Medical Advisory Board September 1, 2006–August 31, 2007

Howard hughes medical institute 2007 annual report What’s Next What’s

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What’s Next Letter from the president 2 The primary purpose and objective of the conversation: william r. lummis 6 Howard Hughes Medical Institute shall be the promotion of human knowledge within the CREDITS Thinking field of the basic sciences (principally the field of Like medical research and education) and the A Scientist 8 effective application thereof for the benefit of mankind. Page 1 Page 25 Page 43 Page 50 seeing Illustration by Riccardo Vecchio Südhof: Paul Fetters; Fuchs: Janelia Farm lab: © Photography Neurotoxin (Brunger & Chapman): Page 3 Matthew Septimus; SCNT images: by Brad Feinknopf; First level of Rongsheng Jin and Axel Brunger; in Bruce Weller Blake Porch and Chris Vargas/HHMI lab building: © Photography by Shadlen: Paul Fetters; Mouse Page 6 Page 26 Brad Feinknopf (Tsai): Li-Huei Tsai; Zoghbi: Agapito new Illustration by Riccardo Vecchio Arabidopsis: Laboratory of Joanne Page 44 Sanchez/Baylor College 14 Page 8 Chory; Chory: Courtesy of Salk Janelia Farm guest housing: © Jeff Page 51 ways Illustration by Riccardo Vecchio Institute Goldberg/Esto; Dudman: Matthew Szostak: Mark Wilson; Evans: Fred Page 10 Page 27 Septimus; Lee: Oliver Wien; Greaves/PR Newswire, © HHMI; Mello: Erika Larsen; Hannon: Zack Rosenthal: Paul Fetters; Students: Leonardo: Paul Fetters; Riddiford: Steitz: Harold Shapiro; Lefkowitz: Capacity Seckler/AP, © HHMI; Lowe: Zack Paul Fetters; Map: Reprinted by Paul Fetters; Truman: Paul Fetters Stewart Waller/PR Newswire, Seckler/AP, © HHMI permission from Macmillan Page 46 © HHMI for Page 12 Publishers, Ltd.: Nature vol. Blat: Kathleen Dooher; Garcia: Page 52 Adapted from HHMI BioInteractive 444/16 November 2006/ Barbara Ries; Broodie: Matthew Rubin: Paul Fetters; Sheng: Growth 22 Page 13 doi:10.1038/nature05284, © 2006 Septimus; Kim: Mark Harmel Jason Grow Todd Hido/Edge Page 28 Page 47 Page 53 Page 14 Illustration by Riccardo Vecchio Rodriguez: Mark Harmel; Sumner: Elgin: Scott Ferguson; Campbell: big Illustration by Riccardo Vecchio Page 30 Keith Weller Jeffrey McCullough Page 16 Ha: John Dixon/AP, © HHMI; Page 48 Page 54 dreamS Svoboda: Paul Fetters; Ehlers: Nanocontainer: Ibrahim Cisse/ Fly (Bonini): Pavan Auluck and Garbers: David Gresham/UT Karen Tam/AP, © HHMI; Neurons: Ha Lab Sebastien Gaumer/Bonini Lab; Southwestern; Gay: Courtesy about Yifan Xu/Ehlers Lab Page 31 Michaeli: David Rolls of Frank William Gay Page 17 Bertozzi: Barbara Ries; Nanoneedle Page 49 small Poliovirus: Boerries Brandenburg/ image: Courtesy of Gautam Rangan Mice (Dulac): Catherine Dulac; things 28 Zhuang Lab; Zhuang: Joshua and Xing Chen/Bertozzi Lab Garcia: Barbara Ries; Massagué: Dalsimer Page 32 Courtesy of Joan Massagué; Page 18 Sebastian Maerkl/Quake Lab Enzyme (Strynadka): Natalie Zuker: Jeffrey Lamont Brown; Fruit Page 33 Strynadka; Neuron (Zipursky, Jan, Building fly eyes: David Yarmolinsky and Donna Carson/AP, © HHMI & Jan): Morgan Sheng and Carlo Andrew Zelhof/Zuker Lab; Animation Page 34 Sala; Jacobs: Sean Kernan Communities image: © 2006 The President and Illustration by Riccardo Vecchio Fellows of Harvard College Page 36 of Page 19 Paul Fetters Produced by the Office of Communications and Public Affairs learNing 34 Gerald Jacobs/Nathans Lab Page 37 © 2007 Howard Hughes Medical Institute Page 20 Jeffrey McCullough Lindquist: Justin Knight; Prions: Page 38 Annual Report Editorial Staff: Avice Meehan, Dean Trackman, Year In Review 41 Courtesy of Peter Tessier and Kris Snibbe/Harvard News Office Cay Butler, Lisa Seachrist Chiu, Elizabeth Cowley, Patricia Davenport, Tom DiCesare/Lindquist Lab Page 39 Shelley Dubois, Patricia Foster, Jim Keeley, Dianne Palmer, Lindsey leadership 56 Page 21 Chris Hildreth Pujanauski, Jacqueline Ruttimann, Katherine Wood Paul Fetters Page 40 Page 22 Gary Strobel Design: VSA Partners, New York hhmi researchers 58 Illustration by Riccardo Vecchio Page 41 Printing: Finlay Printing Page 24 © Photography by Brad Feinknopf advisory boards & committees 63 Pancreas: Qiao Zhou and Douglas Page 42 The Howard Hughes Medical Institute is incorporated in Delaware. Melton; Melton: Joshua Dalsimer Nobel laureates: Paul Fetters; It is qualified as a medical research organization under the federal fellowships & grants 67 Rubin talk: Paul Fetters tax code. It is an equal opportunity employer. finance & investments 78

LETTER FROM THE PRESIDENT

What’s next? That’s a question that scientists associated with the Howard Hughes Medical Institute ask themselves every day. What are the next questions? What experiments might generate answers? How will we get there? With whom can we collaborate? What’s just over the horizon?

The drive toward “next” is an essential part of the scientific endeavor and of HHMI’s culture—a culture that prizes bold thinking and scientific risk taking, a culture that rewards innovation and discovery. Success rarely occurs at predictable intervals, making patience a paradoxical feature of HHMI’s approach to discovery research. HHMI is a patient, long-term investor in people.

Teaching students to think like scientists—to pose questions and then take incremental, challenging steps toward answering them—is also fundamental to HHMI’s approach to education. For two decades, HHMI has sought to hook students on the power of discovery by engaging them

Thomas R. Cech

in hands-on research at all age levels, particularly as undergraduates at the nation’s colleges and universities. HHMI helps train the “next” generation of scientists and scientifically knowledgeable citizens.

This annual report highlights the work of HHMI scientists—investigators, researchers at the Janelia Farm Research Campus, and international research scholars—who have tackled big problems that took many years to solve. For example, Joanne Chory and her colleagues at California’s Salk Institute spent 10 years developing the tools they needed to understand which tissues drive growth in plants. A similar long-term focus yielded new insights into the evolution of color vision at the Johns Hopkins University School of Medicine, where HHMI investigator Jeremy Nathans and his colleagues created genetically engineered mice that can literally see red.

This year we also celebrate the contributions of Craig C. Mello at the University of Massachusetts Medical School in Worcester. Mello shared

What’s Next? the 2006 Nobel Prize in Physiology or Medicine with Andrew Z. Fire, then of the Carnegie Institution of Washington in Baltimore and now at the Stanford University School of Medicine, for their discovery of RNA interference. The two collaborators picked their way through a maze of unusual experimental results and became intrigued by the possibility that double-stranded RNA played a role in silencing gene activity. Undeterred by the apparent absurdity of the idea, they discovered a regulatory system that controls gene expression in both plants and animals, including humans.

Evidence of scientific achievement notwithstanding, Mello recalls that he was an indifferent student and far more interested in playing out- doors near his family’s Virginia home until he encountered academic science courses during seventh grade. Inspired by wonderful teachers, Mello says in an autobiographical essay for the Nobel Foundation that he became “an avid reader of science fiction, an amateur astronomer, and a serious student.” We hope that HHMI’s science education effort—now 20 years old—will continue to nurture both sides of that student-teacher equation, creating communities of learning at different educational stages and in different environments.

This annual report calls attention to a variety of initiatives, from a boot camp for graduate students to a $22.5 million program that over the next five years will link biomedical research institutions with local schools around the nation. We’re even undertaking an educational experiment of our own by taking a direct role in the development of a genomics research course for undergraduates. HHMI has created the Science Education Alliance within the Office of Grants and Special

Howard Hughes 2007 Medical Institute Annual Report

Programs, and the SEA staff will spend the next year working with leading scientists and grantees to develop the course, including a syllabus and resource kits. The goal is to roll out the course to suc- cessive groups of colleges and universities beginning in fall 2008 and, over time, evaluate the impact of the experience for both students and teachers.

No person or organization can focus solely on the future. Indeed, the search for “what’s next” is built on an appreciation of the past and of history. This year we pause to recognize the singular contributions of William Rice Lummis in establishing HHMI as a world leader in biomedical research. For the past 23 years—beginning with his appointment as a charter Trustee by the Delaware Court of Chancery and continuing until his retirement in March 2007—Will Lummis served the Institute with consummate grace, steadfast dedication, and judicious intelligence. His leadership ensured the Institute’s reorganization and set the stage for the success we now enjoy. We’ll give him the next word.

Thomas R. Cech, Ph.D. President

Conversation William R. Lummis

William R. Lummis was nine years old when his dashing cousin Howard Hughes arrived in Houston in July 1938 for a celebration hailing his record-setting plane flight around the world. Hughes stayed at the family home, an encounter that Lummis recalls made him a “big shot” among his friends. Flash forward to 1976. Lummis, by then a distinguished Houston attorney and father of four, was called upon to claim Hughes’s body at the Texas Medical Center following his death. Almost immediately, Lummis assumed responsibility for unwinding the Hughes estate—a sprawling empire that ranged from thousands of acres of Las Vegas real estate to the Howard Hughes Medical Institute, which controlled the Hughes Aircraft Company. After spending three decades in the “Hughes vineyard,” Lummis retired in spring 2007 as one of HHMI’s charter Trustees. Long admired for his leadership in securing the Institute’s future, Lummis reflected on his tenure.

How would you describe Howard Hughes’s What challenges did you and the other greatest legacy? Trustees face?

Hughes’s career was unbelievable. His investments The Trustees started with a clean sheet of paper were in the right places and he focused on mat- in designing a new organization. We had very little ters that were of interest to him. Aviation was very to go on except in those areas we felt reflected important to him—he flew all the time—and so was the desires of Hughes himself, and we were fortunate moviemaking. But at a very early age—in his early in being able to attract tremendously talented 20s—he let it be known that he wanted his estate people. It was clear to the Trustees that we had to to be left for the good of mankind, and that’s what focus on Hughes’s desires for the Institute, and he did. His real legacy is the Institute and his fore- the only way to get the financial resources to do that sight in founding it with that brief charter—namely, was to sell the Hughes Aircraft Company. The “the promotion of human knowledge within the sale was the linchpin of our success because that field of the basic sciences….” He never altered it. $5 billion allowed us to do some serious planning.

What were your hopes for the Institute when What are some of the significant milestones? you sought its reorganization in the Delaware Chancery Court? There have been so many in the evolution of the reorganized Institute that they are difficult to rate Because Hughes died without a will, the estate was in terms of importance. The Institute has been in chaos and besieged by litigation. I thought the extremely fortunate in being able to acquire two attorney general of Delaware could be of assistance important properties—for the headquarters in in calming down the distractions and permitting Chevy Chase [Maryland] and for the Janelia Farm an orderly administration of the Hughes estate. This Research Campus [in Loudoun County, Virginia]. tactic was successful in reaching the desired result. I was very concerned about Janelia Farm in the We were also able to set the Institute on a course beginning, but with the help of some of the financial of fulfilling the promise and charitable purposes people, satisfied myself that we had the resources for which it was originally organized. to do it even though we were biting off a big chew. My hat’s off to [HHMI president] Tom Cech Did you expect to serve as a Trustee for more and the scientific staff for their vision. than 20 years? What do you hope the Institute will accomplish in the future? My experience as a Trustee has been thoroughly exciting, and the long-term association with the other Trustees and staff has been extremely satisfying, I have no idea, but I am assured that its endeavors particularly under the very capable board leader- will be extremely exciting and successful considering ship of George Thorn, Irving Shapiro, and Hanna the quality of management and scientific personnel. Gray. The original group was appointed for life, and The nice thing is that we have control of our own none of us had any idea of how long our services destiny in terms of financial resources. I think we would be required. We all worked together and we have something to be proud of at the Institute. all worked hard.

Thinking Like a Scientist

Scientific research might be described as the re- ing an unexpected pathway for an important tumor- lentless pursuit of what’s next. That insatiable curiosity suppressing protein, HHMI investigators have pushed drives HHMI investigators to delve more deeply when the bounds of scientific understanding. As scientific confronted with perplexing problems. In the quest for disciplines continue to converge, communicating and knowledge, they draw on their creativity and have the collaborating with the best minds in research becomes courage to question their assumptions. From identify- an essential part of thinking like a scientist. ing previously unknown cellular mechanisms to find-

What’s Thinking Like Next? a Scientist

Driven to explore Craig C. Mello, an HHMI investigator at the University of Massachusetts Medical School, has spent his life applying his analytic and creative gifts to exploring the world around him. His curiosity and willingness to entertain new ideas drove the research that led to the 2006 Nobel Prize in Physiology or Medicine, shared with Andrew Z. Fire of the Stanford School of Medicine. The prize recognized their work in discovering RNA interference—gene silencing by double-stranded bits of RNA. Mello and Fire received the ultimate honor for scientific achievement by overturning scientific dogma: rather than being simple cellular debris, short snippets of double- stranded RNA could regulate gene expression. Still, the creative thinking that led them to propose their radical idea doesn’t seem particularly noteworthy to Mello. “I think everybody thinks like a scientist. It’s just a matter of getting better at it. Your average kid is doing it all the time,” Mello argues. “Scientists are just creative in a way that is constrained by reality.”

Cells have numerous mechanisms to of Cold Spring Harbor Laboratory explored Halting keep cancer at bay. None plays as crucial a peculiar fact about cancer cells—the Cancer a role in shutting it down as the tumor- relative lack of mysterious bits of RNA, suppressing protein p53, which is mutat- called microRNAs. Hannon and Lowe ed in half of all cancers. In the 25 years discovered that in addition to interact- since p53 was discovered, the mecha- ing with a host of proteins and DNA, p53 nism by which it encourages damaged activates a family of microRNAs that in cells to die or become dormant has only turn triggers cell suicide or renders a cell been partially described. Shutting down dormant. Hannon says that the hole in proteins known to interact with p53 failed the p53 pathway “may well be filled by to block its ability to control tumors. microRNAs.” The next job is trying to Faced with genetic evidence that p53 understand how the cell integrates all did something more, HHMI investigators the output of p53 activation. Gregory J. Hannon Scott W. Lowe Gregory J. Hannon and Scott W. Lowe

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“I think everybody thinks like a scientist. . . . Scientists are just creative in a way that is constrained by reality.”— —Craig C. Mello 0

A seemingly impossible laboratory result compelled “I guess it’s my personality. I’m not afraid of things Mello to pursue the work that resulted in winning that are weird,” Mello muses. “It’s important to be ex- a Nobel Prize. In 1994, he heard about a graduate cited about odd and unusual results, and in this case it student at a Cornell University lab, Su Guo, who tried to was clearly something interesting.” block a gene in the tiny worm Caenorhabditis elegans Mello discussed these findings with Fire, then at by injecting it with antisense RNA—a strand of RNA the Carnegie Institution of Washington’s Department designed to bind with single-stranded RNA molecules of Embryology in Baltimore. Fire posited that perhaps that have the opposite genetic sequence and prevent double-stranded RNA was responsible for the effect the cellular machinery from using the RNA as a tem- by somehow amplifying RNA’s ability to silence genes. plate to make a protein. It worked just as expected. Because double-stranded RNA forms when single- However, when the Cornell student injected “sense”— stranded RNA loops back on itself, Fire’s idea explained or same sequence—RNA, which shouldn’t affect gene the unusual results first observed in 1994. expression, the gene was similarly blocked. Most “Communication and discussing ideas are integral people assumed that antisense RNA had simply con- parts of science because those conversations gener- taminated the sense RNA preparation. ate ideas more efficiently,” Mello says. “Of course, Mello, however, was fascinated and began explor- you have to do experiments, too.” ing the phenomenon as a project separate from his When Mello and Fire did the experiments, they study of how C. elegans embryos develop. A couple of found that double-stranded RNA was far more efficient serendipitous mishaps in his laboratory presented at silencing gene expression than antisense RNA. additional puzzling results: the gene-silencing effect They published their results on RNA interference spread from parent to offspring and from cell to cell. (RNAi) in the journal Nature in 1998, triggering an Rather than being frustrated, Mello was driven to un- explosion of research. The mechanism they had dis- derstand the strange findings. covered was part of a system regulating the expression

11 What’s Thinking Like Next? a Scientist

nucleus

dsRNA

Dicer Digestion

assembly

RISC

unwinding siRNA

binding

cleavage RNA INTERFERENCE Double-stranded RNA (dsRNA) targets destruction of messenger RNA (mRNA) that has the same sequence it has. The Dicer enzyme cuts dsRNA mRNA into small inhibitory RNA (siRNA), which lures mRNA into the RISC (RNA-induced silencing complex) protein complex, where it is destroyed.

of many genes and included a protein called Dicer, One new interest is global health. As scientists which chops up double-stranded RNA into double- begin to search for potential therapies based on RNAi, stranded fragments 20 to 25 base pairs long. Mello believes most of them will be very expensive. If Mello’s work is now evenly divided between proj- he’s right, those therapies may benefit only a small ects investigating RNAi and embryonic development part of the world’s population. “Any treatments that in C. elegans, and the two fields continue to converge. are developed aren’t going to be simple or inexpen- “It really is the most amazing feeling when you first sive,” he says. “You can’t escape the fact that there see the connections long before you can prove they are huge economic disparities in the world that we as exist,” Mello notes. “There is still so much to learn.” a society need to address.” Since winning the Nobel Prize, Mello has discov- Mello believes solving such problems requires com- ered that he has joined an elite group of scientists munication among a host of different fields, from sci- whose ideas and opinions are highly regarded. He is ence to politics to economics. He has found himself invited to many meetings and workshops on topics in reaching out to other disciplines to learn as much as and outside his areas of expertise. “The Nobel Prize he can about global public health. “I just feel the need has given me the opportunity to educate myself and to be thinking,” he says. learn about some new things,” he says.

Howard Hughes 2007 Medical Institute Annual Report

Systems Biology Boot Camp

In late August 2007, new graduate codirected by HHMI investigator David A. groups attempt to design a new syn students in the systems biology program Agard, and crucial input is also provided by thetic behavior for yeast, and they end at the University of California, San Francisco HHMI investigator Jonathan S. Weissman. up spending days and nights in the lab to (UCSF), entered a grueling two-week boot meet the challenge. These intense experi- camp of 14-hour days filled with lectures, Later in the program, the students—who have ences help develop communication skills seminars, and labs. The boot camp, first backgrounds in fields such as biochemistry, and broaden thinking, preparing the stu- conducted in August 2006, is designed to physics, biology, and biotechnology—take dents to solve the scientific problems of introduce the students to interdisciplinary on a team challenge. Three- to four-member the future. science. Active at the nexus of physics, mathematics, and biology, systems biology explores the interactions between components of biological systems and how these interactions give rise to the function and behavior of the systems.

UCSF is one of 13 institutions chosen to participate in the first phase of an HHMI and National Institute of Biomedical Imaging and Bioengineering (NIBIB) initiative designed to foster Ph.D. scientists who are comfortable conducting interdisciplinary research. “Systems biology requires intense communication across disciplines,” says HHMI investigator and program director Joseph L. DeRisi. “The boot camp breaks down barriers that result from different scientific backgrounds and forces the students to form a cohesive network and act together.” The UCSF program is UCSF graduate students Brittany Belin (right) and Monica Tremont working in the boot-camp lab.

Antiquity’s Control Switch

HHMI investigator Ronald R. Breaker presence of nutrient molecules, he hypoth been seeking to understand the role they from Yale University began his work on esized that such entities must exist in play in higher organisms. In May 2007, he RNA “sensors” as an intellectual exercise nature. In 2002, he found a riboswitch at discovered that a riboswitch in the fungus and discovered a legacy from a time when work in bacteria that helped the micro- Neurospora crassa regulates RNA process- RNA ruled the world. Struck by how effi- organism sense the availability of a certain ing. He continues to investigate how these ciently laboratory-engineered RNA sensors— vitamin. Since then, dozens of riboswitches bits of antiquity exert control in higher dubbed riboswitches—could react to the have been discovered, and Breaker has modern organisms.

seeing in new ways

A long evolutionary history has endowed flies with our eyes fail us when we attempt to observe the routine near 360-degree vision and humans with the ability to activities of molecular biology—we simply can’t see indi- see sharp images of the world in brilliant color. HHMI vidual molecules in action. Faced with such limitations scientists have discovered that in some cases the small- when trying to understand processes like protein folding est of genetic changes is responsible for marked im- and viral infection, HHMI researchers have found new provements in vision. Despite our visual acuity, however, ways to visualize what can’t be seen.

15 What’s Seeing in Next? New Ways

Karel Svoboda Michael D. Ehlers

ILLUMINATING NEURONS HHMI investigator Michael Ehlers genetically engineered a light-sensitive protein into the neurons of mice. This illustration shows a beam of light activating a neuron in the olfactory bulb.

Simply Channeling Complexity A simple flick of a light switch is all you need to see Janelia Farm Research Campus group leader Karel what’s inside a darkened room. Working independently, Svoboda flipped his switch in the brain by introducing two HHMI research teams have found similarly straight- channelrhodopsin-2 into specific subsets of neurons forward ways to turn on a light in the brain. Using the in mice at various stages of embryonic development. light-sensitive protein that enables green algae to migrate Exposing brain slices from these mice to laser pulses, toward light, both techniques offer revolutionary ways Svoboda’s team mapped the signals generated as the to map the function of brain activity. channelrhodopsin-2-laden neurons proceeded to fire. HHMI investigator Michael D. Ehlers and his group Svoboda is using the technique to explore how the at Duke University illuminated the brain by genetically two brain hemispheres connect. Preliminary evidence engineering the algal protein channelrhodopsin-2 into indicates that axons in one area of the brain seek the neurons of living mice. These mice developed and neurons of the same type in different parts of the behaved normally. Ehlers triggered neuronal impulses brain in what Svoboda calls “a simplifying principle of in the live animals by shining an ultrafine fiber optic connectivity.” light source onto the engineered neurons. By focusing Both Svoboda and Ehlers are pushing their tech- the light on the olfactory bulb, he generated impulses niques to the next level by finding more specific ways to the olfactory cortex. Ehlers discovered that the to target neurons genetically. Svoboda plans to ex- cortex couldn’t respond to a single neuron but instead plore the properties of synaptic connections. Ehlers needed input from a distributed array of neurons. “We intends to investigate methods for light stimulation of believe that this light-induced activation technique is a connected brain regions, which could be precursors major technical breakthrough in the functional analysis to new technologies for neural activation in the brain of neural circuitry,” Ehlers says. and spinal cord.

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POLIOVIRUS INFECTION Poliovirus (red) infects a cell by first binding to multiple cell-surface receptors (blue). The cell membrane (green) folds around the virus and creates a sac inside the cell. The virus then releases its RNA genome (pink).

Imaging Infection For decades, scientists have debated how poliovirus infects human cells. Xiaowei Zhuang, an HHMI investi- “We settled the gator at Harvard University, and her colleague James debate.... If the Hogle at the Harvard Medical School found a way to peer at the process and settled the question: unlike viruses don’t viruses that need hours or days to infect a cell, poliovirus get into the cell, needs only minutes to release its genome and initiate an infection. they do not Zhuang and Hogle developed a novel method of release their RNA.”— light microscopy to watch individual viruses entering —Xiaowei Zhuang a cell by tagging the protective shell of the poliovirus with a red fluorescent dye and its RNA genome with one glowing green.Through the microscope, they could “see” the tagged virus enter the cell. Once inside the cell, poliovirus wasted no time releasing its green-glowing RNA genome from the viral shell. “We settled the debate.... If the viruses don’t get into the cell, they do not release their RNA,” Zhuang says. Her research opens new avenues of inquiry because poliovirus enters the cell via a pathway that has yet to be illuminated.

17 What’s Seeing in Next? New Ways

From Primitive to Complex HHMI investigator demonstrated Charles S. Zuker FLUORESCENT EYES the power, and beauty, of evolution when he and his This fruit fly’s compound eyes express a fluorescent reporter protein. Analysis of colleagues at the University of California, San Diego, fly eyes helped determine the crucial role explored the differences between two forms of insect of the spacemaker gene in the construc- eyes. Compound insect eyes come in two varieties: tion and evolution of insect eyes. the complex “open” eye of flies that creates 800 distinct light-gathering units and enhances peripheral vision, and the more primitive “closed” eye of a beetle Charles S. Zuker that fuses those 800 light-gathering units. Zuker found the difference between these two eyes lies in a single regulatory gene called spacemaker. When the spacemaker gene is expressed in a primitive insect eye, it triggers the eye to organize into the more complex version. “It’s not unusual to see alterations in regulatory proteins with a profound effect on form and function,” Zuker said. “This new finding, however, is unique because it illustrates how a change in a single structural protein can lead to such a spectacular change in form and function.”

For most undergraduate biology in scenes documenting cellular activi- The Inner Life majors, the intricate and dynamic mo- ties such as motor proteins plodding of the Cell lecular machines making up the living cell along cellular scaffolding and structural reside in static illustrations in their text- proteins rapidly forming filaments and books. To bridge the gap between science just as rapidly falling apart. Produced education and multimedia, Robert Lue, by XVIVO, a scientific-animation firm an HHMI undergraduate program direc- in Connecticut, the breathtaking eight- tor at Harvard University, initiated an minute animation received a 2006 Telly integrated computer learning system Award, a premier award honoring out- called Biovisions. His research indicates standing local, regional, and cable TV that scientific animations boost student commercials and programs, as well as comprehension by as much as 30 per- video and film productions. The Inner cent. The program’s first animation, Life of the Cell can be viewed at called The Inner Life of the Cell, brings http://multimedia.mcb.harvard.edu. to life the workings of white blood cells

18 Howard Hughes 2007 Medical Institute Annual Report

Seeing Red Humans and other primates maintain a significant ad- vantage over other mammals—they see the world in full color. Mice, like most mammals, are red-green color blind. This discrepancy in color perception lies with the types of photoreceptors present in the eye. Full- color vision (trichromacy) occurs when an animal’s eye harbors photoreceptors capable of detecting blue, green, and red wavelengths. The more limited dichro- matic vision exists when the eye has only blue and green photoreceptors. Building on work exploring the evolution of color vision that began in the early 1980s, HHMI investigator Jeremy Nathans at the Johns Hopkins University School of Medicine and his colleague Gerald Jacobs at the University of California, Santa Barbara, asked color vision what happens when you mimic the crucial event in Colored lights show that the brains of genetically altered mice can process information from new the evolution of color vision by introducing the gene photoreceptors in their eyes. Here, a mouse decid- for the red photoreceptor into the mouse genome. ing that the third colored panel looks different from Would the mice see in full trichromatic color, or would the other two is rewarded with a drop of soy milk. the brain lack the ability to process information from the newly acquired photoreceptor? The researchers found that the brain seamlessly processed the infor- “What we are looking mation from the new red photoreceptor, permitting at in these mice is the the animals to see red. “What we are looking at in these mice is the same same evolutionary event evolutionary event that happened in one of the dis- that happened in one of tant ancestors of all primates and that led ultimately the distant ancestors to the trichromatic color vision that we now enjoy,” Nathans says, noting that a common way the brain of all primates and that may expand our experience of the world is by adding led ultimately to the new sensory receptors. trichromatic color vision that we now enjoy.” —Jeremy Nathans

19 What’s Seeing in Next? New Ways

PRION ASSEMBLY A microarray is used to probe the mechanisms of prion assembly. Two prion species (blue and purple shapes) are washed over a microarray spotted with different segments of the prion Sup35 (green and red dots). The prion species attach to specific sites and form amyloid masses.

Susan L. Lindquist

Probing Prions Faced with a vexing scientific problem, HHMI investi- discovered that amyloid masses coalesced only over gator Susan L. Lindquist at the Whitehead Institute array segments corresponding to two regions involved for Biomedical Research employed commonly used with the conversion to the prion state. The team sus- tools in an entirely new way to study the workings of pects that specific peptides cause the protein to adopt the infectious proteins known as prions. Since their a prion configuration and that those peptides trigger discovery in the early 1980s, prions have confounded amyloid masses to develop. They are now using the scientists. Responsible for fatal brain disorders such arrays to study how prions initially form. as mad cow disease and Creutzfeldt-Jakob disease, By creating a hybrid Sup35 prion that fused an ac- prions exist in two differently folded configurations. tive region from S. cerevisiae to one from the yeast One is innocuous. The other, called the “prion state,” Candida albicans, Lindquist and Tessier established converts normal prion proteins to the prion state, form- that the hybrid Sup35 could interact with both yeast ing brain-destroying protein clumps called amyloid species—but at different temperatures. The finding masses. Lindquist and postdoctoral fellow Peter Tessier illustrates how different prion shapes can play a role used protein microarrays to provide insights into how in jumping the species barrier. The team’s technique prion-state proteins convert normal prion proteins and has the potential to be used in high-throughput drug how prions jump from species to species. screens and to provide generalized insights into Lindquist and Tessier studied a version of the prion protein folding. protein from the yeast Saccharomyces cerevisiae, known as Sup35, by exposing peptides bound to protein microarrays to the nonprion state of Sup35. They

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Q&A A Vision jack e. Dixon of the Future

Jack E. Dixon joined HHMI What is HHMI’s approach What areas of science are ripe How do the HHMI–Wellcome as vice president and chief to funding research that for breakthroughs? Trust International Postdoctoral scientific officer in February fosters new approaches and Fellowships foster communica- 2007 after having served innovation? tion and collaboration? on the Institute’s Scientific Major unsolved problems exist Review Board and Medical everywhere. Why is it we can’t Advisory Board. A professor We identify good people— make a vaccine against the Today’s science is conducted of pharmacology, cellular the innovators and the risk AIDS virus? Why have we made on an international platform, and molecular medicine, takers—and turn them loose for great progress against some and this is one way we can help chemistry, and biochemistry, a sufficient period of time so forms of cancer and virtually foster international collabora- he maintains a bicoastal that they can take a good run none against others? To get tions. In this visiting scientist existence, keeping one foot at the problems. Demanding talented investigators to com- program, postdoctoral fellows in his lab at the University short-term results is short- mit to solving these difficult working in HHMI or Wellcome of California, San Diego, sighted and a sure formula for problems and make true break- Trust laboratories can spend where he studies a family playing it safe. Scientific re- throughs, we have to give them up to a year working in an over- of enzymes called protein search takes time. the freedom—the time and the seas lab. The program promotes tyrosine phosphatases, and money—to explore. collaborative science and one foot at HHMI. His choice develops what we hope are last- keeps him grounded as Do the pace and demands of ing ties between international he pursues his vision for science today require special research labs. HHMI research. attention to new ways to tackle scientific questions?

The biggest difference today is that scientists must communicate and collaborate. Science today involves more people communicating with each other across several disciplines.

capacity for growth

Pluripotent human embryonic stem cells possess the basic biology, plant behavior, and diseases like diabetes. remarkable capacity to mature into all of the more than The path from infinite possibilities to human therapies 200 kinds of cells making up the human body: skin, is fraught with difficult biology and sensitive questions. bone, nerve, blood, heart, muscle, and so on. By their As HHMI researchers delve into the mechanisms by very nature, the cells suggest possible new ways to treat which stem cells maintain their capacity for growth, they devastating diseases such as Alzheimer’s, Parkinson’s, are encountering both the limitations of the current em- cancer, and diabetes. HHMI investigators are exploring bryonic stem cell lines and the possibility of finding new the boundless potential of human, animal, and plant sources of these cells. stem cells in order to make headway in understanding

23 What’s Capacity Next? for Growth

Douglas A. Melton

A DEVELOPING MOUSE PANCREAS A confocal image of an embryonic mouse pancreas at about two weeks shows epithelial cells (blue), a key transcription factor (green), and progenitor cells (red).

Neighborly Differences For more than a decade, HHMI investigator Douglas A. the number of pancreatic progenitor cells dictates the Melton at Harvard University has studied how embry- size of the pancreas. onic stem cells give rise to the pancreas and its insulin- Melton posits that there are two classes of organs: producing beta cells, which are destroyed in patients with one includes organs such as blood, liver, and skin that type 1 diabetes. His quest is to identify new therapies for quickly and efficiently renew themselves. The other that disease. Melton’s most recent research grew in a includes organs such as the pancreas, kidneys, and natural direction when he decided to compare the lungs, which don’t. “It could be that organs that don’t pancreas to the liver. have adult stem cells [which are similar to progenitor Unlike the pancreas, which cannot regrow sections cells] are just not very good at replenishing themselves,” that have been surgically removed, the liver regener- Melton says “Our studies were on the pancreas, but ates into a fully functioning organ just weeks after the my expectation would be that organs like the kidneys removal of as much as two-thirds of its mass. The mo- and the lungs—both of which do not regenerate them- lecular basis for this difference may offer vital clues selves—may fall into this same class.” to help researchers eventually generate beta cells from It’s possible that these organs have a counting stem cells. Melton studied how these developing organs mechanism or respond to external signals, limiting their in mouse embryos responded to the loss of progeni- ability to grow and regenerate. Melton is now teasing tor cells—partially differentiated embryonic stem cells. out the mechanisms that regulate an organ’s capacity His team discovered that the liver reaches its full size to grow. regardless of the number of liver progenitor cells, but

24 Howard Hughes 2007 Medical Institute Annual Report

Pluripotent embryonic stem cells oped into two distinct types of neurons. Boundless hold seemingly boundless potential. The neurons from these two cell lines com- Potential— HHMI investigator Thomas C. Südhof municated via different neurotransmitters Limited at the University of Texas Southwestern and relied on different regulatory factors. Medical Center and stem cell biologist The team suspects that different culture Yi Sun at the University of California, conditions likely played a role in deter- Los Angeles, demonstrated that certain mining these cells’ fates. existing stem cell lines may have more limited potential. “There is absolutely no question that these findings mean there need to be more em- Südhof and Sun generated neurons from bryonic stem cell lines for research pur- two embryonic stem cell lines distributed poses and for use in potential treatments,” through the National Institutes of Health says Südhof. Thomas C. Südhof and discovered that the cell lines devel-

Of Skin and Mice The healing of a simple cut demonstrates the skin’s profound potential to renew itself. That regenerative ability lies with an adult stem cell—the keratinocyte stem cell, which produces skin cells, hair follicles, and oil glands. In a cloning first, HHMI investigator Elaine Fuchs and colleagues at the Rockefeller Uni- versity used these stem cells to clone viable, healthy mice. The technique delivered a high rate of success compared with other methods for cloning mice. Al- though the team efficiently cloned mice, Fuchs is more excited about the possibility for keratinocyte stem cells to produce embryonic stem cells and what that Elaine Fuchs might mean for treating human disease.

CLONING A MOUSE 1. In somatic cell nuclear transfer, or SCNT, the nucleus of an adult body cell—such as a skin cell from a mouse—is plucked out and injected into an unfertilized egg that has had its nucleus removed. 2. A reprogramming phenomenon occurs: the egg cell with the transferred nucleus initiates development. 1 Skin cell egg cell 2 3. The cell begins to divide, eventually forming a ball of cells called a blastocyst. 4. The blastocyst is implanted in a surrogate mother to create a cloned mouse. Alternatively, embryonic stem cells can be harvested from the inner cell mass (dark blue) of the blastocyst.

3 4

25 What’s Capacity Next? for Growth

CONTROLLING GROWTH The cells in a plant’s epidermis both drive and restrict growth. Left: A wild-type Arabidopsis plant (normal). Right: A dwarf plant that has had its receptors for a particular growth hormone blocked. Middle: A former dwarf plant that has had the receptors turned on in the epidermis.

Reaching for the Sun It’s a simple formula for growing plants—sun, soil, and seed. The mystery lies in how a plant decides to put down roots and send up shoots. For more than a century, scientists debated which tissue drove growth in plants: the waxy protective epidermis, the photosyn- thetic mesophyll tissue, or the central vascular tissues. In studies of dwarf Arabidopsis plants, HHMI investigator Joanne Chory of the Salk Institute for Bi- ological Studies and postdoctoral fellow Sigal Savaldi- “If we want to feed Goldstein settled that debate when they discovered over 9 billion people that the epidermis delivers growth instructions to inner tissues. “It took us 10 years to develop the tools by the year 2050, to ask the question,” Chory says. Chory’s team has shown that the cells of the epi- then understanding dermis communicate with those of the inner plant, the basic mechanics both driving and restricting growth. “If we want to feed over 9 billion people by the year 2050, then under- of plant growth standing the basic mechanics of plant growth is re- is required.” quired,” says Chory. “This knowledge will ultimately —Joanne Chory lead to our ability to increase yield, while decreasing the need for fertilizer and pesticides.”

26 Howard Hughes 2007 Medical Institute Annual Report stimulating thought

Nadia Rosenthal Washington, D.C.–area high school students attended the lectures. Human embryonic stem cell research is speakers at “Potent Biology: Stem Cells, were joined by Jonathan D. Moreno, a science at its most promising and conten- Cloning, and Regeneration.” In front of a bioethicist at the University of Pennsylvania tious. The 2006 Holiday Lectures on Science live audience of 189 high school students and a member of HHMI’s Bioethics grappled with both in the latest iteration from the Washington, D.C., area and a Advisory Board, and Debra J.H. Matthews, of this popular series. HHMI investigator webcast audience in 42 states and 14 a geneticist and bioethicist at the Berman Douglas A. Melton from Harvard University countries, Melton and Rosenthal provided Institute for Bioethics at the Johns Hopkins and Nadia Rosenthal, senior scientist at primers on developmental biology and ex- University for a spirited discussion of the European Molecular Biology Laboratory plored the potential of embryonic and ethical issues. The lectures are available in Monterotondo, Italy, were the featured adult stem cells. Melton and Rosenthal at www.hhmi.org/biointeractive/lectures.

Rybp Zfp219 Mapping Requiem Cdk1 Potential Rai14 YY1 Rnf2 Prmt1 EWS Arid3b Oct4 NF45 P66ß Etl1

Wapl HDAC2 Rex1 Sall4 Zfp281

Wdr18

PROTEIN INTERACTIONS Baf155 Sp1 This map sketches out the many protein interac- Nanog ELYS tions that give embryonic stem cells their develop- Nac1 mental prowess. Each circle represents a different Zfp198 protein, and each line indicates an interaction. The Arid3a Tif1ß Rif1 six proteins labeled in red were used as “bait” to Btbd14a fish for additional interacting proteins. The proteins Dax1 that were “hooked” (green, blue, and yellow) were Err2 confirmed by further experiments to be important Sall1 Mybbp for stem cell pluripotency. REST Pelo Zfp609 HHMI investigator Stuart H. Orkin and ing embryonic cell differentiation. Filling in and perhaps destroying embryos,” says his colleagues at Children’s Hospital Boston the details of the map may lead to Orkin’s Orkin. “However, if one could reprogram, have created a detailed map of the protein ultimate goal: reprogramming a mature say, a skin cell to revert to become identical network that regulates an embryonic stem cell to resemble as closely as possible an to an embryonic-type cell, it would obviate cell’s ability to become many different types embryonic stem cell. “The major contro- these ethical issues.” of cell. They have found that the proteins in versy over using human embryonic stem the network are controlled as a group dur- cells is that it requires obtaining oocytes

big dreams about small things

HHMI investigators are expanding scientific under- observe interactions between molecules, allowing for standing by seeking insight from the infinitesimally precise measurements that can help them predict small world of nanotechnology. An interdisciplinary molecular behavior and study cell processes. The in- science that develops tools on the molecular scale, terdisciplinary nature of nanotechnology requires that nanotechnology is providing the means to create test scientists learn to communicate and collaborate with tubes for reactions between single molecules, precisely peers from many branches of science. Nanotechnology tag cells, and build miniaturized laboratories. These today offers a big glimpse of the future wrapped up in nano-sized tools are transforming the way researchers a tiny package.

29 What’s Big Dreams Next? About Small Things

Science and the Single Molecule A new kind of “test tube,” one-thousandth the diameter of a human hair and small enough to hold only a few molecules of DNA, is revolutionizing the way researchers observe the behavior of single molecules of DNA, RNA, and proteins. The test tubes are in truth bubble- like nanocontainers that are porous to small molecules, permitting researchers to feed ions and other chemicals into the ultra-tiny reaction chambers. HHMI investigator Taekjip Ha at the University of Illinois at Urbana-Champaign and his colleagues are the creative force behind the new technology, which “I think this technique will promises to make single-molecule techniques more go a long way toward my accessible and more powerful. Currently, scientists extrapolate the behavior of individual molecules by goal of commoditization observing the collective behavior of many. Ha, an expert of [single-molecule] in single-molecule study, believes scientists can learn techniques, getting them more about the dynamics of the chemical reactions powering biology by studying the behavior of individual out of specialists’ labs molecules. But techniques for single-molecule studies to the general research are limited and often highly specialized. “I think this community.” technique will go a long way toward my goal of commoditization of [single-molecule] techniques, getting —Taekjip Ha them out of specialists’ labs to the general research community,” Ha said. REACTION IN A NANOCONTAINER The pores in a nanocontainer let small molecules, such as ions and other chemicals, pass through but keep large molecules, such as proteins and DNA, inside. Here, a catalyzing solution infused into the container triggers RecA proteins to interact with DNA, forming a filament. Porous nanocontainer

RecA protein CATALYZING SOLUTION DNA (dye labeled)

30 Howard Hughes 2007 Medical Institute Annual Report

Nanoneedle Delivers Tiny tracer molecules are used to study the physics and biochemistry of normal cellular processes. How- ever, introducing such tracer molecules into cells is fraught with peril. Standard methods can damage the cell membrane, and the liquid carrying the tracers can engorge the cell, thereby altering its properties. In an effort to study a cell’s normal state, HHMI investigator Carolyn R. Bertozzi at the University of California,

Berkeley, and the Lawrence Berkeley National Labo- Carolyn R. Bertozzi ratory and her colleagues invented a carbon nanotube needle so small—about one-thousandth the diameter of a human hair—that it can deliver minute amounts of INJECTING TRACERS tracer without disrupting the cell. A carbon nanotube needle (black) pierces the cell membrane and delivers fluorescent quantum “Carbon nanotubes have remarkable properties in dot tracers (red) into the cell. The nanoneedle is that they are very rigid, and their overall strength is so small that it does not disrupt the cell. greater than steel,” says Bertozzi. “So, we thought that if you could somehow load cargo onto a carbon nanotube, it could be used to puncture the relatively soft cell membrane and introduce the cargo into the cell without leaving a huge hole in its wake. At the small diameters of carbon nanotubes, the hole should heal readily.” Bertozzi linked tiny fluorescent quantum dot tracers to a carbon nanotube needle via chemical bonds that break when they encounter the intracellular environment. In doing so, they can precisely deliver the quantum dot tracers into the cell without using liquid carriers. “The good news is that we’ve shown that the nano injector system can introduce such cargoes as quantum dots into cells with little damage,” says Bertozzi. “How- ever, the bad news is that we can only deliver a limited number of molecules.” Bertozzi and her group are working on using the nanoinjector to introduce larger molecules, such as DNA, into cells, as well as exploring whether they can target individual components of the cell.

31 What’s Big Dreams Next? About Small Things

MICROLABORATORY A laboratory about the size of a quarter enables scientists to observe 2,400 chemical interactions simultaneously among molecules such as DNA and proteins. This detail of the microlaboratory Lilliputian Labs shows reaction chambers, each controlled by two valves (orange and green). A button membrane To understand complex biological systems, scientists (blue) is used to trap molecules. must carefully and precisely characterize molecular interactions. It also helps if they like to do a little plumb- ing—very little, that is. HHMI investigator Stephen R. Quake and his colleagues at Stanford University have designed laboratories ranging in size from a quarter “We are hoping to to a credit card that are capable of running miniaturized molecular biology experiments. Quake envisions open a whole new these labs on a chip—made up of dense networks of chapter in how one pipes, valves, and chambers cast in clear rubber— accelerating biological research in the same way the understands the silicon computer chip revolutionized mathematical microbial universe.” computation. Quake’s fascination with the Lilliputian world of —Stephen R. Quake microfluidics, where scientists manipulate fluids one- —Stephen R. Quake hundredth to one-thousandth the volume of a human tear, intersects with his interest in systems biology— the study of how biological networks act in concert. High-throughput technologies have allowed researchers

32 Howard Hughes 2007 Medical Institute Annual Report

Nanotechnology lies at the intersec- Program director Jennifer L. West, a bio- Fostering tion of the biological sciences and nanotechnologist selected as an HHMI Collaboration engineering. Conventional undergradu- professor to employ her creative science ate science and engineering programs, education methods, notes that the however, do little to prepare students undergraduate program is just one of to conduct research in this field. The four initiatives the Rice Institute has Rice Institute of Biosciences and Bioen- undertaken. The institute also offers a gineering’s HHMI Summer Internship high school summer academy targeting in Bionanotechnology is designed to inner-city and minority teens, an accel bridge the gap between disciplines. erated single-semester cell and molecular Engineering and physical science un- biology course, and freshman seminars dergrads chosen from Rice University in bionanotechnology for both science and schools around the nation receive and nonscience majors. Participation in an intensive course in biology before the summer internship program leaves they fan out to laboratories to conduct students primed to overcome the com- interdisciplinary bionanotechnology munication barriers that hinder interdis- research. All the while, the students ciplinary research and ready to participate focus on their ability to communicate in the rapidly changing world of nano- Jennifer L. West with scientists in other disciplines. technology research.

to describe which molecules interact with each other, by the fact that 99 percent of microbes can’t be cul- but they have been hard-pressed to describe how tured and therefore studied and characterized in the they do it—an observation critical to systems biology. lab, Quake sought a means to understand this vast Focusing on measuring the energy required for spe- microbial universe. “Those unstudied organisms are cialized proteins to bind to their DNA targets, Quake biology’s dark matter,” he says. created a lab on a chip capable of conducting 2,400 Because the human mouth is home to more than reactions at once. Using only the physical measure- 700 species of bacteria, most of which haven’t been ments of binding energies, he could predict the bio- characterized, Quake sought to characterize these logical functions of the proteins. members of biology’s dark matter. Using the micro- Quake’s team also used microfluidics techniques fluidics lab on a chip, he amplified, sequenced, and to create a laboratory capable of crystallizing minute characterized 1,000 genes from an organism that amounts of proteins. That effort is ongoing as the had never before been studied. He is now using the team tries to refine the crystallization process and chip to isolate, identify, and sequence the commu- eventually generate crystals for X-ray crystallographic nity of microbes that dwell in termite hindguts, as analysis. well as building custom chips for other researchers The labs on a chip provide a means to answer diffi- seeking to study microbes in other specified envi- cult scientific questions. Quake designed a microflu- ronments. “We are hoping to open a whole new idics laboratory to circumvent the need to culture a chapter in how one understands the microbial uni- bacterial species in order to characterize it. Intrigued verse,” Quake says.

Dreaming Big on a Small Scale

Sweeping vistas of scientific knowledge are being un- earthed in the tiniest of environs. As the next “big thing”, nanotechnology provides vast opportunities to expand scientific knowledge by seekingBU singularities,ILDIN exploring G the depths of our understanding of biological processes, identify unstudied forms ofCOMM life, precisely probing cellularU NITIES processes, and collaborating across disciplines all wrapped up in a tiny package. OF LEARNIN G

Over the past 20 years of grant making in science improving science education for young students. Their education, HHMI has gained an abundance of knowl- innovative strategies are bringing together communities of edge and experience and built an unparalleled net- learning—scientists, teachers, students, families—both locally work of educators and researchers. This provides and nationally. And the Institute is moving beyond its the foundation for the next generation of Institute traditional role as a funder with the creation of its own initiatives. HHMI grantees are addressing issues national program focused on developing groundbreaking such as increasing diversity in the sciences, engaging approaches to science education. undergraduates in real research experiences, and

35 What’s Building Communities Next? of Learning

“We hope that giving students a great research experience early on will encourage more of them to become scientists.” —Tuajuanda Jordan

A SEA Change An experiment that could transform the teaching of The genomics course was created in collaboration college biology is under way at the University of Pitts- with HHMI professor Graham F. Hatfull at the University burgh. Spearheaded by HHMI’s new Science Education of Pittsburgh. Sarah C.R. Elgin at Washington University Alliance (SEA) program, a genomics course is being in St. Louis, HHMI undergraduate program director Brad developed to engage undergraduates from colleges Goodner at Hiram College in Ohio, and A. Malcolm around the country in a research project at the earliest Campbell, director of the HHMI-supported Genome Con- stage in their education. sortium for Active Teaching at Davidson College in North “The course is primarily geared toward freshmen. Carolina, served as advisers. Students in the program We hope they are going to be a national community of will isolate and characterize novel bacteriophages— undergraduate scholars engaged in authentic research,” viruses that infect bacteria—and analyze the viral genomic says SEA director Tuajuanda Jordan. DNA. The DNA will be sent to the Joint Genome Institute SEA, which will be headquartered at the Janelia Farm in Walnut Creek, California, for cloning and sequencing. Research Campus in Northern Virginia, aims to become The students will then finish, annotate, and compare a national resource for science education by develop- DNA sequences. Planning for the pilot project began in ing materials and methods and distributing them to summer 2007, and it was launched at the University of the undergraduate education community. SEA will also Pittsburgh in fall 2007. Jordan will recruit 12 colleges and assemble and support educator networks working on universities to participate in the project in the 2008– common activities. The national genomics experi- 2009 academic year. ment is its first project. “SEA represents the next step “This course is a way to expose students to how in HHMI’s education initiatives,” says Peter J. Bruns, science is done in the real world,” Jordan says. “In the HHMI vice president for grants and special programs. long term, we hope that giving students a great re- “Until now, we have been funding programs. Now we search experience early on will encourage more of will play an active role in their development.” them to become scientists.”

36 Howard Hughes 2007 Medical Institute Annual Report

Q&A Engaging a. malcolm Campbell Undergraduates in Genomics Research

A. Malcolm Campbell is a How was GCAT created? [a Davidson mathematics pro- What’s next for GCAT? professor of biology at fessor] and her undergraduate Davidson College and found- students developed an opening director of the Genome The idea for GCAT first came source, JAVA-based analysis We’re trying to expose schools Consortium for Active when I learned about micro software called MAGIC Tool. to the excitement and feasibility Teaching (GCAT)—an HHMI- arrays at a conference in 1998. GCAT has allowed under- of conducting synthetic biology supported program that Mary Lee Ledbetter [a biology graduates to move from doing research in undergraduate facilitates the use of modern professor from the College of single-gene experiments to classes. Synthetic biology ap- genomic methods in under- the Holy Cross] and I realized analyzing whole genomes. plies engineering principles to graduate education via a that our students could do genomic circuits to construct research-based curriculum. microarray experiments. GCAT How does GCAT foster the small devices—for example, a GCAT is a community of came into being because key development of a community strain of yeast capable of de- teachers and students work- people were willing to donate of learners? tecting different concentrations ing to improve the education services and materials to permit of caffeine. It fosters collabo- of tomorrow’s life-sciences us to develop the protocols, ration and encourages students professionals. During the conduct the research, and an- GCAT has allowed students and faculty to think creatively 2007–2008 school year, alyze the data. Foremost are and faculty to work as col- and across disciplines—and it’s approximately 5,000 under- the gutsy small-college faculty leagues as they decide what much cheaper than microarray graduates in liberal arts and who were willing to learn how research to pursue and analyze experiments. Because the field community colleges in the to do microarray experiments the data derived from the micro- is so new, it offers opportunities United States and in Canada along with their students in or- arrays. This year, two manu- for undergraduates to make will participate. der to bring genomics into their scripts authored by faculty and real contributions. curricula. HHMI investigator undergraduates have been Patrick O. Brown of Stanford accepted or published, and at University donated microarrays least two more are under review. for the first year, and Leroy Hood, cofounder of the Institute for Systems Biology in Seattle, the next two years. Laurie Heyer

37 What’s Building Communities Next? of Learning

Diversifying Science Reaching the Scientists Entering college freshmen from underrepresented Since January 2006, HHMI and the journal Science have minority and disadvantaged groups are just as inter- collaborated on a once-monthly section in the publi- ested in science as other students. While they repre- cation showcasing innovative approaches to teaching sent 23 percent of all college students, at gradua- science. The continuing series of peer-reviewed teach- tion they earn only 13 percent of the science and ing papers has included topics such as using authentic engineering degrees. “We’ve been losing them in our research experiences to teach science, research own house,” says Michael F. Summers, a chemist and universities partnering with local schools to raise the HHMI investigator at the University of Maryland, Bal- level of science education, and innovative methods to timore County. teach mathematics. Inspired by discussions between HHMI professors “The collaboration is valuable because it provides a and undergraduate program directors at a 2004 meet- high profile for science education innovation and gives ing, HHMI launched a series of symposia on diversity people who are involved in it a valued publication out- in the sciences to showcase successful diversity pro- let,” says Peter J. Bruns, HHMI vice president for grants grams and encourage institutions to replicate or adapt and special programs. He points out that the collabo- them. “Diversity in the sciences is about making sure ration supports HHMI’s efforts to couple education we don’t lose the insights that come from a range of ex- with the way scientists do research. “Besides,” he says, periences and backgrounds,” says symposia codirector “we want to reach scientists, and Science is one place Robert Lue of Harvard University. where they are.” Conducted at three locations—Harvard University, the Education Forum articles are available at University of Louisiana at Monroe, and the University www.sciencemag.org/sciext/educationforum. of Washington, Seattle—76 colleges and universities serving an estimated 915,000 students participated in learning about model programs to increase diversity in the sciences. These programs provide early hands- on research opportunities, promote student-faculty interactions, and build a sense of community. Other strategies to increase academic success include intense mentoring by faculty or peers, summer courses to teach study skills, refocusing the way introductory courses are taught, and having students study in groups. Students were key participants. Symposia codirector “Diversity in the sciences Wendy Raymond, an HHMI undergraduate program is about making sure we director at Williams College, notes that their perspectives had a powerful impact on faculty and administration don’t lose the insights attitudes about diversity. that come from a range The series wraps up in early 2008 at a meeting at of experiences and HHMI’s Chevy Chase, Maryland, headquarters. backgrounds.”

—Robert Lue

38 Howard Hughes 2007 Medical Institute Annual Report

“Many of these institutions are reaching out to traditionally underserved populations. They are also engaging girls in science at a particularly critical time in their educational development.” Middle school students at a Duke University summer program —Jill Conley isolated DNA from strawberries.

It’s Never Too Early Medical schools, hospitals, and other biomedical re- The Jackson Laboratory in Bar Harbor, Maine, is reach- search institutions in communities around the country ing out to high school students and their teachers. The are sparking a love and understanding of science, Summer Student Program encourages minority and un- particularly among young students. HHMI has com- derserved students from around the country to spend mitted $22.5 million over five years to 31 institutions the summer engaged in cutting-edge research. Locally, to support their outreach efforts to students in kin- the lab hosts high school students for year-long intern- dergarten through 12th grade, as well as teachers, ships. Maine math and science teachers have the op- families, and other community members. “These grants portunity to take research sabbaticals at the lab. provide a unique opportunity for the biomedical re- Together, the grants will help broaden access to sci- search community to provide hands-on experiences ence across diverse populations. “Many of these insti- and rich content to students and teachers,” says tutions are reaching out to traditionally underserved Peter J. Bruns, HHMI vice president for grants and populations,” says Jill Conley, director of HHMI’s pre- special programs. college science education program. “They are also At Virginia Commonwealth University in Richmond, engaging girls in science at a particularly critical time for example, graduate students and postdoctoral fel- in their educational development.” lows are helping local teachers introduce their students to systems biology—a field focusing on the cell or organism as a whole to better understand disease. In Honolulu, the Queen’s Medical Center is presenting a series of health-science evenings for families to improve health literacy and help Native Hawaiian and Pacific Islander students pursue careers in biomedicine.

39 What’s Building Communities Next? of Learning

Science Posses and Bioprospectors Research scientists selected to be HHMI professors receive $1 million each to put innovative ideas for undergraduate science education into practice. Their efforts to ignite and sustain the scientific spark in a new generation of students are taking them from the rain forest to the inner city. Irving R. Epstein, a chemist at Brandeis University, is working with the Posse Foundation of New York to “It’s not just the diversity form a science posse. The foundation has helped more of faces that matters. than 1,500 inner-city high school students from diverse It’s the diversity of backgrounds thrive at top colleges and universities. It provides students with academic and life skills, mentors, ways of looking at the and regular support at college. The program has one problem.” flaw, however: it hasn’t produced scientists. By tweaking this successful program to include paid —Irving R. Epstein laboratory research positions and a two-week “boot camp” during the summer to bring students’ science skills up to speed, Epstein hopes the 10 New York City–area students who will enter Brandeis in fall 2008 will one day help to diversify the scientific community. “It’s not just the diversity of faces that matters. It’s the diversity of ways of looking at the problem,” Epstein says. “It’s important to get people who don’t all think the same way.” Scott A. Strobel, a molecular biophysicist at Yale University, takes undergraduates from the classroom to the Amazon rain forest and then back to the laboratory to immerse them in the processes of science. Developed with his father, Gary Strobel, a plant scientist from Montana State University, the year-long program has students “bioprospecting” for micro organisms that produce biologically active compounds in plants. After a semester-long seminar, students plan their research projects. During the first Amazon HHMI professor Scott Strobel took expedition, one student collected plants native peo- undergraduate students “bioprospecting” ple used to treat tuberculosis, and another sought out in the Amazon rain forest. trees producing a potential drug-addiction therapy. When the students return from the jungle, they classify and analyze the microbes and then study bioactive molecules extracted from their cultures. The program began its second of four years in September 2007.

40 September 1, 2006–August 31, 2007 year in review

Janelia Farm Research Campus What’s Next?

anelia Farm Research Campus

of this campus, HHMI has yet another venue from which to implement its core belief—that when creative, imagi- native scientists are given the freedom, flexibility, and support to pursue their dreams, they can change the world.”

International Research Scholars Meeting Janelia Farm hosted its first international scientific meeting on September 26–29, 2006. HHMI international research scholars—top biomedical scientists representing 28 countries—gathered to share insights and data from their latest research on some of the world’s toughest medical challenges, including tuberculosis, malaria, and antibiotic resistance. “The campus and the culture of Janelia Nobel laureates gathered for Janelia Farm’s opening symposium. From left: HHMI investigators Roderick Farm were designed to support and MacKinnon and Richard Axel; Janelia Farm senior fellow Sydney Brenner; HHMI Trustees Paul Nurse and encourage collaborative, interdisciplin- Joseph Goldstein; HHMI president Thomas Cech; and HHMI investigators Linda Buck and Eric Kandel. ary research,” says Thomas R. Cech, HHMI president. “Those attributes A New Scientific Community make Janelia Farm a perfect location Opens for Discovery to host a meeting where researchers After six years of intense planning, can share ideas about developing new construction, and recruiting, HHMI cel- scientific strategies for combating ebrated the opening of the Janelia Farm the challenging global problems that Research Campus with five days of HHMI’s international scientists have events in early October 2006. Nearly chosen to tackle.” 300 scientific, civic, and business leaders gathered on October 3 for a gala Visiting Scientist Program dinner to formally open the campus. The Janelia Farm director Gerald M. Rubin spoke to a The visiting scientist program encour- following day, a scientific symposium, packed auditorium at the public open house. ages individual researchers and teams attended by more than 200 scientists, to work on short- and long-term projects HHMI Trustees, and guests, focused on headquarters in Chevy Chase, Maryland, at Janelia Farm. Over the past year, major challenges and opportunities in and a public open house that attracted Janelia Farm welcomed more than neuroscience. Local officials and other more than 3,000 visitors for a day of 20 visiting scientists from the United notables from Loudoun County, Virginia, talks and tours. States, Germany, England, Canada, had an opportunity to view the facilities “The opening of Janelia Farm is a and France to collaborate with Janelia and meet Janelia staff at a reception on watershed event in the history of researchers. About one-fourth were October 5. Closing the festivities were this Institute,” says HHMI president HHMI investigators. Their projects ranged an open house for staff from HHMI’s Thomas R. Cech. “With the creation from two weeks to a year or more.

42 Howard Hughes 2007 Medical Institute Annual Report

Janelia Graduate Program HHMI launched its Janelia Farm graduate program, developed in partnership with the University of Chicago and the University of Cambridge, in September 2006. Students have the choice of earning their doctoral degree from either university, where they generally spend their first year. In most cases, the students conduct research along- side Janelia scientists for the remaining three or four years. “The combination of small labs, an intense research atmo- sphere, unique resources, and creative people makes Janelia an outstanding place to train as a new scientist,” says Gerald M. Rubin, Janelia Farm director. The first student chosen for the graduate program began his studies at the University of Chicago in summer 2007. Janelia Farm lab

Lab of the Year Award will be a magnet for collaboration and improving brightness, signal change, and R&D Magazine, a monthly publication innovation,” says Rick Johnson, one of photostability of a family of genetically highlighting technologies and strategies the judges for the award. “The campus encoded glutamate sensors; building for research and development, named offers all the amenities for discovery— an experimental apparatus to study the the Janelia Farm Research Campus its interaction, stimulation, collaboration, fruit fly’s response to gravity; and studying 2007 Lab of the Year. The criteria for the and a high quality of life and well-being.” the anatomy of the fruit fly brain. Julie award include utility, safety, and archi- Ron Garikes, another award judge, adds, Simpson, a Janelia Farm scientist who tecturally distinguished design that en- “The scale of the structures comple- welcomed a student into her lab, hances the research experience. “Janelia ments the expansive site. The planners hopes the undergraduate program will and architects created an elegant design help “convert smart young minds to solution that also works from a flow, neuroscience.” Janelia plans to expand functionality, and aesthetic perspective.” the program to at least eight students in summer 2008. Summer Research Program for Undergraduates First Season of Janelia In summer 2007, four students partici- Conferences pated in a 10-week pilot program for More than 300 scientists attended the undergraduate research at Janelia first season of Janelia conferences in Farm. Living in on-campus housing, spring 2007. These small, specialized they worked with Janelia scientists on meetings focus primarily on areas cen- a variety of projects: exploring the neutral to the research interests of Janelia First level of Janelia Farm’s laboratory building ral basis of decision making in mice; Farm, and they are intended to foster

43 What’s Next?

collaborative interactions and rapid scientific advances. Participants in the six spring conferences included Janelia Farm scientists, HHMI investigators, HHMI professors, graduate students, and postdoctoral associates. More than 20 percent of the attendees came from outside the United States, including Germany, Japan, the Netherlands, Australia, Italy, China, France, and Switzerland. Topics included “Visual Processing in Insects,” “Expanding the Genetic Toolkit in Mouse,” and “Neural Circuits and Behavior in C. elegans.” Plans call for Janelia to hold about 15 such conferences each year.

Scientists attending conferences at Janelia Farm stay in guest housing on campus.

Five scientists were selected to join Janelia Farm in 2007, bringing New Janelia the total number of research groups to 24. Resident scientists Farm Scientists generally fall into two main categories: group leaders and fellows. Group leaders direct research teams of two to six members, and fellows lead teams of up to two members.

Joshua T. Dudman Albert K. Lee Anthony Leonardo Lynn M. Riddiford James W. Truman Fellow Group leader Group leader Senior fellow Group leader Neurobiologist Neurobiologist Systems neuroscientist Developmental biologist Developmental Uses electrophysiologi- Studies the neural Uses computational Studies the hormonal neuroscientist cal, imaging, and com- basis of learning and experimental tech- control of insect Studies neuronal circuit putational techniques and memory. niques to understand growth, molting, and formation in Drosophila. to explore sensorimotor how behaviors emerge metamorphosis. integration. from neural circuits.

44 Howard Hughes 2007 Medical Institute Annual Report

Institute News

New Public Access Policy beginning their careers. Wellcome Trust in bridging the gap between basic re- for Research Articles postdocs can work in any of the HHMI search and clinical medicine. The other After extensive consultation within the laboratories in the United States, while sought early career scientists studying HHMI community, the Institute announced those from HHMI labs can work in one biomedical problems in a broad array in June 2007 that it will require its scien- of a number of Wellcome Trust laborato- of disciplines, including not only biology tists to publish original research articles ries in the United Kingdom. “The knowl- and medicine but also related areas of in scientific journals that allow the arti- edge and experience that they will gain chemistry, physics, engineering, and cles and supplementary materials to be through the exchange program will be computational biology. The Institute plans made freely accessible in a public repos invaluable to them and will help forge to select approximately 15 physician- itory within six months of publication. links between international research scientists and 50 general biomedical the policy applies to all manuscripts groups,” says Pat Goodwin, head of im- researchers. Unlike all previous investi- submitted on or after January 1, 2008, and munology and infectious disease funding gator competitions, faculty at eligible is an extension of existing policies that at the Wellcome Trust. institutions were able to apply directly require HHMI scientists to share published to HHMI—institutional nominations research materials, databases, and soft- HHMI Forges Partnerships were not part of the process. Selections ware in a timely and useful fashion. Col- to Support Postdoctoral will be announced in fall 2007 for the laborative research articles on which an Research physician-scientist competition and in HHMI scientist is not a major author are HHMI increased its support of outstand- spring 2008 for the general competition. not subject to the policy, but HHMI strong- ing young scientists by entering into ly encourages its scientists and collabo- new collaborations with the Jane Coffin Colleges Compete for rators to meet its public access standards. Childs Memorial Fund, the Helen Hay Education Grants pubMed Central, the free digital ar- Whitney Foundation, and the Damon More than 200 baccalaureate colleges chive of biomedical and life sciences Runyon Cancer Research Foundation and master’s-level universities were literature maintained by the National and renewing its collaboration with the invited to compete for $60 million in grant Institutes of Health, has been designated Life Sciences Research Foundation. The funding to support science education. as the repository for journals in the bio- Institute will fund up to 16 postdoctoral The Institute expects to award approxi- logical sciences. Articles published in fellows annually, who will conduct mately 50 grants ranging from $800,000 journals from other fields are expected research in the laboratories of HHMI in- to $1.6 million to support innovative to be deposited in comparable reposito- vestigators. The fellows receiving HHMI programs that strengthen undergraduate ries and made publicly available within support will be selected competitively research, mentoring, interdisciplinary six months. by the four fellowship organizations. This research, and the computational skills funding allows each of the organizations of students and faculty. Through this HHMI and Wellcome Trust to offer more fellowships than they would competition, HHMI seeks to buttress the Establish International otherwise. The fellowships have three- research capacity of college science Postdoctoral Fellowships year terms, and fellows will be employed departments as it relates to teaching, as HHMI and the Wellcome Trust launched by HHMI. well as to integrate the life sciences an exchange program that enables with disciplines such as mathematics and postdoctoral researchers in the two in- Two Competitions for HHMI computer science in a way that reflects stitutes’ laboratories to spend up to a Investigators the increasingly quantitative nature of year working abroad. The program is de- HHMI held two national investigator modern biological research. The awards signed to promote scientific collaboration competitions this year. The first was will be announced in May 2008. and research opportunities for scientists aimed at physician-scientists interested

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Grants & Fellowships

five Gilliam Fellows selected After proving their mettle as undergraduates doing summer research in HHMI-supported laboratories, five promising young scientists received HHMI’s 2007 Gilliam Fellowships for Advanced Study. The competitive awards provide support for doctoral studies Irene C. Blat Veder J. Garcia in the life sciences to students who are Fluent in Spanish, Blat has volunteered Garcia’s interest in plant biology took from groups underrepresented in the as a translator at free medical clinics root during childhood visits to his sciences or from disadvantaged back- in immigrant communities in Charlotte, grandparents’ farm in El Salvador. grounds. The fellowships are named North Carolina. As an EXROP student, The first in his family to go to college, for the late James H. Gilliam Jr., an she worked with HHMI investigator Tania Garcia graduated with honors and HHMI Trustee who devoted his life to Baker at the Massachusetts Institute of was designated as the Botanical fostering excellence and diversity in Technology to understand how the viral Society of America’s 2006 Young education and science. protein MuB facilitates infection. Blat Botanist of the Year. He hopes to work gilliam fellows are selected from a wants to become an academic biomedical with Salvadoran biology professors to pool of undergraduate students who researcher and stay involved in helping improve environmental education. participated in HHMI’s Exceptional her community. Research Opportunities Program (EXROP). Over the past five summers, more than 200 EXROP students have conducted research in the labs of HHMI investigators and HHMI professors. “The Gilliam fellows are exceptional young people with enormous potential and a burning desire to do biomedical research,” says Thomas R. Cech, HHMI president. “Jim Gilliam would be proud Nisha M. Broodie Eunha Kim to know that fellowships in his name Losing her mother to breast cancer Kim left her family behind in South Korea are enabling these talented students contributed to Broodie’s determination to pursue an education in the United to pursue scientific careers and help to pursue a career in biomedical science. States. She earned bachelor’s and diversify the ranks of American science As an EXROP student, her work in the lab master’s degrees in molecular, cell, and professors.” of HHMI investigator Li-Huei Tsai at the developmental biology and envisions Massachusetts Institute of Technology one day running her own lab and curing helped implicate DNA damage in the diseases such as the one she suffers progression of neurodegenerative dis- from—fibromyalgia, a disorder that causes orders such as Alzheimer’s disease. chronic muscle pain and fatigue.

46 Howard Hughes 2007 Medical Institute Annual Report

Jose A. Rodriguez Arriving in the United States from Jalisco, Mexico, with his family at the age of five, Rodriguez knew no English. In high school, he took advanced-placement science and math classes while working Physician-scientist Charlotte Sumner, recipient of an early career award, as a busboy 20 hours a week. Now a in her lab at the Johns Hopkins University. biophysics major, Rodriguez hopes “to channel the current explosion of Awards Support Physician- International Research technological innovation into the field Scientists’ research Scholars receive awards of biomedical research.” The Physician-Scientist Early Career Award Thirty-nine scientists from Argentina, initiative provides support to promising Brazil, Canada, Chile, Mexico, and young physicians who want to pursue Venezuela were named HHMI international careers in academic biomedical research. research scholars for their accomplish- The 20 awardees selected in 2007 will ments and promising biomedical research. each receive $375,000 over five years Chosen from 546 applicants, each scholar for direct research expenses, and they receives a five-year grant totaling will devote at least 70 percent of their $250,000 to $500,000. “These scientists time to research. The awards are avail- are recognized pacesetters in their fields,” able to alumni of the HHMI Research notes Peter J. Bruns, HHMI vice president Training Fellowships for Medical Students for grants and special programs. and the HHMI–National Institutes of Health Launched in 1991, the international Research Scholars Program. research scholars program supports “Physician-scientists are uniquely outstanding scientists in their own positioned to translate research discov- countries, linking them with each other eries into direct benefits for patients,” and with HHMI scientists in the United says Peter J. Bruns, HHMI vice president States to create an international network for grants and special programs. “The of scientific excellence.T he Institute has research these talented young scientists awarded more than $100 million in grants are doing has the potential to have a to scientists in 32 countries. These new tremendous impact on public health.” awards are HHMI’s fourth round to scientists in Canada and Latin America.

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Research Highlights

In laboratories across the United States, some 300 HHMI investigators and their research groups are advancing knowledge in the most challenging areas of biomedical research today. And in 28 countries around the world, more than 100 international research scholars, who receive grant support from HHMI, are making significant contributions to understanding basic biological processes and disease mechanisms. Highlighted here is a sampling of the important research findings in fiscal year 2007. To learn more about the latest research by HHMI scientists, visit www.hhmi.org/news/research.html.

Switching off Aging in that affects humans who have Sleeping Sickness Parasite Stem Cells SCA3, a disorder that causes loss Can’t Live with Stress A single molecular switch induces of motor coordination. stem cells in the brain, pancreas, Nancy M. Bonini, University of and blood to lose function as they Pennsylvania age. Mice without this switch show considerably reduced aging-related Focusing on Cancer’s decline in stem cell function and Complexity tissue regeneration. In the first large-scale screen of The parasite responsible for African Sean J. Morrison, University of genetic changes in cancer cells, HHMI sleeping sickness causes its victims Michigan Medical School researchers found that a typical plenty of sleepless nights—but the breast or colorectal tumor results parasite itself does not cope well Fruit Fly Model Mimics from mutations in about 90 genes. with stress. New research shows that Genetic Instability of Human Different sets of mutations produce the parasite’s natural response to Neurodegenerative Diseases the same type of cancer. stress is enough to kill it, a weak- Bert Vogelstein, The Johns Hopkins ness that researchers may be able University School of Medicine to exploit. Sanford Markowitz, Case Western Shulamit Michaeli, Bar-Ilan Reserve University School of Medicine University, Israel

Analysis Reveals Extent of Disabling a Sensory Organ DNA Repair Army Prompts Female Mice to Act A new database reveals a 700- Like Male Mice member army of proteins involved By short-circuiting the sensory in the DNA repair response. Scien- organ that detects the chemical Researchers developed a fruit fly tists have already used the database cues mice use to attract mates, model that replicates the genetic to identify two proteins critical to HHMI researchers prompted fe- instability seen in a variety of neuro recruiting BRCA1 to the sites of male mice to behave like male degenerative diseases, including DNA damage. mice in the throes of courtship. spinocerebellar ataxia type 3 (SCA3) Stephen J. Elledge, Brigham and The finding suggests that the neural and Huntington’s disease. The model Women’s Hospital circuits that govern gender-specific carries the same genetic mutation behaviors, such as aggression and

48 Howard Hughes 2007 Medical Institute Annual Report

abnormal activation of four genes drives the spread of breast cancer to the lungs. The studies reveal that the aberrant genes work together to promote the growth of primary breast tumors. Joan Massagué, Memorial Sloan- Kettering Cancer Center lapping with their sister dendrites. courtship, are similar in male and Bacterial Walls Come Researchers found that a much- female brains. Tumbling Down studied gene provides branches of Catherine Dulac, Harvard University nerve cells with the ability to recognize one another and grow apart. Structural Biology Reveals S. Lawrence Zipursky, University How T Cells Recognize of California, Los Angeles Transplanted Tissue Yuh Nung Jan, University of California, San Francisco Lily Y. Jan, University of California, San Francisco

The first detailed images of an Handicapping Tuberculosis elusive drug target in an enzyme May Be the Way to a Better HHMI researchers established how produced on the outer wall of Vaccine the structure of receptors on the bacteria may provide scientists surface of T cells enables them to with enough information to aid recognize self and foreign cells. design of novel antibiotics. The The research could lead to ways to drugs are needed to treat deadly improve the body’s acceptance of infections initiated by Staphylococcus transplanted tissue. aureus and other bacterial patho- K. Christopher Garcia, Stanford gens. The enzyme above has an A genetically altered strain of tuber- University School of Medicine antibiotic bound to the blue region. culosis developed by HHMI scientists Natalie C.J. Strynadka, University and their colleagues elicits a stron- A Genetic “Gang of Four” of British Columbia, Canada ger immune response than the Drives Spread of Breast Cancer current vaccine, bacillus Calmette- Gene Helps Distinguish Self Guérin. The new vaccine improves from Non-Self During Neural survival of infected mice and may Development help put scientists on track to replace The dendritic limbs of developing bacillus Calmette-Guérin, which nerve cells must organize them- has been used for nearly a century. selves to cover as much space as William R. Jacobs Jr., Albert Einstein Studies of human tumor cells they can evenly and efficiently.T hey College of Medicine implanted in mice show that the must also take care to avoid over-

49 What’s Next?

Seeing a Neurotoxin’s In a pioneering study of rhesus Lithium Eases Symptoms of Deadly Grip macaque monkeys, HHMI researchers Fatal Neurological Disorder caught primates in the act of prob- abilistic reasoning. They measured the electrical activity in brain cells as the animals made choices on the basis of their interpretation of a set of visual cues and the potential for reward. Studies in mice have shown that Michael N. Shadlen, University of lithium, a drug widely used to treat Washington School of Medicine mood disorders in humans, can provide relief from the crushing Enhanced Environment symptoms of a fatal brain disease. Two HHMI research teams working Restores Memory in Mice HHMI researchers did a series independently discovered new in- with Neurodegeneration of experiments in mice that showed formation about how the botulinum lithium can ease the symptoms neurotoxin (gray and green above) of spinocerebellar ataxia type 1, shuts down neurons with deadly an inherited neurodegenerative efficiency. By providing detailed disorder. views of the toxin plugged into its Huda Y. Zoghbi, Baylor College of neuronal receptor, the studies could Medicine aid efforts to engineer specialized versions of botulinum neurotoxin Muscle Repair Depends on for treating a wide array of medical Multiple Cell Types problems. Researchers identified a population Axel T. Brunger, Stanford University Mice whose brains were devastated of stem cells that repair muscle Edwin R. Chapman, University of by neurodegeneration regained after damage. Researchers had as- Wisconsin–Madison long-term memories and the ability sumed that all these cells, called to learn after their surroundings satellite cells, had similar properties. Study Reveals Primates, were enriched with toys and other They all seemed to follow the same and Their Neurons, in the sensory stimuli. Scientists achieved developmental path to becoming Act of Reasoning the same results when they treated mature muscle. The new discoveries the mice with a specific type of drug show that the developmental fate that encourages neuronal growth. of a given satellite cell depends on The studies suggest two promising its physical orientation immediately avenues for treatment that might after cell division. alleviate learning deficits and mem- Michael A. Rudnicki, Ottawa ory loss in humans with Alzheimer’s Health Research Institute, Canada Every day, humans make thousands disease or other neurodegenerative of decisions using the information diseases. at hand and their assessment of the Li-Huei Tsai, Massachusetts potential outcome of those choices. Institute of Technology

50 Howard Hughes 2007 Medical Institute Annual Report

Honors & Awards

Szostak Wins Lasker Award Steitz Wins Gairdner Award The 2006 Albert Lasker Award for Basic HHMI investigator Thomas A. Steitz of Medical Research was awarded to Yale University and his colleague Harry F. HHMI investigator Jack W. Szostak of Noller of the University of California, Massachusetts General Hospital, Carol Santa Cruz, were among the five recipients Jack W. Szostak W. Greider of Johns Hopkins University, of the 2007 Gairdner Foundation Inter- Thomas A. Steitz and Elizabeth H. Blackburn of the Uni- national Award. Each awardee received versity of California, San Francisco, for a $30,000 prize. Steitz and Noller are their research on telomerase, the en- credited with identifying the detailed zyme responsible for maintaining the structure and function of the ribosome, ends of chromosomes. Telomerase is the subcellular structure where proteins closely tied to human cancers and ag- are synthesized. Their work has led to ing. The award, given by the Albert and the development of antibiotics that Mary Lasker Foundation, honors “out- have the potential to circumvent resis- standing contributions in basic and clin- tance. The Gairdner Award is presented ical research.” to medical scientists whose work is expected to significantly improve quality Two Investigators of life. Receive Albany Prize HHMI investigators Ronald M. Evans, Lefkowitz Awarded The Salk Institute for Biological Studies, Shaw Prize and Robert J. Lefkowitz, Duke University Robert J. Lefkowitz, an HHMI investiga- Ronald M. Evans Medical Center, were awarded the tor at Duke University Medical Center, Albany Medical Center’s 2007 Prize in was awarded the $1 million Shaw Prize Medicine and Biomedical Research, the in Life Science and Medicine. The inter- Robert J. Lefkowitz largest prize in medicine in the United national award is given to researchers States. The Albany Prize recognizes ex- whose work has achieved worldwide traordinary and sustained contributions significance. Lefkowitz was recognized to improving health care and promoting for “his relentless elucidation of the ma- biomedical research with translational jor receptor system that mediates the benefits for patient treatment. Evans response of cells and organs to drugs and Lefkowitz, along with Solomon H. and hormones.” He is renowned for his Snyder of the Johns Hopkins School of work on G protein–coupled receptors, Medicine, shared the $500,000 award. transmembrane receptors found The three researchers were recognized throughout the body that are the targets for discoveries that reveal how cells use of many well-known pharmaceuticals. receptor molecules to communicate with their environment.

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HHMI Scientists Elected to National Academy of Royal Society Sciences Elects 11 The Fellowship of the Royal Society, In May 2007, 11 HHMI investigators were the national academy of science of the elected to the National Academy of Sci- United Kingdom, elected two HHMI ences. The investigators are David A. Gerald M. Rubin scientists in 2007. Gerald M. Rubin, Agard, University of California, San Fran- HHMI vice president and director of the cisco; David J. Anderson, California Janelia Farm Research Campus, was Institute of Technology; Tania A. Baker, elected as a foreign member for his Massachusetts Institute of Technology; contributions to the field ofDrosophila Sean B. Carroll, University of Wisconsin– genetics and development. HHMI inves- Madison; Brian J. Druker, Oregon Health tigator Morgan Sheng, who studies & Science University; Scott D. Emr, Uni- synaptic ion-channel complexes at the versity of California, San Diego; David Morgan Sheng Massachusetts Institute of Technology, Ginsburg, University of Michigan Medical was elected as a fellow. School; Helen H. Hobbs, University of Tex- as Southwestern Medical Center at Dallas; Eight Elected to the Christopher Miller, Brandeis University; Institute of Medicine Gerald I. Shulman, Yale University School The Institute of Medicine of the National of Medicine; and Wayne M. Yokoyama, Academies elected seven HHMI inves Washington University School of Medicine tigators and one HMMI professor in in St. Louis. October 2006. Members are elected through a highly selective process that National Academy of recognizes people who have made ma- Sciences Honors Six jor contributions to the advancement of HHMI Researchers medical sciences, health care, and public The National Academy of Sciences (NAS) health. The investigators are Linda B. honored six HHMI scientists in April Buck, Fred Hutchinson Cancer Research 2007 with various awards for their out- Center; Stephen J. Elledge, Brigham standing scientific achievements. and Women’s Hospital; Richard A. Flavell, Xiaodong Wang, HHMI investigator at Yale University School of Medicine; the University of Texas Southwestern Stephen P. Goff, Columbia University Medical Center at Dallas, received the College of Physicians and Surgeons; Richard Lounsbery Award for his pio- Susan L. Lindquist, Massachusetts neering work on apoptosis. Institute of Technology; Joan Massagué, the NAS Award in Molecular Biology Memorial Sloan-Kettering Cancer was given to HHMI investigator Gregory J. Center; and Charles S. Zuker, Univer- Hannon of Cold Spring Harbor Laboratory sity of California, San Diego. The for “elucidation of the enzymatic engine HHMI professor is Baldomero Olivera, for RNA interference.” University of Utah. Randy L. Buckner, an HHMI investigator at Harvard University, received one of the Troland Research Awards for

52 Howard Hughes 2007 Medical Institute Annual Report

his “substantive contributions to under- Michel C. Nussenzweig, The Rockefeller standing of the neural mechanisms of University; and Helen Piwnica-Worms, memory formation and retrieval.” Washington University School of Medicine HHMI investigator Jeffrey M. Friedman in St. Louis. The professors are Baldomero at Rockefeller University was given the Olivera of the University of Utah and Jessie Stevenson Kovalenko Medal for Susan R. Wessler of the University his work with leptin and its implications of Georgia. for obesity. the Alexander Hollaender Award in Two Win Bruce Biophysics went to Barry H. Honig, an Alberts Award HHMI investigator at Columbia University, HHMI professor Sarah C.R. Elgin, for his theoretical and computational Washington University in St. Louis, and studies of macromolecular interactions HHMI undergraduate program director and protein folding. A. Malcolm Campbell, Davidson College, Sarah C.R. Elgin HHMI professor Richard M. Losick of received the 2006 Bruce Alberts Award Harvard University was honored with for Excellence in Science Education from the Selman A. Waksman Award in Micro- the American Society for Cell Biology. biology for “discovering alternative bac- Both were recognized for giving under- terial sigma factors and his fundamental graduate students hands-on experience contributions to understanding the with genomics. Elgin is founder of the mechanism of bacterial sporulation.” Genomics in Education Program, which engages students in sequencing and an- A. Malcolm Campbell American Academy of Arts notating genomes. Campbell started the and Sciences Elects 12 Genome Consortium for Active Teaching, The American Academy of Arts and which aims to bring functional genomics Sciences elected 10 HHMI investigators into the undergraduate curriculum and 2 HHMI professors in April 2007. through research. The investigators are Brenda L. Bass, University of Utah School of Medicine; Bonnie L. Bassler, Princeton University; Nancy L. Craig, The Johns Hopkins University School of Medicine; Barry H. Honig, Columbia University; Lily Y. Jan, University of California, San Francisco; Yuh-Nung Jan, University of California, San Francisco; Robert A. Lamb, Northwestern University; Gail Mandel, Oregon Health & Science University;

53 Passages

David L. Garbers, a distinguished scientist and Frank William Gay, a business executive and an HHMI investigator for more than 30 years, died retired HHMI Trustee, died on May 21, 2007, in on September 5, 2006. He was 62 years old. Kingwood, Texas. He was 86.

Garbers was a professor of pharmacology and director Gay’s association with HHMI extended over more than of the Cecil H. and Ida Green Center for Reproductive 30 years. A business associate of Institute founder Biology Sciences at the University of Texas Southwestern Howard R. Hughes Jr., he was one of the eight original Medical Center in Dallas. His science focused on Trustees appointed by the Delaware Court of Chancery sperm biology and signal transduction. While at the to oversee HHMI. He served as a Trustee from 1984 to Vanderbilt University School of Medicine early in his 2006, providing thoughtful guidance and counsel dur- career, he discovered a novel family of receptors on the ing a period of transformation and growth for the Insti- sperm cells of sea urchins that enable sperm to swim tute. Before being appointed as a Trustee, Gay served in the right direction. He later found the same receptors on the Institute’s executive committee from 1971 to 1984. in higher organisms, including mammals. More recently, A successful business executive, Gay held a number of Garbers identified proteins expressed only on sperm positions during his career and association with Howard cells, including an ion channel that gives a sperm the Hughes. He was chairman of the board of directors of wiggle it needs to penetrate the egg membrane. His the Hughes Air Corporation, a senior vice president and research has opened opportunities for new contracep- member of the board of directors of the Hughes Tool tives and ways to increase fertility. Garbers’s scientific Company, and president and chief executive officer of interests also extended to stem cell biology and the Summa Corporation. Gay was active in a number of orga- development of techniques to grow male germ cells in nizations, including the Boy Scouts of America. A veteran the laboratory. of the U.S. Army and the Marine Corps, he was a gradu- garbers was a member of the National Academy of ate of Brigham Young University and was honored with Sciences, as well as the American Academy of Arts its Distinguished Alumni Award in 1976. and Sciences and the Academy of Medicine, Engineering, and Science of Texas.

54 Leadership HHMI Researchers Advisory Boards & Committees Fellowships & Grants Finance & Investments What’s Next?

Trustees & Officers

Trustees Jeremy R. Knowles, D.Phil. Officers James A. Baker, III, Esq. Amory Houghton Professor of Thomas R. Cech, Ph.D. Senior Partner Chemistry and Biochemistry President Baker & Botts Harvard University Craig A. Alexander Richard G. Darman William R. Lummis, Esq. Vice President and General Counsel Partner Former Chairman of the Board The Carlyle Group of Directors and Chief Executive Officer Peter J. Bruns, Ph.D. Chairman of the Board The Howard Hughes Corporation Vice President for Grants and AES Corp. (Through March 16, 2007) Special Programs

Joseph L. Goldstein, M.D. Paul Nurse, F.R.S. David A. Clayton, Ph.D. Regental Professor and Chairman President Vice President for Research Operations Department of Molecular Genetics The Rockefeller University University of Texas Southwestern Joseph D. Collins Medical Center at Dallas Kurt L. Schmoke, Esq. Vice President for Information Technology Dean Hanna H. Gray, Ph.D. Howard University School of Law Jack E. Dixon, Ph.D. Chairman Vice President and Chief Scientific Officer President Emeritus and Anne M. Tatlock (Effective February 1, 2007) Harry Pratt Judson Director, Retired Chairman and CEO Distinguished Service Fiduciary Trust Company Avice A. Meehan Professor of History International Vice President for Communications The University of Chicago and Public Affairs

Garnett L. Keith Edward J. Palmerino Chairman Vice President for Finance and Treasurer SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Gerald M. Rubin, Ph.D. Chief Investment Officer Vice President and Director, The Prudential Insurance Company Janelia Farm Research Campus of America Landis Zimmerman Vice President and Chief Investment Officer

Joan S. Leonard Senior Counsel to the President

56 Howard Hughes 2007 Medical Institute Annual Report

Principal Staff members

Stephen A. Barkanic Reid Knight Kevin Moses, Ph.D. Grants Program Director Director of Human Resources Associate Director for Science and (Through December 31, 2006) Training, Janelia Farm Research Campus Mark A. Barnard Managing Director, Robert J. Kolyer Jr. Robert C. Mullins Private Investments Managing Director, Diversifying Assets Controller

Josephine P. Briggs, M.D. M. Ram Lee Richard A. Pender Senior Scientific Officer Managing Director, Portfolio Strategies Managing Director, Global Equities

Seth Brown Martha Kay Lequeux Philip S. Perlman, Ph.D. Associate General Counsel Director of Human Resources Senior Scientific Officer (Effective April 2, 2007) Winfred J. Clingenpeel Pamela A. Phillips Director of Purchasing Dennis WC. Liu, Ph.D. Director of Research Operations Grants Program Director Jill G. Conley, Ph.D. Susan S. Plotnick Grants Program Director Gregory W. Loftin Assistant Treasurer Director of Internal Audit William R. Galey, Ph.D. Carl D. Rhodes, Ph.D. Grants Program Director Anil Madhok Scientific Officer Managing Director and Chief Heidi E. Henning Operating Officer, Investments Dianne J. Smith Deputy General Counsel Associate General Counsel Margaret Feczko May Marion M. Howard Associate General Counsel Lauren Talner Spiliotes Assistant Controller Associate General Counsel Edwin W. McCleskey, Ph.D. Stephen M. Kitsoulis Scientific Officer Sherry D. White, Ph.D. Managing Director, Fixed Income Director of Special Projects and Planning and Currencies Robert H. McGhee (Through February 2, 2007) Institute Architect and Senior Edward H. Klees Facilities Officer Glen M. Zwicker Associate General Counsel Associate General Counsel Cheryl A. Moore Chief Operating Officer, Janelia Farm Research Campus

57 What’s Next?

HHMI Investigators September 1, 2006–August 31, 2007

Arizona University of California, Berkeley Louis J. Ptácˇek, M.D. University of Arizona Adam P. Arkin, Ph.D. Louis F. Reichardt, Ph.D. Roy Parker, Ph.D. Carolyn R. Bertozzi, Ph.D. Kevan M. Shokat, Ph.D. Carlos Bustamante, Ph.D. Ronald D. Vale, Ph.D. California Jennifer A. Doudna, Ph.D. Peter Walter, Ph.D. California Institute of Technology John Kuriyan, Ph.D. Arthur Weiss, M.D., Ph.D. David J. Anderson, Ph.D. Barbara J. Meyer, Ph.D. Jonathan S. Weissman, Ph.D. Pamela J. Björkman, Ph.D. Eva Nogales, Ph.D. Raymond J. Deshaies, Ph.D. Nipam H. Patel, Ph.D. University of California, Santa Cruz Linda C. Hsieh-Wilson, Ph.D. Randy W. Schekman, Ph.D. David Haussler, Ph.D. Stephen L. Mayo, Ph.D. Robert Tjian, Ph.D. Dianne K. Newman, Ph.D. Colorado Douglas C. Rees, Ph.D. University of California, Los Angeles Colorado State University Erin M. Schuman, Ph.D. Douglas L. Black, Ph.D. Karolin Luger, Ph.D. Paul W. Sternberg, Ph.D. Edward M.F. De Robertis, M.D., Ph.D. David Eisenberg, D.Phil. National Jewish Medical and The Salk Institute for Biological Studies Steven E. Jacobsen, Ph.D. Research Center Joanne Chory, Ph.D. Stephen T. Smale, Ph.D. John W. Kappler, Ph.D. Sascha du Lac, Ph.D. Peter Tontonoz, M.D., Ph.D. Philippa Marrack, Ph.D. Ronald M. Evans, Ph.D. Owen N. Witte, M.D. Joseph P. Noel, Ph.D. S. Lawrence Zipursky, Ph.D. University of Colorado at Boulder Terrence J. Sejnowski, Ph.D. and Health Sciences Center Charles F. Stevens, M.D., Ph.D. University of California, San Diego Natalie G. Ahn, Ph.D. Steven F. Dowdy, Ph.D. Kristi S. Anseth, Ph.D. Stanford University Scott D. Emr, Ph.D. Min Han, Ph.D. Philip A. Beachy, Ph.D. Lawrence S.B. Goldstein, Ph.D. Patrick O. Brown, M.D., Ph.D. Yishi Jin, Ph.D. University of Colorado at Denver Axel T. Brunger, Ph.D. Jamey D. Marth, Ph.D. and Health Sciences Center Gerald R. Crabtree, M.D. J. Andrew McCammon, Ph.D. James L. Maller, Ph.D. Mark M. Davis, Ph.D. Michael G. Rosenfeld, M.D. Lee A. Niswander, Ph.D. K. Christopher Garcia, Ph.D. Susan S. Taylor, Ph.D. David M. Kingsley, Ph.D. Roger Y. Tsien, Ph.D. Connecticut Mark A. Krasnow, M.D., Ph.D. Charles S. Zuker, Ph.D. Yale University Liqun Luo, Ph.D. Ronald R. Breaker, Ph.D. Emmanuel Mignot, M.D., Ph.D. University of California, San Francisco Peter Cresswell, Ph.D. William T. Newsome, Ph.D. David A. Agard, Ph.D. Pietro De Camilli, M.D. Roel Nusse, Ph.D. Jason G. Cyster, Ph.D. Susan Ferro-Novick, Ph.D. Stephen R. Quake, D.Phil. Joseph L. DeRisi, Ph.D. Richard A. Flavell, Ph.D. Matthew P. Scott, Ph.D. Donald Ganem, M.D. Arthur L. Horwich, M.D. Lily Y. Jan, Ph.D. Richard P. Lifton, M.D., Ph.D. Yuh Nung Jan, Ph.D. Ruslan M. Medzhitov, Ph.D. Stephen G. Lisberger, Ph.D. Anna M. Pyle, Ph.D. Richard M. Locksley, M.D. G. Shirleen Roeder, Ph.D.

58 Howard Hughes 2007 Medical Institute Annual Report

David G. Schatz, Ph.D. The Johns Hopkins University Dana-Farber Cancer Institute Gerald I. Shulman, M.D., Ph.D. School of Medicine Todd R. Golub, M.D. Joan A. Steitz, Ph.D. Nancy L. Craig, Ph.D. William G. Kaelin Jr., M.D. Thomas A. Steitz, Ph.D. Harry C. Dietz, M.D. Tian Xu, Ph.D. David D. Ginty, Ph.D. Harvard Medical School Rachel Green, Ph.D. Constance L. Cepko, Ph.D. Illinois Richard L. Huganir, Ph.D. David P. Corey, Ph.D. Northwestern University Alex L. Kolodkin, Ph.D. Stephen C. Harrison, Ph.D. Robert A. Lamb, Ph.D., Sc.D. Jeremy Nathans, M.D., Ph.D. John H.R. Maunsell, Ph.D. Joseph S. Takahashi, Ph.D. Geraldine Seydoux, Ph.D. Norbert Perrimon, Ph.D. Robert F. Siliciano, M.D., Ph.D. Tom A. Rapoport, Ph.D. The University of Chicago Bert Vogelstein, M.D. Albert Bendelac, M.D., Ph.D. Cynthia Wolberger, Ph.D. Harvard University Bruce T. Lahn, Ph.D. Randy L. Buckner, Ph.D. Milan Mrksich, Ph.D. University of Maryland, Baltimore County Catherine Dulac, Ph.D. Joseph A. Piccirilli, Ph.D. Michael F. Summers, Ph.D. David R. Liu, Ph.D. Daphne Preuss, Ph.D. Douglas A. Melton, Ph.D. Harinder Singh, Ph.D. Massachusetts Erin K. O’Shea, Ph.D. Beth Israel Deaconess Medical Center Stuart L. Schreiber, Ph.D. University of Illinois at Christopher A. Walsh, M.D., Ph.D. Xiaowei Zhuang, Ph.D. Urbana-Champaign Taekjip Ha, Ph.D. Brandeis University Massachusetts General Hospital Nikolaus Grigorieff, Ph.D. Jeannie T. Lee, M.D., Ph.D. Iowa Dorothee Kern, Ph.D. Jack W. Szostak, Ph.D. The University of Iowa Christopher Miller, Ph.D. Bruce D. Walker, M.D. Kevin P. Campbell, Ph.D. Melissa J. Moore, Ph.D. Val C. Sheffield, M.D., Ph.D. Michael Rosbash, Ph.D. Massachusetts Institute Edwin M. Stone, M.D., Ph.D. of Technology Michael J. Welsh, M.D. Brigham and Women’s Hospital Angelika Amon, Ph.D. Stephen J. Elledge, Ph.D. Tania A. Baker, Ph.D. Maine D. Gary Gilliland, M.D., Ph.D. David P. Bartel, Ph.D. The Jackson Laboratory Mitzi I. Kuroda, Ph.D. Mark F. Bear, Ph.D. Susan L. Ackerman, Ph.D. Christine E. Seidman, M.D. Stephen P. Bell, Ph.D. Simon W.M. John, Ph.D. Matthew K. Waldor, M.D., Ph.D. H. Robert Horvitz, Ph.D. Richard O. Hynes, Ph.D. Maryland Children’s Hospital Boston Tyler Jacks, Ph.D. Carnegie Institution of Washington Frederick W. Alt, Ph.D. Susan L. Lindquist, Ph.D. Douglas E. Koshland, Ph.D. David E. Clapham, M.D., Ph.D. David C. Page, M.D. Allan C. Spradling, Ph.D. Louis M. Kunkel, Ph.D. H. Sebastian Seung, Ph.D. Yixian Zheng, Ph.D. Stuart H. Orkin, M.D. Morgan Sheng, M.B.B.S., Ph.D. Matthew L. Warman, M.D. Susumu Tonegawa, Ph.D. Morris F. White, Ph.D. Li-Huei Tsai, Ph.D. Leonard I. Zon, M.D.

59 What’s Next?

HHMI Investigators

Tufts University School of Medicine Rutgers, The State University Memorial Sloan-Kettering Andrew Camilli, Ph.D. of New Jersey Cancer Center Ralph R. Isberg, Ph.D. Richard H. Ebright, Ph.D. James P. Allison, Ph.D. Kenneth D. Irvine, Ph.D. Jonathan Goldberg, Ph.D. University of Massachusetts Joan Massagué, Ph.D. Medical School University of Medicine and Dentistry Nikola P. Pavletich, Ph.D. Roger J. Davis, Ph.D. of New Jersey–Robert Wood Johnson Michael R. Green, M.D., Ph.D. Medical School New York University Craig C. Mello, Ph.D. Ann M. Stock, Ph.D. Ruth Lehmann, Ph.D. Dan R. Littman, M.D., Ph.D. Michigan New York Danny Reinberg, Ph.D. University of Michigan Albert Einstein College of Eero P. Simoncelli, Ph.D. James C.A. Bardwell, Ph.D. Medicine of Yeshiva University David Ginsburg, M.D. William R. Jacobs Jr., Ph.D. The Rockefeller University Randal J. Kaufman, Ph.D. Cornelia I. Bargmann, Ph.D. Tom K.W. Kerppola, Ph.D. Cold Spring Harbor Laboratory Günter Blobel, M.D., Ph.D. Sean J. Morrison, Ph.D. Gregory J. Hannon, Ph.D. Robert B. Darnell, M.D., Ph.D. Scott W. Lowe, Ph.D. Jeffrey M. Friedman, M.D., Ph.D. Minnesota Elaine Fuchs, Ph.D. University of Minnesota Medical Columbia University College Nathaniel Heintz, Ph.D. School of Physicians and Surgeons A. James Hudspeth, M.D., Ph.D. Michael B. O’Connor, Ph.D. Richard Axel, M.D. Roderick MacKinnon, M.D. Stephen P. Goff, Ph.D. Michel C. Nussenzweig, M.D., Ph.D. Missouri Iva Greenwald, Ph.D. Michael E. O’Donnell, Ph.D. Stowers Institute for Medical Research Wayne A. Hendrickson, Ph.D. Hermann Steller, Ph.D. Olivier Pourquié, Ph.D. Oliver Hobert, Ph.D. Thomas Tuschl, Ph.D. Barry Honig, Ph.D. Washington University in St. Louis Thomas M. Jessell, Ph.D. North Carolina Daniel E. Goldberg, M.D., Ph.D. Eric R. Kandel, M.D. Duke University Eduardo A. Groisman, Ph.D. Steven A. Siegelbaum, Ph.D. Vann Bennett, M.D., Ph.D. Kenneth M. Murphy, M.D., Ph.D. Gary Struhl, Ph.D. Michael D. Ehlers, M.D., Ph.D. Helen Piwnica-Worms, Ph.D. Rafael Yuste, M.D., Ph.D. Robert J. Lefkowitz, M.D. J. Evan Sadler, M.D., Ph.D. Paul L. Modrich, Ph.D. Wayne M. Yokoyama, M.D. Cornell University, Joan and Robin P. Wharton, Ph.D. Sanford I. Weill Medical College John D. York, Ph.D. New Jersey Shahin Rafii, M.D. Princeton University University of North Carolina Bonnie L. Bassler, Ph.D. Health Research, Inc., at the at Chapel Hill Trudi Schüpbach, Ph.D. Wadsworth Center Yi Zhang, Ph.D. Eric F. Wieschaus, Ph.D. Joachim Frank, Ph.D.

60 Howard Hughes 2007 Medical Institute Annual Report

Ohio Texas Wilhelmus G.J. Hol, Ph.D. Case Western Reserve University Baylor College of Medicine Randall T. Moon, Ph.D. School of Medicine Hugo J. Bellen, D.V.M., Ph.D. Richard D. Palmiter, Ph.D. Sanford Markowitz, M.D., Ph.D. Brendan Lee, M.D., Ph.D. Fred Rieke, Ph.D. Huda Y. Zoghbi, M.D. Alexander Y. Rudensky, Ph.D. Oklahoma Michael N. Shadlen, M.D., Ph.D. Oklahoma Medical Research The University of Texas Southwestern William N. Zagotta, Ph.D. Foundation Medical Center at Dallas Charles T. Esmon, Ph.D. Zhijian “James” Chen, Ph.D. Wisconsin Johann Deisenhofer, Ph.D. University of Wisconsin–Madison Oregon David L. Garbers, Ph.D. Paul Ahlquist, Ph.D. Oregon Health and Science University Nick V. Grishin, Ph.D. Sean B. Carroll, Ph.D. Brian J. Druker, M.D. Helen H. Hobbs, M.D. Edwin R. Chapman, Ph.D. Eric Gouaux, Ph.D. David J. Mangelsdorf, Ph.D. Judith Kimble, Ph.D. Gail Mandel, Ph.D. Rama Ranganathan, M.D., Ph.D. Teresa Nicolson, Ph.D. Michael K. Rosen, Ph.D. Howard Hughes Medical Institute investigators John D. Scott, Ph.D. Thomas C. Südhof, M.D. conduct research in Institute laboratories at host Xiaodong Wang, Ph.D. institutions nationwide in concert with associated University of Oregon Masashi Yanagisawa, M.D., Ph.D. hospitals and medical schools.

Chris Q. Doe, Ph.D. For information on HHMI investigators active Brian W. Matthews, Ph.D., D.Sc. Utah after August 31, 2007, visit www.hhmi.org. University of Utah Pennsylvania Brenda L. Bass, Ph.D. The Children’s Hospital of Philadelphia Bradley R. Cairns, Ph.D. Katherine A. High, M.D. Mario R. Capecchi, Ph.D. Erik M. Jorgensen, Ph.D. University of Pennsylvania Alejandro Sánchez Alvarado, Ph.D. Morris J. Birnbaum, M.D., Ph.D. Nancy M. Bonini, Ph.D. Washington Gideon Dreyfuss, Ph.D. Fred Hutchinson Cancer Amita Sehgal, Ph.D. Research Center M. Celeste Simon, Ph.D. Linda B. Buck, Ph.D. Gregory D. Van Duyne, Ph.D. Steven Henikoff, Ph.D. Cecilia B. Moens, Ph.D. Tennessee James R. Priess, Ph.D. St. Jude Children’s Research Hospital Brenda A. Schulman, Ph.D. University of Washington Charles J. Sherr, M.D., Ph.D. David Baker, Ph.D. Michael J. Bevan, Ph.D. Vanderbilt University Evan E. Eichler, Ph.D. Kathleen L. Gould, Ph.D. Stanley Fields, Ph.D. Philip Green, Ph.D.

61 What’s Next?

Janelia Farm Research Campus September 1, 2006–August 31, 2007

Eric Betzig, Ph.D. Alla Y. Karpova, Ph.D. Elena Rivas, Ph.D. Group Leader Group Leader Fellow

Sydney Brenner, D.Phil. Rex A. Kerr, Ph.D. Charles V. Shank, Ph.D. Senior Fellow Fellow Senior Fellow

Dmitri B. Chklovskii, Ph.D. Loren L. Looger, Ph.D. Julie H. Simpson, Ph.D. Group Leader Group Leader Group Leader

Sean R. Eddy, Ph.D. Jeffrey C. Magee, Ph.D. Scott M. Sternson, Ph.D. Group Leader Group Leader Group Leader

Harald F. Hess, Ph.D. Eugene W. Myers, Ph.D. Karel Svoboda, Ph.D. Director, Applied Physics and Group Leader Group Leader Instrumentation Group Michael B. Reiser, Ph.D. Vivek Jayaraman, Ph.D. Fellow For information on Janelia Farm researchers active after August 31, 2007, Fellow visit www.hhmi.org/janelia. Dmitry Rinberg, Ph.D. Fellow

62 Howard Hughes 2007 Medical Institute Annual Report

Medical Advisory Board September 1, 2006–August 31, 2007

Jack E. Dixon, Ph.D. Sharon R. Long, Ph.D. Carla J. Shatz, Ph.D. Dean of Scientific Affairs Dean, Humanities and Sciences Chairman and Nathan Marsh Professor, Departments of Pharmacology, William C. Steere Jr.–Pfizer Inc. Pusey Professor Cellular and Molecular Medicine, and Professor in Biological Sciences Department of Neurobiology Chemistry and Biochemistry Professor, by courtesy, of Biochemistry Harvard Medical School University of California, San Diego, Stanford University (Effective January 1, 2007) School of Medicine (Through December 31, 2006) (Through January 31, 2007) Bruce Stillman, Ph.D., F.R.S. Gregory A. Petsko, Ph.D. President Gerald R. Fink, Ph.D. Gyula and Katica Tauber Professor Cold Spring Harbor Laboratory American Cancer Society of Biochemistry and Chemistry Professor of Genetics Brandeis University Lubert Stryer, M.D. Whitehead Institute for Adjunct Professor, Department Mrs. George A. Winzer Professor Biomedical Research of Neurology and Center for of Cell Biology, Emeritus Massachusetts Institute of Technology Neurologic Diseases Stanford University School of Brigham and Women’s Hospital and Medicine J. Larry Jameson, M.D., Ph.D. Harvard Medical School Vice President for Medical Affairs and Craig B. Thompson, M.D. Lewis Landsberg Dean Joan V. Ruderman, Ph.D. Chairman Northwestern University, Feinberg Marion V. Nelson Professor of Cell Biology Director School of Medicine Department of Cell Biology Abramson Cancer Center Harvard Medical School University of Pennsylvania

63 What’s Next?

Scientific Review Board September 1, 2006–August 31, 2007

Peter C. Agre, M.D. Jorge E. Galán, Ph.D. Lynn Landmesser, Ph.D. Vice Chancellor, Science and Technology Lucille P. Markey Professor of Microbiology Garvin Professor and Chair Professor of Cell Biology Chairman Department of Neurosciences Duke University Section of Microbial Pathogenesis Case Western Reserve University School (Through December 31, 2006) Yale University School of Medicine of Medicine

Wolfhard Almers, Ph.D. Bertil Hille, Ph.D. Diane Mathis, Ph.D. Senior Scientist Professor Head, Section on Immunology and Vollum Institute Department of Physiology and Biophysics Immunogenetics University of Washington School Joslin Diabetes Center Michael Ashburner, F.R.S. of Medicine Professor of Medicine Professor of Biology (Through December 31, 2006) Harvard Medical School Department of Genetics University of Cambridge Tony Hunter, Ph.D. Steven L. McKnight, Ph.D. Professor Professor and Chairman Michael R. Botchan, Ph.D. Molecular and Cell Biology Laboratory Department of Biochemistry Professor and Co-Chair The Salk Institute University of Texas Southwestern Department of Molecular and Cell Biology (Through December 31, 2006) Medical Center at Dallas University of California, Berkeley (Through December 31, 2006) Thomas J. Kelly, M.D., Ph.D. Steven G. Boxer, Ph.D. Director Keith Moffat, Ph.D. Camille and Henry Dreyfus Sloan-Kettering Institute Louis Block Professor, Department of Professor of Chemistry Memorial Sloan-Kettering Cancer Center Biochemistry and Molecular Biology Department of Chemistry (Through December 31, 2006) Deputy Provost for Research Stanford University The University of Chicago (Through December 31, 2006) Richard D. Kolodner, Ph.D. Member W. James Nelson, Ph.D. Kathryn Calame, Ph.D. Ludwig Institute for Cancer Research, Rudy J. and Daphne Donohue Munzer Professor of Microbiology and San Diego Branch Endowed Professor Biochemistry & Molecular Biophysics Professor of Medicine Departments of Biological Sciences, and Columbia University College of University of California, San Diego, Molecular and Cellular Physiology Physicians and Surgeons School of Medicine Stanford University Executive Director for Laboratory Sciences and Technology Ludwig Institute for Cancer Research, New York

64 Howard Hughes 2007 Medical Institute Annual Report

Roger A. Nicoll, M.D. Robert T. Sauer, Ph.D. Professor Salvador E. Luria Professor Department of Cellular and Department of Biology Molecular Pharmacology Massachusetts Institute of Technology University of California, San Francisco, School of Medicine Carla J. Shatz, Ph.D. Chairman and Nathan Marsh Patrick H. O’Farrell, Ph.D. Pusey Professor Professor Department of Neurobiology Department of Biochemistry and Biophysics Harvard Medical School University of California, San Francisco (Through December 31, 2006) (Through December 31, 2006) Bruce Spiegelman, Ph.D. Eric N. Olson, Ph.D. Professor of Cell Biology Professor and Chairman Dana-Farber Cancer Institute and Department of Molecular Biology Harvard Medical School University of Texas Southwestern (Through December 31, 2006) Medical Center at Dallas David W. Tank, Ph.D. James W. Patrick, Ph.D. Henry L. Hillman Professor of Senior Vice President and Molecular Biology Dean for Research Co-Director, Princeton Baylor College of Medicine Neuroscience Institute Departments of Molecular Janet Rossant, Ph.D. Biology and Physics University Professor of Medical Genetics Princeton University and of Obstetrics and Gynecology University of Toronto David C. Van Essen, Ph.D. Chief of Research Edison Professor and Head The Hospital for Sick Children Department of Anatomy and Neurobiology Washington University School of Medicine Joshua R. Sanes, Ph.D. Professor of Molecular and Cellular Biology Christopher T. Walsh, Ph.D. Director, Center for Brain Science Hamilton Kuhn Professor Harvard University Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School

65 What’s Next?

Janelia Farm Research Campus Advisory Committee September 1, 2006–August 31, 2007

Winfried Denk, Ph.D. Maxine Singer, Ph.D. Craig B. Thompson, M.D. Director President Emerita Director Department of Biomedical Optics Carnegie Institution of Washington Abramson Cancer Center Max Planck Institute for Medical Research Senior Scientific Adviser University of Pennsylvania (Effective January 1, 2007) Carnegie Academy for Science Education Shirley M. Tilghman, Ph.D. Joseph L. Goldstein, M.D. President Regental Professor and Chairman Lubert Stryer, M.D. Princeton University Department of Molecular Genetics Mrs. George A. Winzer Professor of University of Texas Southwestern Medical Cell Biology, Emeritus Center at Dallas Stanford University School of Medicine

Gerald M. Rubin, Ph.D. David W. Tank, Ph.D. Chair Henry L. Hillman Professor of Vice President and Director Molecular Biology Janelia Farm Research Campus Co-Director, Princeton Howard Hughes Medical Institute Neuroscience Institute Departments of Molecular Biology and Physics Princeton University

Bioethics Advisory Board September 1, 2006–August 31, 2007

Jonathan D. Moreno, Ph.D. Laurie Zoloth, Ph.D. David and Lyn Silfen University Chairman Professor and Professor of Medical Professor of Medical Humanities and Ethics and of History and Bioethics and of Religion Sociology of Science Director of Center for Bioethics, Center for Bioethics Science and Society University of Pennsylvania Northwestern University, Feinberg School of Medicine

66 Howard Hughes 2007 Medical Institute Annual Report

Fellowships & Grants September 1, 2006–August 31, 2007

Graduate Science Education Mark P. Chao Ryan K. Funk and Medical Research Stanford University School of Medicine Washington University School of Medicine Training Program Lynn Choi Eric A. Gehrie Research Training Fellowships for New York Medical College Mount Sinai School of Medicine Medical Students (Harvard Medical School)* Craig P. Giacomini Initial Awards: First Year of Research John J. DeCaro Stanford University School of Medicine Stanford University School of Medicine Joel T. Adler (Emory University School of Medicine)* Lia Gracey University of Wisconsin Medical School University of Michigan Medical School Katherine R. Dickman (Stanford University School of Medicine)* Valerie A. Arboleda University of Pittsburgh School of Medicine David Geffen School of Medicine at UCLA (Case Western Reserve University School Ian C. Han of Medicine)* Duke University School of Medicine Joshua P. Aronson Harvard Medical School Andra L. Dingman Stanley Hoang Stanford University School of Medicine Stanford University School of Medicine Amrita Arora University of Chicago, Amir K. Durrani Kimberly M. Hsu Division of Biological Sciences and Cleveland Clinic Lerner College of Medicine Washington University School of Medicine Pritzker School of Medicine of Case Western Reserve University (Northwestern University, Feinberg School (Cleveland Clinic Foundation)* Mark Hsu of Medicine)* Stanford University School of Medicine Rachel S. Edlin Frank J. Attenello New York University School of Medicine Susan J. Huang Johns Hopkins University School (Cornell University, Joan and Sanford Harvard Medical School of Medicine I. Weill Medical College and Graduate School of Medical Sciences)* Jason E. Jaetao Jason M. Baron University of New Mexico School Washington University School of Medicine Damien J. Ellens of Medicine Yale University School of Medicine Irun Bhan Cynthia A. Jimenez Harvard Medical School Robert J. Fenster University of California, San Francisco, Cornell University, Joan and Sanford School of Medicine David C. Caretto I. Weill Medical College and Graduate University of California, San Francisco, School of Medical Sciences School of Medicine (Rockefeller University)*

*A fellowship institution affiliation other than the medical school is indicated in parentheses.

67 What’s Next?

Fellowships & Grants

Kim Jiramongkolchai Ajay Malhotra Tanvi N. Parikh Vanderbilt University School of Medicine Keck School of Medicine of the Cornell University, Joan and Sanford (Harvard Medical School)* University of Southern California I. Weill Medical College and Graduate (Cornell University, Joan and Sanford School of Medical Sciences Sanjat Kanjilal I. Weill Medical College and Graduate (Memorial Sloan-Kettering Cancer Center)* Harvard Medical School School of Medical Sciences)* Nishant D. Patel Maya M. Kasowski Kareem Mawad Johns Hopkins University School Yale University School of Medicine Washington University School of Medicine of Medicine

Charles Kim Paula D. McPoland Priyesh A. Patel University of California, Davis, University of Washington School Duke University School of Medicine School of Medicine of Medicine Bradford A. Perez Somi Kim Charles B. Mikell Duke University School of Medicine Harvard University School of Columbia University College of Physicians Dental Medicine and Surgeons Joshua Schulman Harvard Medical School Robert A. Koeth Eric Milner Case Western Reserve University Washington University School of Medicine Andrew D. Schweitzer School of Medicine Mount Sinai School of Medicine (Cleveland Clinic Foundation)* Camille M. Minder (Albert Einstein College of Medicine)* Duke University School of Medicine Darrin J. Lee Alexandra Snyder University of California, Irvine, Steven C. Minear Mount Sinai School of Medicine School of Medicine Stanford University School of Medicine Sheela C. Toprani Michael S. Lee Sandy Mong Cleveland Clinic Lerner College Duke University School of Medicine Harvard Medical School of Medicine of Case Western (Massachusetts Institute of Technology)* Reserve University Amie Y. Lee (Case Western Reserve University University of California, San Francisco, Anvy T. Nguyen School of Medicine)* School of Medicine University of California, San Francisco, School of Medicine Ryan Ungaro Loretta S.M. Li Mount Sinai School of Medicine Harvard Medical School Krishna N. Parekh Duke University School of Medicine Luis A. Verduzco Sheng-fu L. Lo (University of Pennsylvania School Harvard Medical School Yale University School of Medicine of Medicine)*

68 Howard Hughes 2007 Medical Institute Annual Report

Kyle L. Viani Continued Awards: Christina Brezing University of Michigan Medical School Second Year of Research University of Florida College of Medicine

Shoshana J. Weiner Sudeb Dalai Jorge Caballero Case Western Reserve University School Stanford University School of Medicine Stanford University School of Medicine of Medicine (Cleveland Clinic Foundation)* Andrew Hoover Paul Campion‡ University of Iowa, Roy J. and Lucille A. New York University School of Medicine Elizabeth L. Whitlock Carver College of Medicine Washington University School of Medicine Jessica Choe‡ Charles Rickert Drexel University College of Medicine Robert Wirka Washington University School of Medicine Cleveland Clinic Lerner College of Medicine David Chou‡ of Case Western Reserve University HHMI-NIH Research Scholars† University of Pittsburgh School of Medicine (Cleveland Clinic Foundation)* Amana Akhtar Jonah Cohen Ambrose H.W. Wong University of Michigan Medical School Brown Medical School Washington University School of Medicine (Harvard Medical School)* Sonny Batra Kelly Cushing Stanford University School of Medicine Rush Medical College of Rush University Ashley Wysong Duke University School of Medicine Steven Beaudry Fei Dong (University of North Carolina at Chapel West Virginia School of Osteopathic Case Western Reserve University School Hill School of Medicine)* Medicine of Medicine

Ai-ris Yonekura Christina Bennett Reza Ehsanian‡ Harvard Medical School Indiana University School of Medicine Stanford University School of Medicine

Charles Q. Yu Kristin Berg Chibawanye Ene University of California, Davis, School Creighton University School of Medicine Indiana University School of Medicine of Medicine Jim Boonyaratanakornkit Haven Garber Harras B. Zaid University of California, San Francisco, Ohio State University College of Medicine University of California, San Francisco, School of Medicine and Public Health School of Medicine Steven Brauer Joshua Gordon Elizabeth A. Zambricki Harvard Medical School David Geffen School of Medicine at UCLA Stanford University School of Medicine

†This program is administered through Grants & Special Programs but is budgeted as a research operation. ‡Second year in program as an advanced scholar. 69 What’s Next?

Fellowships & Grants

Rohit Gupta Michelle Longmire Shashank Sinha Duke University School of Medicine University of New Mexico School University of Chicago, Division of of Medicine Biological Sciences and Pritzker School Kirsi Hakkinen of Medicine Harvard University School of Elise Meoli Dental Medicine University of Rochester School Mariel Solares of Medicine and Dentistry University of California, San Francisco, Julie Hall School of Medicine University of California, San Francisco, Eric Muñoz School of Medicine Oregon Health and Science Scott Steward-Tharp University School of Medicine University of Iowa College of Dentistry Jesse Hanisch‡ Creighton University School of Medicine Derek Narendra Matthew Swisher University of Michigan Medical School Duke University School of Medicine Victor Harrison University of Hawaii John A. Burns School Giang Nguyen‡ Brian Sworder‡ of Medicine Albany Medical College Boston University School of Medicine

Brett Jagger Josiah Orina Ashesh Thaker Indiana University School of Medicine Emory University School of Medicine David Geffen School of Medicine at UCLA

Osamu Kaneko Lavanya Palavalli Nicholas Zwang David Geffen School of Medicine at UCLA University of Missouri–Columbia School Harvard Medical School of Medicine Adam Kern James H. Gilliam Jr. Fellowships University of Chicago, Division of Mrinali Patel for Advanced Study Biological Sciences and Pritzker School Duke University School of Medicine of Medicine Irene C. Blat Katie Pricola Massachusetts Institute of Technology Mohammed Khan Stanford University School of Medicine David Geffen School of Medicine at UCLA Nisha Broodie John Quick Harvard University Jung Eun Lee New York University School of Medicine Duke University School of Medicine Veder J. Garcia Abigail Rao University of California, Berkeley Quan Lan Lew Dartmouth Medical School University of Chicago, Division of Eunha Kim Biological Sciences and Pritzker School Andrea Russo Massachusetts Institute of Technology of Medicine Dartmouth Medical School José A. Rodriguez University of California, Los Angeles

70 Howard Hughes 2007 Medical Institute Annual Report

Physician-Scientist Emanual Maverakis Other Graduate Science Early Career Awards East Bay Institute for Research and Education Awards Education Nicholas M. Boulis Association of American Emory University School of Medicine Sridhar Ramaswamy Medical Colleges Massachusetts General Hospital Washington, D.C. Katherine de Castro Crew Grant: AAMC-HHMI Scientific Foundation Columbia University College of Physicians Vicente A. Resto for Future Physicians Committee and Surgeons University of Texas Medical Branch $105,000

Sarah M. Fortune Manish Sagar Cold Spring Harbor Laboratory Harvard University School of Public Health Brigham and Women’s Hospital Cold Spring Harbor, New York Grant: Graduate and Postgraduate Paul J. Galardy Sean I. Savitz Educational Programs Mayo Clinic Rochester University of Texas Medical School $3,000,000 at Houston Aram Hezel The Jackson Laboratory Massachusetts General Hospital Costi D. Sifri Bar Harbor, Maine (2006 awardee) University of Virginia Health Grant: Graduate and Postgraduate Sciences Center Educational Programs Farouc A. Jaffer $2,000,000 Massachusetts General Hospital Jonathan A. Stiber Duke University Medical Center Marine Biological Laboratory Eric C. Johannsen Woods Hole, Massachusetts Brigham and Women’s Hospital Charlotte J. Sumner Grant: Graduate and Postgraduate Johns Hopkins University School Educational Programs Aarif Y. Khakoo of Medicine $4,000,000 University of Texas M.D. Anderson Cancer Center Matthew J. Walter Washington University School of Medicine Nerissa U. Ko University of California, San Francisco, Rebekah R. White School of Medicine Duke University

Ross L. Levine Allan D. Wu Memorial Sloan Kettering Cancer Center David Geffen School of Medicine at UCLA

71 What’s Next?

Fellowships & Grants

Undergraduate Science Jasmine R. Ellis Tim M. Mahanes Education Program Princeton University Georgia State University

HHMI’s Exceptional Research Jasmine D. Garrett Bertrade C. Mbom Opportunities Program (EXROP) Arizona State University Carnegie Mellon University

Nkosi Adejola Daniel B. Gilmer Tyra N. McCray University of Miami Howard University University of California, Davis

Jose Arevalo Laura A. Gonzalez Juan P. Mena-Gonzalez University of California, Berkeley University of Texas at Austin University of Arizona

Ashley L. Bolden Jessica Gutierrez Evin K. Nembhard University of Colorado at Boulder New Mexico State University Harvard University

Christina Brown Tyanna Hadley Nghi K. Nguyen University of California, San Diego University of Delaware Stanford University

Flavian D. Brown Reginald S. Hurtt Oluwatobi A. Ogbechie Carleton College University of Michigan–Ann Arbor Harvard University

Tiara T. Byrd Shani K. Isaac Ujunwa C. Okoye Florida A&M University University of Florida State University of New York at Stony Brook Silvia G. Caballero Christina M. Jones City University of New York, Louisiana State University and Maria K. Ortega Hunter College A&M College University of California, Los Angeles

Scott S. Chilton Doris O. Jones Jose M. Pena Massachusetts Institute of Technology Virginia Commonwealth University University of California, Berkeley

Akanni Y. Clarke Adebimpe Kasumu Markeith A. Pilot University of Massachusetts Spelman College University of California, Riverside

Karla I. Claudio Campos Kristopher J. Kennedy Sacha L. Prashad University of Puerto Rico–Cayey University of California, Los Angeles University of California, Los Angeles

Elias J. Cornejo Maureen W. Kimani Enrique I. Ramos University of Colorado at Boulder Emory University University of Texas at El Paso

Kylie S. Durand Marissa K. Lee Jaime X. Ramos Louisiana State University and Massachusetts Institute of Technology University of California, San Diego A&M College

72 Howard Hughes 2007 Medical Institute Annual Report

Juan M. Romero Other Undergraduate Science Duke University School of Medicine California State Polytechnic Education Awards Durham, North Carolina University–Pomona $749,957 East Tennessee State University Quinn L. Sievers Johnson City, Tennessee Fred Hutchinson Cancer Williams College Grant: Quantitative Biology—Curricular Research Center and Institutional Transformation at the Seattle, Washington Devin Sok Math/Biology Interface $696,000 Stanford University $25,000 Indiana University School of Medicine Joshua J. Solano Hiram College Indianapolis, Indiana Duke University Hiram, Ohio $661,958 Grant: Web-Accessible Genomics Beryl E. Swanson Tools and Research Challenges for Institute for Systems Biology University of Washington Undergraduate Education Seattle, Washington $50,000 $721,734 Constantin N. Takacs Yale University University of Wisconsin–Madison The Jackson Laboratory Madison, Wisconsin Bar Harbor, Maine Gloria R. Tavera Grant: Summer Institute on $749,000 University of Florida Undergraduate Education in Biology $92,000 Lovelace Respiratory Brittany Taylor Research Institute University of Maryland, College Park Albuquerque, New Mexico Precollege Science $742,678 Dyese Taylor Education Program Dartmouth College Marine Biological Laboratory Initiative for Biomedical Woods Hole, Massachusetts Steven Tuyishime Research Institutions $725,225 University of Maryland, Baltimore County Baylor College of Medicine McLaughlin Research Institute Jeffrey Uribe Houston, Texas Great Falls, Montana City University of New York, City College $749,627 $529,308

Natalia Vasco Cold Spring Harbor Laboratory Oregon Health and Science Rice University Cold Spring Harbor, New York University School of Medicine $746,243 Portland, Oregon Valerie M. Villanueva $738,955 College of William and Mary Dartmouth Medical School Hanover, New Hampshire Purdue University West Lafayette Kimberley M. Watson $749,958 School of Veterinary Medicine Swarthmore College West Lafayette, Indiana $749,755

73 What’s Next?

Fellowships & Grants

Queen’s Medical Center University of Texas Medical Branch Washington, D.C., Honolulu, Hawaii at Galveston Metropolitan Area Initiatives $747,644 Galveston, Texas $750,000 Audubon Naturalist Society Stanford University School of Medicine Chevy Chase, Maryland Palo Alto, California University of Texas Southwestern Grant: Greenlabs Environmental $748,330 Medical Center at Dallas Teacher Workshops Dallas, Texas $25,000 University of California, Los Angeles, $749,908 School of Dentistry Chesapeake Bay Foundation Los Angeles, California University of Toledo College of Medicine Annapolis, Maryland $748,337 Toledo, Ohio Grant: Maryland Environmental $749,820 Education Program University of California, San Diego, $150,000 School of Medicine University of Utah School of Medicine San Diego, California Salt Lake City, Utah Eleanor Roosevelt High School $750,000 $750,000 Greenbelt, Maryland Grant: Science and Technology Program University of Cincinnati College University of Wisconsin School $29,000 of Medicine of Medicine and Public Health Cincinnati, Ohio Madison, Wisconsin Montgomery County Public Schools $696,000 $745,500 Educational Foundation Rockville, Maryland University of Florida College Virginia Commonwealth University Grant: Elementary Science of Medicine School of Medicine Leadership Program; Student and Gainesville, Florida Richmond, Virginia Teacher Internship Program; $676,543 $750,000 Teacher Professional Development $651,000 University of Mississippi School Wake Forest University School of Medicine of Medicine Loudoun County, Virginia, Jackson, Mississippi Winston-Salem, North Carolina Initiatives $695,923 $696,000 Loudoun County Public Schools University of Missouri–Columbia Washington University School Leesburg, Virginia School of Medicine of Medicine Grant: Teacher Professional Columbia, Missouri St. Louis, Missouri Development Institute; Academy $750,000 $736,852 of Science; and College Scholarships** $1,000,000 University of Texas M.D. Anderson West Virginia University School Cancer Center of Medicine Houston, Texas Morgantown, West Virginia $750,000 $696,000

**College scholarships: $7,000 for each student.

74 Howard Hughes 2007 Medical Institute Annual Report

College Scholarships Jacquelyn A. Piccolo Fernando A. Goldbaum, Ph.D. Stone Bridge High School Leloir Institute Foundation Chelsea A. Bradley Loudoun County High School Nicole A. Poltash Alberto R. Kornblihtt, Ph.D. Broad Run High School University of Buenos Aires Grace Chen Briar Woods High School Candace D. Rubenstein Javier F. Palatnik, Ph.D. Stone Bridge High School Institute of Molecular and Cellular Candace L. Garramone Biology of Rosario, CONICET Loudoun County High School Emily S. Ryan Potomac Falls High School Armando J. Parodi, Ph.D. Caroline S. Higgins Leloir Institute Foundation Broad Run High School Annemarie C. Thomas Dominion High School Marcelo Rubinstein, Ph.D. Christina K. Holl Institute for Research on Genetic Freedom High School Tae I. Um Engineering and Molecular Biology, Freedom High School CONICET Dina T. Khalf-Allah Briar Woods High School Emily C. Willis Alejandro F. Schinder, Ph.D. Loudoun Valley High School Leloir Institute Foundation Saadia L. Khan Dominion High School Alejandro J. Vila, Ph.D. International Program Institute of Molecular and Cellular Nicholas A. Lopez Biology of Rosario, CONICET Potomac Falls High School Canada and Selected Countries of Latin America Pablo Wappner, Ph.D. Stutay Monga Leloir Institute Foundation Heritage High School Argentina Diego de Mendoza, Ph.D. Marcelo J. Yanovsky, Ph.D. John T. Nguyen Institute of Molecular and Cellular University of Buenos Aires Park View High School Biology of Rosario, CONICET Brazil Matthew E. Parker Ana B. Elgoyhen, Ph.D. Maria F. Leite, Ph.D. Loudoun Valley High School Institute for Research on Genetic Federal University of Minas Gerais Engineering and Molecular Biology, Jasmine B. Paul CONICET Pedro L. Oliveira, Ph.D. Heritage High School Federal University of Rio de Janeiro Alberto Carlos Frasch, D.D.S., Ph.D. Nghi B. Phung Institute for Research in Biotechnology, Alexandre A. Peixoto, Ph.D. Park View High School National University of General Oswaldo Cruz Foundation San Martin

75 What’s Next?

Fellowships & Grants

Canada Nahum Sonenberg, Ph.D. Luis R. Herrera Estrella, Ph.D. Mark Glover, Ph.D. McGill University Center for Research and Advanced Studies University of Alberta of the National Polytechnic Institute (Effective January 1, 2008) Peter St George-Hyslop, M.D., F.R.C.P. (Irapuato) University of Toronto Lea Harrington, Ph.D. Ranulfo Romo, M.D., D.Sc. Ontario Cancer Institute Natalie C. Strynadka, Ph.D. Institute of Cellular Physiology, National (Through December 31, 2007) University of British Columbia Autonomous University of Mexico

Philip Hieter, Ph.D. Michael D. Tyers, Ph.D. Jean-Philippe Vielle-Calzada, Ph.D. University of British Columbia Samuel Lunenfeld Research Institute, Center for Research and Advanced Studies Mount Sinai Hospital of the National Polytechnic Institute Timothy R. Hughes, Ph.D. (Through December 31, 2007) (Irapuato) University of Toronto André Veillette, M.D., F.R.C.P. Venezuela Robert G. Korneluk, Ph.D. Clinical Research Institute of Montreal Raul A. Padron, Ph.D. Children’s Hospital of Eastern Venezuelan Institute for Scientific Ontario Research Institute Yu Tian Wang, Ph.D. Research (Effective January 1, 2008) University of British Columbia Courses Freda D. Miller, Ph.D. Richard W. Wozniak, Ph.D. Hospital for Sick Children University of Alberta Center for Research and Advanced Studies of the National Polytechnic Dana J. Philpott, Ph.D. Jeff Wrana, Ph.D. Institute University of Toronto Samuel Lunenfeld Research Institute, Irapuato, Mexico Mount Sinai Hospital $150,000 Richard A. Rachubinski, Ph.D. University of Alberta Chile University of KwaZulu-Natal Miguel L. Concha, M.D., Ph.D. Durban, South Africa Michael A. Rudnicki, Ph.D. University of Chile $150,000 Ottawa Health Research Institute Mexico Michael W. Salter, M.D., Ph.D. Luis G. Brieba de Castro, Ph.D. Educational Resources Hospital for Sick Children Center for Research and Advanced Studies of the National Polytechnic Institute WGBH Educational Foundation Erwin A. Schurr, Ph.D. (Mexico City) Boston, Massachusetts McGill University Grant: NOVA scienceNOW $1,500,000 Eric A. Shoubridge, Ph.D. McGill University

76 Howard Hughes 2007 Medical Institute Annual Report

Office of Grants and Other Awards Special Programs American Association for the HHMI Investigator Advancement of Science Education Grants Grant: Science’s Education Forum $40,000 David Baker, Ph.D. University of Washington National Academy of Sciences Grant: Rosetta@home—A Protein Grant: Follow-up activities related Modeling Program to the report Guidelines for Human $100,000 Embryonic Stem Cell Research $60,000 (fiscal year 2006) Sean B. Carroll, Ph.D. University of Wisconsin–Madison National Research Council Grant: Work on NOVA evolution Grant: Understanding Interventions program That Encourage Minorities to Pursue $100,000 Research Careers—Major Questions and Appropriate Methods Roger Y. Tsien, Ph.D. $5,000 University of California, San Diego Grant: BioBridge—Translating Today’s American Academy of Arts and Research for Tomorrow’s Scientists Sciences $74,876 Cambridge, Massachusetts Grant: Support of the study Federal Ronald D. Vale, Ph.D. Funding of Science University of California, San Francisco $100,000 Grant: iBioseminars $100,000 United Way of Loudoun County and Other Community Organizations in Loudoun County Leesburg, Virginia $31,425

United Way of the National Capital Area Washington, D.C. $50,000

77 What’s Next?

Finance & Investments September 1, 2006–August 31, 2007

The Howard Hughes Medical Institute is the nation’s largest private sup- DISBURSEMENTS ($ in millions) porter of academic biomedical research. The endowment is the Institute’s $ 1000 principal source of funding. The investment objective is to manage the

800 $781 $727 endowment in a prudent manner that will maintain its purchasing power $717 $653 and will fund the Institute’s research and grants programs on an ongoing 600 $604 basis. At the end of the fiscal year on August 31, 2007, the endowment was $18.7 billion. Classified as a medical research organization by the Internal 400 Revenue Service, the Institute is required to spend at least 3.5 percent of its endowment each year on direct medical research activities and related 200 overhead, exclusive of grants and investment management. 0

FISCAL 2003 2004 2005 2006 2007 Disbursements in Fiscal Year 2007 YEAR Lab Construction and Land Acquisition Disbursements during the fiscal year totaled $727 million: $599 million for Grants and Special Programs HHMI scientific research, including the first year of operations of the Janelia Scientific Research Farm Research Campus in Ashburn, Virginia; $42 million for the completion of Janelia Farm and for headquarters expansion; and $86 million for grants for science education and international research scholars. Over the past SCIENTIFIC RESEARCH ($ in millions) five years, disbursements by the Institute totaled nearly $3.5 billion. $ 1000

800 Scientific Research $694 $641 HHMI’s research activities are conducted principally at Institute laboratories $637

600 $573 at medical centers, teaching hospitals, and universities in the United States $497 by investigators who hold faculty appointments at the host institutions. 400 These individuals, together with their support staffs, are HHMI employees and are compensated directly by the Institute. Investigators may spend up 200 to 25 percent of their time on teaching, administration, or other activities 0 that benefit the host institutions. At the end of fiscal year 2007, the Institute FISCAL 2003 2004 2005 2006 2007 YEAR supported 297 investigators at 64 academic medical centers. Lab Construction and Land Acquisition Equipment and Lab Renovation As of August 31, 2007, the Institute’s investment in laboratory space, equip- Operations ment, and other property amounted to nearly $1.4 billion, with a current replacement value of approximately $1.7 billion.

78 Howard Hughes 2007 Medical Institute Annual Report

Janelia Farm Research Campus GRANTS AND SPECIAL PROGRAMS ($ in millions) In August 2006, HHMI opened its Janelia Farm Research Campus. Situated $ 150 on a 689-acre site along the Potomac River in Ashburn, Virginia, just outside $107 Washington, D.C., the campus provides the setting for interdisciplinary, 100 $87 $86 collaborative research focused on two areas: identifying the general $80 $80 principles that govern how information is processed by neuronal circuits; 50 and developing imaging technologies and computational methods for image analysis. The total development cost was $500 million. 0 FISCAL 2003 2004 2005 2006 2007 YEAR Precollege Education, Educational In its first year of operation, research expenditures at Janelia Farm totaled Materials, and Other approximately $67 million, of which $15 million represented personnel International expenditures and approximately $32 million was for equipment and outfit- Graduate Education Undergraduate Education ting. When Janelia Farm is at full capacity, it will house a permanent research staff of about 250—including 24 group leaders and 20 fellows—and up to 100 visiting scientists. ENDOWMENT ($ in millions) $ 20,000 4 $18,702 2 Grants and Special Programs $16,326 15,000 $14,75 ,326 $12,78 Through its grants program, the Institute supports science education at all 1 $1 levels, from the earliest grades through advanced research training. It also 10,000 directly supports scientists conducting research in the biological sciences in selected foreign countries. The Institute disbursed $86 million to support 5,000 the activities of 577 grantees in 29 countries during fiscal year 2007. 0

FISCAL 2003 2004 2005 2006 2007 Endowment YEAR The Institute’s endowment is managed under the direction of its vice president and chief investment officer. Approximately 69 percent of the endowment Emerging Real markets is invested by external fund managers; the remainder is internally managed. assets Domestic External managers are used principally to manage alternative investments, 5% equity International 6% equity 22% including hedge funds, private equity, and derivatives. 9%

Distressed and At the close of fiscal year 2007, the endowment was $18.7 billion, an 8% ENDOWMENT credit sensitive ALLOCATIONS increase of $2.4 billion from the end of fiscal year 2006. The endowment’s 4% Market neutral 19% return for fiscal year 2007 was 18.6 percent. arbitrage 10% Bonds Hedged 17% The composition of the Institute’s endowment by investment category equity Private on August 31, 2007, is reflected in the graph to the right. equity

79 Statement of Financial Position August 31, 2007, and 2006

Assets ($ in millions) 2007 2006

Cash and cash equivalents $ 105 $ 190

Investments 19,353 16,896

Investment and currency receivables, and other assets 1,421 297

Laboratory space, equipment, and other property—at cost, net of accumulated depreciation and amortization 796 755

Total Assets $ 21,675 $ 18,138

Liabilities ($ in millions)

Accounts payable, accrued expenses, and obligations (208) (209)

Grants commitments (158) (162)

Investment purchases payable, repurchase obligations, short sales, and currency payable (2,049) (858)

Notes and bonds payable (627) (624)

Total Liabilities (3,042) (1,853)

Net Assets $ 18,633 $ 16,285

Financial Information The Institute employs the firm of PricewaterhouseCoopers LLP as its independent auditor. The audited financial statements of the Institute for the year ended August 31, 2007, and the independent auditor’s report thereon are available on the Institute’s Web site at www.hhmi.org/about, or they may be obtained by writing to:

Controller Howard Hughes Medical Institute 4000 Jones Bridge Road Chevy Chase, Maryland 20815-6789

80 Letter from the president 2 The primary purpose and objective of the conversation: william r. lummis 6 Howard Hughes Medical Institute shall be the promotion of human knowledge within the CREDITS Thinking field of the basic sciences (principally the field of Like medical research and education) and the A Scientist 8 effective application thereof for the benefit of mankind. Page 1 Page 25 Page 43 Page 50 seeing Illustration by Riccardo Vecchio Südhof: Paul Fetters; Fuchs: Janelia Farm lab: © Photography Neurotoxin (Brunger & Chapman): Page 3 Matthew Septimus; SCNT images: by Brad Feinknopf; First level of Rongsheng Jin and Axel Brunger; in Bruce Weller Blake Porch and Chris Vargas/HHMI lab building: © Photography by Shadlen: Paul Fetters; Mouse Page 6 Page 26 Brad Feinknopf (Tsai): Li-Huei Tsai; Zoghbi: Agapito new Illustration by Riccardo Vecchio Arabidopsis: Laboratory of Joanne Page 44 Sanchez/Baylor College 14 Page 8 Chory; Chory: Courtesy of Salk Janelia Farm guest housing: © Jeff Page 51 ways Illustration by Riccardo Vecchio Institute Goldberg/Esto; Dudman: Matthew Szostak: Mark Wilson; Evans: Fred Page 10 Page 27 Septimus; Lee: Oliver Wien; Greaves/PR Newswire, © HHMI; Mello: Erika Larsen; Hannon: Zack Rosenthal: Paul Fetters; Students: Leonardo: Paul Fetters; Riddiford: Steitz: Harold Shapiro; Lefkowitz: Capacity Seckler/AP, © HHMI; Lowe: Zack Paul Fetters; Map: Reprinted by Paul Fetters; Truman: Paul Fetters Stewart Waller/PR Newswire, Seckler/AP, © HHMI permission from Macmillan Page 46 © HHMI for Page 12 Publishers, Ltd.: Nature vol. Blat: Kathleen Dooher; Garcia: Page 52 Adapted from HHMI BioInteractive 444/16 November 2006/ Barbara Ries; Broodie: Matthew Rubin: Paul Fetters; Sheng: Growth 22 Page 13 doi:10.1038/nature05284, © 2006 Septimus; Kim: Mark Harmel Jason Grow Todd Hido/Edge Page 28 Page 47 Page 53 Page 14 Illustration by Riccardo Vecchio Rodriguez: Mark Harmel; Sumner: Elgin: Scott Ferguson; Campbell: big Illustration by Riccardo Vecchio Page 30 Keith Weller Jeffrey McCullough Page 16 Ha: John Dixon/AP, © HHMI; Page 48 Page 54 dreamS Svoboda: Paul Fetters; Ehlers: Nanocontainer: Ibrahim Cisse/ Fly (Bonini): Pavan Auluck and Garbers: David Gresham/UT Karen Tam/AP, © HHMI; Neurons: Ha Lab Sebastien Gaumer/Bonini Lab; Southwestern; Gay: Courtesy about Yifan Xu/Ehlers Lab Page 31 Michaeli: David Rolls of Frank William Gay Page 17 Bertozzi: Barbara Ries; Nanoneedle Page 49 small Poliovirus: Boerries Brandenburg/ image: Courtesy of Gautam Rangan Mice (Dulac): Catherine Dulac; things 28 Zhuang Lab; Zhuang: Joshua and Xing Chen/Bertozzi Lab Garcia: Barbara Ries; Massagué: Dalsimer Page 32 Courtesy of Joan Massagué; Page 18 Sebastian Maerkl/Quake Lab Enzyme (Strynadka): Natalie Zuker: Jeffrey Lamont Brown; Fruit Page 33 Strynadka; Neuron (Zipursky, Jan, Building fly eyes: David Yarmolinsky and Donna Carson/AP, © HHMI & Jan): Morgan Sheng and Carlo Andrew Zelhof/Zuker Lab; Animation Page 34 Sala; Jacobs: Sean Kernan Communities image: © 2006 The President and Illustration by Riccardo Vecchio Fellows of Harvard College Page 36 of Page 19 Paul Fetters Produced by the Office of Communications and Public Affairs learNing 34 Gerald Jacobs/Nathans Lab Page 37 © 2007 Howard Hughes Medical Institute Page 20 Jeffrey McCullough Lindquist: Justin Knight; Prions: Page 38 Annual Report Editorial Staff: Avice Meehan, Dean Trackman, Year In Review 41 Courtesy of Peter Tessier and Kris Snibbe/Harvard News Office Cay Butler, Lisa Seachrist Chiu, Elizabeth Cowley, Patricia Davenport, Tom DiCesare/Lindquist Lab Page 39 Shelley Dubois, Patricia Foster, Jim Keeley, Dianne Palmer, Lindsey leadership 56 Page 21 Chris Hildreth Pujanauski, Jacqueline Ruttimann, Katherine Wood Paul Fetters Page 40 Page 22 Gary Strobel Design: VSA Partners, New York hhmi researchers 58 Illustration by Riccardo Vecchio Page 41 Printing: Finlay Printing Page 24 © Photography by Brad Feinknopf advisory boards & committees 63 Pancreas: Qiao Zhou and Douglas Page 42 The Howard Hughes Medical Institute is incorporated in Delaware. Melton; Melton: Joshua Dalsimer Nobel laureates: Paul Fetters; It is qualified as a medical research organization under the federal fellowships & grants 67 Rubin talk: Paul Fetters tax code. It is an equal opportunity employer. finance & investments 78 Howard hughes medical institute 2007 annual report What’s Next What’s

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