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HHMI BULLETIN • Howard Hughes Medical Institute • www.hhmi.org vol. 21 / no. 03 Takaki Komiyama and Liqun Luo Liqun and Komiyama Takaki
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One to One 4000 Jones Bridge Road Maryland 20815-6789 Chase, Chevy www.hhmi.org Observations
32 Eyes Wide Open Nerve cells navigate a remarkably complex path to establish the proper connections during development. Evolutionary biology is a cornerstone of modern science. Yet, many for some of the most pressing social, cultural, and political issues In this 14-day-old mouse embryo’s paw, fluorescent people remain skeptical. A 2008 report from the National Academy of our time. staining charts the maze of sensory nerve cells. Scientists of Sciences, which HHMI is helping to distribute to schools and to the Science and technology are so pervasive in modern society that are using new discoveries about the process to think public, seeks to reveal the strong evidence supporting evolution and students increasingly need a sound education in the core concepts, about how to rewire the brain after injury or disease. its relevance to today’s most important questions. applications, and implications of science. Because evolution has and will continue to serve as a critical foundation of the biomedical As individuals and societies, we are now making decisions that will and life sciences, helping students learn about and understand the have profound consequences for future generations. How should we scientific evidence, mechanisms, and implications of evolution are balance the need to preserve the Earth’s plants, animals, and natural fundamental to a high-quality science education. environment against other pressing concerns? Should we alter our Science and religion are different ways of understanding. use of fossil fuels and other natural resources to enhance the well- Needlessly placing them in opposition reduces the potential of both being of our descendants? To what extent should we use our new to contribute to a better future. understanding of biology on a molecular level to alter the character- istics of living things? From the National Academy of Sciences/Institute of Medicine report None of these decisions can be made wisely without considering “Science, Evolution, and Creationism” © 2008 National Academies Press, biological evolution. People need to understand evolution, its role Washington, D.C. Reprinted with permission of the National Academy of within the broader scientific enterprise, and its vital implications Sciences. For more about the report, visit www.nap.edu/sec. Ian Dingman / lindgrensmith.com Rasi Wickramasinghe / Ginty lab Rasi Wickramasinghe vol. 21 august ’o8 no. o3
DEPARTMENTS
PRESIDENT’S LETTER 0 3 Interconnected
CENTRIFUGE 0 4 Keeping Time 0 5 Fish Out of Water 0 6 The Puzzle Champ
UPFRONT 0 8 Group Dynamic 1 0 Sunny Side Up 1 2 A Devil of a Problem
PERSPECTIVES AND OPINIONS 3 8 Francisco Ayala 4 0 Catherine Dulac 4 2 Q&A – What Olympic sport does your scientific career best qualify you for?
CHRONICLE
Science Education 4 4 Let the Experiments Begin 4 6 Getting Their Feet Wet Institute News 4 7 Asai Named as Undergraduate Science Education Program Director 4 7 HHMI Appoints Carlson as Senior Scientific Officer Lab Book 4 8 A Mutation’s Multiple Effects 4 9 Jumping After Mobile DNA 5 0 Mysterious Protein Protects Against Sepsis In Memoriam 5 1 Jeremy R. Knowles Toolbox 5 2 Next-Generation Sequencing Nota Bene 54 News of recent awards and other notable achievements
OBSERVATIONS Eyes Wide Open
features 14 2o 26 32
Thinking Like Add 56 The Unintentional Nerve Cell An Engineer HHMI’s newest investigators Scientist Navigation Scientists are applying the are willing to sidle up to risk. Joan Massagué was Nerve cells exploit a complex tools and approaches of Their approaches to research— having too much fun to set of cues to wire up properly engineering to solve some and life—dispel many of notice he was building in developing organisms. A practical problems and the myths about the lone, a career—and solving closer view of this process may fathom the basic nature detached scientist. problems of cell signaling ultimately help to correct of things. and cancer metastasis. neurological problems that [COVER STORY] lead to schizophrenia and other disorders.
VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: JOSH COCHRAN contributors
Josh Cochran grew up in Taiwan, Canada, and the United States. You can fnd his artwork in galleries across the States as well as overseas in Copenhagen and Berlin. Various clients also (1) commission his work, including The New York Times, The Discovery Channel, Metropolis, Beau- tiful/Decay, and Pepsi. Cochran lives in Brooklyn with his wife and small dog Porkchop. (1)
Formerly an intern at HHMI, Benjamin Lester is now a crew member aboard the freedom schooner Amistad, somewhere off the eastern coast of the United States. When he’s not sing- ing sea shanties, Lester is an itinerant science writer whose work has appeared in Science and Cosmos magazines, as well as online. (2)
(3) (2) Born and bred a farm boy in Dodge City, Kansas, Jeffrey Lamont Brown began his pro- fessional photography career with The Associated Press, documenting everything from turtle poaching to immigrant smuggling. Having since moved on to the relative safety of advertising photography, much to the pleasure of his wife and 4-year-old son, Brown now makes his home in San Diego, between travel assignments for clients around the world. (3)
Freelancer Elizabeth DeVita-Raeburn writes about science, culture, and society. She is author of The Empty Room, a memoir exploring sibling loss, and is working on a book with her (4) father, Dr. Vincent T. DeVita, on the war on cancer. She lives in New York with her husband, writer Paul Raeburn, and her son, Henry. (4)
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The opinions, beliefs, and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs, viewpoints, or official policies of the Howard Hughes Medical Institute. Josh Cochran, Benjamin Josh Lester, Lamont Jeffrey Coughlin Brown, Paul
2 h h m i b u l l e t i n | August 2oo8 president’s letter
Interconnected
Scientists are accomplished neologists: makers of new words, inventors of new usages for old words, creators of special- ized vocabularies. One might even say that scientists tend toward neophilia—defined by our friends at the Oxford English Dictionary as a love for, or great interest in, what is new. Take some of the “newest” additions to the scientific lexicon. Writing in The Scientist some years ago, the late Joshua Lederberg and linguist Alexa T. McCray sought the origins of -ome and -omics, suffixes of choice in contemporary biology. The term “genomics” may have arisen in the 1970s, but Lederberg and McCray turned to Sanskrit and Greek to understand the holistic meaning of -ome, noting that the Sanskrit syllable Om “encompasses the entire universe “The HHMI community overlaps with in its unlimitedness” and that the Greek letter omega is “the greatest other networks of researchers in this and very last character” of the alphabet, the symbolic last word. country and around the world—what So it is with some trepidation that this issue of the HHMI Bulletin introduces a graphical “interactome” that illustrates the intercon- you might describe as a human interac- nected research interests of the 56 scientists recently selected as new tome seeking to unravel the mysteries HHMI investigators (see page 20). This competition—our first major of the biological interactome. experiment allowing scientists to apply directly to the Institute—has already introduced new variables into the HHMI community. We thomas cech ” received 1,070 applications, and while sifting through so many documents certainly required more work than in the previous What’s compelling about these maps? For starters, they are beau- nomination-based competitions, we achieved our goal of choosing tiful abstractions that, in the words of Lederberg and McCray, direct investigators from a wider, deeper pool of candidates. Seven institu- one’s attention “to an eventual goal, of which only a few parts may tions will be represented by an investigator for the first time, and we be at hand.” They depict a familiar landscape in new ways; over are expanding into intriguing areas of research, including bioengi- time, they may tell us much about the evolving nature of scientific neering, synthetic biology, and the ecology of infectious disease. research, the emergence of new fields, the impact of decisions made As an organization, we frequently describe our approach to today. Taken by themselves, however, these maps provide little guid- supporting science as “people not projects”—that is, we identify highly ance for navigating the present and it’s the present that provides creative researchers working across the spectrum of biomedically cause for concern, notwithstanding our very real excitement about related projects and provide them with resources that will enable them the expansion of HHMI’s scientific community. to make discoveries for the long-term betterment of human health. The pressing question we face today is how to ensure the vitality We also work to ensure that participation in the HHMI community of of our nation’s research enterprise, the future of which will most scientists will generate new connections and new ideas. In fact, it would certainly rely on the next generation of investigators. Scientists who be a fascinating exercise to remap the “Class of 2008” in five or 10 are about to launch their independent research careers after a decade years—along with the existing investigators, the lab heads at the Janelia of specialized postgraduate training currently face daunting obsta- Farm Research Campus, and our International Research Scholars—to cles; conservative funding decisions constrain their opportunities as view the collaborative networks that emerge as well as the ways these well as the larger prospects for potentially transformative research. interactions modify the questions these scientists seek to answer. A committee I chaired for the American Academy of Arts and The HHMI community also overlaps with other networks of Sciences released its findings in June on these very issues. The researchers in this country and around the world—what you might ARISE report—short for “Advancing Research in Science and describe as a human interactome seeking to unravel the mysteries Engineering”—concluded that, while we await a rebound in the of the biological interactome. It goes without saying that the map of level of research funding, we can’t hold off making major changes science itself is both complex and dynamic. in the mechanisms by which research dollars are distributed. Federal Some try to capture the interactive nature of the scientific agencies, universities, and foundations need to take steps to nurture process by building maps. Researchers at both the Sandia National young faculty and invest in high-risk, high-payoff research. These Laboratories and the Bergstrom laboratory at the University of entities can begin remapping their relationships with each other Washington have built maps by sifting through publications, and with young investigators to sustain the landscape of strength and compiled by Thomson Scientific, to understand the strength of innovation that has long characterized the U.S. research enterprise. connections between various disciplines. The resultant diagrams
Bruce Weller resemble, in the words of one of the Sandia creators, “a filamentous microorganism you might see under a microscope.”
August 2oo8 | h h m i b u l l e t i n 3 centrifuge
tion it receives. Between the popular jazz numbers “Zigaboogaloo” and “Up Jumped Spring,” he explains his current thinking: The rapid expansion of the human brain Keeping Time during evolution allowed it to decouple stimulus from response, freeing us from the need to act immediately. As On a quiet back street in Cambridge, England, the Elm Tree soon as that happened, timing became critical to decision pub is fi lling with students and local residents on a Monday making; humans could decide when to act. The paradox is evening in March. They’re here to listen to, and in some cases that people are relatively poor timekeepers. play, jazz. “If I ask you to tap your fi nger to copy a one-second At one end of the room, trumpeter Paul Stubbs and three interval, you’ll probably be out by one to two-tenths of a or four other musicians are setting up drums, keyboard, and second,” he says. “Now if I ask you to copy a two-second bass. A sax, guitar, trumpets, even a tin whistle, will come interval, your margin of error will be double that.” Shadlen and go as the evening progresses. The musicians launch into thinks music might hold some clues to the neural basis of that a song, and the audience sits up, smiling and tapping its feet. temporal wobble. “In a band, everyone comes together,” he The performers never meet outside these sessions, and each says, “What is going on there?” Humans might have invented has only the vaguest idea of what the others do for a living; dancing for a similar reason, he speculates: to marshal a yet they play together as if they always have, their expres- sloppy timing mechanism by imposing rhythm on it. sions varying from ecstasy, to deep concentration, to Which brings us back to jazz. Shadlen is excited because amusement at a shared joke. tonight he might get to play John Coltrane’s modern classic Every so often Stubbs invites a hopeful member of the “Giant Steps.” He considers the piece a beautiful rite of audience to join in with his or her instrument. Soon it’s HHMI passage for all jazz lovers. The challenging number jumps investigator Michael Shadlen’s turn. A neurobiologist at the between three different keys, and it’s very fast. In the end, University of Washington in Seattle, Shadlen is at the the band opts for “Summertime” instead. Shadlen will have University of Cambridge on a one-year sabbatical to explore to wait for another day to play Coltrane and his own compo- decision making in the lab of computational neuroscientist sition, “No Say.” He doesn’t seem to mind, though, and he’s Daniel Wolpert. still on a high when he leaves the pub. “You get this commu- On his arrival last autumn, Shadlen picked up a city guide nication thing going through the music,” he says. and read about Monday nights at the Elm Tree. Jazz is one of —Laura Spinney his passions—he likes to play guitar and compose—so he checked it out the following week and is now a regular. “It’s “It’s a wonderful way to share a wonderful way to share a few hours with brothers and sisters who love this a few hours with brothers and brand of music,” he says, “It’s one of the most delightful and welcoming things sisters who love this brand about Cambridge.” of music. Shadlen is interested in how the brain decides and plans based on the informa- MICHAEL SHADLEN” Illustration: Arkle Peter Photo: Charles Peterson
4 h h m i b u l l e t i n | August 2oo8 Fish Out Of Water
You’re a 21-year-old college student mapping out a cycling vacation when write down the times he hoped to with four days to kill in France. You he stumbled on an article about cycling achieve. Instead, Nead set as his goal to could (a) drink Champagne on the fundraisers. That night he brainstormed make the finals of the Southeastern Champs-Élysées, (b) soak up the sun on the entire project. Conference Championships in the 200- the Riviera, or (c) ride your bicycle 400 Nead drafted letters to family, friends, yard and 400-yard individual medley, miles through unfamiliar countryside to teammates, and others he had met and the 200-yard backstroke. raise money for diabetes research. during a college career that included “I was more interested in how many University of Florida swimmer Kevin athletic and academic All-America points I could score for the team,” Nead—in France at the Institut Pasteur honors as well as numerous awards for Nead says. de Lille last year as part of the universi- community service and scholarship. He In the end, Nead achieved his goal, ty’s HHMI-funded Science for Life steered anyone interested to a blog he making a significant contribution to program—chose the third option and created on the Website of a Gainesville, the university’s second-place finish raised nearly $4,000 for the American Florida, newspaper. and recording personal bests in all Diabetes Association. By the time he climbed on his bike three events. From his broad shoulders and on August 1, Nead had thousands of Then, despite qualifying for the apparent lack of body fat, it’s clear dollars in commitments. Four days and Olympic Team Trials in two events, he Nead is no stranger to strenuous phys- 471 miles later, he arrived in Nantes, on retired. ical activity. As a member of his college the Atlantic coast, and boarded a train “I felt like ending my career with my swim team, he typically swims as much back to Lille, tired but triumphant. team was how I wanted to go out,” as 20,000 yards (over 11 miles) a day. The next week, it was back to work Nead says. So when his laboratory in Lille closed looking for genetic markers for diabetes. Although his collegiate swimming for a week last August, he decided to Though the cycling bug had bit, career has ended, Nead, who extended do something different. Nead wasn’t ready to hang up his his senior year to take an extra class, “Originally, I got on a bike when I customized orange and blue body suit has started a new research project with realized I couldn’t just go to a swim- just yet. When he returned to Florida in University of Florida diabetes ming pool whenever I wanted, like I can December, he dived back in the pool researcher Mark Atkinson and has here,” says the soft-spoken Nead as he with his teammates, doubling his daily begun applying to M.D./Ph.D. programs sits in the lobby of the University of workouts to regain his form as quickly around the country. Florida’s swimming and diving complex. as possible. And now that he’s mastered swim- Soon Nead was cycling hundreds of At a team meeting before the spring ming and cycling, he thinks he’ll try miles a week. He had already started season, each swimmer was asked to triathlons. —Joe Kays
While in France on a research fellowship, two-time Academic All-American swimmer Kevin Nead switched gears for a long-distance bike race to raise money for diabetes research. Daron Dean
August 2oo8 | h h m i b u l l e t i n 5 centrifuge
The Puzzle Champ
Thomas Snyder wears a collared shirt, khakis, and sneakers, looking like any other postdoc on the Stanford University campus. He confesses, though, that he has a very different team. “I didn’t even know I was that lab at Stanford. Snyder works on wardrobe in his closet at home—one good at it,” he says. He placed second fi nding ways to synthesize genes with devoted to sudoku. at the World Championship that year microfl uidics, a technology often His puzzle-based attire—bowling and won in 2007. called “lab on a chip” that uses tiny shirts, jackets, t-shirts—is a perk of Snyder can whip through an easy amounts of reagents to make the being on the U.S. sudoku team and the puzzle in less than one minute; the process fast and cheap. “Solving a reigning World Sudoku Champion. In hard ones might take all of three. He sudoku does something to make me April, he successfully defended his title has won prize money—$10,000 in the happy, but it’s not helping people in at the 2008 World Sudoku Championship U.S. National Sudoku Championship developing countries deal with in Goa, India, adding yet another t-shirt last October. Companies like Google malaria,” he says. “The kind of science and a couple of trophies to his stash. and the Philadelphia Inquirer sponsor we’re doing here in the lab may have Snyder, 28, began doing math and his travel to competitions. He gets those broad-reaching impacts.” logic puzzles as a child but discovered hired to test puzzles and he also The challenge of solving a new his special talent for sudoku just two creates them; his fi rst book, published puzzle is also what draws him to years ago. He’d been trying to get into this spring, features sudokus based on research. “What is the secret? Can I the World Puzzle Championship, which the classic board game Battleship. fi nd it?” he says. “[Sudoku] is kind of features all types of puzzles, with no But Snyder considers puzzle- like science in this way. You have a luck. In 2006, when they added sudoku solving a hobby. His fi rst priority is his bunch of approaches you can take to a to the offerings, Snyder tried out research as a bioengineering postdoc problem you don’t know how to solve online and earned a spot on the U.S. in HHMI investigator Stephen Quake’s yet, but eventually you’re going to fi nd something that starts to work, and then you’re going to build off that.” “The world’s getting quicker. Two years of competing helped Snyder keep his cool in Goa, where I might have to retire pretty soon fi nalists had to solve their puzzles on stage in front of an audience. “The and just start writing puzzles world’s getting quicker,” he smiles. “I for the competition. might have to retire pretty soon and just start writing puzzles for the THOMAS ”SNYDER competition.” —Corinna Wu Illustration: Arkle Peter Photo: Snyder Thomas
6 h h m i b u l l e t i n | August 2oo8 upfront
08 Group Dynamic An interdisciplinary team challenge may be the best way to prepare graduate students for today’s world of collaborative science.
10 Sunny Side Up Stepping out from a neighbor’s shadow is not always a good thing.
12 A Devil of a Problem Scientific sleuths are on the case of a rare kind of cancer that is decimating the population of Tasmanian devils.
Food shortages and endangered species—two hot- button issues being addressed by HHMI scientists who want to help the planet’s inhabitants survive and thrive. One researcher is looking for practical ways to boost crop yield amid escalating food shortages. Another scientist responded to his postdoctoral fellow’s passion for the furry inhabitants of her island home. With advanced techniques, his team may help reveal the genes behind a deadly form of cancer that is spreading quickly through a diminishing popu lation of Tasmanian devils. The animals have already survived one severe threat, and this research group is racing the clock to help them survive another one.
August 2oo8 | h h m i b u l l e t i n 7 upfront
Group Dynamic An interdisciplinary team challenge may be the best way to prepare graduate students for today’s world of collaborative science.
The third-floor lab of Byers Hall on the campus of the University of California, San Francisco (UCSF), is filling quickly. Even before teaching assistant Evelyn Chang arrives with a cart of pipettes and tried the particular redesign they’re having protein samples, one team of students commandeers the bench at the the students do. If any of the students’ designs are good enough, Narlikar has window. Soon, three other groups take up positions within shoving promised to build the molecules. distance of each other. ¶ Technically, this is the first day of spring break. Later that night, in the break room just outside the lab, one team has taken But this morning, the first-year graduate collaborate and helps them break down over a couch next to stacks of empty pizza students—all enrolled in the bioinformatics sociological barriers and form functional boxes, remnants of dinner. Laptops out, the and biophysics programs at UCSF— social networks. students are discussing strange results from assembled to hear about the exercise that “This is how science is done now,” says one of their experiments when a player from will occupy most of their waking hours for HHMI investigator Joe DeRisi, who devel- a competing team pops into the room. He the next week. The 19 students will use oped the training program with UCSF lets them know about a paper that might the equipment Chang just delivered to colleague and HHMI investigator David explain what they saw. analyze a set of mystery histones—proteins Agard. Interdisciplinary collaboration This kind of interaction is what really that help DNA compact in a cell’s nucleus. among scientists is answering questions excites the professors. Kortemme, who had In a nearby computer lab, they’ll use a in fields from neuroscience to aging to most of these students in a class the previous software program to model the large and genomics, and the program organizers are quarter, says the winter challenge they complex histone molecules and propose working to reinforce that concept. DeRisi did with DeRisi seemed to improve their ways for researchers to change a histone’s ran a similar challenge for the students classroom performance; they asked more structure and interaction with the DNA it during winter break. questions and helped each other more than helps compact—changes that might, for The students are doing real science. students in classes that hadn’t been through example, turn a gene from on to off. Assistant professor Geeta Narlikar, who the drill. The exercise, called a team challenge, designed the lab component, studies “Basically, they’d gotten comfortable is part of a new training program, 1 of 10 histones. Her colleague Tanja Kortemme, enough that there are now no stupid ques- funded by HHMI in conjunction with the who created the modeling component, is an tions, because everyone’s stupid at some National Institute of Biomedical Imaging expert in protein redesign. But no one has point,” she says. and Bioengineering that focuses on inter- disciplinary research. The bioinformatics and biophysics programs at UCSF accept “This is how science is students with undergraduate degrees in done now. biology, computer science, math, and physics. The team challenge exercise Joe DeRisi ”
forces students with different expertise to George Nikitin ©HHMI / AP,
8 h h m i b u l l e t i n | August 2008 And, everyone’s expertise matters at who have expertise in those areas—scientists (It hadn’t.) They also borrowed electro- some point. Charlie Kehoe, who has a with whom he might someday collaborate. phoresis gels from a different lab to help master’s degree in engineering from the On Friday evening, when the four teams determine the size of the proteins, as did Massachusetts Institute of Technology and assemble to present their results, the teachers some of the other groups. spent two years at Amazon.com, Inc., before get a chance to learn just how collaborative After the presentations wrap up, the half coming to UCSF, says that two quarters of their students have become. Each team dozen faculty members who have come out biology coursework didn’t give him the same found that one of the histone samples didn’t to watch gather in the hall to discuss the level of “biological intuition” as his team- behave as expected when analyzed with the projects. DeRisi is particularly impressed mates who have biology degrees, but he’s protocol their professors had suggested. with the creativity and resourcefulness good at figuring out what kinds of problems “Something was going wrong, we weren’t of their approach, and several faculty say are amenable to computational solutions. seeing any noticeable binding events,” says they plan to try some of the students’ George Masologites, a biologist by training Masologites, describing the reaction that workarounds in their own labs. The actual and Kehoe’s teammate, wants to do experi- should have helped them analyze their results aren’t bad, either. Kortemme got far mental research, but he’s already worked in sample—if it had worked. So they arranged more plausible design proposals than she a computational lab at UCSF because, he to borrow time on a high-end spectrometry expected. So many, in fact, that she and says, he wants to better understand how those instrument that belongs to another professor, Narlikar need more time to analyze them labs approach questions. Just as important, which allowed them to test whether the before they pick the best of the best to build.
Holly Wales / zeegenrush.com Holly Wales he wants to forge relationships with scientists protein had unfolded from its normal shape. p —Robin Mejia
August 2008 | h h m i b u l l e t i n 9 upfront
Sunny Side Up Stepping out from a neighbor’s shadow is not always a good thing.
Joanne Chory uses genetics to study how plants respond to changes in their environments—from predictable cycles of day “There’s a lot of stuff that a plant and night to unwanted shade and global warming. gives up just so it can get up there, above its competitors.
Joanne” Chory Lamont Jeffrey Brown
10 h h m i b u l l e t i n | August 2008 i T ’s a concep t t h at every kindergar t n e r u n d e r s ta n d s a f t e r watching a seed sprout roots and shoot a stem out of a paper cup, reaching toward the sun. But plant researchers have struggled to identify the molecular pathway that explains this elementary phenomenon— that plants will do anything to get some extra rays of light. Recently, named the enzyme after its function—TAA1, for tryptophan aminotransferase of HHMI investigator Joanne Chory at the Salk Institute for Biological Arabidopsis. The results appeared in the Studies has begun to lead the way out of the shadows. ¶ By studying the April 4, 2008, issue of Cell. “In the shade, wild-type plants make more interactions between plants and their envi- in complete darkness, reasoning that abnor- auxin,” Chory explains. “It seems that sav3 ronment, Chory observes how plants respond malities in these two settings would likely plants can’t do that.” TAA1, they found, is to shade as well as to changes in water, day mean the plants lacked the ability to elon- integral to the synthesis of auxin that’s trig- length, and temperature. She studies gate. Their screen revealed mutations in a gered by plant shade. Arabidopsis—a small flowering mustard number of genes that seemed to be involved Studying the genes and proteins that plant that is a favorite among biologists specifically in shade avoidance, and they cause shade avoidance could help plant biol- because of its fully sequenced genome and focused on one—dubbed sav3 (shade avoid- ogists eventually create plants that don’t avoid easy-to-observe growth changes. ance 3). In the shade, sav3 mutants look like shade, she says. These plants would still need Chory and colleagues recently uncovered they’re growing in bright light—they are light but wouldn’t overreact to just a little a new pathway that is activated when a plant shorter, darker green, and have fuller leaves shade. Instead, they would be green, lush, wants to outgrow an encroaching neighbor. than the nonmutant, or wild type, Arabidopsis and healthy even in crowded conditions. Understanding this chain of events, which seedlings grown in the shade. “In modern agriculture, farmers sow researchers call “shade avoidance syndrome,” After isolating the normal version of this crops very densely,” she explains. “The could help scientists engineer food crops that gene, Tao pinpointed its protein product and plants are always shading each other.” While survive in crowded fields, where plants over- began exploring its function. Realizing the healthy competition is a good thing when it shadow each other. protein was an enzyme that catalyzes changes comes to the natural selection of plants over For a plant, the consequences of shade to small molecules such as amino acids, Tao time, a constant state of shade avoidance is are drastic. Desperate for sunlight and and Chory turned to Salk colleague, HHMI not good because shaded plants produce striving to outgrow its neighbors, a plant’s investigator Joseph P. Noel, an expert in fewer seeds, says Chory. “If the seed is what reaction upon sensing the specific type of determining the function of plant enzymes. you’re eating—like rice—there will be loss shade caused by other plants (plants reflect Noel and Chory reasoned that the enzyme of yield.” far-red light and absorb red light, so their might be involved in the biosynthesis of Yield is becoming increasingly important, shade is low in red light) is to grow straight auxin, a hormone other studies have hinted says Chory, noting that by 2050 the world up, as fast as possible. The plant directs plays a role in shade avoidance. population is projected to exceed 9 billion. most of its energy into stem growth, sacri- Their instincts were right. A series of “It’s all about sustainability,” she says. “You ficing other important activities: leaf growth, experiments revealed that the sav3 plants have to feed all these people, plus today food root development, seed production, and made less auxin, and that adding auxin crops have to compete with energy crops.” p immune function. allowed them to shoot up in the shade. They —Sarah C.P. Williams “There’s a lot of stuff that a plant gives up just so it can get up there, above its competi- tors,” says Chory. The seedlings that have A Deliberate Response been shaded are tall, but unusually skinny with dwarfed, pale leaves. While a plant’s response to shade is quick— it only takes an hour for changes to begin—a plant To find out what molecules might guide takes its time to respond to other environmental cues, and with good reason, says HHMI this growth pattern, Yi Tao, a postdoctoral investigator Joanne Chory. “If a cloud comes over and you’re a plant, do you want to start researcher in Chory’s group, set up a genetic behaving like it’s night? No. If there’s a lightning flash in the middle of the night do you want to start behaving like it’s day? No.” In a paper published in February in PLoS Genetics, Chory screen for mutations that would stop plants and colleagues revealed new information about how plants turn on different sets of genes at from shade-induced gangliness. They looked different times of the day and night, by slowly taking into account their environment. They for plants that didn’t grow in simulated shade found that a full 89 percent of Arabidopsis genes cycle in response to temperature, light, and but that grew normally under full light and circadian variations throughout a 24-hour cycle.
August 2008 | h h m i b u l l e t i n 11 upfront
A Devil of a Problem Scientific sleuths are on the case of a rare kind of cancer that is decimating the population of Tasmanian devils.
The Tasmanian devil has none of the attributes that draw millions to the cause of an endangered species. Though related to the koala, the badger-sized creature is not exactly soft and cuddly. A scavenging marsu- pial, it has a mouth that opens wide, revealing a long fleshy tongue and tumor is treating the entire population frightfully sharp canine teeth, which it puts to good use in middle-of- almost as if it were a single organism.” An the-night tussles with neighboring devils over scraps of road kill. outward feature of the tumors gives a clue to their mode of transmission. The growths During those nocturnal food fights, the The cancer, dubbed devil facial tumor are scaly, and cells can detach readily devil emits its signature “vocalization”—a disease (DFTD), has since spread like an when, for instance, devils fight over food bone-chilling howl-retch that brings to mind, infection, radiating west and south from its or mates. Scientists are now convinced that all at once, a mountain lion’s growl, a snake’s point of origin and claiming up to half of DFTD spreads when an unaffected devil hiss, and a chronic bronchial patient’s early- Tasmania’s devil population, estimated at bites an infected one and dislodged tumor morning throat-clearing. 150,000 before DFTD’s first appearance. cells are absorbed into the bloodstream The fighting that characterizes relations “It’s remarkable to think that all of this from saliva. among the normally solitary devils is more has happened within my lifetime, while I Researchers in Australia have discov- than a curiosity. It’s thought to be respon- was growing up in Tasmania,” says Elizabeth ered that tumors from different Tasmanian sible for the spread of a deadly disease that Murchison, a postdoc in Hannon’s lab devils are genetically identical—clones of has placed Tasmania’s largest remaining who brought the devil’s plight to his atten- one another. The secret of their seemingly marsupial carnivore on the road to extinc- tion several years ago. Murchison and an unfettered journey through the population tion and has cast HHMI investigator Gregory Australian veterinarian and doctoral candi- was the question addressed last year by an J. Hannon and colleagues at Cold Spring date, Hannah Bender, now spearhead an HHMI-supported summer intern working Harbor Laboratory on Long Island, New effort in the lab to characterize the tumors in Hannon’s lab. York, in the role of genomic detectives. associated with DFTD. Karla Claudio Campos, from Puerto A dozen years ago, a wildlife photogra- They want to know how the tumors Rico, examined mitochondria—organ- pher returned from a foray in Tasmania—a spread—not just in individual animals, but elles in the cell best known for their role West Virginia-sized island just off the south- throughout the species. Says Hannon: “The in generating energy for biochemical eastern tip of Australia—with pictures of a devil that many found hard to look at. A grotesque series of tumors had virtually “The tumor is treating the entire consumed the little creature’s face, covering population almost as if it were a its mouth and preventing it from feeding. In single organism. the following months, more animals with similar facial tumors were reported. Greg Hannon ” Zack Seckler ©HHMI / AP,
12 h h m i b u l l e t i n | August 2008 The tumor transcriptome will position the team to find genes that contribute to tumor formation. The key, says Hannon, is in “making comparisons to known networks of oncogenes and suppressor genes in tumors that have been carefully characterized in previous work.” More broadly, he notes, understanding something of devil genomics might support selective breeding of captive animals; this would enable wildlife biolo- gists to maintain maximum diversity in an “insurance population” raised against the Nocturnal scavengers by nature, Tasmanian devils show agression only during communal possibility of eradication. feeding—usually as a bluff, to minimize fighting and establish dominance. There is hope, however, that work in Hannon’s lab and elsewhere will contribute processes. Mitochondria have their own left the devil’s immune system wide open to to an effective treatment strategy in the 20- to genomes, distinct from the genetic mate- an insidious invader like DFTD. 30-year window before the wild devil popu- rial compressed in the cell nucleus, that Hannon’s group is using advanced tech- lation is consumed by DFTD. “We lost the are inherited exclusively from the mother. nologies to learn more about the tumors’ thylacine, or Tasmanian tiger—a striped, Hence, mitochondrial genomes can be characteristic “transcriptome”—the readout dog-sized marsupial carnivore—in the used to trace matrilineal descent. Claudio’s of all the genes expressed in any given tissue 1930s,” says Murchison. “The devils occupy study of mitochondria sampled from devil type. In particular, Murchison and Bender an ecological niche that’s absolutely critical tissues revealed almost no genetic diversity have been using techniques developed by because of the tiger’s extinction. To lose in the animals. Hannon and colleagues to characterize the them as well would be a devastating loss of At some point in recent history, the devil population of small RNAs—a class of gene- species diversity, not only for Tasmania but population evidently came under severe regulating molecules characterized through for all of us.” p – Peter Tarr threat and was nearly extinguished. While Hannon’s pioneering efforts—in tumor-
the species recovered, the surviving popu- laden devil tissue samples. This method FOR MORE INFORMATION: To view the Tasmanian devil on lation is dangerously inbred. It is widely “can give us a signature of cell-type identity,” video and hear its vocalizations, visit www.parks.tas.gov.au/wildlife/mammals/devil.html.
Tim Dub Tim Dub suspected that a lack of genetic diversity has Hannon explains.
August 2008 | h h m i b u l l e t i n 13
Photo: TK Scientists areapplyingthetoolsandapproaches of engineeringtosolvesomepracticalproblems and fathomthebasicnatureofthings. by BenjaminLester|illustrationJoshCochran August 2008 August
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n i t e l l u b 15 When Intel comes out with a new micro- apparatus, or manufacturing processes.... By that credo, engi- processor, its competitors’ inquisitive neering serves not to expand the boundaries of knowledge but rather as the link between existing scientific discovery and tech- engineers soon have that chip under a nological benefit. microscope, figuring out how the device But Chklovskii and others see engineering as a broader set of works by tracing the patterns of transistors ideals: simplicity, practicality, systematic thinking, and the idea on its surface. Dmitri Chklovskii, a group that understanding a thing—or a process or a cell—isn’t ensured until that thing can be built. leader at HHMI’s Janelia Farm Research The line between science and engineering is blurring as engi- Campus, is applying much the same tech- neers and tool makers set their sights—and their engineering nique to fruit flies. minds—on unanswered biological questions, both as a means to solve practical problems and because they too are fascinated by His colleagues dissect the flies’ brains, 50 nanometers at a the basic nature of life. And biomedical researchers, those who time. “It’s like slicing prosciutto,” he says. Extremely thin are after practical solutions to disease and those who seek to push prosciutto—1/1,000th the thickness of a human hair. Each slice the boundaries of knowledge, are reaching over and borrowing reveals a new layer of neurons and synapses, which are carefully techniques and ideals from the engineers’ toolbox. photographed with an electron microscope. Later, Chklovskii’s Rebecca Richards-Kortum, an HHMI professor and biomed- team uses computers to trace each neuron’s axon and dendrites ical engineer at Rice University, sees science and engineering as they snake through the brain. along a spectrum. “At one end, there is pure science, where we Chklovskii is using computer algorithms to trace neural just want to understand how the world works, and at the other is networks, and he thinks the principle of economy underlying pure engineering where we just want to solve a problem like ‘I microchip design may also govern the “wiring” of a neural need a rapid test for HIV that’s 99 percent accurate and costs less network. Nature and microchip engineers may be working from than a dollar.’” There’s a lot of overlap among individual the same playbook. researchers, she says. With its neuroscience focus and interdisciplinary character, Janelia Farm is a perfect place for Chklovskii, who was trained as Eminently Practical a theoretical physicist and is now working to understand how the hhmi investigator kristi anseth has at the root of brain functions. “I consider myself a neurobiologist because I all her endeavors a fundamental question: how does a cell get publish in neurobiology journals and go to neurobiology confer- information from its surrounding environment? But she has ences,” he says. “But I try to think like an engineer.” ambitious practical applications for her findings. What does it mean to think like an engineer? In some circles, “I want to design materials that I can use to culture cells”— engineering is linked to the quest to build things and solve prac- cells for use in reconstructing damaged tissues, such as knees tical problems—for example, putting a man on the moon. ABET, and hearts, says the chemical engineer at the University of Inc., formerly known as the Engineers’ Council for Professional Colorado at Boulder. Development, has defined the discipline as:the creative application It is not yet possible to grow new tissues in a dish. A bit of of scientific principles to design or develop structures, machines, structural engineering is necessary. Anseth creates an artificial
Chklovskii and others see engineering as a broader set of ideals: simplicity, practicality, systematic thinking, and the idea that understanding a thing—or a process or a cell—isn’t ensured until that thing can be built.
16 h h m i b u l l e t i n | August 2008 diseases of the heart. “We’re learning about cells in heart valves and A replacement heart valve that expands as a child grows is one of what goes wrong that leads to these valve defects,” she says. “Once Kristi Anseth’s engineering aims. Dmitri Chklovskii wants to know if we understand what cues may be used to reverse this process, we neural networks follow the same design logic as microchips. can try to regenerate and grow healthy valve structures.” Robert Sah, an HHMI professor at the University of California, scaffold that supports cells from her patients while delivering the San Diego (UCSD), wants to create whole replacement joints— proper molecules to encourage growth. The crux of the problem bone, cartilage, and all—outside the body that can then be is figuring out what signaling molecules are needed—and the surgically implanted into patients with osteoarthritis. answer varies, depending on the tissue being regenerated. The vastness of the problem is one of the things that appeals According to Anseth, with such a complex subject, it’s easy to to Sah, who runs the UCSD cartilage tissue engineering labora- get overwhelmed. “You can’t understand every pathway within tory. “Theories of many materials and systems are very simple the cell, let alone what happens to that cell when it interacts and predictable in terms of the phenomena underlying them— with other cells,” she says. one electrical circuit component can be made almost the same She uses her engineer’s training to reduce the scope of the as the next,” he says. “In biology, it’s orders of magnitude more problem. “I look at a complicated problem where we don’t have difficult to [develop] useful quantitative theories.” The engi- enough information,” she says, “and I try to figure out what’s the neering approach works well, he says, because engineers critical information, and make a judgment that’s 90 percent disregard the information they don’t need. “Engineers reduce a correct.” In most cases, Anseth says, that approach is enough to model to its essential components,” he says. learn what she needs and move forward. In one project, she is To fashion his biological joints, Sah needs to answer some building a replacement heart valve for children with congenital fundamental scientific questions. “We need to understand the valve defects. “There’s no good option for them right now,” she says. physiology of the joint. How is the joint lubricant made and “Most treatments require many surgeries because the children are maintained? How do mechanical forces cause wear and tear or growing so fast. If we could create a living, reengineered valve struc- induce biological responses that may be healthy or damaging?” ture that could grow with a child, that would have lots of benefits.” he says. “During the past decades, scientists and engineers have Anseth is not tackling the complex problem on her own: her worked on the individual pieces, and now some of us are trying
Anseth: Brigid McAuliffe Fetters Chklovskii: Paul team is collaborating with molecular biologists who specialize in to put them all together.”
August 2008 | h h m i b u l l e t i n 17 Loren Looger is motivated by the audacity of his plan: to redesign the way we think. For Robert Sah, it’s the remarkably practical: to engineer biological replacement joints.
Grasping the Fundamentals anseth and sah are engineers by training, and they seek answers to basic scientific questions as a way to solve prac- tical medical problems. But there are scientists looking through the binoculars from the other end, borrowing engineering The purely practical applications that follow, says Baker, can methods to improve their grasp of fundamental concepts— be handled by others. For the past few years, he has run the sometimes along the way they address practical problems, but calculations necessary to predict protein shape with help from that’s a secondary benefit. the computers of laypeople around the world. The distributed At the University of Washington (UW), HHMI investigator computing network is called Rosetta@home and has more than David Baker is fascinated by how the amino acid chains that 200,000 members from all walks of life. Now, Baker and his make up proteins fold into the specific three-dimensional shapes colleagues at UW have devised a multiplayer game for them that allow them to function. In nature, proteins always fold into called Foldit. Players score points for folding amino acid the most thermodynamically stable shape—spontaneously and sequences into the most stable shapes. Later this year, the Foldit rapidly—and Baker is trying to mimic the process on computers. team plans to introduce a design element to allow players to He compared his predictions with data from direct methods of create brand new proteins. The design game aims to turn people structure determination, such as x-ray crystallography. “That was all over the world into competitive molecular engineers. “I a way of testing our understanding of the process,” he says. imagine a 12-year-old in Indonesia who can visualize proteins in Once passing that way station, “we realized that another, just as his head and build a cure for HIV,” Baker says. stringent, challenge was to design new protein structures by Like Baker, Loren Looger, a group leader at Janelia Farm, changing the sequences or coming up with new sequences,” he says. likes to build. At the moment, Looger thinks of his lab as a one- “One of the best tests of understanding is building something.” stop tool shop for his colleagues at Janelia—making new Baker admits to seeing the practical side of his work. “I’m very molecules to assist their research. “People want sensors for all the interested in creating new enzymes to do useful things, which is hot neurotransmitters—serotonin, GABA, glutamate, dopamine,” pretty much an engineering problem,” he says. For example, one he says. “We also make brighter fluorescent proteins, and fluores- of his students is developing an enzyme that can turn carbon cent proteins that can switch colors. Those are useful for different
dioxide—CO2—into sugar, possibly helping to reduce greenhouse modes of imaging.” gases. Other conceivable applications for new enzymes include According to Looger, whose training is in math, synthetic chem- proteins that could speed up pharmaceutical manufacturing or istry, and computer science, making sensors and fluorescent other industrial processes. Baker makes the point, though, that proteins isn’t exactly easy, but “it’s pretty obvious what needs to be while these are problems with eminently practical goals, he’s not done.” In a year or so, after he’s taken care of his colleagues’ pressing tackling them for practicality’s sake. Instead, he hopes to use the needs, Looger plans to turn his prowess in manipulating molecules process of building enzymes as a way to learn more about the to the wiring of neurons. “We’ll start to swing the pendulum back
fundamental principles that govern how they work. toward crazier things, like getting inside neurons and whole-scale Looger: Barbara Ries Sah: Fred Greaves ©HHMI / AP,
18 h h m i b u l l e t i n | August 2008 Following her Obsession the maltose transporter puts Chen’s lab at the leading edge of Jue Chen risked getting nowhere. Chen, a structural biologist the ABC transporter field. who resolves the shape of biologically important molecules by Carlos Brody risked his scientific reputation, and possibly his x-ray crystallography, launched her career at Purdue University dignity. Brody was a computational neuroscientist at Princeton on a long shot. Chen admits that for seven years she was obsessed University, adept at extracting patterns and building mathemati- with the maltose ABC transporter, a mysterious but powerful cal models based on raw data from laboratory experiments. His protein complex that ferries sugar molecules through the cell problem was how individual neurons in the prefrontal cortex membrane to the cell’s interior. Biochemists and geneticists had flip from short-term memory storage to instant decision making. stacked up data for decades that gave them an excellent idea of Brody began building a mathematical model of neural firing what the maltose ABC transporter should be doing, yet no one patterns based on data from monkeys that had been labori- had ever produced atom-by-atom images of the transporter in ously taught a memory-versus-decision game. To test his model, action. When Chen arrived at her first faculty position at Brody needed more data, but the cost and effort of caring Purdue, she made that her goal. Her scientific mentors were for and training monkeys was prohibitive. So he shifted gears worried. The maltose transporter might be too narrow a target. and set up his own rat lab. It involved all the paraphernalia of One warned that, as a junior researcher, Chen could be “betting animal work—cages, care guidelines, and neural wiring harness the farm” on a problem that was beyond current technology. equipment—the kind of bulky equipment that makes most She listened to their advice but stayed the course. In a 2007 computational scientists grateful for having their lab in a laptop. article in Nature, Chen and colleagues published their com- But Brody wanted lots of data from lots of properly trained plete solution of the maltose ABC transporter. Looking back, rats. He designed a computer-run rat academy that could teach Chen says that it wasn’t obstinacy or the chance of having a 20 animals at a time how to remember two differently pitched high-profile publication that motivated her. “I was doing this tones and then decide which way to turn for a reward that came because I was just so interested in the molecule,” she recalls. with the higher-pitched correct answer. With his HHMI investiga- “I told people that I was obsessed. I just had to see it.” Solving tor status in hand, Brody will finally test his mathematical model
Zhe Lu, M.D., Jay T. Groves, Jack Taunton, Wendell A. Lim, Carlos D. Brody, Yang Dan, Ph.D. Christopher J. Ph.D. (15) Ph.D. (16) Ph.D. (17) Ph.D. (18) Ph.D. (19) (20) Chang, Ph.D. (21) University of University of University of University of Princeton University University of University of Pennsylvania School California, Berkeley California, California, California, Berkeley California, Berkeley of Medicine San Francisco San Francisco
Massimo Bernardo L. Mark J. Schnitzer, Leslie B. Vosshall, L. René García, Samuel L. Pfaff, Kang Shen, Ph.D. Scanziani, Ph.D Sabatini, M.D., Ph.D. (24) Ph.D. (25) Ph.D. (26) Ph.D. (27) (28) (22) Ph.D. (23) Stanford University Rockefeller University Texas A&M The Salk Institute Stanford University University of Harvard Medical University for Biological Studies California, School San Diego Lu: Joseph Lu: Kaczmarek Joseph ©HHMI / AP, Groves: Noah Berger ©HHMI George / Nikitin AP, ©HHMI Taunton: / AP, Lim: George Nikitin ©HHMI / AP, Brody: Christopher Barth ©HHMI / AP, Dan: Noah Berger ©HHMI / AP, Chang: Noah Berger ©HHMI / AP, Scanziani: ©HHMI / Denis AP, Poroy B. Sabatini: Robert E. Klein ©HHMI / AP, Schnitzer: George Nikitin ©HHMI / AP, Allan Zepeda ©HHMI / Vosshall: AP, Garcia: Michael ©HHMI Stravato / ©HHMI AP, / Denis Pfaff: AP, Poroy Shen: George Nikitin ©HHMI / AP,
August 2008 | h h m i b u l l e t i n 23 against neuronal patterning data collected from his educated
Opening the Doors Wider rats. Even Brody seems a little startled by his hands-on daring. “In retrospect, it was totally crazy but it seems to be working With this latest round of investigator appointments, HHMI out,” he allows. broadened its talent search. For the first time, HHMI al- Risk is integral to the HHMI investigator program, which lowed faculty with 4 to 10 years experience at more than has always pursued a strategy of funding “people, not projects.” 200 American research institutions to apply directly rather than wait to be nominated by their institutions. The HHMI investigators are given the freedom and flexibility to open process produced a field of 1,076 applicants from follow their ideas where they lead to make “fundamental discov- which the 56 new investigators were chosen. Seven are eries of lasting scientific value and benefit to humanity.”
from institutions that never had an HHMI investigator be- fore: the Aaron Diamond AIDS Research Center, Boston Toppling Stereotypes University, Cornell University–Ithaca, Purdue University, And, as with the existing cadre of investigators, this new group Texas A&M University, Cincinnati Children’s Hospital Medical Center, and the University of Texas at Austin. The challenges many commonplace myths about how science works: new investigators—among them, individuals who got their Scientists have one-track minds and one-track careers: HHMI start in Argentina, Italy, Belgium, China, Israel, and the investigator Michael Eisen has racked up material for four Netherlands—are also branching out into areas that are careers. In 1996, he went from his Harvard Ph.D. commence- newer to HHMI, including bioengineering, synthetic biol- ment to the play-by-play announcer’s booth for the Columbia ogy, and the ecology of infectious diseases. Mules, a minor league baseball team in Columbia, Tennessee. Summer over, Eisen went back to science for a postdoctoral fellowship at Stanford where he helped HHMI investigator Patrick O. Brown perfect the DNA microarray “chip,” now a fundamental tool of the modern laboratory. In 2001, Eisen became a publisher and a cofounder, with Brown and Nobel
David L. Stern, Erich D. Jarvis, John V. Moran, Jonathan K. Michael B. Eisen, Seung K. Kim, Leonid Kruglyak, Ph.D. (29) Ph.D. (30) Ph.D. (31) Pritchard, Ph.D. Ph.D. (33) M.D., Ph.D. (34) Ph.D. (35) Princeton University Duke University University of (32) University of Stanford University Princeton University Medical Center Michigan University of California, Berkeley Chicago
Mercedes Pascual, Paul D. Bieniasz, Dianne K. Duojia Pan, Ph.D. Phillip A. Darrell J. Irvine, Lora V. Hooper, Ph.D. (36) Ph.D. (37) Newman, Ph.D. (39) Newmark, Ph.D. Ph.D. (41) Ph.D. (42) University of Aaron Diamond (38) Johns Hopkins (40) Massachusetts University of Texas Michigan AIDS Research Massachusetts University University of Illinois Institute Southwestern Medical Center Institute at Urbana- of Technology Center at Dallas of Technology Champaign Stern: Christopher Barth ©HHMI / ©HHMI Fredin / AP, Jonathan Jarvis: AP, Moran: Mark Bialek ©HHMI / AP, Pritchard: Aynsley Floyd ©HHMI / AP, Eisen: Noah Berger ©HHMI / AP, Kim: George Nikitin ©HHMI / AP, Kruglyak: Christopher Barth ©HHMI / Mark AP, Bialek Pascual: ©HHMI / AP, Bieniasz: Allan Zepeda ©HHMI / AP, Newman: Robert E. Klein ©HHMI / AP, Steve Ruark Pan: ©HHMI / AP, Newmark: Darell Hoemann ©HHMI / AP, Irvine: Robert E. Klein ©HHMI / AP, Hooper: Amy Gutierrez ©HHMI / AP,
24 h h m i b u l l e t i n | August 2008 By John Fleischman illustration by Peter Arkle
HHMI’s newest investigators are willing to sidle up to risk. Their approaches to research—and life—dispel many of the myths about Seung K. Kim grew up in upstate New York loaded insects and their innards to self-experiments; yet, mod- the lone, detached scientist. reading about the lives of the great microbe ern researchers face their own set of hazards. They risk being hunters like Louis Pasteur, Paul Ehrlich, and Robert wrong. They risk a long education on a short career in a blind alley. They risk missing the big discovery. But when those risks /B==:2@7D3<@3D=:CB7=< Koch. The excitement never left him. “In college,” pay off … the results can be stunning. =QQOaW]\OZZgbVSb]]ZaPcWZbb][OYSO\ ag\bVSaWa´bVSaSO`SbVSb]]ZabVObOZZ]e RWaVbVObQO\[W[WQbVSRg\O[WQ[Ob`Wf Kim recalls, “I read the textbook Molecular Seung Kim risked starting from the wrong premise. He probes Sf^S`W[S\b^]aaWPZSObbOW\aWU\WTWQO\QS ZWTSaQWS\bWabab]R]bVSW`e]`Y¶VSaOga Pgbc`\W\UbVSaWU\OZW\U[]ZSQcZSaQOZZSR Genetics by Stent and Calendar like an adventure the developmental roots of diabetes by studying the progenitor TO`PSg]\RbVSSf^S`W[S\bbVOba^Oe\SR ;`YaWQVWaabcRgW\UbVSW\bS`^ZOgPS ZWUO\Ra]\O\R]TT BVSS\UW\SS`SRac` bVSW`Q`SObW]\ beSS\QSZZaO\RbVSSfb`OQSZZcZO`[Ob`Wf TOQSQ]\aWaba]TOUZOaaaZWRSQ]ObSReWbVO story whose heroes were all scientists.” cells that differentiate into insulin-producing islet cells. In the ;WZO\;`YaWQVZ]dSa^]W\bW\UbVWa]cb ]T^`]bSW\abVObac``]c\RabVS[ac^ ZOgS`]TU]ZRbVW\S\]cUVb]PSb`O\a^O` In June, Kim, a developmental biologist at Stanford Univer- human pancreas, these islet cells measure glucose levels and µ
rewiring,” he says. “There’s that idiom that you don’t really under- don’t optimize their length, you can’t fit a significant circuit on a stand a system until you can redesign how it works.” chip of a limited size.” In his drive to test his understanding of how neurons func- Testing the wiring economy principle on the scale of a whole tion, Looger will change the sequence of amino acids in neuronal brain in fact involves borrowing the tools of a microchip engi- proteins, basically reengineering the proteins that control the neer: tracing every nerve connection in an organism’s nervous add way neurons communicate. “That work is mainly driven by curi- system, then feeding the connection data into a computer and osity … the sheer audacity of trying to redesign the way we comparing its “optimal” layout with the reality of what’s there. think,” he says. A complete wiring diagram for an organism didn’t exist until David C. Chan, Jeffery D. Andrew Dillin, Yigong Shi, Tanya T. Paull, Thomas Walz, Michelle D. Wang, Chklovskii’s group created one by finalizing a partially completed, M.D., Ph.D. (1) Molkentin, Ph.D. (3) Ph.D. (4) Ph.D. (5) Ph.D. (6) Ph.D. (7) Principles of Economy decades-old schematic for a roundworm called Caenorhabditis California Institute Ph.D. (2) The Salk Institute Princeton University University of Harvard Medical Cornell University of Technology University of for Biological Studies Texas at Austin School down the hall from loren looger’s office at janelia elegans, whose 302 neurons make it easy to map. The diagram was Cincinnati College Farm, Dmitri Chklovskii is looking for simple engineering prin- started by Nobel laureate and Janelia Farm senior fellow Sydney of Medicine ciples in the dizzying structure of neural networks. Brenner, who first realized the worm’s potential as a model Chklovskii is investigating a century-old tenet called “the organism. Using the roundworm diagram, the team tested the wiring economy principle.” The idea was formulated by Santiago economy principle. “In most situations, we were able to predict Ramón y Cajal, a Spaniard who won the 1906 Nobel Prize in neuronal locations pretty well,” Chklovskii says, “but some were Physiology or Medicine for his work on the structure of the way off. Some neurons [didn’t] fit into the optimization scheme.” nervous system. Identifying the discrepancies between the wiring economy prin- Ramón y Cajal believed that evolution would act to reduce ciple and real brain wiring is helping Chklovskii refine his the length of connections between neurons to conserve energy thinking about the principles that govern neuronal circuitry. Hongtao Yu, Danesh Moazed, Abby F. Dernburg, Scott Keeney, David S. Pellman, Michele Pagano, Michael B. Elowitz, and materials. The same principle is a key part of microchip The project served as a warm-up for his team’s Drosophila Ph.D. (8) Ph.D. (9) Ph.D. (10) Ph.D. (11) M.D. (12) M.D. (13) Ph.D. (14) University of Texas Harvard Medical University of Memorial Dana-Farber New York University California Institute design: fitting transistors close together on chips allows engineers endeavor, which entails mapping connections among more than Southwestern School California, Berkeley Sloan-Kettering Cancer Institute School of Medicine of Technology to reduce the distance electrons must travel along wires, thereby 250,000 neurons. “The idea is not just to get the structure of the Medical Center at Cancer Center Dallas increasing processing speed. In addition, says Chklovskii, “wires neuronal circuit, but to be able to infer function—to understand
Chan: Jill Connelly ©HHMI / AP, Molkentin: David Kohl ©HHMI / AP, Dillin: ©HHMI / Denis AP, Poroy Shi: Christopher Barth Plunkett ©HHMI / ©HHMI / Jack AP, AP, Paull: Robert E. Klein Kevin Rivoli Walz: ©HHMI / ©HHMI Amy / AP, Gutierrez AP, Wang: ©HHMI Yu: / AP, Moazed: Robert E. Klein ©HHMI / AP, Dernburg: Noah Berger ©HHMI / AP, Keeney: Allan Zepeda ©HHMI / AP, Robert Pellman: E. Klein Allan ©HHMI / Zepeda ©HHMI AP, / Pagano: AP, Elowitz: Jill Connelly ©HHMI / AP, are mostly what take up the room on a computer chip. If you how the brain works,” he says. . open here 56
22 h h m i b u l l e t i n | August 2008 August 2008 | HHMI BULLETIN '
Prize winner Harold Varmus, of the Public Library of Science that successfully destroyed his tumor worked by attacking the (PLoS), the flagship of the “open access” journal movement. At DNA of fast-growing cancer cells. But all such drugs inflict the University of California, Berkeley, Eisen has been building collateral DNA damage in nearby noncancerous cells, raising his own cross-disciplinary lab since 2000, bringing together the risk for new tumors. More than five years later, Keeney is geneticists, biochemists, molecular and cell biologists, ecologists, cancer-free but acutely conscious of how his health and his and computer scientists to explore development and evolution. research are bound up in DNA. Scientists come from science backgrounds: HHMI investigator Science is a solitary profession: HHMI investigator Ning Erich Jarvis grew up under difficult family circumstances in Har- Zheng is a structural biologist at the University of Washington lem but blossomed as a dance student in New York’s famed High in Seattle. One night, Zheng was hunched over his computer, School of Performing Arts. He turned down an audition for the stymied by an unrecognizable compound at the heart of a key nationally renowned Alvin Ailey Dance Theater, however, to study receptor molecule that regulates growth in plants, when his father molecular biology at Hunter College and neurobiology at the called. “I told him we had this structure we couldn’t explain, and Rockefeller University. As an HHMI investigator at Duke Universi- he asked me to describe it,” the younger Zheng remembers. Over ty, Jarvis will continue his epochal work on using songbirds to study the phone, the elder Zheng, a retired biochemist in China, the molecular pathways of learning and the evolution of speech. immediately recognized the compound as the natural alcohol, Scientists must be aloof from human suffering: HHMI inositol phosphate. His son listed him as a coauthor on the 2007 investigator Scott Keeney is a biochemist at Memorial Sloan- paper that landed on the cover of Nature, surely the ultimate Kettering Cancer Center with a highly personal stake in his “Thanks, Dad.” field: the toughness and fragility of DNA. Keeney studies how Scientists have no life outside the lab: HHMI investigator reproductive germ cells undergoing meiosis—the duplication Grant Jensen is a structural biologist at the California Institute and segregation of sex cells into half-sets of genes—damage and of Technology who is pioneering a new microscope technology repair their own DNA. When he was 35, Keeney was knocked called electron cryotomography. It combines an electron flat by a germ cell tumor growing under his sternum. The drugs (continued on page 56)
Wilfred A. van Sangeeta N. David M. Sabatini, James J. Collins, Ning Zheng, Phillip D. Adrian R. Ferré- der Donk, Ph.D. Bhatia, M.D., M.D., Ph.D. (45) Ph.D. (46) Ph.D. (47) Zamore, D’Amaré, Ph.D. (43) Ph.D. (44) MIT-Whitehead Boston University University of Ph.D. (48) (49) University of Illinois Massachusetts Institute Washington University of Fred Hutchinson at Urbana- Institute Massachusetts Cancer Research Champaign of Technology Medical School Center
Christine Julie A. Theriot, Grant J. Jensen, Leemor Youxing Jiang, Jue Chen, Ph.D. Catherine L. Jacobs-Wagner, Ph.D. (51) Ph.D. (52) Joshua-Tor, Ph.D. Ph.D. (54) (55) Drennan, Ph.D. Ph.D. (50) Stanford University California Institute of (53) University of Texas Purdue University (56) Yale University Technology Cold Spring Harbor Southwestern Massachusetts Laboratory Medical Center at Institute Dallas of Technology van van der Donk: Darell Hoemann ©HHMI / AP, Bhatia: Robert E. Klein ©HHMI / AP, D. Sabatini: Robert E. Klein ©HHMI / AP, Collins: Robert E. Klein ©HHMI / AP, ©HHMI / Zheng: Froschauer AP, John Beckham ©HHMI / Zamore: Frederick AP, Robert George Theriot: E. Nikitin ©HHMI / ©HHMI Klein / Froschauer AP, ©HHMI John / AP, Jacobs-Wagner: Jill Jensen: AP, Connelly Ferré-D’Amaré: ©HHMI / AP, Allan Zepeda ©HHMI / AP, Joshua-Tor: Jiang: Amy Gutierrez ©HHMI / AP, Chen: David Umberger ©HHMI / AP, Drennan: Robert E. Klein ©HHMI / AP,
August 2008 | h h m i b u l l e t i n 25 The Unintentional Scientist Joan Massagué was having too much fun to notice he was building a career— and solving problems of cell signaling and cancer metastasis. by Elizabeth DeVita-Raeburn photographs by Mark Mahaney
Joan Massagué sits in his 13th-floor
macists. He’d get his science “fix” other had installed Massagué as chair of its cell office ways—studying geology, for instance, biology program. In 1990, he became an collecting rocks and crystals, a favorite HHMI investigator. When the Cancer at Memorial Sloan-Kettering Cancer hobby since his father bought him his Center created a cancer biology and Center’s new high-rise research building first rock collection for his 13th birthday. genetics program in 2003, Massagué and spreads his hands to indicate both In 1970s Spain, says Massagué, a became its chair. Just before, in 2000, as a what is visible—the modern decor, the bachelor’s degree was considered the run-up to his 50th birthday, Massagué large chunk of quartz on the windowsill, career-defining degree. Few bothered to and his lab had switched their focus to the sepia drawing of two greyhounds pursue an education further. “The Ph.D. metastasis and quickly began electrifying racing—and what is not—the unlikely was extra,” he says. “It was an activity that field, identifying different sets of genes start of his career. He shakes his head with almost to self-cultivate.” that drive the spread of breast cancer cells amusement. “Through the smallest of And the postdoc in the United States? to the bone or the lungs. That work, says back doors,” he says. “I did it because I liked the Ph.D. so Larry Norton, Memorial Sloan-Kettering It’s a good story, and he knows it. In much, I said, ‘What the heck? Let’s enjoy deputy physician-in-chief for breast cancer fact, the trim, dark-haired man with the another two years.’” After earning a Ph.D. programs, “is hot as a pistol.” genteel manner, musical Catalan accent, at the University of Barcelona, he searched and keen memory for Eric Clapton and out a postdoc position overseas and signed A Competitive Streak Bob Dylan lyrics, still seems surprised by on in the lab of a young investigator “It was obvious, right off the bat, that where he’s landed. named Mike Czech at Brown University, [Massagué] had extraordinary talent,” says When Joan (Joe-ahn) Massagué came who was studying insulin receptors. Czech. “He was a dream postdoc, here from his native Barcelona in 1979, it Two years in the United States came someone who really went after the was supposed to be for two years, max. The and went and over the next decade science, and who was dedicated to the plan: do a postdoctoral fellowship at Brown Massagué’s drive took over (“I am deter- sheer fun of discovery.” And unlike many University, publish one paper in the mined and intense by nature”), and two postdocs, Massagué didn’t have the Journal of Biological Chemistry (literary things happened. He became known as distraction of wondering what he was mecca for young biochemists), have a the man who cracked the TGF-beta going to do next, or how he was going to great time, and go back to Spain. He had pathway—a complex molecular “conver- make a name for himself. no intention of making a career of science. sation” by which cells tell their neighbors At the end of the two-year postdoc, That, he says, was not really a possibility in to stop dividing, among other things. And Czech offered Massagué a non-tenure- the Spain of 30 years ago, where the Massagué began to realize just how crit- track assistant professorship, with the handful of science positions were occu- ical that message might be in cancer, a option of spending 50 percent of his time pied by older scientists who didn’t make disease in which cells’ primary mission is on whatever he wanted, at the University room for the next generation. to divide and divide and divide. of Massachusetts Medical School, where Instead, when he returned, he would The cancer community realized the he had relocated his lab. It was an unusual likely settle down at a pharmacy, perhaps importance of these signals, too. By 1989, offer. “We, in academia, don’t usually the one owned by his parents, both phar- Memorial Sloan-Kettering Cancer Center retain people who’ve trained in our depart-
28 h h m i b u l l e t i n | August 2008 ment,” says Czech. “It’s an extraordinary beta—i.e. TGF beta. Growth factors are is just to kill some extra time.’” He’d breach of the way we operate. Joan was chemical telegrams that cells release into already done more than he’d set out to do one of only two exceptions I can think of the space between one another. The in the United States. He had nothing left in 30 years.” growth factors then make their way to to prove to himself. “I thought I was But the honor was lost on Massagué, nearby cells, latch on to them via a receptor already enough of a success,” he says. who didn’t really see the point. He was on the surface of the cell, and deliver their “Had I been a little more sophisticated going back to Spain with his wife, Roser message. Only that’s just the start, because and engaged in the career mode,” he says, Salavert, whom he’d met in Barcelona and the message actually needs to be passed to “I would have been petrified to realize married shortly after starting his postdoc. a number of different players before it’s where I stood.” Massagué asked what gain there would be received and acted upon. Massagué told Czech he needed 100 in it, to which Czech, among other persua- Little was understood about TGF beta, percent of his time for TGF beta, sives, answered that there’d be a few its receptor, the details of how its message obtained an independent investigator thousand extra dollars in his paycheck. got relayed, what the message said, and (R01) grant from the National Cancer “That I understood,” says Massagué. He what happened as a result. It was so Institute, and identified the receptor for had only one more question. What, he complicated, even people in the field kept TGF beta. In fact, somewhat to his asked Czech, was tenure? their distance. dismay, he identified three of them, He took the offer and, with character- “I was told that it was very difficult, which meant triple the work figuring out istic fearlessness, decided to try to identify that I might fail,” says Massagué. “I said, ‘I what they all did. But his curiosity was the receptor for transforming growth factor don’t care, I’m going back to Spain. This piqued. He wanted to know what
A human breast cancer cell (green) lodged in a mouse lung capillary is surrounded by a red disruption of the vascular endothelial cells, caused by the cytokine angiopoietin-like 4, which, according to studies in
Image: David Padua Image: / David Massagué Padua lab Photo: Mark Mahaney Massagué’s lab, is induced by TGF-beta. The weakened endothelium enables the seeding of pulmonary metastases.
August 2008 | h h m i b u l l e t i n 29 happened next. What chemical did that Massagué’s lab. Only occasionally, says “Mechanism on one side, artistic vision receptor make once TGF beta activated Gupta, does one get to see from his point on the other.” it? What gene did that chemical touch? of view, usually when all the experiments As the would-be pharmacist was deci- What did the gene do as a result? Each have been done and it’s time to write the phering the TGF-beta pathway, leading answer only made him want to go further. paper summarizing the results. medical institutions in the United States “I didn’t anticipate working on the entire “That’s when Joan shines,” says Gupta. and Europe courted him. He accepted the pathway,” he says. But Massagué felt “He’s able to craft the story as he saw it, job at Memorial Sloan-Kettering, because driven to know the whole story. Eventually, probably from the very beginning.” And he wanted to apply what he was learning he says, the TGF-beta pathway became he’s able to draw it. His drawings of scien- to a cause—the understanding of cancer. his “playground.” tific processes, says Gupta, are as good as With the 1989 move to Manhattan, During the next six years, he mapped many professional artists’. “I think that’s Massagué says, it became clear that he out most of the molecular minutiae of the how he’s made his career,” says Gupta. wasn’t going back to Barcelona. His pathway. By then, he was working at a feverish pace—and starting to look over his shoulder a bit. “At that point, I was not easygoing about it anymore,” he says. “I had something I really wanted. I saw that I could crack this problem and I wanted to do it.” That’s when a friend gave him the drawing of racing greyhounds. “As naïve as I was, I’m a pretty competitive guy,” he says. “I’m happy not to race, but when I race, I like to win.” His biggest fear, he says, was that he would be foiled somehow in finishing his project. If someone else got there first, it might cut off support or funding. “It was like I was sitting in front of a canvas and I had conceived of a painting. And I had to paint it,” he says. “And I didn’t just want to paint the arm, or the head. I had to paint the whole thing. I was happy to have other greatly talented people right next to me painting the same view. But I had to do my own whole portrait of it.”
His Artistic Vision The ability to imagine the big picture, and to visualize molecules and processes that are too small to see in literal terms is one of Massagué’s unique talents, according to colleagues. “The way he sees things is not always the way in which the conventional scientist sees things,” says Gaorav Gupta, a medical resident at Memorial Sloan- Kettering who was a graduate student in
With roots in New York and Barcelona, Massagué has set out to solve problems of cancer metastasis in his U.S. lab and help
his Spanish hometown build its research infrastructure. Mark Mahaney
30 h h m i b u l l e t i n | August 2008 “As naïve as I was, I’m a pretty competitive guy. I’m happy not to race, but when I race, I like
parents were going to have to find eldest of their six children. “I had a natural someone else to run the pharmacy. And inclination for natural sciences as a kid,” to win.” his daughters, Laia and Marta, both born says Massagué. “I loved butterflies. I fell here, were going to be Americans of in love with minerals. I like bird watching. problem, perhaps the problem of cancer. Catalan heritage. His wife, Roser Salavert, Botany. Sociology. Everything.” “All the chemotherapy, or the bulk of it, today a district community superinten- And when the opportunities came his and the radiation, after the surgeon is dent in Manhattan’s Department of way in the United States, his parents were done, is to prevent metastasis,” says Education, had the foresight to get her supportive. “They never asked, ‘Why are Massagué. “If it were not for metastasis, doctorate in education, just in case the you hanging so long in the U.S.? When cancer would be a minor fraction of the United States became their permanent are you coming back?’” he says. “It was, problem it is today. You’d just go to the home. “We always kept a very open mind,” ‘Go for it. This is lovely. Don’t worry about O.R., have the lump taken out, and go she says. Massagué had embraced the life the rest, the pharmacy, others can run it.’” home. It would be little more than going of a U.S. scientist. to the dentist.” But he wasn’t about to cut his Catalan The Next Challenge To find the key controls for cancer’s ties. Both of his parents grew up in He could have spent the rest of his scien- spread, Massagué had to think up a novel villages. His paternal grandfather was the tific days as the TGF beta guy. But way to collect the cells that had the knack village pharmacist. His maternal grand- around 2000, Massagué got the itch for a both to metastasize and to successfully father was a farmer and the village new problem to solve. set up shop. Not easy; cells aren’t very ironsmith. Eventually, his father’s family Going back to Spain was an option, efficient at the whole metastasis game. moved to Barcelona. His mother was sent but he was already back several times a Primary tumors shed millions of cells there to study to be a pharmacist—an year, to visit family and to help Barcelona into the bloodstream every day. “And unusual decision for a traditional family. expand its research capacity. Since 2005, yet,” says Massagué, “if we die of metas- Unfortunately, her first year of school he has been adjunct director of the new tasis, we don’t die of millions of was 1936—the start of the Spanish Civil Institute for Research in Biomedicine in metastases.” Which cells were the right War. “She had a very hard time,” says Barcelona, whose director is Joan J. ones to study? Massagué. “She went back to her village to Guinovart, Massagué’s Ph.D. thesis He used cells taken from the tumor of find her father and brother gone and did advisor. That, he says, allows him to culti- a woman who had died of breast cancer not know if they were alive.” She lived vate his life “as a man from New York and injected them into immunodeficient with her mother for a time, until her and Barcelona.” mice. Then he collected those that trav- mother was jailed. After the war, the family Characteristically, the new problem eled to the bone—a common site of reunited, and Massagué’s mother, with a he chose was the toughest in cancer metastasis for breast cancer—and injected doggedness she’d pass on to her son, biology: metastasis, the process by which them into yet another batch of mice. In returned to Barcelona and her studies. cancer cells leave the tumor of origin and those mice, bone tumors developed in That’s how she met Massagué’s father. take root in other parts of the body. half the time, indicating that Massagué They married and passed along their love Metastasis was recognized as far back has recruited the worst offenders. of science and learning to Massagué, the as ancient Egypt. But it’s still a huge (continued on page 56)
August 2008 | h h m i b u l l e t i n 31 nerve cell navigation Nerve cells exploit a complex set of cues to wire up properly in developing organisms. A closer view of this process may ultimately help to correct neurological problems that lead to schizophrenia and other disorders. by R. John Davenport illustration by Jon Han
For a human embryo, fashioning a nervous its limitations. For example, it cannot tint influences a single neuron among a group system is a daunting challenge. It must specific types of neurons, or neurons in of normal neurons. direct a tube of cells to morph into the which a particular gene is mutated. Luo has used the technique to under- brain and spinal cord and form the one To improve on the method, HHMI stand how the brain wires up its smell hundred billion neurons, or nerve cells, investigator Liqun Luo of Stanford sensors—olfactory neurons—each of which that twist and turn through the body to University has devised a way to label indi- carries a single olfactory receptor on its link the brain to every limb and organ. vidual neurons by using genetics. In his surface. Because flies carry 50 different odor Each neuron sends a long cable—an MARCM technique, short for “mosaic receptors, they have 50 different types of axon—to branch toward its destination, analysis with a repressible cell marker,” Luo olfactory neurons, with each one tuned to connecting to as many as a thousand other engineers fruit flies so that a small number grab onto a corresponding kind of odor cells along the way. These branches of neurons express a fluorescent protein and molecule. In the brain, all the neurons that enable every muscle, organ, gland, and bit consequently light up under a microscope. produce the same receptor stem from a of skin to transmit control signals. Spindly Moreover, Luo can restrict this labeling to single spot, called a glomerulus. So the fly arms at the opposite end of the neuron, particular types of neurons, so he knows brain has 50 glomeruli, one for each receptor called dendrites, receive information from exactly what kind of cell he’s observing. type. At each glomerulus, axons of the olfac- other neurons. Luo also uses MARCM to spur muta- tory neurons relay smell information to How this maze of neurons establishes tions, so he can manipulate genes and then dendrites of another type of neuron—a itself seems mind-boggling. Yet scientists probe how a neuron grows or makes projection neuron—which transmits the are beginning to discover the navigational connections in response. The approach information throughout the brain. signs that guide neurons and help them offers several benefits. First, it allows Using MARCM, Luo has investigated compete for survival. This knowledge not researchers to identify mutated cells, how olfactory neurons and projection only sheds light on the fascinating problem because each mutated cell glows. Second, neurons find each other during develop- of how brains establish their wiring but scientists can probe how a genetic change ment of the fly brain. “It’s like 50 men and also reveals how faults can lead to prob- lems. “Understanding normal wiring will help us understand miswiring,” says former HHMI investigator Marc Tessier-Lavigne, now executive vice president of research drug discovery at Genentech, Inc., in South San Francisco. “And how it might be possible to rewire the brain following injury or disease.”
Sniffing Out a Wiring Diagram Since the late 1800s, neuroscientists have used Golgi staining, named for its inventor, Italian Nobel laureate Camillo Golgi, to trace the paths of neurons. In fixed tissue, Golgi staining randomly colors a small number of neurons and reveals their complex structure: the bulbous cell body in the middle, a bushy canopy of dendrites on one side, and the long sinewy cable-like axon on the other. But Golgi staining has
Larry Zipursky University of California, Los Angeles João Canziani João
34 h h m i b u l l e t i n | August 2008 50 women on a dance floor, each needing response to pheromones cluster on the to find dancing partners,” he says. His team other side of the lateral horn. Scientists has found that the dance floor isn’t mapped “You have a special fruit-processing out before the neurons get there. Instead, area and a special pheromone-processing one partner—a projection neuron—sets area,” says Luo. “From our mapping, this are up where each match will take place. becomes very clear.” According to the Then olfactory neurons come in and find smells that neurons sense, the cells sepa- the right partner. Luo and his colleagues rate into areas that control different beginning have discovered many of the guidelines for biological functions. Presumably, other accomplishing this quest. Neurons seem to neurons use information from the “fruit divide up the problem. First, one set of area” to spur the fly to eat or information to molecular cues directs neurons to the from the “pheromone area” to tell the fly general vicinity, like a dancer looking for a to start a courtship dance. partner near the bandstand and ignoring discover the rest of the room. Then, another set of Turn Signals cues helps neurons move systematically Researchers also want to understand how the from cell to cell in the vicinity until finding neurons decide to change direction at the exact meeting spot. waypoints during the developmental Luo and his team are also mapping journey. David D. Ginty, an HHMI inves- navigational how projection neurons connect olfactory tigator at Johns Hopkins University, is neurons with other parts of the brain. studying the mouse to examine a set of They mark projection neurons that link to neurons whose axons travel along arteries signs particular olfactory receptor neurons and away from the spinal cord to the face. At then take snapshots of fly brains with those one point, these projections hit a fork in neurons lit up. So far they’ve mapped 35 the road: one group of axons follows the that of the 50 types of fly olfactory receptors. external carotid artery to the salivary They now want to overlay the maps of glands, while another meanders along the different neuron types, but each brain is internal carotid artery bound for the eye, guide subtly different from another in the size pineal glands, and other destinations. and arrangement of its parts. So they use Something must tell the axons to go one neurons computer programs to align each image way or the other. To identify possible with a “master brain,” from which they signals, Ginty and his team extracted bits of are creating a unified map of the fly’s each of the arteries and looked for genes and olfactory system. activated in the external carotid artery, but Luo knows whether a particular olfac- not in the internal carotid artery; they tory receptor detects, for example, fruit pinpointed particular genes that encode help (the fly’s food source) or pheromones members of the endothelin protein family. (chemicals one individual emits to spur Although this group of molecules is behaviors, such as mating, in another). As involved in regulating blood pressure, the them a result, the map illuminates not just where finding that more of the molecules appeared neurons go but what kind of smell infor- in one artery than in the other suggested mation each one communicates. The that the proteins might direct axons down compete method has already yielded important the external carotid artery, the researchers findings. Neurons that detect signals reported in the April 2008 issue of Nature. for related to fruit cluster on one side of the In mice that lacked certain members of lateral horn, a brain center for interpreting the endothelin family, neurons did not smell data, Luo’s team reported in March course down the external carotid artery, survival. 2007 in Cell. Neurons that twitter in according to the team’s findings. However, neurons grew down the internal carotid artery just fine, suggesting that endothelins beckon axons in one direction. The find- ings also support the idea that neurons use cues at various waypoints to navigate as opposed to taking a random path.
August 2008 | h h m i b u l l e t i n 35 It’s an “unexpected and exciting boring neurons are unlikely to make the the fly version does, and how rodent discovery” that endothelins, which work in same versions. Because dendrites from the neurons establish independent identities the circulatory system, help guide certain same neuron would bear the same DSCAM remains to be seen. neurons, says Tessier-Lavigne. Ginty is variants, these molecules might allow the Many other important questions also now looking for related molecules, such as dendrites to recognize and grow away from remain, says Zipursky. Is DSCAM’s sole job those that guide neurons down the internal each other, Zipursky proposed. Later exper- to tell a neuron to avoid itself or does it carotid artery. iments suggested that was the case. carry out other tasks too? Do cells always In recent work, the three teams inde- use a random assortment of DSCAMs or do Mutual Avoidance pendently used Luo’s MARCM technique particular variants identify subsets of Once neurons arrive at their destinations, to wipe out DSCAM in a small set of fly neurons? To investigate those questions, his they split into a tree of branches that cozy neurons. Dendrites of neurons lacking group is generating flies that are missing up to the target tissue and make their final DSCAM frequently crossed, showing that specific sets of DSCAM variants. connections. Several research groups are the protein is required for them to avoid discovering the cues that guide this phase. each other. DSCAM is made up of several The Right Connections Branches of a single neuron rarely cross. parts, including one that protrudes inside To make connections correctly, neurons A protein called DSCAM keeps dendrites the cell. Zipursky’s team further showed also need signals from skin, muscle, or other from snarling, according to a trio of studies that dendrites repel each other only when tissues they ultimately connect to. Ginty last year: one from HHMI investigators the protein bears this internal portion; knew that such target tissues release a mole- Lily Jan and Yuh Nung Jan of the University without it, they cling together. cule called NGF, or nerve growth factor, of California, San Francisco; one from DSCAM also exists in mice, and a study which prompts certain kinds of neurons to HHMI investigator Lawrence Zipursky of earlier this year revealed that it might carry branch and supports their survival. He then the University of California, Los Angeles, out a similar function: mice without it have found that neurons exposed to NGF ramp who collaborated with Wesley Gruber (Yuh neurons that clump and don’t spread. “The up production of a gene-controlling mole- Nung Jan’s former postdoctoral fellow); molecule used for self-avoidance seems to cule called SRF. Further genetic studies and a third from a team headed by Dietmar have been conserved,” says Yuh Nung Jan. revealed that SRF relays NGF’s order for a Schmucker (Zipursky’s former postdoctoral But the mammalian version of DSCAM neuron to branch and penetrate the target fellow) of Harvard University. doesn’t come in the plethora of flavors that tissue. However, SRF is not necessary to Eight years ago, Zipursky and his colleagues found—to their surprise—that a single DSCAM gene could generate a huge number of subtly different variants of the protein—38,000 variations, in fact. Aside from the vertebrate immune system, which can generate a vast array of antibody proteins by shuffling single genes, getting such a large number of different proteins out of the same gene is unusual. Zipursky wondered if this extraordinary capability related to DSCAM’s role in organizing neuron growth. Test-tube experiments revealed that each variant binds to itself but not to other variants. Each neuron makes a random assortment of these variants and neigh-
David Ginty Johns Hopkins University Jennifer Bishop Jennifer
36 h h m i b u l l e t i n | August 2008 Liqun Luo Stanford University
the death molecules appear to override the NGF signal. The right balance between the forces that make neurons strong and those that kill them helps an organism wire up just the right number of connections. Studies such as these are revealing new clues about how normal brains and nervous systems develop as an embryo matures. But the research may also illuminate causes of disease. Problems in wiring can crop up, resulting from genetic miscues or other causes, as an embryo develops. Growing evidence suggests that this kind of faulty wiring may underlie neurological disorders such as schizophrenia. Understanding how and why wiring gets fouled up during development might lead to ways to correct the problem before it’s too late. communicate NGF’s survival message— nucleus. Because cells see NGF at their In addition, some of the strategies that without SRF, neurons exposed to NGF growing end, “it wasn’t intuitive that you’d help an embryo set up a working nervous survive. Some other molecules must prevent need signaling all the way to the nucleus.” system might also keep the nervous system cells from dying. One reason for such an ornate process in proper order during adulthood; defects The role of SRF is intriguing, says might be that neurons must shift modes. that develop later in life could contribute to Ginty, because the molecule exists only in “Until it reaches the target region, the role neurodegeneration. Finally, one way to fix a neuron’s nucleus—not in its growing tip, of a neuron is to grow, grow, grow,” he says. a damaged nervous system might be to where the neuron first encounters NGF. But once it arrives, it must penetrate the reactivate the processes an embryo uses and He is keen to understand how NGF tissue, branch, and form connections. spur the body to regrow parts of the system. communicates with the nucleus. In Ginty’s NGF might be the trigger that tells the The new insights about how neurons preferred model, the cell membrane at the neuron to switch on all the genes required find their path, avoid themselves, and neuron’s end pinches off, forming small to perform the new gymnastics. establish appropriate connections reveal spheres that capture NGF and transport Ginty’s work is also defining how sets of many of the instructions for weaving the the growth factor along with its receptor all connections involving many neurons are intricate tapestry of the nervous system. the way back to the cell body, where the fine-tuned. As an organism establishes its “We already know a lot of the molecules nucleus resides. The model makes sense nervous system, it sends more neurons that are involved,” says Tessier-Lavigne, because defects in this transport system are than necessary to a particular place. Ginty “but these studies highlight the fact that implicated in neurodegenerative disorders and his team have found that neurons use many additional players remain to be such as Parkinson’s disease and amyo- a series of genetic feedback loops to deter- discovered.” Many of the overarching navi- trophic lateral sclerosis, or ALS (often mine which cells live and which ones die. gation strategies likely remain undiscovered referred to as Lou Gehrig’s disease). As a result, when a group of neurons see as well, he suggests. Further efforts will What is remarkable, says Ginty, is that NGF, some of them become more sensi- provide even more nuanced views, not NGF influences an axon’s growth and tive to the molecule and consequently only of the journey that each neuron takes branching by tweaking genes in the cell’s become robust survivors, Ginty and his to create a working nervous system but also colleagues reported in the April 18, 2008, of ways to preserve the wiring’s integrity issue of Science. and to keep brains healthy. p In addition, the hearty cells churn out molecules that kill off neighboring
George Nikitin ©HHMI / AP, neurons. Those neighbors see NGF, but
August 2008 | h h m i b u l l e t i n 37 perspectives & opinions
Francisco Ayala Evolution and Creationism t h e c o n f l i c t l i e s i n p e r c e p t i o n . Dani Brubaker
38 h h m i b u l l e t i n | August 2oo8 In his native Spain, Francisco Ayala attended Catholic schools, where he studied evolution in science class and creationism in religion class. No one saw a conflict. Having moved to the United States in 1961, he was shocked when, in the mid- 1970s, California sought to introduce an antievolution curriculum into its public schools. How could this be, in the most scientifically advanced country in the world? His bewilderment led Ayala to a lifelong study of how evolution is, or is not, taught in public schools.
You are the lead author of a major 2008 report arguing that gion predisposes citizens in this country toward the perception evolution is settled science, and creationism should not be of a conflict with science. On top of that, the idea is pervasive taught in science classes. Many people assumed that this that science tends to be materialistic. issue was resolved in 2005, with the court ruling in Dover, Pennsylvania, that “intelligent design”—the latest face of Meaning? creationism—is religion, not science. Is there still a problem? Materialism is a philosophical position, affirming that nothing Yes, unfortunately so. The courts have settled the issue many exists beyond “matter,” that which we can experience with times, starting with a decision of the Supreme Court in 1968 our senses. I would say that science is methodologically that Arkansas could not prohibit the teaching of evolution in its materialist: it can deal only with the world of matter. But public schools. Then came the idea of “creation science,” and it is not philosophically materialist; it does not imply that the Court ruled in 1987 that it was actually religious teaching nothing can exist beyond what we experience with our and therefore could not be mandated in the public schools. senses, as religion requires. One can accept scientific prin- Next, the conversion to “intelligent design” took place. ciples and also hold religious beliefs. Some school boards tried, as in Dover, to introduce it as a But, many people are ignorant of science and just assume scientific theory, comparable to evolution. The federal court it is contrary to their religion. Of course, the proponents of in the Dover district decisively knocked down this claim. The intelligent design and creationism are also spreading a lot judge, John Jones, said that intelligent design is creationism of propaganda. The only way to deal with the problem is and the Dover school board was trying to introduce religion education and specifically science education, which is into public school classes, which the U.S. Constitution forbids. unfortunately lacking, by and large, and not only in this But that court does not have authority in the rest of the country. United States. Creationism is still a live issue in Florida, Kansas, Louisiana, Alabama, Michigan, and Missouri—other Don’t most mainstream theologians actually endorse evolution? places. One new tactic is to seek to protect any teachers who Yes. In Christianity, Islam, and Judaism, the compatibility attempt to debunk evolution in their classes, as a matter of of science and religion has long been accepted by most “academic freedom.” scholars, by most theologians. Pope Pius XII said in 1950 that Catholics should accept what science demonstrates Some argue that schools should teach the controversy between about evolution, while holding that God creates the human intelligent design and evolution. soul. In 1996, Pope John Paul II spoke very strongly in Yes, even the president of the United States said that not so support of evolution and the idea that evolution and religion long ago, to which my response was, well, maybe we should are quite compatible. The current pope, Benedict XVI, says teach astrology with astronomy, and alchemy with chemistry, there is plenty of scientific proof for evolution and that it is and witchcraft with medicine. Because intelligent design is absurd to assume there is a conflict between evolution and not science, it is not something to be taught as an alternative. religious faith.
Almost half of Americans, according to recent Gallup Polls, Interview by Harvey Leifert. Francisco Ayala is a say that evolution and religion cannot coexist. Why is evolu- professor of biology and philosophy at the University of tion so contested in the United States, at least in certain areas? California, Irvine. For more information about the National The United States was largely founded by people who were Academy of Sciences/Institute of Medicine report, “Science, being persecuted for religious reasons. I think love for reli- Evolution, and Creationism,” visit www.nap.edu/sec.
August 2oo8 | h h m i b u l l e t i n 39 perspectives & opinions
Catherine Dulac Collective Inspiration a r e l u c t a n t d e p a r t m e n t c h a i r f i n d s g r e a t v a l u e i n a d i v e r s i t y o f o p i n i o n s . Jason Grow Jason
40 h h m i b u l l e t i n | August 2oo8 Catherine Dulac left her native France 15 years ago to pursue her commitment to scientific research. Since becoming a member of the Harvard University faculty in 1996, she has made illuminating discoveries about the pathways involved in odor and pheromone reception in mammals. A year ago, this HHMI investigator added department chair to her busy workload as a teacher, mentor, and laboratory head.
My dream is to spend my entire workday doing science, The department’s dynamic has some amusing similarities so it took quite a bit of arm-twisting from my colleagues to with temperature control in honey bee hives. Bees vigorously convince me to take on the responsibility of chairing flutter their wings to cool their hive when the temperature Harvard’s Department of Molecular and Cellular Biology. rises, and they contract their muscles to warm the hive when In the end, the quality essential to my research— the temperature falls. The fascinating aspect of this process is passion—also drove me to accept the job as chair. Harvard that it requires genetic diversity. If the entire colony is geneti- enabled me to flourish as a scientist and teacher, in large cally identical, all the bees react simultaneously, and the part because of the inspiring community of students and hive’s temperature is prone to brutal oscillations. Genetically scientists, and I care very much about giving something diverse bees, in contrast, have different response thresholds back. It made sense that my turn would come one day, and to heat and cold. When one moves its wings, another feels that I would spend time and energy helping my colleagues nothing, and their actions balance to keep the hive’s temper- and my department move forward. ature stable. Similarly, members of an academic department And I knew I wouldn’t be alone. The chair rotates on a are quite different from each other. If some members are three-year cycle. Any one of about 30 faculty members, in more sensitive than others about a specific point, that is a theory, might become chair at some point, and that realiza- useful warning signal and the community is much richer, tion fosters a collegial atmosphere. We know each other and more fun, for its diversity. quite well and, together with the chair, many faculty and I was acutely aware that taking the role of chair would superb administrators are highly engaged in running the carry a price. So, when I need to rely on people in my lab to department. point out key scientific papers, rather than discovering them I view the job as being a listener, a cheerleader, and myself, I can’t complain. Or, when I wasn’t able to run my someone who gets things done. If the members of the fifth Boston Marathon, or even keep running regularly, I department are not enthusiastic about something, it won’t had to get over it. I need to fight hard to squeeze out quality happen. I have no decision-making power, which is perfectly time to think about science, my lab, and funding for fine. My role is to organize, entice people to come together, research, but thankfully I’m still able to maintain some of promote dialogue, listen to others’ points of view, and take my daily routine. I bike to work every day whether it’s sunny advantage of the collective desire and motivation of my or snowy. I cycle or walk to get groceries. I cook all meals—I colleagues and of all the members of our community: never view it as a waste of time. For me, it’s wonderfully students, postdocs, staff. relaxing, particularly if there is good wine to go with it! That is very much the same approach I take in the lab, I don’t regret the decision to become chair. This year where I’ve always found it advantageous to promote collec- was really challenging, but it was productive. There is a real tive brain power. Nobody can pretend to always have the sense of collective achievement in the department that best idea and I’m always interested to hear somebody delights me. I am especially proud of the interdisciplinary improve on a suggestion, or even completely disagree with graduate program that members of the molecular biology, it. One of the challenges in becoming chair is to recognize chemistry, and evolutionary biology departments produced. that everyone won’t necessarily agree with you: it is much I’m excited to see what we can accomplish in the year more valuable to use this diversity as an advantage rather ahead, and I am already discussing several interesting ideas than an impediment. with my colleagues.
Interview by Carol Sliwa. Catherine Dulac received her Ph.D. from the University of Paris and did her postdoctoral work with Richard Axel at Columbia University. She was elected a fellow of the American Academy of Arts and Sciences in 2004 and a member of the French Academy of Science in 2007.
August 2oo8 | h h m i b u l l e t i n 41 Q & A What Olympic sport does your scientific career best qualify you for? At this month’s summer Olympics, there will be no medals for fastest pipetting, highest resolution microscopy, or most time spent at a lab bench. But four HHMI scientists tell the Bulletin that their research careers have nonetheless given them skills to compete in unlikely athletic contests. — EDITED BY Sarah C.P. Williams
Diane K. O’Dowd Michael D. Ehlers Gabrielle T. Belz Paul W. Sternberg HHMI Professor HHMI Investigator HHMI International HHMI Investigator University of California, d U k e U n i v e r s i ty M e d ic a l Research Scholar C a l i f o r n i a I n s t i t u t e o f Irvine Center t H e Walter and E l i z a H a l l Technology Institute of Medical “Keeping both my research “My scientific career has “My first thought is dry land Research, Melbourne, and teaching programs in best qualified me for Australia luge, where you lie on your good form is a constant bal- archery—keeping an eye “I would have to say cycling— back on a skateboard ancing act, so I think I’m on the target. Or perhaps if it’s a unique combination of careening down a moun- best suited for a spot on the team archery were a sport, speed, wit, tactics, razor tain road, but I don’t think gymnastics team.” that would be a better sharp skills, and endurance.” that’s an Olympic sport yet. analogy. A large part of a But seriously ... I’d say scientific career is training biathlon—a professional students and postdocs to scientist has to multitask be better shots than you.” and be able to change activities in a split second. You have to switch motor tasks—from moving an incubator to precise pipet- ting under time pressure. And you have to switch mental activities—from obsessing over a calculation to musing about possible connections of maybe-facts.” O’Dowd: John O’Dowd: Hayes John ©HHMI / AP, Ehlers:©HHMI / Karen AP, Belz: Tam David Rolls Sternberg: Danny Turner
42 h h m i b u l l e t i n | August 2oo8 chronicle
44 Science Education Let the Experiments Begin / Getting Their Feet Wet
47 Institute News Asai Named as Undergraduate Science Education Program Director / HHMI Appoints Carlson as Senior Scientific Officer
48 Lab Book A Mutation’s Multiple Effects / Jumping After Mobile DNA / Mysterious Protein Protects Against Sepsis
51 In Memoriam Jeremy R. Knowles
52 Toolbox Next-Generation Sequencing
54 Nota Bene National Academy of Sciences Elects HHMI Scientists / Steitz Wins Albany Prize
A piece of RNA that can jump between different stretches of DNA and RNA was visualized using x-ray crystallography (see page 49). Here, one portion of an electron density map of that intron is shown, in purple. The backbone of the molecule is traced in beige. Kevin Keating / Pyle lab
August 2oo8 | HHMI BULLETIN 43 science education
Let the Experiments Begin
HHMI grants offer schools the chance to try new things.
S o m e t i m e s experiment s d o n ’ t s ta r t i n t h e l a b . Franklin & Marshall College in Pennsylvania has joined forces with a In fact, the experiments in science education being conducted clinic where children from Amish and Mennonite communities are by HHMI’s newest undergraduate grantees take place in middle treated for inherited metabolic disorders. A few dozen students will schools and on movie sets, in dormitories and on school buses. work at the clinic to mine the wealth of genetic information that has This year, HHMI awarded $60 million in grants to 48 colleges been gathered from children with these diseases. and universities to test some innovative approaches and find out if Barnard College in New York will integrate research into classes they work. by focusing on the tobacco hornworm Manduca sexta, a pest that Take Edison Fowlks of Hampton University, who wants to recruit attacks tomatoes and potatoes. The classes will probe the worm’s future science Ph.D. students to his historically black college the sense of smell and taste with experiments examining and altering same way basketball coaches recruit future NBA players. its behavior and genetics, which have never before been fully exam- Or Norine E. Noonan of the College of Charleston, who wants to create “learning communities” where first-year students “The undergraduate years are vital to live, work, and breathe science from the attracting and retaining students who will classroom to the dorm room. Or Jeffrey Bartz of Kalamazoo College, be the future of science.
who will send his science students far and Thomas Cech even worldwide to pursue their scientific ” dreams, rather than keep them on campus. “Our HHMI funds allow us to do something other universities ined. “This will enable our students to do cutting edge research in a think is a little bit nuts,” he says. lab class context,” says Paul E. Hertz, Barnard’s program director. These are just a few examples of the wide-ranging experiments The colleges also want to prepare students for the science of the coming out of HHMI’s 4-year science education grants to under- future—which is likely to be more wide-ranging and quantitative. graduate colleges. “We want to help create successful models for Some will add modern techniques or interdisciplinary classes to teaching science that can spread throughout the higher education their traditional curriculum, while others will redesign their biolog- community,” says Peter J. Bruns, HHMI’s vice president for grants ical science majors. and special programs. The theme for many of the biology departments could be “More The 2008 college grant winners are a diverse group—traditional Math!” Several schools will require more math and computer liberal arts colleges, large state schools, small religious institutions, science as part of their regular biology curriculum. Harvey Mudd and historically black colleges and universities from 21 states and College in California is combining its introductory biology and Puerto Rico—and they face an equally diverse set of challenges. computer science classes into one year-long course. And Carleton Their experiments in science education match that wide range: College in Minnesota is bringing computer modeling and math alternative approaches to student research, new classes or majors into all its science disciplines. that unite previously walled-off disciplines, better ways to excite But none of these classes will generate more science majors precollege students about science, and unorthodox tactics for if you can’t get students interested in science in the first place. recruiting minorities traditionally underrepresented in science. Outreach programs are major components of many of the educa- “The undergraduate years are vital to attracting and retaining tion experiments. The University of Texas–Pan American is taking students who will be the future of science,” HHMI President science to its rural neighbors with a bus converted into a mobile Thomas R. Cech says. “We want students to experience science as lab. On the bus, sixth through ninth graders dig into research on the creative, challenging, and rewarding endeavor that it is.” forensics and real-world problems, like sickle cell anemia and HIV. Much of that excitement still comes from hands-on research, and With complementary teacher training, the school hopes the excite- schools are taking different approaches to bringing research to students. ment about science will carry on beyond the two-day bus visit.
44 h h m i b u l l e t i n | August 2oo8 Clockwise from top left: Barnard students Christine Chang and Ayelet Spitzer use fluorescence microscopy and digital imaging to determine whether cells are dividing in fruit fly testes; Charlie Weiss, a student at Carleton College, performs air-sensitive filtration work under the watchful eye of chemistry professor Gretchen Hofmeister; biology majors Darrylynn Nelson and Elizabeth Adeyemi, of Spelman College, evaluate the role of a gene in yeast; Harvey Mudd College students Jay Markello and Marissa Quitt ask a question of professor Eliot Bush in a new biology class called Computational Approaches to the Genome.
North Carolina Central University, a historically black college, plans to start a mentorship program and create a full-length docu- will start recruiting promising science students to the school as early mentary about the lives of its graduates pursuing scientific careers. as middle school and will support them though high school and “The film will focus on lifestyle choices Spelman graduates have college, with everything from SAT-prep workshops to mentoring made as scientists and as women struggling to balance their work and career support. The program “will give continuity, which lives and home lives,” says Cynthia Bauerle, the HHMI program we think assures greater success,” says Sandra White, co-program director at the college. “We hope the movie will speak to young director of the HHMI grant. alumnae who are struggling with the same issues and help keep
Encouraging participation by underrepresented minorities in them in the field.” p —A ndrea Widener science is a key goal at Spelman College, a historically black liberal arts college for women. Spelman has focused its efforts on making FOR MORE INFORMATION: To see a full list of the colleges and universities that received grants and to learn more about their programs, visit www.hhmi.org/news/college20080422.html.
Matthew Septimus, Noltner, John Nathan Bolster, Kevin Mapp / Harvey Mudd College sure its students see successful women and minority scientists and
August 2oo8 | h h m i b u l l e t i n 45 science education
Getting Their Feet Wet
A weekend program offers mid-Atlantic high school students a chance to experience the Chesapeake Bay hands-on.
I t ’ s a s unny Friday a f ternoon in A pril and high s c h o o l summer. The lodge is off-the-grid—the few appliances are powered by senior Devon McCurdy stands on the beach using a pocketknife to solar panels on the roof, and the toilets are self-composting; a wood dissect a round, marble-sized sea squirt. stove is the only heat source. Before they can wash dishes after each “This is so cool,” she keeps saying. meal, the students pedal a bicycle in the kitchen to raise the pressure “I think that’s the digestive system right there,” says Susan Faibisch, in a well and start the water running. her science teacher, as she leans over McCurdy’s shoulder and points When they arrived on the island earlier in the day, the group to a tiny brown curlicue inside the squirt. was greeted by Adam Wickline, the CBF educator who lives on Fox A few feet away, two sophomore girls are knee-deep in the ocean Island all summer. “Ask Adam” becomes a refrain both students and and dragging a net between them, hoping to dredge up more shallow- teachers repeat all weekend. He can rattle off the scientific names of water critters. They’re mostly getting winter jellyfish (it’s still too cold for birds, fish, and invertebrates and takes every question seriously. larger summer jellyfish)—which they were squeamish about picking Wickline spends the weekend encouraging the visitors to immerse up at first but now transfer from nets to buckets without hesitation. themselves in the environment. “We’re on island time here,” he says. Students and teachers have had to part with their watches, cell phones, and iPods. “This is a time for you to slow down and enjoy the Chesapeake Bay.” Enjoy, and recognize that chances to enjoy the Bay are disappearing, he says. Sitting on the beach Friday night, Wickline talks about how much Fox Island has physically shrunk in the past decade due to erosion. “Within our lifetimes, Fox will probably disappear entirely,” he says. Don Baugh, CBF’s vice president for education, has worked for the foundation for 32 years and says that those years have brought scientific progress in understanding the Chesapeake watershed but also worsening of the Bay’s condition. “We gave [the Bay] a D on its latest report card,” he says. Two Chesapeake Bay Foundation educators and two Walkersville High “And it’s failing because of what we’re doing on the land.” School students examine the washed up shell of a horseshoe crab on Fox Island in Virginia. That’s why CBF’s trips try to inspire students to care about environmental issues. The group—14 students and 2 teachers—is from Walkersville High “We bring kids to the water,” says Baugh. “That automatically School in Maryland. They’re spending three days mucking around engages them. Who isn’t interested in being out on the water and the mud of the Chesapeake Bay through an HHMI-funded education dredging things up, seeing what’s down there?” program run by the Chesapeake Bay Foundation (CBF), a nonprofit The approach seems to be working. This is 18-year-old McCurdy’s group dedicated to improving the health of the Bay. HHMI funds such second trip—she came last fall and couldn’t wait to return once more programs to inspire the next generation of scientists. before graduation. “Coming here really brings it all home,” she says. This is Faibisch’s ninth trip with CBF—she comes both fall and “We sit in science class all year reading our textbooks. Then we get to spring with any Walkersville science students who are game for a come here and experience this for ourselves and it makes it about so long weekend of canoeing, crabbing, hiking, exploring, and learning much more than just numbers and lectures.” about the history, health, and importance of the Chesapeake Bay. When she laughs that she now wants to become a professional sea This weekend, they’re staying on Great Fox Island, Virginia, 6 miles squirt dissector, McCurdy is joking, but she later says more seriously off the eastern shore of the Chesapeake Bay—a three-hour drive and an that biology is on the shortlist of college majors she’s considering, in
hour-long boat ride from Washington, D.C. This 50-acre archipelago part, she says, because of Fox Island. p —S a r a h C . P. W i l l i a m s houses one of a dozen CBF education centers. About 18 class trips run every spring in April and May, leaving few quiet days in between, and FOR MORE INFORMATION: To see CBF’s State of the Bay 2007 Report Card, visit www.cbf.org/site/DocServer/2007SOTBReport.pdf?docID=10923.
teacher training institutes and leadership programs are held here in the Williams Sarah C.P.
46 h h m i b u l l e t i n | August 2oo8 institute news
Asai Named as HHMI Undergraduate Science Education Program Director
W h e n Dav i d a S ai delivered hi s f i r s t lecture to a s e a o f disciplines? How can students be best sophomores taking an introductory biology class, his sole training as prepared to learn about science? How a public speaker consisted of a high school debate class. That’s can the ranks of scientists be diver- when he realized that teaching students about science required sified? How can faculty members more than a Ph.D. become better teachers? Now Asai has been named director of HHMI’s undergraduate Going out on a limb in education science education program and he hopes to rewrite the rule book programs will lead to the answers, Asai for how science, and science teachers, should be taught. He comes believes. “HHMI grants cause the to HHMI from Harvey Mudd College. In his new position, he will institutions to commit to trying some- oversee an annual portfolio of over $50 million in initiatives that are thing new,” he says. “It really is a quid pro quo. You want this grant? reinvigorating life science education at research universities and liberal You’ve got to do something different.” arts colleges and engaging the nation’s leading scientists in teaching. Asai, who grew up in Hawaii, got hooked on science through a “We support innovative programs that bring the content, excite- National Science Foundation summer research program for high ment, and relevance of science to students and David has shown school students, similar to programs funded by HHMI. He received that he can deliver exactly this sort of program,” says Peter J. Bruns, his undergraduate degree from Stanford University and then went HHMI’s vice president for grants and special programs. to graduate school at the California Institute of Technology. His A cell biologist, Asai knows firsthand the impact the Institute’s research has focused on understanding the structure of dynein—a grants can have: he has overseen HHMI programs at both Purdue molecular motor responsible for many cellular activities. University and Harvey Mudd College. After 19 years as a faculty member at Purdue, Asai was recruited Asai hopes that, with HHMI support, his college and university to Harvey Mudd, where he served as biology department chair for colleagues will take on big questions: How is science best taught across the last 5 years, teaching and continuing his research. p
HHMI Appoints Carlson as Senior Scientific Officer
M a r i a n B . C a r l s on, a genetici s t humans, these protein kinases are associated with metabolic disor- and microbiologist, has been appointed ders such as diabetes and obesity. as senior scientific officer of HHMI. Together with scientific officer Carl Rhodes, Carlson will be the Carlson will support the research of driving force behind HHMI’s new Early Career Scientist Program, HHMI investigators in more than 300 launched in March 2008. She will work to identify opportunities laboratories across the nation. for the Institute to assist young researchers in managing successful Coming to HHMI is “an opportu- laboratories. nity to have a broader impact on the “Marian Carlson brings a richness of academic and administrative scientific research community,” she perspectives to the HHMI science department,” says Jack E. Dixon, says, “because HHMI is an organization with the resources to fund vice president and chief scientific officer. innovative science, at a time when NIH funding is tight.” Carlson is no stranger to HHMI. She is married to HHMI inves- Previously, she was at Columbia University College of Physicians tigator Stephen P. Goff of the Columbia University College of and Surgeons, where she was vice dean for research as well as a Physicians and Surgeons, who studies the replication of retroviruses. professor of genetics and development and microbiology. She has Carlson received her A.B. summa cum laude in biochemical been a faculty member at Columbia since 1981. She joined HHMI sciences from Harvard College and her Ph.D. in biochemistry April 1, 2008. from Stanford University. She did her postdoctoral training at Carlson will continue to manage her laboratory at Columbia, the Massachusetts Institute of Technology. She is a fellow of where she studies a family of proteins, known as the SNF1/ the American Academy of Arts and Sciences and a fellow of the AMP-activated protein kinases, that plants, animals, and fungi use American Academy of Microbiology, and has also served as presi-
Asai: Mark Harmel Fetters Carlson: Paul to alter their metabolism and gene activity in response to stress. In dent of the Genetics Society of America. p
August 2oo8 | h h m i b u l l e t i n 47 lab book
A Mutation’s Multiple Effects The mutation that causes a motor neuron degenerative disease also produces defects in basic cellular machinery.
Spinal muscular atrophy—a degeneration of motor neurons that the University of Pennsylvania School of Medicine found that not causes muscle wasting—stems from mutations in a protein called all the snRNPs were affected in the same way. “Rather than a “survival of motor neurons” (SMN). SMN does more than just uniform decrease in the levels of all the snRNPs, some were more keep motor neurons alive and functioning; it is vital in every cell in affected than others,” says Dreyfuss. the body for splicing unneeded genetic bits out of RNA after it is To explore whether this varied response might affect tissues in copied from its DNA blueprint. SMN’s task is to construct small different ways, the researchers turned to SMN-deficient mice. RNA-protein complexes, known as small nuclear RNA ribonucleo- “We found a different snRNP repertoire change in every tissue proteins (snRNPs)—the building blocks of the cell’s splicing we looked at,” says Dreyfuss. apparatus (the “spliceosome”). When the scientists looked at how RNA was spliced in these Since all cells need this housekeeping activity, it’s been a mice, they also found tissue differences. “The abnormalities we mystery why mutations in SMN affect only motor neurons. Now, saw told us clearly there is something aberrant about the splicing researchers have discovered clues to the mechanism that allows the process,” explains Dreyfuss. “Not only did we see basic splicing mutation to have defects, we also saw spliced RNA forms never before detected in varied responses in normal mice in any tissue.” different tissues. The results, which appear in the May 16, 2008, issue of Cell, When they engi- don’t answer why motor neurons are affected so drastically, but neered cultured they do reveal that SMN is a key orchestrator of the splicing process human cells with and illustrate how different tissues respond in a unique way to reduced SMN levels, mutations in a protein needed by all. Knowing that patients with
Spinal muscular atrophy causes motor researchers led by spinal muscular atrophy have spliceosome defects in more than neurons, shown here as they connect to HHMI investigator just neural cells, Dreyfuss says, suggests that future therapies should skeletal muscle, to degenerate. Gideon Dreyfuss of target the whole body. p —Sarah C.P. Williams
IN BRIEF
Toxic RNA in Neurodegeneration peutically, this means knocking down the can think of—the lung, pancreas, brain, colon,” The explanation for one neurodegenerative RNA to prevent expression of the toxic says Rafii. “If you have a marker expressed on disease just got more complex. Mutated protein is really a two-pronged approach— all these mature cells, then it’s hard to RNA, which folds back on itself in a hairpin, you get rid of both toxicities.” conclude that CD133 is a stem cell marker.” is partially to blame for the loss of motor In addition, by growing cancer cells that control associated with spinocerebellar Cancer’s Elusive Stem Cells expressed CD133 as well as ones that didn’t, ataxia type 3 (SCA3), according to a study A protein that researchers once believed Rafii showed that some of each could by HHMI investigator Nancy M. Bonini. flagged only colon cancer stem cells— initiate new cancers. The research appears Previously, scientists believed the symp- hypothesized to be the seeds that keep a in the June 2, 2008, issue of The Journal of toms of SCA3 were due only to an accumu- tumor growing—has now been shown to be Clinical Investigation. lation of irregular, toxic proteins. far more common. The new research, by While cancer stem cells could exist, Rafii Bonini, at the University of Pennsylvania, HHMI investigator Shahin Rafii and his says his findings emphasize how hard it is generated a fruit fly model of SCA3—which colleagues at Cornell University, casts to find them. “We need a functional defini- is caused by a long string of repeated doubt on the very idea that cancer stem tion of a cancer stem cell rather than a nucleotides inserted in a gene. After two cells exist. marker,” he says. genetic experiments hinted to Bonini that Since the 1960s, researchers have been RNA might be involved, her team replaced aware that not all cancer cells can cause Exposing a Parasite’s the repeats of “CAG” nucleotide triplets cancer. So when scientists pinpointed a Vulnerability with some “CAA” repeats. These triplets protein—CD133—that seemed to exist only Like the words in a sentence, the order of code for the same amino acid—and so the in a small percentage of colon cancer cells, amino acids in a protein is typically vital to same protein in the end—but the “CAA” they guessed that it could be unique to stem its meaning. But one malaria parasite, version didn’t make the RNA fold up. cells—a cancer stem cell marker. But Rafii researchers have shown, can recognize Toxicity decreased, despite the protein looked closer at the protein’s localization. proteins whose amino acids are randomly being identical. In addition, Bonini and her Instead of injecting human colon cancer scrambled—as long as the whole protein colleagues engineered flies that produced cells into mice, Rafii used mice with a mouse still has certain characteristics. repetitive RNA but no protein. They still version of colon cancer. And instead of Led by HHMI international research saw neural degeneration, they reported in staining segments of tissue to locate CD133, scholars Geoffrey McFadden at the Nature on June 19, 2008. as others have done, Rafii and his colleagues University of Melbourne and Alan Cowman “There’s toxicity at the level of the used a genetic method to track the protein. at the Walter and Eliza Hall Institute of protein, but also at the level of the RNA,” What they found surprised them. “It’s all Medical Research—both in Australia—the says Bonini. “We would argue that, thera- over the place, in every epithelial lining you scientists wanted to find out the required Kent Wood / Photo Kent Wood Researchers, Inc.
48 h h m i b u l l e t i n | August 2oo8 Jumping After Mobile RNA Scientists reveal the structure of RNA that can leap around the genome.
Not all RNA is content to inactively remain in linear genetic frag- structure. The results ments. Some bits of RNA can break away, or self-splice, and invade appear in the April 4, other areas of RNA and DNA, driving the evolution of new genes. 2008, issue of Now a group of scientists, led by HHMI investigator Anna Marie Science. Pyle of Yale University, has determined the structure of one of They found that these feisty stretches of nucleotides. the RNA folds into a Unlike DNA—typically found in basic double helices—RNA globular shape, with frequently adopts intricate structures, folding back on itself, making the active parts of the loops and hairpins and globs. Predicting how any given bit of RNA molecule—needed will arrange itself is exceedingly difficult given the possibilities. for the splicing— And studying this type of mobile RNA—known as group II nestled inside. These introns—presents its own problems because the RNA is often active parts, they
reluctant to jump when it’s not inside a cell. noticed, bear striking The tertiary structure of the intron, with the Therefore, Pyle and her colleagues first had to find one that similarity to sub active center of the molecule in red. would cooperate in a test tube. After screening group II introns structures in the from a number of organisms—the jumping RNA exists in almost spliceosome—a complex of RNA and proteins that normally removes all bacteria, and in some plants, fungi, and animals—the group unneeded sections from a strand of RNA before it is used to code for identified an intron from a deep-sea bacterium that readily self- a protein. spliced in the laboratory. “I had high hopes that we would learn a lot from this molecule They isolated the intron—once it had already hopped out of its about the way RNA folds,” says Pyle. “And indeed, it really surprised spot in the genome but before it had barged into a new gene—and us about the kind of structures that RNA can adapt. This was a used x-ray crystallography to generate a detailed picture of its treasure trove of structures.” p —Sarah C.P. Williams
IN BRIEF
properties for a protein to gain entry into a uncovered hints as to how flies evolved “It really is an interesting issue from an compartment of a malaria parasite. The specialized neurons for sensing carbon evolutionary perspective,” he says. The compartment—a plastid—is essential for dioxide. research appears in the February 29, 2008, the parasite’s survival. Interfering with it The researchers, led by Lawrence issue of Science. could be a way to kill the parasite. The Zipursky, an HHMI investigator at the plastid is guarded by a cellular gatekeeper University of California, Los Angeles, were Diversity of the though, which lets only certain proteins examining flies for an unrelated study when Human Genome Revealed inside. they noticed a peculiar fly under the micro- By comparing nine human genomes, scien- Using a computer program, the scope. Most fruit flies have carbon dioxide- tists have produced the first high-resolution researchers looked for similarities among sensing neurons only in their antennae, but map showing the structural variation the 500 or so proteins that the gatekeeper this fly also had the neurons in the part of between individual genomes. Much genetic allows in. They found that all the proteins the nose called the maxillary palp. research focuses on identifying small differ- are at least 24 amino acids long, are posi- Looking closer at the mutant fly, they ences within single genes that can make a tively charged, and include the two amino found that the unusual neurons expressed person more susceptible to a disease. But a acids asparagine and lysine. So the both carbon dioxide-sensing receptors team of researchers led by HHMI investi- researchers designed new proteins fitting and another receptor for other odors typi- gator Evan E. Eichler at the University of this description. They reported in the cally detected by neurons in the maxillary Washington was curious whether an March 25, 2008, online edition of the palp. And following the path of the approach could be developed to systemati- Proceedings of the National Academy of neurons revealed that they led to two cally discover and sequence larger struc- Sciences that, as long as the proteins fit areas in the brain—responsible for inter- tural differences between people’s the guidelines that the computer preting the two senses. genomes: insertions, deletions, duplications, predicted, they were able to sneak into The researchers then found the genetic and inversions of large chunks of DNA. the malaria plastid. mutation responsible for the mixup. It Their comparison revealed that these “There is potential to use this relative codes for a short stretch of RNA—called a larger differences are extremely common. lack of sophistication in the system as a way microRNA—that can regulate the transla- In various parts of the genome, some to confound [the parasite],” says McFadden. tion of genes in neurons. Zipursky thinks people have segments that others don’t. In the hybrid neuron they stumbled on, and other areas, large genetic regions may be How Flies Sense Carbon Dioxide the gene responsible for it, represents an flipped. Across the nine genomes, the Carbon dioxide—an odorless, tasteless gas evolutionary intermediate that could have researchers found 1,695 regions with these to humans—is an important messenger in preceded the fly’s specialized carbon differences—all longer than 6,000 base the insect world. HHMI scientists have dioxide-sensing neurons. pairs. In some locations, they report in the Kevin Kevin Keating / Pyle lab
August 2oo8 | h h m i b u l l e t i n 49 lab book
Mysterious Protein Protects Against Sepsis Researchers find a link between a liver receptor and blood clotting.
One of the most deadly consequences of an infection is sepsis—a Marth’s team traced the origin of the receptors’ function by first drastic, full-body response characterized by inflammation and showing that a change in that specific glycoprotein decreases platelets blood clotting. in the blood. Marth realized that the pathogen Streptococcus pneu- A study led by HHMI investigator Jamey D. Marth of the monia also causes the same glycoprotein change, outside of the University of California, San Diego, reveals that a protein whose bloodstream, on its way to infecting cells. function has mystified scientists for decades helps protect against this To figure out whether there was a link between the Ashwell extreme response. receptor and the pathogen, the researchers infected normal mice and The protein—a receptor named after biochemist Gilbert those lacking the receptor with S. pneumonia. They saw that the Ashwell—coats liver cells in vertebrates (organisms with a backbone), bacteria caused glycoprotein alterations in two factors that lead to and binds to a specific type of glycoprotein. But its role during health blood clotting—von Willebrand Factor and platelets. The Ashwell or illness had not been defined. Mice engineered to lack the receptor receptors then recognized the modified glycoproteins and signaled the appeared healthy. liver to remove them from circulation. Mice without Ashwell receptors could not remove these coagula- tion factors and underwent more severe clotting and tissue damage, which increased the likelihood of death. Clinicians have assumed that a low platelet count during sepsis was the result of platelets being used up by the extreme blood clot- ting, but Marth’s research suggests something different. “It’s an adaptive response by the liver,” he says, “enabled by the Ashwell receptors.” The finding, published in the June 2008 issue of Nature Medicine, clears up many questions about the Ashwell receptor, but raises others, says Marth. “Does its protective response extend to Platelets and red blood cells clump together to form a blood clot, one other pathogens? Can it be employed to increase the chance of dangerous consequence of sepsis. human survival in severe sepsis?” p —Sarah C.P. Williams
IN BRIEF
May 1, 2008, issue of Nature, all nine it, the blindness would be reversed. branches within an individual neuron, genomes were different, while in others just They used a viral vector that infects cells known as dendritic branches, can also one or a few people had variants. and introduces a gene into the nucleus of become stronger, HHMI researchers have “What’s exciting to me,” Eichler says, “is the cells it enters. Because retinal cells don’t shown, offering a new complexity to how that we now have, in essence, eight new divide or get replaced, they didn’t have to information in the brain is stored. reference human genomes.” And, under- worry about the gene being copied—they Jeffrey C. Magee and his colleagues at standing their variations—which are just needed it to enter the nucleus. HHMI’s Janelia Farm Research Campus primarily caused when DNA misaligns It worked in a first, small clinical trial, the created a way to observe how a single during the process that produces sperm results of which appeared in the New neuron responds to stimuli. They exposed and eggs—could lead to a better under- England Journal of Medicine on May 22, only a small portion of a highly branched standing of diseases. 2008. Three patients—ages 19 to neuron to neurotransmitters and saw a 26—received injections of the gene-carrying spike of localized activity within the stimu- Novel Gene Therapy vector into the subretinal space. All three lated dendritic branch. Improves Vision experienced improved vision. “They went With continued stimulation the branch’s By introducing a genetic vector into the from only being able to see a hand moving activity got stronger, the scientists reported cells of the retina of the eye, researchers in front of them, to being able to read a few in the March 27, 2008, issue of Nature. Over have created a way to partially restore lines on an eye chart,” explains High. time, they observed, the localized activity vision to people with an inherited disease. The next steps, she says, are to increase became so strong that it propagated to the Leber congenital amaurosis (LCA), dosage and to try the treatment in younger main part of the neuron—the axon—and which can be caused by a missing enzyme children. caused a nerve impulse. This behavior— vital to regenerating rhodopsin in the eye stemming from the dendritic branches—is after exposure to light, causes blindness New Neural Mode of distinct from the strengthening of a signal early in life. The team of scientists, led by Information Storage in the synapse. The next step, Magee says, HHMI investigator Katherine High at the It’s not just the junction between two is to study living animals to determine Children’s Hospital of Philadelphia, reasoned neurons, called the synapse, that gets whether changing the environment of an that if they could get the gene for the stronger as information is repeatedly trans- animal leads to changes in the dendritic missing enzyme into the cells that needed mitted from one cell to the next. The branches. Steve Gschmeissner / Photo Researchers, Inc.
50 h h m i b u l l e t i n | August 2oo8 In Memoriam Jeremy R. Knowles 1935–2008 jeremy knowles, an accomplished scientist and an hhmi trustee, died april 3, 2008. he was 72 years old.
Jeremy R. Knowles, an HHMI Trustee for nearly a decade, particular delight in returning to the classroom upon step- died April 3, 2008, at his home in Cambridge, Massachusetts, ping down as Dean. following a long bout with prostate cancer. He was 72. Born in England, Knowles attended Magdalen College “Jeremy had a deep concern for and pride in the Institute School in Oxford and served as an officer in the Royal Air and its work and the highest of standards for its science Force before reading chemistry at Balliol College at Oxford and scientists,” said Hanna H. Gray, Chair of the Trustees. University, receiving his B.A. in 1959 and his D.Phil. in “His warmth and intelligence made him both loved and 1961. Upon completing a postdoctoral fellowship at the respected by his colleagues everywhere.” California Institute of Technology, Knowles returned to An accomplished chemist whose research traversed the Oxford as a Fellow and Tutor of Wadham College and was boundaries of chemistry and biochemistry, Knowles was appointed to a University Lectureship in 1966. known for his luminous intelligence, penetrating judgment, Knowles’ scientific interests lay at the intersection of elegant speech, and refined wit. He was a towering figure chemistry and biochemistry and he made lasting contribu- at Harvard University whose faculty he joined in 1974 as tions to understanding the chemistry of enzyme action. He Professor of Chemistry. He became Dean of the Faculty of returned to the United States in 1969 and 1971 as a Visiting Arts and Sciences in 1991, at a critical moment that required Professor in the Departments of Molecular Biophysics and firm leadership and a deft touch. He served for 11 years and Chemistry at Yale University before coming to Harvard in then reprised the role from 2006 to 2007. 1973 as Sloan Visiting Professor. Although he returned to “As an HHMI Trustee, Jeremy was completely engaged Oxford from 1983 to 1984, Knowles remained at Harvard in both the Institute’s scientific and educational activities. for the rest of his career in academia. Among many other contributions, he provided thoughtful The Harvard University Gazette, in recounting Knowles’ advice concerning the development of HHMI’s Janelia accomplishments, noted that he advised more than 50 Ph.D. Farm Research Campus,” said Thomas R. Cech, President recipients during his career at Oxford and Harvard and of the Institute. authored more than 250 research papers. He was elected a Knowles played an equally significant role in shaping Fellow of the Royal Society in 1977 and a Foreign Associate the vision of the Institute’s programs in science educa- of the National Academy of Sciences in 1988. He received tion and chaired a Trustee subcommittee that served as an many other honors and awards. important sounding board for new initiatives. That keen Knowles is survived by his wife, Jane; their three children, interest reflected his own commitment to teaching; he took Sebastian, Julius, and Timothy; and seven grandchildren. p Jon Chase Jon / Harvard News Office
AugustMay 2oo8 | h h m i b u l l e t i n 51 toolbox
Next-Generation Sequencing New sequencing technologies speed up large sequencing projects— for scientists prepared for a fl ood of data.
gail mandel, an hhmi investigator at the oregon to conduct experiments once considered too expensive or simply Health & Science University (OHSU), wanted to understand the impossible. role of a particular protein in nerve cell function. She wanted to In 1975, biochemist Frederick Sanger developed one of the fi rst prove that it was a master regulator for neuronal genes. Using tech- manual sequencing systems that enabled scientists to determine the niques she developed with colleagues at Brookhaven National order of the nucleotides—known by the letters A, T, C, and G—that Laboratory and OHSU, her lab prepared to sequence all the genes make up DNA. The process became automated in the 1980s. In in the mouse genome that bound this protein. Before they could today’s version of Sanger sequencing, each type of nucleotide is determine the extensive sequence of the thousands of DNA nucle- labeled with a different colored fl uorescent tag. DNA fragments otides, they had to prepare numerous pools of DNA, each differing by only a single nucleotide are separated on the basis of representing a particular section of the region to be sequenced. The size. Special optics detect the fl uorescent nucleotides, creating entire process took more than a year. images that can be “read” as a DNA sequence. Meanwhile, another group of researchers at Caltech studying Next-generation systems also analyze fragments of DNA but step up the same protein came up with virtually the same result. “Our data the process by multiplying the number of sequencing reactions that were very similar. But it took them much less time to get more occur on each piece of template DNA (see fi gure), yielding vastly more sequence information,” says Mandel. data. Solexa produces shorter DNA sequence reads than traditional While her lab’s approach relied on traditional sequencing methods of sequencing, but many more of them—up to 50 million methods that yield a maximum of 96 short stretches of DNA sequences in a single two-day run. 454 and SOLiD use different tech- sequence at a time, the other group used the “next-generation” niques for sequencing but likewise produce large amounts of data. Solexa sequencing platform from Illumina, Inc., which produces HHMI has purchased 15 of the $500,000 Solexa sequencers for tens of millions of DNA sequences in a single run. its investigators, and its investment in next-generation sequencing Welcome to the new world of warp-speed DNA sequencing. equipment is already paying dividends. Researchers agree that Solexa and two competing systems (the Joe DeRisi, an HHMI investigator researching malaria and Roche (454) GS FLX sequencer and the SOLiD sequencer from emerging viral diseases at the University of California, San Francisco, Applied Biosystems) represent a breakthrough in sequencing that gives the example of a fragment of a novel virus discovered in his lab
is speeding the pace of discovery, making it feasible for researchers a couple of years ago. Greg Hannon
52 h h m i b u l l e t i n | August 2oo8 A B C D Next-generation DNA In the Solexa sequencing The Solexa sequencing Though it may seem sequencers are designed system (Illumina, Inc.) strategy uses modified complex, the process to read sequences from two kinds of amplifica- nucleotides: each base works remarkably well. The a very large number of tion primers—short pieces bears a different fluores- Solexa platform permits individual DNA molecules of DNA—are fixed to a cent group that also blocks short sequence reads, with within a mixed sample. glass surface, much like further nucleotide addition. reliable reports of 50 nucle- However, not even the a microscope slide. Then, All four nucleotide bases otides being obtained from new techniques are sensi- the mixture of template are flowed simultaneously each template. Moreover, tive enough to truly read DNA fragments is added over the surface, and each the system can read tens of a sequence from a single to the slide, where indi- template can incorporate millions of DNA sequences molecule of DNA. Instead, vidual molecules bind at only a single nucleotide. A simultaneously. individual DNA strands random positions to the laser activates each fluo- must be immobilized and surface-bound primers. rescent group in turn and amplified in a fixed location Multiple cycles of amplifica- optics collect images of to form a group of many tion yield double-stranded the surface. The pattern identical strands that can DNAs, which are created of colored light emission provide enough signal for a by bridging between the can be used to read the sequence to be read. As a two types of surface- sequence directly from first step, DNA mixtures are bound primers. Because each spot (see magnifi- prepared by fragmenting each molecule of DNA cation at left). Once the the DNA to be sequenced can reach only so far, this fluorescent group and into small sizes (~100–500 approach tends to create blocking group are cleaved bases); then, defined snip- a “forest” of fragments at from the growing DNA pets of DNA are added a given spot on the slide. strand, the next base can be to the two ends of each By controlling the number read by precisely the same resulting fragment. of input DNA molecules, strategy. the density of the amplified spots can be set as desired.
“This virus was very different than anything that had ever been HHMI investigator Greg Hannon, whose team uses the published before,” he says. “A very talented postdoc threw every- Solexa instrument at Cold Spring Harbor Laboratory to study thing but the kitchen sink at this project, trying to sequence a gene regulation, says it produces a terabyte, or one trillion bytes, complete copy of the virus’ genome and was unable to do so.” of raw data. That’s more data than can be transferred easily via The DeRisi team was stumped. Last year, they began working the Internet. So his team started filling hard drives with the data with the Solexa sequencer and decided to revisit the problem. and “transferring” the information by foot to cars for delivery to They attempted to sequence the whole pool of DNA from which a data center. He calls this a “sneaker protocol.” That’s sneaker the virus fragment was isolated. as in shoes. “After a single run, we had recovered the entire genome in one “Many investigators are not prepared to deal with this large go. In two days we were able to accomplish in totality what we amount of data,” says Thomas Tuschl, an HHMI investigator at couldn’t in over a year of hard trying,” says DeRisi, whose team is Rockefeller University who studies the role of RNA in gene preparing to publish their discovery. silencing. “They do two runs and then they’ll spend a year trying DeRisi points out that the new technologies are not a replace- to build up the software to interpret it.” ment for traditional sequencing methods, which are ideal for Over the years, Tuschl has built relationships with experts in sequencing a very specific piece of DNA. But because of the ability bioinformatics, who have built software to handle his deluge of of the new technologies to tackle large projects or complex mixtures data. He expects the new platforms will double the pace of of DNA, he and other HHMI researchers have great expectations. discovery in his lab, while lowering costs fivefold. Cancer researcher Bert Vogelstein, an HHMI investigator at Hannon, also, isn’t put off. “This is the natural evolution of Johns Hopkins University, can now go through millions of genes to every technology. It goes from the effort required to learn to drive a find the rare, tumor-specific ones that provide clues about the car to thinking about where you’re going to go.” origins of disease—and about targets for therapy or cancer tests. As for Mandel, her experience convinced her to purchase a “Before, it was just too expensive to study a lot of patients, but Solexa system. She says Solexa will not only give her more data now we can,” Vogelstein says. more quickly, it will also enable her to piece together more easily The technology isn’t without its challenges, however. For example, the big picture of the proteins involved in neurological function. p the new systems spew out data with the force of a fire hose. – Howard Wolinsky
August 2oo8 | h h m i b u l l e t i n 53 nota bene
spotlight
National Academy of Sciences Elects HHMI Scientists
top row: Michael Bevan, Gail Mandel, David Mangelsdorf, Gary Struhl bottom row: Jasper Rine, Michael Botchan, Janet Rossant
A total of four HHMI investigators, one HHMI professor, and two members of HHMI advisory boards were elected to the National Academy of Sciences in April 2008. They were among 72 new members and 18 foreign associates elected in recognition of their distinguished and continuing achievements in original research. In addition to these new members, 120 HHMI investigators are members of the Academy. The investigators are Michael J. Bevan, University of Washington School of Medicine; Gail Mandel, Oregon Health & Science University; David J. Mangelsdorf, University of Texas Southwestern Medical Center at Dallas; and Gary Struhl, Columbia University College of Physicians and Surgeons. The HHMI professor is Jasper Rine, University of California, Berkeley. Michael R. Botchan, a member of the HHMI medical advisory board, and Janet Rossant, a member of the HHMI scientific review board, were also elected.
Philip A. Beachy, an HHMI investigator members elected to the American Academy University. HHMI Trustee James A. at the Stanford University School of of Arts & Sciences in April 2008. The inves- Baker, scientific review board member Medicine, received the 2008 March of Dimes tigators are Graeme I. Bell, University of Mary Beckerle, and medical advisory Prize in Developmental Biology. He shares Chicago; Linda B. Buck, Fred Hutchinson board member Bruce W. Stillman were the award, recognizing original research on Cancer Research Center; Lawrence S. B. also elected. how genes regulate organ growth during Goldstein, University of California, San embryonic and fetal development, with Diego; John Kuriyan, University of The National Marfan Foundation awarded Clifford J. Tabin of Harvard Medical School. California, Berkeley; Stephen G. HHMI investigator Harry C. Dietz of Lisberger, University of California, San The Johns Hopkins University School of HHMI investigator Michael J. Bevan, Francisco; Craig C. Mello, University of Medicine with a “Hero with a Heart Award” an immunologist at the University of Massachusetts Medical School; Norbert for his commitment to clinical medicine Washington, received the 2008 Cancer Perrimon, Harvard Medical School; and research on Marfan syndrome. Research Institute William B. Coley Award Louis J. PtáCˇek, University of California, for his research on T cells. San Francisco; and Leonard I. Zon, Jo Handelsman, an HHMI professor at Children’s Hospital Boston. The professors the University of Wisconsin–Madison, Nine HHMI investigators, three HHMI are Utpal Banerjee, University of received the 2008 American Society for professors, one Trustee, and two members of California, Los Angeles; Jasper Rine, Microbiology Roche Diagnostics Alice C. the Institute’s advisory boards are among the University of California, Berkeley; and Evans Award. The annual award recognizes
190 new fellows and 22 foreign honorary Huntington F. Willard, Duke contributions toward the advancement of Bevan: Clare McLean Mandel: C. Bruce Mangelsdorf: Forster Rine: Fetters Charles Struhl: George Ford Paul Nikitin ©HHMI / AP, Botchan: Michael Botchan Rossant: Hospital The for Sick Children, Research Institute
54 h h m i b u l l e t i n | August 2oo8 women in microbiology. Handelsman spotlight researches the structure and function of microbial communities and is codirector of the Women in Science and Engineering Steitz Wins Albany Prize Leadership Institute at the University of Wisconsin. HHMI investigator Joan A. Steitz of the Yale University School of Medicine and Elizabeth H. Blackburn of the University HHMI investigator David Haussler of of California, San Francisco, were the first the University of California, Santa Cruz, was two women to receive the Albany Medical awarded the 2008 International Society for Center Prize in Medicine and Biomedical Computational Biology Senior Scientist Research. The prize, awarded annually Accomplishment Award. The prize recog- since 2001, honors innovative biomedical research. Steitz studies RNA and is best nizes his pioneering use of mathematical known for discovering and defining the computer models for analyzing DNA, RNA, function of small nuclear ribonucleopro- and protein sequences. teins—complexes of RNA and proteins Joan Steitz that are involved in splicing introns from RNA strands. HHMI investigator Wayne A. Hendrickson of Columbia University received the Kaj Linderstrøm-Lang Prize for 2008 from the Kaj Linderstrøm-Lang Endowment Fund in recognition of his Ricketts Award from the University of Foundation in recognition of his contribu- work in the field of structural biology. Chicago. The annual award is given in tions to fruit fly genomics. memory of Dr. Ricketts, the scientist for Arthur L. Horwich, an HHMI investi- whom the Rickettsia class of microorganisms Karel Svoboda, a group leader at gator at the Yale University School of is named. Medzhitov studies the immune HHMI’s Janelia Farm Research Campus, Medicine, received the 2008 Lewis S. system and how it detects and becomes acti- received the 2008 Gill Young Investigator Rosenstiel Award for Distinguished Work in vated by infection. Award from the Linda and Jack Gill Center Basic Medical Science from Brandeis for Biomolecular Science at Indiana University. He shared the annual award with HHMI investigator Jack W. Szostak was University, Bloomington. Professor Ulrich Hartl of the Max Planck awarded the 2008 Dr. H.P. Heineken Prize Institute. Horwich studies how chaperonin for Biochemistry and Biophysics—an inter- Debi Thomas, a junior in the HHMI helps proteins fold and how protein misfolding national prize given by the Royal Netherlands Biology Undergraduate Scholars Program at causes neurodegenerative disease. Academy of Arts and Sciences. Szostak is one the University of California, Davis, was one of the forefathers of today’s genetic research of two recipients of the 2008 Pauletta and Tyler Jacks, an HHMI investigator at the with “knockout mice” and has conducted Denzel Washington Family Scholar in Massachusetts Institute of Technology, was pioneering research on telomeres. His recent Neuroscience Award. named president-elect of the American work explores the origin of life. Association for Cancer Research, the world’s HHMI investigator Arthur Weiss of the oldest and largest cancer research organization. HHMI investigator H. Sebastian Seung University of California, San Francisco, was of the Massachusetts Institute of Technology elected president of the American Association HHMI investigator Thomas M. Jessell received the 2008 Ho-Am Prize in of Immunologists. of Columbia University was a recipient of Engineering for his mathematical models of the first annual Kavli Prize in Neuroscience neural networks in the brain. The Ho-Am The University of North Carolina at Chapel for his research on how neural cells assemble Prize is an annual Korean award for Hill named HHMI investigator Huda Y. into circuits. He shares the prize with Pasko outstanding research. Zoghbi of Baylor College of Medicine as the Rakic of Yale University. recipient of the 2008 Perl-UNC Neuroscience Allan C. Spradling, an HHMI investi- Prize. The annual prize recognizes a seminal Ruslan M. Medzhitov, an HHMI inves- gator at the Carnegie Institution of achievement in neuroscience and was tigator at the Yale University School of Washington, won the 2008 Gruber Genetics awarded to Zoghbi for her 1999 discovery of
Paul Fetters Paul Medicine, received the Howard Taylor Prize from the Peter and Patricia Gruber the gene responsible for Rett syndrome.
August 2oo8 | h h m i b u l l e t i n 55 continued from page 25 tist at Stanford who has developed a range of optical “needles,” fiber (add 56) optic filaments honed into microscope lenses from 350 micrometers microscope beam, a cryogenic “plunge freezing” to fix a biological to 1,000 micrometers in diameter (a human hair is about 85 microm- sample, and a motor-driven stage to tilt it, one degree at a time, eters across). These are the eyes of a “microendoscope” that can be in- through two axes while a charge-coupled device camera reels off serted into the deep brain structure of a living, moving mouse. Using still shots of the sample. This river of images and positional data laser pulses and fluorescent dyes, Schnitzer focuses his microendo- flows to a tomographic computer program, which merges it all and scope on individual neurons or up to a hundred brain cells at a time. calculates three-dimensional models. With those, Jensen makes Schnitzer’s science goes far beyond gee-whiz technology. His in- moving pictures of things once invisible. It is visually startling, sertable microscope is already moving toward human applications technically astounding work but is balanced by other interests in to guide surgeons to better placements of cochlear implants or give Jensen’s life. His highest priorities are his wife and their six children. researchers the inside view of muscle contractions at the level of sar- “I am a family man,” he says simply. Jensen spends time each week comeres, the basic contractile unit in striated muscle. “In imaging driving to piano, violin, and dance lessons; coaching basketball and science, the data can be both informative scientifically and beauti- soccer; and camping with scouts. “At night, I read bedtime stories to ful to the eye,” he says. Schnitzer sees the wonder all right. p kids and sometimes rock our baby to sleep,” says Jensen. Most of all, scientists have no sense of wonder: Which brings us to FOR MORE INFORMATION: To learn more about the new 56, see HHMI investigator Mark Schnitzer, a physicist turned neuroscien- www.hhmi.org/news/20080527.html.
continued from page 31 What’s more, two drugs already on the Of what comes next, Massagué is (The Unintentional Scientist) market—Erbitux and Celebrex—can coun- circumspect. “I don’t know. I’m the guy Among the things he has discovered teract the action of these genes in mouse who initially was thinking in terms of five from those wrongdoers: cells both start out studies. Clinical trials may begin as soon as more months,” he laughs. Then his ambi- with the capacity to metastasize and a year from now, says Norton, who is collab- tion surfaces and he gets serious. “Right acquire it later. (Previous theories had orating with Massagué on this work. now we are in the thick of deconstructing been in the either/or category.) His team Meanwhile, Massagué’s team has also genes to see how they are used in metas- also discovered that many of the genes discovered that certain microRNAs—small tasis and how one can intervene. I see that support metastasis need to work in nucleotides that suppress gene function— myself, for at least another five years, concert to achieve their goal. Activating are in short supply in some metastatic cells, wholly pushing, painting this new canvas: just one or two of them doesn’t do the suggesting, again, that a brake has been metastasis.” TGF beta, he says, has recently trick. In 2003, he reported on the gene turned off somewhere. Adding them back been implicated in metastasis of breast combination found in breast cancer cells to cells appears to turn off genes involved cancer to the lung—a neat connection of that are prone to spread to the bone. More in cell proliferation and migration, neutral- his work that he intends to explore. recent research by Massagué, published izing the cells’ ability to spread. There are, he says, plenty of questions in 2007, has focused on four genes that “If you silence the genes with microRNA to be asked—and answered. Why, for regulate blood vessel growth and appear to molecules, or you silence their products example, do different types of breast cancer be critical to the spread of breast cancer to with drugs that work against them, you migrate to the same organs—but use the lungs. accomplish a synergistic slow down of metas- different genes to do so? He’s finally Experiments in mice revealed that tasis,” Massagué says. “In the pharmaceutical thinking about career trajectories—but silencing these genes individually decreased armamentarium we have, there may already maybe someone else’s. “One could start a tumor cells’ ability to set up house in the be many things that one can resort to while career studying metastasis in his or her lungs and that silencing them all basically waiting the proverbial 10 to 15 years to thirties and retire having worked on shut the tumor down. develop a drug on a newly found target.” nothing else.” p
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