Hhmi Bulletin

HHMI BULLETIN

M ay ’06 Vo l .19 • N o . 0 2 •

Howard Hughes Medical Institute HHMI BULLETIN •

www.hhmi.org Courtesy of Ulrich von Andrian, Katharina Engelke, and Harry Leung Courtesy of Ulrich

Even static images of a moment captured in time can suggest Peering Into a movement. In this section through a bone marrow cavity in the skull of a live mouse, rapid blood flow (green) can be seen in the upper portion of the vessel on the right. Nuclei and mito- Skull’s Marrow chondria, stained red, can be seen in the blood-forming cells that adhere within the vessels. The cavity is enclosed in solid bone, which appears black.

The dynamic–and unanticipated–choreographyaction! nonprofit org. of the immune system us postage paid 4000 Jones Bridge Road Hyattsville, md Chevy Chase, Maryland 20815-6789 permit no. 61 www.hhmi.org

Change Service Requested vol. 19 / no.

In this issue: Modern Mitochondria • Archiving • Dancing the Human Genome 02

Observations

Answering Socrates

Knowing, from a career’s worth of research, how faulty our memories really are, Columbia University neuroscientist Eric R. Kandel saved four decades of written correspondence, personal mementos, the minutes of every Society of Neuroscience annual meeting, and more. The HHMI investigator and Nobel laureate tapped deeply into that lode to write a memoir on his lifelong search for the physical basis of memory. Kandel donated his collected miscellany to 38 the Columbia University library, which Apple as metaphor will curate his archives. Extolling the singular beauty of every apple, Liz Lerman For biologists working on the brain, the mind Dance Exchange performers loses none of its power or beauty when experi- ponder the potential impact— mental methods are applied to human behavior. good and bad—of genetic Likewise, biologists do not fear that the mind research on our lives. The will be trivialized by a reductionist analysis, production had input from which delineates the component parts and HHMI-supported scientists, activities of the brain. On the contrary, most educators, and students. scientists believe that biological analysis is likely to increase our respect for the power and complexity of the mind. Indeed, by unifying behaviorist and cogni- tive psychology, neural science and molecular biology, the new science of mind can address philosophical questions first raised in Western thought more than twenty-five hundred years ago. Ever since Socrates and the early Platonists speculated about the nature of the human mind, serious thinkers have struggled with certain questions: How does the mind acquire knowledge of the world? How much of the mind is inherited? Do innate mental functions impose on us a fixed way of experiencing the world? What physical changes occur in the brain as we learn and remember? How is an experience lasting minutes converted to a lifelong memory? Such questions are no longer the province of speculative metaphysics; they are now fertile areas of experimental research.

From the book In Search of Memory: The Emergence of a New Science of Mind, by Eric R. Kandel, M.D. ©2006 Eric. R. Kandel. Reprinted here with permission of the publisher, W.W. Norton & Company. Michael Mazzola Illustration: Shonagh Rae vol. 19 / m a y ’0 6 / no. 02

3 38 50 DEPARTMENTS President’s Letter Perspectives and Opinions Chronicle: Lab Book Reshaping the Landscape Liz Lerman, Philip Silverman, From Tree to Harpoon / Hamster Chill

and Q&A Time / Shining Light on Vitamin B12

4 44 53 Centrifuge Chronicle: Science Education Chronicle: Ask a Scientist Flying Indoors / Major League Twenty More Renaissance Profs / Is it possible to “steal” the genes of Med Student / Into the Wilds— Undergraduates Abroad / Making It successful performance horses—for and Music Relevant to Human Health / Awards example, by pulling a few hairs—and Bring Science to the Community / create genetic copies through cloning? Gilliam Fellows Reward Determination 8 49 54 Upfront Chronicle: Institute News Chronicle: Nota Bene Where the Antigens Are / Evolution Edward Palmerino Named Vice News of recent awards and other of a Dance / A Few Good Neurons / President for Finance and Treasurer notable achievements Whittling Thousands to a Few

Inside Back Cover Observations Answering Socrates features

16 22 28 33

Lymphocytes, There’s Gold The Powerhouse— Extreme Shopping Camera, Action! in Those Archives and Sentinel—of To design, stock, and staff Digital video vignettes of the Scientists need to store all the Cell the Janelia Farm Research immune system in action are of their data, not just what’s Mitochondria are doing Campus, a handful of creative opening scientists’ eyes. published. more than just keeping the planners are doing some [COVER STORY] cell’s furnace stoked. major procuring.

VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND RELEVANT LINKS: http://www.hhmi.org/bulletin COVER IMAGE: JONATHON ROSEN contributors president’s letter

Reshaping the Landscape

Marc Wortman’s career demonstrates the lifelong value of a liberal arts education. Since earning Motorists traveling this spring through Ashburn, a doctorate in comparative literature at Princeton, he gains a fresh education in the biomedical (1) Virginia, on Leesburg Pike might think that construction of sciences each time he writes an article. He is an award-winning freelancer whose work has appeared in many national publications. His book, The Millionaires’ Unit: The Aristocratic Flyboys Who HHMI’s Janelia Farm Research Campus had just commenced, Fought the Great War and Invented American Air Power, appeared in bookstores this month. (1) particularly if they happened to see numerous tractors crawling

After earning her doctorate in biochemistry at the University of Washington in Seattle, Rabiya over the landscape moving massive dirt piles. No laboratory Tuma launched a freelance writing career in 2001. Now based in Berkeley, California, she is a building is in plain sight and, after 4 years of furious activity, the regular contributor to the Economist and a corresponding writer for Oncology Times, the Journal of the National Cancer Institute, and the Journal of Cell Biology. Her work has also been published (3) (2) most visible changes on the property are four squat, cylindrical in CURE, Discover, O Magazine, SELF, and The New York Times. (2) towers sheathed in corrugated metal. Appearances are deceptive. In fact, Janelia Farm is poised to An award-winning photographer who has covered stories from Iraq to Chiapas to Northern Ireland, Jason Grow has also photographed lots of really smart people in the worlds of finance, begin operation, with the first group of neuroscientists, physicists, “As in the literal landscape that’s computers, software, medical research, and just about everything in between, for clients as and computer scientists expected to move into their laboratories by diverse as Time, BusinessWeek, Sports Illustrated, and Forbes. A transplant to the East Coast growing up around Janelia Farm, from San Francisco, he now makes his home in Gloucester, Massachusetts, with his wife, Sarah, midsummer. Some will aim to trace neuronal circuits responsible we do believe that the constituent and three daughters, whose surfing skills are quickly surpassing his. Grow is a recently elected (4) for complex behavior while their colleagues invent new micro- City Councilor for Gloucester. (3) scopes for functional imaging to blaze the trail. parts will combine in surprising Karyn Hede is a science writer and editor based in Richland, Washington, who has written on Inside the low-profile, terraced structure that looks out toward ways. topics ranging from the genetics of autism to how the Pacific atolls formed. Her freelance stories have appeared in Scientific American, New Scientist, and MIT’s Technology Review, among oth- the Potomac River, the atmosphere has been anything but calm. thomas cech er publications; she is currently a news correspondent for the Journal of the National Cancer Equipment, laboratory cabinets, and furniture have been pouring in . A recent accomplishment of which she is exceptionally proud is helping to preserve a ” Institute for months, and are being installed by several hundred workmen. local mountain in its natural state. (4) A reshaped landscape is forming around the research building. graduate program with our international partners, the University of More than 100 different types of plants and trees are being put Chicago and the University of Cambridge. in place, drawn from sources around the country and the world. Participation by HHMI’s university-based investigators has HHMI TRUSTEES HHMI OFFICERS They range from Little Bluestem prairie grasses (native to North been—and will continue to be—essential to the success of our fledg- James A. Baker, III, Esq. Thomas R. Cech, Ph.D. / President America) and Dawn Redwood trees (presumed extinct until redis- ling campus. They have worked with Rubin and outside scientists Senior Partner / Baker & Botts Craig A. Alexander / V.P. & General Counsel covered in China) to three century-old spreading yews that once to shape the research program. They have spent countless hours Richard G. Darman Peter J. Bruns, Ph.D. / V.P. for Grants & Special Programs Partner / The Carlyle Group David A. Clayton, Ph.D. / V.P. & Chief Scientific Officer formed part of a maze in the State of Washington. helping review and evaluate candidates. We also expect them to be Chairman of the Board / AES Corp. Joseph D. Collins / V.P. for Information Technology It’s hard to believe that 7 years have passed since David Clayton, among the first—and most enthusiastic—visitors to Janelia Farm Frank William Gay Joan S. Leonard, Esq. / Senior Counsel to the President Gerry Rubin, and I first began discussing a possible new direction this coming fall when we hold a series of scientific meetings at Former President & CEO / SUMMA Corporation Avice A. Meehan / V.P. for Communications & Public Affairs Joseph L. Goldstein, M.D. Edward J. Palmerino / V.P. for Finance & Treasurer within HHMI’s science program. After the initial scientific planning, the campus. In addition, as new microscopes and computational Professor & Chairman, Department of Molecular Genetics Gerald M. Rubin, Ph.D. / V.P. & Director, Janelia Farm Research Campus Bob McGhee’s steady vision and guidance as Institute architect have methods begin to emerge from the laboratories at Janelia Farm, our University of Texas Southwestern Medical Center at Dallas Landis Zimmerman / V.P. & Chief Investment Officer kept the project on track. He organized the writing of the initial investigators will be among the first to have the opportunity to work Hanna H. Gray, Ph.D., Chairman HHMI BULLETIN STAFF President Emeritus & Harry Pratt Judson program document we used to select Rafael Viñoly as the architect with these tools and, we hope, will play a critical role in their devel- Distinguished Service Professor of History Mary Beth Gardiner / Editor for the campus, and he consistently provides a mix of hard-edged opment. The University of Chicago Cori Vanchieri / Story Editor project management and visionary ideas for laboratory design. Janelia Farm represents a mix of the historical and the exper- Garnett L. Keith Jim Keeley / Science Editor SeaBridge Investment Advisors, L.L.C. Jennifer Donovan / Education Editor This issue of the HHMI Bulletin offers a behind-the-scenes imental. We’ve drawn inspiration from some long-famous Former Vice Chairman & Chief Investment Officer Patricia Foster / Associate Director of Communications glimpse at what it takes to equip a facility like Janelia Farm—as institutions, including Bell Labs in Murray Hill, New Jersey, and The Prudential Insurance Company of America for Web & Special Projects well as a look at the operational team, led by Cheryl Moore, that is the MRC Laboratory of Molecular Biology in Cambridge, England. Jeremy R. Knowles, D.Phil. Dean Trackman, Maya Pines / Contributing Editors Dean Emeritus & Amory Houghton Professor of Additional ContrIButors charged with getting the campus up and running. Moore, the chief Indeed, many of the physicists and biologists we have recruited have Chemistry & Biochemistry / Harvard University Laura Bonetta, Cay Butler, Nicole Kresge, operating officer for Janelia Farm, has assembled an extraordinary ties to Bell Labs or the MRC and are eager to return to an envi- William R. Lummis, Esq. Steven Marcus, Kathy Savory team of experts in the areas of scientific support, information ronment that supports small, highly interactive research groups. Former Chairman of the Board of Directors & CEO VSA Partners, NYC / Concept & Design The Howard Hughes Corporation technology, facilities, conference services, finance, and human Yet Janelia Farm differs from its historical models and is based on Paul M. Nurse, Ph.D. resources. Each team member is focused on creating an environ- what Gerry Rubin likes to describe as a working hypothesis, that its President / The Rockefeller University ment that will support the novel research culture at Janelia Farm. distinctive culture will foster unusually creative research. Kurt L. Schmoke, Esq. Dean / Howard University School of Law As Moore has focused on the myriad operational details, We won’t know for many years whether Janelia Farm will succeed Anne M. Tatlock Telephone (301) 215.8855 • Fax (301) 215.8863 • www.hhmi.org Director Gerry Rubin and Kevin Moses, the associate director for in generating discoveries that will alter the scientific landscape. As Chairman & CEO / Fiduciary Trust Company International ©2006 Howard Hughes Medical Institute science and training, have continued their recruiting efforts. To in the literal landscape that’s growing up around it, we do believe The opinions, beliefs, and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reflect the opinions, beliefs, viewpoints, add to the eight group leaders who will move into Janelia Farm that the constituent parts will combine in surprising ways. or official policies of the Howard Hughes Medical Institute. later this year, they have identified a new crop of candidate group

Photos courtesy of Marc Wortman, Rabiya Tuma, Jason Grow, and Karyn Hede Jason Tuma, Rabiya Photos courtesy of Marc Wortman, Fetters Paul leaders and fellows. Meanwhile, Moses has begun to shape a

2 hhmi bulletin | May 2006 May 2006 | hhmi bulletin 3 president’s letter

Reshaping the Landscape

Motorists traveling this spring through Ashburn, Virginia, on Leesburg Pike might think that construction of HHMI’s Janelia Farm Research Campus had just commenced, particularly if they happened to see numerous tractors crawling over the landscape moving massive dirt piles. No laboratory building is in plain sight and, after 4 years of furious activity, the most visible changes on the property are four squat, cylindrical towers sheathed in corrugated metal. Appearances are deceptive. In fact, Janelia Farm is poised to begin operation, with the first group of neuroscientists, physicists, “As in the literal landscape that’s and computer scientists expected to move into their laboratories by growing up around Janelia Farm, midsummer. Some will aim to trace neuronal circuits responsible we do believe that the constituent for complex behavior while their colleagues invent new microscopes for functional imaging to blaze the trail. parts will combine in surprising Inside the low-profile, terraced structure that looks out toward ways. the Potomac River, the atmosphere has been anything but calm. thomas cech Equipment, laboratory cabinets, and furniture have been pouring in ” for months, and are being installed by several hundred workmen. A reshaped landscape is forming around the research building. graduate program with our international partners, the University of More than 100 different types of plants and trees are being put Chicago and the University of Cambridge. in place, drawn from sources around the country and the world. Participation by HHMI’s university-based investigators has They range from Little Bluestem prairie grasses (native to North been—and will continue to be—essential to the success of our fledg- America) and Dawn Redwood trees (presumed extinct until redis- ling campus. They have worked with Rubin and outside scientists to covered in China) to three century-old spreading yews that once shape the research program. They have spent countless hours helping formed part of a maze in the State of Washington. review and evaluate candidates. We also expect them to be among It’s hard to believe that 7 years have passed since David Clayton, the first—and most enthusiastic—visitors to Janelia Farm this coming Gerry Rubin, and I first began discussing a possible new direction fall when we hold a series of scientific meetings at the campus. In within HHMI’s science program. After the initial scientific planning, addition, as new microscopes and computational methods begin to Bob McGhee’s steady vision and guidance as Institute architect have emerge from the laboratories at Janelia Farm, our investigators will kept the project on track. He organized the writing of the initial be among the first to have the opportunity to work with these tools program document we used to select Rafael Viñoly as the architect and, we hope, will play a critical role in their development. for the campus, and he consistently provides a mix of hard-edged Janelia Farm represents a mix of the historical and the experi- project management and visionary ideas for laboratory design. mental. We’ve drawn inspiration from some long-famous institutions, This issue of the HHMI Bulletin offers a behind-the-scenes including Bell Labs in Murray Hill, New Jersey, and the MRC glimpse at what it takes to equip a facility like Janelia Farm—as Laboratory of Molecular Biology in Cambridge, England. Indeed, well as a look at the operational team, led by Cheryl Moore, that many of the physicists and biologists we have recruited have ties to is charged with getting the campus up and running. Moore, the Bell Labs or the MRC and are eager to return to an environment chief operating officer for Janelia Farm, has assembled an extraor- that supports small, highly interactive research groups. Yet Janelia dinary team of experts in the areas of scientific support, information Farm differs from its historical models and is based on what Gerry technology, facilities, conference services, finance, and human Rubin likes to describe as a working hypothesis, that its distinctive resources. Each team member is focused on creating an environ- culture will foster unusually creative research. ment that will support the novel research culture at Janelia Farm. We won’t know for many years whether Janelia Farm will succeed As Moore has focused on the myriad operational details, in generating discoveries that will alter the scientific landscape. As Director Gerry Rubin and Kevin Moses, the associate director for in the literal landscape that’s growing up around it, we do believe science and training, have continued their recruiting efforts. To that the constituent parts will combine in surprising ways. add to the eight group leaders who will move into Janelia Farm later this year, they have identified a new crop of candidate group

Paul Fetters leaders and fellows. Meanwhile, Moses has begun to shape a

May 2006 | hhmi bulletin centrifuge hhmi

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WHERE THE ANTIGENS ARE PG.8 EVOLUTION OF A DANCE PG.10 A FEW GOOD NEURONS PG.12 In allergy research, scratching the surface has Artists, scientists, and ethicists collaborate on a Remembrances of things past do not necessarily made for a surprising advance. multimedia exploration of genetic science. involve a great many nerve cells.

WHITTLING THOUSANDS TO A FEW PG.14 The key to identifying yeast proteins of interest is to get a handle on them.

upfront It’s sneezin’ season again. If your drippy nose and watery eyes seem worse than usual this spring, you are not alone. Allergy specialists around the world say hay fever has reached “epidemic proportions.” Pollen is often the culprit this time of year when trees, grasses, and weeds reawaken. Molecules on pollen’s bumpy surface may be the key, according to some HHMI researchers. Understanding their role may open new avenues for preventing those irritating sniffles and the more serious health risks of asthma.

May 2006 | hhmi bulletin 7 upfront

Where the Antigens Are In allergy research, scratching the surface has made for a surprising advance.

A patient reported a n a l l e r g i c

reaction after eating strawberries, yet came up negative on conventional skin testing. So the doctor tried something unconventional. He applied the juice of a fresh straw- berry—as opposed to processed extracts—directly to the skin, and got the reaction his patient described. HHMI investigator Daphne Preuss, a plant biologist, likes to share this story of her physician friend. “It tells us that we’re missing something when it comes to allergies,” she says. “We need greater diagnostic precision, and treatments that home in on the exact allergens involved in a reaction.” Her work could make that happen. In collaboration with HHMI investigator Albert Bendelac, Preuss is identifying the molecular components of pollen cells that may hold the key to innovative detection and therapy for allergies. Several years ago Preuss was investigating how female plant structures recognize a “fit” among the thousands of male pollen grains that arrive on the wind or are dropped by bees. In the process of identifying “recognition genes” that code for proteins on the outer surface of pollen cells, Preuss began to wonder if these extracellular surface

proteins might also be involved in allergies. Illustration: Brian Cronin

hhmi bulletin | May 2006 Plant biologist Daphne Preuss and immunologist Albert Bendelac study why pollen triggers allergies. “In the process of working out methods for purifying surface materials from many

If pollen’s surface molecules have been Preuss is indeed moving in this direction different pollen overlooked as causative factors in allergies, in the search for human genes associated species, we’ve been it is largely because skin-testing extracts are with immune responses and the identifi- able to demonstrate “washed,” a process that removes the outer coat. cation of plant cell fractions that contain “Inadvertently, conventional preparations led allergens. As an alternative to current allergy that humans create to purification of mostly molecules inside the testing, which screens for pollen allergies antibodies to pollen’s pollen cell,” Preuss says. She arranged for her but doesn’t usually tease out which species outer coat. lab to receive unwashed batches of pollens. In elicit allergic reactions in genetically predis-

the process of learning how to extract surface posed individuals, she and her colleagues daphne preuss materials from many different pollen species, have designed a diagnostic chip that carries ” Preuss noted that pollen’s outer coat carries extracts of pollen material. “These extracts many lipid compounds. are primarily protein from 22 different Preuss presented her work at the annual Enter Bendelac, an immunologist whose species. We probe the chip with patient sera meeting of the American Academy of Allergy, work has been instrumental in demonstrating and can detect specific antibodies,” Preuss Asthma, and Immunology on March 3. “By that lipids are involved in inflammation, a says. “In the process of working out methods discovering the specific antigens that elicit biological phenomenon now understood to be for purifying surface materials from many allergic responses,” adds Weiss, “it may be a critical factor in such maladies as diabetes, different [unwashed] pollen species, we’ve possible to alter or prevent those responses.” heart disease—and asthma and allergies. been able to demonstrate that humans And at that point, adds Preuss, “We will be “Lipids are a major component of create antibodies to pollen’s outer coat. This looking at new therapeutic opportunities.” p pollens,” Bendelac says, “and when immune is an exciting proof of concept.” — R i c h a r d C u r r e y cells encounter lipids, they release hormone- like factors that orchestrate inflammation and immune responses.” Bendelac has devised The Big Pic t u r e Gesundheit! sensitive assay techniques that detect these

immune responses to lipids—techniques that R agweed is one of the most prolific producers of allergy-causing pollen.A single ragweed have proved integral to Preuss’s research. plant can generate a million grains of pollen a day. And, no doubt about it, those light, dry In addition to surface lipids, Preuss is grains can travel. Scientists have collected samples of ragweed pollen 400 miles out at exploring the allergenic properties of pollen sea and 2 miles high in the air, according to the National Institutes of Health. >> Fl amboyant surface proteins. HHMI investigator Arthur f l ow e r s usually aren’t the culprits in seasonal allergies. The types of pollen that most commonly cause allergies are produced by the more unassuming—and abundant—plain- Weiss, a clinical immunologist based at the looking plants, such as trees, grasses, and weeds. When allergy-causing pollen lands on the University of California, San Francisco, mucous membranes of the nose, local mast cells release a chemical called histamine. As a notes that “a vital aspect of Daphne Preuss’s result, small blood vessels in the nose dilate, nasal passages swell, and congestion results. work is understanding the properties of Histamine also causes itching, irritation, and excess mucous production. Prostaglandins pollen’s surface antigens that make them so and leukotrienes play a role in allergy symptoms as well. >> Cu rr e n t a l l e rgy t r e at- work to block histamines, constrict blood vessels to reduce swelling, or inhibit immunogenic. Knowing that might lead to m e n t s mucous production. Most of those products have annoying side effects, such as drowsi- a better understanding of why allergies ness, while others take several days or weeks to work. Allergy shots—injected diluted develop in the first place, and why they extracts of pollen under the skin—are expensive and time-consuming (they have to be

Photos: Lisa Predko develop in response to specific stimulants.” given many times with gradually increasing doses), and don’t work for everyone.

May 2006 | hhmi bulletin upfront

Evolution of a Dance Artists, scientists, and ethicists collaborate on a multimedia exploration of genetic science.

At center stage, Martha Wittman—a dancer in her 70 s —contemplates a partially peeled apple that she holds in her hand. Noting the resemblance of the peel to the spiral shape of DNA, she reflects on the many varieties of apples, how different they look and taste, and the many wonderful ways her mother used to prepare them. ¶ A younger dancer bursts onto Grabel had kept her dance and science the stage in a wheelchair. Born with osteogenesis—an inherited disorder separate for 30 years, noting, “There’s not that causes bones to break easily—she dances defiantly on wheels, and much call for a dancing biologist,” she found Lerman’s idea provocative. then on crutches, whirling among Wittman and other more able-bodied After that meeting, Wesleyan invited the members of the Liz Lerman Dance Exchange. The fury of the scene recedes, Dance Exchange, based in Takoma Park, Maryland, to establish a residency program and Wittman wanders off the stage, admiring her apple and shaking her at the university, using the Connecticut head at the thought of genetic manipula- campus as home base for the genome tions that might render all apples uniformly dance project. Lerman immersed herself in red and tasteless. “No more tart surprises,” the history of genetics and consulted with she sighs. biologists at Wesleyan and elsewhere. She In Ferocious Beauty: Genome, choreogra- also learned from the students. An HHMI pher Liz Lerman and HHMI investigator and science education program at Wesleyan fellow MacArthur Award recipient Bonnie sponsored a student symposium where Bassler have joined hands with artists, scien- dancers and undergraduate scientists tists, and ethicists across the country to tell compared how they approach problems the story of the human genome. A visual and and do their work. auditory tapestry of dance, music, speech, Bassler, a Princeton University costume, light, and video, the uncommon researcher who studies how bacteria “talk” production premiered in February 2006 at to one another, became an adviser to the “I just want Wesleyan University, in collaboration with project, initially spending a day with the people to leave HHMI’s undergraduate science education performers to explain her research and program there. watch them experiment with ways to express saying, ‘Oh, I can Three years in the making, the project it in movement. understand this. was sparked in 2003 when Pamela Tatge, What if scientists were choreographers? Big things are director of Wesleyan’s Center for the Arts, Eight dancers glide and slide in and out of saw Lerman’s intergenerational modern molecule-like formations—first intertwined, coming, and I dancers perform. Afterward, she heard the then breaking apart. On an enormous video can play a part choreographer speak of her desire to screen behind them, Eric Jakobsson, director in them. develop a dance about genetic research of the Center for Bioinformatics and and its implications for humanity. So Tatge Computational Biology at the National liz ”lerman arranged for Lerman to meet the then- Institute of General Medical Sciences, dean of natural sciences and math at ponders the question. “You could start by Bonnie Bassler (left) and Liz Lerman collaborated to bring genetic science to the Wesleyan, Laura Grabel, who had been a laying dancers out head to foot, end to end,

fore in an unusual way—on stage. professional dancer herself. Though head to foot....” Shawn Henry

10 hhmi bulletin | May 2006 Harris Lewin, a professor of immuno genetics at the University of Illinois, replaces Jakobsson, superimposed on the whirling dancers and supersized on the screen. “It’s the genome shuffle,” he suggests. “We’re all very similar. The chromosomes are basically the same. We just reshuffle the pieces of our ancestors’ genomes.” Bassler marks that day as one of the most fascinating of her life. “What they do is so different from what I do,” she says, “and yet in some ways, it’s so similar. Cells communicate with a chemical language, I communicate with spoken language, and dancers communicate with movement.” Lerman, whose “nonfiction dances” often have political and ethical themes, also consulted ethicists in creating Ferocious Beauty: Genome. The performance’s first act deals with the rigor and wonder of scientific discovery, focusing on Gregor Mendel, the 19th-century monk renowned for his genetic experiments with peas. The Ferocious Beauty: Genome expresses the power, momentum, shorter second act presents issues raised by shape, and beauty of biology, as well as the sense of simultaneous genetic science, such as aging, the search connection—and separation—inherent in our genetics. for perfection, and our common ancestry. Thomas Dwyer, silver-haired and gaunt, lost, he circles his chair and explores the walls Ferocious Beauty: Genome to stages at perches on a folding chair, hemmed in by as scenes from his life flash across them. universities and performance centers across brick walls that look a lot like microarrays. The Yet Lerman didn’t want her production the country. Each audience will see a soundtrack is a heartbeat. “New laws for old to become a soapbox. “It poses some small slightly different show. “Like biology, it will folks” flash across his walls: “Age 70—cease and large questions, but it doesn’t attempt keep evolving,” Lerman promises. “I’m still and desist wearing seat belts; Age 75— to answer them,” she insists. “I just want trying to understand the piece myself.” p

—J e n n ifer boeth d o n o VA N ck mandatory skydiving; Age 80—cross traffic on people to leave saying, ‘Oh, I can under- fi red light; Age 85—mandatory smoking….” stand this. Big things are coming, and I can Perturbed, depressed, frustrated, and finally play a part in them.’” FOR MORE INFORMATION: For a schedule of performances, visit http://www.danceexchange.org/

Kevin Kenne angered by what he’s losing and what he’s Lerman and her dancers are taking

May 2006 | hhmi bulletin 11 upfront A Few Good Neurons Remembrances of things past do not necessarily involve a great many nerve cells.

Cornelia Bargmann joins forces with “We are watching the nervous a tiny worm to study how the brain’s wiring influences behavior. system translate experience into its own language. Cornelia Bargmann ” Matthew Septimus

12 hhmi bulletin | May 2006 I f y o u ’ v e h a d this unple a s a nt experience, you won’t forget it: You ate something bad and got sick as a dog. Even years later, the thought of eating that particular food again makes your stomach turn.¶ This response, called conditioned taste aversion, is one of the strongest forms of learning in mammals, says Cornelia I. Bargmann, an HHMI investigator system understands. The fact that it is the at the Rockefeller University. “All it takes is a single experience to form very same neurotransmitter that Kandel’s lab saw in classical conditioning in Aplysia long-lasting memories.” And the process is not unique to mammals. Fish, snails, leads Bargmann to suggest that scientists and the cuttlefish (a relative of octopus and squid) show a similar response. might be beginning to unravel the grammar of this molecular language common to all In the November 10, 2005, issue of Nature, Bargmann’s team reported creatures. that Caenorhabditis elegans, a nematode with only 302 neurons, does too. So how many neurons do we humans need to remember a particular Rembrandt If a worm with so few neurons can to watch as one type of neuron in the circuit masterpiece or to recall a conversation learn such a sophisticated behavior, just increased production of the neurotransmitter we had with a close friend? There are how many neurons does it take to estab- serotonin (which strengthens signaling no specific answers yet, but Kandel and lish a memory? Theoretically, only two: a between neurons) in response to bad food, in others predict that the molecular aspects of sensory neuron to detect a stimulus and a this case, toxic bacteria. When the scientists memory storage in humans will be similar motor neuron connected to a muscle that knock out the receptors for serotonin, they to those in Aplysia and other model systems. will carry out a behavior. But in actuality, inhibit learning. The size of the human brain, however, neural circuits are never quite this simple “We are watching the nervous system adds enormous complexity. Even simple and invariably involve more—though not translate experience into its own language,” circuits, such as those described above, will necessarily a great many—cells. says Bargmann. The worm experiences an be layered many times over. And there will The laboratory of Eric R. Kandel, an infection from eating the wrong bacteria, be a concomitant increase in combinatorial HHMI investigator at Columbia University and the nervous system transforms that options to mix and match pathways. “We who won the 2000 Nobel Prize in physi- experience into an increase in serotonin, can’t dissect out each bit yet,” says Kandel, ology or medicine for his work on memory, a molecular language that the nervous “but eventually we will.” p — r A b i y a T u m a has studied the sea slug Aplysia. This animal rapidly learns to associate a noxious stimulus, like an electrical shock, with an innocuous cue, such as a light touch on its siphon. It will Table for One? subsequently withdraw its gill in a protective behavior in response to just the light touch. Have a question about nematode behavior? Ask Cornelia Bargmann. She’s figured out what makes some of these The circuit that underlies such classical 1-millimeter-long worms social eaters while others prefer to eat conditioning can be reduced to about 20 alone, and she can tell you how they know bad food when they or 30 neurons if one focuses on only one smell it. The HHMI investigator at the Rockefeller University has also determined how the worms, known as Caenorhabditis aspect of gill movement, says Kandel. In the elegans, can recognize and distinguish among thousands of full-blown behavior, 50 to 60 neurons are odors in their environment. Their keen sense of smell and small number of neurons make C. elegans an ideal model for likely to be involved. Bargmann and other researchers to understand the interface Bargmann doesn’t yet know what the between genetics and experience. Since neuronal genes, like most other genes, are conserved among all animals, she circuit looks like that controls conditioned expects that her research on the worm’s brain will improve taste aversion in nematodes, but she estimates understanding of the human brain. The gene she found that determines whether a worm prefers a table for one or family- that, here too, some 60 neurons are involved. style dining, called npr-1, is related to human proteins involved

©MPG/epa/Corbis Significantly, her team used molecular tools in appetite and anxiety regulation.

May 2006 | hhmi bulletin 13 upfront

Whittling Thousands to a Few The key to identifying yeast proteins of interest is to get a handle on them.

K i n a s e s c a l l a lot of the shots inside cells. T hese essenti a l e n z y m e s regulate a vast array of processes, such as whether cells grow normally or become cancers. But the functions of many of the more than 120 kinases that exist in yeast are mysteries—and no simple method exists to determine ATP (adenosine triphosphate), shearing off each one’s modus operandi. Now, chemical and genetic engineering has a phosphate, and adding it to the protein. allowed a team of researchers at the University of California, San Francisco, Using radioactive ATP as a source of phosphate is one way to mark targeted proteins led by HHMI investigators Erin K. O’Shea (now at Harvard University) so that they can be identified amid a sea of and Kevan M. Shokat, to pinpoint the protein substrates acted on by a yeast others. But all 120 kinases exist in test tube extracts of yeast, and each of those can affix kinase called Pho85. “To understand the function of a particular kinase, radioactive phosphate to proteins. To get around this problem, O’Shea we need to know what kinds of proteins it and Shokat developed the first step of their “We think controls,” says O’Shea. method—a molecular trick that allows only the trick will be The researchers expect their two-step the kinase of interest to grab the radioactive generalizable method will prove useful for many kinases, ATP. They added a chemical tab to radioac- especially because no one else has come tive ATP and engineered Pho85 to have a slot to almost every up with a systematic approach to identi- to match the chemical tab, making them fit kinase. fying a kinase’s constellation of substrates. together much like pieces of a jigsaw puzzle. Kinases activate proteins by grabbing So only the Pho85 is capable of transferring a ” the cellular energy–supplying molecule radioactive phosphate to its proteins.

The Big Pic t u r e A Family of Overachievers

Protein kinases belong to a very large family of enzymes. The human genome contains about 500 protein kinase genes, or about 2 percent of the total. Kinases play a major role in controlling many key activities of the cell and are particularly prominent in transmitting signals within a Kevan Shokat cell and in coordinating the steps of cellular replication.>>A protein kinase modifies other proteins by chemically adding phosphate groups to them—a process called phosphorylation. The process usually results in a change in the target protein’s activity, its location within the cell, or its interactions with other proteins. Each kinase can be a multi-tasker, having several substrates and

acting as a substrate for other kinases.>> Pr eci se con trol of protein phosphorylation is critical to normal cell behavior. Uncontrolled kinase activity is a frequent cause of disease. For example, in cancer, kinase-mediated regulation of many aspects of cell growth, movement, and death is disrupted. For these reasons, compounds that inhibit the activity of protein kinases are being studied as therapeutic agents. In fact, some kinase inhibitors are already available for treating

patients, including the two anticancer drugs Gleevec (imatinib mesylate) and Iressa (gefitinib). George Nikitin/AP. ©HHMI.

14 hhmi bulletin | May 2006 “To understand the function of a particular kinase, we need to know what kinds of proteins it controls. But how to find those proteins that Pho85 controls in yeast cells? Step two: The team erin o’shea ” designed yeast proteins to have unique molecular “handles.” These antigenlike upon. The importance of making such spotlighting two dozen possible Pho85 handles can be snagged with an antibody strains, says O’Shea, was to keep the kinase substrates. As an added bonus, one of the that recognizes them specifically and pulled in an environment close to its natural proteins had been previously reported to be out of the extract by a method called tandem habitat, thereby reducing the possibility under Pho85’s control, affirming the value affinity purification (TAP). Within a yeast that the kinase would behave in any way of their method. cell, only one type of protein out of the multi- different from normal. Besides Pho85, Shokat has made more tude present is marked with a TAP handle. After adding Pho85 to a mash of pooled than 75 additional slotted kinases, all but The researchers then created 4,250 yeast strains, the team pulled out all the three of which work well with the modified yeast strains, all identical except for the proteins displaying a TAP handle. The ones radioactive ATP. “We think the trick will unique TAP-handled protein each strain that showed up with a dab of radioactivity— be generalizable to almost every kinase,” makes. This bevy of strains represents a from Pho85—could be investigated further. says Shokat. If so, this technique will help large percentage of all the proteins a yeast O’Shea and Shokat found 24 proteins researchers move many kinases off the

O’Shea: Christopher Jones Illustration: Joel Lardner cell makes—and that a kinase can act that came through the steps radioactive, mystery list. p – M a r y B e c k ma n

May 2006 | hhmi bulletin 15

D i g i t a l v i d e o

vignettes of

the immune system in action

are opening

scientists’ eyes.

Lymphocytes ,

c a m e r a , a c t i o n !

by Marc Wortman illustration by Jonathon Rosen

May 2006 | hhmi bulletin 17 “You can’t understand complex,

changing natural phenomena

with just one snapshot.…With video imaging, we can look at the gears turning and

what cells do and how they do it.” M a r k D a v i s

In a laboratory at Stanford University School of Medicine, graduate students and postdocs spend a lot of time watching movies. Their mentor, HHMI investigator Mark M. Davis, doesn’t mind a bit. In fact, animals). These systems, known as multi- he encourages them, and proudly shows off photon microscopes, include special video the product of a protégé’s doctoral thesis, camcorders that produce layers of images at which he unofficially titles, “Immune different microscopic depths as well as post- System: The Movie.” The student composed production software that recomposes the digital video recordings of immune cells and changing much like the first two cells, images into three-dimensional videos. Thus going about their machine-like business— they cluster around the lymphoma cell and equipped, scientists like Davis can watch not unlike Hollywood’s “Terminator”—of prepare to kill it. how the immune system works at the nuts- seeking out, recognizing, and destroying (or Davis’s team has recorded numerous and-bolts level and observe what happens stimulating) other cells. videos of fluorescently tagged proteins on the when it goes awry. Davis calls up a video on his monitor surface of the immune system’s T lympho- “You can’t understand complex, changing showing the immune system in action. He cytes—the specialized white blood cells natural phenomena with just one snapshot,” watches three cells clump together, much that move through the body with the flow of says Davis. “We want to see where the mole- like a basketball and two softballs lined up in blood until they bump up against foreign or cules are, what they are doing, and how an a row. The largest of the three is a cancerous diseased cells. If the T cell’s surface proteins organism responds to a threat. With video lymphoma cell. The two smaller cells—one link up with a sufficient number of counter- imaging, we can look at the gears turning blue, the other red—are components of the part proteins on the unhealthy cell, the T and what cells do and how they do it.” immune system scanning the unhealthy cell cell recognizes it as an enemy. At that point, and communicating with one another about the immune system swings into attack mode what they are “seeing.” against the invader. M o r e t h a n The time-lapse images follow the two Only with recent advances in visual E n t e r t a i n m e n t immune cells as their colors swiftly inten- imaging systems have Davis and other inves- Microscopic observation of living sify and change to green. This color change tigators been able to generate these types of cells on a slide (in vitro) or in a living is a laboratory-generated display of the live-action videos. Their productions are organism, which goes by the general name internal biochemical changes the immune changing the way scientists think about the of “intravital microscopy” (IVM), is not cells undergo when they recognize the immune system. new. It was pioneered by German physi- lymphoma cell and signal to other nearby The imaging systems couple ultra-high– ologist Rudolph Wagner in 1839. But the immune cells to mobilize against it. Their resolution microscopes with lasers (which present sophistication of the process and the murderous business is swift and relentless. send out pulses of light that illuminate level of resolution now possible are indeed Nearly a dozen other cells charge in like a fluorescently labeled protein probes, even new, and filled with promise. When Davis vengeful mob. With their colors intensifying deep within the intact tissues of living and others began to generate videos in

18 hhmi bulletin | May 2006 F r o m l e f t t o r i g h t : Mark M. Davis, Dan R. Littman, Philippa Marrack

“You can’t understand complex,

changing natural phenomena

with just one snapshot.…With video imaging, we can look at the gears turning and

what cells do and how they do it.” Mark Davis

required hours or even days of continuous communication between T lymphocytes and antigen-presenting cells (the cells that engulf cells infected with viruses and, through communication with T cells, T h e S e c r e t L i f e initiate the process that will kill the virus). o f t he Lymphocyt e Video microscopy revealed, instead, that Nearly all real-time knowledge of the late 1990s, however, some in the field these two fundamental immune-system the immune system comes from studying questioned their value. They were seen as a components engage in a day-long minuet T cells circulating in the blood. Yet, while fancy way of showing what scientists already beginning with multiple short contacts. a T cell typically spends only about 30 knew through static images. Each lasts only a few minutes, yet these minutes in the bloodstream, it might spend Coming up against such attitudes, Davis fleeting encounters prove sufficient to acti- hours or even days migrating through other had trouble finding a journal willing to vate the T cells. “Few people anticipated the organs, querying cells for antigens. Because publish his early papers. Editors feared they enormous rapidity with which cells move,” “there is no evidence out there for what goes would be opening the doors to ridicule about says Ulrich H. von Andrian, an immunolo- on inside an organ,” says Dan R. Littman, the MTV generation taking over scientific gist at the CBR Institute for Biomedical an HHMI investigator at the New York research. “The convention was that videos Research, an affiliate of Harvard Medical University (NYU) Medical Center, only a were more about entertainment than infor- School, and a leader in the use of video small fraction of the life of the lymphocyte mation,” he says. “It was almost impossible microscopy. has ever been observed. He and others have to persuade people that video can have Many unstable cellular structures begun to open up that hidden life. much more information than a still image.” collapse when they are prepared for static In his laboratory, Littman, in collabora- Soon, though, as new knowledge began observation. As a result, says von Andrian, tion with Michael Dustin at the Skirball emerging from video microscopy, the same static studies may have given scientists a Institute of NYU, uses IVM in mice to editors were clamoring for him to submit false conception of living immune system observe the living immune system within more video-based papers. mechanics. Studying the immune system in organs that are accessible by surgical proce- Now, those dramatic images have shown its natural state, he says, “provides an essen- dures. He started with the liver, where that the immune system is far more dynamic tial reality check for determining which natural killer T (NKT) cells, the immune and actively choreographed than previous phenomena are different in living animals system’s sentinels against virus-infected static-image studies had led scientists to and not faithfully reproducible” statically. cells, have long been known to concentrate. believe. Davis and others are zooming in Davis agrees: “It’s like seeing an animal in Scientists had observed NKT cells in the on that activity in molecular detail. Until its natural environment, rather than in a bloodstream, but little was known about how moving images showed them otherwise, zoo. It’s really important to see where they they functioned within the complex stew of most biologists thought that the signaling are and how they behave in different stages nutrients, toxins, lipids, and other chemi-

Davis: David Powers Littman: Chris Denney Marrack: Louie Psihoyos / Scienceprocess Faction Images leading to an immune response of their lives in their native habitat.” cals trapped in the labyrinth of microscopic

May 2006 | hhmi bulletin 19

S tudying the immune system

in its natural state

“provides an essential reality check for

determining which phenomena

are different in living animals and not faithfully reproducible” statically.

U l r i c h H . von Andri a n

vesicles that pervade the liver. By opening a flap in the membrane covering the organ, the researchers could deploy IVM to observe and record fluorescently labeled NKT cells going about their business. Nothing in previous studies of NKT cells prepared the scientists for what they saw. Like other lymphocytes, NKT cells get pushed along by the blood’s flow through the circulatory system. But inside the liver, their behavior A ttack of is entirely different. The video images showed little self-propelled machines that crawled, amoeba-like, through the organ’s tiny blood the hungry hookworm vessels. They moved swiftly yet seemingly at random, passing one another, changing direc- Watching how the immune system responds throughout the body to a localized tion, and even traveling against the flow of threat has provided new insights into autoimmune disorders, asthma, and allergies. blood. Such apparently directionless, self-gener- Richard M. Locksley, an HHMI investigator at the University of California, San ated surveillance behavior—which continued Francisco, has engineered a mouse with fluorescent probes in its immune-signaling until the NKT cells detected damage or infec- system that light up when mucosal barriers, such as the intestinal lining or lung, tion and stopped in the vicinity of the problem come under attack. He introduced hookworms into the mouse’s gut and then sliced to launch an immune response—had never and analyzed tissue from the entire mouse to find where the immune cells that signal before been observed. such an attack, called effector cells, glowed. “This allowed us to find where every NKT cells are believed to play an effector cell in the body ended up,” Locksley says. As expected, certain known types important role in inflammation and may of effector cells lit up in the intestinal lining where the hookworms bit. He was be involved in triggering chronic hepatitis. surprised, however, to find effector cells widely distributed, even in areas such as Now, says Littman, armed with knowledge the lungs where the worms had not been. Watching these cells appear in such large numbers in the lungs in response to intestinal worms led Locksley to believe he had about their normal movement in the liver, identified a response that overlaps with the lung’s response to airborne irritants in “We need to get at the mechanistic aspects asthma and other allergic disorders. He has made the mouse model freely available of the NKT cells’ surveillance behavior. to the scientific community, encouraging others to use it to test new therapies for Can we manipulate it in disease systems?” hookworms or other parasites, and to monitor effector cell activation and movement Developing ways to regulate that behavior into unexpected places, such as the lungs and skin. “It’s early days,” he says, “but could potentially lead to treatments that I’m convinced we’re on the right track to show how these cells might contribute to reduce the inflammatory response in hepa- chronic diseases like asthma. Eventually, manipulating the distribution and survival

titis and other liver diseases. of these potent effector cells may provide new pathways for treating these diseases.” Courtesy of the University of California, San Francisco

20 hhmi bulletin | May 2006

S tudying the immune system Still frames from a video of T cells interacting with GFP-labeled (green) antigen-presenting cells. Color overlaid on the cells highlights the intracellular calcium concentration of the T cells: Blue in its natural state indicates low concentration; red is high. To watch the video, visit http://cmgm.stanford.edu/hhmi/mdavis/

“provides an essential reality check for

determining which phenomena

are different in living animals and not faithfully reproducible” statically.

U l r i c h H . von Andri a n

Owen N. Witte has also been able to visu- alize—and quantify—the generation of an immune response deep in the body. In his laboratory at the University of California, N e w P r e d i c t i v e P o w e r Los Angeles, Witte and his team used PET The surface proteins, or ligands, on to detect radioactive chemical tracers in an invading cell must dock in a key-in-the- immune cells of mice with a solid tumor. Dendritic cells gather antigens in tissue and lock fashion with the T cell’s own surface The PET studies could track the immune then carry them into lymph nodes where receptors for the T cell to launch an response throughout the mice’s bodies. T cells they activate the T-cell response. immune response. But Davis, who gained normally remain relatively inactive in lymph Now her laboratory is going to use multi- wide attention two decades ago for identi- nodes, which serve as T-cell reservoirs, but in photon microscopy to find out if the T cells’ fying and cloning T-cell receptor genes for his PET studies, nodes even some distance competition leads the “winning” T cell to the first time, observed that the binding of from a tumor showed T-cell activity at least 10 deny other T cells access to the antigen. just one or two receptor-ligand pairs was times higher than normal levels. This may prove important to the design of not enough to signal the mobilization of The tracers enabled the scientists to multivalent vaccines, which are composed of an immune response. Because the videos observe specific immune cells as they two or more antigens to stimulate a broader that Davis’s laboratory produces are so sprang into action in response to the cancer. response to infection or a response to more exquisitely precise that a viewer can literally “This lets us see not only how but where” than one type of disease. By recording the count how many ligands a T cell must “see” the body is responding to disease, Witte immune response in action when two anti- before it reacts, he and his colleagues were explains. Eventually, he believes, such PET gens are present, she hopes to determine able to observe that it takes at least 3, and scans could allow clinicians to observe the whether T-cell competition is undermining typically around 10 ligands, for the immune ebb and flow of the immune system over the immune response to multiple antigens. system to spring into action. the course of a disease, such as cancer or an If so, perhaps this competition needs to be “In the long term, [quantifying such autoimmune disorder, and to evaluate the taken into account when designing certain interactions] is the way to determine that a effectiveness of treatment. types of multivalent vaccines, particularly certain input creates certain consequences complex DNA vaccines such as those being for a cell,” says Davis. “And you can only do developed against HIV. this by imaging. That’s how you get to the A C o m p e t i t i v e E d g e According to Davis, “You always have predictive power that has not been a part of Meanwhile, HHMI investigator Philippa more questions to ask than the current state cell biology before.” As director of Stanford’s Marrack, a onetime doubter of the benefits of the technology is capable of answering.” Institute on Immunity, Transplantation, of video recordings of the immune system But he believes the broadening array of and Infection, Davis hopes this newfound in action, has been converted. Her team at video imaging studies will eventually lay out capability will yield tools to outsmart cancer the National Jewish Medical and Research the molecular choreography of the immune cells, improve organ transplantation, and Center in Denver will soon begin recording system. Knowing just which steps and devise better vaccines. T cells to probe a phenomenon they dis missteps occur in that biochemical dance Using a different imaging technology— covered. They found that T cells compete may be key in improving health for all—from positron emission tomography (PET)—to with each other for antigens on a type of developing new vaccines to helping the body

Courtesy of Davis lab scan the immune system, HHMI investigator antigen-presenting cell called a dendritic cell. rid itself of cancer cells. p

May 2006 | hhmi bulletin 21

Scientists need to store all of their data, not just what’s published. There’s Gold in Those Archives

by Karyn Hede // photograph by Fredrik Brodén

May 2006 | hhmi bulletin 23 In fall 2003, Beth Chen, a graduate student at the Watson at MRC, convincing them to let him become the keeper of all that School of Biological Sciences, Cold Spring Harbor Laboratory, went potentially useful worm image data. on a treasure hunt. Her quest was to fill knowledge gaps in the neural There was a time when EM was a workhorse of biological circuitry of the roundworm Caenorhabditis elegans—that ubiquitous research. But in the early 1980s, the genome revolution forced experimental-model organism. Chen indeed “discovered” several new a radical change as scientists abandoned EM slides for DNA neural synapses and neuromuscular junctions, but she did it without sequencing gels in a quest to get at the genetic secrets of C. elegans. so much as lifting a pipette or looking through a microscope. Lost in this shift of resources was a massive amount of primary The secret of her success was an archive of Sydney Brenner’s data, including maps of the complete neural circuitry of C. elegans work, a gold mine of many of the Nobel laureate’s laboratory note- collected mainly by Brenner and John G. White, now at the books and thousands of his electron-microscopy (EM) images, University of Wisconsin–Madison, while at MRC. mostly unpublished, on C. elegans anatomy. Chen spent several “By the mid-1990s, I was the only person left who could make sense months poring over a dozen laboratory notebooks and more than of the records,” says Hall, an expert on C. elegans anatomy. “It would 10,000 electron micrographs at the Albert Einstein College of Medicine’s worm image archive, painstakingly reconstructing the neural connections that will inform her own research in the lab of Dmitri Chklovskii, an assistant professor at Cold Spring Harbor Helpful Hints from the Professionals Laboratory and incoming group leader at With more than 45 years’ experience helping scientists archive their life’s work, HHMI’s Janelia Farm Research Campus. the American Institute of Physics has put together a short guide to assist scien- Chen prevailed because the Brenner tists in maintaining their personal archives: http://aip.org/history/source.htm ¶ For archive was safely in the hands of David H. biomedical researchers searching for a home for their archives, Paul Theerman, Hall, director of the Center for C. elegans head of images and archives at the National Library of Medicine (NLM)’s History of Anatomy at Einstein, after it had sat mold- Medicine Division, suggests first contacting the library at your home institution. If ering in boxes at the Medical Research that fails, NLM will try to work with you to find a permanent home for them (http:// www.nlm.nih.gov/hmd/about/contactus.html). ¶ For advice on storing primary Council (MRC) Laboratory of Molecular data, HHMI has put together a guide to managing the scientific laboratory: www. Biology in Cambridge, England, for more hhmi.org/labmanagement ¶ For more information about the Jackson Laboratory’s than 15 years. Hall had long cajoled people Mouse Gene Expression Database, visit http://www.informatics.jax.org/mgihome/ GXD/aboutGXD.shtml “There is no way we can have the f oresight to know what wil l be important 10 or 50 years from now.”

24 hhmi bulletin | May 2006 all have been lost. I took a personal interest to make sure that didn’t happen. My data sets and the MRC data sets were extremely complementary. It just made sense to put them together in one place.” The research community has lately come full circle, however, because scientists are now eager to connect their molecular data to the detailed anatomical studies that Brenner, White, and their colleagues labored over for years. Researchers are flocking to access Hall’s treasure trove of data; he gets 20 to 30 visitors and thousands C o n s ta n c e C e p k o The challenge of storing the vast amount of data generated of Web site hits per week. Hall is in the by her research has her searching for commercial solutions. process of digitizing as many of the approximately 200,000 images as possible, with about 5,000 now available at his Web site (www.wormimage.org). important 10 or 50 years from now.” “We couldn’t have done everything,” says Brenner about cata- But saving data goes way beyond collecting a pile of graduate loging the collection. “There was too much data there for the one student notebooks and theses on a dusty top shelf. A quiet crisis looms project. But it testifies to the integrity of the result that it can be in many labs as the volume of data generated by large-scale science used over and over again. And it shows the importance of keeping grows at an alarming rate. Individual laboratories are struggling to find primary data where others can use it.” efficient and economical ways to store and retrieve key data. Many Remarkably, no one besides Hall seems to have foreseen that the researchers have coped alone thus far, but some are now looking to worm images would become so valuable. Although most scientists large centralized archiving systems to bear part of the burden. And would agree that primary data should be saved, in some cases data the rapidity of technology development, for example, has prompted can become outdated to the point that no one can interpret them. Spieth to resequence parts of the C. elegans genome rather than rely on “There will always be a need to go back and look at primary decade-old sequence data produced by technology that is now consid- data,” says John Spieth, group leader at the Genome Sequencing ered antiquated. Reacquiring data may work for large centralized data Center at Washington University in St. Louis School of Medicine. centers, but in individual labs, changing technology has often meant “There is no way we can have the foresight to know what will be keeping antiquated equipment around so that data are not lost. “Computer hardware and software quickly become obsolete, so that unless you hold on to your old computers the data you backed up with them may become difficult if not impossible to recover,” says Terrence J. Sejnowski, a computational neuroscientist and HHMI investigator at the Salk Institute for Biological Studies in La Jolla. “It’s something “There is no way we have to live with.”

A r c hiving large databases we can have the f oresight Retaining all that material is easier said than done, however. “It’s a problem for everybody,” says HHMI investigator Constance L. Cepko, a neurobiologist at Harvard Medical School who studies the structure and function of the eye in vertebrates. “In trying to link to know what wil l be DNA clones, in-situ images, and microarray data, we can generate 30,000 data points in one experiment.” She and her colleagues consid- ered commercial data-management packages and high-tech start-up services for archiving such data, but none filled their needs. At present, important 10 or 50 years an M.D.-Ph.D. student is setting up a customized relational database, but it is just a temporary solution. Cepko says that because the volume of data her lab generates from now.” is rapidly filling servers, she is looking to a centralized archiving Jason Grow

May 2006 | hhmi bulletin 25 26 hhmi J AWOL Go Data and Articles When of your research, he warns, think again. think warns, he research, your of record a as serving articles published your Institute of Technology, believes the answer may lie in more intelli- being, heisstoringitall. time the for sets.” So, data the in value real has what out figure to is not very mature yet. We need to spend more time on data analysis is what know worth keeping in these yet large-scale studies because the [RNAi] field not do we that is now facing are we that issue as well of as storing beingdata more selective, says Perrimon. “The full-time programmerstogetthejobdone. two hire to him allowed which Health, of Institutes National the screens in Drosophila. Its infrastructure was funded by a grant from interference RNA lab’s his of results the store to database public problems—at least, for the time being—by setting up a centralized Harvard Medical School, found the solution to his data-management for anyonelabtohandleonitsown.” muchtoo is them managing that unwieldy so become have “Data all of his lab’s large data sets. “You have to find a partner,” he insists. San Diego Supercomputing Center, which and maintains archives database. toitscurated,annotated primary data adding and soliciting actively is mouse and data, of proteomic and genomic archive leading the Health, of Institutes National the by funded database, the make to aims TJL hands. her off data the system, such as the Mouse Gene Expression Database at the the of at some take to Maine, Database Harbor, Bar in (TJL) Expression Laboratory Jackson Gene Mouse the as such system, M E R E Paul W. Sternberg, an HHMI investigator at the California California the at investigator HHMI an Sternberg, W. Paul ways cheaper on depend will solution the run, long the in But HHMI investigator Norbert Perrimon, who studies cell signaling at the with agreement an has Sejnowski spirit, same the much In

bulletin N y THANS N A H AT

a 2006 May If you’re counting on on counting you’re If and sent a grainy PDF file. But Nathans was scannedwhooriginalthe print document downthearticle ical literature. abstracts and for virtually citations all includes published PubMed which biomed- the database, to articles computer-era beenmissed in the process had of adding article pre– The nothing. found He 1978. journal the in appeared which PubMed quick a search be to would link it to find the to original way article,fastest the figured he hand, in Citation cation. article an he for considers to searching be a landmark remembers publi- Medicine, theatJohns Hopkins University School of Nathans, Jeremy ¶ Eventually, Nathans tracked bycontacting theauthor, an HHMI investigator investigator HHMI an omplete rec d r In his 1965 co e r e t e l p m co A revealed one of the rarely uttered secrets of scientists. “We have a “We have scientists. of secrets uttered rarely the of one revealed and organize thoughts and ideas—and have instant recall.”and organize thoughtsandideas—andhaveinstant then how would I ever find it again? In form, youdigital can search “But Sternberg. says notebook,” [paper] my of margin a in thing of kind that kept have would “I ideas. and observations recording for lab’sintranet the private on blog personal a keeps students uate grad- his of One says. he notebooks,” electronic with comfortable when sourcesareassessedindividually. combining what he calls “weak hints,” which tend to be overlooked from disparate sources, allowing them to develop new hypotheses by working on systems that will allow scientists to combine primary data archiving and making retrievable unpublished primary data.” He is what already exists out there. Digital storage is cheap. We should be we think we do in biology,” he says. “We aren’t gent searching. taking “My general fullfeeling is that we advantage know a lot of more than ratory mainstay, the lab notebook. “The new generation is more more is generation new “The notebook. lab the mainstay, ratory unpublished information.” of amount larger likely the access could we if do could we what is published valuable,”and available data Sternberg says. “Imagine mining that know “We now yeast. and flies, fruit roundworms, in to integrating published data on how genes interact with each other approach howdescribed computational colleagues a such apply to n h Mrh 0 20, su of issue 2006, 10, March the In Sternberg believes this idea also extends to updating that labo- that updating to extends also idea this believes Sternberg Nature Nobel Prize address, physicist Richard P. Feynman in in issue of supplemental data supplemental of issue divorced from the published article.” muchsupplementalin data, andthatgets so putto journalstellingnoware us“But dataisbypublishing them,” says Nathans. store to way best the that believe us of print out along with the main article. “Aalways not lot do and online, available only journalarticle ispublished. These data are a when“supplemental data”of ranks the alsodisappear when they are relegated to electronicarchive.) has since added that particular article to its there “it’s as PubMed if it had on never existed.” searches, heavily ( hereasoned, ifitdoesn’t so appear rely scientists Because feeling. uneasy an with left still Science ¶ Research¶ results , Sternberg and and Sternberg , is becoming becoming is Nature ¶ “This can

Bill Denison Jason Grow s andshould treatedbe such.”as at all, they are an integral part of an article datatheimportantare enoughincludeto the data into print, but I would argue that of ifall put toeconomic decisionnotan as at the National Library of Medicine. “I see it offers free access that to PubMed full-text to journal complement articleselectronic policycoordinator forPubMed Central, an bigger,”Edwinbiggersaysand scientists are providing such supplemental sionwillsurvive. thinksHe that longasas thatthose types of materials in its posses- goesout of business, there’s no guarantee publisher a If archiving. for articles their providesupplemental datawhensending City. “What curators at scientific collections do isn’t splashy, but but splashy, isn’t do collections scientific at curators “What City. curator of research collections at The Explorers Club, in New York oping sciencepolicy. devel- into go that processes thought the glean historians science help also may but research their in colleagues scientific help only not which notebooks, lab and correspondence especially and ings, meet- scientific of minutes photos, correspondence, manuscripts, historical value.It’samatterofkeepingcompleterecord.” have to likely are that documents their all want “We Physics. of us,” says understanding R. Joseph an Anderson, at archivist the American Institute trouble have “Scientists literature. scientific the in presented ideas of progression logical and clean the from, missing or in, hidden often are which road, the in bumps in, say, interested highly often are archivists and historians science But pieces. other many the save to need the overlook times ultimate some- they that work life’s the their of archive as literature published of describe how you had the wrong idea first.” tracks, to not worry about the blind alleys or the all cover possible toto finished as as work articles publishedscientificin journals make the to writing “in observed, he habit,” ays ays “People think of archives as quaint,” says Clare Flemming, Flemming, Clare says quaint,” as archives of think “People of versions early as such materials keep should scientists Thus, think to acculturated so are Scientists S equeira, not all journal publishers publishers journal all not ¶ Further,¶ S equeira, participating publishers by using a Web Web a using by publishers participating from content published newly collects mental data in the digital age. age. digital the in data mental of role the storing published maintain articles and their will supple- libraries how the with grappling and are community scientific publishers, Librarians, sition. tran- in is role that age digital the in but archives, long-term maintain to libraries Traditionally, ¶ complement. they article the with along nals are supplying them to PubMed Central materials,they should make sure thejour- L called system, The Libraries. University a potential consortium organized by by organized consortium O C to manage his his manage to b r o N K SS solution is now being explored by (http://lockss.stanford.edu) (http://lockss.stanford.edu) e r t P e publishers have relied on relied have publishers r r M I R o NA interference data. interference NA n have hadthat,”Spectresays. most of her correspondence before she died. “We sure would like to destroyed McClintock survived, elements genetic transposable on

Nobel laureate’s laboratory notebooks describing her seminal work 1983 the of most while that says Spectre Philadelphia. in Society Philosophical American the at Papers McClintock Barbara the described and organized who archivist an Spectre, Miriam says able tobeduplicated.” being information on predicated The is then? science of happens foundation whole what data, the find can your one with no and disagrees result, and later along comes someone If ingless. mean- is provenance without material it, about think you when A grant funded the centralized public database he set up up set he database public centralized the funded grant A Still, “It’s hard to know what’s going to be helpful in the future,” S tanford tanford ¶ ¶ e O n are participating. wellas others scattered around the world, i infancy. To date, 80 major research librariessystem,intothebuytoitsstillwhich inis s data can be restored from any of the other problem,technical a has site one If sites. of participatingall at copies stored datapublished multiple making by content complete to guarantee access to long-term libraries mechanism a provides engineers, and librarians of team small a by initiated system, The discrepancies. b collectedwith thesame content collected has itcontent thecompares thatcrawler n the Unitedthe n ites. y other L other y S p ome scientific publishers have begun O C S KSS tates and 25 in Europe,as in 25 andtates a 2006 May users and repairs any any repairs and users (continued on page

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bulletin 56 ) 27 M i t o c h o n d r i a

a r e d o i n g

m o r e t h a n

j u s t k e e p i n g

t h e c e l l ’s f u r n a c e

s t o k e d . T h e P o w e r h o u s e — a n d S e n t i n e l — o f t h e C e l l by Karen F. Schmidt

L ook up “mitochondria” in any science text and invariably these tubular bags of enzymes that float in the cell’s interior are called “the power houses of the cell.” Of course, the role they play as cellular furnaces, converting nutrients and oxygen into energy, is immensely important. Every cell needs ATP—the chemical fuel generated by mitochondria—and some cells are particularly demanding: a muscle cell that pushes the leg into a sprint, a beta cell in the pancreas that synthesizes the hormone insulin, a brain cell that fires a signal to help create a thought. Each of these kinds of cells contains as many as 10,000 mitochondria, and it’s no secret that those tiny organelles keep the home fires burning. • However, recent studies suggest that mitochondria do much more than generate energy. They are intimately involved in cell signaling, raising a red flag during times of cellular stress, such as when viruses invade or oxygen levels drop. photograph by Mark Hooper

28 hhmi bulletin | May 2006

It now appears that subtle abnormalities triggering a signaling cascade that leads Monitoring to see what would happen, they in mitochondria contribute not only to to cell suicide, usually during embryonic found that the cells had gained antiviral rare metabolic disorders but also to many development or in response to cellular stress immunity. Conversely, when they silenced common diseases, including chronic hepa- or damage. Then, in 2001, the late HHMI the protein’s expression, the resulting cells titis, cancer, and certain aging-related investigator Stanley J. Korsmeyer reported were swamped with replicating viruses. diseases, such as type 2 diabetes. Says Gerald that the activation of a pore in the mito- The big surprise came when the group I. Shulman, an HHMI investigator at Yale chondrial membrane launches this process broke open the cells, spun them in a centri- University School of Medicine whose area by enabling the cytochrome c signal to flow fuge, and found this protein not in the of expertise is diabetes, “We’re moving into into the rest of the cell. liquid extract but in the fatty membrane areas that affect large numbers of people— Now, another protein in the mitochon- fraction. Using confocal microscopy, they the 7 percent of the population with dia- drial membrane has been discovered that pinpointed its location in the mitochon- betes—and that gets a lot of attention.” for the first time links this organelle to the drial membrane and so decided to name it These days, mitochondria often take immune system. Zhijian “James” Chen, an Mitochondrial Antiviral Signaling Protein, scientists by surprise. “Researchers keep HHMI investigator also at the University of or MAVS. “It was quite surprising, but also stumbling into mitochondria,” says Gerald Texas Southwestern Medical Center, found a very exciting,” says Chen, because this was S. Shadel, a molecular biologist at Yale protein in the mitochondrial membrane that the first time anyone had found a protein University School of Medicine who studies contributes to viral defense. Chen wanted to involved in immunity that was part of mitochondria and disease. “That prob- know how cells detect and mount a response the mitochondrion. In fact, several other ably reflects the fact that mitochondria to infection by a virus—in particular, what groups had encountered the same protein are involved in many things besides what activates the cell to produce important anti- but didn’t figure out its cellular location, was historically assigned to them; people viral molecules called interferons (which are which, Chen’s team found, is essential for in many fields are now making important also used as medical therapies). His team the signaling function of MAVS. connections.” searched for signaling proteins involved in The group reported their findings in antiviral immune responses and found a the September 9, 2005, issue of Cell; soon Signaling Immunity protein that appeared to activate two tran- after, Science STKE named the discovery of Research on mitochondria scription factors known to trigger interferon MAVS one of the “signaling breakthroughs” heated up in the 1990s, when production. They then engineered cells of the year. Eric A. Shoubridge, a human studies revealed that they that express large amounts of this protein geneticist and HHMI international research play a key role in signaling and grew them in culture with viruses. scholar at McGill University, in Montreal, programmed ce ll d e a t h . Canada, says, “Chen’s work is pretty exciting In 1996, Xiaodong Wang, an HHMI investi- stuff. Random bits of information had gator at the University of Texas Southwestern suggested that mitochondria might be Medical Center at Dallas, made the involved in signaling and the immune system, surprising discovery that mitochondria release a molecule called cytochrome c,

Confocal microscopy images show a cell stained with an antibody for the MAVS protein (left, green) and a mitochondria-specific dye (center, red). An overlay of the green and red images (right) indicates the mitochondrial localization of MAVS. Courtesy of Rashu B. Seth and Zhijian “James” Chen

30 hhmi bulletin | May 2006 but this work is the clearest evidence yet—it’s December 6, 2005, issue of the Proceedings of to neighboring membrane proteins and tell very convincing.” the National Academy of Sciences. them to trigger cell suicide? Theoretically, it Once he discovered MAVS, Chen investi- Chen’s team further observed that a would make sense for cells to use suicide as gated whether some viruses could specifically change in just one letter of the MAVS genetic an additional antiviral strategy; plant cells are target the protein to cripple a host’s defenses. code—the kind of simple mutation that typi- known to use it to limit the spread of infection “After we found MAVS, we suspected maybe cally distinguishes the DNA of one individual for the benefit of the whole organism. “Maybe it was the long-sought-after target for the hepa- from that of another—protects it from being if a mammalian cell can’t produce enough titis C virus,” he explains. Of the 170 million clipped by the viral protease. This observation interferons, then it will need to die,” Chen people in the world with hepatitis C, about may explain why some people are better than theorizes. However, any link between MAVS 80 percent have persistent, chronic infections; others at fighting off hepatitis C infection and and cell suicide is still speculative, he says. their interferon production is suppressed. Sure suggests an important target for drug treat- enough, Chen’s group discovered that the ments. “If we could come up with an inhibitor Low-Oxygen Alert hepatitis C virus, using an enzyme called a of the viral protease, we could prevent viral I n most tissues, mitochon- protease, can clip MAVS off the mitochondrial replication and also restore [interferon produc- dria consume 90 percent of the membrane, effectively breaking the signaling tion in] the host immune system—like killing oxygen that enters the body, pathway that triggers interferon production. two birds with one stone,” says Chen. so it makes sense that mito- The group reported these findings in the A lot more remains to be learned about chondria would function as MAVS. Chen’s group is exploring whether oxygen sensors as well. M. Celeste Simon, other viruses also target MAVS, whether other an HHMI investigator at the University mechanisms can be used to cripple it, and of Pennsylvania (continued on page 32) whether MAVS serves any other functions in N u m b e r s the cell. For instance, does MAVS ever talk g a m e : blood, and too much fat in the low numbers, or vice versa. I s m o r e their muscle and liver And how important are mito- cells. • So his group developed chondrial numbers? “Having a novel method to tell how more mitochondria might seem b e t t e r ? well mitochondria are func- studied this group and detected to be better, but it’s probably tioning, using NMR methods reduced rates of oxidation and not as simple as that,” says to noninvasively measure rates ATP production in their muscle Shulman. • Scientists still of oxidation and ATP produc- cells. Next, Shulman’s team have much to learn about how Scientists have known for tion. In 2003, Shulman’s decided to take tissue samples the cell senses that it should more than two decades that team reported evidence in lean, and use an electron micro- make more mitochondria or type 2 diabetes begins its healthy, elderly volunteers scope to count the number of has enough already, according development as “insulin resis- that an age-related decline in mitochondria. The samples— to David A. Clayton, HHMI’s tance,” in which tissues such mitochondrial function may which already exhibited large vice president and chief scien- as muscle respond poorly to the contribute to insulin resistance. amounts of intracellular tific officer. “The Holy Grail hormone insulin and, there- They hypothesized that reduced fat, insulin resistance, and in this field at every seminar fore, don’t facilitate glucose mitochondrial function predis- signs of impaired insulin is: How does the cell regulate transport out of the blood and posed these older people to signaling—had on average 38 the number of mitochondria? into muscle cells where it is accumulate fat in muscle and percent fewer mitochondria It’s a challenging question.” metabolized. It made sense to liver cells, and that, in turn, led than normal. The results of the Researchers know that nuclear Gerald I. Shulman, an HHMI to defective insulin signaling and study appear in the December genes control the biogenesis investigator at Yale University then insulin resistance. • In an 2005 issue of the Journal of of mitochondria (which have School of Medicine, that interesting twist, however, Clinical Investigation. “Our their own DNA), that tissues insulin resistance might be Shulman’s most recent study data suggest that reduced naturally have 100 to 10,000 linked to mitochondrial func- suggests that reduced mitochon- mitochondrial function in this mitochondria per cell, and that tion. After all, mitochondria drial function might also be young group can be attrib- exercise increases the number convert glucose and fatty acids caused by low overall numbers uted to their low numbers of of mitochondria in muscles. As into energy—by a process of mitochondria—at least mitochondria,” Shulman says. scientists fill in the details, they called oxidation—and people in young, lean adults whose Now, the team is trying to expect to find many additional with diabetes have too much parents have type 2 diabetes. determine whether intracellular signaling pathways at the cross- unburned glucose in their The researchers had previously fat accumulation might cause roads, Clayton notes.

May 2006 | hhmi bulletin 31 School of Medicine, decided to explore this normal response to low oxygen. These results idea in 1997. “Understanding how oxygen suggest that ROS is a necessary signal to cause levels are sensed and adapted to is fundamen- HIF accumulation during hypoxia. tally important to dealing with pretty much Simon’s working hypothesis is that all of the major diseases that we encounter— ROS are released into the fluid portion of the atherosclerosis, autoimmune disease, stroke, cell’s interior, where they inhibit enzymes and cancer,” she says. For instance, solid called HIF hydroxylases that lead to HIF tumors begin to grow outside the body’s degradation when oxygen levels are normal. circulatory system, where oxygen levels are Thus, HIF builds up and then sets in motion low, and they do so by turning on signals the cell’s hypoxic response—activating the that tell tissues to sprout new blood vessels. myriad genes that lead to blood vessel devel- Understanding how to disrupt this signaling opment and cell motility, for example. Yale’s might lead to new cancer treatments. Normal Shadel comments, “Simon has uncovered adult tissues, such as kidneys, can also experi- how this oxygen sensing has consequences ence low oxygen because of poor circulation beyond respiration—mitochondria are not and other dysfunctions. In that case, if doctors just sensing oxygen for their own need but are could enhance the signaling process, they telling the cell that it’s low in oxygen and that might be able to promote blood vessel devel- it needs to initiate a response.” opment and restore an organ’s function. Some other labs have reported findings Research on how cells respond to low that support the theory that HIF hydroxylases oxygen, or hypoxia, took off in 1995, when a (the enzymes leading to HIF degradation) transcription factor named hypoxia-inducible serve as oxygen sensors. Simon reconciles the factor, or HIF, was isolated and later shown data by suggesting that two separate pathways C e l e s t e S i m o n studies cellular responses to oxygen deprivation. to activate blood vessel formation and make may operate, one under extreme hypoxia cancer more aggressive. When Simon began (0.1 percent oxygen) and the other under her studies, a key question needed answering: modest hypoxia (1–3 percent oxygen). Her “ U n d e r s t a n d i n g What signals cause HIF to accumulate when results indicate that when oxygen is nearly oxygen levels drop? Some researchers theo- absent, mitochondria cease to be the domi- how oxygen levels are rized that HIF directly sensed oxygen, but nant player and HIF hydroxylases become the Simon and others decided to look to mito- oxygen sensor. However, she adds, cells in the chondria for signals. The first clue came when body are more likely to encounter the condi- sensed and adapted to her research team suppressed mitochondrial tions of modest hypoxia that she studies. metabolism in a cell culture and found that Understanding how mitochondria are HIF no longer accumulated during hypoxia. involved in sensing and signaling may ulti- is fundamentally Now, after a series of experiments, Simon’s mately lead to new models for many diseases group has strong evidence that metabolic and their treatments. Researchers now know important to dealing by-products generated inside mitochondria that mitochondrial dysfunction could affect called reactive oxygen species, or ROS, serve more than just the cell’s ability to produce with pretty much all of the as important signals that stabilize HIF during energy, says Simon. “Many metabolites hypoxia. The team reported its most recent produced in the mitochondria have an findings in Cell Metabolism in June 2005. impact on the rest of the cell, and these will major diseases that we For these studies, Simon’s team developed be really important to consider in disease.” As a tool to measure extremely small changes Shadel puts it, “The role of mitochondria in encounter—atherosclerosis, in ROS in real time under the microscope. the cell is grossly underestimated, as is their With this probe, they showed that ROS are role in human disease.” p a u t o i m m u n e d i s e a s e , produced in larger amounts in mitochondria during hypoxia. Next, the team tinkered stroke, and cancer.” with the cells to suppress the amount of ROS they could produce—first by knocking out an

C e l e s t e S i m o n important gene and then by adding an enzyme that specifically scavenges ROS. In both cases,

without ROS the cells could not launch the William Vazquez

32 hhmi bulletin | May 2006 The vision is set. The structures are built. Time to fi ll the empty spaces. Janelia Farm, HHMI’s new research community in Loudoun County, Virginia, will be “a place for passionate, excited scientists to interact and collaborate, free from many of the distractions that make life in a modern university so hectic and sched- uled,” says Janelia Farm Director Gerald M. Rubin. Making that happen means hiring the staff and buying the supplies and equipment that will outfi t the main campus building and its 21 labs, plus fi nding just the right amenities for the 96-room hotel and 53 apartments to make visiting scientists feel at home—and ready to work. No time to waste. Janelia Farm is slated to open its doors to research this summer.

E XTRE M E S HO P PING TO DESIGN, STOCK, AND STAFF THE JANELIA FARM RESEARCH CAMPUS, A HANDFUL OF CREATIVE PLANNERS ARE DOING SOME MAJOR PROCURING. B Y K AT H R Y N B R O W N ILLUSTRATIONS BY CHRISTOPH NIEMANN

May 2006 | HHMI BULLETIN 33 SCIENTIFIC EQUIPMENT ( FOR 21 LAB AREAS) Floor-mounted bollards (service pedestals): 500 Industrial robotic systems to wash mouse cages and move ﬂ ies: 4 Lab robotic systems to sequence DNA, do molecular biology: up to 5 Freezers: 52 Hoods (fume and biosafety): 30 Computer-aided manufacturing tools to build machines: 3 Transmission electron microscopes: 3 Optical microscopes: 30 Pipetting devices: 300 Dry ice (est. lbs per year): 20,000 Items in central laboratory supply stockroom (includes beakers, chemicals, bench-top centrifuges, etc.): 500 Mouse cages (capacity): 7,000

“Unlike any other lab in the country, the lab benches at Janelia Farm back up to ﬂoor-mounted bollards, or service pedestals, that look kind of like tombstones. The bollards—which include electrical power outlets, computer connections, and more—allow the labs to be dismantled and reconﬁgured for computer use, lab work, or other needs.” ROBERT H. M C GHEE, H HMI ARCHITECT AND SENIOR FACILITIES OFFICER, JANELIA FARM

“Getting the gigantic boilers to Janelia was quite an adventure. They came in on a 150-foot fl atbed trailer. It took hours for crews to H O T E L AND APARTMENTS (a 96-room hotel plus carefully navigate the stretch 53 apartments) from Route 7 to Janelia’s Bed and bath linen sets: 78 boiler room—which is probably Irons and ironing boards: 150 no more than half a mile.” Clock radios: 189 HOWARD MICHAEL DAY, Full-length mirrors: 53 D IRECTOR OF FACILITIES, Platform beds: 189 JANELIA FARM Dining chairs: 198 Plasma televisions: 143 MECHANICAL GUTS Gas-fi red steam boilers (two 1500 hp, one 900 hp): 3 D A Y C A R E Cooling towers (1,200 tons each): 5 (fi ve classrooms for 50 Chillers (1,200 tons each): 5 children ages 5 and under) Air handling units (45,000 Outdoor toys: 31 cubic feet per minute): 15 Children’s cots: 20 Electrical substations Cribs: 8 (35 kilovolt-amperes): 3 Wooden chairs: 22 Books and indoor toys: 644 Diaper pail: 1

34 HHMI BULLETIN | May 2006 STRUCTURAL S U P P O R T C O M P U T E R Glass (square feet): 147,000 SYSTEM Concrete (cubic yards): 66,000 Fiber-optic and copper Reinforcing steel (tons): 4,700 computer wiring (miles): 350 Hardwood (board feet): 35,000 CPUs (central processing units, or computer brains): 1,000 Computational power (teraﬂ ops): 7.5 Computer storage, initially (terabytes): 150

“One-hundred-and-ﬁ fty terabytes of computer disk storage, our initial capacity at JFRC, is enough to hold the complete contents of the Library of Congress—15 times over. That amounts to 7.5 teraﬂops of computational power, or 7.5 billion calculations per second.”” MARSHALL R. PETERSON, DIRECTOR OF I NFORMATION TECHNOLOGY, JANELIA FARM

W O R K S P A C E FURNISHINGS Whiteboards: 38 Rugs: 41 Ofﬁ ce desks: 240 Lab chairs/stools: 400 Game tables/workout equipment: 40 Campus pub barstools: 32 Auditorium chairs: 299

G R E E N ROOF (26 roof gardens) Meadow grass mixtures: 60 Plant varieties: 30 Soil medium (Stalite; cubic yards): 12,000 Drainage media (crushed rock, etc.; cubic yards): 5,000 Starter plants (sedum; 3-inch plugs): 15,000

May 2006 | HHMI BULLETIN 35 C H E RY L M O O R E : T H E WO M A N BEHIND THE INFRASTRUCTURE

CHERYL MOORE lives within 10 miles of her office, gets 8 hours of sleep most nights, and limits “CREATING AN herself to one cup of coffee a EASY ENVIRONMENT day. Those numbers, she says, where she served as senior vice IS NO EASY JOB.” are “the only constant sanity” president/chief operating officer in her workweek. for The Burnham Institute, a As Janelia Farm’s chief nonprofit organization devoted that issue with the appropriate operating officer, Moore to biomedical research. Today, person. Then, during meetings spends her time creating, the view from Moore’s offi ce is or chance hallway chats, out from scratch, the environ- decidedly mid-Atlantic, with a our researchers. They’ll just comes the notebook. ment that will greet Janelia window framing the Virginia need to explain to us what And there are plenty of Farm scientists when they meadow that tops Janelia they’re trying to do, and we’ll encounters, planned or other- arrive on the campus, which Farm’s green roof. figure out how to get them wise. Every week, in addition formally opens this summer. “Everything I am working what they need. This is the to dozens of informal conversa- Decisions—from budgets and on is designed to create a type of customer service–driven tions, Moore holds an individual staffi ng to operations, and culture in which science support team we’re building.” hourly meeting with Moses involving issues profound and can move forward, free from The difficult part of her job, and with each Janelia Farm mundane—dominate her days: bureaucratic hassle,” says Moore admits, is that “none operational director. “About six How can HHMI ensure that Moore, who started planning of this exists yet.” She begins or seven times a day, we’ll have scientists on campus frequently for Janelia’s opening 2 years each day by scanning her to- a quick stand-up meeting in the rub elbows, engaging in a social ago. “If we succeed,” she says, do list, which typically runs hall to brief those who need to form of Brownian motion? Are “scientists at Janelia will enjoy a several pages, with a half-dozen know about a change that’s just we ordering the right supplies kind of tunnel vision, focusing must-do-immediately tasks and happened,” she says. Rubin and for the stockroom? How much on their work in an environ- an additional 40 to 50 with a Moore also share the occasional should soda cost on campus? ment of quiet comfort. My turnaround time of about a marathon planning session. Willowy and brisk, Moore, goal is to use common sense, week. Although addicted to Until recently, Moore— age 40, has a quick, confi dent rather than a detailed rule her BlackBerry and Microsoft a semi-vegetarian who favors laugh and an air of quiet focus. book, to respond to situations Outlook, Moore says her ethnic dishes such as spicy Her offi ce is a cheerful yellow, that arise. The trick is to make favorite organizational tool is black bean soup—typically evoking her previous home in the complexity of federal, state, decidedly retro—a spiral note- worked through lunch, eating sunny San Diego, California, and Institute rules invisible to book. In it, she reserves a page at her desk. But having noticed for each of Janelia Farm’s five that most of Janelia Farm’s operational directors as well current staff was doing the as for other staff—including same, she began booking the Gerry Rubin (Janelia’s director) conference room at noon to and Kevin Moses (associate encourage everyone to come director for science and together and eat. training). When an issue pops In much the same way, up, she jots a reminder on she is making nuts-and-bolts

the indicated page to discuss decisions aimed at enabling Cheryl Moore: Paul Fetters

36 HHMI BULLETIN | May 2006 charge card, how to order supplies, where the support labs are, and how to get a interaction among Janelia’s computer account as well as future workforce. In fact, lunch dozens of other issues big and is one example. When the small. “When they walk out M A K I N G IT H A P P E N As Cheryl Moore assembled an operational campus formally opens for busi- of those sessions,” she expects, team, she looked for staff who could fit the ness, the cafeteria will offer a “they’ll be ready to hit the culture of Janelia Farm—working from minimal compressed lunch hour. The ground running.” rules and maintaining their focus on the scientific mission. Her team includes: idea, Moore says, is to balance A bigger and more immediate a scientist’s desire to grab a task for Moore is interviewing quick lunch and return to work candidates for jobs at Janelia with HHMI’s desire to foster Farm. A comprehensive admin- Howard Michael Day DIRECTOR OF FACILITIES brainstorming and bonding on istrative and support staff will At Janelia, Day’s job is to oversee the proper campus. “We want to increase include individuals to run the functioning of the lab, conference, and housing spaces. He brings 27 years of expe- people’s opportunity to bump campus machine shop, elec- rience in supervising facilities—small (the into each other,” she explains. tronic library, shared scientific 150,000–square-foot Carnegie Institution of Washington, Broad Branch Road Campus) But quickly feeding hundreds of resources, computer network, and large (the 3.8 million square feet of scientists isn’t a piece of cake, so and other services. When educational spaces that constitute the Arlington, Virginia, public school system). to speak. To help make it work, fully operational, Janelia Farm Janelia Farm will implement will employ an estimated 300 a cashless purchase system in resident scientists, 100 visiting Jennifer L. Farris DIRECTOR OF CAMPUS SERVICES which staff members use swipe scientists, and 80 other staff. Short- and long-term housing, food, and cards to pay for lunch, thereby “The details of each day fitness are Farris’s domain. She most recently managed Northeastern University’s speeding checkout. vary, with different decisions The Warren Conference Center & Inn, located in Ashland, Massachusetts. Her goal To cultivate contact in the to be made,” Moore says. “But at Janelia: “to create comfortable spaces afternoon, the facility will host I’m always working on the that encourage creativity.” a daily 30-minute tea, with free same basic thing: infrastructure snacks, in the campus pub. for creating an environment Reed A. George Rubin and Moore plan to attend. in which science can move DIRECTOR OF SCIENTIFIC SERVICES Like Moore, George arrived at Janelia by Another item on the agenda forward. That means setting way of California, where he helped found is how to design orientation our top priorities, constantly a biotechnology consulting business and worked in Drosophila genomics. He now for Janelia Farm researchers. reviewing them, and slowly directs Janelia’s shared resource labs, Moore and others have decided working our way through the including facilities for microscopy, instru- ment design, and molecular biology. George that incoming scientists will list.” There are days when also heads up materials management and attend one full day of orienta- that list seems to stretch to the environmental health and safety. tion that covers practical topics horizon. Thankfully, drugstores such as how to get a cashless stock lots of spiral notebooks. p Marshall R. Peterson DIRECTOR OF INFORMATION TECHNOLOGY Peterson is no stranger to big data and big ideas. He’s a former vice president for Celera Genomics in Rockville, Maryland, a commercial organization that sequenced the human genome. He also has designed missile guidance systems and processed satel- lite data. Peterson is the brains behind the design, implementation, and support of Janelia’s scientific computing infrastructure.

Joanne M. Theurich DIRECTOR OF ADMINISTRATION AND FINANCE Theurich has built, developed, and managed the ﬁnance and administrative functions of several start-up healthcare organizations. She will be responsible for the development and management of Janelia Farm’s ﬁnance, purchasing, human resource administration, “SCIENTISTS AT JANELIA and library, and will oversee technology- WILL ENJOY A KIND OF transfer issues.

Photos: Paul Fetters TUNNEL VISION.”

May 2006 | HHMI BULLETIN 37 perspectives & opinions

Liz Lerman To Entertain, Stimulate, and Enlighten a choreographer with a wide-ranging curiosity and social consciousness takes on the human genome. Paul Fetters

38 hhmi bulletin | May 2006 For 30 years, Liz Lerman has been creating dance performances that are at once joyful and thought-provoking. Through her company, the Liz Lerman Dance Exchange (based in Takoma Park, Maryland), she seeks to explore, in movement, concepts no less profound than nature, faith, identity, and ancestry. In her latest work, Ferocious Beauty: Genome, Lerman addresses challenges to humanity posed by the unlocking of the human genetic code.

in the spring of 2002, I was asked to lead a public about capitalism, or religion, or nutrition, or population discussion on “Gene(sis),” an exhibit at the Henry control. It could be about race and identity, or about Art Gallery in Seattle that revolved around genetic ethics, or about policy and professionalism. It could research—its discoveries, its potential, its implications. be strictly about the mechanics of the genome, using Preparing for the event got me thinking about my teenage dance to describe biological processes. It could be about daughter and the choices her generation might face. the future. Ultimately, the piece poses small and large Soon after, when a radio interviewer asked me what my questions, but it doesn’t try to address all the questions next project would be, I found myself saying I’d like to currently being generated by scientific research. No develop a project on the genome. single work of art ever could. I often approach new areas of interest this way, as The first act gives the audience some basic scientific making dances gives me a platform on which to muse, information, through videos of scientists, text, and dance, to talk, to learn. It’s a fabulous educational process. and it spotlights the interaction of science and art. It is During the development of Ferocious Beauty: Genome, also when they’re introduced to Gregor Mendel, who I met with many wonderful scientists. At a lunch with makes regular appearances and acts as kind of a spiritual science faculty at Wesleyan University, I asked them to guide. I think it’s useful for us to be reminded that he was think about how a performance piece might teach the a religious figure doing science. public about the genome. Because they had to filter their For the second act, I picked three issues: ancestry, the remarks through a picture of what it means to present this pursuit of human perfection, and the nature of aging and knowledge theatrically, their answers were far different death and our desire for greater longevity. from their usual ones. I didn’t mean for the piece to be so much about evolu- When the lunch was over, I thought to myself, “If tion, but of course it is. I thought I understood evolution nothing else happens with this project, at least we’ll all before, but I didn’t really get it. In the performance, go back to our laboratories newly energized. Both artists we have a character who is full of angst and ennui. She and scientists will be better off because we had this doesn’t know who she is at all. But Mendel leads her to fresh thinking.” the skeleton of a whale, which is shown through a video It has been a goal of mine to see whether people who to be one of our (her) ancestors. It’s a powerful moment. may not know math or science, but who might be worried I hope that the audience not only loves the perfor- about genetics and the future, could walk away feeling mance but also, when they next read or hear about that they have some understanding of this and maybe genetics, will have a little more insight. They don’t have even do something about it. I don’t want to scare the to feel numb about it. hell out of people or make them depressed. On the other One thing art can do is wake you up. I think that the hand, I don’t want to make it an easy ride. piece begins to do this. p I must also say that once we entered the very large realm of genetics, genomics, and developmental biology, I nterview by Alici a Au lt Liz Lerman’s work has been we realized we had tumbled into a place far deeper and commissioned by Lincoln Center, the American Dance stranger than where Alice landed after her fall down the Festival, BalletMet, and the Kennedy Center, among rabbit hole. I soon realized that this project could be many others.

May 2006 | hhmi bulletin 39 perspectives & opinions

Philip M. Silverman What Science teachers taught a scientist training teachers takes more than inviting them into the lab for a few weeks. Misty Keasler

40 hhmi bulletin | May 2006 After 11 years as director of the Oklahoma Science Project, molecular biologist Philip M. Silverman has learned some lessons worth passing on. The Oklahoma Medical Research Foundation (OMRF) launched a program in 1988 to provide an 8-week summer research experience for Oklahoma public high school teachers. Some teachers were inspired by their experience but were left with nothing to take back to their students except enthusiasm, which quickly faded. Today, the program looks very different but is having its intended impact.

What were the obvious things that needed to change when Did it make a difference? you began observing the program? The teachers loved it. I grew up scientifically in the era The original program, called the Foundation Scholar of phage; I knew it intimately. I could convey the experi- Program, was based on the expectation that working on a ments themselves, but also the context and flavor of the cutting-edge project under the tutelage of a professional times. The teachers loved that too. With passing summers research scientist would somehow make the participants we added new research topics (antibiotic resistance more effective science teachers. But science education and regulated gene expression, for example). All of the and scientific research are separate activities. Teachers experiments are derived from materials that the teachers need research training they can take back and use in (and later, their students) isolate themselves (livestock their classrooms, which can be hard to find in a high-tech manure became the most popular and reliable source of research lab. How many high school laboratories have a bacteria and bacterial viruses), and from questions that DNA sequencer? How many even have gas for Bunsen the isolation generates in their own minds. Still, it wasn’t burners? Additionally, the teachers worked in separate translating to the classroom. I would get e-mails from labs on different techniques and topics. They needed an the teachers when they went back to their schools about environment that encouraged ongoing interactions—with science fair projects but not about using the experi- their mentor and each other—to develop experimental ments in the classroom. By the second and third year, skills and confidence, to model a research dynamic, and the teachers faded away. I stopped hearing from them. to work out ways to bring back what they were learning at OMRF to their students. They needed to be together in What was missing? the same lab. Eight weeks wasn’t enough. We give a grad student 5 years to do independent research and get a Ph.D., but How did you decide on the right experiments to use? we expect teachers to go through a transformation in It hit me when I was reading the second edition of 8 weeks? I began allowing teachers to return to the Phage and the Origins of Molecular Biology, edited by summer course for 4-week intervals as often as they John Cairns, Gunther Stent, and Jim Watson (expanded wanted. This “Return to Science,” as I called it, increased edition, Cold Spring Harbor Laboratory Press, N.Y., teachers’ confidence and was certainly popular. It was 1992). In the preface, Cairns wrote that all of the scien- kind of a circus, with new and returning teachers sharing tists who had done these fantastic phage experiments lab space, but it was fantastic. Nevertheless, it didn’t were dying off. He said, “The era of phage is over.” When entirely solve the problem of classroom use. I read that, I thought, “Wait a minute. It’s not over at all. The teachers would love these experiments.” The science Did you ever think, “This just isn’t going to work”? is fundamental and significant and the technology is The idea entered my mind, but I immediately rejected it cheap and simple. That’s when I asked to try out my ideas because I had 8 weeks with these teachers. I knew their with some teachers. I crowded a group of teachers into abilities in the lab and how excited they were when they did my laboratory, taught them the classic plaque assay for these experiments. I just had to ask why this enthusiasm bacterial viruses, gave them some muddy lake water, and wasn’t spilling over into the classroom, what other possibilities started them virus hunting. constituted barriers to classroom use. (continued on page 56)

Interview by cori vanchieri Philip Silverman wants to help high schoolers pose questions and find answers through experiment.

May 2006 | hhmi bulletin 41

perspectives & opinions

Q & A How are you saving your lab notebooks and correspondence for posterity? From those coveted eureka moments of insight to workaday data collection, scientists endlessly jot, note, print, and save. Today, researchers can catalog their typical science and occasional brainstorms in more ways than ever before. Here, several HHMI investigators share their strategies for preserving the details of their labors. — E D i t e D b y K At h r y n b r ow n

J o s e p h D e R i s i Erik M. Jorgensen Christine E. Seidman Roderick MacKinnon A ssociate Professor, Professor, B i o l ogy, Professor, Genetics Professor, Molecular B i o c h em i s t r y a n d Un iversity of Utah and Medicine, Harvard N e u r o b i o l o gy a n d B i o ph y s i c s , University “I am not saving my M e d i c a l S c h o o l B i o phy s i c s , t He of California, S a n “While my desk gives Rockefeller Un i v e r s i ty F r a n c i s c o notebooks for posterity. I’m saving them for the truest answer to I generally don’t save my “For lab notebooks, I still Stewart and Feder [self- this question (no wood correspondence, but I do opt for the tried-and- appointed fraud is visible), our lab hope the best and true approach: a stuffed investigators at NIH]. keeps important data brightest information cabinet in my office. The notebooks are in on computer because winds up in my scientific Nothing fancy. We use my office. I have them Harvard Medical School thinking! I keep reams our servers to back up all, going back to my (HMS) Department of of synchrotron and e-mail, data, code, and report in fifth grade Genetics has a really electrophysiological more. True to biology, about the Komodo dragon, terrific backup system. data on computer disks, we’re redundant. Once a which is a lizard that HMS also mandates tapes, and CDs. All of year, we dump data onto grows up to 10 feet long keeping the data in lab my biochemical data— DVDs. Ideally, these and eats goats.” books for 7 years. When dried gels, pictures, and would be stored in an we moved into a new chromatography profiles— off-site location.” building almost 3 years go into notebooks.” ago, we faced the choice of pitching a lot of stored paper data. Despite the memories those lab books held, we simply didn’t have space to keep them, and they were destroyed. We’d like to think that our published manuscripts provide the best legacy of what we did and why.” DeRisi: George Nikitin/AP. ©HHMI. Jorgensen: Steve Wilson/AP. ©HHMI. Seidman: Justin Knight Photography MacKinnon: Robert Rathe

42 hhmi bulletin | May 2006 chronicle

science Education pg.44 institute news pg.49 lab book pg.50 Twenty More Renaissance Profs / Undergraduates Edward Palmerino Named Vice President From Tree to Harpoon / Hamster Chill Time /

Abroad / Making It Relevant to Human Health / for Finance and Treasurer / Avian Flu: A Shining Light on Vitamin B12 Awards Bring Science to the Community / Global Update Gilliam Fellowships Reward Determination

ASK A SCIENTIST pg.53 nota bene pg.54 Even as this country’s worst mumps outbreak in nearly 20 years spreads through the Is it possible to “steal” the genes of successful per- Björkman Lauded by L’ORÉAL-UNESCO / Midwest, a new finding by HHMI researchers formance horses—for example, by pulling a few Two Investigators Win Gairdner Awards gives insight into how the mumps virus is hairs—and create genetic copies through cloning? so successful at infecting its hosts (pg. 50). Courtesy of Lamb lab

May 2006 | hhmi bulletin 43 science education

Creative thinking by undergraduate professors like Susan Wessler (left) and Scott Strobel is inspiring a new generation of scientists.

ideas on improving undergraduate science teaching,” says Sharon R. Long, dean of the School of Humanities and Sciences at Stanford University and chair of the panel that reviewed 150 applications from 100 leading research universities. New HHMI Professor Susan R. Wessler of the University of Georgia is a pioneer in the study of plant genomes’ transposable elements, which reveal evolutionary history. Wessler will guide her students in computa- Twenty More tional and genetic analyses of such elements Renaissance Profs to see evolution in action. It’s all the more important, she says, given that Georgia is A n e w c l a ss of HHMI Professors—v i s i o n a r i e s enmeshed in controversy over the proposed i n r e s e a r c h a n d t e ac hi n g —aim s to e n e r g i z e teaching of “intelligent design” in schools. u n d e r g r a d uat e s c i e n c e e d u c at i o n . Scott A. Strobel, a professor of molecular biophysics and biochemistry at Yale University, I m a g i ne yourself , as a college junior, exploring a rainforest to bioprospect for medically believes that students can best be inspired by useful microbes, studying plant genomes to observe evolution in action, or analyzing your own scientific research if they are given “owner- DNA to determine the origins and wanderings of your ancient ancestors. That’s just a taste of ship.” He has designed classes so that instead what the 20 recently chosen HHMI Professors are cooking up to tantalize undergraduates, fire of being “minor technical players in the big their imaginations and develop their skills, and ultimately enhance the ranks of science. science of a typical laboratory, students will The awardees—teacher-researchers all—will each receive $1 million over 4 years be completely vested in an original project in to test-drive ideas that depart from traditional curricula, which tend to emphasize fact which they have full autonomy.” memorization and laboratory experiments with predetermined “right” answers. Instead, In each of the professorship’s 4 years, the Professors will engage students in open-ended research projects using the techniques Strobel and his father, Gary, a plant patholo- and tools of working scientists. gist at Montana State University, will lead These 20 represent the A-team in pursuit of teaching innovations, but the talent pool a dozen undergraduates on a spring-break

was deep and their selection was not easy. “Every proposal I read gave me new insights and expedition to one of the world’s rainforests, Wessler: Imke Lass Strobel: Amy Etra

44 hhmi bulletin | May 2006 where they will explore the ecosystem Jasper Rine, professor of genetics and The 2006 Professors are successors to and collect biological samples. Then, in a development at the University of California, the original group of 20 selected in 2002 to summer laboratory course, the students will Berkeley, wants to remodel introductory show that productive scientists can also be isolate, characterize, test, and potentially biology labs to “create a real interface between committed, innovative teachers of under- even name and patent the products of those chemistry, math, computing, and biology.” graduates—a skill often undervalued at rainforest organisms. One area his students will explore is personal high-powered research universities. This Winston A. Anderson, a professor of genetic information—often discussed in goal was well met, says Stanford’s Long, as biology at historically black Howard lectures as a societal issue, he says, but rarely the 2002 Professors “stimulated and trans- University, in Washington, D.C., is creating addressed in laboratory curricula. Rine plans formed entire institutions, and have even an ambitious research-oriented academic to have students’ distinctive mitochondrial facilitated new nationwide conversations program to give undergraduates a “compet- DNA sequenced commercially, whereupon on science teaching and mentoring.” p itive edge” for entering biomedical science they will each use computational tools to — r I c h a r d S a lt u s careers. Active researchers will mentor the construct a “tree” of their heredity. students in laboratory courses on genomics, proteomics, and metabolomics. Anderson is also planning summer exchange programs that will take undergraduates to African “[Instead of being] minor technical players in the countries such as Ghana, Ethiopia, Mali, big science of a typical laboratory, students will and Nigeria to learn about infectious trop- be completely vested in an original project in ical diseases and ethnopharmacology—the study of indigenous plants used for medic- which they have full autonomy. inal and other purposes. Scott Strobel ”

this summer. Here, three undergraduates who participated during the summer of 2005 share their experiences of science and culture abroad. When searching for an international research opportunity, Rokhsanna Sadeghi, a senior at Rensselaer Polytechnic Institute, in Troy, New York, looked for a location Undergraduates Abroad and a project that would allow her to learn laboratory-based biochemistry and directly Wo r k i n g w i t h r e s e a r c h e r s i n ot h e r connect her research to health issues in co u n t r i e s e n r i c h es students’ sc i e n t i f i c the local community. Working with Valerie a n d c u lt u r a l o u t lo o k . Mizrahi in her lab at the University of the Witwatersrand and the National Health Zebras, hippos, and wildebeests; frenetic minibus rides through Johannesburg; Swaziland Laboratory Service in Johannesburg, South women doing the graceful, rhythmic Reed Dance—for Rokhsanna Sadeghi last summer, just Africa, Sadeghi came to better understand

leaving her dorm each morning brought a new adventure. Every day, she explored the tangled how vitamin B12 regulates the produc- but beautiful web of science and culture in South Africa. tion of methionine—an essential amino W i t h w orld-class sc i e n c e now being practiced on a truly worldwide basis, American acid—which in turn affects the growth and scientists often spend time doing research in foreign lands. This is not the case for most virulence of bacterial strains that cause students—especially undergrads—who rarely have the necessary resources or credentials. tuberculosis, a disease that wreaks havoc But for the past 5 years, an HHMI program has been pairing undergraduate students for among HIV/AIDS patients in that region. summer research with the Institute’s international research scholars. More than 40 students In her free time, Sadeghi sought out

Robert Rathe have been placed so far, from Mexico to India, and at least 20 more will have their chance South African students and church groups

May 2006 | hhmi bulletin 45 science education

“[Combining research and community emotional stamina, she says. “You are depen- dent on this whole set of circumstances: how service] renewed my faith that these are things I smart the monkey is, how much it wants to be want to do and can do. trained, and whether it stays healthy.”

rokhsanna sadeghi Overwhelmingly, her summer experience ” has deepened her love of Latin-American culture. In her free time, Cekanaviciute’s who brought food and medical care to stimuli. Sifting through detailed statistical growing ﬂuency in Spanish allowed her homeless people. Accompanying them, analyses of the resulting data, she helped to explore. She hiked through jungles and sometimes to burned-out buildings on dispel the widely assumed notion that climbed pyramids in the Yucatan peninsula. bitterly cold evenings, she helped medical monkeys’ brains sort and compare tactile She learned about the struggles of guerillas students take patient histories and arrange information based on repeating patterns of in the state of Chiapas and the poverty of for medical referrals among the people that stimulation. young children selling fowers on the streets. her laboratory research might ultimately Cekanaviciute also learned to appreciate After she graduates next year, benefit. This combination of research and working with these higher animals, especially Cekanaviciute plans to spend a year south community service invigorated and inspired compared with her previous efforts—with cell of the border, perhaps in Mexico or Peru, her, Sadeghi says. “It renewed my faith that cultures. “Cells are not cute, they’re not fuffy, before pursuing graduate work. “It’s very these are things I want to do and can do.” and they’re not smart,” she says. “You don’t important to travel,” she advises future Another student opted for an assign- get attached to them; you don’t name them.” participants. “It’s a must to go and see every- ment north of the border in Canada, just Working with animals requires patience and thing you can.” p— S a r a h W e b b 400 miles from his home base at Michigan’s Kalamazoo College. Michael Glista, a senior, immersed himself in Alzheimer’s disease research by spending his summer at Peter St George-Hyslop’s University of Toronto lab. Throughout the summer, postdoc Hiroshi Hasegawa mentored Glista as they worked with recombinant proteins in an effort to reconstruct the molecular puzzle pieces that interact as cells produce the disease’s telltale ß-amyloid plaques in the brain. His experience, Glista says, resulted in a published paper and a direction to pursue in his intended career as a researcher and clinician. Making It Relevant to Although he didn’t journey far for his Human Health research project, Glista says the international mix of colleagues in the St George-Hyslop A new HHMI p r o g r am aim s to i n c r e a s e t h e n u m b e r o f lab—from Japan, China, Poland, and b a s i c r e s e a r c h e r s w h o a r e c l i n i c a l ly l i t e r at e . Canada—and their passionate commitment to their work left a strong impression. i t all comes do w n to a frame of mind. The best physician-scientists have it. Their Her summer in Ranulfo Romo’s lab laboratory research is aimed directly at benefiting human health. at Mexico City’s National Autonomous A new HHMI program aims to instill that sensibility in Ph.D. students to expand the University of Mexico allowed Egle pool of investigators steeped in rigorous scientific techniques but also familiar with clin- Cekanaviciute, a junior at Harvard ical practice. HHMI’s Med into Grad Initiative recently awarded $10 million over the University, to explore neuroscience research next 4 years to 13 innovative graduate-training programs that combine medical knowl- with animals. She trained a rhesus monkey edge with basic science. to respond differently when two distinct “The goal is to integrate clinical science and medical information so the students are vibration frequencies were applied to its trained to think about the relevance of what they do to health or disease, and to emphasize hands; then she watched her colleagues an understanding of how things work in the human body,” says Martha K. Cathcart, a cell implant electrodes to understand how the biologist and director of one of the new training programs at the Cleveland Clinic Lerner

monkey’s brain distinguished between those College of Medicine of Case Western Reserve University. (continued on next page) Kay Chernush

46 hhmi bulletin | May 2006 Awards Bring Science to the This new medical school was established in partnership between Case Western and the Community Cleveland Clinic Foundation to train physician-scientists. HHMI will support a Ph.D. program in its Department of Molecular Medicine, where an intensive “core curriculum”—classes A new HHMI grant initiative will in the fundamentals of basic and clinical research—will be taught during the students’ first harness the resources of biomedical 15 months. Advanced coursework can be taken there as well and on Case Western’s nearby research institutions to increase campus. Students will be assigned a clinical mentor and a research mentor. public understanding of science and If a student wished to do her thesis research on the molecular and cellular biology of broaden access to science for people of all ages. These outreach efforts cardiac ion channels and how they relate to human diseases, Cathcart explains, she would be will be aimed at improving science mentored by a clinical researcher in the Cleveland Clinic’s Department of Cardiovascular education for elementary, middle Medicine. The student would attend biweekly conferences sponsored by the clinic’s atrial- school, and high school students. fibrillation group—cardiologists, cardiac surgeons, radiologists, electrophysiologists, geneticists, “Research institutions have unique cell biologists, nurses, and social workers who share a common interest in cardiac dysrhyth- resources for sparking an interest in mias—to discuss challenging cases and the latest advances in clinical and basic research. science and transforming science education,” says Jill Conley, director At the end of the semester, the student would make a presentation to the group focused of HHMI’s Precollege Science on a relevant translational-research problem—such as development of new targeted thera- Education Program. “For example, pies directed against specific cardiac ion channels or the use of genomic tools to identify they have modern research facilities, novel genetic changes associated with heightened risk of atrial fibrillation. And throughout cutting-edge scientiﬁc knowledge, the semester, her mentor would bring her to specific clinical sites to observe clinicians and and the ability to offer authentic research experiences to students.” clinical researchers engaged in activities related to a disease of current interest. HHMI has committed $22.5 mil- Houston’s Rice University is working with neighbor University of Texas’s M.D. Anderson lion to fund about 30 grants for Cancer Center to train future biomedical engineers in drug design for cancer therapeutics, 5-year projects. Almost 300 nonproft tissue engineering for reconstructive procedures following surgery, and imaging tools for U.S. institutions have been invited early cancer detection. Students take five courses and then do clinical rotations in special- to apply. They include medical ties such as diagnostic imaging, radiotherapy, and bone marrow transplantation. “Our goal schools, academic health centers, independent research institutions, is to get students to understand the challenges physicians face in their practice and how and schools of veterinary medicine, bioengineering can be clinically useful,” says Rebecca Richards-Kortum, a bioengineer and dentistry, and public health. To HHMI professor at Rice University who codirects the program. deliver their programs, the research At Stanford University, first-year graduate students take basic biomedical science classes along- institutions may collaborate with side medical-school students. They also attend seminars in translational medicine and do an community-based organizations, including school systems and science intensive 1- to 2-month clinical rotation. In their second year, students pick labs and mentors for centers. Two previous competitions their thesis research. “With only an extra year-and-a-half of training,” says neurologist Ben Barres, have awarded 96 grants totaling the program’s director, “we can generate a $33 million. The outreach programs group of basic researchers who understand will be directed at teachers, students, what goes on in the clinical wards.” families, and others in the commu- Among the key elements emphasized at nity. Research institutions can design activities in a variety of areas, such the program of the University of Alabama at as building students’ scientifc skills; Birmingham (UAB) are techniques of supporting professional development modern drug discovery. By working alongside for teachers; improving scientifc scientists at Birmingham’s Southern Research literacy among parents, caregivers, Institute, “Students can learn firsthand what “The goal is to integrate and others; involving undergraduate and graduate students and post- it takes to get a drug to the marketplace,” clinical science and doctoral fellows in K–12 education; says Thomas Clemens, a pathology professor and developing science education at UAB and the program director. medical information resources. “We want to nurture These programs, as well as the others so the students are students’ fascination with the supported by the Med into Grad Initiative, aim natural world when they’re young trained to think about to provide graduate students in basic sciences and curious,” Conley says. “This the relevance of what may happen in school, but we’ve also with the skills to take their own research find- seen a positive correlation between ings and apply them to clinical situations. In they do to health or students’ science profciency and the that way, translating basic scientific discoveries disease. importance placed on science outside into new medical treatments will be not only school.” HHMI will announce the

Mike Sands, Case Western Reserve University better but faster. p — l i n d a m a r s a Martha Cathcart awards for biomedical research insti- ” tutions in June 2007. May 2006 | hhmi bulletin 47 science education

Gilliam Fellowships Reward Determination

s I x y o u n g b i o m e d i cal researchers who have battled adversity are winners of HHMI’s 2006 Gilliam fellowships. These students all established impressive scientific credentials as undergraduates, marking them as promising research scientists. All of them also faced personal challenges that helped turn their sights toward careers in science. • Gilliam fellowships provide support for doctoral studies for disadvantaged students, including minorities underrepresented in the sciences. They are named for the late James H. Gilliam, Jr., a charter Trustee of HHMI who spent a lifetime fostering excellence and diversity in education and science. HHMI awarded Gilliam fellowships for the first time in 2005. • Gilliam fellowships are open to students who participated in HHMI’s Exceptional Research Opportunities Program (EXROP) as undergraduates. EXROP students conduct research in the labs of HHMI investigators and HHMI Professors. These new Gilliam fellows will have leadership roles at EXROP meetings—speaking on panels, leading discussions of graduate student life, or chairing a scientific session—to enhance their own mentoring skills and to motivate upcoming EXROP students.

Jonathan Abraham John P. Cassady postbaccalaureate r e s e a r c h f e l l o w g r a d u at e s t u d e n t n at i o n a l i n s t i t u t e s o f h e a lt h massachusetts i n s t i t u t e o f t e c h n o l o g y After moving to Queens, New York, the Canadian-born Haitian became Cassady switched from a major in nuclear engineering to biology and became painfully aware of the misconception that Haitians were responsible for the committed to research on HIV while working with HHMI investigator spread of AIDS in the United States. Abraham plans to conduct infectious Bruce Walker at Massachusetts General Hospital. Cassady’s long-term goal disease research and help dispel myths that degrade minorities. is to develop a stem cell–based treatment for HIV infection.

Ana G. Cristancho Tam M. Nguyen m . d .- p h . d . s t u d e n t g r a d u at e s t u d e n t u n i v e r s i ty o f pennsylvania s c h o o l o f m e d i c i n e wa k e f o r e s t u n i v e r s i ty At age 11, Cristancho lost her father to brain cancer. She is determined Nguyen remembers her childhood in Saigon in the wake of the to become a pediatric oncologist and cancer biologist. As an EXROP Vietnam War, walking past poor Vietnamese citizens suffering on the steps student, she helped develop a mouse model for the childhood cancer Ewing’s of hospitals, unable to get medical care. She hopes to establish a foundation sarcoma in the MIT lab of HHMI investigator Tyler Jacks. to bring better medical care and equipment to her native Vietnam.

Kevin B. O’Brien Edwin H. Rodriguez g r a d u at e s t u d e n t undergraduate u n i v e r s i ty o f w i s c o n s i n – m a d i s o n s ta n f o r d u n i v e r s i ty ( g r a d u at e s c h o o l u n d e c i d e d ) O’Brien plans to study the viral pathogenesis of avian inﬂuenza virus, Watching his mother battle kidney disease—and recover with a kidney including its lingering effects on the immune system. His mother’s transplant—Rodriguez became interested in biomedical science. autoimmune disease led him to focus on how acute and persistent viral He is studying the effects of hypoxia, or low oxygen, on kidney cancer. infections may induce autoimmune disease later in life. He wants “I want a life in academic medicine, treating patients and leading my to help diversify research and teaching faculty. own lab to new understandings of disease.” Jonathan Abraham: Tom Kochel Tam M.John Nguyen: P. Cassady: David KathleenGraham DooherKevin B. AnaO’Brien: G. Cristancho: David Nevala David EdwinGraham H. Rodriguez: Barbara Ries

48 hhmi bulletin | May 2006 institute news

T h e T rustees of the H o wa r d H u g h e s M e d i c a l I n s t i t u t e have elected Edward J. Palmerino as the Institute’s new vice president for finance and treasurer. He assumed his new role in January. Palmerino, 58, has served as the Institute’s controller since 2001. He will oversee all of the purchasing, accounting, and business systems for the Institute, as well as internal audit and facilities management. HHMI’s finance department oversees an Institute- wide annual budget of more than $660 million. “Ed Palmerino has deftly streamlined many of the Institute’s business practices during his years at HHMI,” says president Thomas R. Cech. “His selection as head of the finance department ensures that the Institute’s resources will continue to be used wisely in support of our mission of research and science education.” When Palmerino joined HHMI as assistant controller in 1986, his first task was to hire and train accounting and finance staff for relocation to the new headquarters site in Edward Palmerino Maryland. Since that time, he has been instrumental in ensuring the efficient manage- Named ment of the resources of the Institute, whose endowment had reached $14.8 billion by the close of fiscal year 2005. Vice President Among the technological and operational changes introduced by Palmerino are the for Finance implementation of the first major computerized accounting system and the electronic storage of invoices and tax returns. He has developed procedures to ensure that the and Treasurer Institute’s spending meets the government requirements for a medical research organization, and has also coordinated the borrowing of $500 million through tax-exempt bonds to finance the construction of the Institute’s new Janelia Farm Research Campus. Palmerino has a bachelor’s of business administration degree in accounting from Nichols College in Massachusetts. Prior to joining HHMI, he was a financial director for the American Red Cross for 11 years, including 6 years as the national director of accounting.

Avian Flu: A Global Update

In March, HHMI and the Center for Strategic and International Studies (CSIS) presented a symposium on the global spread of avian flu and the preparedness of surveillance and public health systems to address that spread. The Capitol Hill event was headlined by a noted panel of speakers (above center), including Jeffery K. Taubenberger (left), Chair, Department of Pathology, Armed Forces Institute of Pathology; David Nabarro (center), Senior Coordinator for the United Nations System for Influenza Coordination; and Nancy J. Cox (right), Director, CDC Influenza Division, and Director, WHO Collaboration Center for Surveillance, Epidemiology, and Control of Influenza. HHMI investigator Robert A. Lamb of Northwestern University chaired the panel. Photos: Paul Fetters

May 2006 | hhmi bulletin 49 lab book From Tree to Harpoon SHAPE-SHIFTER PROTEIN GIVES A VIRUS DRAMATIC ENTRÉE TO ITS TARGET CELLS.

HIV, influenza, and other enveloped viruses infiltrate host cells by The researchers’ initial efforts to solve the prefusion structure of fusing their outer surface with the membrane of their target, then F were thus thwarted by its volatility. But they found that by adding dumping their genetic material inside. Scientists from the labs of a small piece of a foreign protein known to act as a kind of Velcro to HHMI investigator Robert A. Lamb and Theodore S. Jardetzky, the end of F, they could trick the mercurial protein into holding its both at Northwestern University, have now provided a clear picture prefusion shape. This allowed them to solve that elusive structure— of how one protein—the F protein of the paramyxovirus—facili- and to envision F’s dramatic remodeling during membrane fusion. tates this fusion. It lies in wait until a target cell is nearby and then Understanding this viral-fusion process, which had previously snaps into an entirely new shape to initiate infection. been revealed only for influenza, should help in the design of drugs The reconfiguration of the F protein—responsible for measles, targeting the vast family of paramyxoviruses, Lamb notes. p mumps, and a host of respiratory infections—is one of the most – Jennifer MichalowsKi dramatic that scientists have observed in any protein. It starts out shaped like a tree, Lamb says, with its trunk anchored on the viral surface—a form that allows a great deal of energy to be stored. When the virus nears a susceptible cell, F uses its energy to extend like a harpoon into the target’s membrane, then collapses on itself, drawing the two membranes together. Scientists have known that viral-fusion proteins rely on a shape change to accomplish their task, but visualizing these structures has been challenging, in large part because the prefusion form is so eager to spring into action. “It’s really sort of hair-triggered,” Lamb explains. “It’s sitting there ready to go, and if you disturb it, that’s it.” Moreover, he and his colleagues observed that removing the F protein from the membrane for structural analysis “was like The virus that causes mumps and measles infects cells via its F protein, which adopts a harpoonlike shape to gain entry. releasing the spring. The whole thing unraveled.”

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How Sperm Cra c k t h e w H i p beginning to answer questions about create better vaccines, including vaccines Researchers have identified a key compo- what they are and what they do.” that target parasites before they develop nent of the mechanism spermatozoa use in the liver. Their development in lymph to abruptly convert their tail motion from M a l a r i a P a r a s i t e s nodes could be one reason why there is so a steady swimming undulation to the Develop in L y m p h N o d e s much tolerance to these parasites, Ménard whip-cracking snap that thrusts them In the first quantitative, real-time imaging suggests. into an egg. The finding may help scien- study of the travels of the malaria parasite tists recognize additional forms of male Plasmodium through mammalian tissue, W o r m s M a y H e l p R e v e a l infertility and design contraceptives to researchers at the Pasteur Institute in Paris S e c r e t s o f P e c u l i a r T u m o r s thwart sperm entry into the egg. found the parasites developing in an unex- HHMI researchers have developed a What’s more, the exquisitely delicate pected place: lymph nodes. genetic model in the nematode Caenor- analytical technique the researchers The parasites’ presence in the lymph habditis elegans that may help scientists used to eavesdrop on the electrical nodes almost certainly has implications understand how a specific kind of tumor currents inside the squirming sperm cell for the mammalian immune response, develops from germline cells. could open a new window into its largely says Robert Ménard, an HHMI international The tumors are called teratomas, a mysterious inner workings. research scholar who led the study. Ménard name derived from teroton, the Greek word HHMI investigator David E. Clapham and colleagues reported their findings in the for monster. True to their name, teratomas and his Harvard Medical School colleagues February 2006 issue of Nature Medicine, are a monstrous mix of cell types—usually published their findings in the February 9, published online on January 22, 2006. appearing with bits of hair, teeth, and bone 2006, issue of the journal Nature. Until now, researchers believed that, wrapped into a metastatic ball. According to Clapham, the finding although both blood and lymphatic vessels Researchers have had a difficult time represents the beginning of an important take up Plasmodium, the parasites all end understanding how and why these tumors research pathway. “It’s like opening a up in the liver. Says Ménard, “Nobody had form. But an article in the February 10, chamber in an ancient pyramid, because proposed that they actually might stop” in 2006, issue of Science provides new clues no one had ever seen inside sperm cells the lymph nodes and develop there. to some of the genetic missteps that may to measure all the currents that control Understanding the intricacies of the occur. In the article, HHMI investigator their activity,” he says. “We are already mammalian immune response to Plas James Priess and colleagues at the Fred measuring many of these currents and infection might help scientists Hutchinson Cancer Research Center in

modium Courtesy of Lamb lab

50 hhmi bulletin | May 2006 Hamster Chill Time THE UPS AND DOWNS OF DAILY ACTIVITY ARE CONTROLLED BY A PROTEIN IN THE BRAIN.

Couch potatoes, take heart. That irrepressible urge to veg out K r a v e s t e s t e d t h e might just be a matter of brain chemistry—at least, in hamsters, protein directly by inject- according to former HHMI predoctoral fellow Sebastian Kraves ing it into the brains of and his neurobiologist mentor Charles J. Weitz of Harvard Medical lab hamsters and then School. The researchers reported in the February 2006 issue of keeping track of their Nature Neuroscience their discovery of a brain protein that modu- wheel-running routines. lates rodents’ daily activity patterns. Strikingly, the treatments As anyone with pet hamsters knows, rodents lie low a good part completely abolished of the day. That makes evolutionary sense, Kraves explains. Lest it the animals’ urges to run become breakfast for a predator, for example, a rodent might do on their wheels during best to sit tight in its burrow if it doesn’t have some good reason to normal exercise periods. be out and about. But what’s behind those lulls? When Kraves stopped the By logging running sessions on an exercise wheel, scientists protein administration, know that the timing of rodents’ daily movement (locomotor) cycles the hamsters resumed repeats with a precision almost down to the minute. But if the rodent exercise right on schedule Having the CLC “laziness” protein (red) in its brain might be a hamster’s receives an injury to its suprachiasmatic nucleus (SCN), a tiny region at their next cycle. signal for a siesta. in the brain that controls daily rhythms, this periodicity falls apart. What’s more, blocking

Drawing on prior research, Kraves and Weitz surmised that the CLC’s brain receptor—a protein called GP130—spurred the SCN must release substances that trigger receptors in the brain hamsters to run at times when they normally would rest,

to regulate locomotor cycles. They dug through piles of papers, indicating that CLC and GP130 work together to exert control on searching for suitable candidates. After compiling a list of over 50 locomotor activity in rodents. likely compounds, they put them through a number of behavioral Though these proteins are also present in human brains, Kraves and biochemical tests, and found one protein, called cardiotro- cautions, “We don’t believe we’re close to being able to extrapolate phin-like cytokine (CLC), that seemed to fit the bill. these results to humans.” p – Paul Muhlrad

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Seattle report that they switched off two Berkeley. Doudna’s research team used The researchers said their findings genes in C. elegans, prompting gonad cells x-ray crystallography to assemble a detailed promise greater understanding of how to grow into teratomas. three-dimensional picture of Dicer. In cells, the virus, Kaposi’s sarcoma–associated

9, 212-219. ©2006. Similar to human ovarian teratomas, the enzyme jump-starts RNA interference, herpesvirus (KSHV), persists in the multi- the nematode teratomas appear to result a process that causes genes to be turned plying cells of growing tumors. More from germ cells that have entered but not off, which, in turn, prompts a host of key broadly, however, the researchers said completed meiosis, a specialized type of developmental events, ranging from brain their studies dramatically change how cell division in which chromosomes development to stem-cell differentiation. they view nucleosomes—beadlike struc- recombine before differentiating as sperm With the structure of Dicer solved, tures of DNA and histone proteins that

Nature Neuroscience or eggs. “Although there’s not a lot known Doudna’s group showed that the enzyme form the core of chromosomes. The new about how teratomas form, we now have is more than a molecular cleaver—it also findings indicate that nucleosomes, once a relatively simple model for studying carefully measures and snips strands of thought to be simple scaffolds around them,” says Priess. RNA into precise increments. When Dicer which DNA wound itself, are active cleaves large strands of RNA into smaller docking stations for a number of regula- M o l e c u l e D o e s M o r e fragments, it initiates the process of RNA tory molecules that affect gene function. t H a n S l i c e a n d D i c e r n a interference. “This really changes the way we think A team of HHMI scientists has peeled “The bottom line we’ve learned from about nucleosomes,” Luger says. “Now, away some of the mystery about how the structure is that Dicer is a molecular we see them as much more dynamic cells are able to turn off genes selectively ruler,” Doudna explains. “It gives us a lot of protein assemblages that can actually to control critical developmental events. insight into how the mechanism works.” serve as binding platforms for all kinds of The new insights arise from the first clear cellular factors.” molecular images of the structure of Dicer, F ollowing a Hit chh i k e r The research, published in the February 10, an enzyme that enables cells to dissect f o r C l u e s t o V iral Survival 2006, issue of Science, was a collabora- genetic material precisely. HHMI researchers have discovered how tion between the laboratories of Kenneth The finding, reported in the January 13, the virus that has a causative role in M. Kaye at Harvard Medical School and 2006, issue of Science, came out of a study Kaposi’s sarcoma, a cancer associated Brigham and Women’s Hospital and led by Jennifer A. Doudna, an HHMI inves- with HIV infection, hitches a ride inside Karolin Luger, an HHMI investigator at tigator at the University of California, cells to ensure its survival. Colorado State University. Image reprinted with permission from Macmillan Publishers Ltd:

May 2006 | hhmi bulletin 51 lab book

Shining Light on Vitamin B12 AN HHMI PROFESSOR’S TEACHING STUNT LEADS TO A LONG-SOUGHT DISCOVERY.

Scientific discoveries sometimes emerge from the most unexpected graduate microbial-genetics course, Walker found that adding places. HHMI Professor Graham C. Walker, for instance, never household laundry brightener to dishes containing S. meliloti caused predicted that a classroom experiment with soil bacteria would uncover some of the bacterial colonies to glow white under ultraviolet light, a missing link in the biochemical pathway for manufacturing vitamin depending on the genes present. He thought the serendipity might

B12. Walker, a professor of biology at the Massachusetts Institute of make for a fun lab unit because “undergrads love glowing bacteria.”

Technology, studies the symbiotic relationship between certain The link between the bacteria and vitamin B12 surfaced bacteria and alfalfa plants. The microbes, called Sinorhizobium meli- when Walker’s graduate student, Gordon R. Campbell, isolated loti, invade the plants’ roots, where they convert nitrogen gas from the S. meliloti mutants that fluoresced especially intensely in the laundry- atmosphere into a form that the plants, and animals that consume brightener test. One of the brightest-glowing variants turned out to them, can tap for nourishment. In an ecological quid pro quo, the have a mutation in an uncharacterized gene, whose sequence was microbe, in turn, gets its required nutrients from the plant. similar to that of a gene, called bluB, found in another bacterium.

Years ago, while searching for engaging experiments for his under- Scientists had implicated bluB in vitamin B12 biosynthesis.

Vitamin B12 is a large compound that requires more than 30 different enzymatic steps to assemble, Walker notes. The enzyme that catalyzes one of them—building a part of the molecule called DMB—had never been identified. The Walker team determined that bluB appears to be needed for that step. Their results were published in the March 21 issue of the Proceedings of the National Academy of Sciences. “Many labs have been trying to figure out this missing part of the pathway for years,” Walker says. “It was amazing to me to discover that there was something as basic as building a vitamin that wasn’t com- Under ultraviolet light, bacteria with a mutant bluB gene outshine those pletely known by 2006. Solving this mystery was a nice coming together without the mutation. of my interests in teaching and research.” p – Paul Muhlrad

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A N e w L o o k a t M o l e c u l a r functions one by one, and the better we cell’s internal molecular machinery. But M o t o r s understand how they are related, the understanding how the toxin—one of An innovative method for categorizing faster that will occur.” seven neurotoxins produced by the bacte- myosins—one of the three types of molec- So far, molecular motors have been rium Clostridium botulinum—enters nerve ular “motors” that produce movement in found in all organisms but bacteria, red cells has proved elusive for scientists. the cells of the body—has increased the algae, and the parasite Giardia. Soldati and Despite a decade-long search for the information available about these essential her colleagues became interested in receptor by labs around the world, proteins. The studies lay the groundwork myosins after they discovered that the researchers came up empty-handed. for development of treatments for con- molecular motors enabled toxoplasmosis Now, a research team led by HHMI ditions ranging from certain kinds of and malaria parasites to force their way into investigator Edwin R. Chapman reports blindness and kidney disease to neurode- human cells. The new myosin classification that it has identified the cellular receptor generative disorders and parasitic diseases system should help researchers make for botulinum neurotoxin A. The University such as malaria. advances in a wide variety of fields, from of Wisconsin–Madison group’s work was Researchers led by Dominique Soldati, veterinary medicine to tropical diseases. published in the March 16, 2006, edition of an HHMI international research scholar at The work appeared on February 6, ScienceXpress, which provides electronic the University of Geneva, in Switzerland, 2006, in an advance online publication of publication of selected Science papers in developed a new system of classifying the Proceedings of the National Academy advance of print. The finding offers impor- myosins. Up to now, researchers have of Sciences. tant new insights that suggest how the studied only approximately 130 myosins toxin shuts down nerve cells with deadly at a time. The new system includes 250 B o t u l i s m T o x i n ’ s I n s i d i o u s efficiency. myosins and increases the number of R o u t e i n t o N e r v e C e l l s The identification of SV2 as the neuro- myosin subclasses from 18 to 24, enabling Botulinum neurotoxin A can be either the toxin A receptor raises the possibility of researchers to better understand each greatest wrinkle remover or one of the designing protective drugs that interfere myosin’s function. world’s most potent biological weapons. with the toxin’s action. Chapman plans to “Myosins that belong to the same To perform either job, however, the toxin aid such efforts by focusing his research class work in similar ways but can have must first find a way to enter cells. on developing a more detailed under- very different functions,” explains Soldati. Researchers have long known how standing of the molecular interaction “We will have to discover the myosins’ botulinum neurotoxin A attacks the nerve between the toxin and its receptor. Michiko Taga

52 hhmi bulletin | May 2006 ask a scientist

Q. Is it possible to “steal” the genes of successful Submitted by a U.S. performance horses—for example, by pulling a few hairs— high school student and create genetic copies through cloning?

Born on March 13, 2005, Paris Texas is a bay-colored colt and the first horse successfully cloned in North America. He was spawned from adult skin cells collected from a valuable performance stallion in Europe. The cloning was done at Texas A&M University by a research team led by Katrin Hinrichs, veterinarian and professor, and Young Ho Choi, associate research scientist, in collaboration with Eric Palmer, chairman of the French company Researched . Cryozootech. Horses have been cloned twice elsewhere; a number of other mammalian by AlexeyA Veraksa species have also been cloned. Can genes be stolen in much the same way as, say, valuable documents? The fact that this cloning effort used adult cells tells us that the same method could be used for nefarious purposes. However, let me give a few reasons why I think we are not quite there yet.

The scientific process First, cloning procedures—which proved especially difficult for the horse—still require starts with a question. state-of-the-art laboratories and years of experience. Our gene thief would need to find When a scientific inquiry piques the highly sophisticated collaborators. interest of a high Second, the success rate of these experiments remains low. The cells present in a few school or college student and answers hairs probably would not be adequate, even after culturing, to get the number required to can’t be found in class or in a textbook, achieve successful cloning. students can turn to Third, even though the cloned horse was reported to be healthy, cloned animals are HHMI’s Ask a Scientist Web site. There, generally more prone to illnesses and weaker than naturally produced offspring. A cloned working scientists field a wide range of performance horse may not become a champion, because competitions test the extremes of biomedical questions. what an organism can achieve physically. “Cloning is not a way to produce competitors,” notes Hinrich. “There is just too much TO SEE OTHER QUESTIONS Visit Ask a Scientist, variability in the environment that a cloned foal experiences, both in the uterus and after www.hhmi.org/askascientist birth. Just the fact that he spent his first 7 days in an incubator can affect Paris Texas’s growth rate after birth, and even his performance as an adult.” On the other hand, Hinrich points out that, as a sire, Paris Texas should produce the same quality of foals as did the donor stallion, because the two carry identical sets of genes. Finally, the breeding of performance horses is highly regulated. Professional associations of breeders recognized a potential for fraud some time ago, especially since performance horses can bring substantial amounts of money to their owners. One of those groups, the Jockey Club, monitors thoroughbred racing in North America and tightly controls breeding practices. The rules allow only natural breeding methods, not cloning or even artificial insemination. Horse breeders must submit DNA proof that their foals were bred naturally. DNA testing would reveal a cloned foal—it would be a duplicate of a single horse rather than a mix of two. So, even if a horse were successfully cloned and raised into a healthy championship- caliber performer, there would be no possibility for it to participate in some types of competition, such as thoroughbred racing. However, a few biotechnology companies are seeking well-heeled customers interested in cloning their favorite horses.

r e s e a r c h e d B Y a l e X E Y V e r a K s a , Assistant Professor, Biology Department, University of Massachusetts, Boston (former HHMI predoctoral fellow)

May 2006 | hhmi bulletin 53 nota bene

Nicholas D. Andersen, an HHMI Michael D. Ehlers, an HHMI investi- Association for Cancer Research. Kaelin was medical fellow at Harvard Medical School, gator at Duke University Medical Center, was honored for his discoveries related to the won the 2005 Young Investigator Award selected to receive a 2006 Fulbright Scholar von Hippel-Lindau tumor suppressor gene. from the International Society for Applied Award. Ehlers will work at the Université Cardiovascular Biology. Victor Segalen Bordeaux 2 in France. M. Yashar Kalani, an HHMI medical fellow at Stanford University School of Elizabeth Azzato, a student supported David Ginsburg, an HHMI investigator Medicine, was recently selected as a Soros by HHMI’s undergraduate grants program at the University of Michigan Medical Fellow. The Paul & Daisy Soros Fellowships at Washington and Jefferson College in School, won the 2005 Jeanette Piperno for New Americans are given “to provide Washington, Pennsylvania, was selected as a Memorial Award from Temple University opportunities for continuing generations of 2006 NIH-Cambridge University Scholar in School of Medicine for his work in the ﬁeld able and accomplished New Americans to Biomedical Research. Up to six scholars are of thrombosis. achieve leadership in their chosen felds.” named each year for the academic award. Lily Y. Jan and Yuh Nung Jan, HHMI Cody J. Locke, a student supported by Seven HHMI investigators, three Professors, investigators at the University of California, HHMI’s undergraduate grants program at and two board members were elected San Francisco, each received a 2006 the University of Alabama, Tuscaloosa, was fellows of the American Association for the Distinguished Alumni Award from the named to the 2006 USA Today College Advancement of Science in 2005. The California Institute of Technology. Academic All-Stars 1st Team. investigators elected are Tania A. Baker, Massachusetts Institute of Technology; William G. Kaelin, an HHMI investi- Joan Massagué, an HHMI investigator Joanne Chory, The Salk Institute for gator at the Dana-Farber Cancer Institute, at Memorial Sloan-Kettering Cancer Biological Studies; Harry C. Dietz, The won the 2006 Richard and Hinda Rosenthal Center, received the inaugural Vilcek Prize Johns Hopkins University School of Foundation Award from the American in Biochemical Research. The award is Medicine; Philip Green, University of Washington; J o e l F. H a b e n e r , Massachusetts General Hospital; Stephen S p o t l i g h t C. Harrison, Harvard Medical School; and Milan Mrksich, The University of Chicago. The Professors are Leslie A. Leinwand, University of Colorado, Boulder; Susan R. Wessler, University of Georgia; and H u n t i ng to n F. Willard, Duke University. Also elected were P e t e r C . a G r e , Duke University, Björkman Lauded who serves on HHMI’s scientiﬁc review by L’ORÉAL-UNESCO board, and Bruce W. Stillman, Cold Spring Harbor Laboratory, who serves on HHMI’s medical advisory board. Pamela J. B j ö r k m a n

Thomas R. Cech, president of HHMI, received the 2006 Award for Exemplary HHMI investigator Pamela J. Björkman at the California Institute of Technology Contributions to Education by the American won the 2006 L’ORÉAL-UNESCO For Women in Science Award for North America. The esteemed award, which honors female scientists who are leaders Society for Biochemistry and Molecular in their fields, also went to recipients inA frica, Asia/Pacific,E urope, and Latin Biology. This is the inaugural year for the America. ¶ Björkman was honored “for her lifetime commitment to decoding annual award. protein structures, one of the seminal accomplishments in immunology and a major step toward new HIV therapies.” ¶ As a graduate student and postdoc- David E. Clapham, an HHMI investi- toral fellow in the Harvard University laboratory of the late HHMI investigator Don C. Wiley, Björkman solved the crystal structure of a human histocompati- gator at Children’s Hospital Boston, received bility molecule. She continued her postdoctoral training at Stanford University the 2006 Bristol-Myers Squibb Foundation School of Medicine with HHMI investigator Mark M. Davis, where she worked Freedom to Discover Distinguished Achieve on T-cell receptors. Currently, her Caltech laboratory is focusing on protein- ment Award in cardiovascular research. protein interactions, particularly those mediating immune recognition. Danny Turner

54 hhmi bulletin | May 2006 S p o t l i g h t

given by the Vilcek Foundation to honor outstanding creative achievement by immi- grants to America. Massagúe was born in Barcelona, Spain.

Craig C. Mello, an HHMI investigator at the University of Massachusetts Medical School, won the 2006 Paul Ehrlich and Ludwig Darmstaedter Prize from the Paul Ehrlich Foundation in Germany. Mello shares the award with Andrew Z. Fire, L e ft to r i g ht : r o n a l D m . e va n s a n d J oa n A . S t e it z Stanford University School of Medicine, for the discovery of double-stranded small inter- Two Investigators fering RNAs (siRNAs) and their role in RNA Win Gairdner Awards interference (RNAi). Ronald M. Evans, an HHMI investigator at The Salk Institute for Biological Studies, and Joan A. Steitz , an HHMI investigator at Yale University School Rafael Radi, an HHMI international of Medicine, are among the five researchers who are 2006 winners of the research scholar at the University of the Gairdner International Award for Medical Research. ¶ The Gairdner Foundation Republic in Uruguay, was recently elected a recognized Evans “for his discovery and characterization of nuclear hormone Foreign Member of the Brazilian Academy receptors and their fundamental links with physiology, nutrition and disease, of Sciences. including diabetes, atherosclerosis and cancer.” Steitz was honored “for her discovery of the reactivity of autoimmune sera with nuclear riboprotein parti- cles and elucidation of the roles of small nuclear RNAs in gene expression.” Trudi Schüpbach, an HHMI investi- ¶ The Gairdner Foundation was created in 1957 by James Arthur Gairdner, a gator at Princeton University, received the successful stock broker and industrialist. Gairdner’s lifelong interest in the E.G. Conklin Medal from the Society of convergence of medical research and clinical medicine led to his conviction Developmental Biology for her contribu- that the achievements of medical scientists should be tangibly recognized. tions toward understanding fly development The prestigious International Award is given to individuals from diverse fields for outstanding discoveries or contributions to medical science. and for supportive mentoring of students and postdoctoral fellows Roger Y. Tsien, an HHMI investigator at Ahmet Yildiz, a postdoc in the University Margaret Somosi Saha, an HHMI the University of California, San Diego, won of California, San Francisco, laboratory of undergraduate program director and the 2006 Lewis S. Rosenstiel Award for HHMI investigator Ronald D. Vale, was the professor of biology at the College of Distinguished Work in Basic Medical Science. GE Healthcare & Science Young Scientist William and Mary in Williamsburg, He shared the award with Martin Chalfe at Award grand prize winner, the highest prize Virginia, was one of 15 educators to receive Columbia University for the development of given in the international competition. a 2006 Outstanding Faculty Award from the tools that allow direct visualization of molecules Yildiz’s essay was titled, “Elucidating the Commonwealth of Virginia. in living cells. Tsien also won the 2006 ABRF Mechanism of Molecular Motor Movement.” Award from the Association of Biomolecular Christine E. Seidman, an HHMI inves- Resource Facilities for outstanding contribu- Yi Zhang, an HHMI investigator at the tigator at Brigham and Women’s Hospital in tions to biomolecular technologies. University of North Carolina at Chapel Boston, is one of fve individuals recently Hill, won the 2006 Junior Achievement named by the National Institutes of Health Thomas Tuschl, an HHMI investigator Award from the Society of Chinese to serve as a member of the Advisory at the Rockefeller University, received the Bioscientists in America. Committee to the Director. 2006 Molecular Bioanalytics Prize from Roche Diagnostics, based in Basel, Leonard I. Zon, an HHMI investigator Sarah Siegrist, a graduate student in Switzerland; the 2005 Meyenburg Prize, at Children’s Hospital, Boston, of Harvard the University of Oregon laboratory of given by the Wilhelm and Maria Meyenburg Medical School, received the 2006 Simon HHMI investigator Chris Q. Doe, was one Foundation at the German Cancer Research Gratz Research Prize for Jefferson Medical of 16 graduate students from North America Centre in Heidelberg, Germany; and the College alumni in recognition of his contri- and Asia to receive the 2006 Harold M. 2005 Ernst Schering Prize from the Ernst butions to medical research of practical Weintraub Graduate Student Award. Schering Foundation in Berlin, Germany. value to the care of patients. Evans: Misha Gravenor Steitz: Ethan Hill

May 2006 | hhmi bulletin 55 CONTINUED FROM PAGE 27 a shopping list. You need 400 petri plates? (DATA GO AWOL) We’ll pour them for you. You need ﬁ lters to Science News “If publishers go out of business isolate your own phage? We’ll send them. their online resources can vanish,” says We send these kits overnight so they have At Your Michael Seadle, assistant director for them when they need them, and they are Fingertips information technology at Michigan State the key. Now we’re getting repeats. Teachers University and a LOCKSS user. “We want are asking for this stuff year after year. RSS to make sure that scholars, 10 or 100 years from now, will still have access to these You plan to train other scientists to do data. LOCKSS is a way to make sure that what you do. What will you tell them?

published information doesn’t disappear, I’ll tell them you’re not trying to turn these If you use an RSS news reader, while respecting the publishers’ copyright. teachers into scientists but into better science you can now subscribe to the It’s a security policy for everyone.” teachers. Don’t try to dazzle them with your HHMI News feed to monitor intellect or with the cost of your toys. articles describing the latest CONTINUED FROM PAGE 41 Effective scientist-mentors will under- research discoveries by HHMI (PHILIP SILVERMAN) stand this perspective. I will also tell them scientists, the activities of HHMI grantees, and announce- The answer? that to fully engage teachers it really helps ments from the Institute. They needed classroom support. It was naïve to be a bit of a ham—mentoring is part to expect the teachers to ﬁ nd time to pour performance art. Finally, I will tell them Find out more about the HHMI 400 petri plates. It’s so obvious when I say it, that teachers are great about telling you News feed at: www.hhmi.org but it’s amazing how long it took for this to what they think. Listen to them. They Find out more about RSS at: sink in. So we asked the teachers to send us might even make you a better teacher. p www.whatisrss.com

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56 HHMI BULLETIN | May 2006 OBSERVATIONS

Answering Socrates

Knowing, from a career’s worth of research, how faulty our memories really are, Columbia University neuroscientist Eric R. Kandel saved four decades of written correspondence, personal mementos, the minutes of every Society of Neuroscience annual meeting, and more. The HHMI investigator and Nobel laureate tapped deeply into that lode to write a memoir on his lifelong search for the physical basis of memory. Kandel donated his collected miscellany to 38 the Columbia University library, which APPLE AS METAPHOR will curate his archives. extolling the singular beauty of every apple, liz lerman for biologists working on the brain, the mind dance exchange performers loses none of its power or beauty when experi- ponder the potential impact— mental methods are applied to human behavior. good and bad—of genetic likewise, biologists do not fear that the mind research on our lives. the will be trivialized by a reductionist analysis, production had input from which delineates the component parts and HHmi-supported scientists, activities of the brain. on the contrary, most educators, and students. scientists believe that biological analysis is likely to increase our respect for the power and complexity of the mind. indeed, by unifying behaviorist and cogni- tive psychology, neural science and molecular biology, the new science of mind can address philosophical questions fi rst raised in Western thought more than twenty-fi ve hundred years ago. ever since socrates and the early platonists speculated about the nature of the human mind, serious thinkers have struggled with certain questions: How does the mind acquire knowledge of the world? How much of the mind is inherited? do innate mental functions impose on us a fi xed way of experiencing the world? What physical changes occur in the brain as we learn and remember? How is an experience lasting minutes converted to a lifelong memory? such questions are no longer the province of speculative metaphysics; they are now fertile areas of experimental research.

From the book in search of memory: the emergence of a new science of mind, by Eric R. Kandel, M.D. ©2006 Eric. R. Kandel. Reprinted here with permission of the publisher, W.W. Norton & Company. Michael Mazzola Illustration: Shonagh Rae HHMI BULLETIN

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