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FALL 2017 PARADIGM BRANCHING OUT CHEMISTRY OF LIFE STEWARDING SOLUTIONS LIFE SCIENCES AT WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH

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FALL 2017

PARADIGM

BRANCHING OUT

CHEMISTRY OF LIFE

STEWARDING SOLUTIONS

LIFE SCIENCES AT WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH

An Enduring ModelThirty-five years ago, entrepreneur and philanthropist Edwin C. “Jack” Whitehead had a singular vision for an institute focused on biomedical innovation and discovery. That vision came to fruition in a research center that remains culturally unique and uniquely productive. Whitehead Institute sparks development of novel research methods, ever-more effective diagnostic tools, and powerful treatments for a range of diseases. And we produce scientific leaders—investigators trained in our labs, who go on to direct research programs across the globe. Simply put: Whitehead science has impact.

Whitehead researchers—drawn from more than 40 nations—are driven to question fundamental assumptions and test wholly new ways of approaching longstanding challenges. Our 19 Institute Members and Fellows, and the 400 world-class scientists working with them, conduct not just cutting-edge science but “courageous” science; carving new paths into realms few would consider entering.

As a result, Whitehead is a powerhouse of discovery. Our Members are among the most influential scientists in the world, leading their fields with transformative science, and our scientists collectively published an astonishing 121 peer-reviewed studies and reviews last year alone. This extraordinary influence and productivity derives from Jack Whitehead’s original vision: Give stellar scientific minds the freedom to ask questions no one has yet asked, and empower them to define the future of medicine and biotechnology.

Amgen CEO Bob Bradway, who recently spoke at the Institute, believes that we stand at the dawn of the “Bio Century”—that life sciences will be to the 21st century what physics and engineering were to the 20th. That feels right to us. And we are laser-focused on ensuring that Whitehead Institute remains a pioneering scientific force, a driver of the Bio Century.

To that end, we’ve undertaken a broad-based strategic planning process. We’ve begun by asking ourselves fundamental questions about, for example, the emerging research challenges we should address; how to continue attracting the best young researchers and mentor them in the most effective way; and what new resources our building should have. We’ve also added four Members to the leadership team—senior scientists who will work with me to plan and implement major initiatives (while still maintaining their labs). Terry Orr-Weaver is director of the Whitehead Fellows Program—one of our “crown jewels”—which enables stellar young scientists to establish their own labs right out of doctoral training. Iain Cheeseman, Peter Reddien, and David Sabatini are associate directors of the Institute; they’ll help drive leadership projects, facilities planning and upgrading, faculty recruitment, and junior faculty mentoring.

Along with these four new leaders, I welcome your thoughts on the next 35 years of the Whitehead story.

David Page Director, Whitehead Institute

PARADIGM FALL 2017 1

FALL 2017FEATURES

BRIT D’ARBELOFF Stewarding Solutions at Whitehead 2

BRANCHING OUT Capturing the Power of Plant Biology 10

METABOLOMICS A New Lens on the Chemistry of Life 18

RESEARCH NEWS

Growing Human Breast Tissue in the Lab 4

New Approaches, Fresh Insights on the Brain 5

The Essential Role of Hydrogen Peroxide 6

Knockout Genomics 6

Of Flies and Forks 8

Launching the Careers of Leaders 9

COMMUNITY NEWS

Johnson & Johnson Endows Chair Honoring Susan Lindquist 24

Sebastian Lourido Appointed as Whitehead Institute Member 25

David Sabatini Elected to National Academy of Sciences 25

Fellow Olivia Corradin Choreographs a Career in Science 26

Whitehead Connects Bridging Biopharma and the Life Sciences 27

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Brit d’Arbeloff’s gift supports research conducted in the lab of Whitehead Director David Page (right) by creative and dedicated scientists, such as postdoctoral researcher Adrianna San Roman (left) and graduate student Sahin Naqvi (center right).

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For more than five decades, Brit d’Arbeloff has seen and experienced the particular challenges facing women in science and engineering. When she earned her master’s degree at Massachusetts Institute of Technology in the 1960s, she was the sole woman in the school’s mechanical engineering department. She built a career in computer software development, in part because the field was so desperate for anyone with “geeky creative thinking capacity,” as d’Arbeloff describes it, that it welcomed women. She enjoyed that career immensely, until the field evolved and women were increasingly made to feel unwanted. Throughout those years, she also watched the hurdles thrown in the way of women audacious enough to think they would make good biomedical researchers.

But it was just in the last few years that she came to understand that the gender gap existed not only in the research workforce, but in the research itself. “Until the 1990s, most medical research ignored women,” d’Arbeloff says. “Even though it was clear that women and men often experienced disease differently—heart attack symptoms being the most obvious example—basic research and clinical trials excluded women, because we ‘threw off’ the results.” This willful ignorance often resulted in women receiving ineffective preven-tive, diagnostic, and therapeutic care. And, d’Arbeloff learned, the problem persists today, harming women in every part of the world, including the United States.

That’s why, last year, she made a $5 million gift to support Whitehead Institute’s Sex Differences in Health and Disease Initiative, a major research program led by Institute Director David Page. “The biomedical research enterprise has lost so much time on what one would think is a fundamentally important topic,” Page says. “And Brit d’Arbeloff’s philanthropic support has helped us hit the ground running.”

“The fact that women are now incorporated into trials is important but insufficient,” d’Arbeloff explains. “Researchers still lack the tools and data necessary to understand why results differ between men and women.” Whitehead Institute’s Sex Differences in Health and Disease Initiative is addressing those shortcomings from the bottom up: building a fundamental understanding of how the female and male genome, proteome, metabolome, and microbiome differ. In the long run, determining the practical implications of those differences should lead to better, more effective treatments for both women and men.

“This is a biomedical quest, as challenging today as the Human Genome Project was in 1991,” d’Arbeloff says. “No institution is better positioned to lead it than Whitehead Institute. And, as a strong advocate of basic research, I can’t think of a better long-term investment in the health of my grandchildren and their children.”

STEWARDING SOLUTIONS AT WHITEHEAD

Brit d’Arbeloff

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RESEARCH NEWS

A hydrogel scaffold created by Whitehead researchers supports the growth of human mammary tissue from patient-derived cells.

Breast cancer research has been largely confined to studying transformed cell lines in a dish or implanting cells from established human tumors into mice and other animal models of the disease. Although these models provide some insight into a cancer’s machinations at the cellular level, they fall short for investiga- ting the disease’s initiation and progres-sion within human tissue.

The ideal is to grow human mammary glands in the laboratory that mimic the body’s breast tissue, including its response to hormones that trigger deve- lopment during pregnancy and lactation. Similar models are available for other

human tissues, including intestine and brain, but establishing mammary models has proved problematic.

Problem no more: Scientists in the lab of Whitehead Member Piyush Gupta have created a hydrogel scaffold replicating the environment found within the human breast. The scaffold supports the growth of human mammary tissue from patient- derived cells and can be used to study normal breast development as well as the initiation and progression of breast cancer.

Working on the theory that the key lay in the in vitro matrix where the mammary

Growing Human Breast Tissue in the Lab

glands were being grown, the researchers designed a hydrogel scaffold that closely mimics the extracellular matrix of the breast. When patient-derived primary human mammary cells were seeded in the new hydrogel matrix, the cells orga-nized themselves, grew, and differentiated into the ducts and lobes found in human breast tissue.

The hydrogel-based models also respond to steroid, pituitary, and lactogenic hormones that stimulate breast develop-ment. This breakthrough approach cre-ates a range of opportunities for modeling breast cancer development and testing treatments.

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Using a lightsheet microscope, this 360- degree imaging of human “mini-brains” shows smooth appearance of normal organoid (left) and surface folding in PTEN mutant organoid (right).

New Approaches, Fresh Insights on the Brain Understanding the specific processes underlying the development and function of brain neurons is essential for identifying treatments and preventive interventions for neurodevelopmental diseases. Researchers in the lab of Whitehead Institute Founding Member Rudolf Jaenisch are gaining fresh insights into normal and abnormal neurodevelopment.

One research group in Jaenisch’s lab has been exploring what drives the growth of the human cortex, which is likely the foundation for our unique intellectual abil-ities. To explore the question, the group grew 3D human cerebral organoids, or “mini-brains.” These lab-grown versions of specific human brain structures can model molecular, cellular, and anatomical processes of human brain development. The investigators used the mini-brains to study a specific genetic pathway that appears to regulate the growth, structure,

and organization of the human cortex. The approach itself was novel, as were two major findings. “Increased prolif-eration of neural progenitor cells (NPs) induces expansion of cortical tissue and cortical folding in the mini-brains,” says Yun Li, a postdoctoral researcher in the Jaenisch lab. “And deleting a specific gene—PTEN—allows increased growth factor signaling that unleashes cells’ growth potential and stimulates their proliferation.”

These findings support the notion that increases in the proliferative potential of NPs contributes to the expansion of the human cerebral neocortex and the emergence of surface folding. “Our observation is that PTEN-deleted NPs experienced more rounds of division and retained their progenitor state for an extended period, enabling the organoids to grow significantly larger, with sub-

stantially folded cortical tissue,” explains Julien Muffat, also a Jaenisch lab post-doctoral researcher.

Understanding the physiological alterations in brain circuits is another fundamental challenge that is key to finding the roots of neurodevelopmental disorders. To gain insight on the changes in brain circuitry underlying Rett syn-drome—an autism-like condition that causes visual impairment—another group in the Jaenisch lab conducted technically challenging in vivo recordings of both individual synapses and large groups of neurons in the visual cortex of mice with a Rett-causing mutation. The researchers found that the mutation affected both excitatory and inhibitory signaling, interfering with information processing through the neuronal circuit, and that the abnormal signaling ap-peared to cause the visual impairment typical in Rett patients.

There is a direct practical benefit to these findings. “Based on previous work with our colleagues at Massachusetts Institute of Technology (MIT), clinical trials have shown that a human growth factor has beneficial effects in treating Rett. This work helps to explain why there is therapeutic benefit and lays the foundation for more targeted use of growth factors and other treatments,” says Jaenisch, who is also a professor of biology at MIT.

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The Essential Role of Hydrogen PeroxideHydrogen peroxide does much more than bleach hair and disinfect wounds. In cells, it induces signaling related to aging and myriad chronic diseases. Under-standing how these hydrogen perox-ide-cued signals function could lead to new therapies for a variety of conditions.

In a major advance, Whitehead Institute scientists discovered that hydrogen peroxide triggers a distinct signaling cascade—the Syk pathway—that affects many cellular processes, including transcription, translation, metabolism, and the cell cycle. They also found that the mitochondrial respiratory chain activates the Syk pathway.

“Scientists may find this controversial. It’s long been thought that hydrogen peroxide’s effect was broad and non-spe-cific, and these findings go against that

established paradigm,” says Whitehead Institute Founding Member Harvey Lodish, who is also a professor of biology and of biological engineering at Massa-chusetts Institute of Technology. “But Heide Christine Patterson put all of the pieces together.” Patterson, a postdoc-toral researcher in the Lodish lab, led the pioneering research.

Life evolved to interpret levels of hydro-gen peroxide (and related compounds) as cues to cellular processes and re-sponses to environmental conditions. For example, increased cellular respiration generates an abundance of hydrogen peroxide in the mitochondria as a byproduct—which, in turn, triggers cell activation and differentiation. However, its actual mechanism of action was uncertain and over the years, scientists

suggested dozens of cellular targets as the potential initiator of signaling.

Patterson reasoned that the cellular responses to hydrogen peroxide are far too important to depend on processes so messy and radically different from other signal transduction cascades. Reviewing several neglected, decades-old studies implicating Syk in hydrogen peroxide signaling in chicken B cells, she intuited something important: Hydrogen peroxide signaling has many hallmarks of a traditional signal transduction cascade—with the distinction that the mitochon-drial respiratory chain triggers the signal.

Therefore, she undertook to block individual components of the pathway to show, step by step, how the signal catalyzed by hydrogen peroxide flows downstream from the respiratory chain

The process of “knocking out” individual genes to deter-

mine their effect is key to advancing biomedical research

on myriad fronts and has been supercharged by the

gene-editing tool CRISPR. Whitehead Institute Member

David Sabatini and his colleagues have used it to make

fundamental discoveries about the genetics of cancer and

the human immunodeficiency virus (HIV).

Knockout Genomics Cancer is a heterogeneous disease, with many distinct subtypes that differ in their genetic roots and their responses to therapeutic agents. The challenge for researchers is to precisely define those diverse roots and pinpoint vulnerabilities that may serve as targets for new treatments. Sabatini and Tim Wang, a doctor-al student in his lab, recently took an important step in that direction: They identified the genes required for cellular proliferation and survival in 14 human acute myeloid leukemia (AML) cell lines. Mapping those genes revealed liabilities related to the “Ras” oncogene, the most

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This microscope image of a B lymphocyte shows the location of the mitochondria (red) in relation to the nucleus (blue) and plasma membrane (green).

commonly mutated oncogene in human cancers, that could be exploited for new therapies for an array of cancers. “The mutant Ras protein itself has been considered ‘undruggable,’” Wang says. “There-fore, researchers have sought to find genes that Ras-mutant cancers rely on and see if they are druggable.”

That has been difficult—until Wang and Sabatini applied CRISPR in a nov-el way. “Our process rapidly enabled us to identify the short list of genes required in only Ras-mutant cells,” says Sabatini, who is also a professor of biology at Massachusetts Institute of Technology (MIT) and a Howard

Hughes Medical Institute investiga-tor. “We think this general approach can be applied to finding vulnerabili-ties in many cancers.” Indeed, Wang believes that they have just scratched the surface. “Broadly applied,” he says, “we could reveal a huge amount about the functional organization of genes in many diseases.”

In another project using CRISPR, the researchers—along with colleagues from the Ragon Institute of MGH, MIT and Harvard, and the Broad Institute of MIT and Harvard—iden-tified three promising, previously un-recognized targets for the treatment of human HIV infection. The targets

are genes essential for HIV infection but not for normal cellular survival.

HIV mutates rapidly and drug- resistant strains emerge frequent-ly. “But being able to target the few human genes involved in infection—out of a pool of more than 18,500 genes—offers the promise of treat-ments less susceptible to develop resistance,” says Sabatini, who is also a member of Broad Institute. And as with the process used to identify Ras liabilities, this new method can be used to identify therapeutic targets for other viruses and infec-tious diseases.

along the Syk pathway. In the process, she pinpointed the Syk pathway’s targets and the responses it controls, demonstrating that Syk pathway proteins are located together between the mitochondrial membranes within physical proximity to their activator, the respiratory chain. Notably, she also showed that the pathway is similarly important across different species and types of tissues.

“The one thing we haven’t yet pinpointed is hydrogen peroxide’s receptor,” says Patterson. “That’s the million-dollar question we are focusing on now.” But the answers she has already offered—and the potential long-term impact of her work—are invaluable.

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Of Flies and Forks

“We know that improper replication can lead to genome instability and changes in chromosome copy number, which is a marker in many kinds of cancer cells. Until now, however, we’ve not been able to directly observe the process,” says Whitehead Member Terry Orr-Weaver, who is also an American Cancer Society Research Professor of Biology at Massa-chusetts Institute of Technology. But a new approach developed in her lab—using both imaging and sequencing technologies—enables investigators to do just that and potentially learn a lot about cancer progression.

In testing the approach, the researchers used Drosophila, or fruit fly, ovarian follicle cells. Those cells’ tightly regulated replication process is ideal for identifying the sites of double-strand breaks, determining their likely cause, and observing mechanisms by which the cells attempt repair.

The replication process in those cells is facilitated by two-pronged structures

called “replication forks,” which move along the double-stranded DNA, un- winding it to create two single strands for copying. Scientists had previously surmised that double-strand breaks occur when replication forks collide. But until now, none had shown it. “Our new approach uses a combination of imaging and sequencing technologies that provides very high resolution,” says Jessi-ca Alexander, a graduate student in the Orr-Weaver lab. “It enables us to observe that the DNA breaks occur where replication forks stalled, almost certainly because of a collision.”

Alexander and Orr-Weaver have made two additional significant findings: First, that the double-strand breaks must be repaired for the forks to complete the replication process. And second, that these breaks are repaired through a process that is rapid, but prone to mistakes compared to a different process that takes longer but is known to be more accurate. Speed seems to be key; accuracy, less so.

Bringing new clarity to one cause of genomic damage, Whitehead Institute researchers have employed a novel approach to examining the double-strand breaks that occur during DNA replication and can create chromosomal abnormalities found in malignant cells.

“The fact that the repair pathway causes lots of mutations appears irrelevant, because Drosophila ovarian follicle cells drop away in the course of development and the mutations will not affect the organism,” Alexander notes. But cells with mutations are not necessarily lost in humans.

This new approach will enable research-ers to learn more about how other organisms’ cells repair double-strand breaks—and, sometimes, create cancer-causing mutations.

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Launching the Careers of Leaders

Whitehead Member Terry Orr- Weaver is widely respected for her research into the basic mechanisms of cell division. Less well known is that she also directs one of the most distinguished career develop-ment initiatives in biomedical research, the Whitehead Fellows Program. Since 1984, the program has launched the careers of brilliant young scientists destined to be visionary researchers and leaders. Its alums range from a NASA astronaut to an interna-tionally renowned cancer researcher at Massachusetts Institute of Technology (MIT) to the Dean of Harvard Medical School. In this Q&A, Orr-Weaver describes what makes the program and its participants so singular.

Paradigm: How does the Whitehead Fellows Program differ from traditional re-search positions after graduate school?

Terry Orr-Weaver: Traditional postdoctoral researchers are the backbone of biomedi-cal research institutions; we have scores of these smart, talented investigators working in Institute Members’ labs. By contrast, the Whitehead Fellows Program enables four extraordinary researchers to create and run their own labs, guided by their own ideas and objectives. They receive five years’ support to pursue their research as creatively as they dare. The Whitehead Fellows Program is unique, both in the support it provides for Fellows to launch bold, independent research programs, and in our Fellows’ subse-quent successes.

P: What distinguishes Whitehead Fellows as individuals?

TOW: They have achieved a very high level of scientific accomplishment and demon-strated two key qualities: the confidence to independently pursue questions that others dare not; and the capacity to solve major research problems. They have displayed uncommon leadership, vision, and commitment—and convinced us that they will help shape the future of biomedical research.

P: What kind of financial and technical support do the Fellows receive?

TOW: Fellows receive dedicated lab space and funds for equipment, lab operations, salary, and core staffing—plus access to Whitehead’s shared technical facilities. They also receive mentoring from our faculty, who serve as resources and actively integrate the Fellows into the Institute’s richly collaborative culture.

P: A program of this nature requires significant funding. How is it underwritten?

TOW: Whitehead’s endowment underwrites the program—but cannot expand its funding beyond the current level. The result is a good news/bad news situation. Good: these highly motivated and deeply creative scientists very quickly build research programs that outstrip the resources we provide. Bad: additional resources are hard to get, especially since most science-funding organizations tend to support established investigators or those on a traditional career track—not young Fellows doing high-risk/high-reward science.

But—more good news—individual donors are stepping forward. They want to support these future research pioneers and give them the resources necessary to fulfill their visions of discovery. I’m optimistic that donors will decide to endow the overall Fellows Program and create research seed funds for each Fellow.

P: How successful has the Whitehead Fellows Program been in fostering leaders?

TOW: There’s no single way to nurture scientific leaders, but Whitehead’s Fellows Program is a proven success. Former Whitehead Fellows are faculty at leading research universities across the country. Five former Fellows are Howard Hughes Medical Institute investigators, eight are members of the National Academy of Sciences (NAS) and/or the National Academy of Medicine, and five are recipients of the NAS Award in molecular biology. Their ranks include George Daley, dean of Harvard Medical School; Angelika Amon, MIT professor and cancer research superstar; Eric Lander, president and founding director of Broad Institute; Kate Rubins, NASA astronaut and space biologist; David Page, Whitehead Institute Director; and Peter Kim, former president of Merck Research Laboratories. It’s a track record we’re proud of—and that only gets richer.

BRANCHINGBy analyzing the biological mechanisms that plants use, Whitehead Members Mary Gehring and Jing-Ke Weng are gaining insights into how human cells function.

BRANCHINGOUT

capturing the power of plant biology

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It’s easy for nonsci-entists to overlook the mouse-ear cress, a nine-inch-high weed found mostly along road-sides and railways,

and in tilled land. An annual with a quick six-week life cycle, it has a rather imbal-anced look, with a rosette of leaves near its base, a few serrated leaves stepping up the stem, and a cluster of small, self-pollinating flowers at the top. It’s edible—related to the mustard plant, good in a salad or cooked—but few people bother to try it.

Humble the mouse-ear cress seems; even its genome is notably small. But it is, in reality, a botanical Clark Kent. Known by its scientific alter ego, Arabidopsis thali-ana, it is the Superman of plant biology research.

The first plant to have its genome sequenced, Arabidopsis is widely used to study plant genetics, evolution, development, and disease resistance. It has also become an important tool in the study of human biology. Over the decades, some of Whitehead Institute’s most notable bioscience discoveries grew from Arabidopsis seedlings.

Arabidopsis thaliana is the Superman of plant biology research.

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It’s easy for nonsci-entists to overlook the mouse-ear cress, a nine-inch-high weed found mostly along road-sides and railways,

and in tilled land. An annual with a quick six-week life cycle, it has a rather imbal-anced look, with a rosette of leaves near its base, a few serrated leaves stepping up the stem, and a cluster of small, self-pollinating flowers at the top. It’s edible—related to the mustard plant, good in a salad or cooked—but few people bother to try it.

Humble the mouse-ear cress seems; even its genome is notably small. But it is, in reality, a botanical Clark Kent. Known by its scientific alter ego, Arabidopsis thali-ana, it is the Superman of plant biology research.

The first plant to have its genome sequenced, Arabidopsis is widely used to study plant genetics, evolution, development, and disease resistance. It has also become an important tool in the study of human biology. Over the decades, some of Whitehead Institute’s most notable bioscience discoveries grew from Arabidopsis seedlings.

Arabidopsis thaliana is the Superman of plant biology research.

PARADIGM FALL 2017 13

Perched on the Institute’s roof, White-head’s greenhouse and plant lab form one of the technical core facilities available to all the Institute’s researchers. The 400- square-foot greenhouse holds 30 tiered growth shelves, each equipped with fluorescent fixtures that keep the space filled with light on even the cloudiest days. Every shelf is covered by trays holding dozens of small pots, each filled with a single plant. During the average day, four or five researchers will visit, checking on their plants’ status, watering and feeding as necessary. The lack of an automatic watering system is deliberate; it encour-ages researchers to interact directly with their plants on a regular basis.

A doorway through one of the green-house’s glass walls leads to the plant biology lab. There sit several large devices that from the outside look and sound much like industrial refrigerators. They are botanical growth chambers; and inside are bright, warm, carefully controlled environments with specific levels of light, temperature, and humidity. (Plants are very responsive to their environments, and certain experiments can be thrown off when growing condi-tions vary even slightly.)

Beyond the growth chambers stand two flow hoods that create sterile environ-ments for placing seeds on agar plates that are used for growing transgenic plants. There’s also a work area with several microscopes used for dissecting plants’ tiny organs—although some research daredevils with perfect eyesight do the work without magnification. The most sophisticated piece of equipment is the charge-coupled device camera; an extraordinarily sensitive device that operates at ultra-cool temperatures, it tracks the expression of specific plant genes that carry luminescent tags. And then, of course, there’s the “dirt room,” where just the right balance of organic materials and nutrients is mixed into the standard growing medium.

Arabidopsis is by far the most prevalent species growing in the greenhouse and growth chambers; and what look like many different kinds of plants are actually genetically mutated generations of that one plant type. It was the Arabidopsis grown in the Institute greenhouse that helped lure Mary Gehring to become a Member of Whitehead Institute in 2010. “I was excited by Whitehead’s history of significant accomplishment generally, and with plant models specifically. But, knowing I’d be the first plant biologist on the faculty, I did wonder, ‘Where will I grow plants in the middle of downtown Cambridge?’” she recalls with a chuckle. “Seeing the wonderful greenhouse sealed the deal for me.”

Gehring studies plant development and epigenetic reprogramming—changes in gene expression caused by mechanisms other than DNA mutations. She uses Arabidopsis in her research because many of the drivers of epigenomic change in the plant are at work in other species, including mammals. Epigenetic processes

appear to be important to the success of later generations of Arabidopsis—and Gehring believes they will also prove relevant for human biology and the development of human disease.

One way that gene expression can be controlled is through the addition of a molecule called a methyl group to cytosine, one of the four bases of DNA. When a section of DNA is thus “methyl-ated,” it changes the instructions a gene gives to the cell; often the gene is wholly silenced (although Gehring is discovering intriguing exceptions to this rule). In Arabidopsis and other plants, methylation is reversible and changes throughout the life cycle. Gehring is particularly interest-ed in how the methylation state changes during plant reproduction, from the point where reproductive cells develop through to seed maturation. DNA demethylation is essential for seed development: mutate one of the DNA demethylase genes and the plants grow normal-looking leaves and flowers, but not viable seeds.

Cockscomb (Celosia argentea) is among the plants that can be found in the greenhouse.

Arabidopsis thaliana is the Superman of plant biology research.

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During normal seed development, the expression of some genes is imprinted—meaning that the two copies of a gene are expressed differently depending on which parent they were inherited from; some are expressed only from the maternal copy, while the paternal copy is silenced, and the reverse can also be true. Gene imprinting isn’t restricted to plants. It occurs during mammalian fetal develop-ment too—and when it is disrupted, it can cause disease. In both plants and mam-mals, imprinted expression is controlled by differences in methyl marks between the two copies of a gene. Mutating the DNA demethylase abolishes the estab-lishment of imprinted expression. Gehring studies how imprinted genes function during seed development and are marked as imprinted, what changes are wrought by methylation or demethylation, and whether specific effects on individual genes are retained through subsequent generations of a plant.

“In plants, methylation patterns can be passed from one cell generation to the next and from one plant to its offspring,” she explains. “Unlike animals, which designate reproductive cells early in embryo development, plants form

reproductive cells as adults—which means that methylation changes accrued during a lifetime could be passed to the plant’s progeny.”

By studying the epigenetic profile of multiple generations of both wild-type plants and those with altered methylation, Gehring seeks to learn whether accrued epigenetic changes can ultimately lead to evolutionary changes. Recently, her lab has found that while disrupting the balance between methylation and demethylation can initially affect the entire genome, over multiple generations the epigenome seems, to a large extent, to repair itself. This suggests that plants have several backup mechanisms to maintain a stable epigenome even in the face of major insults. Part of Gehring’s lab is now focused on discovering what these backup mechanisms are. Her unique approaches to epigenetics have earned her wide acclaim, including being selected as a Pew Scholar in Biomedical Sciences and being given the Rosalind Franklin Young Investigator Award (jointly admin-istered by the Gruber Foundation, the Genetics Society of America, and the American Society of Human Genetics).

“Plants are amazingly plastic in their responses to the environment and they can tolerate lots of biochemical insults and gene mutations,” Gehring observes. “Alter methylation in a plant and in many instances it will survive; make the same change in a mouse and it dies quickly. This means that plants like Arabidopsis offer a great experimental system for dissecting the function of dynamic DNA methylation changes during development.”

And, she suggests, “Answering funda-mental questions about DNA methylation in plants may offer wholly new ways to address human disease.”

DEEP ROOTS

On Gehring’s arrival in 2010, Whitehead Institute Director David Page said her appointment “represents a welcome return to Whitehead Institute’s roots in plant biology.” It was a well-chosen pun because for two decades Whitehead was a fertile source of Arabidopsis- based discovery.

Founding Member and former Institute Director Gerry Fink is renowned for his development of common baker’s yeast as a model organism to explore critical

Answering fundamental questions about DNA methylation in plants may offer wholly new ways to address human disease.

PARADIGM FALL 2017 15

pathways in cell growth and metabolism. He also played an instrumental role in introducing Arabidopsis as a model organ-ism for studying plant development. “Over the last 25 years,” Fink notes, “science has learned more about Arabidopsis than any other plant. This fundamental knowledge offers hope that we will be able to in-crease the yield of our food crops in the face of a rapidly changing environment.” Fink’s lab used Arabidopsis, for example, to identify a key mechanism of hormone signaling, and to uncover mutants that enable plants to be grown in water as salty as seawater. In 1998, he and his colleagues characterized an Arabidopsis gene—Ethylene Insensitive Root 1 (EIR1)—that plays a critical role in the ability of roots to grow toward the earth in re-sponse to gravity. Roots of mutant weeds lacking EIR1 lose their ability to respond to gravity and to grow downward into the soil. The findings provided insights into age-old mysteries about root growth and have had tremendous implications for the agricultural industry.

In the early 2000s, Whitehead Institute Member David Bartel and the researchers in his lab used Arabidopsis samples to discover that plants have microRNAs,

which are tiny ribonucleic acids (RNAs) that regulate the expression of pro-tein-coding genes in cells. The Bartel lab was also among those to find that humans and other animals each have hundreds of microRNAs, implying that many different genes are regulated by these tiny RNAs—although, at the time, very few of these regulatory targets were known. In their analysis of the plant microRNAs, the Bartel lab identified 50 regulatory targets, which greatly outnum-bered the three that had been identified in animals. This breakthrough provided many new opportunities to study micro- RNA function, and within the next 18 months the Bartel lab had four members working in the greenhouse full time, discovering essential roles for microRNAs in directing the development of plant embryos, leaves, and flowers. They also discovered many additional microRNAs and regulatory targets in Arabidopsis and

developed reliable methods to identify genes regulated by the microRNAs of humans and other animals. Among other findings, their analyses indicated that well over a third of human protein-coding genes are targets of microRNAs, and that microRNAs also influence the expression or evolution of a large majority of the mammalian messenger RNAs.

The late Whitehead Member and former director Susan Lindquist used Arabidopsis as an important model in pioneering studies on the role of heat shock protein 90 (Hsp90) in facilitating proper protein folding. In the early 2000s, her lab suggested that Hsp90 served as a genetic buffer, keeping many naturally occurring mutations dormant and allowing them to accumulate without having an effect. Indeed, subsequent studies in the Lindquist lab found that when environ-mental stresses compromise the ability of

Answering fundamental questions about DNA methylation in plants may offer wholly new ways to address human disease.

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Early plants began colonizing earth approximately 450 million years ago. “To survive since then in challenging and evolving ter-restrial environments,” explains Whitehead Member Jing-Ke Weng, who is also a professor of biology at Massachusetts Insti-tute of Technology, “plants’ met-abolic systems produced a pano-ply of natural chemicals that enabled them to adapt to the tremendous change taking place—chemicals that attract pollinators and seed dispersers, for example, or that deter patho-gens and herbivores. Ultimately, these metabolic products led to the diversity of plant ecosystems that form the base of the global food chain today.” His research teases apart the specific chemi-cal steps of the evolution of those complex metabolic traits. “When we understand them,” he says, “we will be able to make use of them in myriad important ways.”

Hsp90 to fold its critical target proteins, the mutations manifest an effect. While most mutations are harmful, a few produce valuable traits, thereby spurring evolution. Further work on Arabidopsis more clearly demonstrated the effects of lowering Hsp90 function: Plants exposed to environmental stresses that undercut Hsp90’s effective-ness produced an array of previously hidden genetic mutations, often differing even among genetically identical plants. Examples include leaf shape, increased length of stem and root, delayed flowering, pigmenta-tion, and hairy roots—and these variations persisted in the plants’ offspring. “One of the great mysteries of biology is how life could have evolved so rapidly,” Lindquist observed when a key study was pub-lished. “This research gives at least one plausible explanation for the speed of evolution and for the evolution of complex traits affected by several genes.”

In a report published this spring, Lindquist lab researchers showed that the mutation-buffering effect of Hsp90 studied in Arabidopsis can also be observed in diseased human cells—notably including those with the cancer-predisposing syndrome Fanconi anemia. In the long run, this basic knowledge may help clinicians predict who is at risk to develop a disease and who is most likely to respond well to specific treatment approaches.

ANCIENT CURES AND ILLUMINATING TREES

In 2013, Whitehead Institute added to its complement of dedicated plant biologists on the faculty with the appointment of Jing-Ke Weng, whose research focuses on plant metabolism and its link to complex disease biology. Weng’s studies have far-reaching implications for how we use plants—in both science and our daily lives—and for under-standing and treating complex human diseases ranging from diabetes to neurodegeneration.

“Jing-Ke is a prime example of an accomplished young Whitehead Institute scientist who pioneers new realms of bioscience inquiry and experimentation,” says Page. “In more colloquial terms, investigators like Jing-Ke Weng and Mary Gehring are helping to make plant biology hot again as a realm of bioscience research.”

Weng often uses Arabidopsis and other model systems. But one of his lab’s key thrusts is developing the tools to make use of nonmodel systems—that is, most of the earth’s flora and fauna—to better understand their metabolic processes and observe the effects of their metabolites. “Currently, there is no simple way to watch the processes occurring in nonmodel species,” Weng notes, “which means it’s challenging to compare two similar traits—for example, comparing Arabidopsis pigmentation with how and why pigmentation developed as a survival trait in other plant or animals.” As a result, researchers can’t currently access the vast numbers of plant and animal metabolic processes that have potentially important uses for medicine, agricul-ture, or energy generation. Weng’s lab is addressing that problem through what he calls a “multi-omics” approach: harnessing

PARADIGM FALL 2017 17

systems-level information on genes, proteins, and metabolites, and using their evolutionary histories to decode unknown molecular mechanisms—such as how plants manufacture medicinal natural products and how these products interact with the human body to arrive at specific therapeutic effects.

Since joining the Institute, Weng has been applying this multi-omics approach in novel ways, including connecting basic research in plants to practical therapeu-tics for human disease. For example, he is delving deeply into the biochemistry of botanicals that have been used medicinal-ly for thousands of years. One such study focuses on the medicinal plant goat’s rue (Galega officinalis), used since medieval times to treat symptoms that, we recog-nize today, result from diabetes. Weng has found that goat’s rue metabolizes the molecule galegine, which shares bio-chemical properties with the modern diabetes drug metformin. “Researchers don’t yet understand exactly how met-formin controls blood glucose levels,” Weng notes. “But if we can understand how and why a plant makes galegine, we may be able to determine the therapeutic mechanisms underlying both the modern drug and its ancient precursor—and learn how to use each for more effective treatments.”

Weng’s quest to open whole new realms of biomedical research through under-standing and taming plant chemistry stirs great hopes about long-term drug development for treating human diseases. But the potential of his work is not limited to medicine. His lab has also been studying bioluminescence in fungi, insects, and ocean life, which converge on a striking underlying mechanism among the 20-some species known to have bioluminescent capabilities: All create light using the enzyme luciferase to oxidize a specialized chemical (luciferin). Perhaps more fascinating, Weng says, “In each of these species, from fireflies to jelly fish, the metabolites have a unique molecular structure. No two are the same, and each developed along a completely different evolutionary path.”

More intriguing still are the ways Weng’s discoveries on bioluminescence could be used—ranging from noninvasively tracking the effects of cancer treatments to creating luminescing plants. “Imagine being able to gene-edit a line of trees, bushes, and houseplants that light up in the dark and go dark during the day,” Weng muses. “How much energy could be saved in industrialized countries by replacing streetlights and porch lights with luminescent trees and bushes? In less-developed countries where electric generation and distribution is limited, how

many more people could read at night with luminescent plants? It’s not science fiction—we know the science and have the necessary gene-editing capacities. We just have to make it happen.”

Weng’s scientific rallying cry—just like Gehring’s fundamentally important observation on plants’ amazing plasticity in response to the environment—reminds us that the raw materials of innovation are all around us, ready to improve people’s lives, if only we can learn nature’s recipes. As Whitehead scientists’ work makes clear, even an unremarkable weed growing by the roadside can drive pio-neering discoveries. And the glass panes of a small rooftop greenhouse can be lenses on a future illuminated by new knowledge.

Institute Member Weng uses Arabidopsis thaliana and other model plant systems that are grown in Whitehead’s greenhouse.

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Metabolomics

Whitehead Member David Sabatini guided the establishment of one of Whitehead’s newest scientific resources — the Metabolite Profiling Core Facility.

PARADIGM FALL 2017 19

A New Lens on the CHEMISTRY OF LIFE

Metabolomics

A few years ago, Dohoon Kim was investigating two genes key to the survival of glio-blastoma, the most common and aggressive human brain tumor. The vast majority of primary malignant brain tumors are gliomas and, because their cells are very resistant to conventional therapies, patient survival rates are low.

Glioblastoma cells proliferate, in part, by altering their metabolism, and Kim determined that the two particular genes formed a co- dependent metabolic relationship. Inhibiting one gene could cause a toxic accumulation of the protein expressed by the other gene—killing the glioblastoma cells.

Kim, then a postdoctoral researcher at Whitehead Institute and now a faculty member at University of Massachusetts Medical School, wondered whether this phenomenon might be a key to glioblastoma’s undoing. But testing this hypothesis—and then identifying the mechanisms underpinning the results—would require large-scale, systematic, cellular metabolic analysis.

Kim was the latest in a growing number of Whitehead researchers wanting to dive deeply into the field of metabolomics. The study of small molecule metabolites that result from chemical reactions within biological systems (such as the human body), metabolomics is one of the “omics” fields that have become central to biomedical research—including genomics, proteomics, transcriptomics, and microbiomics. Kim’s glioblastoma investigations were part of an expanding need for sophisticated metabolomic analyses for Institute researchers, and for the broader Massachusetts biomedical research community.

Responding to the growing demand, Whitehead established the Metabolite Profiling Core Facility in 2013. Whitehead Member David Sabatini guided its creation with the assistance of two colleagues: Michael Pacold, then a senior scientist in the Sabatini lab and now an assistant professor of radiation oncology at New York University; and Eric Spooner, manager of Whitehead’s Proteomics Core Facility, who had deep experience with mass spectrometry. Elizaveta Freinkman, a Sabatini lab postdoctoral researcher who had developed strong interest in the field, became the Metabolite Profiling Core Facility’s first director and is credited with turning it into a highly effective research platform. She was succeeded in 2016 by Caroline Lewis, who had completed a postdoctoral fellowship in cancer metabolism at the Koch Institute for Integrative Cancer Research at MIT.

During the past four years, the Metabolite Profiling Core Facility has both met a need and been a catalyst for extensive new work in a burgeoning field. Indeed, it is helping to define the field of metabolomics.

20 PARADIGM FALL 2017

A highly technical process, metabolomics is part science and part art. Unlike genomics, which analyzes the handful of uniform bases of DNA and RNA, metabo-lomics measures chemical products that can vary widely—ranging, for example, from water-soluble compounds like lactic acid to water-insoluble compounds like triglycerides—which complicates the identifica- tion process. Then there’s the question of how many metabolites exist: In 2007, the Human Metabolome Project identified 2,500 metabolites; the current Human Metabolome Database (Version 3.6) lists 42,032 endogenous human metabolites; and some experts suggest that the number of metabolites produced in the human body could be much larger. Finally, there is the challenge of understanding the chang-ing role that individual metabolites play from one tissue type to another.

Metabolism is the sum of life-sustaining chemical reactions occurring at the cellular and organismal levels. These reactions include breaking down food to release energy, converting food to the building blocks needed by cells, and eliminating waste. To keep these processes in balance, cells and organisms tweak their metabolic reactions in response to disease and envi-ronmental changes.

That disease alters metabolism has been known implicitly for millennia. Around 1500 BCE, Chinese doctors used ants to test for high sugar content in patients’ urine, which is now recognized as a symptom of diabetes. Today, we know that the human genome codes for about 2000 metabolic enzymes, and specific metabolic pathways play a significant role in a range of biological pro-cesses—from normal proliferation of cells and the differentiation of stem cells, to pathologies underlying diabetes and hyper-growth of cancer cells.

The identification and study of metabolites have also advanced from a reliance on ants: Researchers now use analytical chemistry to separate and detect compounds. The most widely employed approach to metabolite profiling combines liquid chromatography with mass spectrometry. In that process, a biological sample is loaded into the chromatography unit, where the metabolites are carried by liquid solvents through a column of porous material. The nature of the column and of the solvents is chosen based on the desired metabolites’ chemical properties, including polarity, charge, and size. As the metabolites pass through the column, these properties deter-mine how strongly they are attracted to the column material, changing the speed with which they move through the column.

Once the metabolite passes through the column it is injected into a mass spectrometer, where it is ionized, giving it either a positive or negative charge, and the relative intensity of its mass-to-charge ratio is measured. Together with a library of several hundred known standards, the combination of exact mass and chromatographic separation over time permits the posi-tive identification of most common cellular metabolites.

Technological improvements have enabled researchers to identify many new metabolites—and have simultaneously created the analytic challenge of characterizing the relevance of each. “The ability to detect thousands of small molecule metabolites is no longer the limiting factor,” Lewis explains. “Instead, researchers are struggling with how to simultaneously identify and analyze these thousands of metabolites across hundreds of samples.”

A dearth of effective software for this process requires researchers to rely on a combination of automated, software-driven data analysis and manual checking, which requires time and expertise. The direct, hands-on approach offered by the facility is key. “You can’t study metabolism indirectly,” ob-serves Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology. “You have to measure the metabolites made by the specific enzymes of interest.

“Nor can an investigator just send a sample to a commercial lab for a generic test that can be expected to yield useful data. It’s essential to be able to work directly and iteratively with a specialist—a real scientist—who understands

PARADIGM FALL 2017 21

precisely what you want to investigate and can suggest specific experiments that get the particular data you’re looking for.”

Lewis both manages the facility and consults with researchers on how best to design their studies and develop sam-ples for analysis. She collaborates with two highly trained technicians—Tenzin Kunchok and Bena Chan, who perform data analysis, sample preparation, and the day-to-day operation and fine-tuning of the very sensitive liquid chromatogra-phy/mass spectrometry (LCMS) sys-tems. Regular fine-tuning is a necessity: The facility’s two LCMS systems run day and night, processing up to 192 samples every 24 hours.

During the last four years, they have sup-ported more than 159 individual research projects, and demand is steadily increas-ing. The Institute is considering a third LCMS, a purchase that would cost close to $750,000, when all is said and done.

“The Metabolite Profiling Core Facility has been—and will continue to be—a significant investment. But having that capacity at our fingertips has been game changing,” says Sabatini. “Twenty years ago, metabolites were measured one or two at a time. Now we can measure hun-dreds, investigate metabolism in individ-ual cellular spaces, and assess metabolic processes at any particular moment of cellular activity.” In fact, investigators’

metabolomic reach exceeds their grasp; they can measure the signals of metab-olites which have no known function. “But knowing they exist is the precursor to learning their relevance,” Sabatini observes.

The Metabolite Profiling Core Facility has enabled researchers to more effectively explore a broad spectrum of topics, from characterizing drug pharmacokinetics to tracking the general metabolic im-pact of individual enzymes, to observing the effects of specific diets on overall metabolism. It has also shed light on the metabolic effects of viral infection and aging, and on how cancer cell metabo-lism differs from that of normal cells.

Caroline Lewis (center), director of the Metabolite Profiling Core Facility, and technicians Bena Chan (right) and Tenzin Kunchok (left) assist scientists from Whitehead and the greater Boston scientific community design experiments and develop samples for analysis.

22 PARADIGM FALL 2017

Increasingly, the facility is also key to the development of new research tools and techniques. For example, investigators in Sabatini’s lab wanted to better understand the metabolic function of the mitochondria; so, they developed an elegant new method to extract intact mitochondria from cells so that their metabolites could be measured. But the approach was useful only because the metabolomics facility existed to analyze the extracted material. The facility was also indispensable to Sabatini lab researchers who—to demonstrate that a cell’s environment is an important determinant for its metabolic function—developed a culture medium containing polar metabolites at concentrations found in human plasma. This new medium may offer an important alternative for many kinds of cell culture experiments in the future.

Most metabolomics research focuses on basic biochemical mecha-nisms, yielding incremental discoveries and new methods, like those from Sabatini’s lab, that have practical benefit over the long-term. Those gains add up and are themselves worth the investment that goes into creating a state-of-the-art metabolomics facility. But, not infrequently, a discovery can provide a significant leap forward with clear, practical value. For example, metabolomic analysis has identified an amino acid that, when elevated, can be a preclinical marker of pancreatic cancer. Because the disease is generally diagnosed too late to be effectively treated, a metabolomics-based early diagnostic could have major benefit for patients. Metabolomic analysis has also identified a meta- bolite that results from the expression of a gain-of-function mutation associated with certain blood and brain cancers; monitoring that metabolite is a good way of knowing if patients are responding to thera-pies meant to inhibit the expression of the cancer-causing enzyme.

The glioblastoma work being done by Dohoon Kim could prove to be another such practical advance, as metabolomic analysis has initially borne out his hypothesis on the metabolic codependency of two en-zymes that support glioma tumors. “The beauty of metabolomics is the breadth of insights it can provide, at levels ranging from small organelles to entire bodies, and on every organ and tissue type,” Sabatini observes.

The benefits—short and long-term—of Whitehead Institute’s invest-ment in the Metabolomic Profiling Core Facility become clearer each day. It’s the kind of high-risk, high-reward venture that enables both new and well-established researchers to continue pushing back the frontiers of biomedical knowledge and shedding fresh light on the mysteries of life.

PARADIGM FALL 2017 23

Be a smart philanthropist

Give through your IRA

“I admire Whitehead Institute’s achievements in

biomedical research, and I feel a strong desire

to help secure its future. I’ve named Whitehead

Institute as a beneficiary of my IRA. It will receive a

portion of my IRA funds when I die, and not a cent

will go to taxes.” —Jerome Link

There are two smart ways to use your IRA to make tax-free gifts supporting science at Whitehead.

Fund a bequest with your IRA or other qualified retirement plan like a 401k or Keogh. Naming Whitehead Institute as a beneficiary of your retirement accounts allows you to control your assets during your life, and then pass them on free of estate and income tax at your death.

Make an outright gift from your IRA or Roth IRA. Transferring a gift of up to $100,000 from your IRA allows you to see your philanthropy at work right away, without those distributions counting as income.

There are guidelines and restrictions on these kinds of gifts. We can provide the right language to use and walk you through the steps to implement these gifts.

To discuss how to use IRAs and other estate planning vehicles to achieve your philanthropic goals, contact Sharon Stanczak, Vice President of Institutional Advancement, at [email protected] or 617-258-5103.

Photo: David C. Page (left) with Jerome Link

24 PARADIGM FALL 2017

When the widely respected Whitehead Institute Member Susan L. Lindquist died last October, she left a legacy of soaring scientific accomplishment and deep personal commitment. She changed how scientists viewed the role of cellular proteins in hu-man health, evolution, and biomaterials. And she was a leader who, through the example of her career and through her personal en-gagement, fostered the careers of women determined to fulfill their potential as scientists.

In order to honor Lindquist, Johnson & Johnson has endowed the Susan Lindquist Chair for Women in Science at Whitehead Institute, to be awarded to a distinguished female scientist who is advancing biomedical research. In addition to serving as a Member of Whitehead Institute and a professor of biology at Massachusetts Institute of Technology, Lindquist was a member of the Johnson & Johnson Board of Directors from 2004, serving as Chairman of its Science, Technology, and Sustainability Committee, and she was also a member of its Regulatory, Compliance, and Government Affairs Committee.

“Sue was a prolific scientific pioneer who changed fundamental understanding of the biology of human health. As part of the Johnson & Johnson Board of Directors, she challenged us to use science and technology in new ways to help improve the health and

Johnson & Johnson Endows Chair Honoring Susan Lindquist

Former Whitehead Institute Director and Member Susan Lindquist was one of the nation’s most lauded scientists.

COMMUNITY NEWS

lives of people all around the world,” says Alex Gorsky, Chairman and Chief Execu-tive Officer of Johnson & Johnson. “We are pleased to establish this Chair in Sue’s name, recognizing a greatly respected and beloved scientist and a passionate advocate for women in science.”

The Chair will be held by a female White-head Institute Member, whose title would be the Susan Lindquist Professor for Women in Science. “The title’s phrasing— ‘for women in science’—was specifically chosen by Sue and endorsed by White-head Institute leadership,” explains Whitehead Institute Director David Page. “It is deliberately open-ended and consciously provocative. We want incumbents to have great flexibility in how they pursue Sue’s legacy of stellar science and courageous leadership. We hope it spurs discussion in the broader science community.”

“Susan was a force of nature and a force for good,” reflects Cori Bargmann, President of Science for the Chan Zuckerberg Initiative and a professor at The Rockefeller University. “The beauty of her own scientific trajectory shows how depth and focus lead to advances. First asking how chaperones help proteins fold, then learning how misfold-ed yeast proteins propagate across generations, then using that knowledge to probe protein misfolding in human neurodegenerative diseases.”

Endowed, named chairs are important to Whitehead Institute. They create a lasting legacy for the donor and the many distinguished scientists who will be chair holders. They also strengthen Whitehead Institute’s endowment, the financial bedrock that enables its pursuit of the most innovative basic research.

PARADIGM FALL 2017 25

When Sebastian Lourido was an under- graduate at Tulane University in the early 2000s, he was of two minds: one artistic and the other scientific. “I was a visual artist—a painter and printmaker—who was fascinated by the systems and structures that make up biological life,” he recalls. “For a while, these seemed like divergent paths. But the more science I learned, the more I realized that a career as a research scientist offered much of the creativity I had sought through the arts.”

That merging of the technical with the creative has brought Lourido to a unique place: the faculty of Whitehead Institute. Lourido is only the 28th person ever to be named to the Whitehead Institute faculty, and he becomes one of 16 cur-rent Members. He is very familiar with the Whitehead Institute community; since 2012, he has been a Whitehead Fellow, which allowed him to establish his own lab and pursue an independent research program in lieu of traditional postdoctoral training in a senior scientist’s lab.

Sebastian Lourido Appointed as Whitehead Institute Member

“We are absolutely delighted that Sebastian will continue to be part of our community, now as a Member of the faculty,” says Whitehead Institute Direc-tor David Page. “His formidable talents as an investigator, scientific leader, and research colleague are matched by his skills as a writer, teacher, and explicator of science. And his innate creativity is an essential part of his special capacity as a researcher and communicator.

“We believe that Sebastian’s work—un-covering fundamental processes behind some of the most ubiquitous and lethal infections burdening global health—will substantially broaden and deepen White-head Institute’s worldwide impact.”

Reflecting on his appointment, Lourido said, “As a Whitehead Fellow, I have experienced firsthand the extraordinary intellectual community that has made the Institute a powerhouse of innovation for more than three decades. It is an honor and an extraordinary opportunity to become a Member of this scientifi-cally dynamic and personally nurturing organization.”

Concurrent with his Whitehead Institute appointment, Lourido has been named Assistant Professor of Biology at the Massachusetts Institute of Technology.

Lourido received the NIH Director’s Early Independence Award in 2013, which recognizes the work of highly regarded early-career investigators. The award was accompanied by a five-year grant to study signaling pathways involved in regulating motility in Toxoplasma gondii, a parasite that infects an estimated 25 percent of the world’s population and can cause se-rious disease in pregnant women, infants, and immunocompromised patients.

“I am very interested in the adaptive capability that allows T. gondii to invade

Sebastian Lourido studies Toxoplasma gondii, a common single-celled parasite that can cause serious disease in pregnant women, infants, and immunocompromised patients.

and establish a replicative niche within host cells,” Lourido says. “To under-stand this ability, we performed the first genome-wide functional analysis of an apicomplexan—that is, a single-celled parasite—revealing the genes needed to infect human cells. We have also teased apart the structure of enzymes vital to the infectious process, identifying a potentially ‘druggable’ target that could prevent parasites from entering and exiting host cells.”

For Lourido, this work is both technical and creative, enabling him to bring to bear the full range of his skills, knowl-edge, and talent to understanding and illustrating the complex beauty of life on earth.

David Sabatini Elected to NAS

The National Academy of Sciences has elected Whitehead Institute’s David Sabatini as a member in recognition of his distinguished and continuing achieve-ments in original research. Sabatini’s election occurred during the Academy’s 153rd annual meeting. Established in 1863 by a congressional act of incorporation, the National Academy of Sciences is a private organization of scientists and engineers that acts as an official adviser

26 PARADIGM FALL 2017

Olivia Corradin is unraveling the role noncoding DNA variants play in defining human disease susceptibility.

With a father in sales, a mother in dentistry, and siblings into computer networking, architecture, and dance, how did Olivia Corradin find her way to basic science research?

“My parents said, ‘Do what you love and do it well,’ and my mother described me as having insatiable curiosity,” says Corradin, Whitehead Institute Fellow. But, growing up in Muskegon, Michigan, she couldn’t have known that combining the advice and the trait would lead her into curiosity-driven research. In fact, throughout high school, she pursued both her passions—dance and science—and planned to do the same at Marquette University.

But, she needed a reality check on whether her love for science would endure; so the evening before moving into her college dorm, she got a job in a lab on campus. It was an unqualified success. “I declared my biochemistry major the first week there,” she recalls. She also devoted at least 20 hours a week to teaching choreography and dance in a local studio. The combination proved highly effective: ballet, jazz, and hip hop provided a cre-ative outlet that often opened her mind to very productive scientific thinking.

During her graduate studies at Case Western Reserve University, Corradin began probing how noncoding regions of the genome—once erroneously referred to as “junk DNA”— affect gene expression, exploring how variants in these regions contribute to disease. She developed computational tools to predict the gene targets of enhancer elements and examined the effects of combined DNA variants on human diseases. As she approached completing of her PhD in genetics and genome sciences, she considered her next step. She worried that a traditional postdoctoral position might require shifting her research focus, which she was loathe to do. Her advisers suggested programs where she could es-tablish her own laboratory and research plan—such as the highly selective early indepen-dence programs at University of California San Francisco, Cold Spring Harbor Laboratory, and Whitehead Institute.

And here she is, serving as the first Scott Cook and Signe Ostby Fellow and investigating the role of noncoding DNA variants in opioid addiction and autoimmune disorders. Yes, there’s much less time for dance; she’s happy nonetheless.

Fellow Olivia Corradin Choreographs a Career in Science

to the federal government on matters of science and technology. Election to its ranks is among the highest honors accorded to United States scientists.

A pioneer in the study of the key cellular regulatory metabolic pathway known as mTOR (for mechanistic target of rapa-mycin), Sabatini has been discerning the individual roles mTOR’s protein compo-nents play in diseases such as cancer and diabetes, and in the aging process. Appointed a Whitehead Fellow in 1997 after completing the MD/PhD program at Johns Hopkins University School of Medicine, Sabatini was named a Member in 2002. He is also a professor of biology at Massachusetts Institute of Technology and an investigator of the Howard Hughes Medical Institute. Among Sabatini’s many honors are the Paul Marks Prize for Can-cer Research and the National Academy of Sciences Award in Molecular Biology.

Sabatini becomes the ninth current Whitehead Member elected to the National Academy of Sciences—along with David Bartel, Gerald Fink, Rudolf Jaenisch, Harvey Lodish, Terry Orr- Weaver, David Page, Robert Weinberg, and Richard Young.

PARADIGM FALL 2017 27

WhiteheadCONNECTSBridging Biopharma and the Life SciencesIt began with a seemingly simple question: “How can we provide the Whitehead Insti-tute community with an insider’s view on the relationship between academic science and industry?”

While such a glimpse would surely be interesting to a variety of the Institute’s con-stituencies, for Whitehead’s graduate students and postdoctoral researchers, it could have important career implications. Facing a future likely to be marked by constrained federal funding for biomedical research and far more PhD scientists than tenure-track faculty positions, many young scientists are apt to look to industry for a return on their enormous personal investments in the life sciences.

Thus was born Whitehead Connects, a program that brings renowned biology, bio-technology, and life sciences leaders to Whitehead Institute to share lessons learned from careers spanning academic and commercial realms. At the inaugural session, Joan Brugge, then chair of the department of cell biology at Harvard Medical School and a member of the scientific advisory boards of eFFECTOR Therapeutics and Agios Pharmaceuticals, addressed a crowd of more than 100. She spoke of her early-career stint as scientific director of ARIAD Pharmaceuticals, and of the importance of identi-fying potential collaborators and nurturing successful partnerships. Following her talk, Brugge joined a group of Whitehead postdocs and other attendees for a networking reception.

The kickoff was such a success that a second event followed just a few months later, and Whitehead Connects officially became a series.

Whitehead Connects prompts an engaging discussion between Deval Patrick, former Massachu-setts Governor and a member of Whitehead’s board of directors, and Jasmine DeCock, a former graduate student in Robert Weinberg’s lab.

The roster of participants has been stellar, including:

• Harvard Business School professor and former Vertex Pharmaceuticals president Vicki Sato, who discussed the experience of moving science from “.edu to .com.”

• Former Cubist Pharmaceuticals CEO and current Institute Board of Directors member Mike Bonney, who spoke on the intersection of science and policy in the battle against “superbugs.”

• Arsia Therapeutics CEO, Polaris Part-ners venture partner, and current Insti-tute Board of Directors member, Amy Schulman, who shared lessons from a vibrant career spanning global pharma and biotech startups.

• Former Massachusetts Governor and Whitehead Board of Directors member Deval Patrick, who discussed the goals and achievements of his administra-tion’s billion-dollar investment in the state’s life sciences infrastructure.

• Amgen Chairman and CEO Robert Bradway shared his thoughts on the role of biology and basic science in improving human health in the 21st century.

• Noubar Afeyan, founder, senior man-aging partner, and CEO of Flagship Ventures, spoke about his path to be-coming founder and CEO of a scientific innovation firm and shared tips for how to succeed in an evolving industry.

28 PARADIGM FALL 2017

Nurturing Science’s FutureFostering the next generation of biomedical pioneers and innovators is central to Whitehead Institute’s mission. Each Member’s lab includes talented and highly motivated undergraduate and graduate students and postdoctoral researchers who participate in research projects. Often, the students pursue investigations of their own design—independent studies that can lead to path-breaking discov-eries and technological innovations.

That is the case with Rhogerry “Gerry” Deshycka, a recent graduate of the Massachusetts Institute of Technology (MIT) who worked in Founding Member Harvey Lodish’s lab throughout his undergraduate years. This spring, Deshycka received two MIT prizes for outstanding undergraduate research in life sciences and bioengineering. “Gerry has enormous potential to develop into a top research scientist,” says Lodish. Indeed, he has already created what could be a revolutionary new approach to cholesterol reduction.

Initially working on a red blood cell-based method for binding “bad” LDL choles-terol to eliminate it from the bloodstream, Deshycka quickly intuited that it would not be effective. So, he independently conceived a different approach—a complex process that effectively enabled liver cells and other cell types to absorb larger amounts of circulating LDL cholesterol and degrade it through natural cellular processes. Working patiently over the years, Deshycka developed each step of the new method, then demonstrated its success in mouse models. Today, Lodish thinks it could become a blockbuster cholesterol-lowering strategy.

Tim Wang is another Whitehead trainee driving science forward. An MIT doctoral student, Wang has been working with Whitehead Member David Sabatini on new ways to identify specific genes essential for a cancer’s cellular proliferation and survival. This past spring, Wang authored a major journal study that identified the genes essential to 14 human acute myeloid leukemia (AML) cell lines. These genes are now natural targets for wholly new approaches to treating AML.

The study was possible because Wang had developed a CRISPR-based gene editing technique that enabled the researchers to identify the short list of genes that are not essential for normal cells but are required for AML cells to survive. “What’s particularly exciting about this work is that we have just begun to scratch the surface with our method,” Wang says. “By applying it broadly, we could reveal a huge amount of information about the functional organization of human genes and their roles in many diseases.”

By training talented and creative young researchers like Wang and Deshycka—and scores more—Whitehead Institute is nurturing the future of biomedical science.

“What’s particularly

exciting about this work

is that we have just begun

to scratch the surface with

our method,” says doctoral

student Tim Wang.

“By applying it broadly,

we could reveal a huge

amount of information

about the functional

organization of human

genes and their roles in

many diseases.”

PARADIGM FALL 2017 29

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WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH is a nonprofit research and educational institution. Wholly independent in its governance, finances, and research programs, Whitehead shares a teaching affiliation with Massachusetts Institute of Technology. Whitehead brings together a group of world-class biomedical researchers in a highly collaborative and supportive environment and empowers them to pursue the questions that engage them most.

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P A I DCambridge, MA

PERMIT NO. 56998

For more than 25 years Whitehead Institute has given high school and middle school teachers and students first-hand exposure to state-of-the-art research working directly with world-class scientists. Whether monthly workshops for teachers or weeklong summer science camps for middle schoolers, our public programs enhance the teaching of science, spark a lifelong appreciation for scientific research, and cultivate the nation’s next generation of scientists. But we couldn’t create these programs without strong philanthropic support from individual donors and corporations. The Expedition: Bio summer science program, for example, is supported by a generous contribution from the Amgen Foundation, with additional schol-arship support provided by Sanofi Genzyme.

ON THE COVER A peptide found in the flower and seed of the cockscomb plant (Celosia argentea) could lead Whitehead Member Jing-Ke Weng to a novel pain reliever.