-tion, a leading venture capital firm. Steinberg invested in risky and innovative biomedical research.

Late in 1987, Hockmeyer realized Praxis was in trouble. The board of directors fired the CEO, many employees left, and the stock price tumbled. Hockmey-er considered his options and decided it was a good time to pursue one of his dreams. Even in the Army, he says, I had thought about starting my own compa-ny. He arranged a meeting with Steinberg.

Hockmeyer lacked business experience, but he se-cured $3.5 million to start a company in Gaithersburg, Maryland called Molecular Vaccines. He was fortu-nate, he admits, that Steinberg often based investment choices on gut feelings: He would make decisions by betting on people, and he bet on me.

For help with the venture, Hockmeyer turned to Franklin Top, his former commander at WRAIR, and a seasoned research manager. The two men respected each other, and enjoyed working together. Hockmeyer extended an invitation.

Top was born into a medical family. He grew up in Detroit, where his father directed the Herman Keifer Hospital, the citys largest clinic for tuberculosis and other communicable diseases. The son elected to follow in the fathers footsteps.

As a medical student at Yale, Top decided to spe-cialize in pediatrics and preventive medicine, including

Betting the FarmTwenty Years Ago

December 15, 1995, Gaithersburg, Maryland

Employees milled around the halls. Most chatted happily and toasted each other with champagne. Othersexhausted from months of work and worrytipped their plastic glasses with quiet nods and a sense of collective accomplishment. Company co-founders Wayne Hockmeyer and Franklin Top breathed sighs of relief. They joined their employees in the hallways, eating, drinking, and relishing the moment.

Earlier in the day, an FDA advisory panel had recommended approval for RespiGam, MedImmunes new antiserum against respiratory syncytial virus (RSV). It was a breakthrough product, an important medical advance, and a foundation for the companys future.

MedImmune recently celebrated the twenty-fifth anniversary of its founding. It is now a great biotech success, but those on hand in December 1995 remember a time when the company struggled to survive.

Franklin Top


vaccination. In 1966, he accepted a post in WRAIRs virology department (along with a military commis-sion) and conducted research on adenovirus, influenza, Japanese encephalitis, and dengue fever.

In 1983, he was named Director and Commandant of the entire institute. He found the job challenging and fulfilling, but it was short-lived. In 1987, he was transferred to the Pentagon for a new job that seemed to him more about politics than science or medicine.

A year later, Top was frustrated and ready for a change. He resigned his commission, accepted the title of medical director at Molecular Vaccines, and began recruiting immunologists and virologists to develop vaccines and antisera against cytomegalovirus (CMV), hepatitis B, HIV, and Lyme disease. As the company branched out, it was renamed MedImmune.

Top soon learned of an antiserum against CMV in development at a state public health lab in Boston. CMV is closely related to the viruses that cause chicken pox and mononucleosis. Infections are usually asymp-tomatic in healthy individuals, but can be life threaten-ing for those with compromised or suppressed immune systemsAIDS patients, for example, or transplant recipients on immunosuppressants to reduce chances of tissue rejection.

MedImmune acquired a license to the product in 1990, completed clinical trials, and asked for a review from the FDA. In 1991, CytoGam was approved for use in kidney transplant patients, and later for those receiving new lungs, livers, and hearts, as well.

On the strength of the approval, MedImmune made an initial public offering of stock in May 1991, and garnered proceeds of $29 million to fund an encore performance. Hockmeyer and Top reviewed the companys product pipeline and concentrated develop-ment efforts on prophylactics for HIV and respiratory syncytial virus (RSV).

There were high hopes for the HIV program due to the discovery of a monoclonal antibody called MEDI-488 that killed several viral strains in laboratory tests. The results prompted pharmaceutical giant Merck & Co. to enter into a two-year development agreement

and pledge $13 million to the project in October 1991. The price of MedImmunes stock soared to $52.75, from $9.25 six months earlier.

Publicly, the company urged caution, warning investors that it was a long journey from the laboratory

to an approved product. Privately, Hockmeyer and Top worried that the bubble could burst at any moment. Indeed, by the end of 1993, MEDI-488 had stopped delivering consistently positive results. The project faltered, and the bottom dropped out of the stock.

MedImmune turned its attention to an experi-mental antiserum against RSV derived from human plasma. RSV had fascinated Top since it was first isolated in 1956, when he was a new medical student. In adults and healthy children, symptoms of RSV infection are usually mild, but in babies born prema-turely, the virus can cause life-threatening pneumonia. It is especially dangerous for children with weakened immune systems.

MedImmunes antiserum was in the midst of a

MedImmune headquarters, Gaithersburg,

Maryland


three-year clinical trial. The company was confident that the treatment would pass muster, but in Decem-ber 1993, an FDA advisory panel voted not to approve it. MedImmune had failed to recognize the agencys discomfort with the study design. The FDA was giving subtle warnings, says Top, but we just werent picking them up.

Panel member Paul Meier, a Columbia University statistician, was especially harsh in his criticism. He called the trials a tragic squandering of three years of research. Other reviewers expressed frustration that the company hadnt demonstrated the antiserums great potential. Infectious disease specialist Louis Katz said, I just feel terrible about this. This is a drug that really might benefit someone.

It was another disastrous turn of events. The com-panys stock plummeted further and there was nothing to fall back on. Both the HIV and RSV projects had collapsed.

MedImmunes senior staff closely examined the FDAs report and acknowledged the methodological problems with their initial studies. We made some mistakes and didnt even realize it, says Hockmeyer. The companys inexperience had left it in a terrible

predicament.Hockmeyer and Top still believed in the RSV anti-

serum product. They agonized over the decision either to conduct a second trial, or to retrench, cut staff, and attempt to revive the company by selling off research assets. They knew that another round of trials would consume all of the companys remaining resources.

It was very scary, says Top. He praises Hockmey-ers leadership: He didnt waver a bit, even in the worst times. Hockmeyer refused to go backwards: I decided to bet the farm on RSV.

The company designed and organized another set of trials. Top remembers many sleepless nights: The pres-sure was unbelievable. We were truly underpowered, but we couldnt afford more people. MedImmunes employees understood the seriousness of the situation. People were tense, says Hockmeyer. They were single-minded. They were focused. The entire organiza-tion hummed.

One morning in early November 1994, about a week before the second round of testing began, Top went for a swim. While getting dressed afterwards, he felt a searing pain, and soon realized he was having a heart attack. He believes it was stress-induced. Fortu-

The farm


nately, it was minor. The clinical trials got underway while he recovered in the hospital.

The trial results came back in the spring. The com-pany was running on fumes, Top recalls. We only had a few months left. MedImmune analyzed the trial data through June and July, and in August, presented its findings to the FDA.

The agencys advisory committee was scheduled to announce its recommendation on December 15, 1995. That morning, Hockmeyer ordered champagne and lunch for all employees. We had no way of knowing what they would doyou never do, says Hockmeyer. But Im an optimist.

When the announcement was made, corks began poppingthis time, the panel had recommended ap-proval. For Hockmeyer and Top, it was a huge relief. On January 18, 1996, MedImmune received a fax from the FDA indicating that the product, now called RespiGam, was cleared for sale. The company had survived what Hockmeyer calls its nuclear winter.

MedImmune went on to achieve great things. In 1998, it introduced a blockbuster treatment for RSVSynagis, the first monoclonal antibody approved for treatment of an infectious disease. The price of the

companys shares rose to $71, making it one of the ten most valuable biotechnology firms in the world.

MedImmunes outsized success also made it an anchor for the expansion of the commercial biotech industry in the greater Baltimore/Washington, DC metropolitan area, and especially along DNA Alley, the fifteen-mile stretch of I-270 that links Bethesda and Gaithersburg in Montgomery County, Maryland.

Hockmeyer stepped down as CEO in 2000 (but stayed on as chairman). Top left in 2003. Hockmeyers successor, David Mott, steered Synagis to nearly $1 billion in annual sales, oversaw the launch of FluMist, MedImmunes nasal spray influenza vaccine, and negotiated the sale of the company to AstraZeneca for $15.6 billion in 2007. Today, MedImmune remains operationally independent as the pharmaceutical com-panys biologics research and development arm.

Despite the grueling intensity of the RespiGam episode, Top feels that all in all, the experience was just a kick. The product saved young lives. I dont think there is anything more exciting than that, he says. Hockmeyer is also justifiably proud. It's not every day, he says, that you go from zero to a $15 billion-plus company.


Leonard HerzenbergObituary

Geneticist, cell biologist, and immunologist Len Herzenberg passed away on October 27, 2013 in Palo Alto, California, at the age of eighty-one.

* * *

Len Herzenberg made numerous contributions to science (many in collaboration with his wife and scientific partner, Lee), but he became best known for building a machinethe fluores-cence-activated cell sorter (FACS). The FACS broadly impacted the development of the life sciences and biomedicine in the late twentieth century, and it remains a key enabling technology in many different fieldsit is an extraordinarily versatile piece of equipment.

The machine was originally designed to solve problems in immunology. Herzenberg was trained as a molecular geneticist, but moved into immunology as a new faculty member at Stanford University in the early 1960s. It was an opportune timethe field was about to experience a renaissance. Promising lines of research were plentiful, as was government funding. The known universe of immunological objects and processes was expanding. Cytokines, lymphokines, and complement proteins were discovered by the dozens, and a host of new immune cell types and functions were identified.

Herzenberg commenced studies of antibody genetics and lym-phoid tumors, but soon found that his tools were inadequate. He was tagging lymphocytes (antibody-producing cells) with fluores-cent proteins to permit the characterization of cells by fluorescence microscopy, but the resolution was poor and he lacked the means to isolate different cell types.

In 1965, while scouring relevant literatures for a solution, Herzenberg learned that IBM had developed a fluorescence-based cell sorter, and physicists at the Los Alamos National Laboratory had built an apparatus that separated particles, including cells, by electrostatic charge. The IBM device proved unsuitableit was intended for use by pathologists and did not preserve viable cellsso Herzenberg traveled to New Mexico to talk to the Los Alamos inventors about making a machine that incorporated fluorescence photometrics. The physicists begged off, explaining that their mis-sion was to improve radiation detection, but they agreed to supply blueprints for their particle separator.

Herzenberg returned to California and began applying for grants to support a development project in Palo Alto. In 1966, he engaged engineers William Bonner and H. Russel Hulett, university affiliates working in Stanfords NASA-funded exobiology program. The trio went on to design a series of prototypes that combined fluorescence photometry and laser spectroscopy with

inkjet fluidics and electrostatic separation technologies borrowed from the Los Alamos device.

The FACS works by propelling a fluid mixture of cells, some carrying fluorescent tags, through a rapidly vibrating nozzle. The nozzle transforms the liquid stream into droplets, each containing a single cell. On exit from the nozzle, the cells pass through the beam of an argon-ion laser calibrated to excite fluorescent proteins. Light detectors record the intensity of the fluorescence (which indicates the number of tags on or within cells) and the scatter of the laser beam around cells (which indicates cell size and shape). A computer analyzes these inputs and translates them into electrical pulses that charge the droplets according to the kinds of cells they contain. Finally, the charged droplets are deflected as they pass through an electromagnetic fieldthey are sorted.

A host of engineering problems had to be resolved before the sensitive instrument would work properly. Achieving sufficient speed and throughput without destroying cells was a particular-ly vexing issue. There was some discussion, Herzenberg later recalled, about repealing the laws of physics, but eventually an en-gineer came up with a solution and we were off and running again.

Len and Lee Herzenberg were married for sixty years. For

more than fifty of them, they ran a laboratory together at

Stanford University.


In 1969, the group published an article in Science on the successful use of a prototype to separate mouse spleen cells from Chinese hamster ovary cells. In 1972, a patent was filed, and the technology was licensed to Becton Dickinson & Company for commercial development. The first machines were shipped in 1975. Sales started slowly but gained momentum as research-ers learned what the device could do.

The FACS eventually became a fixture in biological and biomedical laboratories across the country and around the world. Tens of thousands have been manu-factured and sold. The FACS reinvigorated cell biology and many related areas, and laid technical foundations for stem cell research and regenerative medicine.

Herzenberg soon became involved in another adventure: he played an important role in the develop-ment and commercialization of hybridoma technology, the manufacture of monoclonal antibodies. In 1976, he spent a sabbatical year in Csar Milsteins lab in Cambridge, England, just as Milstein and co-inventor Georges Khler were refining the process. Herzenberg learned the technique, and became a proselytizer. When he returned to Palo Alto, he began distribut-ing Khler and Milsteins P3-X63Ag8 myeloma cell linean essential resource at that timeto colleagues at Stanford.

The recipients included new assistant professor Ron Levy and postdoc Ivor Royston, who began using monoclonals to characterize blood and lymph cancers.

Royston went on, with scientific and business partner Howard Birndorf, to co-found Hybri-tech, the worlds first monoclo-nal antibody company. Eight years later, after Hybritech was acquired by Eli Lilly & Company, Royston and Birndorf joined Levy in the formation of Idec Pharmaceuticals. Idec produced the worlds first anti-cancer antibody.

Herzenberg saw from his first introduction that monoclonal antibodies would be a boon to fluores-cence-based cell analysis. Because they seek out and bind molecular targets with exquisite specificity, monoclonals are superb at delivering fluorophores to select cell surface receptors. Their use greatly enhanced the power of the FACS to make fine distinctions between cells, and Herzenberg successfully pressed Becton Dickinson to manufacture and sell them as companion reagents.

Over the course of his career, Herzenberg conduct-ed research on a wide range of immunological topics with relevance to biomedicine. Most employed the FACS, and he never gave up improving the invention and developing new applications. In 2006, at the age of seventy-four, he reflected on the Los Alamos blue-prints he obtained in 1965: Little did I know when I brought these plans back to Stanford that I was starting on a lifework that continues today.

There was some discussion about repealing the laws of physics, but eventually an engineer came up with a solution and we were off and running again.

cell type A

cell type B

cell type C

Laser

Photomultiplier tube

Electrical wire

Computer


Fred SangerObituary

Nobel Prize-winning biochemist Fred Sanger passed away on Novem-ber 19, 2013, in Cambridge, England, at the age of ninety-five.

* * *

Fred Sanger dedicated his entire scientific career to working out the order of things. His business was sequences, and he was good at itgood enough to win two Nobel Prizes. He was honored in 1958 for determining the amino acid sequence of insulin, and again in 1980, for methods he devised to identify nucleotide se-quences in RNA and DNA molecules. His accomplishments were worthy of special recognition, not only because they enriched basic understandings of biochemistry, but because they enabled great leaps forward in biomedicine and biotechnology.

Sanger grew up the son of a Quaker physician in the west of England, in the village of Rendcomb, Gloucestershire. Of his unexceptional youth, he later wrote: Unlike most of my scientific colleagues, I was not academically brilliant. I never won scholar-ships. He had the good fortune to study at Cambridge as an un-dergraduate, but only, he admitted, because his family was fairly rich. He did, however, receive a top score on his exit exam, and inquired about graduate work in biochemistry. He found several faculty members who would be glad to have a PhD student, espe-cially one like me, who did not need money. Sanger worked with Bill Pirie and Albert Neuberger, and completed a thesis on lysine metabolism in 1943.

Afterwards, he stayed on at Cambridge with a grant from the British Medical Research Council (MRC) to study the chemical composition of insulin. Much about it was unknown. The pains-taking work proceeded glacially, but eight years later produced a stunning result. By modifying existing chemistries and taking advantage of new fractionation techniques, Sanger managed, with collaborator Hans Tuppy, to map the entire sequence of the B chain of the bovine insulin molecule (there are two chains, A and B), and to demonstrate empirically that it consisted of thirty amino acid residues arranged in precise linear order.

In 1953, Sanger reported the A chain sequence, and two years later, described the three invariant disulfide bonds that stabilize the molecule. It was a complete biochemical rendering, the first of its kind. The work revolutionized protein chemistry, and exemplified Sangers methods-driven approach to biological inquiry. Through-out his career, Sanger made scientific progress by refining existing procedures, taking advantage of new tools as they became avail-able, and, when all else failed, devising wholly novel approaches.

Sanger described his scientific output between 1955 and 1962 as lean. He made no major discoveries, but continued to expand his repertoire of experimental techniques. He began working with

radioisotopes and followed developments in chromatography, electrophoresis, and autoradiography. He would later incorporate these tools into new sequencing systems.

In 1962, Sanger made a revitalizing move from the Depart-ment of Biochemistry to the MRCs new Laboratory of Molecular Biology on the outskirts of Cambridge, to begin working alongside Sydney Brenner, Francis Crick, and Max Perutz. Crick and Perutz joined him that year in the circle of Nobel laureates. It took Bren-ner a bit longer (he was honored in 2002).

Sanger soon shifted the focus of his research from proteins to nucleic acids, and began looking for ways to sequence RNA molecules. By 1968, he had developed a viable method and used it to determine the sequence of a piece of ribosomal RNA containing 120 bases. It was, at the time, the longest recorded nucleic acid sequence.

Next, Sanger turned his attention to DNA, along with many others. In the 1970s, it became clear (in conjunction with other breakthroughs, including the discovery of restriction enzymes and the invention of recombinant DNA technology) that advances in sequencing would significantly boost the capabilities of molecular biologists to manipulate genes. In 1975, Sanger disclosed the plus and minus method of DNA sequencing, and his assistants used it to generate the first complete sequence of a DNA-based genome,


that of a virus, bacteriophage X174. The genome contains about 5,000 base pairs. It took two years to read them.

By the time the X174 genome was published, Sanger had already developed a much faster sequencing protocol known as the dideoxy or chain termination method. Harvard University biochemists Allen Maxam and Walter Gilbert had also invented a high-speed alternative. Both proce-dures afforded great gains in efficiency and throughput, and each had ad-vantages, but eventually the Sanger method became the preferred choice for most purposes. It was simpler, required fewer toxic chemicals and radioactive isotopes, and turned out to be scalable.

In 1980, Sanger shared the Nobel Prize in Chemistry with Gilbert and Stanfords Paul Berg for fundamental studies of the biochemistry of nucleic acids. The following year, he was offered a knighthood, but turned it down. In 1983, at the age of sixty-five, he retired from science and took up gardening.

Around the same time, biologist Leroy Hood gathered laser expert Lloyd Smith, engineer Mike Hunkapiller, and computer scientist Tim Hunkapiller in his Caltech laboratory to automate

Sangers sequencing chemistry. The group designed a working system that relied on fluorescent dyes rather than radioisotopes to tag nucleotides, and on cameras and computers for data collection and analysis. The technology was transferred to engi-neers at Applied Biosystems, Inc. (ABI) for commercial development. The first semi-automated DNA sequencers were sold in 1986.

When the Human Genome Project got underway in the early 1990s, the MRC and the Wellcome Trust established the Sanger

Centre, a sequencing facility ten miles outside of Cambridge, to assist in the effort. The Sanger Centre purchased late model ABI machines, still based on the Sanger method, to read and record the code. The Centre eventually contributed one-third of the projects final sequence.

Subsequent innovations in DNA chemistry have increased se-quencing speeds by many orders of magnitude. In 2003, with a tip of the hat to Fred Sanger, a team led by J. Craig Venter constructed a synthetic version of the X174 genome using a method called polymerase cycle assembly. The synthetic genome was stitched together in two weeks.

Of the three main activities involved in scientific research, thinking, talking, and doing, I much prefer the last and am probably best at it.

The Sanger Institute, a genomics research center located outside Cambridge, UK


Jim VincentObituary

Jim Vincent, former CEO and Chairman of Biogen, Inc., passed away at his home in Weston, Massachussets on December 5, 2013, at the age of seventy-three.

* * *

Some careers unfold predictably, ascending through established chains of command or series of positions with increasing respon-sibility within organizations or business sectors. Jim Vincents ca-reer wasnt one of these. He cut a unique path across late twentieth century technology-based industries.

Vincent began his career in business at AT&T and Bell Tele-phone in 1963, as a new MBA out of the Wharton School at the University of Pennsylvania. He was put in charge of Bells south Philadelphia unit, a group of 200 employees with the worst perfor-mance record in the entire company. He turned it around.

Two years later, a recruiter from Texas Instruments (TI) contacted him. By 1965, TI had become an industry leader in sol-id-state electronics, and had started manufacturing computers with silicon chips. Defense contracts were its bread and butter, but the firm was making a push to sell consumer products internationally. Vincent joined an exciting company in an exciting industry, at an exciting time.

He was assigned to Freising, Germany, a small town in Bavaria, about thirty kilometers outside Munich. TI had built a small manufacturing plant there to make solid-state and semiconductor products. Vincents mission was to penetrate European markets.

Recent advances in electronics and computing were just beginning to offer glimpses of the high-tech future, but they had yet to make an impression on continental electronics corporations. As far as the Germans were concerned, Vincent recalled, the idea that we would take on companies like Siemens and Philips was laughable. But by the time we were finished, they didnt know what hit them.

Vincents next assignment was the Far East. In the late 1960s, Western companies began establishing low-cost manufacturing op-erations in Asia. TI was one of the first. The company built plants in Japan, Taiwan, and Singapore, and Vincent was centrally in-volved. Still shy of thirty years old, he was called to negotiate with senior government officials. He also managed a joint venture with Sony. Every six months, he reported personally to Sony cofounders Masaru Ibuka and Akio Morita.

By 1972, Vincent was ready to move back to the United States, but he wasnt enthused about his probable future as an admin-istrator at the company headquarters in Dallas. He had saved some money, so he resigned and took time off to contemplate his next move. He decided that he wanted to get into the healthcare

business.After talking to a number of prospective employers, Vincent

accepted an offer from Abbott Laboratories in Chicago. He started in a temporary position: president of the companys underperform-ing diagnostics division. It was a small operation with about 100 employees and $10 million in annual sales. Vincents job was to sell it.

He never got it done: After spending some time on it, he later said, I saw an enormous opportunity to go after the human diag-nostics market worldwide. I proposed that to the board and told them Id do it. For the next ten years, Vincent worked on turning Abbotts afterthought division into the worlds leading diagnostics company. It was his second turnaround.

In 1975, he hired a new vice president of R&D, a chem-ist named George Rathmann. Rathmann generated a series of innovative products for the division, and then became interested in late advances in biologyrecombinant DNA and hybridoma technology.

A few years later, Rathmann announced that he was leaving to join a new biotech company in Southern California called Amgen.

Jim Vincent graduated from the Pratt School of Engineering at Duke University in 1961, and maintained a lifelong connection to the institution. He served as a university trustee from 1994 to 2009.


Vincent tried to hold himhe proposed that Rath-mann could lead a biotech unit inside Abbottbut to no avail. Abbott made an investment in Amgen, and Vincent began watching developments in biotechnol-ogy.

By 1982, Vincent was second in command at Abbott, president and chief operating officer of the entire company, but he didnt see eye-to-eye with recently appointed CEO Robert Schoellhorn. Once again, he elected to resign. He was soon in touch with Allied Chemical, which was planning to diversify into healthcare. As Vincent described it, Nobody at Allied could spell healthcare, so they offered me the job of president of the new division. I signed on and off we went.

In the spring of 1985, Vincent received a call from Hugh DAndrade, a vice president at Schering-Plough and a director of Biogen, a biotechnology company located in Geneva, Switzerland and Cambridge, Massa-chusetts. Biogen was in trouble, headed for bankrupt-cy. DAndrade was looking for a chief executive who could turn it around.

Vincent had already been approached by several biotech firms about taking up positions of leader-shipGenetics Institute, Cetus, and Genentech among them. For various reasons, he had put them off, but his circumstances had changed. Allied had

recently merged with two large engineering companies. Vincent now doubted the big corporations commitment to building a healthcare business.

He followed his proven formula for making important career decisions: Clear the air, clear your head, and do some clear thinking about what you want to do and why you want to do it. Vincent realized that he en-joyed growing businesses more than occupying senior administrative positions in large corporations. It was the difference, he said, between rolling out of bed in the morning and jumping out of bed in the morning.

He called DAndrade back to discuss Biogens pre-dicament. Vincent knew that the company had good science. That gave it a shot at recovering. Assured that he would have operational control, he took the job and began the processpainful for allof reorganizing and refocusing the organization.

The company was in the black within two years, with sufficient resources to turn its most promising asset, recombinant beta interferon, into a blockbuster drug with annual sales in excess of $1 billion. It was Jim Vincents third successful turnaround, and Biogen still stands. Vincent served as CEO until 1997 and as chairman of the board until 2002.

Clear the air, clear your head, and do some clear thinking about what you want to do and why you want to do it.


Restriction enzymes are remarkable molecules. For billions of years, they have cut up DNA in the service of microbes. Now they work for people, too. The contemporary story begins in the early 1950s when scientists found that some bacteria were susceptible to viral infection while others resisted. Eventually, the mystery of this protective characteristic was unrav-eled: enzymes in resistant strains were chewing up viral DNA and preventing viral replication. Scientists speculate that restriction evolved in bacteria as a natural defense.

Since they were first isolated and characterized in the late 1960s, restriction enzymes have become indispensable tools for life scientists and biotech-nologists. They have facilitated important advances in genetics and cell biology, and they have enabled industrialists to manipulate and make use of genes in the production of valuable medical, agricultural, and industrial goods. To date, more than three thousand restriction enzymes have been identified, and more than six hundred are available commercially.

In October 2013, Cold Spring Harbor Laborato-rys Genentech Center for the History of Molecular Biology and Biotechnology hosted a special con-ference to commemorate fifty years of research on restriction enzymes. Pioneering figures in the field (including Werner Arber, Herb Boyer, Stu Linn, Matt Meselson, Rich Roberts, Ham Smith, and Bob Yuan) gathered with colleagues old and new, students, journalists, historians, and archivists to consider the past, present, and future of biologys workhorse molecules.

The event was organized by Herb Boyer, Stu Linn, Rich Roberts, and Mila Pollock, executive director of the Cold Spring Harbor Laboratory (CSHL) Library & Archives. The Library & Archives are preserving CSHLs distinguished history and documenting the work of a generation that transformed the discipline of biology from a quiet science of collection and clas-sification into a powerful force capable of interven-ing in fundamental life processes and reshaping the human condition in the twenty-first century.

The History of Restriction EnzymesCold Spring Harbor LaboratoryOctober 19-21, 2013

left photo:Rich Roberts

welcomes guests to Cold Spring

Harbor Laboratory.

right photo:The conference

organizers (left to right) Rich Roberts,

Mila Pollock, Stu Linn and Herb Boyer. Pollock

is the Executive Director of the

CSHL Library and Archives.

right photo: Ham Smith shared

the 1978 Nobel Prize with Werner

Arber and Dan Nathans, for

his discovery of HindII, the first

Type II restriction enzyme.


Second Century: Cold Spring Harbor and the Biotechnology Revolution

Cold Spring Harbor Laboratory (CSHL) was estab-lished in 1890, on the north shore of Long Island, as a training facility for high school and college biology teachers. Over the course of the twentieth century, it grew into an internationally recognized center for research in molecular genetics. But thats not the whole story. As a recent article by CSHL historians Robert Wargas and Ludmila Pollock shows, the insti-tution contributed significantly to the development of the US biotechnology industry. When the fruits of molecular biology demonstrated economic value in the 1970s and 1980s, CSHL became an incubator for marketable technologies. Second Century: Cold Spring Harbor and the Biotechnology Revolution recounts how CSHL became a locus of industrial in-novation while maintaining its commitment to excel-lence in basic biological research.

Herb Boyer discovered EcoR1, the restriction enzyme that enabled recombinant DNA technology.

left photo: Nobel Laureates enjoy a break in the conference proceedings. Jim Watson (left), with Rich Roberts.

right photo:Matt Meselson won the Lasker Prize in 2004 for a lifetime of contributions to molecular biology.

Werner Arber (left) shared the 1978 Nobel Prize for his work on restriction enzymes. Bob Yuan (right) was the first to isolate a restriction enzyme (in collaboration with Matt Meselson).

All photographs by Constance Brukin, CSHL

cont. on pg 30


James Watsons memoir, The Double Helix: A Personal Account of the Discovery of the Structure of DNA, was published in 1968. Twenty-five years later, histo-rian Horace Freeland Judson noted that among molecular biologists, the event was remembered with the same intensity as the Kennedy assassination. Months of speculation and rumor preceded it; a flurry of reviews appeared soon after. The book became an instant literary sensation, and spent eighteen months on the New York Times bestseller list. It has since been re-printed dozens of times and translated into numerous languages.

The Double Helix was a first-of-its-kind account of a great scientific discovery. It de-scribed the technical aspects of the process in fine detail, but scattered them through-out an autobiographical narrative. The book focused on personalities, friendships and feuds, and the dynamics of collab-oration, competition, and institutional politics. It also featured the authors unex-pectedly frank opinions of his colleagues. The book brought science to life in a way

usually hidden from the general public, and exposed elements of discovery customarily expunged from scientific papers.

Many in the scientific community felt that by inviting readers into the backrooms of science, Watson had violated the trust and privacy of his colleagues. In a 1968 review published in Science, biochemist Erwin Chargaff wrote: We often get the impression that we are made to look through a keyhole at scenes with which we have no business. The books harshest critics suggested that some of Watsons portrayals and imputations bordered on libel. Other reviewers took the appearance of The Double Helix as an opportunity to engage in cultural criticism. The book, they suggested, illustrated the erosion of scientif-ic inquiry from an honorable, gentlemanly pursuit into an unseemly scramble for advantage and reward.

The candor of the manuscript nearly derailed its publication and threatened to destroy the authors relationships with friends and scientific collaborators. Harvard University Press backed out of a contract

Inspired by The Double Helix

I had the barest awareness of DNA before reading

The Double Helix. My awareness of molecular biology came upon its first reading. The Double Helix was for me an historical record, a morality play, a great scientific treatise, and an adventure story all at once. It made a deeper impression on me than anything I had read before or since, with the exception of Aesops Fables, the Bible, and Kafkas The Castle. The horizons of the possible reopened. The world was not bleak. I had just taken the wrong view.

Molecular biologist Michael Wigler

You know I wasnt

just saying things to piss people off. It was a good story, some people liked it. The people who were involved had very different reactions to it. It didnt bother me in the

slightest.

James D. Watson

I had all the usual preconceptions about

scientists that proved as phony as the whole notion of the priesthood of science that Jim Watson overthrew when he lifted the veil. Scientists are just like other people except they are more competitive than any trial lawyer I ever met, more competitive than most businessmen I have met, for the reason that in science you get no prizes for being the runner-up. If youre not first,

youre nothing.

Patent attorney Tom Kiley

What They

Said

I just couldnt put it down. But there were a lot of arguments at the parties there, and some people were absolutely outraged. They were quite polarized about it. I think its a very honest book and very self-revealing, too. Watson is not kind to himself in his book. I thought it was great.

Molecular biologist Seymour Benzer


to publish the book when Maurice Wilkins and Francis Crick protested and threatened legal action. Two trade houses, Athene-um in the United States, and Weidenfeld & Nicholson in the United Kingdom, subsequently picked up the offering and released it on schedule. Crick shared his final thoughts on the matter in a special retrospective issue of Nature, published in 1974. Acknowledging repeated invitations to publish a book of his own, he wrote: I confess I did get as far as composing a title (The Loose Screw) and what I hoped was a catchy opening (Jim was always clumsy with his hands. One had only to see him peel an orange) but found I had no stomach to go on.

Watson remained unapologetic, and to make matters worse, seemed to revel in the bickering. Joan Steitz, a graduate student in Watsons Harvard lab, later recalled how he pinned irate letters from those portrayed in the book to the laboratorys bulletin board. At the time, she feared that her academic career might suffer from association with the self-fashioned enfant terrible. Of course, the concern was unwarranted, for the furor eventually died down, and most of Watsons critics came to agree that,

whatever its faults, his book had usefully demythologized science and scientists.

Today, the lasting legacy of The Double Helix is the broad interest it has generat-ed in science, and molecular biology, in particular, as a profession and a way of life. In 1968, many practitioners believed Watson had painted an unflattering portait of the field, one that would deter young talent from entering. More than forty-five years later, it appears that the effect was just the opposite: for a generation of students and budding investigators, the book was inspirationalit portrayed science as a vital and exciting human enterprise in which they wanted to take part.

Before writing The Double Helix, Watson authored a textbook, The Molecu-lar Biology of the Gene, which was equally innovative, if less inflammatory. First published in 1965, it quickly became a best-selling classic, a staple in undergrad-uate molecular biology classes around the world. The seventh edition was released in 2013. Leading molecular biologist and Watson protg Tom Maniatis writes that Watsons books have helped new genera-tions become captivated by the elegance and power of an exciting field.

I started reading books when I was in the army, to

keep my mind active, and I read The Double Helix. I thought, wow! This is really exciting. I saw genetics as the future.

Peter Meldrum, Myriad Genetics CEO

I really feel that the image

of the race for the double helixand the paradigmatic character of that storyhas done enormous damage, because it has created the notion that thats how the best science gets done, thats how the best science must be done, by racing for the prize. And thats how young scientists are

trained.

Biologist Ruth Hubbard

In 1970, Craig Venter was twenty-four years old, and taking

courses at the College of San Mateo, in California. Given an

assignment to review two books for an English literature class,

his first choice, selected more or less randomly, was The Double

Helix; the second was Francis Chichesters account of his solo

round-the-world yacht expedition. Both books stuck in his

memory, but he recalls that he was intrigued by the story of the

original bad boys of molecular biology.

When you describe what went on in your head as the truth haltingly staggers upon you and passes on, finally fully recognized, you are describing how science is done. I know, for I have had the same beautiful and frightening experience.

Physicist Richard Feynman, in a letter to Watson

When Nancy Chang left her home in Taiwan in 1974 to attend Brown University, she purchased The Double Helix at the

LSF Magazine Winter 2014

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