Howard Hughes Medical Institute 2008 Annual Report

Howard Hughes Medical Institute Institute Medical Hughes Howard Report Annual 2008

www.hhmi.org 20815-6789 4000 Jones Bridge Road Bridge Jones 4000 Maryland Chase, Chevy Mission statement The primary purpose and objective of the Howard Hughes Medical Institute shall be the promotion of human knowledge within the field of basic sciences (principally the field of medical research and education) and the effective application thereof for the benefit of mankind. 2 14 39 Letter from the President Creative Connections Year in Review Innovative science benefits from The past year was one of connections between cultures robust growth and renewal for and styles of diverse disciplines. HHMI’s research and education 6 programs. Ask Big Questions Nobel laureate Mario Capecchi 22 and other HHMI investigators Putting New Approaches tackle seemingly unanswerable 61 to the Test questions and make remarkable HHMI People and discoveries. To spark an inquisitive fire and Financials train the next generation of scientists, HHMI is undertaking some experiments of its own. 30 Probing Complexity With scientific curiosity and advancing technology, researchers have begun exploring problems of enormous complexity. Letter from the President

For nearly a decade, I have had the 2007 Nobel Prize in Physiology the honor and privilege of serving or Medicine with Oliver Smithies and as president of the Howard Hughes Sir Martin Evans. Medical Institute. This office, which Capecchi’s deep curiosity and drive I will relinquish on March 31, 2009, to have him pressing ahead with new return to full-time research in Colorado, research challenges, and that’s my goal has allowed me to think deeply about as well. Much as I have delighted in the future of science and how best to leading HHMI, I also want to get back educate successive generations of to my laboratory at the University of scientists. I treasure the experience. Colorado at Boulder—and it’s not simply The theme of this annual report is the view of the Rocky Mountains that’s “Uncommon Curiosity,” because out-of- drawing me back. For me, nothing is more the-ordinary inquisitiveness is an absolute invigorating than hashing out new exper- requirement for achieving success in imental approaches with students and research. We begin with Mario Capecchi delving into the structure and function of of the University of Utah, whose unusual telomeres—those all-important caps at trajectory prompted him to leave the the ends of our chromosomes that keep cozy academic confines of Cambridge, them healthy and functioning properly. Massachusetts, and head west. Salt Lake Come to think of it, they keep my intellect City was hardly a frontier in the classi- healthy and functioning properly as well! cal sense, but it provided just the right In Colorado, I will also direct a new environment to enable Capecchi to make institute in interdisciplinary science. discoveries that have paved the way This role will bring me full circle, back to for the development of animal models the conversations about the importance for human disease. For this, he shared of breaking down the barriers between research disciplines that I had with Gerry Rubin and David Clayton as I began my

2 Out-of-the-ordinary inquisitiveness is an absolute requirement for achieving success in research.

tenure as HHMI’s president. Those basic principles—people not projects, conversations—which began in Boulder generous resources, extended time the year before my move to HHMI’s head horizon—remain unaltered. Nonetheless, quarters in Maryland—culminated in we made modest yet significant changes development of the Janelia Farm Research that have altered the composition of the Campus. Now directed by Rubin, this new investigator community and brought community enables chemists, computer new scientific disciplines, as well as scientists, and physicists to work side by institutions, into the fold. At the urging side with biologists in a vibrant environ- of Joseph Goldstein, David Nathan, and ment enriched by students, visitors, and Craig Thompson of our Medical Advi- collaborating scientists from around the sory Board, we undertook two focused world. Janelia Farm represents a big step competitions to expand the number for HHMI, and we set big goals. Were we of patient-oriented physician-scientist realistic or excessively bold? Only time investigators in the Institute. will tell, but we’re certainly excited by More recently, under the leadership the progress so far. of Jack Dixon as HHMI’s chief scientific When I succeeded Purnell Choppin officer, we opened up the process for as HHMI’s president nine years ago, the selecting new investigators by allowing Institute’s flagship investigator pro- scientists to apply directly, replacing the gram was a powerful force for discovery previous process of institutional nomina- and innovation in American science, tions. The new mechanism has enhanced and it remains so today. The program’s the perception of HHMI’s fairness and openness and has also resulted in a wonderful diversity among institutions,

3 scientific disciplines, and the new Another new effort has focused on investigators themselves. I have equally building connections between HHMI high hopes for our newest initiative— investigators and our educational pro- another open-access competition, this grams to achieve an important goal: time designed to select highly talented increasing diversity among the ranks scientists at the very outset of their inde- of academic scientists. The exceptional pendent research careers. research opportunities program (EXROP At HHMI, our experiments are not for short) allows us to provide summer limited to the laboratory. Our grants research experiences in HHMI laborato- program, led by Peter Bruns, actively ries for promising college students who encourages colleges and universities to are disadvantaged or from groups that seek more effective ways to engage stu- are underrepresented in the sciences. dents. For example, we created the HHMI We’ve taken it one step further, building professors program to support accom- a community among these students by plished research scientists in their efforts bringing them together and providing to implement high-impact, inquiry-based additional mentoring. Fully half of our undergraduate education at their own EXROP students are now in graduate institutions, and to share with the school—and that doesn’t count those broader community the methods, curri- who opted for medicine! A decade from cula, and materials they create. now, I fully expect to see many of them in front of classrooms and in the ranks of accomplished scientists.

4 HHMI Annual Report 2008 Letter from the President

As president, my first obligation has been to be a wise steward—of the intellectual freedom that our scientists require to do their best work, of the potential embodied by the students we reach through our grants, of the financial resources that make it possible for us to carry out our mission. To the extent that I have succeeded, it is a tribute to the many gifted collaborators—including the staff at our administrative headquarters and HHMI’s Trustees—who have joined me in this work. Together, we have set the Institute’s course for a new and no doubt fascinating future.

Thomas R. Cech, Ph.D. President

5 James Watson, who shared the Nobel Prize for discovering the structure of DNA with Francis Crick and Maurice Wilkins, is well known for thinking big. Indeed, he often admonished graduate students and postdocs “not to waste time asking small questions.” Many HHMI investigators have taken that advice to heart. Ask Big Questions HHMI Annual Report 2008 Ask Big Questions 1. Mario R. Capecchi 2. Embryonic Stem Cells Using mouse ES cells, Capecchi created the first knockout mouse. 3. DNA Deoxyribonucleic acid carries the genetic information of a cell.

A Bold Approach HHMI investigator Mario R. Capecchi, a former student of James Watson, profited from his men- tor’s advice to think big. Capecchi’s relentless curiosity about seemingly unanswerable questions has changed the way scientists explore mammalian genetics. His research earned him the 2007 Nobel Prize in Physiology or Medicine. Now in his 70s, Capecchi, at the University of Utah, is preparing to ask another big question: what makes a mouse a mouse? “Scientific questions are often exceedingly complex,” Capecchi says. “Then a new technology comes in and it changes what questions are acces- sible. Hopefully, when you ask a question that is beyond your technological capability, that leap is within the realm of possibilities.” Capecchi himself is a technology developer. In the 1980s, he described how to use the cell’s machinery to target and alter genes. Spurred by a 1977 report from Richard Axel (now an HHMI 1. investigator) and Michael Wigler at Columbia University demonstrating that cells in culture would occasionally take up and incorporate DNA, Capecchi created a nuclear injection proce- dure to make the uptake process more efficient and then study it. He and his students discovered that sometimes cells used “homologous

8 2. 3.

Capecchi’s relentless curiosity about extensively to study mammalian genetics. The seemingly unanswerable questions men shared the 2007 Nobel Prize in Physiology or has changed the way scientists explore Medicine for their efforts. mammalian genetics. Not content to focus on a single field or question, Capecchi changes the direction of his lab recombination”—the physical rearrangement of every 8 to 10 years. His group has studied bac- genetic material between two strands of DNA—to teriophages, neuroscience, and cancer. “I enjoy stitch together multiple copies of the same DNA. thinking about new things,” Capecchi says. “It’s a With that finding Capecchi submitted a grant challenge. It shakes up your neurons. proposal to the National Institutes of Health “You are sort of naïve when you enter a new (NIH) to use the cells’ homologous recombina- field.” Capecchi views this as an advantage that tion machinery to target and alter genes. The permits him to ask the big questions that scien- NIH reviewers told him to focus on the less risky tists immersed in a given subject might not ask. aspects of the proposal. Capecchi gambled his His latest foray is an exploration of the genetic career by ignoring that dictate and used the basis for how nature evolved the great diversity funds on the very high-risk—and ultimately of life on the planet. “When molecular biologists high-reward—effort to target genes in mamma- compare enzymes from two different species, lian cells. By the time his NIH grant was up for they are looking at what makes us similar,” renewal, he had succeeded. Capecchi says. “I want to know what happened Through collaborations—and some friendly in evolution to make us different.” competition—Capecchi, Sir Martin Evans at Capecchi believes that most differences Cardiff University in the United Kingdom, and among species arise as a result of additive muta- Oliver Smithies at the University of North Caro- tions, and he wants to use bats and mice to test lina at Chapel Hill revolutionized mammalian the mechanics of evolution. The two animals genetic techniques. Evans cultured mouse embry- are about the same size and share physiologi- onic stem (ES) cells, Capecchi created a targeted cal similarities, including body temperature and mutation in those cells, and Smithies corrected heart rate. Yet they are profoundly different: bats a genetic defect in ES cells. The work culminated in 1989 when Capecchi announced he had created a mouse lacking a gene entirely—the first “knockout” mouse. Today, knockout mice are used

9 HHMI Annual Report 2008 Ask Big Questions

fly and use echolocation to navigate the world; mice scurry on all fours and rely on smell. “How- ever,” Capecchi points out, “the genetic content is nearly identical between the two animals.” Because individually inserting bat genes into mice would require approximately 25,000 mouse strains, Capecchi is taking a bolder approach. In work supported by HHMI, he plans to transfer large spans of bat genome into mouse embryos and see if the resulting mice have new characteristics. He doesn’t expect to make the mice fly 1. or echolocate, but he does think that his team may find mice with elongated fingers or changes “One of the things that is nice about in their auditory systems that make them more nature is that if something works, similar to bats. He doesn’t rule out profound nature will use it,” Capecchi says. changes, however; animals can evolve new characteristics quite rapidly. mice displaying batlike characteristics, he will “One of the things that is nice about nature break them down gene by gene. Capecchi recog- is that if something works, nature will use it,” nizes the project may not bear fruit for 10 to 20 Capecchi says. “And it is possible that, when a years. Still, he was optimistic enough to submit change is so rapid, only a handful of genes are the project for an NIH grant shortly before his involved.” Nobel Prize was announced. The NIH reviewers Even so, his plan to explore evolution in this flatly turned him down. fashion is ambitious—he is still developing the “I sent them a letter back saying, ‘Déjà vu,’ and technology that will allow him to insert such large resubmitted the grant without the speculative swaths of bat genome into mice. If he does find parts,” Capecchi laughs, noting that the second version received funding. But he sees a loss in focusing on projects deemed most likely to suc- ceed. “One of the things that’s unpredictable about science is the science itself.”

10 1. Pluripotent Human embryonic stem cells can mature into any cell type depend- ing on the biochemical signals they receive. 2. George Q. Daley 3. Douglas A. Melton

Is there an easier way to rebuild a pancreas? The discovery of human embryonic stem (ES) cells—the source material for every cell in the body—has given great hope to people struggling with degenerative disorders such as diabetes and Parkinson’s disease. ES cells offer the potential to replace damaged tissues and eradicate disease. 2. Those cures, however, lie in the future. Researchers have been trying to coax ES cells Disease-specific stem cell lines along precise pathways to become specific nerve, George Q. Daley, a new patient-oriented HHMI cardiac, or pancreatic cells. HHMI investigator investigator at Children’s Hospital Boston, and Douglas A. Melton, who is committed to curing colleagues created a powerful resource that allows scientists to replicate human diseases in a Petri diabetes, asked whether it was really necessary dish. They added four genes, called reprogram- to start with ES cells to make insulin-producing ming factors, to cells from patients with 10 genetic pancreatic β cells. Could there be a shortcut? disorders—including Parkinson’s disease, muscu- Melton started with neighboring cells—fully dif- lar dystrophy, and type 1 diabetes. And the cells ferentiated pancreatic exocrine cells that produce reverted to the embryonic state. These cells, which digestive enzymes—and attempted to repurpose are being made widely available to other researchers, should offer lots of new ways to address the them in mice: stop making enzymes, start making root causes of the diseases, Daley says. “We think, insulin. He and his postdoctoral fellow Qiao “Joe” we hope, we’ll be able to make lines from just Zhou discovered they needed to deliver only three about any patient with any disease.” regulatory genes to the mice to complete the “extreme makeover” efficiently and quickly. The researchers changed the function of adult cells without using ES cells or relying on techniques to reverse a cell’s genetic programming. The work demonstrates that regenerating tissues may not require a march back to the beginning to reach the end, but could allow physicians to alter nearby cells to replace damaged tissue. “My obsession to find a new treatment for diabetes [drove this work],” says Melton, who is codirector of the Harvard Stem Cell Institute. “I wake up every day trying to think of a new way to make a β cell.”

11 1. Metastasis A human breast cancer cell (green) Massagué and his c0lleagues found lodged in a mouse lung capillary that the most invasive, aggressive can spread when surrounded by weakened endothelial cells (red). human breast tumors are missing 2. Joan Massagué three critical microRNA molecules. 3. Anna Marie Pyle 4. Jumping RNA An electron density map of the group II intron.

What drives cancer’s spread? Metastasis is a problem as big as any in cancer research. HHMI investigator Joan Massagué continues to make inroads on cancer’s deadly spread to other organs since it became the focus of his work in 2000. Massagué and his colleagues at Memorial Sloan-Kettering Cancer Center first identified different sets of genes that collude to permit breast cancer to spread to various tissues, like the lungs and bone. Silencing four of the genes that work together to encourage metastasis to the lungs, for example, eliminated tumor growth and spread. This year the team found that the most invasive, aggressive human breast tumors are missing three critical microRNA mole- 1. cules. When the three molecules were added back to human breast cancer cells in mice, the tumors lost their ability to spread. “The tiny RNAs prevent the spread of cancer by interfering with the expression of genes that give cancer cells the ability to proliferate and migrate,” Massagué says. His team’s findings may lead to drugs that interfere with metastasis and perhaps form the basis of tests to determine which breast cancers are most likely to spread.

12 HHMI Annual Report 2008 Ask Big Questions

How does an RNA parasite escape? HHMI investigator Anna Marie Pyle of Yale University took a snapshot of a genetic parasite isolated from a deep-sea bacterium and found answers to how specialized stretches of RNA escape from the genome. Once free, these wandering bits of RNA, called group II introns, invade new RNA and DNA, and that mobility has had a profound influence on evolution by 4. promoting diversity among the world’s most ancient organisms. “This genetic parasite really has fangs,” For the past 16 years, Pyle has worked to Pyle says. “It’s ready to go out and reveal the structure of group II introns to under- react with something.” stand how they free themselves. Painstaking biochemical analysis led her to seek the detailed information available from x-ray crystallography. Pyle chose to explore the stable group II intron from the alkaline-loving deep sea bacterium Oceanobacillus iheyensis. She found that these movable RNAs folded into a globular shape with a central portion containing the parts of the RNA needed for splicing RNA and DNA with metal ions. “This genetic parasite really has fangs,” Pyle says. “It’s ready to go out and react with something.” What’s more, the shape is remarkably similar to the cell’s spliceosome—a structure of proteins and RNA that normally removes unneeded sections of RNA. Pyle’s work confirmed many anticipated similarities between the group II intron and the RNA in the spliceosome and hints that the spliceosome may have derived from an ancient group II intron.

13 Innovative science benefits from connections between the cultures and styles of diverse disciplines. Whether it means seeking the physicist down the hall or the biochemist across the globe, HHMI scientists are reaching beyond their usual disciplinary boundaries to answer pressing questions in science and medicine. Creative Connections 1/2. Blocking Disease Levels of HIV (red) dropped when scientists blocked a protein in human cells (blue). 3. Stephen J. Elledge 4. Gregory J. Hannon

Massive Screens HHMI investigator Stephen J. Elledge found more than 200 new targets for blocking the human immunodeficiency virus (HIV) because he saw a problem—outside his field—and thought he could help. In his first foray into HIV biology, Elledge, at Brigham and Women’s Hospital, provided a detailed road map describing how HIV hijacks

1. 273 human cellular proteins to infect critical immune cells and destroy the immune system. Viruses are needy. They lean heavily on their host cells to invade successfully. HIV is no different—it has a mere 9 genes that make only 15 proteins. Every one of the human proteins that aid HIV’s assault on the immune system is a potential new therapeutic target to stop the virus. Researchers had discovered some of the pathways Elledge and his team identified, but more than 200 of the proteins were new finds.

2. “This is a tremendous resource for the entire field of HIV research,” says Dan R. Littman, HHMI investigator and an HIV expert at New York Uni- versity Langone Medical Center. “It’s been known for a long time that these host factors were out there, but there had never been a systematic approach to identify them. I don’t think anyone could have imagined how many would turn up.” Elledge, who studies the cell cycle, used his expertise in RNA interference—a process by which

16 HHMI Annual Report 2008 Creative Connections

“We wanted to get this information out to the field,” Elledge says. “It will allow people to think more deeply about the life cycle of HIV and how to impede it.” small RNA molecules shut off genes—to disrupt genes one by one and observe whether HIV could still establish itself and reproduce. The team plod-

ded through 21,000 disrupted genes to isolate the 3. 4. ones HIV required. Now drug developers can try to shut down those proteins, or at least go after the The Full Genome Approach proteins that the host can live without. Stephen J. Elledge has taken on cancer too, partnering “We wanted to get this information out to the with HHMI investigator Gregory J. Hannon at Cold field,” Elledge says, noting that pharmaceutical Spring Harbor Laboratory to reveal new target pro- companies are doing similar work privately. “It teins for anticancer drugs. The two invented a genetic will allow people to think more deeply about the screening method that quickly and inexpensively probes breast and colon tumors for genes that help life cycle of HIV and how to impede it.” them thrive. They generated a library of short hairpin RNAs (shRNAs) that trigger RNA interference and turn genes off. They inserted the shRNAs into retroviruses and used them to infect normal and cancer cells. The shRNA binds to similar stretches of RNA in the cell and shuts off the corresponding gene, preventing its translation into protein. If the protein is critical to survival, the cell dies. If the protein is a growth inhibitor, the cell multiplies and thrives. Screening thousands of RNAs and their related genes would normally require thousands of experiments. But Hannon and Elledge devised a genetic barcoding method to track the effects of thousands of RNAs in a single pool of cells in a single lab dish. They found dozens of genes that, when shut down by the shRNAs, damaged the cancer cells but didn’t harm normal cells.

17 “I love to roll up my sleeves and write the code,” Myers says, noting that the unique atmosphere at Janelia Farm encourages cooperative work.

Six Degrees of Gene Myers For a man who has never taken a biology course, Janelia Farm group leader Gene Myers is immersed in complex biological questions. Trained as a mathematician, computer scientist, and engineer, Myers has a growing network of collaborators throughout Janelia and the world. The principal architect of a tool that permitted Craig Venter and Celera Genomics Corporation to sequence the human genome in three years, Myers has turned his focus to image analysis. Current projects include: Developing software with Janelia’s Julie Simpson, Jim Truman, and Gerry Rubin for cataloguing images of stained fly brains. 2. Refining and improving the interpretation of raw Creating methods for tracking and measuring data produced by the PALM microscope, a power- cellular processes during the first anterior/pos- ful light microscope developed by group leader terior mitotic division in Caenorhabditis elegans Eric Betzig and Harald Hess for discerning the pre- with Tony Hyman of the Max Planck Institute of cise location of proteins within cells. Molecular Cell Biology and Genetics, Dresden. Developing software and a microscope with Producing with Stuart Kim of Stanford University Janelia’s Karel Svoboda, Jeff Magee, and Scott 3-D stacks of in situ worm preparations in which Sternson that track sets of stained neurons in all 81 muscle cell nuclei are stained a different 3-D stacks tiling the cerebral cortex of the mouse. color. By creating enough data sets, the researchers hope to develop a neural atlas of the mouse brain This range of collaborations suits Myers just revealing how neurons connect to each other. fine. “I’m a very hands-on kind of guy. I have lots of ideas. I love to roll up my sleeves and write the code,” he says, noting that the unique atmosphere at Janelia Farm encourages cooperative work. “We have the opportunity to do really exciting science.”

18 1. Gene Myers HHMI Annual Report 2008 Creative Connections 2. Human Neuron The spindly ends at the bottom of this neuron connect to muscle fibers. 3. David Baker 4. Protein Folding The complex three-dimensional structure of HIV reverse transcriptase.

Gamers, Protein Scientists Unite! It may not be as hot in the online gaming community as World of Warcraft, but the new game Foldit enlists gamers to “solve puzzles for science.” The brainchild of HHMI investigator David Baker at the University of Washington and colleagues, Foldit (www.fold.it) is a free online game that pits players against each other to design proteins rather than battle evil orcs.

3. Rosetta@home, Baker’s distributed computing network aimed at protein folding, was humming along, using downtime on people’s computers around the world to perform trillions of random calculations to fold proteins. But participants saw lots of useless calculating going on and suggested the program could use some human intervention. Foldit, developed with a special grant from HHMI, brings human brainpower to the effort by allowing players to solve protein structures from nature after successfully completing a few training levels. This fall, gamers will be able to design all-new proteins that ultimately could become useful tools for developing new agents to cure disease or clean the environment. “My dream is

4. that a 12-year-old in Indonesia turns out to be a prodigy and builds a cure for HIV,” Baker says. “My dream is that a 12-year-old in Indonesia turns out to be a prodigy and builds a cure for HIV,” Baker says.

19 1. Alan F. Cowman 2. Geoffrey McFadden 3. Sergey Lukyanov 4. Fluorescent Frogs Katushka, a new red fluorescent protein, lights up muscle fibers in this frog. 5. Gerald M. Rubin

1. 2.

On a Mission Against Malaria HHMI international research scholar Alan F. Cowman longs to work himself out of a job, if it means the end of malaria, and he’s formed several collaborations to make it happen. The malaria expert from Australia’s Walter & Eliza Hall Institute of Medical Research most recently teamed up with HHMI international research scholar Geoffrey McFadden, at the University of 3. 4. Melbourne, to explore how a gatekeeper inside the malaria parasite decides which proteins gain Pet Shop Beauty entry. McFadden and Cowman discovered that The bright red fluorescent protein Katushka out- this cellular gatekeeper enforced rather lax rules: shines other existing fluorescent proteins 10 to 1. And it exists because HHMI international research as long as a given protein was at least 24 amino scholar Sergey Lukyanov spied a brilliant red sea acids long, had a positive charge, and included anemone at his local Moscow pet shop and wouldn’t the amino acid asparagine, it could gain entry go home without it. He won a bidding war against into the parasite’s cellular compartment called a another customer and returned to the lab with the plastid. The researchers were able to sneak their sea creature to develop the protein. His colleague at the Shemyakin-Ovchinnikov Institute of Bioorganic own engineered protein past the gatekeeper, Chemistry, HHMI international research scholar making them think it should be relatively simple Andrey Zaraisky, established Katushka’s suitability to trick the gatekeeper into letting an invader as a tracer in live animals, such as this African clawed inside to kill the malaria parasite. frog Xenopus laevis. And the pet-store anemone? Just a piece of one tentacle was needed to isolate the protein. The animal resides in one of Lukyanov’s aquariums, with other anemones and marine fish.

20 Q&A

Gerald M. Rubin Sowing Seeds of Collaboration 5.

Gerald M. Rubin, the Drosophila Q What does it take to change Q Are the scientists at Janelia biologist and former HHMI a culture? Farm connecting as you investigator who now directs envisioned? A The ability to collaborate the Janelia Farm Research readily is a vital tool, but our A When we were planning Campus, likes to think big and scientists need the mind-set to Janelia, we asked: what impor- to work collaboratively. As he use that tool. It requires con- tant biological problem would noted some years ago, “I have stant reinforcement. you tackle if you could assemble a knack for dealing with highly 100 people for 10 years with creative, quirky, high-mainte- Q Janelia Farm is fairly small generous funding? None of our nance people and getting them compared to a university. Does projects has reached that scale, to work together.” Those spe- that limit collaborations? but I can see the seeds in some. cific qualities came into play A No, the small size facilitates when Rubin led a novel effort Q Can you give an example? collaboration, as individuals to sequence the Drosophila working in different fields are A There’s an attempt to genome, and they’re very much not segregated into depart- create a map of the fly brain on display as he strives to create ments. That said, many of our and then relate specific neurons a collaborative research com- projects benefit from wider to specific sensory and motor munity at Janelia Farm. expertise than we can have at activities. The project requires Q Why do you believe Janelia Janelia Farm, a deficiency we the development of new ana- Farm Research Campus is more address through our visiting sci- tomical methods, numerous conducive to collaborative entist program. Scientists come high-throughput behavioral efforts than academia? for three weeks, a full sabbatical assays, and developments in year, or a series of short visits molecular genetics and in meth- A Academia rewards individual spread over multiple years— ods that allow physiological achievement, not collaboration. we’re open to any arrangement measurements of the function Certain scientific problems that makes sense. of individual neurons in flies as are best studied in an interdis- they perform various behaviors. ciplinary environment where It’s a wide-ranging project in collaboration is the expectation, which nine resident labs and and research groups are encour- several visiting scientists cur- aged to self-assemble to solve rently participate. problems.

21 The pursuit of science begins with curiosity, but real insight comes from forming and testing hypotheses. To spark an inquisitive fire and train the next generation of scientists to take up research in an ever more complex and interdisciplinary scientific world, HHMI is undertaking some experiments of its own. Putting New Approaches to the Test HHMI Annual Report 2008 Putting New Approaches to the Test

Undergraduate Variations HHMI issued a challenge to the nation’s top undergraduate institutions: identify creative new ways to engage students in biological sciences. Close to 200 replied, and now 48 liberal arts colleges in 21 states and Puerto Rico will test their resourceful, imaginative approaches to science education with newly won HHMI grants. This is the largest number of new grantees in a decade; more than a quarter of the institutions have never received an HHMI grant before. “The undergraduate years are vital to attract- ing and retaining students who will be the future of science,” says HHMI President Thomas R. Cech. “We want students to experience science as the 1. creative, challenging, and rewarding endeavor that it is.” “We want students to experience HHMI has pledged a total of $60 million to sup- science as the creative, challenging, port the programs devised by the colleges and and rewarding endeavor that it is,” universities. The institutions include traditional says Tom Cech. liberal arts colleges, historically black colleges and universities, small religious schools, and larger state institutions. Using grants ranging from $700,000 to $1.6 million, they will focus on teaching modern laboratory techniques, designing interdisciplinary classes, and boost- ing outreach. Some are entirely redesigning their biological science majors. The following are a few of the new programs: Franklin & Marshall College in Lancaster, Pennsylvania, is taking advantage of a genomic science resource in its backyard: the D. Holmes Morton Clinic for Special Children specializes

24 1. Liberal Arts Education Darrylynn Nelson and Elizabeth Adeyemi, students at Spelman College, evaluate the role of a gene in yeast. 2. Hands-On Science Barnard College students Christine Chang and Ayelet Spitzer use fluorescent microscopy and digital imaging to see if cells are dividing in fruit fly testes.

in diagnosing and treating inherited metabolic classes, and live together during their first year. disorders in children from Amish and Old Order Each learning community will be assigned a junior Mennonite communities. The clinic has gathered or senior who is doing research in a relevant genetic data on more than 80 different metabolic area. This student will serve as a peer facilitator disorders. Thirty-two students from the college and coordinate weekly discussion sessions. The will work at the clinic and on campus to mine college has used learning communities in other and analyze this wealth of information looking disciplines and successfully improved grades and for distinctive patterns of mutation, deletion, or increased retention, particularly among under repetition that might underlie these disorders. represented groups. The grant will also support an additional 32 stu- Spelman College in Atlanta is going Hollywood dents to work on other projects in bioinformatics and using some of its grant to fund student film and genomics. makers as they create a full-length documentary The Spokane Tribe of Wellpinit, Washington, examining the lives of recent Spelman graduates taught Gonzaga University biology professor who are pursuing successful scientific careers. Brook Swanson and his colleagues that Native The historically black women’s college is also Americans don’t view science as a discrete topic: revamping its mentoring program in the bio- everything is interconnected. “How you interact logical sciences to pair successful alumni in the with your environment is an integral part of your sciences with female high school students from community and your spirituality,” Swanson says. the Atlanta area. In addition, the mentoring Now Gonzaga University’s biology department is program will expand to place Spelman students using part of its first HHMI grant to strengthen during the summer in the labs of top minority its outreach to a community that is not often women scientists at research universities across attracted to science careers. The grantees are the United States. developing a new curriculum for the tribe’s K–12 “This diverse pool of grant recipients and large school that is filled with context and nuance numbers of first-time awardees shows that HHMI conveyed through stories, case studies, and the is committed to funding new ideas and new ways history of science. They hope the project will of approaching science education,” says Peter J. attract more Native Americans to science as well Bruns, HHMI’s vice president for grants and spe- as other students who benefit from learning cial programs. “We want to help create successful in context. models for teaching science that can spread Through “learning communities,” the College of throughout the higher-education community.” Charleston will encourage and support first-year students interested in computational biology, chemical biology, and neuroscience. About 30 to 40 students with similar interests will study, take

25 1.

Sink-or-Swim Proteomics HHMI professor Pavel A. Pevzner believes that without more bioinformatics specialists, researchers will either drown in genetic and protein sequence data or, worse, miss the key connections that undergird human health or disease. Pevzner’s solution is to push undergraduate students into the deep end of bioinformatics to see if he can train them to be experts in genome annotation. In a University of California, San Diego, course innocently titled “Research Experience for Under- graduates,” Pevzner thrust students into the 2. lab to figure out the genome of three species of Shewanella, an important “metal-munching” “Instead of meeting with the students in genus of bacteria. Armed with raw mass spec- a room, we will meet them on the Web. troscopy data for the bacterium’s proteins plus Students in India and China and in what- genomic sequence information, the students set ever place in the world can collaborate to work designing experiments and writing com- with each other,” says Pevzner. puter algorithms to link the two sets of data. Pevzner and seven undergraduates from the With a proof of principle in hand, Pevzner and class published their results in the July 2008 issue graduate student Nitin Gupta are taking the of Genome Research. In that paper they unveiled experiment worldwide via their UBER-GRID— an entirely new branch of bioinformatics that the Undergraduate Bioinformatics E-Research Pevzner calls “comparative proteogenomics.” Grid. “We will put our projects on the Web and invite every student in the world to collaborate,” Pevzner says. “Instead of meeting with the students in a room, we will meet them on the Web. Students in India and China and in whatever place in the world can collaborate with each other.” The lab will post links to required data sets, genome repositories, downloadable software tools, prediction programs, and literature references.

26 1. Pavel A. Pevzner HHMI Annual Report 2008 Putting New Approaches to the Test 2. Metal Muncher Shewanella oneidensis grows on the iron oxide mineral hematite. 3. Analyzing Insect Sounds Janelia Farm’s Gus Lott (right) describes his software to students from Singapore and Virginia.

Engineering a Class Summer break for a group of college students from some of the best engineering colleges in the country meant returning to their Greenbelt, Maryland, high school to design a top-flight 3. engineering curriculum. Students at Eleanor Roosevelt High School, a science and technology Collaborations Across the Oceans magnet, will pilot-test several of the new modules How crickets evolved different songs is a research this fall. They will redesign the Taj Mahal, build question bringing together students from Loudoun an SUV, and guide a robot using the latest in com- County, Virginia, and the island nation of Singapore. puter programming. Through this HHMI-supported project, these stu- Faced with a high school engineering curricu dents are getting their first taste of international lum that hadn’t been revised since 1976, science scientific collaboration. and technology program coordinator Jane Hemelt Pairs of students from the Academy of Science and teachers Rocco Mennella and Michael “Pudge” (AOS) at Dominion High School and the presti- Samordic turned to a group of alumni who’ve gious Hwa Chong Institution (HCI) teamed up to been excelling in college engineering programs. explore six research questions. The cricket project Supported in part by HHMI, these 10 students even drew in Janelia Farm scientist Gus Lott, who culled their knowledge and that of almost 50 engi- brought to the table software he developed to neering professors to develop course modules analyze insect sounds. that focus on the practical aspects of engineering The international collaboration experiment while including as much physics and mathematics is the brainchild of AOS director George Wolfe, as possible. And because science and technology a former Peace Corps volunteer who traveled teachers can be hard to find, they designed the three years ago to train teachers in Singapore. modules to be taught by teachers who are not On a later trip, he suggested to HCI’s principal engineering experts. research consultant that “our students collabo- With refinements based on feedback from pilot rate like real scientists.” Last fall, the HCI students testing, and development of more modules over visited Loudoun County for some face-to-face the next several years, Hemelt hopes to make the interaction. The AOS students went to Singapore curriculum widely available. “Who knows, this this summer and the teams presented their final could become a model for the state and maybe a results together. model for the country,” Hemelt says.

27 1. Steven E. Jacobsen 2. Ronald M. Evans 3. David Asai

1. 2.

A Wide-Screen View of Silence Exercise in a Pill Turning on the wrong gene at the wrong time can The genetically engineered mice ran longer and wreak havoc in a cell. Scientists have known for faster than normal mice and they resisted weight decades that cells use DNA methylation to keep gain even when fed a high-fat diet. HHMI inves- unneeded genes turned off, but their understand- tigator Ronald M. Evans at the Salk Institute for ing of how DNA methylation accomplishes this Biological Studies pursued the next obvious—and critical task has been stymied because they could electrifying—question: is it possible to create a examine methylation only one gene at a time. drug to duplicate the athletic abilities of his HHMI investigator Steven E. Jacobsen at the Uni- “marathon” mouse? versity of California, Los Angeles, has given the Evans’ team found two drugs that target the scientific community an important new tool to critical gene PPAR-delta, which serves as a master explore the gene silencing process: a molecular regulator of several genes. The two compounds, and computational approach that delivers a wide- GW1516 and AICAR, increased the activity of screen, whole-genome view of DNA methylation. PPAR-delta in mice. Treated mice also had higher “There’s lots of evidence that when genes’ endurance than untreated mice. GW1516 had a methylation patterns are not properly maintained, more dramatic effect, but only when combined that is a major cause of cancer,” says Jacobsen. with exercise. Sedentary mice receiving AICAR “So if we can learn enough about these methy- ran longer and farther than those receiving exer- lation mechanisms, we may someday learn to cise training. Like exercise, the two drugs trigger manipulate them and treat cancer.” a variety of changes such as an increase in the During DNA methylation, small molecules number of energy-generating mitochondria in called methyl groups attach to specific sites on cells and a shift in metabolism to favor burn- DNA where they signal the cellular machinery to ing fat. “We have now created the potential for silence genes in a specific region. Using the plant a really simple intervention in an area of major Arabidopsis thaliana, Jacobsen and his compu- health problems,” Evans says. tational biologist colleagues Matteo Pellegrini The drugs could also be used by athletes and Shawn Cokus, with researchers from the bio- seeking an advantage over their competitors— technology companies Illumina and New England especially the exercise-enhancing GW1516. For BioLabs, developed novel techniques to rapidly that reason, Evans has developed a test to detect and correctly identify more than 90 percent of the whether the drugs are being used for perfor- methylation sites across the plant’s entire genome. mance enhancement. He has provided it to the With their validated tool in hand, Jacobsen and col- World Anti-Doping Agency, for retroactively test- leagues are analyzing other organisms to see how ing samples from athletes who competed in the widely conserved methylation patterns are. 2008 Olympics.

28 Q&A

David Asai Experiments in Education 3.

David Asai has served as a director at a large research insti- Q What goals do you hope to program director at Purdue tution and an undergraduate achieve in the next year? University and most recently at liberal arts college. I’ve learned A Long term, I want to find Harvey Mudd College. He joins that big research universities ways to consider the entire HHMI as Director of Precollege and little liberal arts colleges continuum of science education and Undergraduate Science have things to teach each other. from pre-K through college in Education, calling it a once- Research institutions obviously a holistic way. I would also like in-a-lifetime opportunity to have more resources, but liberal to encourage institutions to do encourage educators to test arts colleges can be more nim- more hypothesis-based experi- new ideas. ble when it comes to trying out ments in science education and new ideas. We need to encour- Q The Undergraduate Science give them the opportunity and age exchange between the two Education program and the incentive to try new and some- so they can learn from each Precollege Science Education times risky ideas. Even if the other. program just merged. What’s hypothesis fails, it will be use- the benefit? Q How is the transition from ful as long as we do it right and Harvey Mudd proceeding? disseminate the results. A Your knowledge about Short term, we have two science doesn’t begin as a fresh- A My National Science Foun- program officer openings in our man in college. Merging the two dation (NSF) grant was just group. I would like to fill the programs means we can focus renewed, and back at Harvey positions with people who have on collaborating across the Mudd, I have four seniors, three been successful in academic continuum of science educa- sophomores, and two postdocs teaching and research. For one tion from pre-K through college studying the dynein motors of the positions, we plan to use rather than emphasizing discon- responsible for intracellular the NSF model where people tinuities. Now, we just need a transport. There will be a lot of take a leave from their home clever acronym for the program! videoconferencing and travel- institutions for a couple of years ing back and forth, but I think it Q As an HHMI program direc- and then return to academia. is important that our grantees tor, what is the biggest thing This “rotator” model provides understand that those of us you’ve learned about under- the opportunity for the regular who work at headquarters also graduate teaching and learning? and frequent refreshing of our have labs and teach. This per- perspectives. A I’ve been very fortunate spective helps us understand to have served as a program the challenges they face.

29 With scientific curiosity and advancing technology, researchers have begun exploring problems of enormous complexity. Several HHMI investigators have made exciting new discoveries about some mystifying diseases, such as autism. Probing Complexity 1. Christopher A. Walsh 2. Communication Breakdown Nerve cells reach out to each other to exchange information at the synapse. 3. Thomas C. Südhof 4. Huda Y. Zoghbi 5. Li-Huei Tsai

Revealing the Roots of Autism Autism strikes with heartbreaking timing. Just as a toddler should be gleefully interacting with family members, the child regresses and pulls away from the world. Most children with autism are slow to develop language, have poor social skills, and repeat stereotypical behaviors, but the extent of their difficulties can range from subtle to devastating. This wide variability has confounded attempts to understand the disorder. 1. In just the past year, however, several HHMI investigators and others have made key discoveries about the autistic brain. Their findings have zeroed in on the synapses—the tiny chemical- filled gaps between neurons. Synapses create powerful information-processing networks that enable humans to think and remember, interpret sensory information from the outside world, and navigate the challenges of social relationships. Synapses also appear to be central to Rett syndrome and fragile X syndrome, two rare genetic disorders with autistic features. “There’s lots of evidence to suggest that this process of synaptic learning is key to autism,” says HHMI investigator Christopher A. Walsh at 2. Beth Israel Deaconess Medical Center. In 2008, discovery by using a new strategy to compare Walsh and clinical collaborators in the Middle genes from autistic and nonautistic siblings from East found six synapse-related genes that, when 88 large Middle-Eastern families. Most of the mutated, contribute to autism. They made the mutations were found in regions that serve as on-off switches to nearby genes that are involved in learning. Walsh posits that these broken on-off switches could serve as targets for therapeutics or could help identify children likely to respond to intensive behavioral intervention.

32 HHMI Annual Report 2008 Probing Complexity

Another dramatic development in autism research came in 2007 when HHMI investigator Thomas C. Südhof, then at the University of Texas Southwestern Medical Center at Dallas, and colleagues developed a mouse model of autism 4. spectrum disorders. He engineered the mice with a mutation in the human gene neuroligin-3, part of a family of genes (along with the neurexins) that he linked to synapses in the 1990s. These genetically altered mice were far less social than normal mice, but they were also smarter—they learned the location of a platform submerged in murky water in fewer days than normal mice. “Usually, when you impair mouse cognitive function, they’re just stupid,” says Südhof, now at

Stanford University. He adds that the results 5. “validate the whole idea that autism is related to synapses.” tion of 2,500 genes, which she says helps explain HHMI investigator Huda Y. Zoghbi has continued the broad and varied symptoms of the disorder. her investigations of the gene mutations involved By genetically engineering mice deficient in in Rett syndrome, a devastating disorder that a protein called Cdk5, HHMI investigator Li-Huei robs (mostly) girls of their speech, motor control, Tsai at the Massachusetts Institute of Technol- and social development after 6 to 18 months of ogy (MIT) also drew attention to the role of the normal development. Zoghbi, a pediatric neurolo- synapse. Without Cdk5, a second protein called gist and geneticist at Baylor College of Medicine, CASK does not interact with neurexin proteins discovered in 1999 that 95 percent of all Rett cases and synapse formation is profoundly defective. involve a mutation in a gene on the X chromosome “Proteins implicated in autism all seem to overlap called MECP2. Zoghbi’s group reported in 2008 in this particular area of synaptic development,” that the MECP2 protein interferes with the regula- Tsai says.

33 HHMI Annual Report 2008 Probing Complexity 1. Mark F. Bear 2. Fragile Tip In fragile X syndrome, the X chromosome holds a mutation that makes it easily break near one tip. 3. Philip S. Perlman

Autism-associated defects in synapses may be reversible, according to recent mouse studies of Rett syndrome and of the most common form of inherited mental retardation, fragile X syndrome. HHMI investigator Mark F. Bear, also at MIT, devised a new strategy for treating fragile X. Bear had previously established that a neurotransmitter called mGluR5 weakens neural connections by increasing the amount of protein made at a synapse. He and his colleagues also established that the frag- 1. ile X mental retardation protein (FMRP), which is mutated in fragile X syndrome, serves as a foil to mGluR5 and puts the brakes on protein synthesis. When FMRP is absent, protein synthesis at the synapse goes unchecked. Bear and his colleagues tested whether elimi- nating one copy of mGluR5 in mice with fragile X syndrome would reduce seizures and memory impairment. In December 2007, they reported that indeed the mice with dampened mGluR5 expression showed few fragile X symptoms. mGluR5 antagonists have been moved into human studies. With these and other findings that place the synapse front and center, researchers are showing the first signs of optimism that they may find a way to treat autism and related disorders.

34 Philip S. Perlman Herding Mice 3.

When Philip S. Perlman joined of genotyping, colony management System, developed by HHMI HHMI as a senior scientific offi- ment, and problems getting the investigator Simon W.M. John. cer in 2004, he brought years of Jackson Laboratory repository And, with HHMI support, the Jack- research experience on mitochon- to accept mice that were no son Lab repository has accepted drial genes in yeast. Naturally, he longer being used for active more than 200 new mouse strains. was charged with finding a way research, but needed to be The price came down signifi- to help HHMI investigators man- maintained for future studies. cantly when the lab found a way age the costs of mouse research. Now, mouse genotyping is out- to switch from freezing mouse With input from 18 HHMI sourced through Memphis-based embryos from each breeding pair mouse researchers from around company Transnetyx: more than to sperm cryopreservation. Perl- the country, Perlman learned 70 researchers have used the ser- man is not stopping there. Etched a thing or two about mice, vice at a special price negotiated ear tag identifiers are in the and devised an Institute-wide by HHMI. Sixty-five investigator works, as is research to identify initiative to address the investi- labs have completed training on the optimal number of mice per gators’ top concerns: the costs the Jackson Lab’s Colony Manage- colony cage.

Top 10 Things Yeast Geneticist Philip Perlman Learned About Mice 1 Mouse research is slow. Mice 4 Mice are much better models 7 Mouse studies need institu- take 4 months between genera- than yeast for human diseases tional approval. Yeast are not tions; yeast reproduce 18 times such as diabetes, cancer, and animals, so no animal care or in 24 hours. cardiovascular disease. ethics rules are involved. 2 Mice need clean cages, food 5 Mice are harder to share with 8 Mice have better health care and water, air conditioning, and your colleagues. You can send than many humans. toys. You can store yeast in the yeast via regular mail the same 9 Mouse research is irresistible. freezer. day the request comes in. Mice Once it enters an investigator’s take six months to breed and 3 A mistake in mouse research program, it never leaves. genotype before they can be sets you back months. See shipped—special delivery. 10 Yeast smell like bread and number 1. beer; mice smell like … 6 Mice have cute, furry faces. Yeast are just furry.

35 Two Approaches to Protecting Motor Neurons Everyday tasks like getting out of bed or stepping into a car require coordination of dozens of muscles, guided by hundreds of motor neurons that connect the muscles with the spinal cord.

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s 1. disease, is one neurodegenerative disease that destroys motor neurons. In work that could help aid drug discovery for ALS, HHMI investigator Thomas M. Jessell, at Columbia University College of Physicians and Surgeons, working with Jeremy Dasen of New York University and Philip Tucker of the University of Texas at Austin, identified a key gene responsible for making motor neurons and ensuring they make critical connections between the spinal cord and muscles. 2. 3. FoxP1 is required to generate motor neurons, according to the new research. And, importantly, HHMI international research scholar Rafael the level of the protein FoxP1 expressed by devel- Radi is taking a different approach to ALS, based oping neurons dictates the precise subtype they on an unexpected result of his research on the will form. FoxP1 is an essential cofactor for many immune system’s macrophages. Motor neurons of the Hox proteins that, according to Jessell’s rely on companion cells, called astrocytes, for previous work, orchestrate motor neuron devel- nourishment and protection. Radi’s lab found opment and connectivity. Hynek Wichterle and that peroxynitrite, used by macrophages to kill Mirza Peljto at Columbia are using this Fox-Hox bacteria, can also turn astrocytes into motor neu- recipe to develop “a promising screening for ron killers and lead to ALS. Radi and his team at identifying drugs that prevent or slow the degen- the Universidad de la República in Uruguay used eration of motor neurons,” says Jessell. an antioxidant to reverse peroxynitrite buildup and block motor neuron destruction in rats with a form of ALS. “I think peroxynitrite is a central mediator in cell death,” he says. “It can kill patho- gens, but it can also kill your own cells.”

36 1. Astrocyte Cells HHMI Annual Report 2008 Probing Complexity Immunofluorescent light micro- graph of mammalian brain cells. 2. Rafael Radi 3. Thomas M. Jessell 4. Fidgeting Enzyme Three-dimensional structure of adenylate cyclase. 5. Dorothee Kern

Twitching Proteins HHMI investigator Dorothee Kern has changed the way scientists think about enzymes. To draw out the dynamic personality of adenylate kinase, Kern and her team at Brandeis University used x-ray crystallography for structural information, examined the internal motion of the enzyme with nuclear magnetic resonance, and used a super- computer to generate a movie of the enzyme opening and closing. Kern called on her brother, physicist Christian

Huebner, at Martin Luther University Halle- 4. Wittenberg in Germany, to make sense of discrepancies between methods. Huebner had designed and built a unique ultrasensitive laser that allowed precise measurements and time resolution in microseconds. The new measurements showed that, contrary to conventional wisdom, the enzyme doesn’t always wait for its substrate to change shape. It adopts an inter- mediate half-open, half-closed state every few nanoseconds. It only rarely closes all the way, snapping its lid shut in milliseconds. “That’s when the enzyme is getting down to business and can 5. bind with its substrates to perform catalysis,” says Kern. It took a technological tour de force, HHMI investigator Dorothee Kern but Kern and her team ultimately revealed the has changed the way scientists think enzyme’s hidden moves. about enzymes.

37 HHMI Annual Report 2008 Probing Complexity 1. Dendrite Targets Two-photon image of a neuron showing different spatial patterns of excitatory input onto a dendrite branch. Target shows location of neurotransmitter uncaging. 2. Jeffrey C. Magee

Information Storage in the Brain The human brain is composed of 100 billion neurons, each sporting roughly 10,000 synaptic connections to other neurons. The signals that flood through these myriad connections become stored information through a process called synaptic plasticity, which occurs when the strength of input changes because of what we experience or the thoughts we produce. Group leader Jeffrey C. Magee and colleagues at the Janelia Farm Research Campus used a new technique to show that neurons fine-tune their information processing through a second type of plasticity that he calls “dendritic plasticity.” Dendrites, the large branches that extend from 1. the main body of a neuron, represent the receiving end of nerve impulses. They are covered with receptors for chemical signals, or neurotransmitters. As neurotransmitters flood the dendrites, they trigger an electrical wave called a dendritic spike that, when powerful enough, can propagate a nerve impulse through the body of the neuron. Using neurotransmitters sequestered in a molecular “cage” that Magee could release with a laser pulse, his team targeted the exact spot on a dendrite they wished to stimulate. Just as syn- 2. aptic inputs can be strengthened or weakened to presumably transmit and later store information, Magee’s group showed that neurons use dendritic plasticity to adjust how they respond to incoming signals from other neurons. “This form of plasticity is distinct from—and complementary to—the more traditional synaptic plasticity,” he says.

38 Year in Review

Shaping the Future New Trustee Janelia Farm News Science Education Research Highlights Honors and Awards Passages Shaping the Future

The past year was one of remarkable growth and renewal “We decided to focus on scientists who for HHMI’s research programs. The Institute announced three major initiatives, representing a total investment have led their own laboratories for several of roughly $1 billion over the next six to eight years, years because many of these scientists which will shape the character of HHMI research for years are at a high point of their creativity just to come. as they see their start-up funds and early- October 2007 saw the selection of 15 patient-oriented researchers as HHMI investigators, a powerful reaffirma- career awards ending,” says Cech. tion of the Institute’s commitment to ensuring that basic Just as HHMI impels its scientists to take on high-risk, research discoveries are translated into improved treat- high-reward projects, it asks the same of itself in consid- ment for patients. These physician-scientists are a special ering programs to add to its scientific portfolio. In early breed; their scientific work is guided by their interaction 2008, the Institute unveiled a bold initiative to provide with patients. The 15 new investigators were selected in a much-needed support to about 70 of the nation’s best nationwide competition that drew close to 250 applicants. early-career faculty at a time when they most need the HHMI has completed two such targeted competitions help. The Early Career Scientist Program was carefully for patient-oriented translational research in the last conceived to provide a lifeline to researchers who have six years. run their own labs for two to six years and are at a criti- Exceptional ingenuity and curiosity were also distin- cal point in establishing their own vibrant, independent guishing features of the 56 scientists selected in May 2008 research programs. Each Early Career Scientist appointed to become HHMI investigators. That group, which included in spring 2009 will receive a six-year, nonrenewable 42 men and 14 women, represented 31 institutions appointment to HHMI as well as the substantial sup- nationwide, including 7 institutions that added an HHMI port necessary to move his or her research in creative, investigator for the first time: the Aaron Diamond AIDS new directions. Research Center, Boston University, Cornell University– When deliberating where the Institute’s resources could Ithaca, Purdue University, Texas A&M University, Cincinnati have the greatest impact outside its core HHMI Investiga- Children’s Hospital Medical Center, and the University of tor Program, President Thomas R. Cech and others saw a Texas at Austin. The group includes scientists with roots clear opportunity. “We decided to focus on scientists who outside the United States, including Argentina, China, have led their own laboratories for several years because Israel, and the Netherlands, and with equally diverse intel- many of these scientists are at a high point of their creativ- lectual backgrounds in fields as varied as bioengineering, ity just as they see their start-up funds and early-career immunology, and synthetic biology. awards ending,” Cech says. “Some of them may still be in line for their first NIH R01 grant, while others may have their first grant but are facing the very challenging first renewal of that grant. It is this period of career vulner- ability that the HHMI Early Career Scientist Program aims to bridge.”

40 1. Thomas R. Cech HHMI Annual Report 2008 Year in Review

Apply Directly Two years ago, HHMI’s scientific leadership began to examine the nomination and application processes for the Investigator Program. Although the Institute’s flagship program has been undeniably successful—producing 12 Nobel laureates and 124 members of the National Academy of Sciences— President Thomas R. Cech and others wondered whether the process of picking investigators could be improved. And so began a series of discussions 1. that led to a radical reworking of the process. Instead of inviting research institutions to “We know our pool of candidates has nominate the very best of their faculty for HHMI been excellent in past competitions,” investigator positions—as HHMI has done since says Cech, “but how can it not be even 1994—the new model would ask eligible researchers to nominate themselves directly. Many factors deeper and broader if we open up the played a role in the policy shift, but one stood above process?” all others: “We know our pool of candidates has been excellent in past competitions,” says Cech, “but how can it not be even deeper and broader if we open up the process?” HHMI used the direct application process for the first time in the 2007 Investigator Competi- tion in Patient-Oriented Research and in the 2008 HHMI Investigator Competition. The results were so positive that the Institute has decided to use direct application for the 2009 HHMI Early Career Scientist Competition.

41 15 New Patient- Oriented Researchers

Vivian G. Cheung Arul M. Chinnaiyan George Q. Daley Elizabeth C. Engle The Children’s Hospital of University of Michigan Children’s Hospital Boston Children’s Hospital Boston Philadelphia Medical School

Joseph G. Gleeson Daniel A. Haber Friedhelm Hildebrandt S. Ananth Karumanchi University of California, Massachusetts General University of Michigan Beth Israel Deaconess San Diego, School of Medicine Hospital Medical School Medical Center

Christopher V. Plowe Kerry J. Ressler David H. Rowitch Charles L. Sawyers University of Maryland Emory University University of California, San Memorial Sloan-Kettering Medical School School of Medicine Francisco, School of Medicine Cancer Center

42 “We would like to identify as many HHMI Annual Report 2008 Year in Review primary causes of kidney diseases in children as possible,” says Friedhelm Hildebrandt, University of Michigan Medical School, who analyzes patient blood samples for disease genes. “Then, we finally might be able to do something about the disease itself, and not just treat the symptoms.”

1. Translating Discoveries into Treatments People often talk about translating Engle, based at Children’s Hospital laboratory discoveries into patient care, Boston, became a new HHMI inves- but inspiration can flow in the reverse tigator in 2007, along with 14 other direction as well. In 1992, an encounter distinguished physician-scientists. with a toddler whose eyes were frozen In July 2008, she led an international in a downward gaze led pediatric neu- team of researchers that identified a Erol Fikrig rologist Elizabeth C. Engle to a trove gene mutated in Duane syndrome, a Yale School of Medicine of previously unrecognized congenital common disorder that restricts move- disorders that rob patients of normal ment of the eyes. Engle’s team zeroed control of their eye movements. Explor- in on the Duane syndrome gene by ing the clinical and genetic features studying DNA extracted from blood or of these disorders, Engle and her col- saliva samples provided by multiple leagues have defined a new category members of different families. The gene of syndromes resulting from errors in mapped to the locus identified in the brain-stem motor neuron development. genetic linkage studies. By screening Engle pored over journals looking genes in the linked region, Engle’s group for case reports and families with identified a unique mutation in the similar conditions and contacted gene CHN1 in each of seven families. clinicians around the world. She even- CHN1 encodes a signaling molecule, tually located more than 700 families 2-chimaerin, which is essential for nor- Beth Levine affected by this newly described disor- mal upper motor neuron axon guidance. University of Texas der or others related to it. Using DNA Engle says she hopes her research Southwestern Medical Center linkage and mutation analysis, Engle will one day have a direct impact on at Dallas identified the genetic causes for a her patients’ lives. “One of my ultimate series of these disorders and found that goals as a clinician-scientist,” she says, each perturbed development of one or “is to move our research back to the more cranial nerves. These syndromes bedside by finding better treatments for are now termed congenital cranial these early defects in brain-stem motor dysinnervation disorders. Among neuron development.” them: Duane syndrome, horizontal gaze palsy, Moebius syndrome, and congenital ptosis.

Andrey S. Shaw Washington University School of Medicine in St. Louis

43 56 New Investigators

1. A Rewarding Obsession There are many paths by which multiple exposures, Chen gradually scientists find their calling and retain builds three-dimensional computer their curiosity about the world. In May models that expose the architecture of 2008, that sense of exploration was these natural nanomachines. palpable as 56 new HHMI investigators When Chen joined Purdue in 2002 for descended on HHMI headquarters for her first faculty position, she set up a a two-day orientation. new crystallography laboratory. Solving One of those in the crowd, Jue Chen, the structure of the maltose transporter Sangeeta N. Bhatia Purdue University’s first HHMI inves- became the central goal of her new Massachusetts Institute tigator, exemplifies the tenacity and research group. Scientific mentors sug- of Technology perseverance characteristic of this new gested that it might be too narrow a group of investigators. For seven long project. One adviser warned that as a years, Chen was obsessed with the junior researcher, Chen could be “bet- maltose ABC transporter, which ferries ting the farm” on a problem that was life-sustaining sugar molecules through beyond current technology. a cell’s membrane to its interior. She Chen listened to their advice but wanted to produce detailed pictures of stayed the course. Her decision paid the transporter in action. off five years later. In 2007, she and Chen is a structural biologist and an her colleagues published a complete expert in x-ray crystallography. Like all structure of the maltose transporter in structural biologists, she wants to see its elusive midaction position, putting 1. cells or parts of cells going about their Chen’s lab on the leading edge of the Jue Chen business resolved in exquisite detail ABC-transporter field. Purdue University at the atomic and molecular levels. Looking back, Chen says that it Chen crystallizes the proteins she is wasn’t obstinacy or the chance of interested in and then bombards them having a high-profile publication that with x-rays. Computers help capture motivated her. “I was doing this because the diffraction patterns that bounce I was just so interested in the molecule,” off the atomic lattice. By rotating the she recalls. “I told people that I was crystallized protein complexes through obsessed. I just had to see it.”

Catherine L. Drennan Massachusetts Institute of Technology

44 “My philosophy is slightly different; I tend to follow my nose. If I find something interesting and I think I can solve a problem, I'll go ahead and tackle it,” says Paul D. Bieniasz, Aaron Diamond AIDS Research Center at Rockefeller University. As a result, our understanding of HIV is much deeper.

Paul D. Bieniasz Carlos D. Brody David C. Chan Christopher J. Chang Aaron Diamond AIDS Princeton University California Institute University of California, Research Center of Technology Berkeley

James J. Collins Yang Dan Abby F. Dernburg Andrew Dillin Boston University University of California, University of California, Salk Institute Berkeley Berkeley, Lawrence Berkeley for Biological Studies National Laboratory

Michael B. Eisen Michael B. Elowitz Adrian R. Ferré-D’Amaré L. René García University of California, California Institute Fred Hutchinson Cancer Texas A&M University Berkeley of Technology Research Center

45 56 New Investigators

Jay T. Groves Lora V. Hooper Darrell J. Irvine Christine Jacobs-Wagner University of California, University of Texas Massachusetts Institute Yale University Berkeley Southwestern Medical Center of Technology at Dallas

Scott Keeney Seung K. Kim Leonid Kruglyak Wendell A. Lim Memorial Sloan-Kettering Stanford University Princeton University University of California, Cancer Center San Francisco

Dianne K. Newman Phillip A. Newmark Michele Pagano Duojia Pan Massachusetts Institute University of Illinois New York University The Johns Hopkins University of Technology at Urbana-Champaign School of Medicine School of Medicine

46 “The intestinal immune system is radically HHMI Annual Report 2008 Year in Review different from the more familiar immune cells that police invaders in the blood- stream,” says Lora V. Hooper, University of Texas Southwestern Medical Center at Dallas. “Although much has been learned over the past several years, it's still a big black box."

Erich D. Jarvis Grant J. Jensen Youxing Jiang Leemor Joshua-Tor Duke University Medical California Institute University of Texas Cold Spring Harbor Center of Technology Southwestern Medical Laboratory Center at Dallas

Zhe Lu Danesh Moazed Jeffery D. Molkentin John V. Moran University of Pennsylvania Harvard Medical School Cincinnati Children’s Hospital University of Michigan School of Medicine Medical Center

Mercedes Pascual Tanya T. Paull David S. Pellman Samuel L. Pfaff University of Michigan University of Texas at Austin Dana-Farber Cancer Institute Salk Institute for Biological Studies

47 56 New Investigators “I want to understand how thought and sensation are organized in time and space,” says Massimo Scanziani, University of California, San Diego.

Jonathan K. Pritchard Bernardo L. Sabatini David M. Sabatini Massimo Scanziani The University of Chicago Harvard Medical School Massachusetts Institute University of California, of Technology San Diego

Kang Shen Yigong Shi David L. Stern Jack Taunton Stanford University Princeton University Princeton University University of California, San Francisco

Wilfred A. van der Donk Leslie B. Vosshall Thomas Walz Michelle D. Wang University of Illinois The Rockefeller University Harvard Medical School Cornell University at Urbana-Champaign

48 HHMI Annual Report 2008 Year in Review

2. Don’t Know Much Biology As a graduate student in HHMI inves- the human histone deacetylase gene tigator Stuart L. Schreiber’s lab at and revealed its identity as a regula- Harvard University, Jack Taunton exhib- tor of gene expression. Not bad for ited an early penchant for following his a chemist. own scientific instincts—and curiosity. Taunton, a new HHMI investigator at A chemist by training, Taunton knew he the University of California, San Fran- needed to learn more biology before cisco, is designing novel molecules that he could tackle projects that inter- reveal how human diseases develop ested him. and progress. He began reading the “classics”: The He is creating a cache of small mol- Journal of Cell Biology, Cell, and other ecules to explore the inner workings of journals. “I didn’t take classes in biology, the cell. Protein kinases were squarely but I was surrounded by very talented in his sights from day one because they biologists who taught me everything I regulate nearly all cellular processes Mark J. Schnitzer know,” Taunton says. and are intimately involved in many Stanford University After he learned to synthesize mol- human diseases. The real challenge, ecules found in nature, a “dramatic however, is that there are 500 or so career turn” steered Taunton away from kinases encoded by the human genome, making compounds to understanding and all are remarkably similar. “Distin- how they function, which he found guishing one kinase from the other 500 more challenging intellectually. with a small molecule is very challeng- His next project led to the synthesis ing in terms of molecular recognition,” of trapoxin, a biologically fascinating he says. His preference is to go after compound. “Trapoxin influenced cancer kinases with no known inhibitor. cells to change shape and look more like As Taunton expands beyond kinases normal cells—and they stopped divid- to other enzymes and protein-protein ing,” he explains. He also identified its interactions, he’ll continue to aim for protein target, histone deacetylase, an uncharted waters. “Part of the success Julie A. Theriot enzyme that had been widely sought I’ve had has been choosing problems Stanford University but never purified or cloned. He cloned that others aren’t working on,” he says. School of Medicine

Hongtao Yu Phillip D. Zamore Ning Zheng University of Texas University of Massachusetts University of Washington Southwestern Medical Medical School School of Medicine Center at Dallas

49 HHMI Annual Report 2008 Year in Review

Flood Recovery Renovating Places During the severe flooding that of Learning devastated much of the Midwest For more than a century, scien- in 2008, the Iowa River surged over tists have gathered at the Marine its banks and across the University Biological Laboratory in Massa- of Iowa campus. The university’s chusetts and Cold Spring Harbor Roy J. and Lucille A. Carver College Laboratory in New York to work of Medicine escaped direct dam- together and exchange ideas. age, but the biomedical research Both institutions have thriving being conducted within suffered New Trustee: research training programs, and with the shutdown of the campus thousands of scientists come to Charlene Barshefsky power plant. The plant provides the campuses each year to teach Ambassador Charlene Barshefsky, the steam that is essential for air and learn. As their programs grow, senior international partner at the law conditioning and heat, plus hot both institutions face the need firm WilmerHale in Washington, D.C., water and autoclave operations. to provide additional laboratory and former U.S. Trade Representative HHMI contributed $1 million to and classroom space and renovate during the administration of President the university’s recovery efforts existing facilities. This year, HHMI William Clinton, was elected a Trustee to help ensure the continuity of contributed $15 million toward of the Institute in January 2008. biomedical research at the Carver major infrastructure upgrades Barshefsky served as the nation’s College of Medicine—home to at each institution. principal trade negotiator and policy four HHMI investigators. The The funds will enable Cold maker from 1997 to 2001 and as acting money is helping pay for tempo- Spring Harbor Laboratory to build and deputy trade representative from rary systems to provide steam six new research buildings and a 1993 to 1996. She is best known interna- and chilled water to the college’s 12,241-square-foot building with tionally as the architect and negotiator facilities while the university course laboratories and a com- of China’s historic World Trade Organi- spends several months to restore puter classroom, and to renovate zation agreement. A 1972 graduate of its power systems. a teaching laboratory building the University of Wisconsin–Madison, erected in 1926. It will also help Barshefsky received a law degree from purchase major equipment for the Columbus School of Law at Catho- high-resolution microscopy and lic University in 1975 and has been protein analysis. The Marine named one of the 50 most influential Biological Laboratory will use women lawyers in the United States by the HHMI support to renovate its The National Law Journal. Loeb Building, which is used for summer courses and lectures. The building, built in 1970, suffers from inadequate heating, ventilation and air-conditioning systems, and an outdated electrical system.

50 1. Visiting Janelia Dan Bogenhagen, SUNY Stony Brook, visits Janelia Farm to use super-resolution imaging techniques developed in Eric Betzig’s lab to study mechanisms of nucleoid replication in mitochondria.

New Janelia Scientists At the end of 2008, the Janelia Farm Research Campus has grown to include 27 resident scientists. Three new scientists set up their labs this year.

S.E. Roian Egnor, a fellow, wants to understand how neurons control animal behavior in complex, unpredictable environments. Although real- world complexity is often absent in laboratory settings, Egnor is working to re-create some of it. She is allowing mice to live and socialize in large groups and seeking out strains for study that are most like their wild counterparts. She is studying vocalization and other behaviors in these mice.

Group leader Mats G.L. Gustafsson is creating light microscopy techniques that enable scientists to see and track biological structures 1. far smaller than those that can be viewed with traditional light microscopes. Although the wave- Visiting Scientists length of light limits the spatial resolution of most optical microscopy techniques, Gustafsson The collaborative nature of Janelia is devising ways to overcome those restrictions. Farm extends well beyond its glass walls into the international research Luke Lavis, a fellow, uses organic chemistry to community. New connections were add new, more powerful fluorescent dyes to the made, ideas exchanged, and knowl- selection currently available to biologists. His edge and skills shared as a steady goal is to develop probes that can be turned on stream of scientists visited Janelia and off with stimuli such as light and enzymes Farm from around the world in 2008. as well as dyes that can be used to visualize Some gathered for a few days for structures and processes inside living organisms. a conference to discuss the latest developments in fields such as bio- imaging and neural circuits; others stayed longer to collaborate with Students at Janelia Farm serving as mentors. Janelia Under- Janelia scientists and take advantage graduate Scholars worked on of the campus’s resources. Twenty- This summer, 12 undergraduates from developing genetic tools to allow four scientists—from Germany, colleges and universities in the United scientists to visualize signaling in France, Spain, Canada, Portugal, and States and the United Kingdom spent specific subpopulations of neurons; the United States—participated in 10 weeks immersed in the culture of learning how flies use visual cues Janelia Farm’s Visitor Program in 2008, research at Janelia Farm. Selected to know when to turn during flight; staying for up to two years. Among from more than 100 applicants, the and testing a method to implant their studies were investigations into students carried out independent electrodes into the mouse brain to aggression in fruit flies and the appli- research projects in Janelia Farm measure neuronal activity without cation of integrated circuit design labs, with group leaders and fellows disrupting behavior. techniques to study the brain.

51 HHMI Annual Report 2008 Year in Review 1. Holiday Lectures Bruce D. Walker and Bisola O. Ojikutu speak with D.C. area high school students.

Nationwide Science Education Experiment Begins Fortified by hands-on workshops held this summer at the Janelia Farm Research Campus, faculty and teaching assistants at 12 colleges and universities have begun teaching a genomics course created through HHMI’s Sci- ence Education Alliance (SEA). SEA aims to elevate U.S. science education from cookbook-based experiments to hands-on, inquiry- 1. based learning. The new course, which utilizes SEA-produced mate- AIDS Lectures Educate, the virus’s life cycle, its evolution, rials, allows students to do real and its effect on the immune system; research in a classroom setting by Inspire Students and the disease’s impact on society, finding, sequencing, and labeling Students from around the Washing- including drug distribution and vac- bacterial viruses, known as phages. ton, D.C., area and across the country cine development. Both physicians “The phage genomics course is the learned about the hurdles facing shared their experiences treating beginning of the transformation that physicians, scientists, and others HIV/AIDS patients in Boston and the Science Education Alliance hopes on the front lines of the global AIDS South Africa’s KwaZulu-Natal Prov- to bring to science education,” says epidemic in the 2007 Holiday Lectures ince, which has among the highest HHMI’s Tuajuanda C. Jordan, a bio- on Science. HIV/AIDS prevalence rates in the chemist and the director of SEA. AIDS: Evolution of an Epidemic was world. HIV-positive people from SEA is already recruiting more presented by HHMI investigator Bruce both continents described how they schools to expand the program next D. Walker, a leading AIDS researcher became infected with HIV and their year, to reach 36 participating institu- and clinician at Harvard Medical battles with treatment and discrimi- tions in three years. School and Massachusetts General nation. The students were captivated Through two seminars, SEA pro- Hospital, and Bisola O. Ojikutu, an when a nurse administered a real-time moted hands-on science education to infectious disease specialist at Mas- HIV blood test to both Ojikutu and an a broader audience, as well. Genomics: sachusetts General Hospital and HIV-positive activist from South Africa. Opportunities, Tools, and Challenges director of the Office of International HHMI’s Educational Resources depart- gave educators an overview of current Programs in Harvard Medical School’s ment created a DVD of the lectures and future techniques for biology Division of AIDS. with extra animations for classroom education. A Quantitative Biology One hundred eighty high school use. More than 13,600 copies of AIDS: workshop brought together college attendees—and 2,100 students across Evolution of an Epidemic have been math and biology professors to figure the United States watching by same- distributed to teachers and students out the best way to make students day webcast—learned about the across the country. It is available free ready for a more integrated future. genesis of HIV and the AIDS epidemic; at www.hhmi.org/catalog/.

52 Students Awarded Gilliam Fellowships “A doctor can help one person at a time, but a researcher can help 10,000 people with a single discovery.” This sentiment, expressed by new Gilliam fellow Daniel Gilmer, is echoed by several of the students awarded the 2008 Gilliam Fellowship for Advanced Silvia Caballero Lee “Shoa” Clarke Study. The award, for promising Until she worked on HIV/AIDS in As a child of a struggling single students from groups traditionally the lab of HHMI investigator Bruce mother, Clarke dreamed of becom- underrepresented in the sciences, Walker, Caballero didn’t know that ing a physician to help people in pays for up to five years of study researchers could so directly help need. But his college premed toward a Ph.D. in the sciences wher- patients. Now this Peru native classes were missing one subject ever the student chooses to attend who moved to the United States he loves: math. Now Clarke is bring- graduate school. The winners are at age 16 wants to pursue a doc- ing the two pursuits together in former participants in HHMI’s Excep- toral degree in immunology or an M.D./Ph.D. program, where he tional Research Opportunities (EXROP) virology to develop a new genera- hopes to combine computer-based program, which places underrepre- tion of treatments and bring them research with genetics. sented students in the labs of HHMI to patients. investigators. The 2008 awardees are:

Alejandra Figueroa-Clarevega Daniel Gilmer Bertrade (Betty) Mbom Figueroa-Clarevega grew up in rural After years volunteering close to his Mbom had a hard time in her first Honduras, where she volunteered home outside Orlando, Florida, and year at Carnegie Mellon University. with the international medical bri- doing missionary work in Kenya, But rather than complain, Mbom, gades who treated local children. Zimbabwe, and South Africa, Gilmer whose parents immigrated from Those early experiences, combined thought the best way to combine Cameroon, created a program at the with a stint at the Pan American community service and science was school to help other students from Health Organization, sealed her to be a medical doctor. But several traditionally underrepresented focus: to pursue research at the in-lab experiences convinced Gilmer groups cope during their first years intersection of public health, he can do more good as a scientist. in college. She is taking that same genetics, and infectious diseases, So this Howard University graduate assertiveness to science, with plans especially neglected diseases such dropped plans for medical school to get a Ph.D. in biology and then as river blindness. and will pursue a Ph.D. become a professor.

Physician-Scientists Encouraged research programs during this vulnerable time in their careers. The awards are available to alumni of the HHMI by Early Career Awards Research Training Fellowships for Medical Students Nineteen promising physician-scientists at 14 academic and the HHMI–National Institutes of Health Research medical centers have received Early Career Physician- Scholars Program, also known as the Cloister Program. Scientists awards to pursue research that brings science Their research is focused on important problems in cancer, and medicine together. These young physicians will heart disease, asthma, diabetes, kidney disease, and receive $375,000 over five years to help them develop their HIV infection.

53 1. Death Signal Research Highlights Triggering cancer cells’ own suicide bomb. 2. Pared-Down Cell Protocells consist of only genetic material surrounded by a fatty acid membrane.

be activated to drive perceptions and behavior and that signal strength in one neuron influences signal strength in neighboring neurons. This discovery demonstrates that even short bursts of activity in a few neurons can influence learning and decision- The Tick-Tock of the making. Bacterial Circadian Clock Karel Svoboda, Janelia Farm Researchers discovered how a bacte- Research Campus rial circadian clock keeps time using 1. only three interacting proteins. The cellular equivalent of this clock’s pen- Smac-ing Lung Cancer dulum and timing gear is so rugged to Death that it can keep precise time for weeks, HHMI scientists developed a small even after its components have been molecule that turns the TNFα survival isolated from bacteria and placed in a signal of cancer cells into a death sig- test tube. nal. The molecule mimics the activity Erin K. O’Shea, Harvard University of Smac, a protein that triggers the Plants Can Sense suicide of some types of cancer cells. Midnight The new compound may be useful Plants “know” when the clock strikes as a targeted treatment for lung and midnight. New HHMI research shows other cancers. that midnight is crucial to plants Xiaodong Wang, University of because it marks the start of tasks Texas Southwestern Medical Center such as growth and protein synthesis, at Dallas which are typically neglected during the day. Stress Boosts Learning Joanne Chory, Salk Institute for Emotional encounters supercharge Biological Studies learning in a way that indelibly imprints those experiences in memory. HHMI researchers have shown that the stress hormone norepineph- rine boosts learning by strengthening connections between neurons. New Studies Illuminate the Richard L. Huganir, The Johns Computational Power of Hopkins University School of Single Neurons Medicine Using light to activate individual neurons in mice, scientists found that relatively few neurons need to

54 system on their way to invading individual to individual, they found the liver, according to an HHMI substantial structural variations, international research scholar. The many more than 6,000 base pairs long. pursuit starts earlier than once Evan E. Eichler, University of thought—right after the mosquito Washington injects the parasite through the skin. Previous studies indicated that the From Millions of Points of Light chase began only after the parasites to Detailed 3-D Images reached the liver. Recent advances in fluorescence Robert Ménard, Institut Pasteur, Paris microscopy let scientists peer inside cells with far better clarity than that achieved with traditional optical imaging techniques. HHMI researchers developed new imaging technology that permits them to 2. see the complete 3-D architecture of many of the tiniest structures of cells. Model Protocell Created Xiaowei Zhuang, Harvard University A New Drug for Three Kinds in the Lab of Leukemia Simple protocells are thought to have Three years after discovering a given rise to Earth’s earliest life forms. genetic mutation that causes a trio of HHMI scientists created model proto- leukemias, HHMI researchers helped cells in the lab and demonstrated how move a new leukemia drug into they might have taken up the nutri- clinical trials. The three leukemias, ents that propelled their growth. polycythemia vera, essential throm- Jack K. Szostak, Massachusetts bocytosis, and primary myelofibrosis, General Hospital Genome-Wide Survey Nets affect about 80,000 to 100,000 people Key Melanoma Gene in the United States. The drug is now A newly discovered protein helps in phase 1 clinical trials at several can- determine whether a pigment- cer centers in the United States. producing skin cell that grows too D. Gary Gilliland, Brigham and fast becomes a benign mole or a Women’s Hospital deadly melanoma. This natural defense mechanism against cancer could help researchers design new Mutant Mouse Mimics therapies for melanoma. Human Bone Cancer Michael R. Green, University of Massachusetts Medical School A new mouse model will allow researchers to investigate the genetic underpinnings of osteosarcoma, the most common form of bone cancer. Human Genome Is More The disease, which usually affects Complex than Expected adolescents and young adults, results The first high-resolution maps of from the unregulated growth of the several human genomes are helping cells that form bone matrix. This researchers understand how humans animal model offers opportunities to differ from each other. A large team develop new therapeutic approaches Malaria Parasite Makes of scientists compared the genomes to counter the fast-spreading cancer. High-Speed Dash to Liver of eight people—of African, Asian, Stuart H. Orkin, Children’s Hospital Malaria parasites duck in and out or Western European descent—with Boston of cells to evade the body’s immune a reference human genome. From

55 Research Highlights 1. 330 Vertebrae Snake embryos form from head to tail.

New Flu Treatments May Come Help for Children Who from Fruit Fly Study Can’t Fight Infection The influenza virus easily mutates HHMI international researchers to develop resistance to therapies discovered a genetic flaw in a criti- that target the virus directly. To iden- cal immune system gene that leaves 1. tify genes and proteins within the children vulnerable to meningitis. host that aid viral infection, HHMI Children with defective or missing How the Snake Got Its scientists infected fruit fly cells with copies of the MYD88 gene were prone Vertebrae modified influenza virus and found to infections with Streptococcus Thirty-three vertebrae enable the 100 or more host cell genes that pneumonia even though they could human spine to twist and bend, the virus relies on for infection. The fight off infections by other bacteria. whereas a snake’s slither requires researchers hope these new targets The MyD88 protein controls many more than 300 vertebrae. Both spe- will offer improved treatment pos- of the most important immune sys- cies’ spines are formed when cells sibilities by more stably suppressing tem receptors involved in fighting in a developing embryo pinch off the virus and leaving it unable to microorganisms. into a string of identical segments, quickly evolve resistance. Jean-Laurent Casanova, Necker which will later sprout blood vessels, Paul Ahlquist, University of Hospital for Sick Children, Paris peripheral nerves, and muscle. HHMI Wisconsin–Madison researchers discovered how cells know when to stop this process to ensure that each animal ends up with the appropriate number of vertebrae. Olivier Pourquié, Stowers Institute for Medical Research

56 Honors and Awards 1. Ana Belén Elgoyhen 2. Thomas M. Jessell 3. Robert J. Lefkowitz

Druker Wins Keio Prize Society for Cell Biology, is awarded for HHMI investigator Brian J. Druker of lifetime contributions to cell biology. Oregon Health & Science University won the 2007 Keio Medical Science Jessell Receives Kavli Prize Prize from Keio University in Tokyo, HHMI investigator Thomas M. Jessell Japan, together with Hiroaki Mitsuya 1. of Kumamoto University and the U.S. of Columbia University received the National Cancer Institute. Given annu- first annual Kavli Prize in Neurosci- ally, the ¥20 million (about $183,000) ence for his research on how neural prize awards outstanding achieve- cells assemble into circuits. He shares ments in medical and life sciences. the $1 million prize with Pasko Rakic Druker was recognized for his devel- of Yale University and Sten Grillner opment of Gleevec, the first drug to of the Karolinska Institute. This new target the genetic defects of a par- prize comes from the Norwegian 2. ticular cancer, chronic myelogenous Academy of Science and Letters, the leukemia. Kavli Foundation, and the Norwegian Ministry of Education and Research.

Elgoyhen Receives L’Oréal-UNESCO Award National Academies Book Award Goes to Kandel HHMI international research scholar Ana Belén Elgoyhen of the Institute Eric R. Kandel, an HHMI investigator 3. for Research on Genetic Engineering at the Columbia University College and Molecular Biology, CONICET, in of Physicians and Surgeons, won Buenos Aires, Argentina, won the 2008 the 2007 Best Book Award from the L’Oréal-UNESCO Award for Women National Academies for In Search of in Science for Latin America. The Memory: The Emergence of a New $100,000 prize, awarded annually, Science of Mind. The book blends a recognizes five outstanding women personal memoir with an explanation researchers worldwide. of the science of memory.

Hynes Awarded National Medal of Science E.B. Wilson Medal Awarded to Lefkowitz The 2007 E.B. Wilson Medal went to President George W. Bush bestowed HHMI investigator Richard O. Hynes, Robert J. Lefkowitz with the nation’s Massachusetts Institute of Technol- highest award for science. Lefkowitz, ogy, for his work on how cells adhere an HHMI investigator at Duke Univer- to one another. The medal, the high- sity Medical Center, received the 2008 est science honor of the American National Medal of Science. Lefkowitz studies G protein–coupled receptors

57 Honors and Awards 1. Nahum Sonenberg 2. Joan A. Steitz 3. Angelika Amon 4. Todd R. Golub 5. Gregory J. Hannon

involved in fundamental processes such as pain tolerance, glucose Steitz Shares Albany Prize metabolism, and the regulation of HHMI investigator Joan A. Steitz of the heart rate and blood pressure. Yale University School of Medicine and Elizabeth H. Blackburn of the Uni- versity of California, San Francisco, 1. Lifton Receives Wiley Prize were the first two women to receive HHMI investigator Richard P. Lifton the Albany Medical Center Prize in of Yale University School of Medi- Medicine and Biomedical Research. cine received the 2008 Wiley Prize in The $500,000 prize, awarded annually Biomedical Sciences. Awarded by the since 2001, honors innovative biomed- Wiley Foundation, the annual $35,000 ical research. Steitz discovered and prize recognizes a scientist whose defined the function of small nuclear 2. contributions have opened new fields ribonucleoproteins—complexes of of research or advanced new con- RNA and proteins involved in splicing cepts within biomedicine. Lifton was introns from RNA strands. chosen for his discovery of the genes that cause many forms of high and low blood pressure in humans. Tuschl Awarded Delbrück Medal HHMI investigator Thomas Tuschl, of The Rockefeller University in New 3. Sonenberg Wins Gairdner York, received the 2007 Max Delbrück Award Medal, from the Max Delbrück Center Nahum Sonenberg, an HHMI inter- for Molecular Medicine in Berlin, for national research scholar at McGill his development of RNA interference— University, received a 2008 Gairdner a technique that helps scientists International Award. These annual investigate the function of individual awards recognize outstanding dis- genes. Tuschl was also honored with coveries and contributions to medical the 2008 Ernst Jung Prize for Medicine, science. Sonenberg, who received an annual award from the Hamburg- $30,000, studies how cells control pro- based Jung Foundation for Science tein synthesis. and Research that recognizes young medical researchers.

Gruber Prize Goes to Spradling Allan C. Spradling, an HHMI investigator Three Investigators Receive at the Carnegie Institution of Wash- Paul Marks Prize ington, won the 2008 Gruber Genetics Three HHMI investigators were Prize of $500,000 from the Peter and honored with the 2007 Paul Marks Patricia Gruber Foundation for his Prize for Cancer Research. Named contributions to fruit fly genomics. for Paul A. Marks, president emeritus

58 HHMI Annual Report 2008 Year in Review

4. 5.

of Memorial Sloan-Kettering Cancer medical advisory board, and Janet Center, the biennial prize aims to Rossant, a member of the HHMI scien- American Academy of Arts and recognize significant contributions tific review board, were also elected. Sciences Elects 14 to the field of cancer research made Eight HHMI investigators, three HHMI by young investigators. The winners professors, one Trustee, and two were Angelika Amon, of the Massachu Seven Elected to Institute of members of the Institute’s advisory setts Institute of Technology, who Medicine boards are among the 190 new fellows studies the effects of chromosome In October 2007, six HHMI investiga- and 22 foreign honorary members segregation in cancer cell growth; tors and one HHMI international elected to the American Academy of Todd R. Golub, of the Dana-Farber research scholar were elected mem- Arts and Sciences in April 2008. The Cancer Institute, who employs micro bers of the National Academy of investigators are Linda B. Buck, Fred arrays in order to better classify Sciences’ Institute of Medicine. The Hutchinson Cancer Research Center; subtypes of cancer; and Gregory J. investigators are James P. Allison, Lawrence S.B. Goldstein, University of Hannon, of Cold Spring Harbor Labo- Memorial Sloan-Kettering Cancer California, San Diego; John Kuriyan, ratory, who studies the role of RNA Center, New York; Katherine A. High, University of California, Berkeley; interference in cancer initiation and The Children’s Hospital of Philadel- Stephen G. Lisberger, University of progression. phia; William G. Kaelin Jr., Dana-Farber California, San Francisco; Craig C. Cancer Institute, Boston; Louis J. Mello, University of Massachusetts Ptácˇek, University of California, San Medical School; Norbert Perrimon, Seven Elected to National Francisco; Matthew P. Scott, Stanford Harvard Medical School; Louis J. Ptácˇek, Academy of Sciences University School of Medicine; and University of California, San Francisco; Four HHMI investigators, an HHMI Thomas C. Südhof, University of Texas and Leonard I. Zon, Children’s Hospi- professor, and two members of HHMI Southwestern Medical Center at tal Boston. The professors are Utpal advisory boards were elected to the Dallas (now at Stanford University). Banerjee, University of California, Los National Academy of Sciences in HHMI international research scholar Angeles; Jasper Rine, University of April 2008. They were among 72 new Peter St George-Hyslop is at Univer- California, Berkeley; and Huntington F. members and 18 foreign associates sity of Toronto. Willard, Duke University. Also elected elected in recognition of their distin- were HHMI Trustee James A. Baker, guished and continuing achievements scientific review board member Mary in original research. The investiga- Two HHMI Professors Beckerle, and medical advisory board tors are Michael J. Bevan, University Elected to National Academy member Bruce W. Stillman. of Washington School of Medicine; of Engineering Gail Mandel, Oregon Health & Science HHMI professors Rebecca Richards- University; David J. Mangelsdorf, Kortum, Rice University, and David University of Texas Southwestern Walt, Tufts University, were elected in Medical Center at Dallas; and Gary February 2008 to the National Acad- Struhl, Columbia University College of emy of Engineering. Physicians and Surgeons. The HHMI professor is Jasper Rine, University of California, Berkeley. Michael R. Botchan, a member of the HHMI

59 Passages

Richard Gordon Darman Jeremy R. Knowles Richard Gordon Darman, a financial executive with Jeremy R. Knowles, a Trustee of the Howard Hughes a distinguished career in public service and a Trustee Medical Institute for nearly a decade, died April 3, of the Howard Hughes Medical Institute, died Janu- 2008, in Cambridge, Massachusetts. He was 72. ary 25, 2008, in Washington, D.C. He was 64. An accomplished chemist whose research Darman was elected a Trustee in 2005, serving traversed the boundaries of chemistry and bio- as chairman of the Audit and Compensation Com- chemistry, Knowles was known for his luminous mittee and as a member of the Finance Committee. intelligence, penetrating judgment, elegant speech, Armed with a powerful intellect and irrepressible and refined wit. He was a towering figure at Harvard humor, he made his mark at HHMI—often by asking University, whose faculty he joined in 1974 as profes- a deceptively simple question that generated lively sor of chemistry. He served as dean of the Faculty discussion. of Arts and Sciences from 1991 to 2002, reprising the Throughout his tenure in the federal government, role from 2006 to 2007. Darman played key roles in the development of tax, Knowles helped shape the vision of the Institute’s spending, and economic policies. He served four science education programs and chaired a Trustee presidents, holding positions in the White House, the subcommittee that served as an important sounding Office of Management and Budget, and six cabinet board for new initiatives. That interest reflected his departments. As deputy treasury secretary during own commitment to teaching; Knowles delighted the Reagan Administration, Darman received the in returning to the classroom upon stepping down Treasury’s highest award—the Alexander Hamilton as dean. medal—for his contributions to the 1986 Tax Reform Born in England, Knowles served as an officer in Act and two international monetary policy accords. the Royal Air Force before reading chemistry at Balliol Darman joined The Carlyle Group, a global private College at Oxford University. He received his B.A. in equity firm, in 1993 as a partner. He was also chair- 1959 and his D.Phil. in 1961. man of the board of AES Corp., an international power Through his research, Knowles made lasting con- company. Darman served as a trustee of several pub- tributions to understanding the chemistry of enzyme licly traded mutual fund groups and as chairman of action. In addition to many honors and awards, he the board of the Smithsonian National Museum of was elected a fellow of the Royal Society in 1977 American History. A graduate of Harvard College and and a foreign associate of the National Academy of the Harvard Business School, Darman wrote widely Sciences in 1988. about public policy and politics.

60 HHMI People and Financials

Leadership HHMI Researchers Advisory Boards & Committees Fellowships & Grants Finance & Investments 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 (Deceased April 3, 2008) Craig A. Alexander Ambassador Charlene Barshefsky Vice President and General Counsel Senior International Partner Paul Nurse, F.R.S. WilmerHale President Peter J. Bruns, Ph.D. (Effective January 1, 2008) The Rockefeller University Vice President for Grants and Special Programs Richard G. Darman Kurt L. Schmoke, Esq. Partner Dean David A. Clayton, Ph.D. The Carlyle Group Howard University School of Law Vice President for Research Operations Chairman of the Board AES Corp. Anne M. Tatlock Joseph D. Collins (Deceased January 25, 2008) Director, Retired Chairman and CEO Vice President for Information Fiduciary Trust Company Technology Joseph L. Goldstein, M.D. International Regental Professor and Chairman Jack E. Dixon, Ph.D. Department of Molecular Genetics Vice President and Chief Scientific University of Texas Southwestern Officer Medical Center at Dallas Avice A. Meehan Hanna H. Gray, Ph.D. Vice President for Communications Chairman and Public Affairs President Emeritus and Harry Pratt Judson Distinguished Edward J. Palmerino Service Professor of History Vice President for Finance and Treasurer The University of Chicago Gerald M. Rubin, Ph.D. Garnett L. Keith Vice President and Director, Chairman Janelia Farm Research Campus SeaBridge Investment Advisors, L.L.C. Former Vice Chairman and Landis Zimmerman Chief Investment Officer Vice President and Chief Investment The Prudential Insurance Company Officer of America ..... Joan S. Leonard Senior Counsel to the President

62 Principal Staff HHMI Annual Report 2008 HHMI People and Financials Members

David J. Asai, Ph.D. Edward H. Klees Robert C. Mullins Grants Program Director Associate General Counsel Controller (Effective August 1, 2008) Robert J. Kolyer Jr. Richard A. Pender Mark A. Barnard Managing Director, Diversifying Assets Managing Director, Global Equities Managing Director, Private Investments M. Ram Lee Philip S. Perlman, Ph.D. Managing Director, Portfolio Strategies Senior Scientific Officer Josephine P. Briggs, M.D. Senior Scientific Officer Martha Kay Lequeux Pamela A. Phillips (Through January 12, 2008) Director of Human Resources Director of Research Operations

Seth Brown Dennis WC. Liu, Ph.D. Susan S. Plotnick Associate General Counsel Grants Program Director Assistant Treasurer

Marian B. Carlson, Ph.D. Gregory W. Loftin Carl D. Rhodes, Ph.D. Senior Scientific Officer Director of Internal Audit Scientific Officer (Effective April 1, 2008) Anil Madhok Dianne J. Smith Winfred J. Clingenpeel Managing Director and Associate General Counsel Director of Purchasing Chief Operating Officer, Investments Lauren Talner Spiliotes Jill G. Conley, Ph.D. Margaret Feczko May Associate General Counsel Grants Program Director Associate General Counsel Glen M. Zwicker William R. Galey, Ph.D. Edwin W. McCleskey, Ph.D. Associate General Counsel Grants Program Director Scientific Officer

Heidi E. Henning Cheryl A. Moore Deputy General Counsel Chief Operating Officer, Janelia Farm Research Campus Marion M. Howard Assistant Controller Kevin Moses, Ph.D. Associate Director Stephen M. Kitsoulis for Science and Training, Managing Director, Janelia Farm Research Campus Fixed Income and Currencies

63 HHMI Investigators September 1, 2007 – August 31, 2008

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

64 HHMI Annual Report 2008 HHMI People and Financials

University of Colorado at Denver Jonathan K. Pritchard, Ph.D. University of Maryland, and Health Sciences Center Harinder Singh, Ph.D. Baltimore County James L. Maller, Ph.D. Michael F. Summers, Ph.D. Lee A. Niswander, Ph.D. University of Illinois at Urbana-Champaign University of Maryland Connecticut Taekjip Ha, Ph.D. School of Medicine Yale University Phillip A. Newmark, Ph.D. Christopher V. Plowe, M.D. Ronald R. Breaker, Ph.D. Peter Cresswell, Ph.D. Iowa Massachusetts Pietro De Camilli, M.D. The University of Iowa Beth Israel Deaconess Susan Ferro-Novick, Ph.D. Kevin P. Campbell, Ph.D. Medical Center Erol Fikrig, M.D. Val C. Sheffield, M.D., Ph.D. S. Ananth Karumanchi, M.D. Richard A. Flavell, Ph.D. Edwin M. Stone, M.D., Ph.D. Christopher A. Walsh, M.D., Ph.D. Arthur L. Horwich, M.D. Michael J. Welsh, M.D. Christine Jacobs-Wagner, Ph.D. Brandeis University Richard P. Lifton, M.D., Ph.D. Maine Nikolaus Grigorieff, Ph.D. Ruslan M. Medzhitov, Ph.D. The Jackson Laboratory Dorothee Kern, Ph.D. Anna Marie Pyle, Ph.D. Susan L. Ackerman, Ph.D. Christopher Miller, Ph.D. G. Shirleen Roeder, Ph.D. Simon W.M. John, Ph.D. Michael Rosbash, Ph.D. David G. Schatz, Ph.D. Gerald I. Shulman, M.D., Ph.D. Maryland Brigham and Women’s Hospital Joan A. Steitz, Ph.D. Carnegie Institution of Washington Stephen J. Elledge, Ph.D. Thomas A. Steitz, Ph.D. Douglas E. Koshland, Ph.D. D. Gary Gilliland, M.D., Ph.D. Tian Xu, Ph.D. Allan C. Spradling, Ph.D. Christine E. Seidman, M.D. Yixian Zheng, Ph.D. Matthew K. Waldor, M.D., Ph.D. Georgia Emory University The Johns Hopkins University Children’s Hospital Boston School of Medicine School of Medicine Frederick W. Alt, Ph.D. Kerry J. Ressler, M.D., Ph.D. Nancy L. Craig, Ph.D. David E. Clapham, M.D., Ph.D. Harry C. Dietz, M.D. George Q. Daley, M.D., Ph.D. Illinois David D. Ginty, Ph.D. Elizabeth C. Engle, M.D. Northwestern University Rachel Green, Ph.D. Louis M. Kunkel, Ph.D. Robert A. Lamb, Ph.D., Sc.D. Richard L. Huganir, Ph.D. Stuart H. Orkin, M.D. Joseph S. Takahashi, Ph.D. Alex L. Kolodkin, Ph.D. Matthew L. Warman, M.D. Jeremy Nathans, M.D., Ph.D. Morris F. White, Ph.D. The University of Chicago Duojia Pan, Ph.D. Leonard I. Zon, M.D. Albert Bendelac, M.D., Ph.D. Geraldine Seydoux, Ph.D. Bruce T. Lahn, Ph.D. Robert F. Siliciano, M.D., Ph.D. Milan Mrksich, Ph.D. Bert Vogelstein, M.D. Joseph A. Piccirilli, Ph.D. Cynthia Wolberger, Ph.D.

65 HHMI Investigators

Dana-Farber Cancer Institute Richard O. Hynes, Ph.D. Missouri Todd R. Golub, M.D. Darrell J. Irvine, Ph.D. Stowers Institute for Medical Research William G. Kaelin Jr., M.D. Tyler Jacks, Ph.D. Olivier Pourquié, Ph.D. David Pellman, M.D. Susan L. Lindquist, Ph.D. Dianne K. Newman, Ph.D. Washington University in St. Louis Harvard Medical School David C. Page, M.D. Daniel E. Goldberg, M.D., Ph.D. Constance L. Cepko, Ph.D. H. Sebastian Seung, Ph.D. Eduardo A. Groisman, Ph.D. David P. Corey, Ph.D. Morgan Sheng, M.B.B.S., Ph.D. Kenneth M. Murphy, M.D., Ph.D. Stephen C. Harrison, Ph.D. Susumu Tonegawa, Ph.D. Helen Piwnica-Worms, Ph.D. John H.R. Maunsell, Ph.D. Li-Huei Tsai, Ph.D. J. Evan Sadler, M.D., Ph.D. Danesh Moazed, Ph.D. Andrey S. Shaw, M.D. Norbert Perrimon, Ph.D. Tufts University Wayne M. Yokoyama, M.D. Tom A. Rapoport, Ph.D. School of Medicine Bernardo L. Sabatini, M.D., Ph.D. Andrew Camilli, Ph.D. New Jersey Thomas Walz, Ph.D. Ralph R. Isberg, Ph.D. Princeton University Bonnie L. Bassler, Ph.D. Harvard University University of Massachusetts Carlos D. Brody, Ph.D. Randy L. Buckner, Ph.D. Medical School Leonid Kruglyak, Ph.D. Catherine Dulac, Ph.D. Roger J. Davis, Ph.D. Trudi Schüpbach, Ph.D. David R. Liu, Ph.D. Michael R. Green, M.D., Ph.D. David L. Stern, Ph.D. Douglas A. Melton, Ph.D. Craig C. Mello, Ph.D. Eric F. Wieschaus, Ph.D. Erin K. O’Shea, Ph.D. Melissa J. Moore, Ph.D. Stuart L. Schreiber, Ph.D. Phillip D. Zamore, Ph.D. Rutgers, The State University Xiaowei Zhuang, Ph.D. of New Jersey Michigan Richard H. Ebright, Ph.D. Massachusetts General Hospital University of Michigan Kenneth D. Irvine, Ph.D. Daniel A. Haber, M.D., Ph.D. James C.A. Bardwell, Ph.D. Jeannie T. Lee, M.D., Ph.D. Arul M. Chinnaiyan, M.D., Ph.D. University of Medicine and Dentistry of Jack W. Szostak, Ph.D. David Ginsburg, M.D. New Jersey–Robert Wood Johnson Bruce D. Walker, M.D. Friedhelm Hildebrandt, M.D. Medical School Randal J. Kaufman, Ph.D. Ann M. Stock, Ph.D. Massachusetts Institute Tom K. Kerppola, Ph.D. of Technology John V. Moran, Ph.D. New York Angelika Amon, Ph.D. Sean J. Morrison, Ph.D. Albert Einstein College of Medicine Tania A. Baker, Ph.D. of Yeshiva University David P. Bartel, Ph.D. Minnesota William R. Jacobs Jr., Ph.D. Mark F. Bear, Ph.D. University of Minnesota Stephen P. Bell, Ph.D. Medical School H. Robert Horvitz, Ph.D. Michael B. O’Connor, Ph.D.

66 HHMI Annual Report 2008 HHMI People and Financials

Cold Spring Harbor Laboratory New York University Oklahoma Gregory J. Hannon, Ph.D. Ruth Lehmann, Ph.D. Oklahoma Medical Research Leemor Joshua-Tor, Ph.D. Dan R. Littman, M.D., Ph.D. Foundation Scott W. Lowe, Ph.D. Michele Pagano, M.D. Charles T. Esmon, Ph.D. Danny Reinberg, Ph.D. Columbia University Eero P. Simoncelli, Ph.D. Oregon Rafael Yuste, M.D., Ph.D. Oregon Health and Science University The Rockefeller University Brian J. Druker, M.D. Columbia University Cornelia I. Bargmann, Ph.D. Eric Gouaux, Ph.D. College of Physicians and Surgeons Günter Blobel, M.D., Ph.D. Gail Mandel, Ph.D. Richard Axel, M.D. Robert B. Darnell, M.D., Ph.D. Teresa Nicolson, Ph.D. Joachim Frank, Ph.D. Jeffrey M. Friedman, M.D., Ph.D. Stephen P. Goff, Ph.D. Elaine Fuchs, Ph.D. University of Oregon Iva Greenwald, Ph.D. Nathaniel Heintz, Ph.D. Chris Q. Doe, Ph.D. Wayne A. Hendrickson, Ph.D. A. James Hudspeth, M.D., Ph.D. Brian W. Matthews, Ph.D., D.Sc. Oliver Hobert, Ph.D. Roderick MacKinnon, M.D. Barry Honig, Ph.D. Michel C. Nussenzweig, M.D., Ph.D. Pennsylvania Thomas M. Jessell, Ph.D. Michael E. O’Donnell, Ph.D. The Children’s Hospital of Philadelphia Eric R. Kandel, M.D. Hermann Steller, Ph.D. Vivian G. Cheung, M.D. Steven A. Siegelbaum, Ph.D. Thomas Tuschl, Ph.D. Katherine A. High, M.D. Gary Struhl, Ph.D. Leslie B. Vosshall, Ph.D. University of Pennsylvania Cornell University, Ithaca North Carolina Morris J. Birnbaum, M.D., Ph.D. Michelle D. Wang, Ph.D. Duke University Nancy M. Bonini, Ph.D. Vann Bennett, M.D., Ph.D. Gideon Dreyfuss, Ph.D. Cornell University, Joan and Michael D. Ehlers, M.D., Ph.D. Zhe Lu, M.D., Ph.D. Sanford I. Weill Medical College Erich D. Jarvis, Ph.D. Amita Sehgal, Ph.D. Shahin Rafii, M.D. Robert J. Lefkowitz, M.D. M. Celeste Simon, Ph.D. Paul L. Modrich, Ph.D. Gregory D. Van Duyne, Ph.D. Memorial Sloan-Kettering Robin P. Wharton, Ph.D. Cancer Center John D. York, Ph.D. Tennessee James P. Allison, Ph.D. St. Jude Children’s Research Hospital Jonathan Goldberg, Ph.D. University of North Carolina Brenda A. Schulman, Ph.D. Scott Keeney, Ph.D. at Chapel Hill Charles J. Sherr, M.D., Ph.D. Joan Massagué, Ph.D. Yi Zhang, Ph.D. Nikola P. Pavletich, Ph.D. Vanderbilt University Charles L. Sawyers, M.D. Ohio Kathleen L. Gould, Ph.D. Case Western Reserve University School of Medicine Sanford Markowitz, M.D., Ph.D.

67 HHMI Investigators

Texas Washington Howard Hughes Medical Institute Baylor College of Medicine Fred Hutchinson investigators conduct research in Institute Hugo J. Bellen, D.V.M., Ph.D. Cancer Research Center laboratories at host institutions nationwide Brendan Lee, M.D., Ph.D. Linda B. Buck, Ph.D. in concert with associated hospitals and medical schools. Huda Y. Zoghbi, M.D. Steven Henikoff, Ph.D. Cecilia B. Moens, Ph.D. For information on HHMI investigators active The University of Texas Southwestern James R. Priess, Ph.D. after August 31, 2008, visit www.hhmi.org. Medical Center at Dallas Zhijian “James” Chen, Ph.D. University of Washington Johann Deisenhofer, Ph.D. David Baker, Ph.D. Nick V. Grishin, Ph.D. Michael J. Bevan, Ph.D. Helen H. Hobbs, M.D. Evan E. Eichler, Ph.D. Lora V. Hooper, Ph.D. Stanley Fields, Ph.D. Youxing Jiang, Ph.D. Philip Green, Ph.D. Beth Levine, M.D. Randall T. Moon, Ph.D. David J. Mangelsdorf, Ph.D. Richard D. Palmiter, Ph.D. Michael K. Rosen, Ph.D. Fred Rieke, Ph.D. Xiaodong Wang, Ph.D. Alexander Y. Rudensky, Ph.D. Masashi Yanagisawa, M.D., Ph.D. John D. Scott, Ph.D. Hongtao Yu, Ph.D. Michael N. Shadlen, M.D., Ph.D. William N. Zagotta, Ph.D. Utah University of Utah Wisconsin Brenda L. Bass, Ph.D. University of Wisconsin–Madison Bradley R. Cairns, Ph.D. Paul Ahlquist, Ph.D. Mario R. Capecchi, Ph.D. Sean B. Carroll, Ph.D. Erik M. Jorgensen, Ph.D. Edwin R. Chapman, Ph.D. Alejandro Sánchez Alvarado, Ph.D. Judith Kimble, Ph.D.

68 Janelia Farm HHMI Annual Report 2008 HHMI People and Financials Research Campus September 1, 2007 – August 31, 2008

Eric Betzig, Ph.D. Alla Y. Karpova, Ph.D. Dmitry Rinberg, Ph.D. Group Leader Group Leader Fellow

Sydney Brenner, D.Phil. Rex A. Kerr, Ph.D. Elena Rivas, Ph.D. Senior Fellow Fellow Fellow

Dmitri B. Chklovskii, Ph.D. Luke Lavis, Ph.D. Charles V. Shank, Ph.D. Group Leader Fellow Senior Fellow

Joshua T. Dudman, Ph.D. Anthony Leonardo, Ph.D. Julie H. Simpson, Ph.D. Fellow Group Leader Group Leader

Sean R. Eddy, Ph.D. Loren L. Looger, Ph.D. Scott M. Sternson, Ph.D. Group Leader Group Leader Group Leader

S.E. Roian Egnor, Ph.D. Jeffrey C. Magee, Ph.D. Karel Svoboda, Ph.D. Fellow Group Leader Group Leader

Mats G.L. Gustafsson, Ph.D. Eugene W. Myers, Ph.D. James W. Truman, Ph.D. Group Leader Group Leader Group Leader

Harald F. Hess, Ph.D. Hanchuan Peng, Ph.D. Director, Applied Physics and Senior Computer Scientist For information on Janelia Farm Instrumentation Group researchers active after August 31, 2008, Michael B. Reiser, Ph.D. visit www.hhmi.org/janelia. Vivek Jayaraman, Ph.D. Fellow Fellow Lynn M. Riddiford, Ph.D. Senior Fellow

69 Medical Advisory Board September 1, 2007 – August 31, 2008

Michael R. Botchan, Ph.D. Rowena G. Matthews, Ph.D. Carla J. Shatz, Ph.D. Richard and Rhoda Goldman G. Robert Greenberg Professor Emeritus Director, Bio-X Distinguished Professor of Biochemistry of Biological Chemistry and Research Professor of Biology and Neurobiology Co-Chair of the Department of Professor Emeritus James H. Clark Center Molecular and Cell Biology Life Sciences Institute Stanford University University of California, Berkeley University of Michigan (Effective January 1, 2008) (Effective January 1, 2008) Bruce Stillman, Ph.D., F.R.S. President Gerald R. Fink, Ph.D. Gregory A. Petsko, D.Phil. Cold Spring Harbor Laboratory Herman and Margaret Sokol Professor Gyula and Katica Tauber Professor of Whitehead Institute for Biochemistry and Chemistry and Chair Lubert Stryer, M.D. Biomedical Research Department of Biochemistry Mrs. George A. Winzer Professor of Massachusetts Institute of Technology Brandeis University Cell Biology, Emeritus Adjunct Professor Stanford University School of Medicine J. Larry Jameson, M.D., Ph.D. Department of Neurology and Center Vice President for Medical Affairs for Neurologic Diseases Craig B. Thompson, M.D. and Lewis Landsberg Dean Harvard Medical School and Chair Northwestern University, Brigham & Women’s Hospital Director Feinberg School of Medicine (Through December 31, 2007) Abramson Cancer Center University of Pennsylvania Joan V. Ruderman, Ph.D. Marion V. Nelson Professor of Cell Biology Department of Cell Biology Harvard Medical School

70 Scientific HHMI Annual Report 2008 HHMI People and Financials Review Board September 1, 2007 – August 31, 2008

Wolfhard Almers, Ph.D. William A. Catterall, Ph.D. Richard D. Kolodner, Ph.D. Senior Scientist Professor and Chair Member Vollum Institute Department of Pharmacology Ludwig Institute for Cancer Research, Oregon Health and Science University University of Washington San Diego Branch School of Medicine Professor of Medicine Michael Ashburner, F.R.S. (Effective January 1, 2008) University of California, San Diego, Professor of Biology School of Medicine Department of Genetics Sara A. Courtneidge, Ph.D. Executive Director for Laboratory University of Cambridge Professor and Director Science and Technology Tumor Microenvironment Program Ludwig Institute for Cancer Research, Mary Beckerle, Ph.D. Director of Academic Affairs New York Ralph E. and Willa T. Main Burnham Institute for Medical Research Presidential Professor (Effective January 1, 2008) Lynn Landmesser, Ph.D. Executive Director Garvin Professor and Chair Huntsman Cancer Institute Jorge E. Galán, Ph.D. Department of Neurosciences University of Utah Lucille P. Markey Professor of Case Western Reserve University (Effective January 1, 2008) Microbiology School of Medicine Chairman Stephen J. Benkovic, Ph.D. Section of Microbial Pathogenesis Michael A. Marletta, Ph.D. Evan Pugh Professor and Yale School of Medicine Aldo DeBenedictis Distinguished Eberly Chair in Chemistry Professor of Chemistry The Pennsylvania State University Richard H. Goodman, M.D., Ph.D. Professor of Biochemistry (Effective January 1, 2008) Director, Vollum Institute and Molecular Biology Oregon Health and Science University University of California, Berkeley Michael R. Botchan, Ph.D. (Effective January 1, 2008) (Effective January 1, 2008) Richard and Rhoda Goldman Distinguished Professor of Biochemistry Margaret K. Hostetter, M.D. Gail R. Martin, Ph.D. Co-Chair of the Department Jean McLean Wallace Professor and Professor and Vice-Chair, of Molecular and Cell Biology Chair Department of Anatomy University of California, Berkeley Department of Pediatrics University of California, San Francisco (Through December 31, 2007) Professor of Microbial Pathogenesis (Effective January 1, 2008) Yale School of Medicine Kathryn Calame, Ph.D. (Effective January 1, 2008) Diane Mathis, Ph.D. Professor Emerita of Microbiology and Head, Section on Immunology Biochemistry & Molecular Biophysics and Immunogenetics Columbia University College Joslin Diabetes Center of Physicians and Surgeons Professor of Medicine Harvard Medical School

71 Scientific Review Board

Keith Moffat, Ph.D. Gregory A. Petsko, D.Phil. David C. Van Essen, Ph.D. Louis Block Professor, Department of Gyula and Katica Tauber Professor of Edison Professor and Head Biochemistry and Molecular Biology Biochemistry and Chemistry and Chair Department of Anatomy Deputy Provost for Research Department of Biochemistry and Neurobiology The University of Chicago Brandeis University Washington University Adjunct Professor School of Medicine W. James Nelson, Ph.D. Department of Neurology and Rudy J. and Daphne Donohue Munzer Center for Neurologic Diseases Christopher T. Walsh, Ph.D. Professor Harvard Medical School and Hamilton Kuhn Professor Department of Biology and of Brigham & Women’s Hospital Department of Biological Chemistry Molecular and Cellular Physiology (Effective January 1, 2008) and Molecular Pharmacology The Bio-X Program Harvard Medical School Stanford University Janet Rossant, Ph.D. University Professor of Molecular Huntington F. Willard, Ph.D. Roger A. Nicoll, M.D. Genetics and of Obstetrics Director, Institute for Genome Professor and Gynecology Sciences & Policy Department of Cellular and Molecular University of Toronto Nanaline H. Duke Professor Pharmacology Chief of Research of Genome Sciences University of California, San Francisco, The Hospital for Sick Children, Toronto Duke University School of Medicine (Effective January 1, 2008) (Through December 31, 2007) Joshua R. Sanes, Ph.D. Professor of Molecular and Eric N. Olson, Ph.D. Cellular Biology Professor and Chairman Paul J. Finnegan Family Director, Department of Molecular Biology Center for Brain Science University of Texas Southwestern Harvard University Medical Center at Dallas Robert T. Sauer, Ph.D. James W. Patrick, Ph.D. Salvador E. Luria Professor Professor of Neuroscience Department of Biology Baylor College of Medicine Massachusetts Institute of Technology

David W. Tank, Ph.D. Henry L. Hillman Professor Department of Molecular Biology Co-Director Princeton Neuroscience Institute Princeton University

72 Janelia Farm Research Campus HHMI Annual Report 2008 HHMI People and Financials Advisory Committee September 1, 2007 – August 31, 2008

Winfried Denk, Ph.D. Carla J. Shatz, Ph.D. David W. Tank, Ph.D. Director Director, Bio-X Henry L. Hillman Professor Department of Biomedical Optics Professor of Biology and Neurobiology Department of Molecular Biology Max Planck Institute for Medical James H. Clark Center Co-Director, Princeton Neuroscience Research Stanford University Institute Princeton University Joseph L. Goldstein, M.D. Maxine Singer, Ph.D. Regental Professor and Chairman President Emerita Shirley M. Tilghman, Ph.D. Department of Molecular Genetics Carnegie Institution of Washington President University of Texas Southwestern Senior Scientific Advisor Princeton University Medical Center at Dallas Carnegie Academy for Science Education

Gerald M. Rubin, Ph.D. Lubert Stryer, M.D. Chair Mrs. George A. Winzer Professor Vice President and Director, of Cell Biology, Emeritus Janelia Farm Research Campus Stanford University School of Medicine Howard Hughes Medical Institute

Bioethics Advisory Board September 1, 2007 – August 31, 2008

Patricia A. King, J.D. Harriet S. Rabb, J.D. Laurie Zoloth, Ph.D. Carmack Waterhouse Professor of Law, Vice President and General Counsel Chair Medicine, Ethics, and Public Policy The Rockefeller University Professor of Medical Humanities Georgetown Law School and Bioethics and of Religion Georgetown University Harold T. Shapiro, Ph.D. Director of Center for Bioethics, President Emeritus and Professor Science and Society Jonathan D. Moreno, Ph.D. of Economics and Public Affairs Northwestern University, David and Lyn Silfen University Princeton University Feinberg School of Medicine Professor and Professor of Medical Ethics and of History and Sociology of Science Center for Bioethics University of Pennsylvania

73 Fellowships & Grants September 1, 2007 – August 31, 2008

Graduate and Medical Education Rex Cheng Michael Galvez Programs Duke University School of Medicine Stanford University (University of California, San Francisco, School of Medicine Research Training Fellowships School of Medicine)* for Medical Students Matthew Goldstein Hao Jun Chong Stanford University Initial Awards: First Year of Research University of California, School of Medicine San Francisco, School of Medicine Shaka Bahadu Divakar Gupta Weill Cornell Medical College Lisa Chu Duke University School of Medicine University of California, Hasani Baharanyi San Francisco, School of Medicine Mohamad Halawi Yale School of Medicine Duke University School of Medicine (Harvard Medical School)* Raul Clavijo University of California, Seunggu Han Kristopher Bosse San Francisco, School of Medicine University of California, University of Pennsylvania (Stanford University San Francisco, School of Medicine School of Medicine School of Medicine)* Asaff Harel Lior Braunstein Justin Cohen University of Pittsburgh Harvard Medical School Yale School of Medicine School of Medicine

Rebekah Browning Mackenzie Cook Le He Ohio State University College Duke University School of Medicine Case Western Reserve University of Medicine and Public Health (University of Wisconsin School of School of Medicine Medicine and Public Health)* Ann Cai Karim Helmy Harvard Medical School Agnieszka Czechowicz University of Medicine and Dentistry Stanford University of New Jersey–New Jersey Medical Justin Chan School of Medicine School (Memorial Sloan-Kettering Mount Sinai School of Medicine Cancer Center)* Neil Desai Jennifer Chen Yale School of Medicine Heidi Hillesland Johns Hopkins University University of New Mexico School of Medicine Susan Emmett School of Medicine (Stanford University Duke University School of Medicine School of Medicine)* Susan Hiniker Lauren Frazer University of Michigan Medical School University of Pittsburgh School of Medicine

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

74 HHMI Annual Report 2008 HHMI People and Financials

Suejy Hobson Carson Lam Nikhil Nayak David Geffen School of Medicine Northwestern University, Yale School of Medicine at UCLA The Feinberg School of Medicine Paul Nuyujukian Michael Hodavance John Lewis Stanford University Duke University School of Medicine Duke University School of Medicine School of Medicine

Jennifer Hong Christopher Liu Sarina Pasricha Stanford University Baylor College of Medicine Northwestern University School of Medicine The Feinberg School of Medicine Gene Ma Jeffrey Hsu Stanford University Jeremy Pearl David Geffen School of Medicine School of Medicine Stanford University at UCLA School of Medicine Allan Mabardy Ryan Huss University of Massachusetts David Perlmutter Stanford University Medical School University of Rochester School of Medicine School of Medicine and Dentistry Kimberley Mak Timothy Johnson Harvard Medical School Rebecca Pomerantz Emory University (Memorial Sloan-Kettering University of Pittsburgh School of Medicine Cancer Center)* School of Medicine

Michelle Jonelis Priya Malik Makeda Robinson University of California, Cleveland Clinic Stanford University San Francisco, School of Medicine Lerner College of Medicine of School of Medicine (University of California, Case Western Reserve University San Diego, School of Medicine)* Karl Staser Sean McEvoy Indiana University Amit Khera Yale School of Medicine School of Medicine University of Pennsylvania School of Medicine Justin Mendel Rosalyn Sulyanto Emory University Harvard University Thomas Kosztowski School of Medicine School of Dental Medicine Johns Hopkins University School of Medicine Yasha Modi Tina Tailor Yale School of Medicine Duke University School of Medicine

75 Fellowships & Grants

Corinne Taraska Corinna Zygourakis Amar Bansal University of Washington Harvard Medical School New York University School of Medicine School of Medicine Continued Awards: Patrick Varley Second Year of Research Ayush Batra New York University Cleveland Clinic School of Medicine David Caretto Lerner College of Medicine of University of California, Case Western Reserve University Matthew Vestal San Francisco, School of Medicine Yale School of Medicine Steven Beaudry‡ Mark Chao West Virginia School of Guadalupe Villarreal Stanford University Osteopathic Medicine Harvard Medical School School of Medicine Kevin Blaine Joshua Weiner Craig Giacomini Cleveland Clinic Yale School of Medicine Stanford University Lerner College of Medicine of (Harvard Medical School)* School of Medicine Case Western Reserve University

Kari Wellnitz Maya Kasowski Patrick Blake University of Texas Yale School of Medicine Cleveland Clinic Health Science Center at Houston Lerner College of Medicine of Steven Minear Case Western Reserve University Emily Williams Stanford University University of Pennsylvania School of Medicine Jim Boonyaratanakornkit‡ School of Medicine University of California, Sheela Toprani San Francisco, School of Medicine Sima Yazdani Cleveland Clinic Duke University School of Medicine Lerner College of Medicine of Ian Buchanan Case Western Reserve University Warren Alpert Medical School Hasan Zaidi (Case Western Reserve University of Brown University Johns Hopkins University School of Medicine)* School of Medicine Marianne Castillo HHMI-NIH Research Scholars† University of Medicine and Dentistry of Zachary Zumsteg New Jersey–New Jersey Medical School David Geffen School of Medicine Shila Azodi at UCLA Texas Tech University Jessica Chang Health Sciences Center Duke University School of Medicine School of Medicine

* A fellowship institution affiliation other than the medical school is indicated in parentheses. † This program is administered through Grants & Special Programs but is budgeted as a research operation. ‡ Second year in program as an advanced scholar.

76 HHMI Annual Report 2008 HHMI People and Financials

Rachel Chard Lillian Guenther Steve Khachi Oregon Health & Science University State University of New York Des Moines University School of Medicine Downstate Medical Center College of Osteopathic Medicine College of Medicine Jenny Chen Angela Lee Indiana University Jason Hawkes Harvard Medical School School of Medicine University of Utah School of Medicine Elise Meoli‡ Audree Condren University of Rochester University of Oklahoma Caitlin Hicks School of Medicine and Dentistry College of Medicine Cleveland Clinic Lerner College of Medicine of Derek Narendra‡ Jeremiah Davis Case Western Reserve University University of Michigan Medical School George Washington University (Deferring until 2009) School of Medicine and Health Sciences Rell Parker Brett Jagger‡ University of California, Davis, Chibawanye Ene‡ Indiana University School School of Veterinary Medicine Indiana University of Medicine School of Medicine Justin Poling Guy Jones Vanderbilt University Natasha Fewkes University of Medicine and Dentistry of School of Medicine Oregon Health & Science University New Jersey–New Jersey Medical School School of Medicine Matthew Reilley Samantha Jordan Dartmouth Medical School Cedar Fowler Tufts University Tufts University School of Medicine School of Dental Medicine Paul Romesser Boston University Rachel Giese Anusha Kalbasi School of Medicine University of Texas David Geffen School of Medicine Health Science Center at San Antonio at UCLA Sarah Rusk School of Medicine Case Western Reserve University Wee-Tin Kao School of Medicine Joshua Gordon‡ State University of New York David Geffen School of Medicine at Stony Brook Alex Ryder at UCLA Health Sciences Center Vanderbilt University School of Medicine School of Medicine

Amelia Keaton University of South Carolina School of Medicine

77 Fellowships & Grants

Michelle Samuel Jered Wendte John Chang, M.D. University of Pennsylvania Oklahoma State University University of Pennsylvania School of Veterinary Medicine Center for Veterinary Health Sciences School of Medicine

Logan Schneider Caroline Yeager Hyung Chun, M.D. University of Florida Duke University School of Medicine Stanford University College of Medicine School of Medicine James H. Gilliam Jr. Fellowships Abigail Shearin for Advanced Study Todd Fehniger, M.D., Ph.D. University of Pennsylvania Washington University School of Veterinary Medicine Silvia G. Caballero School of Medicine City University of New York, Hubert Shih Hunter College* Matthew Freedman, M.D. David Geffen School of Medicine (Deferring fellowship) Dana-Farber Cancer Institute at UCLA Lee Shoa Long Clarke Timothy Graham, M.D. Scott Steward-Tharp‡ Stanford University Beth Israel Deaconess Medical Center University of Iowa College of Dentistry Alejandra Figueroa-Clarevega Ari Green, M.D. Jayesh Thawani Washington University in University of California, University of Michigan Medical School St. Louis* San Francisco, School of Medicine (Deferring fellowship) Mari Tokita Fred Hsieh, M.D. Warren Alpert Medical Daniel B. Gilmer Cleveland Clinic Foundation School of Brown University Rockefeller University Hanlee Ji, M.D. Jessica Valdez Bertrade C. Mbom Stanford University University of New Mexico Stanford University School of Medicine School of Medicine Physician-Scientist Regina LaRocque, M.D. Dean Wang Early Career Awards Massachusetts General Hospital Cleveland Clinic Lerner College of Medicine of Yvonne Chan, M.D. Eduardo Mendez, M.D. Case Western Reserve University University of Pittsburgh University of Washington School of Medicine Medical Center Frederick Wang Yale School of Medicine Goutham Narla, M.D., Ph.D. Mount Sinai School of Medicine

‡ Second year in program as an advanced scholar. * Undergraduate Institution.

78 HHMI Annual Report 2008 HHMI People and Financials

Mark Onaitis, M.D. The Jackson Laboratory Calvin College Duke University School of Medicine Bar Harbor, Maine Grand Rapids, Michigan Grant: Graduate and Postgraduate $1,100,000 Tipu Puri, M.D., Ph.D. Educational Programs University of Chicago, $2,000,000 Carleton College Division of Biological Sciences and Northfield, Minnesota Pritzker School of Medicine Marine Biological Laboratory $1,500,000 Woods Hole, Massachusetts Benjamin Purow, M.D. Grant: Graduate and Postgraduate City University of New York, University of Virginia Educational Programs Hunter College School of Medicine $4,000,000 New York, New York $1,400,000 Joshua Roffman, M.D. Harvard Medical School Undergraduate Science Colby College Education Program Waterville, Maine Allan Tsung, M.D. $1,000,000 University of Pittsburgh Baccalaureate and School of Medicine Master’s Degree Institutions Colgate University Hamilton, New York Arun Venkatesan, M.D., Ph.D. Amherst College $1,200,000 Johns Hopkins University Amherst, Massachusetts School of Medicine $1,300,000 College of Charleston Charleston, South Carolina Paul Yu, M.D., Ph.D. Barnard College $1,500,000 Harvard Medical School New York, New York $1,500,000 College of Wooster Other Graduate Science Wooster, Ohio Education Awards Bowdoin College $1,000,000 Brunswick, Maine Cold Spring Harbor Laboratory $1,100,000 Davidson College Cold Spring Harbor, New York Davidson, North Carolina Grant: Graduate and Postgraduate Bryn Mawr College $1,500,000 Educational Programs Bryn Mawr, Pennsylvania $3,000,000 $1,200,000 Drew University Madison, New Jersey California State University–Fullerton $1,100,000 Fullerton, California $1,200,000

79 Fellowships & Grants

Franklin & Marshall College Hope College San Jose State University Lancaster, Pennsylvania Holland, Michigan San Jose, California $1,300,000 $1,400,000 $1,300,000

Furman University Kalamazoo College Smith College Greenville, South Carolina Kalamazoo, Michigan Northampton, Massachusetts $1,200,000 $1,000,000 $1,300,000

Georgetown College Lewis and Clark College Spelman College Georgetown, Kentucky Portland, Oregon Atlanta, Georgia $1,300,000 $1,300,000 $1,400,000

Gonzaga University Morehouse College Swarthmore College Spokane, Washington Atlanta, Georgia Swarthmore, Pennsylvania $1,200,000 $1,400,000 $1,600,000

Grinnell College Mount Holyoke College Trinity University Grinnell, Iowa South Hadley, Massachusetts San Antonio, Texas $1,200,000 $1,500,000 $1,500,000

Gustavus Adolphus College North Carolina Central University University of Louisiana at Monroe Saint Peter, Minnesota Durham, North Carolina Monroe, Louisiana $1,000,000 $900,000 $700,000

Hampton University Oakwood College University of Puerto Rico– Hampton, Virginia Huntsville, Alabama Mayaguez $1,200,000 $1,200,000 Mayaguez, Puerto Rico $1,400,000 Harvey Mudd College Occidental College Claremont, California Los Angeles, California University of Richmond $1,500,000 $1,400,000 Richmond, Virginia $1,400,000 Haverford College Saint Joseph’s University Haverford, Pennsylvania Philadelphia, Pennsylvania University of Texas–Pan American $1,400,000 $1,000,000 Edinburg, Texas $1,200,000

80 HHMI Annual Report 2008 HHMI People and Financials

Vassar College Erwin Cabrera Jeremy Flores Poughkeepsie, New York University of Maryland, University of Texas at Austin $1,500,000 Baltimore County Philia Gau Washington and Jefferson College Angela Castellanos Cornell University Washington, Pennsylvania Stanford University $1,000,000 Deric Griffin Lesley Chapman Louisiana State University and Washington and Lee University Duke University A & M College Lexington, Virginia $1,300,000 Sarah De Leo Shuo Han Louisiana State University Massachusetts Institute Wellesley College and A & M College of Technology Wellesley, Massachusetts $1,200,000 Ryan Dosumu-Johnson Akil Jackson University of California, Los Angeles Morehouse College Wesleyan University Middletown, Connecticut Omer Durak Sarah Jackson $1,400,000 California Institute of Technology Trinity University

Whitman College Mariam El-Ashmawy Pouya Jamshidi Walla Walla, Washington Arizona State University University of California, San Diego $800,000 Melody Esmaeili Melissa Kemp Wilkes University University of California, Berkeley Williams College Wilkes-Barre, Pennsylvania $1,000,000 Jason Espinoza Espoir Kyubwa University of Arizona University of California, San Diego HHMI’s Exceptional Research Opportunities Program (EXROP) Terry Felton Luis Lazaro Xavier University of Louisiana Rice University Jarrad Aguirre Yale University Marty Fernandez Kristen Lessl University of Florida University of Michigan–Ann Arbor Julian Artunduaga University of Maryland, Christopher Ferreira Yendi Linares College Park University of Massachusetts Emory University

81 Fellowships & Grants

Sylvester Marshall III Cindy Puente Gabriel Walton Washington University City University of New York, University of Miami Hunter College Janielle Maynard Sarah Whiteside Howard University Jacqueline Ramirez Massachusetts Institute College of William and Mary of Technology Carlo Mejia University of California, Riverside Erica Rangel Patrick Williams University of Colorado at Boulder University of Pittsburgh Christina Moore University of California, Berkeley Brandon Roane Ramone Williams Duke University Emory University Brittney Newby Florida A & M University Karen Rodriguez Anna Zelaya University of Colorado at Boulder California State Polytechnic Kathy Ngo University–Pomona University of California, Damaris Rosado Los Angeles University of Texas at El Paso Other Undergraduate Science Education Awards Jacqueline Nkuebe Stephanie Rosales Harvard University Columbia University Grinnell College Grinnell, Iowa Ugochi Nwosu Cristine Santiago Grant: Survey of Undergraduate Harvard University University of Puerto Rico–Cayey Research Experiences and Classroom Undergraduate Research Experiences Casandra Panea Krystal St. Julien $240,000 Yale University University of Washington University of Wisconsin–Madison Jude Phillip Daisha Steadman Madison, Wisconsin City University of New York, Georgia State University Grant: Summer Institute on City College Undergraduate Education in Biology Cindy Thomas $150,000 Dami Phillips State University of New York Carnegie Mellon University at Stony Brook

Christopher Pina Valerie Vassor University of California, Davis Swarthmore College

82 HHMI Annual Report 2008 HHMI People and Financials

Precollege Science Loudoun County, Sonnya Keunju Im Education Program Virginia, Initiatives Briar Woods High School

Washington, D.C., Loudoun County Public Schools Kevin Isa Izadpanah Metropolitan Area Initiatives Leesburg, Virginia Potomac Falls High School Grant: Teacher Professional Audubon Naturalist Society Development Institute; Academy Lesley Anne Luginbill Chevy Chase, Maryland of Science; Student Research; Briar Woods High School Grant: Greenlabs Environmental Curriculum Development; Teacher Workshops and College Scholarships‡‡ Andrew James Mann $25,000 $1,000,000 Broad Run High School

Chesapeake Bay Foundation College Scholarships Chesney Sarah Oravec Annapolis, Maryland Stone Bridge High School Grant: Maryland Environmental Amanda Victoria Below Education Program Stone Bridge High School Gurleen Pahal $150,000 Potomac Falls High School Nhat-Minh Le Bui Eleanor Roosevelt Heritage High School Premkumar Periyasamy High School Broad Run High School Greenbelt, Maryland Maria Elizabeth Chopivsky Grant: Science and Technology Program Loudoun County High School Mickinjit S. Sahni $29,000 Freedom High School Justin Michael Cook Montgomery County Dominion High School Sanam Shahid Public Schools Educational Foundation Freedom High School Rockville, Maryland Mikaela Anita Finnegan Grant: Elementary Science Leadership Heritage High School Kevin Matthias Shea II Program; Student and Teacher Loudoun Valley High School Internship Program; Teacher Bethany Lynn Hansberger Professional Development Park View High School Elizabeth Sara Stevens $651,000 Loudoun County High School Patricia Diane Hicks Loudoun Valley High School Emily Louise Wilson Dominion High School Lisa Huynh Park View High School

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

83 Fellowships & Grants

Other Precollege Science Education Educational Resources Albert Einstein College of Medicine Awards Bronx, New York American Society for Cell Biology Grant: To support the work Institute for Systems Biology Bethesda, Maryland of Sarita Shah, M.D., M.P.H. Seattle, Washington Grant: CBE-Life Sciences Education $57,557 Grant: Building Parent Partnerships $400,000 in Science Education American Association for the $25,000 WGBH Educational Foundation Advancement of Science Boston, Massachusetts Grant: Science’s Education Forum University of Mississippi School Grant: NOVA scienceNOW $40,000 of Medicine $4,500,000 Jackson, Mississippi Brigham & Women’s Hospital Grant: A Muse of Fire: Boston, Massachusetts Stimulating Student Inquiry with Office of Grants and Grant: To support the work Red Imported Fire Ants Special Programs of D. Branch Moody, M.D. $50,000 $90,000 HHMI Investigator Education Grants Edendale Hospital, International Program KwaZulu-Natal Sean B. Carroll, Ph.D. Peitermaritzburg, South Africa Courses University of Wisconsin–Madison Grant: To support the work of Grant: Work on NOVA evolution program Douglas Wilson, M.B.Ch.B. Federal University of $100,000 $81,000 Minas Gerais Belo Horizonte, Brazil Catherine Dulac, Ph.D. Harvard University $150,000 Harvard University School of Public Health Grant: Equipment for use in research- Boston, Massachusetts University of Rijeka based course in experimental and Grant: To support the work of Rijeka, Croatia cellular biology Sarah Fortune, M.D. $150,000 $150,000 $89,492

Other International Grants Other Awards Harvard University School of Public Health Institute of Biotechnology, Albert Einstein College of Medicine Boston, Massachusetts National Autonomous University Bronx, New York Grant: To support the work of of Mexico Grant: To support the work Eric Rubin, M.D., Ph.D. Cuernavaca, Mexico of Jacqueline Achkar, M.D. $89,492 Grant: Frontiers in $88,457 Genomics Program $20,000

84 HHMI Annual Report 2008 HHMI People and Financials

Massachusetts General Hospital HHMI Awards Boston, Massachusetts Grant: To support the work of Marcus United Way of Loudoun County Altfeld, M.D., Ph.D. and Other Community Organizations $119,520 in Loudoun County Leesburg, Virginia University of KwaZulu-Natal $39,028 Durban, South Africa Grant: To support the work of Prashini United Way of the National Capital Area Moodley, M.B.Ch.B., M.Med., Ph.D. Washington, D.C. $81,000 $50,000

University of KwaZulu-Natal Durban, South Africa Grant: To support the work of Yunus Moosa, M.B.Ch.B., Ph.D. $81,000

University of KwaZulu-Natal Durban, South Africa Grant: To support the work of Thumbi Ndung’u, B.V.M., Ph.D. $81,000

University of KwaZulu-Natal Durban, South Africa Grant: To support the work of Alexander Pym, M.D. $162,000

University of Pittsburgh Pittsburgh, Pennsylvania Grant: To support the work of Graham Hatfull, Ph.D. $90,000

Yale University New Haven, Connecticut Grant: Course in Durban, South Africa $30,000

85 Finance & Investments September 1, 2007 – August 31, 2008

The Howard Hughes Medical Institute is the nation’s largest private Disbursements supporter of academic biomedical research. The endowment is the ($ in millions) Institute’s principal source of funding. The investment objective is to 1000 manage the endowment in a prudent manner that will maintain its $781 purchasing power and will fund the Institute’s research and grants $764 $726

800 $717 programs on an ongoing basis. At the end of fiscal year on August $653

31, 2008, the endowment was $17.5 billion. Classified as a medical 600 research organization by the Internal Revenue Service, the Institute is required to spend at least 3.5 percent of its endowment each year on 400 direct medical research activities exclusive of grants and investment management expenses. 200 Disbursements in Fiscal Year 2008 Disbursements during the fiscal year totaled $764 million: $658 mil- 04 05 06 07 08 lion for scientific research including operations at the Janelia Farm Lab and HQ Construction Grants and Special Programs Research Campus; $83 million for grants for science education and Scientific Research international research scholars, and $23 million to expand the HHMI headquarters campus and to purchase equipment for the Janelia Farm Research Campus. Over the past five years, disbursements by Scientific Research ($ in millions) the Institute totaled approximately $3.6 billion. 1000 Scientific Research Research activities are conducted principally at Institute laboratories 800 $694 $681 $640 at medical centers, teaching hospitals, and universities in the United $637 $573 States by investigators who hold faculty appointments at the host 600 institutions. These individuals, together with their support staffs, are HHMI employees and are compensated directly by the Institute. 400 Investigators may spend up to 25 percent of their time on teaching, administration, and other activities that benefit their institutions. At 200 the end of fiscal year 2008, the Institute supported 335 investigators at 66 academic medical centers. 04 05 06 07 08 As of August 31, 2008, the Institute’s investment in laboratory space, Lab Construction equipment, and other property amounted to greater than $1.4 billion, Equipment and Lab Renovation Operating with a current replacement value of approximately $1.8 billion.

Janelia Farm Research Campus The Janelia Farm Research Campus, situated on a 689-acre site along the Potomac River in Ashburn, Virginia, just outside Washington,

86 HHMI Annual Report 2008 HHMI People and Financials

D.C., provides the setting for interdisciplinary, collaborative research Grants and Special Programs focused on two areas: identifying the general principles that govern ($ in millions) $87 $86 how information is processed by neuronal circuits; and developing $83 100 $80 $80 imaging technologies and computational methods for image analysis.

The total development cost of the project was more than $500 mil- 50 lion. In its first two years of operation, expenditures at Janelia Farm totaled approximately $163 million. In fiscal year 2008, expenditures 04 05 06 07 08 at Janelia Farm totaled $96 million, of which $22 million represented Precollege Education, Educational Materials, and Other personnel expenditures and approximately $47 million was for International equipment and for completing construction of specialized research Graduate Education facilities. When Janelia Farm is at full capacity, which is expected Undergraduate Education to occur by the end of fiscal year 2012, it will house a permanent research staff of about 250—including 25 group leaders and 20 fel- Endowment lows—and up to 100 visiting scientists. ($ in millions)

20,000 $18,702 Grants and Special Programs $17,499 $16,326

Through its grants program, the Institute supports science educa- $14,754 15,000 tion at all levels, from the earliest grades through advanced research $12,782 training. It also directly supports scientists conducting research in the biological sciences in selected foreign countries. The Institute 10,000 disbursed $83 million to support the activities of 585 grantees in 29 countries during fiscal year 2008. 5,000

Endowment 04 05 06 07 08 The Institute’s endowment is managed under the direction of its Vice President and Chief Investment Officer. Approximately 78 percent of Endowment Allocations the endowment is invested by external fund managers; the remain- der is internally managed. External managers are used to manage Real assets Domestic virtually all asset classes, including public equities and alternative equity 9% investments, including hedge funds and private equities. International 16% equity 13% At the close of fiscal year 2008, the endowment value was $17.5 billion, a decrease of $1.2 billion from the end of fiscal year 2007. The 16% Bonds endowment return for fiscal year 2008 was negative 2.01 percent. Distressed and credit 11% sensitive The composition of the Institute’s endowment by investment cat- 4% Market neutral egory on August 31, 2008, is reflected in the graph at right. arbitrage 12% 19%

Hedged Private equity equity

87 Statement of Financial Position August 31, 2008 and 2007 ($ in millions)

Assets ($ in millions) 2008 2007

Assets

Cash and cash equivalents $ 202 $ 105

Investments 18,270 19,358

Investment and currency receivables, and other assets 2,259 1,416

Laboratory space, equipment, and other property—at cost, net of accumulated depreciation and amortization 836 796

Total Assets $ 21,567 $ 21,675

Liabilities

Accounts payable, accrued expenses, and obligations 203 208

Grants commitments 202 158

Investment purchases payable, repurchase obligations, short sales, and currency payables 3,047 2,049

Notes and bonds payable 700 627

Total Liabilities 4,152 3,042

Net Assets $ 17,415 $ 18,633

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, 2008, 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

88 Credits

Page 5 Page 34 Groves: Noah Berger/AP, ©HHMI Page 51 Cech: Bruce Weller Bear: Jason Grow Hooper: Amy Gutierrez/AP, ©HHMI Egnor: Paul Fetters Page 8 X chromosome (Bear): Biophoto Irvine: Robert E. Klein/AP, ©HHMI Gustafsson: Paul Fetters Capecchi: Ramin Rahimian Associates/Photo Researchers, Inc. Jacobs-Wagner: Frederick Beckham/ Lavis: Paul Fetters Page 9 Page 35 AP, ©HHMI Bogenhagen: Paul Fetters Stem cells (Capecchi): Andrew Paul Perlman: James Kegley Jarvis: Jonathan Fredin/AP, ©HHMI Page 52 Leonard/Photo Researchers, Inc. Page 36 Jensen: Jill Connelly/AP, ©HHMI Holiday Lectures: Paul Fetters DNA (Capecchi): Biophoto Associates/ Astrocytes (Radi): N. Kedersha/ Jiang: Amy Gutierrez/AP, ©HHMI Page 53 Photo Researchers, Inc. Photo Researchers, Inc. Joshua-Tor: Allan Zepeda/AP, ©HHMI Caballero: Matthew Septimus Page 10 Radi: David Rolls Keeney: Allan Zepeda/AP, ©HHMI Clarke: Barbara Ries ES cells (Capecchi): Prof. Miodrag Jessell: Paul Fetters Kim: George Nikitin/AP, ©HHMI Figueroa-Clarevega: Ben Weddle Stojkovic/Photo Researchers, Inc. Page 37 Kruglyak: Christopher Barth/ Gilmer: Tom Kochel Page 11 Adenylate cyclase (Kern): Kern lab AP, ©HHMI Mbom: Annie O’Neill Daley: M. William Lensch Kern: Robert Klein/AP, ©HHMI Lim: George Nikitin/AP, ©HHMI Page 54 Melton: Joshua Dalsimer Page 38 Lu: Joseph Kaczmarek/AP, ©HHMI O’Shea: Christopher Jones Page 12 Pyramidal neuron (Magee): Attila Moazed: Robert E. Klein/AP, ©HHMI Huganir: Paul Fetters Breast cancer (Massagué): David Losonczy/Magee lab Molkentin: David Kohl/AP, ©HHMI Cell suicide (Wang): ©2007 Richard P. Padua/Massagué lab Magee: Bruce Weller Moran: Mark Bialek/AP, ©HHMI Howdy, Jr; concept by Sean Peterson Massagué: Mark Mahaney Page 41 Newman: Robert E. Klein/AP, ©HHMI Svoboda: Paul Fetters Page 13 Cech: James Kegley Newmark: Darell Hoemann/AP, ©HHMI Chory: Jeffrey Lamont Brown Pyle: Ruthanna Terreri Pages 42–43 Pagano: Allan Zepeda/AP, ©HHMI Page 55 Group II intron (Pyle): Kevin Keating/ Pyle lab Cheung: Peter Wodarczyk/PR Pan: Steve Ruark/AP, ©HHMI Zhuang: Joshua Dalsimer Page 16 Newswire, ©HHMI Pascual: Mark Bialek/AP, ©HHMI Green: Paul Fetters Blocked HIV (Elledge): Abraham Chinnaiyan: Don Alley/PR Newswire, Paull: Jack Plunkett/AP, ©HHMI Ménard: David Rolls Brass/Elledge Lab ©HHMI Pellman: Robert E. Klein/AP, ©HHMI Gilliland: Alexis Bywater Page 17 Daley: M. William Lensch Pfaff: Denis Poroy/AP, ©HHMI Eichler: Ron Wurzer/AP, ©HHMI Elledge: Webb Chappell Engle: Walter Urie Pritchard: Aynsley Floyd/AP, ©HHMI Protocell (Szostak): Janet Iwasa Hannon: Zack Seckler/AP, ©HHMI Fikrig: Robert Lisak/PR Newswire, Sabatini, B.: Robert E. Klein/ Orkin: Sam Ogden Page 18 ©HHMI AP, ©HHMI Page 56 Myers: Paul Fetters Gleeson: Fred Greaves/PR Newswire, Sabatini, D.: Robert E. Klein/ Snake (Pourquié): Pourquié lab Neuron (Myers): James Cavallini/ ©HHMI AP, ©HHMI Ahlquist: University of Wisconsin- Photo Researchers, Inc. Haber: Darren McCollester/PR Scanziani: Denis Poroy/AP, ©HHMI Madison Page 19 Newswire, ©HHMI Schnitzer: George Nikitin/AP, ©HHMI Casanova: David Rolls Baker: Brian Smale Hildebrandt: Don Alley/PR Newswire, Shen: George Nikitin/AP, ©HHMI Page 57 HIV protein (Baker): Laguna Design/ ©HHMI Shi: Christopher Barth/AP, ©HHMI Elgoyhen: David Rolls Photo Researchers, Inc. Karumanchi: Kaye Evans-Lutterodt/ Stern: Christopher Barth/AP, ©HHMI Jessell: Paul Fetters Page 20 PR Newswire, ©HHMI Taunton: George Nikitin/AP, ©HHMI Lefkowitz: Stewart Waller/ Cowman: Walter and Eliza Hall Levine: Tim Sharp/PR Newswire, Theriot: George Nikitin/AP, ©HHMI PR Newswire, ©HHMI Institute of Medical Research ©HHMI Van der Donk: Darell Hoemann/ Page 58 McFadden: Hagai Ginsburg Plowe: Kaye Evans-Lutterodt/ AP, ©HHMI Sonenberg: David Rolls Lukyanov: Ekaterina Bogdanova PR Newswire, ©HHMI Vosshall: Allan Zepeda/AP, ©HHMI Steitz: Paul Fetters Frog (Lukyanov): Andrey Zaraisky Ressler: Parker Smith/PR Newswire, Walz: Robert E. Klein/AP, ©HHMI Amon: Paul Fetters Page 21 ©HHMI Wang: Kevin Rivoli/AP, ©HHMI Page 59 Rubin: Paul Fetters Rowitch: Andy Kuno/PR Newswire, Yu: Amy Gutierrez/AP, ©HHMI Golub: Robert Bachrach Page 24 ©HHMI Zamore: Robert E. Klein/AP, ©HHMI Hannon: Zack Seckler/AP, ©HHMI Spelman: Nathan Bolster Sawyers: Liz Baylen/PR Newswire, Zheng: John Froschauer/AP, ©HHMI Page 60 Page 25 ©HHMI. Page 50 Knowles: Jon Chase/Harvard News Barnard: Matthew Septimus Shaw: Sarah Conard/PR Newswire, Barshefsky: Charlene Barshefsky Office Page 26 ©HHMI Pevzner: Fred Greaves/AP, ©HHMI Pages 44–49 Shewanella (Pevzner): PNNL Bhatia: Robert E. Klein/AP, ©HHMI Page 27 Produced by the Office of Communications and Public Affairs Bieniasz: Allan Zepeda/AP, ©HHMI Students: James Kegley ©2008 Howard Hughes Medical Institute Brody: Christopher Barth/AP, ©HHMI Page 28 Chan: Jill Connelly/AP, ©HHMI Jacobsen: John Hayes/AP, ©HHMI Annual Report Editorial Staff: Cay Butler, Lisa Seachrist Chiu, Michelle Evans: Fred Greaves/PR Newswire, Chang: Noah Berger/AP, ©HHMI Cissell, Elizabeth Cowley, Patricia Davenport, Mary Beth Gardiner, ©HHMI Chen: David Umberger/AP, ©HHMI Jim Keeley, Nicole Kresge, Olga Kuchment, Avice Meehan, Jennifer Page 29 Collins: Robert E. Klein/AP, ©HHMI Michalowski, Dianne Palmer, Kathy Savory, Cori Vanchieri, Andrea Asai: Mark Harmel Dan: Noah Berger/AP, ©HHMI Widener, Sarah C.P. Williams. Page 32 Dernburg: Noah Berger/AP, ©HHMI Walsh: Joshua Dalsimer Dillin: Denis Poroy/AP, ©HHMI Illustrations: Lara Harwood Synapses (Walsh): Eye of Science/ Drennan: Robert E. Klein/AP, ©HHMI Design: VSA Partners, Inc., New York Photo Researchers, Inc. Eisen: Noah Berger/AP, ©HHMI Printing: Finlay Printing Page 33 Elowitz: Jill Connelly/AP, ©HHMI Südhof: Misty Keasler Ferré-D’Amaré: John Froschauer/ The Howard Hughes Medical Institute is incorporated in Delaware. It is Zoghbi: Jack Thompson AP, ©HHMI qualified as a medical research organization under the federal tax code. Tsai: Matt Kalinowski García: Michael Stravato/AP, ©HHMI It is an equal opportunity employer.