HHMI Bulletin August 2010 Vol. 23 No. 3

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10 ’ . UG A PLANARIANS KEEPING CELLS HAPPY HAPPY CELLS KEEPING PLOWE & DJIMDÉ PLOWE WORLD OF THE HUMAN GUT. HUMAN GUT. OF THE WORLD GOING DEEP IN THIS ISSUE IN THIS RESEARCHERS ARE DIVING INTO THE COMPLICATED COMPLICATED THE INTO ARE DIVING RESEARCHERS

HHMI BULLETIN r Howard Hughes Medical Institute r www.hhmi.org vol. 23 / no. 03 Andrew Syder / The Rockefeller University Rockefeller The / Syder Andrew to read more about the work. Biological Mime Biological Bulletin and visit the online organize patterns of liver cells onto glass plates. Then they added various patterns of liver organize supporting cells to mimic the liver’s three-dimensional environment. Their environment. Their three-dimensional the liver’s supporting cells to mimic cells unwilling to grow on flat Petri dishes, she thought adding a dimension a dishes, she thought adding Petri on flat cells unwilling to grow collection of parts. So when HHMI investigator Sangeetacollection of parts. So when HHMI investigator Bhatia found liver now Bhatia is building mini-livers. See “Into the Third Dimension,” page 24, “Into the Third Dimension,” See mini-livers. Bhatia is building now a membrane protein in green, and a cell junction protein in red) thrived, and and a cell junction protein in green, a membrane protein There’s nothing flat about the human body. It is a three-dimensional, dynamic dynamic It is a three-dimensional, flat about the human body. nothing There’s might help. Her lab group coopted methods from computer chip fabrication to help. Her lab group might creative thinking paid off—the liver cells (in this illustration, cell nuclei in blue, in blue, (in this illustration, cell nuclei creative thinking paid off—the liver cells 4000 Jones Bridge Road Bridge Road 4000 Jones Maryland 20815-6789 Chase, Chevy www.hhmi.org 28 the worm grewahead.Now which way isforward? took aturnforthebizarre.Atevery incisionsite, protein, ß-catenin, theplanarian’s regenerationskills that whentheyblockedtheproduction ofjustone get 200newcreatures.ButHHMI researchersfound more than200pieces, and in aboutaweek, you’ll Planarians areregeneration’s superstar. Sliceoneinto Are sixheadsbetterthanone?Askthis flatworm.

Christian Peterson and Peter Reddien

Daniel Zalkus OBSERVATIONS the mountains,wherealargebirdofprey spentthedaylight the giftofﬁre, heorderedPrometheuschainedto aboulderin discovered that Prometheushadsnuckdown to earthto return ering humansandtook ﬁreaway fromthemortals.WhenZeus the leaderofGreekgods,resented Prometheusfor empow- skills asastronomy, mathematics, medicine, andnavigation. Zeus, (according to someversions ofthestory) andtaughtthemsuch According to Greekmythology, Prometheuscreated humans ing repairing tissue damageandgrowing organs for today’s research toward potential future usesofstem cells, includ- the pluripotent cells were discovered. Suchstories alsodirected say thesestories hinted attheexistence ofstem cells longbefore Goldstein andMegSchneider, authorsof tales springfrom observant witnesses to strange events. Lawrence Humans have forever beenstorytellers andmany ofouroldest BIOLOGY INMYTHOLOGY Stem Cells for Dummies transplant. ,

Publishing, Inc. Goldstein, Ph.D., andMegSchneider. Copyright 2010 by Wiley Excerpted from battle-wounded soldiers. grow back—something they may have observed fromtreating the ancientGreeksknew that livers (butnototherorgans) could tissue. Prometheus’s story iswidelyviewed asanindication that that cangenerate acomplete organfromafraction oftheoriginal fact, asfar asresearchersknow, theliver istheonlyinternal organ even ifasmuchthree-quarters oftheliver tissue isdamaged.In Scientists now know that thehumanliver canregenerate itself, again thenext day. Prometheus’s liver grew backovernight sothat thebirdcould feast hours eating Prometheus’s liver. At dusk,thebirdﬂew away, and Stem Cells for Dummies , by Lawrence S.B. august ’1o vol. 23 · no. o3

web only content Learn how a handful of researchers are bringing 3-D to cell culture. See photos of Janelia Farm’s community garden makeover. Read about Joaquin Espinosa’s unusual take on the p53 suppressor gene. Peer into the brain of a walking fly with Vivek Jayaraman. Join us at www.hhmi.org/bulletin/aug2010. 24 28 Features Departments COVER STORY PRESIDENT’S LETTER INSTITUTE NEWS GUT REACTION 03 A Lasting Imprint 40 Change in Leadership of 12 The vibrant ecosystem inside the HHMI Trustees CENTRIFUGE human gut does more than just 41 Bishai Named Director of K-RITH 04 The Garden That Science Built digest food. 05 Rock Face LAB BOOK TWO ROADS TO AN END 06 High-Stepping Horses 42 Driving Thirst 18 Though separated by an ocean, 43 Mustard’s Mini-Me UPFRONT Christopher Plowe and Abdoulaye 44 Double-Checking Doublesex 08 When Passion and Skill Converge Djimdé are bound by their 10 Death Be Not Programmed ASK A SCIENTIST determination to stop malaria’s 45 How can jellyfish of the same global toll. PERSPECTIVES AND OPINIONS kind gather in a group if they don’t 34 Stem Cells 101 INTO THE THIRD DIMENSION have brains? 36 Q&A—What “For Dummies” book 24 Where 2-D cell cultures fall flat, are you most qualified to write? NOTA BENE scientists are adding another 46 News of recent awards and other dimension to make cells happy. CHRONICLE SCIENCE EDUCATION notable achievements MASTER OF REGENERATION 38 Making Research Personal OBSERVATIONS 28 Once a high school biology oddity, 39 National Awards to Foster Science Biology in Mythology planarians are moving into the Education spotlight to reveal secrets of self-renewal.

VISIT THE BULLETIN ONLINE FOR ADDITIONAL CONTENT AND ADDED FEATURES: www.hhmi.org/bulletin COVER IMAGE: TOMER HANUKA contributors

TOMER HANUKA (cover art) is an illustrator and a cartoonist based in New York City. He works on projects for magazines, book publishers, ad agencies, and ﬁlm studios, with clients such as The New Yorker, DC Comics, Nike, and Microsoft. In 2008, a book cover he created won the (1) British Design Museum award, and in 2009, “Waltz with Bashir,” an animated documentary featuring Hanuka’s art, was nominated for an Oscar and won a Golden Globe. He teaches at the School of Visual Arts and is working on a graphic novel with his twin brother Asaf and writer Boaz Lavie. (1)

Once a self-proclaimed “liquid transfer specialist” at a human genetics lab, CHRISTIE ASCHWANDEN (“Rock Face,” page 5) now happily makes her living as a science journalist. Her work has appeared in the New York Times, Men’s Journal, Mother Jones, NPR.org, the Los Angeles Times, (3) (2) and O, The Oprah Magazine. She lives with her winemaker husband on a small farm in western Colorado where she raises heritage poultry and spends her spare winter hours snowboarding and coaching the local college ski team. (2)

After fulltime gigs at U.S. News & World Report and National Geographic, science writer HELEN FIELDS (“Making Research Personal,” page 38) launched a freelance career in 2008. Since then she has spent six weeks on an icebreaker in the Bering Sea and two months at a newspaper in Berlin, where she wrote about monkeys and telescopes in moderately competent (4) German. A resident of Washington, D.C., and an avid knitter, her current projects include a stegosaurus and a hermit crab. (3)

JOHN DOLE (“Stem Cells 101,” page 34) is a professional photographer who specializes in por- trait, music, lifestyle, and ﬁne art photography. Lately, he’s been having a great time shooting photos with his iPhone and its different photo applications, which makes him wonder, is it wrong to show up at a photo shoot with just your iPhone? (4)

HHMI TRUSTEES HHMI OFFICERS James A. Baker, III, Esq. Robert Tjian, Ph.D. / President Senior Partner / Baker Botts LLP Craig A. Alexander / V.P. & General Counsel Ambassador Charlene Barshefsky Peter J. Bruns, Ph.D. / V.P. for Grants & Special Programs Senior International Partner Jack E. Dixon, Ph.D. / V.P. & Chief Scientific Officer WilmerHale Mohamoud Jibrell / V.P. for Information Technology Joseph L. Goldstein, M.D. Avice A. Meehan / V.P. for Communications & Public Affairs Regental Professor & Chairman, Department of Molecular Genetics Edward J. Palmerino / V.P. for Finance & Treasurer University of Texas Southwestern Medical Center at Dallas Gerald M. Rubin, Ph.D. / V.P. & Director, Janelia Farm Research Campus Hanna H. Gray, Ph.D. Landis Zimmerman / V.P. & Chief Investment Officer President Emeritus & Harry Pratt Judson Distinguished Service Professor of History HHMI BULLETIN STAFF The University of Chicago Mary Beth Gardiner / Editor Garnett L. Keith Cori Vanchieri / Story Editor Chairman / SeaBridge Investment Advisors, LLC Jim Keeley / Science Editor Former Vice Chairman & Chief Investment Officer Andrea Widener / Science Education Editor The Prudential Insurance Company of America Patricia Foster / Associate Director of Communications Fred R. Lummis for Web & Special Projects Chairman & CEO Sarah C.P. Williams Platform Partners LLC / Assistant Editor Maya Pines / Contributing Editor Paul Nurse, F.R.S. President / The Rockefeller University ADDITIONAL CONTRIBUTORS Alison Richard, Ph.D. Cay Butler, Michelle Cissell, Vice-Chancellor Nicole Kresge, Heather McDonald The University of Cambridge VSA Partners, NYC / Concept & Design Clayton S. Rose, Ph.D. Finlay Printing / Printing & Binding Senior Lecturer, Harvard Business School Former Head of Global Investment Banking, J.P. Morgan & Co. Kurt L. Schmoke, Esq., Chairman Dean / Howard University School of Law Anne M. Tatlock Director, Retired Chairman & CEO Telephone (301) 215.8855 • Fax (301) 215.8863 • www.hhmi.org Fiduciary Trust Company International ©2010 Howard Hughes Medical Institute The opinions, beliefs, and viewpoints expressed by authors in the HHMI Bulletin do not necessarily reﬂect the opinions, beliefs, viewpoints, or ofﬁcial policies of the Howard Hughes Medical Institute. Tomer Hanuka, Christie Aschwanden, Helen Fields, John Dole John Helen Fields, Hanuka, Christie Aschwanden, Tomer

2 HHMI BULLETIN | August 2o1o president’s letter

A Lasting Imprint

HANNA HOLBORN GRAY THINKS DEEPLY ABOUT LEARNING, scholarship, and the role of the university in sustaining the cultural and intellectual vitality of our nation and an increasingly global society. Indeed, many American institutions of higher learning— colleges and universities alike—will long bear the imprint of her incisive intelligence and vision. As an historian and academic “Thanks in no small measure leader, she has an uncommon ability to balance the imperatives of the present with an unwavering commitment to the highest stan- to Hanna Gray’s leadership, dards of scholarly inquiry. HHMI remains a distinctive Over the past 26 years, few organizations have benefited more organization, one that resists from Hanna Gray’s insight than the Howard Hughes Medical Institute. Her association began in 1984. Then president of the easy categorization. University of Chicago, she was asked by the Delaware Court of ROBERT TJIAN ” Chancery to join with seven other leaders from business and aca- deme to rebuild the Institute after its founder’s death. The Charter Trustees—as they have come to be known—were appointed for life Thanks in no small measure to Hanna Gray’s leadership, HHMI and, under the leadership of the late Irving Shapiro, worked with remains a distinctive organization, one that resists easy categoriza- diligence and collegiality to resolve the myriad financial, legal, tion: as a medical research organization, we are neither a university administrative, and programmatic challenges that faced the Insti- nor a foundation but display features of each in the way we carry out tute in those early, fragile days. our biomedical research mission. Our scientists comprise a com- It came as a surprise to no one—except, perhaps, Hanna Gray munity of contemporary scholars dispersed among more than five herself—that Irving Shapiro and her colleagues elected her Trustee dozen universities, research institutes, and medical schools around chair in 1997. In that capacity, she has served as a guide and mentor the country and are known for the quality of their thought. But to her fellow Trustees as well as to three successive HHMI pres- “tenure” with the Institute is conditional: we set a stringent standard idents. Purnell W. Choppin, Thomas R. Cech, and I have each for quality balanced by a willingness to invest in the most talented relied on her, recognizing that her effectiveness stemmed equally for the long term. from the quality of her judgment and the depth of her abiding Indeed, Hanna Gray has been unbending in the defense of the affection for the Institute. intellectual and scientific integrity at the heart of the Institute’s work: Hanna Gray decided some time ago to step away from her role the searching out of new knowledge for the benefit of humanity as Trustee chair, a decision that became effective in May 2010 with within a structure that permits scientists the freedom and flexibility the election of her successor, Kurt Schmoke, currently dean of to engage in wide-ranging inquiry over the long term. Her vaunting the Howard University Law School. She will remain an active and ambition on behalf of our mission and place in the world of science engaged part of our life as a Trustee, but this transition gives me a echoes the challenge that she issued to the University of Chicago at welcome opportunity to reflect publicly on her many contributions her inauguration as its 10th president: “The greatest danger, large to the Institute. because also least tangible and most wasting, would be to engage in Working in tandem with Institute leadership, the Trustees have an apparently principled descent to decent mediocrity.” set the Institute on a trajectory of steady growth and considered And decent mediocrity will not do. Not for Hanna Gray and not innovation: the expansion of the Investigator program beyond a for HHMI. So it’s fitting that our Trustee Boardroom has now been handful of institutions, the development of a grants program aimed named in honor of Hanna Gray and in recognition of that stalwart at cultivating new generations of scientific leadership, support group of Charter Trustees. for international scientists, the development of the Janelia Farm Research Campus as HHMI’s first independent campus, and now the KwaZulu-Natal Research Institute for Tuberculosis and HIV in Durban, South Africa. In each of these activities—and many others—Hanna Gray played an essential role as sounding board,

Barbara Ries thoughtful critic, consensus builder.

August 2o1o | HHMI BULLETIN 3 centrifuge

initiation fee of $20 goes toward the 1500-gallon water tank that feeds the irrigation system as well as chicken wire and tools. An additional $10 lays claim to a 4x4-foot plot for one year— the organizers hope to lower that by half next year, as new members come on board. “It’s amazing what you can get out of these plots,” says Nyce. Biochemist Jonathan Marvin took a particularly strategic approach, constructing an elaborate trellis that, according to calculations, will quadru- ple the yield from his heirloom tomato plants. Janelia group leader Bruce Baker, a year-round gardener, con- verted his eight plots into tiered raised beds, using precisely stacked lumber joined at mitred corners. Susan Michael, a histologist who grew up in the country, has four plots this year. “It’s kind of a compulsion,” The Garden That Science Built she says. “Once you start, you can’t stop.” This season, she added gladiolas It’s July, high noon, and the sun is What a difference a year makes. to the mix. “Gotta have a little food for at its peak. Most people, given a choice, With its neatly bordered plots, irri- the soul.” are somewhere keeping cool—inside, gation system, and compost bin in Water is a primary concern to the where it’s air conditioned, or maybe place, the garden is bursting with red gardeners. Last summer’s low rainfall under a shade tree. But at the edge of tomatoes, yellow squash, and green- had them organizing bucket brigades Janelia Farm Research Campus, near striped melons shining against rich to carry water from the main building. the delivery gate, a handful of people brown mulch. Midgley, a software engineer at Janelia, bend over in the hot glare, weeding The idea for a community garden designed the gravity-flow irrigation and watering a burgeoning organic first came to Nyce and fellow Janelian system that now keeps the garden lush, vegetable garden. Frank Midgley in 2008, during a despite this month’s triple-digit tem- The oasis of leafy, fruit-laden plants conversation around lunch. Three co- peratures. He also designed and built stands in stark contrast to the hard- workers joined them in submitting a the compost bin, which receives a daily scrabble, baked earth just outside its proposal to Janelia administrators. delivery of produce scraps from the fence line. Strewn with small boulders “They were a wonderful sound- Janelia Farm kitchen. and metal scrap, the area used to be ing board and very supportive,” says Midgley says he’s met people out a dumping ground for construction Nyce. Since then, Janelia has donated in the garden that he wouldn’t have debris. The dramatic transformation fencing, lumber, and other essen- met inside the building. “It’s hard to has taken time, sweat, muscle—and a tial materials. get people to break away from their dose of scientific ingenuity. Dubbing their group “The Garden intense work,” he says. “Last year felt like Jamestown,” Club,” the organizers have recruited For Susan Michael, it’s a real high- says Kristen Nyce, an administrative 30 or so Janelia small-scale farmers, light. “You work in the sciences, it’s kind assistant at Janelia who helped start with expertise ranging from novice to of sterile. So it’s nice to muck around in the community garden. “I’m just glad certified Master Gardener, to take part the dirt and create some little miracles.”

we didn’t have to live off it.” in the communal effort. A one-time —Mary Beth Gardiner Arkle Peter

4 HHMI BULLETIN | August 2o1o You think there’s no way we can do this. But then you start and you just keep going, and maybe you have to adjust your plans as you go, but eventually you finish.” With climbing routes just minutes from his lab at the University of Colo- rado, Espinosa sneaks away to a crag whenever he can spare a few hours. Since moving to Boulder, a rock climbing mecca, five and a half years ago, Espinosa has expanded his climbing résumé to include El Capitan and Half Dome in Yosemite, numerous routes in the Rocky Mountain National Park, and Cerro Mocho in Patagonia, a mountain- ous region in South America’s southern tip renowned for its picturesque and difficult climbing. While Patagonia’s rugged climbs might seem the riskiest, Espinosa’s most serious injury happened much closer to home. Last year, he broke his leg in an accident at Eldorado Canyon outside of Boulder. He says it was a careless rappel- ling mishap on familiar terrain, but the incident was a wake-up call. “I gained a lot of perspective after the accident,” he says. “Climbing is very therapeutic for me, perhaps the only activity that can create a mental blank slate after weeks of thinking of nothing but experiments. But you are always only one mistake away from your last climb.” He has reasons to exercise extra caution—his twin four year-old daughters, whose names, Azul and Paloma, are tattooed on the inside of each forearm. Though he doesn’t take his Rock Face daughters climbing—yet—he’s built them a climbing cave in the basement. In the dark of night, Joaquín Maximil- career scientist. With the aid of head- As a parent, he’s become more iano Espinosa was hugging two fellow lamps, they’d intended to finish the cautious, and in the eight months Argentine rock climbers on a narrow ascent without pause, but darkness and of rehab that followed his accident, ledge high above Yosemite Valley. cold were taking a toll, so they stopped Espinosa gave a lot of thought to the Espinosa, ruggedly handsome with a on a ledge under a protective alcove. dangers of climbing. In the end, he melodic Latin accent, wasn’t showing “We had one sleeping bag for the three decided that it is worth the risk. “It’s affection for his climbing buddies, he of us so we just cuddled there for a a beautiful activity that I cannot do was trying to keep them warm. They few hours and then kept on climbing,” without—it gives me sanity and friend- were more than halfway to the top of he says. They eventually reached the ships,” he says. “When properly done, El Capitan, a 3,000-foot vertical rock summit and have returned to Yosemite it has a rare purity. It’s just you and face in Yosemite National Park, and twice since that trip in 2007 to tackle nature, with no buffer in between.” they needed a rest. other climbing routes. —Christie Aschwanden They knew spending the night on Rock climbing, like science, requires the route was a possibility, but that endurance and, often, an alternative WEB EXTRA: To see a video of Espinosa and was a plan B they were hoping to avoid. plan, says Espinosa. “Some of the his friends on El Capitan, visit www.hhmi.org/ “We all had this Patagonian climbing research projects that we’re doing bulletin/aug2010. And to learn about Espinosa’s attitude—roughing it, going out with seem monumental at first—like stand- unique take on p53, see Perspectives & Opinions, “Web of Influence,” in the same online edition.

Carmel Zucker very little gear,” says the HHMI early ing at the base of El Cap looking up.

August 2o1o | HHMI BULLETIN 5 centrifuge

High-Stepping Horses It’s early spring, and horse trailers from 27 states ﬁll the sprawling parking lot at the Great Southwest Equestrian Center in Katy, Texas. More than 1,600 horses are in town for the nation’s old- est horse show, the Pin Oak Charity Horse Show. Likely Suspect, a brown American Saddlebred with a black mane and tail, is there. Wearing a saddle and bridle that glitter with silver, he’s ready to compete in the championship for western-style horses. Likely Suspect comes from nearby Houston, with his owner, Nancy Moreno, a biologist at Baylor College of Medicine. Moreno directs an HHMI-funded program that creates partnerships between elementary school teachers and early career researchers. to do what it’s being asked to do. You Likely Suspect won second place for Today, Moreno wears a black, feel a bit emotional about your horse’s Saddlebreds in the western division, sequined vest and cowboy hat as she effort. It’s a 1,000- to 1,200-pound ani- and Jigsaw Johnny won ﬁrst place for and Likely Suspect await their cue to mal. Why will they try so hard for us?” the breed in pleasure driving, an event enter the 4,000-seat arena. The bugle Moreno nearly missed out on the in which Moreno drove Johnny from sounds, and “you come through a equestrian world. Growing up in upper a two-wheeled cart. The ringmaster chute on your horse into a huge lighted Michigan, she built life-sized horses helped place a striped blue, red, and arena,” says Moreno. “You feel a blast out of snow but rarely rode real ones. yellow grand champion sash around the of cold air as you enter, and your horse Her connection to horses was mostly horse’s neck, and Moreno drove Johnny comes to life. It’s thrilling.” imaginary: “I read all the horse books once more around the ring. The horse Moreno will compete in three multiple times: Misty of Chincoteague, always senses that he has won, she says. events with Likely Suspect and two Black Beauty, you name it. I was one Moreno feels elated, too. “There are with Jigsaw Johnny. (Her third show of those horse-deprived children.” So, very few times in life when you get to horse, It’s East Wing, stayed home.) when Moreno’s daughter, Helena, asked take a victory pass.” —Cathy Shufro Moreno’s horses are American Saddle- for riding lessons at age 9, her mother

breds; she loves the breed. “American decided to join her. They found a stable WEB EXTRA: To see video of Moreno with Likely Saddlebreds are very exciting horses in the Houston phonebook and stum- Suspect, Jigsaw Johnny, and It’s East Wing, visit in the ring. They’re these powerful bled upon the Saddlebred breed. That www.hhmi.org/bulletin/aug2010. high-stepping horses, and they look was 20 years ago. like they’d be just impossible to con- Helena doesn’t ride much anymore, Ed. note: Nancy Moreno’s horses were involved trol.” In fact, she says, Saddlebreds but Moreno competes in 8 to 10 shows in a serious truck and trailer ﬁre in June, on the way to a show. Likely Suspect was severely are versatile and eager to please. “It’s annually. She has ﬁlled a dresser with burned, but is expected to recover. Moreno’s

remarkable how hard a horse will try award ribbons. At the 2010 Pin Oak, other two horses escaped injury. Arkle Peter

6 HHMI BULLETIN | August 2o1o upfront

08 WHEN PASSION AND SKILL CONVERGE A supportive mentor and a Gilliam fellow find a new drug target against a virus that strikes hardest in poor, rural regions.

10 DEATH BE NOT PROGRAMMED The ordered chain of events that is cell necrosis can be blocked to curtail the effects of some crippling diseases.

web only content Even someone slim may be hiding signs of type 2 diabetes, according to research by Gerald Shulman and Richard Lifton. Read the story at www.hhmi.org/bulletin/aug2010.

“Where there is an open mind, there will always be a frontier.” Inventor Charles F. Kettering’s axiom could be the motto for the scientists featured here. One thought his findings on heart cell death might possibly apply to a degenerative disease— and now he’s testing a promising treatment option. A Gilliam fellow’s mentor credits him for keeping an eye open for unexpected findings and acting on them; as a result, the scientists learned how a deadly South American virus grabs hold. Another investigator questioned standard theories and revealed hidden, dangerous liver fat in outwardly lean men. New frontiers.

August 2o1o | HHMI BULLETIN 7 upfront

When Passion and Skill Converge A supportive mentor and a Gilliam fellow find a new drug target against a virus that strikes hardest in poor, rural regions.

IN THE SPRING OF 2007, JONATHAN ABRAHAM CAME HOME— IN A SENSE. The Harvard M.D./Ph.D. student returned to a familiar place, the laboratory of HHMI structural biologist Stephen Harrison. Three years earlier, Abraham, then a Harvard undergraduate, had joined Harrison’s United States: both experience high rates of HIV, tuberculosis, and infant mortality. lab at Harvard Medical School as part of HHMI’s Exceptional Research And so Abraham set out to become a sci- Opportunities Program to learn about viral mechanics—specifi- entist to discover new cures, and to become cally, how pathogens like HIV and Ebola grab onto and enter cells. a physician to heal. Even in high school, he decided he wanted to work in Haiti and To Abraham’s disappointment, his “It was obvious that I should go back to other regions where health care is scarce. undergraduate project with Harrison didn’t Harrison’s lab and start a collaboration,” “I want to do science with direct application produce publishable results. But this time, says Abraham, who is funded by an HHMI to patient care,” he says. Abraham was onto something exciting and Gilliam Fellowship for Advanced Study. “It Abraham had noticed Machupo virus Harrison was just the person to help. Working felt like coming back to my family.” because it attacks poor and underserved with Harvard virologists Hyeryun Choe and communities in South America. Like Michael Farzan, Abraham had isolated the An Emerging Threat Ebola, its much more well-known African human cell surface receptor that an obscure Abraham’s interest in infectious diseases cousin, Machupo can cause debilitating, but deadly South American virus, called began in high school. His family moved bloody hemorrhagic fevers. With outbreaks Machupo virus, latches onto during infec- from Haiti to Quebec in the 1970s, and of Machupo and other closely related New tion. Nature published the paper in 2007. Abraham grew up speaking French. He World hemorrhagic fever viruses assault- While planning his next step and read- learned little English until he moved to ing rural regions of Bolivia, Venezuela, ing up on the molecule, called transferrin Queens, New York, for high school. There, Argentina, and Brazil, public health experts receptor 1, Abraham discovered that his old Abraham was shocked to hear some of his consider the group an emerging threat. mentor had a history with it too: Harrison classmates blame Haitians for the AIDS During an outbreak, the death rate can and co-workers had determined the molec- epidemic. He was further chastened when exceed 30 percent, and the virus can rip ular structure of the transferrin receptor in he learned of a disturbing parallel between through clinics and hospitals, spreading to the 1990s. Haiti and low-income communities in the doctors and nurses. The only known treat-

8 HHMI BULLETIN | August 2o1o ments, antiviral drugs, are expensive and the Machupo virus docks to the transfer- imentalist is common sense—for example, have limited effectiveness. rin receptor at an out-of-the way arm of the noticing out of the corner of your eye that By discovering Machupo’s human molecule. Harrison thinks that blocking this something is happening that you expected handhold, Abraham had made a signifi- site with an antibody, for instance, could or didn’t expect, and then modifying what cant step toward finding new treatments. slow infection while allowing the receptor you’re doing to respond to that observation. His collaboration with Harrison, Choe, to perform its vital task of shuttling iron Jonathan has that.” Farzan, and Kevin Corbett at Harvard pro- into cells. With his Ph.D. finished and his final two duced another big stride. Within a year, While it’s too early to say whether new years of medical school ahead, Abraham they had determined the molecular struc- treatments for Machupo virus will result, remains focused on his goal. “I’d like to ture of the transferrin receptor bound to Harrison knows that he has succeeded in dedicate my career to working on under- the Machupo surface protein, a finding another way: molding a skilled, creative studied pathogens in underserved parts of they published in the April 2010 Nature scientist. the world,” he says. His ongoing partnership Structural & Molecular Biology. “Jonathan is a very smart guy, he’s highly with Harrison has prepared him well. “I’m As Abraham and Harrison had hoped, motivated, and he has developed into an a product of the mentorship I’ve received,” this structure points to new drug targets. extremely good experimentalist,” Harrison he says. Someday, the whole world might

VSA Partners The images made by the team show that says. “The key quality of a really good exper- benefit, too. W –BRIAN VASTAG

August 2o1o | HHMI BULLETIN 9 upfront

Death Be Not Programmed The ordered chain of events that is cell necrosis can be blocked to curtail the effects of some crippling diseases.

If the drug works in dogs with an aggressive form of MD,

Jeffery Molkentin is hopeful that it will help children as well. Willis Jonathan

10 HHMI BULLETIN | August 2o1o NECROSIS IS NOT SUBTLE. ONE OF THE BODY’S NATURAL FORMS OF

cell death, it can be likened to a ship hitting an iceberg, exploding the boiler, and capsizing, all at once. Cell necrosis occurs as a result of The gene for human Duchenne MD, sudden death by trauma, by pathogenic infection, or by the proverbial identified in 1986, produces a defective last straw laid on accumulated damage. ¶ Underneath all that seeming version of dystrophin, which, along with its chaos, however, cell necrosis is actually an ordered chain of steps, says helper proteins, normally passes through the sarcolemma, the membrane sheath Jeffery Molkentin, an HHMI investigator heart muscle cells, or cardiomyocytes, that around skeletal muscle fibers. at Cincinnati Children’s Hospital Medical follows an ischemic event—a short cut-off In Duchenne MD, defective dystrophin Center. Moreover, Molkentin and others of blood to the heart. Cardiomyocytes can’t causes the sarcolemma to tear. Calcium are crafting treatments for several “untreat- renew themselves, so cellular necrosis after pours through the torn membrane and into able” degenerative diseases by uncoupling ischemia leads to heart dysfunction and fail- the skeletal muscle cells. Unable to tolerate key steps that drive necrosis forward (see ure. The tipping point in the cardiomyocyte the extra calcium, the cells’ mitochondria Web Extra, “Blocking a Protein’s Punch,” is the sudden swelling of mitochondria, the swell and burst. Cell necrosis then spreads www.hhmi.org/bulletin/aug2010). cell’s internal power plants. Excess calcium from cell to cell through the long bundles Although he made his first discovery in floods in through a regulated pore, finally of skeletal muscle fibers. the field of necrosis while studying dam- bursting the organelles, blacking out energy Because of this mitochondrial link, aged heart cells, Molkentin is focusing on production and spewing toxic proteins. Molkentin decided to crossbreed his cyclo- Duchenne muscular dystrophy (MD). The Molkentin discovered that he could philin D-null mouse with mice carrying most common form of the genetic muscle- stop mitochondrial swelling by blocking engineered genetic defects that model MD. wasting disease affects one in every 3,500 the action of cyclophilin D, a protein that In his office at Cincinnati Children’s, males born in the United States; boys with controls the so-called mitochondrial perme- Molkentin pulls up a video on his com- Duchenne MD typically live only into their ability transition pore, or MPTP. Without puter. “Look here,” he says. “These mice late teens and early 20s. cyclophilin D, the MPTP stayed firmly shut. that lack the gene producing laminin 2 have Molkentin has used engineered trans- genic mice to show how the relentless muscle “These mice that lack the gene producing laminin 2 damage that drives Duchenne MD can be interrupted. Now, he has a “proof of prin- have full-blown MD, are dramatically undersized, ciple” drug study underway in Brazil, using barely move, and are close to death. a small colony of golden retriever dogs that JEFFERY MOLKENTIN ” spontaneously develop an aggressive form of MD similar to human Duchenne MD. The drug is related to the immune suppres- It was startling, says Molkentin, that full-blown MD, are dramatically under- sant cyclosporine, but instead of targeting mouse cardiomyocytes with their cyclo- sized, barely move, and are close to death.” the immune system it blocks a crucial step philin D neutralized were protected from Molkentin’s double-null mouse—null for in the cell necrosis pathway in skeletal mus- mitochondrial swelling and death due to laminin 2 and cyclophilin D—has an awk- cles, according to Molkentin. calcium overload. There was something ward gait, but it’s mobile and lives well into This drug does not correct the genetic here beyond a vulnerable protein, he real- adulthood. The double-null mouse is living defect that drives MD—mistakes in a giant ized. Cyclophilin D appears to be one with MD because cell necrosis is stalled. muscle-connecting protein called dystro- player in a network of proteins that create an But mice are mice, Molkentin con- phin—so it is no cure for the disease. But ordered process that he calls programmed cedes. If the drug being tested in Brazil stopping cell necrosis could curtail MD’s cell necrosis. over the next year can do this for the golden crippling effects. Though results are not in, To explore programmed necrosis in a retrievers, he says, there will be good rea- Molkentin believes that “if this drug fixes the living animal, Molkentin created a mouse son to move toward clinical trials with golden retrievers, it’s going to work in kids.” model lacking the gene Ppif, which produces children. W –JOHN FLEISCHMAN cyclophilin D. The mouse sailed through The Mitochondrial Link laboratory-induced ischemic events, prompt- FOR MORE INFORMATION: Read about HHMI Molkentin came to the idea of blocking ing Molkentin to wonder if cell necrosis investigator Kevin Campbell’s efforts to identify the function cell necrosis through his earlier studies of could be blocked in a genetic disease like of the tight complex of proteins bound up with dystrophin cardiac hypertrophy, the enlargement of MD, where damage builds up over time. (www.hhmi.org/research/investigators/campbell.html).

August 2o1o | HHMI BULLETIN 11 THE VIBRANT ECOSYSTEM INSIDE THE HUMAN GUT GUT DOES MORE THAN UST DIGEST FOOD.RE ACTION

BY SARAH C.P. WILLIAMS of the Yale School of Medicine, who also studies the microbiota. “And that’s not just a metaphor; they really shape our biology in many ways.” While the studies of Knight, Gewirtz, and Ley hint at the importance of the microbiota in human health, scientists have more questions than answers. After all, most of the bacteria swarming in our guts remain unidentified. Many cannot survive outside the complex environment of the intestines and so are difficult to culture in the lab. Plus, the microbiota of any one person is shaped not only by genetics but also by diet and environment, meaning that they change over time, complicating experiments even more.

genetics of the fat and skinny mice: identical. Their ages: all the CENSUS TAKERS same. The food in front of them: the same bland pellets in every Knight’s background is in ecology, studying the interplay of cage. But the billions of bacteria teeming through each mouse’s plants and animals in natural environments. He views the human intestines: vastly different. body as another environment to study, in the same way he would The variation in gut bacteria between lean and obese mice study a jungle, marsh, or arctic tundra. Except, he says, bacteria isn’t just a consequence of their health, it’s a cause, according are a lot more convenient to study. “Instead of having to do field to work by Rob Knight, an HHMI early career scientist at the seasons every year for a decade, you can draw out four quadrants University of Colorado at Boulder, Emory University patholo- on your forearm and have your field season in your office in gist Andrew Gewirtz, and their colleagues. Transferring gut fifteen minutes.” bacteria from obese mice with insulin resistance and metabolic The first thing an ecologist does in an environment is take syndrome to healthy mice makes the healthy mice develop meta- a census of what’s there. So that’s Knight’s first task when it bolic syndrome, they found. Giving the mice antibiotics before comes to the intestines, and it’s the goal of microbiota research- the bacterial transfer can prevent the syndrome. Moreover, the ers worldwide. Rather than a butterfly net and microscope, they researchers discovered that the changed microbiota doesn’t just use cutting-edge DNA sequencing technology to get snapshots affect molecules inside the mouse gut, it also affects outward of the genetic makeup—called the microbiome—of individuals’ behavior: the mice eat more than their healthy counterparts who particular microbial mixtures. didn’t receive transferred bacteria. Knight takes samples of bacteria—from skin, feces, and the “Out of all our studies on obesity and microbes, this was intestines of mice or humans—and sorts out every copy of one the most shocking thing to me,” says Ruth Ley, one of Knight particular gene encoding a bacterial ribosome. The ribosome and Gewirtz’s collaborators in data analysis at Cornell University. is the cellular factory that produces proteins. It varies enough : Creative Commons “To have microbes actually affecting behavior.” among bacteria that its sequence can place a bacterium (even These researchers and a growing number of other scientists a previously unknown one) into what’s called a phylotype— study the microbiota—the microbes that make our bodies their essentially, “a spot on the tree of life,” says Knight. Similar homes. While bacteria call to mind disease-causing germs that ribosomes are from similar bacteria and therefore appear on require antibacterial soaps and drugs to exterminate them, the nearby branches of the tree. Knight originally developed a

bacteria in healthy intestines are relatively tame. In fact, animals computational method, called UniFrac, to study the ribosomal E. coli and Campylobacter from snakes to mice to humans wouldn’t survive without them. differences among bacterial communities in sediment, ice, and They turn food into energy, synthesize vitamins that their hosts’ water. Now, his team is using the same technique to tackle medi- bodies can’t produce, and engage in a complex and vital interplay cal questions. with the immune system. In a 2009 Science paper, Knight’s lab group reported : dieaktivisten.de/UFZ Researchers are also showing that the composition of a per- using UniFrac to analyze bacteria from 27 sites on the bod- son’s microbiota can predispose him or her to diseases—from ies of nine individuals, collected on four different dates. He

asthma and allergies to cancers, infections, and inflammatory found that bacterial communities varied drastically from per- Helicobacter bowel disease. son to person and changed to a lesser extent in one person “Our individuality is not just us genetically, it’s us plus all the over time. Only 3 percent of bacterial phylotypes appeared in

microbes we carry,” says HHMI investigator Ruslan Medzhitov all individuals on all occasions. In a separate paper, Knight Previous pages:

14 HHMI BULLETIN | August 2o1o and collaborators showed that people’s skin bacteria differ With that in mind, he wants to use UniFrac to observe the enough that you leave behind unique molecular fingerprints complicated dynamics between human health and the diversity on everything you touch—a finding that could change foren- of phylotypes in the gut. sic science. While Knight’s initial goal is to use UniFrac to characterize SEA OF MICROBES the microbiomes of healthy individuals, he says it will take the Martin Blaser, a doctor of infectious diseases and chair of medi- field only so far. Significant findings in ecology often come not cine at New York University Langone Medical Center, thinks from studies of healthy environments but from observations of there’s already a disturbance going on in human guts that’s not disturbances within a community. unlike the disappearance of wolves from Yellowstone. From early “If you went to Yellowstone and ground up a cubic mile human history until the 20th century, Blaser says, a bacterium of it and analyzed the DNA, you wouldn’t find a lot of wolf called Helicobacter pylori was universal. DNA,” says Knight. But scientists know that wolves are a “You can actually trace human migration by looking at species crucial to maintaining Yellowstone’s diversity because variations in Helicobacter,” he says. Today, Helicobacter is still of the radical changes that took place when they were removed ubiquitous in developing countries around the world. In the from Yellowstone in the early part of the 20th century. Elk United States, though, fewer than 6 percent of children have populations skyrocketed and the condition of the woodlands Helicobacter in their mix of gut bacteria. And in a series of recent deteriorated. In 1995, scientists reintroduced wolves to Yellow- studies, Blaser showed that children lacking Helicobacter are stone and have since observed the elk population stabilize at a more likely than their peers to develop child-onset asthma. While healthier number. the presence of Helicobacter predisposes people to ulcers, he In the gut, Knight says, there could be bacteria that, while not thinks the disappearance of the microbe could explain not only abundant, keep the populations of other microbes in check. rising rates of asthma but also allergies and obesity.

RUSLAN MEDZHITOV AND BRETT FINLAY ARE INVESTIGATING HOW CHANGING A PERSON’S MICROBIOTA IMPACTS HEALTH. Medzhitov: Chris Jones Finlay: Birthe Piontek Birthe Piontek Finlay: Medzhitov: Chris Jones

August 2o1o | HHMI BULLETIN 15 LORA HOOPER AND ROB KNIGHT HAVE APPLIED AN ECOLOGICAL APPROACH TO STUDYING THE HUMAN GUT.

“We evolved in this sea of microbes, and now we’re living as organisms that thrive in low-oxygen soil he can now apply to the germ-free as we can,” agrees Brett Finlay, an HHMI international gut. And the big question that Schmidt hopes to answer resonates research scholar at the University of British Columbia. “It’s a major with both environments. light going on right now, that this could have consequences.” “It’s a fundamental ecological question: how resilient is this Blaser says microbiota research is at the cusp of a scientific community?” says Schmidt. “In soil, we look at what happens revolution and touching medicine at all its edges. “It’s permeating after you change the land from agriculture to abandoned, or from so many different fields,” he says. “In my role in medicine, I talk grassland to agriculture. In the gut, we look at what happens after to nephrologists about the link to kidney disease; I talk to oncolo- a course of antibiotics, or in a new colon. How quickly can the gists about the link to cancers. And I think we’re going to keep community recover to its previous state? Does it recover at all?” finding new links to diseases.” Finlay has some of the same questions. He wants to know how One disease increasingly linked to the makeup of the gut antibiotics change the bacterial community in the gut and how microbiota: colitis, an inflammation of the colon. Tom Schmidt, this shift can lead to, or prevent, disease. He uses techniques simi- a microbial ecologist at Michigan State University, is collabo- lar to Knight’s to get a snapshot of a mouse’s microbiome. Then rating with doctors at the University of Chicago to study this he gives the mouse an antibiotic and takes a new snapshot. One connection when it comes to one particular form of colitis. study, by another lab group, showed that pretreating mice with When doctors remove someone’s colon—because of infec- antibiotics shifted their gut microbes so that they became resis- tion, weak spots, or cancer—they replace it with a new colon, tant to Salmonella infection. Other findings, by Finlay and his built from other nearby tissue. At first, this pouch is void of bac- colleagues, suggest that shifts in the microbiota caused by differ- teria. Gradually, a microbial community develops. But in almost ent antibiotics can weaken the immune system. half of all pouches, symptoms of colitis develop. So Schmidt and “When researchers compare mice with different degrees of his collaborators are following patients with new colons and track- susceptibility to disease, they’ve always searched the mouse genes ing the development of the microbiota in each case. They hope for the explanation and not found much,” Finlay says. “Now to discover how the intestinal flora keeps some colons healthy and we’re learning that’s because the difference isn’t in the mouse others prone to infection and inflammation. genes, it’s in the microbiota.” Schmidt, like Knight, comes at the microbiota with an ecology background. His expertise is in soil ecology, and soil has NOT SO BLACK AND WHITE surprising similarities to the gut, he says. Both environments In any kind of census, it’s necessary to group individuals into

are low in oxygen. So the techniques he developed to cultivate categories that oversimplify their differences. In a human census, ©HHMI Knight: Carmel Zucker Hooper: Amy Gutierrez / AP,

16 HHMI BULLETIN | August 2o1o that means checkboxes that reduce people to race, gender, stimulated immune responses, helped detoxify compounds the income, and marital status. In the microbiota census occupying mice ate, stimulated the growth of new blood vessels, allowed scientists’ minds, it means the temptation to group gut bacteria proper tissue development, and performed countless meta- into good and bad, pathogens versus commensals (microbes that bolic tasks. don’t cause disease). But this process hardly paints a full picture When she moved to her own lab, Hooper took another look of what’s going on in our intestines, says Yale’s Medzhitov. at the plethora of genes that shot up in expression levels when “The difference between commensals and pathogens is not a mouse was first exposed to gut bacteria. She chose one to study that they are two very different types of microbes,” Medzhitov in more depth. Her lab quickly discovered that it was the gene explains. In fact, microbes considered commensals in one organ- for a protein dubbed RegIIIƢ, and it had a rare job for a protein: ism’s gut, or in one situation, can act pathogenically in a host it’s an antibiotic. She’s gone on to show that RegIIIƢ can kill with a compromised immune system or in a different organism. bacteria by drilling a hole in their outer layers, allowing their “So the distinctions between the two are in many ways arbitrary,” contents seep out. Hooper speculates that RegIIIƢ may help Medzhitov says. to shield the intestinal epithelium from the bacteria sloshing In reality, each bacterium in our gut falls along a spectrum around inside the gut. between pathogenic and commensal. Medzhitov thinks that “The epithelium itself is a barrier, but you want to minimize instead of lumping bacteria into these extremes, based on their even having bacteria attach to that,” says Hooper. “So these anti- outcomes (disease or health), scientists should focus on how each microbial proteins, and probably many other immune molecules, bacterium interacts with its host—the human body. likely help to set up a secondary barrier.” Humans have intricate immune systems exquisitely tuned to In patients with inflammatory bowel disease, more bacterial identify intruders. Medzhitov studies a class of receptors—called cells reach the intestinal lining, indicating that the chemical bar- Toll-like receptors—that recognize invading bacteria and signal rier is inadequate—one hint toward a cause of this chronic disease. the immune system to act. His lab has found that Toll-like receptors recognize bacteria that could do harm to the body, and they PERSONALIZE THE GUT also help keep the intestinal microbiota balanced by detecting Though there’s a growing body of evidence that links variations bacteria that are less virulent. in the microbiota to diseases—from Knight’s studies on meta- “There’s something about the environment of the gut that bolic syndrome to Blaser’s work on asthma and Schmidt’s colitis controls this interaction so that, under healthy conditions, Toll- research—the mechanisms of these links are still too sketchy to like receptors sense commensals and don’t react to them as translate them into clinical medicine. harmful,” says Medzhitov. Of course, if those same tame bacteria A 2009 paper in the Proceedings of the National Academy of sneak out of the gut into the bloodstream—during surgery, for Sciences by Jeremy Nicholson at Imperial College London and example—the receptors will respond with fury, leading to danger- collaborators at the drug company Pfizer found that variations ous inflammation and sepsis. Medzhitov wants to know what it is in one type of gut bacteria lead to differences in how people about the intestines that keeps Toll-like receptors in check. metabolize acetaminophen (Tylenol) and different propensities And that’s far from the only way the immune system inter- for liver toxicity. The authors proposed that “assessing the effects acts with gut bacteria. HHMI investigator Lora Hooper, at the of microbiome activity should be an integral part of pharmaceuti- University of Texas Southwestern, is fascinated by the subtleties cal development and of personalized health care.” of the interaction. The concept resonates strongly with Knight. The vast variation “I’ve been studying this for 15 years and it’s still not clear to he’s seen between individuals’ microbiomes leads him to think me—how can you have a hundred trillion bacteria in your gut that gut bacteria will be targeted with drugs, or personalized con- and you don’t get sick?” says Hooper. coctions of healthy bacteria, in the future. When she first started studying the microbiota, as a post- “In terms of developing personalized medicine,” he says, doctoral fellow in the lab of Jeffrey I. Gordon at Washington “it seems like it makes more sense to develop medicines based on University in St. Louis School of Medicine, Hooper began work- the microbiome, where the variation is so great, rather than ing with germ-free mice. These mice are raised from birth in on the human genome, where the variation is so little.” sterile environments—they eat sterilized food, live in germ-free For now, though, patients and doctors are stuck at the impasse bubbles, and interact only with other germ-free mice. These between knowing (or guessing) the cause of a disease and having cleaner-than-clean mice allow researchers to study the effects of a treatment. Someone can blame their diabetes or inflammatory individual bacteria strains in a simple system. bowel disease on the churning mass of bacteria that lives inside Hooper and Gordon’s first experiments with germ-free mice their intestines, but there’s no magic pill to change the dynamics gave them a glimpse at some of the jobs of gut bacteria: they of that complicated world of the human microbiome. W

August 2o1o | HHMI BULLETIN 17 by Robert Koenig illustration by Mark Weaver

Though separated by an ocean, Christopher Plowe and Abdoulaye Djimdé are bound by their determination to stop malaria’s global toll.

18 HHMI BULLETIN | August 2o1o Firstname Surname Firstname

August 2o1o | HHMI BULLETIN 19 WHENChristopher Plowe traveled to Mali in western Africa to test a the lab as well as in the field.” But the two scientists took vividly technique for detecting drug-resistant malaria, he was struck by disparate routes to the field of malaria research. the intelligence and skill of a local pharmacist who had volunteered to help. It didn’t take long before that volunteer, Abdoulaye PERSONAL TRAGEDY Djimdé, “rose to the top,” Plowe recalls, and was offered a lab When Djimdé was a preteen living with his family in Koro, a stint at the U.S. National Institutes of Health (NIH). Later on, Dogon village in eastern Mali, his 3-year-old brother, El-Hajj, Djimdé would become Plowe’s first Ph.D. student. suddenly spiked a high fever. “We took him to the hospital, but That African encounter in 1993 led to a thriving collabora- it was too late for proper treatment.” The boy died from cerebral tion and friendship between the two researchers—an M.D. from malaria a few hours later. “It was a shock for the whole family,” South Dakota and a pharmacist from malaria-ravaged Mali. recalls Djimdé, who was one of fifteen children. “That was the Malaria infects hundreds of millions of people worldwide and turning point when I decided to be a doctor and take care of sick kills an estimated 900,000 a year, taking an especially high toll on kids who had malaria.” children in sub-Saharan Africa. Despite more than a half century In those days, villagers relied on traditional healers to treat of research, no effective malaria vaccine has been approved, and malaria. The common form of the malady is called the “green sea- the resilient parasite that causes the disease has developed resis- son disease” because it appears when mosquitoes breed during the tance to numerous drugs. rainy months. The more serious cerebral malaria is considered a Plowe and Djimdé share a passion for fighting malaria and are spiritual affliction called “wabu,” which healers treated with potions. leaders in important research projects. Plowe—an HHMI investi- Determined to get away from tribal remedies and introduce gator at the University of Maryland School of Medicine—focuses more effective Western medications and treatment, Djimdé mainly on vaccine development. Djimdé, an HHMI interna- worked hard in school with the goal of becoming a medical doc- tional research scholar at the University of Bamako’s Malaria tor. The Mali educational system steered him to pharmacy school, Research and Training Center, studies antimalarial drugs and the however, and in 1989 he opened his own pharmacy. But Djimdé emergence of the malaria parasite’s resistance to them. was still interested in malaria research, and when he heard about “Chris Plowe has been a major figure in the development of Plowe’s project, he volunteered to help. Soon, Djimdé moved to malaria research in Mali, especially with his work with the human the U.S. to work with Plowe in Wellems’ NIAID lab. populations,” says Thomas E. Wellems, chief of the Malaria and Vector Research laboratory at the National Institute of Allergy PLOWE’S PATH and Infectious Diseases (NIAID)—and the researcher who first Born in South Dakota, Plowe had never traveled outside North sent Plowe to Mali. “Both he and Djimdé perform brilliantly in America. He studied philosophy in college and after graduating “WE SPENT A LOT OF HOURS TOGETHER IN THE LAB AND IN THE FIELD,” RECALLS PLOWE, WHO DESCRIBES DJIMDÉ AS “AN INCREDIBLY TALENTED SCIENTIST WHO I

AM PROUD TO CALL FRIEND.” / PR Newswire, ©HHMI Djimdé: David Rolls Previous page: Plowe: Kaye Evans-Lutterodt

20 HHMI BULLETIN | August 2o1o enrolled in Cornell University Medical College, planning to spe- The two young researchers eventually became close friends dur- cialize in surgery or psychiatry. Then he spent a summer doing ing their time in Wellems’ lab at NIAID. “We spent a lot of hours epidemiology research in Indonesia and two years later—while together in the lab and in the field,” recalls Plowe, who describes still in medical school—he “got hooked on malaria research” dur- Djimdé as “an incredibly talented scientist who I am proud to call ing a stint in western Kenya setting up a research project led by friend.” Djimdé calls Plowe “a mentor who always went the extra Naval Medical Research Center scientist Steve Hoffman. mile to help me get established as a scientist.” “Steve convinced me that malaria was the most important Even after Plowe left Wellems’ lab for a stint as a fellow at the disease in the world and the most challenging biological prob- Johns Hopkins University School of Medicine, he kept working with lem,” Plowe recalls. Hoffman was impressed with Plowe’s talents Djimdé and the NIAID group on malaria projects. “When Tom’s at working with both African villagers and Western scientists. “He lab found the gene that causes chloroquine resistance, Djimdé and played a leadership role in getting that study off the ground,” I developed a fairly robust test to detect mutations of the gene. Even Hoffman says. Eventually published in Science, the study “was a before that was published, we shared the protocol with the World testimony to the kind of groundwork Chris did, and it was predic- Health Organization so it could be used in the field.” tive of his later success.” After he finished his residency in New York, Plowe spent three years as a postdoc in Wellems’ NIAID lab, where he studied the molecular biology of malaria parasites. POTENT BUZZ: A Whole-Parasite Vaccine He also got involved in developing a test for “Mosquito Crossing” warns the yellow road-caution sign. The attention-grabbing notice hangs resistance to chloroquine—then the most on the door to the “challenge room” of Chris Plowe’s insectarium, at the University of widely used antimalarial drug. At that time, Maryland, Baltimore. Inside, volunteers roll up their pant legs while researchers press a Dixie in the early 1990s, chloroquine resistance cup with four or five malaria-infected mosquitoes against their ankles. The blood-swollen was spreading rapidly across the sub-Saharan insects are collected for analysis and blood samples are drawn from the volunteers. The work is part of a “challenge study”—the first clinical trial of a promising “attenuated sporo- region, from eastern into western Africa. zoite” vaccine being developed by Sanaria Inc., a company headed by Plowe’s early mentor, Monitoring patients for resistance was former Navy researcher Steve Hoffman. There are dozens of other vaccine candidates in cumbersome, so it was difficult for doctors various stages of development—the farthest along being GlaxoSmithKline’s RTS,S vaccine, to know what antimalarial drugs to pre- now in Phase III tests at 11 African sites—but Plowe says “the Sanaria vaccine is the only scribe. The Wellems group had identified vaccine that uses the whole [parasite] organism.” The others, he says, which focus on one a gene associated with resistance but was antigen variant, “are like trying to stop an elephant with a BB gun.” The concept, Hoffman searching for a practical way—rather than explains, is to use sporozoite-stage parasites—an early, motile stage that infects the liver—that have been weakened (attenuated) by exposure to radiation. Although the weakened parasites freezing blood samples and shipping them cannot complete their life cycle, they survive long enough to awaken the human immune to labs—to use the genetic marker in remote system and confer protection against malaria. The overall challenge study is being led by clin- areas. Plowe wanted to use blood spots on ical investigators Kirsten Lyke at the University of Maryland’s Center for Vaccine Development filter paper to extract DNA for analysis, and Judith Epstein at the Navy’s research center. Right now, Plowe’s is a supporting role but even though previous efforts had failed. eventually he will design and implement studies of the vaccine in Africa. In a sense, the He succeeded, and the project put current challenge trial is part of a Maryland tradition. The first malaria vaccine trials in Plowe on the map as an internationally humans—with an attenuated sporozoite vaccine developed by researchers at New York University—were done in the early 1970s by University of Maryland professor David Clyde. known malaria researcher. “It was exciting (Previous malaria vaccine research had been done on ducks and rodents as far back as the to take a scientific advance and translate it 1920s.) “The early-1970s Maryland vaccine trials proved the principle that sporozoites can into a public health tool that has had real give protection,” says Hoffman. “But they couldn’t produce sporozoites that met regulatory impact,” Plowe says. standards—that is, sterile, pure, highly attenuated, and still potent.” That is what Sanaria is Adds Wellems: “It was a big challenge, now trying to do in a painstaking process that is taking years to develop and test. Plowe says but Chris made it work. Now that technique he’s “excited about taking a whole-organism vaccine to Africa” for clinical trials, which prob- is used by researchers around the world.” ably will begin within a few years. “With the attenuated sporozoite vaccine, even if you have diversity in one antigen, hopefully you’ll have 10 other antigens. You are taking it from the genetic level to the genomic level.” Hoffman says Plowe is the right researcher to design and WORKING IN TANDEM implement vaccine trials in Africa and apply genomics to understand how a whole-parasite Plowe met Djimdé while testing his filter vaccine works. “He has the capacity to work with not only his biomedical colleagues but also paper technique in the villages of Mali. the people in Africa who suffer the most from this disease.” —R.K.

August 2o1o | HHMI BULLETIN 21 “We don’t have the right tools yet to track and monitor artemisinin resistance, which is why I’ve shifted my attention on the drug-resistance side to Southeast Asia,” says Plowe. “We’re trying, in a much more accelerated fashion, what it took Tom Wellems 15 years to do in pinpoint- ing chloroquine resistance.” In a project that involves scientists at Oxford University, Mahido University in Thailand, and the U.S. Armed Forces Institute of Medical Sciences in Bangkok, Plowe’s lab is doing genomic studies to pinpoint gene loci that could be used as markers for that resistance. The goal is to give scientists around the world access to comprehensive data to help determine which antimalarial drugs should be used in which regions. “The whole discussion of malaria eradication and elimination will come to a screeching halt if artemisinin resistance spreads throughout Asia and gets to Africa,” he says. “We’re trying to develop the tools to detect that resistance and head it off.”

Chris Plowe and Abdoulaye Djimdé met in Mali, in the 1990s (upper left), while testing AN ELUSIVE PARASITE a new technique for monitoring malaria drug resistance. Once mentor and student, now Plowe, who became an HHMI investiga- they mentor each other’s students and stay with each other’s families while traveling. tor in June 2008, likes to show off his lab’s new DNA extraction robot that “has vastly And when Plowe joined the University of Maryland faculty in increased our throughput,” supporting the shift in his lab’s focus 1995, he convinced Djimdé to become his first Ph.D. student. from drug resistance to gene resistance. Djimdé’s thesis focused on the molecular mechanisms of malaria That transition is crucial to developing next-generation tools to resistance to chloroquine. fight malaria. Ever since British researcher Ronald Ross identified “It was an emotional time for me. We were the first to docu- the malaria parasite in mosquitoes in 1897, thousands of scien- ment that resistance in the field, showing that this gene was tists around the world have searched for effective treatments and responsible for chloroquine resistance in Mali,” says Djimdé, vaccines. But that resilient organism—Plasmodium falciparum who returned to his home country to continue his research in causes the deadliest form of human malaria—keeps developing 2001. “When the paper came out in the New England Journal of resistance to drugs and presenting hurdles to vaccine makers. Medicine I got calls and e-mails from all over the world.” At the heart of the problem is the parasite’s complexity, Plowe says the thesis work “has been extremely influential. It with its life-cycle stages and uncanny ability to fool the body’s laid an important foundation for the study of the molecular basis immune system. Delivered by a mosquito’s bite, the parasite’s for malaria resistance.” thread-like sporozoite stage travels through the human blood- Plowe’s own interest in that area has led him to assess the stream and settles in the liver. There it morphs and multiplies new wave of resistance to artemisinin-based combination thera- into tear-shaped merozoites that reinvade the circulatory system pies, or ACTs, which replaced chloroquine over the last two and burst red blood cells, releasing toxins that sicken or kill the decades as the most commonly prescribed antimalarial drug. human host. Also in the bloodstream are the parasite’s reproduc- Used for centuries in China, artemisinin compounds were intro- tive gametocytes, which biting mosquitoes suck from the human duced in Africa to treat malaria in the 1980s and appeared to host into their salivary glands to begin a new cycle of infection. be thwarting the typical trend of drug resistance. But research- “It has a very plastic genome,” says Plowe. “Every 48 hours, ers found signs of artemisinin resistance in western Cambodia the parasite multiplies roughly 10-fold,” speeding the genetic

a few years ago. recombination that strengthens resistance. Courtesy of Chris Plowe

22 HHMI BULLETIN | August 2o1o Vaccine developers target the parasite at one stage or the analysis to narrow down the number of variations the immune other, using specific parasite proteins to incite a human immune system must recognize to prevent illness. response. The challenge, Plowe explains, is to target the right The studies have indicated that “we might be able to reduce combination of proteins, which can vary based on genetic code. the number of variants we would need to address [in a vaccine] “Part of the difficulty is the speed of mutations of the parasite and from more than 200 to just 10 or so—maybe even fewer,” Plowe the other part is not knowing the basis of immunity in the human says. A vaccine based on just one of those variants was tested first, populations,” he says. with the Phase I trial among children reported in the recent PLoS With support from the NIH, Plowe developed a vaccine test One paper and the first efficacy (Phase II) trial results expected to be site in the same village where Djimdé did his groundbreaking reported in a paper later this year. While the results of the Phase II study of chloroquine resistance. Plowe and his colleagues in trial aren’t yet public, Plowe offers a hint, saying “We haven’t hit a Mali are testing vaccines developed by scientists at the Walter home run, but I think we’ve finally made it to first base. Reed Army Institute of Research, combined with an adjuvant “The big question is: Can you get overall efficacy based on a (immune system booster) from vaccine manufacturer Glaxo- single variant when there are over 200 variants in a village?” he SmithKline Biologicals. adds. “Or, if you don’t get broad overall protection, do you at least Among the most promising of those candidates is the AMA-1 get the information that you need to go back and develop a more blood-stage vaccine. Plowe’s group reported in the February 2010 broadly protective vaccine?” issue of PLoS One that the vaccine candidate produced a 100-fold increase in antibodies against the AMA-1 malaria protein in 75 MOSQUITOES IN MALI children in a Phase I study at the Mali test site. Like Plowe, Djimdé divides his time between the lab and Following 100 kids over time in Mali, his group sequenced the field, where he is focusing his research on the genetics of the gene for AMA-1 in more than 1,300 infections. “By looking at drug resistance. which changes in the AMA-1 sequence in consecutive infections “We’ve been looking at a more holistic approach to under- were more likely to make a child sick,” Plowe says, “we could standing drug resistance,” says Djimdé, which would take into pinpoint the genetic differences that seem to be important for account “the many factors related to the response to anti- clinical immunity.” malarial drugs.” Those factors include the genetics of the human The new approach is aimed at a persistent problem with hosts—including acquired immunity and how people metabolize malaria vaccines, he says—the fact that “all the vaccines in the malaria drugs—and of the malaria parasites and the mosquitoes clinical pipeline were designed with no knowledge of whether that spread them. “We are trying to understand the interplay the variant that was picked to put in the vaccine was the most among the parasite, the mosquito, and the drug,” he says. “How common or the least common in nature.” Plowe suspects that drug resistance is established in a community, and how it spreads genetic differences that matter most in natural immunity will turn across time and geography.” out to be the same ones that drive vaccine-induced immunity. Collaborating with entomologists, Djimdé’s group catches (See sidebar, “Potent Buzz.”) mosquitoes in the villages being studied, harvests their eggs, and In one previous trial, a malaria vaccine candidate was found develops new generations of the insects that are kept in the labo- ineffective, most likely because it used a protein variant that was ratory and used for experiments. rare in the Kenyan community where the vaccine was tested. In They also work closely with villagers. “It can take several Mali, Plowe’s team has identified more than 200 variants of the months of preparatory work before a community agrees” to take AMA-1 protein in a single village, but the group is using genomic (continued on page 48) “I DON’T THINK WE HAVE THE TOOLS TO [ERADICATE MALARIA] YET. THIS WILL REQUIRE SUSTAINED FUNDING AND

DECADES OF RESEARCH.”—Abdoulaye Djimdé

August 2o1o | HHMI BULLETIN 23

INTOINTOINTO THETHETHE THIRDTHIRDTHIRD DIMEN-DIMEN-DIMEN- SIONSIONSION

To overcome the shortcomings of standard 2-D cell culture, scientists are adding another dimension to make cells happy. by Richard Saltus | illustration by Steve Wilson cells in 2-D cultures may overestimate their potency, because the cells are more vulnerable to being killed. So scientists in a wide range of fields are turning to more complex and realistic three-dimensional (3-D) culture methods to provide cells with a more familiar home away from home. Generally, these microenvironments are gel-like materials with components of the basement membrane and the ECM. The differences are spectacular. Now, cells are being coaxed to form blood vessels or potential implantable repair tissues, including miniature livers and other organs; they can form tiny spheres that mimic breast tissue for use in breast cancer research; and the methods are showing great promise for stem cell research. IRST SHE DOTTED GLASS SLIDES WITH liver cells to study infection. Now her larger assemblies of REALISTICREALISTICREALISTIC REACTIONSREACTIONSREACTIONS cells, in a disc about the diameter of a soda can, are being “It is remarkable how much we can learn from these three- implanted into rodents to carry out most of the liver’s 500 dif- dimensional systems,” says Shahin Rafii, an HHMI investigator ferent tasks. Thinking big but starting small, Sangeeta Bhatia at Weill Cornell Medical College who recently reported a major is closing in on her ambitious goal: growing human livers in the advance in sustaining adult stem cells in the lab (see Web Extra, lab from scratch. Nurturing Stem Cells). For one thing, he explains, “When you “We hope we’re on the way to growing big pieces of liver for introduce a third dimension, cells turn on a whole slew of new people,” says Bhatia, an HHMI investigator who has pioneered physiologically relevant genes.” For example, in 3-D cocultures sophisticated methods of removing cells and keeping them happy with vascular cells, stem cells start to behave like stem cells in and behaving much as they would in their natural habitats. It’s their natural niche, initiating preset programs for self-renewal been a formidable challenge. “Primary liver cells are difficult to and differentiation. culture,” she says. “When you take them out of the body, they A 3-D culture also recapitulates what happens in devel- lose all their functions.” opment, Rafii adds. Compared with stem cells grown on flat Since the 1950s, scientists have probed the molecular secrets cultures, cells nurtured in Rafii’s 3-D environments experience a of cells plucked from the body and grown in the laboratory on more normal physiological, biochemical, metabolic, and physi- flat plates or Petri dishes. These standard cultures have taught us cal milieu in vivo, enhancing their viability for transplant. about normal cell biology, cancer, and other diseases. HHMI investigators Kristi Anseth at the University of Colo- From a cell’s point of view, however, these two-dimensional rado at Boulder and Sangeeta Bhatia at the Massachusetts (2-D) habitats—dubbed “plastic palaces” by one researcher—are Institute of Technology have created 3-D systems in ambitious a poor substitute for real life. Scientists have come to realize that a tissue engineering projects. Bhatia’s functioning miniature livers cell’s surrounding microenvironment plays a much larger role in implanted in mice bring her closer to her goal of helping patients directing its growth and shaping its behavior than anyone under- with liver disease (see Web Extra, “Livers in the Lab”). Anseth is stood 10 or 20 years ago. tinkering with the composition of 3-D gel matrix materials that In the body, cells are accustomed to living large, in three someday might allow doctors to repair cartilage and bone defects dimensions, embedded within an extracellular matrix (ECM). with cell implants activated by light from outside the body. With Through the pores of the fibrous ECM, a cell is bathed in HHMI investigator Natalie Ahn, Anseth is using 3-D cultures to nutrients and signaling molecules. A thin basement membrane learn just how cancer cells move around—and finding more sur- anchors the cell to surrounding connective tissues and emits prises (see Web Extra, “Smart Scaffolds”). chemical signals that regulate some cell processes. In addition, “I think everybody now is considering whether their experi- physical forces push and pull the cell from all directions. mental questions might be better answered in a 3-D setting,” says Without this extracellular community, cells grown in single Joan Brugge at Harvard Medical School. layers on standard flat cultures will proliferate, but they usually Since the early 1990s, Brugge, a former HHMI investigator, don’t differentiate into specialized cells forming structures such has been studying the development of breast cancer by insert- as capillaries. They can be inadequate models yielding mislead- ing oncogenes into “hollow cyst-like structures that resemble ing results. For example, researchers testing drugs against cancer the milk-secreting glandular structures found in the human

26 HHMI BULLETIN | August 2o1o breast,” she says. “In 3-D, different oncogenes induced distinct The extract was eventually sold commercially under the architectural changes that resembled structural variations seen in name Matrigel, the first and still widely used basement mem- different types of breast cancer.” brane substrate for 3-D cultures. A common application is to Noting that the microenvironment surrounding cancer cells study metastasis: cancer cells placed on a thick slab of the gel helps determine their invasiveness—a process difficult to model will migrate to the interior, modeling a process that can’t be rep- in 2-D systems—oncogene pioneer Robert Weinberg at the licated in two dimensions. Whitehead Institute wrote in a 2002 review, “Suddenly, the study of cancer cells in two dimensions seems quaint, if not archaic.” AAA 3-D3-D3-D BRIDGEBRIDGEBRIDGE An early multiuse 3-D cell culture technique came from The rise of 3-D cultures does not spell the demise of standard research on the basement membrane, which underlies epithe- cultures, by any means. Even in cancer research, says Brugge, lial cells that line hollow organs. Made up of collagen and large 2-D methods are still useful for studying cell cycle progression proteins called laminins, it is a protective barrier, an anchor, and pathways, apoptosis, protein interactions in signaling pathways, a source of signals that regulate processes such as blood vessel and some aspects of drug sensitivity. formation and wound healing. Scientists say that 3-D culture is establishing itself as a bridge In the mid-1980s, Hynda Kleinman at the National Institutes between traditional cell culture and animal models. Cells grown of Health (NIH) had been studying an extract of mouse tumors in the new systems can replicate the features of some diseases that produces a basement membrane. Kleinman’s lab group was better than costly animal models do. Functions of genes and pro- analyzing basement membrane chemistry, unrelated to cell biol- teins can be studied first in these cultures before going on to more ogy. Some of her colleagues had suggested seeing what effect the laborious experiments in animals. And, of course, conditions can extract would have on cells. be controlled much more easily in a 3-D culture experiment than In 1983, in anticipation of a site visit by Harvard cell biologist in a living animal. Elizabeth Hay, Kleinman (who was traveling) told a postdoc to The list of applications of 3-D studies goes on and on: new place some endothelial cells—the building blocks of blood ves- assays for blood vessel formation, drug discovery, and cancer inva- sels—on a sample of the matrix extract. “I had no clue as to what siveness; studies of the effectiveness of drug delivery methods; would happen,” recalls Kleinman. tissue engineering experiments of all kinds. “He threw some endothelial cells on it, and they went crazy. Surveying the leaps that 3-D methods have made in a little Within hours they had formed capillary-like vessels with hollow more than 20 years, NIH’s Kleinman says, “I’m just blown away lumens,” says Kleinman. “The reviewers and Dr. Hay loved it! by the very creative ways people are using it.” W They took some home with them. Then we published on this and on many other cell types, and a lot of people wanted to use WEB EXTRA: For more depth on efforts to use 3-D cell cultures to grow livers in the lab,

it in their research.” regenerate joints, and extend the lives of stem cells, see www.hhmi.org/bulletin/aug2010.

NATALIE AHN, KRISTI ANSETH, AND SANGEETA BHATIA ARE LEARNING THAT PHYSICAL FORCES AND CHEMICAL SIGNALS FROM ITS NEIGHBORS

Ahn: Carmel Zucker Anseth: Carmel Zucker Bhatia: Jason Grow Bhatia: Jason Anseth: Carmel Zucker Ahn: Carmel Zucker MAKE A CELL BEHAVE MORE LIKE A CELL.

August 2o1o | HHMI BULLETIN 27

MASTER OF REGENERATION ¤

by Kendall Powell Once a high school biology oddity, planarians illustration by Jason Holley are moving into the spotlight to reveal secrets of self-renewal.

As the plane touched down in Barcelona on a Saturday afternoon in September 1998, Alejandro Sánchez Alvarado was excited to see the runway pavement slick from a recent rainfall. Rain would have ﬁlled up the abandoned fountains in Parc de Montjuïc where he and Phil Newmark hoped to trap their quarry. »

August 2o1o | HHMI BULLETIN 29 works, shouldn’t we be using the master of The conventional thinking at the time was THE TWO regeneration, the planarian? It’s a simple that regeneration was simply a recapitula- flatworm with rudimentary eyes, brain, tion of embryonic development pathways. HURRIED gut, and gonads but no circulatory or respi- That logic never sat right with Sánchez ratory systems. A fraction of the worm, Alvarado. IN A CAB 1/279th or just 0.3 percent, can regenerate “If animals are just redoing embryolog- TO THE a whole new animal. Cut off its head, a ical developmental events, then everyone new one grows back within 10 days. should do it. And we wouldn’t care as NEAREST Aside from its capacity to self-renew, much about having health insurance the planarian is a beguiling creature with plans,” he says. “Instead, you are asking an BUTCHER its googley-eyed cartoonish look con- adult animal to form a de novo structure trasted with a gliding swimming elegance. within an adult context.” FOR A SLAB But when these researchers started, the After reading Morgan’s 1901 book animal had only a handful of identified Regeneration, Sánchez Alvarado was OF SHEEP’S genes. How to grow them optimally in the convinced that regeneration was actu- laboratory even needed work. ally a broad phenomenon in the animal LIVER, kingdom, not just an evolutionary quirk their target’s preferred dinner, and then REGENERATION REVIVAL relegated to a handful of strange animals. went straight to their hotel room to fashion The scientists had all worked their way Happy to get lost in the stacks of the traps by stuffing the liver bait into empty through the literature back to Thomas Library of Congress, Sánchez Alvarado bottles. They needed to set the traps in Hunt Morgan, who studied regeneration marched through the literature and found half a dozen of the park’s fountains before in planarians around the turn of the 20th examples of regeneration in every animal nightfall. They had only a long weekend century. Before he became the father of phylum, from the ancient Cnidarian hydra and they were taking a big gamble that modern genetics and championed the right up to the Chordata, or vertebrate, their traps would lure swarms of what they fruit fly Drosophila melanogaster as a salamander. More surprising to him were hoped would be developmental biology’s model organism, Morgan made a rich set the examples in all the phyla in between. next important model organism: the pla- of observations about the planarian’s abil- “Almost every phylum has an example narian flatworm, Schmidtea mediterranea. ity to regrow itself. Through meticulous of an animal that can regenerate tissues Transforming the planarian worm cutting and weighing, he calculated the when faced with injury and amputa- from a fountain-dwelling, biology class- 1/279th fraction. He also noted that if he tion,” says Sánchez Alvarado, now at the room novelty—cut one in quarters, get made large cuts to amputate the head and University of Utah. Even humans, after four worms—to a workhorse of molecular the tail of an animal, leaving only a very all, can regenerate significant portions of developmental biology was an adventure thin middle section, he sometimes got a organs such as skin and liver. “Maybe the both inside and outside the laboratory. two-headed animal in its place. thing to do was to identify an invertebrate The quest took Newmark and Sánchez Work on planarians petered out in the in which you could test hypotheses rap- Alvarado—and later Peter Reddien—to art 1960s and 1970s as organisms more user- idly and begin ruling out what is and is stores, to amputation assembly lines, and friendly for genetic and molecular tweaking, not happening in regeneration,” he says. into the genome that controls one of the like the fruit fly and the roundworm Cae- “ Planarians really fit the bill.” most robust abilities to regrow body parts norhabditis elegans, took center stage. anywhere in the animal kingdom. In 1995, Sánchez Alvarado became a A CHANCE MEETING All three men—Sánchez Alvarado and staff associate in the department of em- Amid antique locomotive engines at Newmark are now HHMI investigators, bryology at the Carnegie Institution for the National Railway Museum in York, Reddien is an HHMI early career scien- Science in Baltimore, Maryland. He made England, Sánchez Alvarado sat next to tist—arrived at the same brilliant idea: if it his mission to find the best organism to Newmark at the 1996 annual meeting we want to understand how regeneration study regeneration in an adult animal. banquet of the British Society for Devel-

30 HHMI BULLETIN | August 2o1o Below: Alejandro Sánchez Alvarado says that all model organisms are chosen because they exaggerate a particular biology.

opmental Biology. At the time, Newmark Newmark. “There were plenty of people stem cells—which are called neoblasts was in Jaume Baguñà’s lab at University [along the way] who thought this was and make up roughly 30 percent of the of Barcelona as a Damon Runyon Cancer craziness.” animal’s cells—the team had to work Research Foundation postdoctoral fellow, The two personified dogged persis- through trial and error. They figured out learning everything he could about funda- tence. Early on, they spent a sleepless how to label the neoblasts and began mak- mental planarian biology to eventually set weekend cutting heads and tails off of ing libraries of the genes expressed during up a line of research in the United States. about 1,000 animals. These experiments various stages of regeneration. “Here I found another member of my would tell them in the coming months During his time at Carnegie, New- tribe,” recalls Sánchez Alvarado. The two which genes were expressed in intact mark also created a genetically identical contemporaries, just one year apart in heads and tails compared with regen- line of worms by cutting and growing up age, hatched a plan to convince the Carn- erating heads and tails. Newmark also pieces from one individual collected from egie Institution and Damon Runyon to worked on modifying an in situ hybrid- the Barcelona park. That line has been let Newmark be a postdoc with Sánchez ization protocol, which is used to mark going for almost 12 years and is used by all Alvarado. The two would attempt to turn specific genes with a dye to see where the the planarian laboratories in the United planarians into a cultured lab animal that gene is turned on in the whole animal. It States. No more mucking through dor- could serve as a system for deconstruct- wasn’t easy. The animals’ mucus covering mant fountains. ing the molecular pathways that control tended to suck up the dye and turn every- In 1998, Andrew Fire, working down- regeneration. thing dark blue. stairs from the two at Carnegie, had Both Carnegie and Damon Runyon With almost any method they discovered a way to silence specific genes “really took a risk and supported us,” says attempted for tracking the planarians’ in C. elegans. The method, called RNA Ramin Rahimian

August 2o1o | HHMI BULLETIN 31 Below: Along with Sánchez Alvarado, Phil Newmark (left) and Peter Reddien brought planarians into the molecular era.

interference, or RNAi, works by introduc- Now they had a loss-of-function assay LEARNING CURVE ing a double-stranded RNA that matches for the planarians—a tool with which Reddien discovered Morgan’s work during the message of the gene a researcher to ask, if this gene is missing, how does his graduate studies. That quickly led him wants to knock down. The RNAi sets it affect the regeneration mechanism? to Sánchez Alvarado and Newmark’s 1999 off a process in the cell that destroys All they needed was some regeneration- Proceedings of the National Academy of the mRNA message. The method, for specific genes to test. Sciences paper on the RNAi work. which Fire shared the 2006 Nobel Prize “We needed to clone genes like there “The things they had shown gave in Physiology or Medicine with HHMI was no tomorrow so that we could do me hope that turning planarians into a investigator Craig Mello, effectively turns RNAi screening. That kept us occu- molecular model organism would work,” off the gene. pied for eight years or so,” says Sánchez Reddien recalls. “They were bold with Fire asked Newmark and Sánchez Alvarado. Newmark calls the RNAi work their choices and had taken a massive risk.” Alvarado to try RNAi in planarians to see if a crucial breakthrough from their years at Reddien joined Sánchez Alvarado as the method would work beyond C. elegans. Carnegie: 1997 to 2001. a postdoc at the Utah laboratory and his Sánchez Alvarado first tried silencing the “Now we could do functional biol- first task was to use RNAi for a large screen planarian tubulin and myosin genes since ogy. We could ask whether inhibiting the of planarian genes. It was still unclear if the resulting proteins are found in every expression of a given gene could disrupt this approach could silence genes well cell and he had the dyes to track them. He the regenerative process. We could really enough to show phenotypes—that is, to recalls looking at the treated worms under learn something from these animals. It show physical or behavioral defects, such the microscope at 1:00 or 2:00 a.m.: their was a fantastic time,” says Newmark, now as improper regeneration in a worm. regeneration stumps, or blastemas, had no at the University of Illinois at Urbana– He first chose to test 30 genes from a list tubulin or myosin. Champaign. of nearly 4,000 genes cloned and sequenced Newmark: Darrell Hoemann / AP, ©HHMI Reddien: Jason Grow Jason ©HHMI Reddien: Newmark: Darrell Hoemann / AP,

32 HHMI BULLETIN | August 2o1o at Carnegie but was disappointed to see no defects in the first trial. He speculated THIS IS THE TYPE OF that perhaps the worms had to go through two rounds of regeneration before defects SCIENCE YOU DREAM would appear. That did the trick. “I started seeing phenotypes,” he says. ABOUT AS A KID. WE ARE “Animals would fail to regenerate, or were STUDYING PROCESSES paralyzed, or had weird lesions all over their bodies. It was very dramatic and THAT ARE DRAMATIC AND very exciting.” So much so, the entire lab headed to Squatters brew pub in Salt Lake BROADLY IMPORTANT. –Peter Reddien City for a celebratory Champagne toast. Not all of Reddien’s postdoc time went “I was getting the first collection of planar- subset of these genes are specific to flat- so swimmingly, however. Working with ian phenotypes the world had ever seen,” worms. Newmark jumped on that subset, a worm virtually unknown in molecular recalls Reddien. The work was published because it opens up an opportunity to circles and handled by only a few labs in Developmental Cell in 2005. understand a neglected tropical disease. around the world had its headaches. With the molecular tools in hand to Schistosomiasis affects 200 million peo- Reddien played with tricking the light up, track, and silence the planar- ple worldwide who come in contact with worms into gobbling up the bacteria that ian’s stem cell genes, as well as much of its waters infested by a close planarian rela- produced the double-stranded RNA. He genome completed (a project also spear- tive, the schistosome. The female worms also made trips to an art supply store to find headed by these three), the scientists could lay eggs in an infected human, causing the best materials, like heavy black paper, begin to map genes onto the key stages of inflammatory reactions that can damage for taking photographs of the semitranslu- regeneration. They could move on to the the liver and intestines and cause malnu- cent worms through the microscope. tasks that really charged them up: find- trition and learning difficulties in children. “That was part of the fun and adventure ing genes that give the neoblast cells their Newmark’s findings could lead to a way to for me, but it was also very challenging,” stem cell identity, genes that direct them disrupt egg production in schistosomes. says Reddien, now at the Massachusetts to respond to a wound, genes that help “It’s fascinating biology and we’re in a Institute of Technology’s Whitehead Insti- form the regeneration stump, or blastema, good position to contribute to understand- tute for Biomedical Research. “There is and—most intriguing of all—genes that ing a very important disease that’s not no protocol book that you can just pull tell the animal which body part is missing. getting much attention,” he says. out and implement. We have to start from Reddien’s group continues to pursue scratch each time we would like to use a EYE-CATCHING MODEL genes he identified in the RNAi screen new method.” These questions will occupy the three labs that gave some of the most interest- Reddien eventually optimized the (and any others that crop up from their ing regeneration defects. In a follow-up RNAi to do a large-scale screen to knock descendants) for the next decade. New- screen, he and his postdoctoral fellow down 1,065 planarian genes and search mark’s group has set out to understand Chris Petersen discovered the most eye- for defects. Reddien and two lab mates how neoblasts become other kinds of cells, catching worm to date. made more than 53,000 amputations particularly germline cells. Planarians can “Chris came across the two-headed to worms with a razor blade during the resorb their whole reproductive tract in phenotype. When I looked through the screen. They found 240 genes that when times of starvation and then regrow ova- microscope I just about fell out of my silenced produced some kind of defect; ries, testes, sperm, and eggs when food is chair. We knew we had something very 85 percent of these genes are conserved in plentiful again. They also regenerate germ important,” says Reddien. other animals, including humans. cells after amputation. Morgan had observed the two-headed As a model organism, the goofy-looking His lab group has identified genes worm, which plays a perpetual game of flatworm had arrived at a critical juncture. that block germ cell differentiation and a (continued on page 48)

August 2o1o | HHMI BULLETIN 33 PERSPECTIVES & OPINIONS

Lawrence Goldstein STEM CELLS 101 DO WHAT IT TAKES TO COMMUNICATE THE FACTS. John Dole John

34 HHMI BULLETIN | August 2o1o A long-time and vocal champion of science’s value to society, Lawrence Goldstein, an HHMI investigator at the University of California, San Diego, is reaching out beyond policymakers in an unorthodox way. With the same publisher that taught millions how to plan a budget wedding, do a 15-minute workout, and bake bread, he’s co-written Stem Cells for Dummies.

There is a tendency among scientists, and I understand it, hadn’t done anything terrible. It was an efficient process. The to focus on your science and let someone else worry about book, with its 22 chapters and almost 350 pages, took us about the problems of funding and policy and regulations. But six months to write. the scientists know what we know and don’t know, what are The book is filled with analogies and inviting stories that reasonable judgments, and how good the data are. If those I’ve used to present complicated scientific ideas during my perspectives don’t inform political and public debates, bad years of teaching and speaking to nonscientific audiences. An things for science can happen. early example in the book likens different organisms—like In the early 1990s, I spent time in Washington talking to fruit flies, mice, and people—to different motorized vehicles legislators about how research into the detailed workings of as a way to explain that, despite differences in details, these cells brings value to society, from the blue-sky, understand- living things share many of the same basic mechanisms the-world perspective and also from the perspective of and parts. practical applications. When Jamie Thomson [of the Univer- Another one I like: “In plants, stems are the center of plant sity of Wisconsin–Madison] announced he’d established the growth, giving rise to leaves, flowers, and fruit. In animals, first line of human embryonic cells in 1998, I became a go-to stem cells are the unique cells that give rise to other types person to discuss how to balance issues of law, ethics, scien- of the body’s cells, such as skin, blood, and nerve cells.” tific freedom, and scientific opportunity. (Although in the spirit of good collaboration, neither Meg Early last year, a literary agent asked me to participate in a nor I remembers which of us came up with this one.) stem cell book for the public. I saw it as a new opportunity to The work of Dummies’ resident cartoonist Rich Tennant use and extend the communications skills I had been develop- also helped with the challenge of communicating basic ing in my public policy work. When I found out it was a Stem aspects of science and technology. In one, he makes the point Cells for Dummies project, I worried that the “For Dummies” that stem cell research doesn’t quickly translate into medical part might be a little undignified. Would it be bad for my treatments. A bunch of funny looking bald guys are in a lab. reputation as a serious scientist? Would it be bad for my insti- The one in the middle is chatting with a woman. The caption tution’s credibility? I consulted trusted friends and colleagues reads: “Believe me, if there were an easy stem cell fix for bald- and they all told me it was a great idea and that I should do it. ness, our team would have found it by now.” The agent, Barb Doyen, hooked me up with a profes- The book has gotten a lot of good press coverage for me, sional writer, Meg Schneider, who is smart, writes well, and and by extension for the university, and for the cause of seri- has done other For Dummies books. We worked entirely by ous and rigorous science. Books like Stem Cells for Dummies phone and e-mail. We never met in person. can help people make their own decisions about the societal For each chapter, we prepared a detailed outline. I would value and moral status of stem cell research based on their do the reading I needed to bring myself up to industry stan- own views but informed by accurate information. dard on the topic. Then I dictated into a recorder the content and structure so that a smart, non-scientifically trained jour- INTERVIEW BY IVAN AMATO. Larry Goldstein is director nalist like Meg could convert my words into the For Dummies of the Stem Cell Research Program at the University of style prose. Meg would send me her work and I would revise California, San Diego. it. We would go back and forth. I sent every chapter to people who knew more than me about the topic to make sure we FOR MORE INFORMATION: see Observations, “Biology in Mythology,” inside back cover.

August 2o1o | HHMI BULLETIN 35 Q & A What “For Dummies” book are you most qualified to write? In this issue of the Bulletin, one HHMI researcher describes the birth of Stem Cells for Dummies. Here, a few name the Dummies book they’d like to write.

— EDITED BY SARAH C.P. WILLIAMS

Luís Nunes Amaral Karolin Luger Trudi Schupbach Neil Hunter HHMI EARLY CAREER HHMI INVESTIGATOR HHMI INVESTIGATOR HHMI EARLY CAREER SCIENTIST COLORADO STATE UNIVERSITY PRINCETON UNIVERSITY SCIENTIST NORTHWESTERN UNIVERSITY UNIVERSITY OF “I would write a Synchrotron “ How to Produce Fruit CALIFORNIA, DAVIS “I would love to write a book Survival Guide for Dummies Fly Designer Babies for “I feel amply qualified to named Childish Curiosity for researchers tediously Dummies. The book would write a Daydreaming for for Dummies. Since I can collecting data from these describe how to perform Dummies guide, especially remember, I have been large particle accelera- mutagenesis and would one targeted at scientists. curious about everything tors. Practical tips would outline various selection Daydreaming is gener- from physics to history. include: bring a toothbrush schemes to identify desired ally considered lazy and As a teenager, I gravitated to combat the 3 a.m. fuzzy embryo phenotypes. Sample unproductive, but I find toward physics because of mouth feeling and warm pictures of shaven-baby and it incredibly productive! the math and the fact that sweaters for the midnight bigbrain embryos would be Useful daydreams can be observations could be made draft. Chocolate-covered shown. Strategies for estab- had in the shower, while quantitative—black and coffee beans are a must. lishing fruit fly families that brushing your teeth, or white, so to speak—instead Another section would will continue to produce during your commute of relying on qualitative describe how to interact the desired embryos for to work. The secret to arguments. The goal of my with synchrotron staff— many generations would productive daydreaming book would be to teach the make sure you have their be discussed. I would also is to alternate it with data reader to see the beauty cell phone numbers, and provide a list of my favorite input, such as reading/ in different disciplines. bring appeasement gifts music for getting through reviewing papers, analyzing A beautifully conceived if you have to call them the more tedious parts data, talking over projects experiment or model leaves at 2 a.m. (Swiss chocolate of the procedures. The with students or postdocs, me in awe, whether it is the works best). Finally, bring final chapter would cover and listening to talks at a ultimatum game (which is your invisibility cloak in good ways to take pictures conference. I’m convinced played in economic experi- case you trip the entire of the embryos to share that our best thoughts and ments) or the Ising model beam and you need to with colleagues, friends, ideas—especially those that (a mathematical model in escape the wrath of dis- and family.” require complex problem statistical mechanics).” gruntled researchers. If solving—come during these you don’t have one, bring ‘distracted’ periods.” more chocolate.” Amaral: Andrew Campbell Luger: John Eisele / CSU Schupbach: Laura Wieschaus Hunter: Paul Fetters Hunter: Paul Laura Wieschaus Eisele / CSU Schupbach: Amaral: Andrew Campbell Luger: John

36 HHMI BULLETIN | August 2o1o chronicle

38 SCIENCE EDUCATION 46 NOTA BENE Making Research Personal / National Awards to Twelve Elected to National Academy of Sciences / Foster Science Education Bertozzi Wins Lemelson-MIT Prize / 2010 Gairdner Award Goes to Kaelin 40 INSTITUTE NEWS Change in Leadership of HHMI Trustees / Scientists can peek inside the brain of this tethered Bishai Named Director of K-RITH fruit fly as it balances on a freely moving ball. It’s a creative solution, by HHMI scientists, to the prob- 42 LAB BOOK lem of how to visualize neurons in a living fly as it Driving Thirst / Mustard’s Mini-Me / moves about. Visit www.hhmi.org/bulletin/aug2010 Double-Checking Doublesex to read about the new apparatus and see photos of 45 ASK A SCIENTIST its assembly. How can jellyfish of the same kind gather in a group if they don’t have brains? Eugenia Chiappe

August 2o1o | HHMI BULLETIN 37 science education

Making Research Personal A WEST VIRGINIA PROGRAM PULLS STUDENTS INTO SCIENCE BY TEACHING THEM ABOUT THE HEALTH PROBLEMS IN THEIR OWN COMMUNITY.

ON A COLD MORNING IN LATE JANUARY, TERRIFIED TEENAGERS organized the club’s project around nutrition. Students brought arrived one by one in the health clinic waiting room in Welch, West family recipes from home and devised ways to make them health- Virginia. They were there to have blood drawn for a cholesterol test. ier—for example by substituting skim milk for whole. Some were crying. “I said, ‘Suck it UP!’” says teacher Lori Bishop, For this year’s project, the Bishops dreamed up a plan to have the glaring over her glasses. “Just go back there and close your eyes!” 20 students in the program monitor their cholesterol levels and look Bishop, an English teacher at Mount View High School, which for changes related to activity and what they ate. They arranged to shares a building with the clinic, says she wasn’t being mean for have the kids’ blood tested three times—in January, February, and the heck of it. The students had chosen to become subjects in March—as they boosted their exercise. their own research project on cholesterol. Bishop and her science Before the first test, Lori Bishop remembers some of the students teacher husband, Bob, run one of the state’s 80 Health Sciences and telling her they were thinking, “oh, the chubby kids are going to Technology Academy (HSTA) clubs. HSTA is an HHMI-funded have the bad cholesterol.” But the worst cholesterol level in the class program to get West Virginia high schoolers excited about science turned out to belong to a thin junior. “She might have gone years and college. The program focuses on the major health problems before she had her cholesterol checked. When we sent the first set of West Virginia: diabetes and obesity. Meanwhile, the students’ of results home, her mother immediately took her to a doctor.” research has clarified just how common obesity is in the state. Between the first and second tests, however, nature changed The Bishops have a reputation for coming up with creative proj- their plans. Harsh winter storms closed local schools for 10 days. ects for their students. Last year, the couple joined Weight Watchers The blood test was delayed. and experimented with ways to modify family recipes. “So we said, On a bright note, the students were much calmer about the

‘Why don’t we try to do something like this with the kids?’” They blood draw the second time around. But for many, cholesterol Leger Patrick

38 HHMI BULLETIN | August 2o1o levels rose. “My cholesterol went up,” says ninth-grader Jenna online training on research ethics. To date, hundreds of high school- Muncy. “The reason why is, it was snowing and I didn’t get out.” ers, including the teens in Welch, have taken the surveys home. Lori Bishop agrees: “They were just sitting around eating junk, The survey helps scientists learn about a particular slice of the watching TV, and playing video games.” state population, Branch says. “These are really the most rural Before the final blood test, the students got busy. “We had them communities, up the little valleys—some of the poorest of West do as much exercise as we could,” says Bob Bishop. The club met Virginia,” he says. Among the people surveyed in an earlier year, two or three times a week. On nice days, they walked circles around half the adults were obese. Those results were published Octo- the outside of the school; in bad weather, they walked the halls. It ber 2009 in Clinical and Translational Science in an article by worked. By the third test, in March, most had lower cholesterol. Branch and Chester about having adolescents carry out community The study also showed that the athletes had an advantage. research while inspiring them to go into science careers. “My cholesterol never went high or low because I stayed in Interestingly, a statewide study, conducted at the same time by sports. I do cheerleading, volleyball, tennis, and all that stuff,” the U.S. Centers for Disease Control and Prevention, found that says junior Joanna Bailey. Like many people in this rural county, only 31 percent of West Virginia adults are obese. That suggests to Joanna’s parents have diabetes, so the family also eats carefully, says Branch that HSTA, which is aimed at students who are low income, her mother, Patsy Bailey. African American, or the first in their family to attend college, may be reaching a particularly unhealthy slice of the population. A Family Study The HSTA program has had great success inspiring high schoolers This year, the Baileys and other parents were the subjects of a to go to college. While only 58 percent of high school graduates in research project carried out by HSTA students across the state. West Virginia go to college, Chester says, 97 percent of HSTA stu- Students surveyed their families—mostly parents, but also aunts, dents do—thanks in part to a state program that waives tuition and fees uncles, and grandparents—about their health, particularly obesity for students who finish the program. And more than half of HSTA stu- and diabetes. Bob Branch, a pharmacologist at the University of dents who graduate from college go into careers in health and science. Pittsburgh, organized the survey. In 2007, Ann Chester, director The Bishops and Branch hope it does even more: they’d like of HSTA, invited him to teach a week-long summer program on students all over West Virginia to carry home lessons about healthy clinical trials to HSTA students, but he was worried about boring eating and healthy living as a step toward improving the whole his teenage charges. community’s health. “We’re trying to make a difference in their “I asked the kids, rather than just me telling you how to do things, lives,” Lori Bishop says. “The way they eat and the way they look would you like to do it yourself? The response was an enthusiastic at food.” W –HELEN FIELDS ‘yes,’” he says. They designed the study together and, as in any serious clinical study, they got institutional review board approval from West FOR MORE INFORMATION: To learn more about the history of the HSTA program, visit Virginia University. Every student who administers the survey takes www.hhmi.org/bulletin/august2006/features/appleseeds.html.

National Awards to Foster Science Education

IN MAY, HHMI ANNOUNCED $79 MILLION OF NEW GRANTS TO HELP to give more students vital experience working in the lab; and to universities strengthen undergraduate and precollege science edu- improve science teaching from elementary school through college. cation nationwide. The resources will allow faculty at research Some grantees will work to improve their introductory courses and universities to develop creative new ways to teach and inspire stu- to offer research opportunities to community college students. Others dents about science and research. plan to focus on increasing diversity in the sciences through outreach HHMI is making the awards through its Precollege and Under- and mentoring of middle and high school students. And some insti- graduate Science Education Program and the HHMI Professors tutions will use portions of their funds to provide better scientific Program—two complementary initiatives aimed at transforming training and research experiences for future K–12 science teachers. science education in the United States. In addition to the grants to research universities, $9 million “HHMI is committed to funding education programs that excite over four years will go to 13 HHMI professors, a small group of students’ interest in science,” says HHMI President Robert Tjian. leading research scientists who are committed to making science “We hope that these programs will shape the way students look at more engaging for undergraduates and K–12 students. The HHMI the world—whether those students ultimately choose to pursue a professors will focus on solving important problems facing science career in science or not.” education, such as how best to bring research into the classroom, Fifty research universities in 30 states and the District of teach large introductory science courses, and encourage students Columbia, including five first-time awardees, will collect a total of from diverse backgrounds to become scientists. W $70 million through the undergraduate program. The schools will use the grants, which range from $800,000 to $2 million over four FOR MORE INFORMATION: Visit www.hhmi.org/bulletin/aug2010 to see lists of the universities years, to develop creative, research-based courses and curricula; and professors receiving the HHMI awards.

August 2o1o | HHMI BULLETIN 39 institute news

Change in Leadership of HHMI Trustees KURT SCHMOKE SUCCEEDS HANNA GRAY AS CHAIRMAN.

KURT L. SCHMOKE, DEAN OF THE HOWARD University School of Law, was elected Chairman of the Trustees of HHMI at the May meeting of the Trustees. He succeeds Hanna H. Gray, President Emeritus of the University of Chicago, who has chaired the Trustees since 1997. Schmoke, 60, is an attorney who has dedicated much of his life to public service at all levels of government, including three terms as mayor of Baltimore. One of 11 Trustees of the Institute, he was elected in 2005 and has served as a member of the Executive Committee as He is also a director of Legg Mason and The McGraw-Hill Com- well as chair of the Audit and Compensation Committee. panies. Schmoke previously served as senior fellow of the Yale A 1971 graduate of Yale University, Schmoke attended Oxford Corporation, the university’s governing body, and as a trustee of University as a Rhodes Scholar and received his law degree in 1976 Tuskegee University. from Harvard University. After a year in private practice, he joined Hanna Gray was named a Trustee of the Institute in 1984 by the President Jimmy Carter’s White House domestic policy staff in Delaware Court of Chancery, joining seven distinguished business 1977 and then returned to his native city of Baltimore to become and academic leaders in rebuilding the Institute after the death of an assistant U.S. Attorney in 1978. Schmoke was elected State’s its founder. She succeeded the late Irving S. Shapiro as chairman in Attorney for Baltimore City in 1982. 1997 and will continue to serve as a Trustee. Schmoke came to national prominence in 1987 when he became Gray is the Harry Pratt Judson Distinguished Service Professor of the first African American to be elected mayor of Baltimore. During History at the University of Chicago, where she continues to teach. three terms in office, he focused on improving the city’s school A graduate of Bryn Mawr College, she received her Ph.D. from system and on broad economic development programs, with an Harvard University in 1957 and taught there for several years before emphasis on expanding home ownership and job opportunities. joining her husband, Charles Montgomery Gray, on the faculty of Schmoke joined the law firm of Wilmer, Cutler, & Pickering the University of Chicago. Gray was named dean of the College of in 1999 after declining to seek a fourth term as mayor. He became Arts and Sciences at Northwestern University in 1972 but left two dean of the Howard University School of Law in Washington, years later to become provost and professor of history at Yale Uni- D.C., in 2002. A respected and thoughtful advisor to a number of versity, where her father Hajo Holborn had taught for many years. educational and other organizations, Schmoke recently served She served as Yale’s acting president for 14 months and was inau- as a mediator between the District of Columbia school sys- gurated president of the University of Chicago in 1978, a post she tem and the Washington Teachers’ Union. He is a trustee of the held for 15 years. Carnegie Corporation of New York, a director of the Children’s In addition to the Institute, Gray has served as a director or Health Forum, and a member of the Council on Foreign Relations. trustee of some of the nation’s most well-known organizations: the Harvard Corporation, the Yale Corporation, the Smithsonian (Clockwise from lower left) Hanna H. Gray; Gray and Kurt L. Schmoke; Institution, the Andrew W. Mellon Foundation, the Council on Schmoke; HHMI Charter Trustees: (Standing, left to right) William R. Lummis, Hanna H. Gray, James H. Gilliam Jr., Donald S. Frederickson. (Seated, left to Foreign Relations, the Mayo Clinic, the Brookings Institution, and

right) Helen K. Copley, Irving S. Shapiro, Frank William Gay, George W. Thorn. Bryn Mawr College. W Carl Fried Joel Charter Trustees: Geiger Gray: willcrockett.com William Schmoke: Fetters Paul Gray and Schmoke:

40 HHMI BULLETIN | August 2o1o Bishai Named Director of K-RITH

A PROMINENT TUBERCULOSIS RESEARCHER AND DOCTOR WILL and HIV and, more importantly, train a new generation of scientists become the first permanent director of the KwaZulu-Natal Research in Africa, an integral objective of this institute,” said UKZN vice chan- Institute for Tuberculosis and HIV (K-RITH). After a year-long cellor and principal Malegapuru William Makgoba at the announce- international search, William R. Bishai was named director by the ment of Bishai’s directorship in Durban, South Africa, in May. University of KwaZulu-Natal (UKZN) and HHMI in May. Bishai, “Is it not great to know that the best research facilities anywhere a professor of medicine at the Johns Hopkins University School of on the planet for developing and training future scientists in this Medicine, will assume the role in September 2010. particular area are located here at UKZN within the continent “As a physician and a scientist, Bill Bishai understands the scale of Africa?” Makgoba continued. “If I were young and choosing a of human suffering caused by tuberculosis and the daunting chal- career, I would reflect profoundly on this.” lenges faced by researchers seeking to identify new strategies for The new K-RITH facility, including biosafety laboratories nec- responding to this epidemic,” says HHMI President Robert Tjian. essary for TB research, will be integrated with the existing Doris “He is just the kind of leader we hoped to recruit.” Duke Medical Research Institutes. The total cost of constructing As codirector of the Center for Tuberculosis Research at Johns the building, which will begin in September 2010, is estimated at Hopkins, Bishai focuses his research on understanding how and why about $50 million, with HHMI providing substantial support toward the tuberculosis (TB) bacillus is so successful at infecting humans. its completion. Bishai says that understanding the fundamental interactions that K-RITH’s resident research staff will eventually grow to more occur between the microbe and human cells is a critical step in than 110 people, including eight senior scientists, 40 pre- and developing new drugs and vaccines to treat tuberculosis. “If one postdoctoral students, and a support staff of 40. In 2008, HHMI wants to target the infection with drugs, knowing the mechanisms awarded seed grants totaling more than $1.1 million to scientists of pathogenesis is an important roadmap for making those drugs,” in the United States and South Africa as part of a K-RITH develop- says Bishai. He plans to use the same strategy at K-RITH to develop ment plan and continues to support the initial programs. quicker, cheaper tools for diagnosing TB infection. Bishai, 50, received both his medical degree and doctorate South Africa has more residents infected with HIV than any from Harvard University. He completed his fellowship training in other nation—an estimated 5.7 million in 2008—and one of the the Division of Infectious Diseases at the Johns Hopkins Univer- highest per capita rates of TB in the world. KwaZulu-Natal prov- sity School of Medicine and was a Howard Hughes Postdoctoral ince, home to more than 10 million people, bears an even greater Research Fellow in the laboratory of Nobel laureate Hamilton burden of disease than the nation as a whole, with as much as Smith. He has authored more than 150 papers in peer-reviewed 40 percent of the population positive for HIV. journals and receives grant support from the National Institutes of “Under Bill Bishai’s bold leadership I believe that the studies un- Health. He serves on several editorial boards and review panels, and dertaken at K-RITH will make major scientific contributions that will he is cochair of the World Health Organization Stop TB Partner- go a long way in providing insights and possible solutions in the con- ship’s Working Group for New TB Drugs. Bishai and his family trol, diagnosis, and treatment of the devastating coepidemic of TB expect to relocate to Durban in 2011. W

At a May press conference in Durban, South Africa, William Bishai, new director of K-RITH, was given a formal

Courtesy of UKZN welcome by University of KwaZulu-Natal vice chancellor and principal Malegapuru William Makgoba (center right).

August 2o1o | HHMI BULLETIN 41 lab book

Driving Thirst SCIENTISTS IDENTIFY A GENE THAT SENDS FLIES TO THE WATER BOWL.

Camels sport humps on their backs to store it and geese fly thousands onds, mutant flies sipped for only 3 seconds. When researchers of miles in search of it. The need for water is ubiquitous, yet the under- reintroduced the gene into mutant flies, their taste neurons fired lying genes that motivate animals to seek it have remained mysterious. when they drank water, and they went on to drink it for 12 seconds. Now, Kristin Scott, an HHMI early career scientist at the The results indicate that both ppk28 and taste neurons are nec- University of California, Berkeley, has uncovered a gene, called essary for sensing and consuming water. To confirm the role of the pickpocket 28 (ppk28), that regulates fruit flies’ ability to detect gene in detecting water, Scott and her team expressed ppk28 in water and how much time they spend drinking. neurons normally activated only when flies taste something bitter. Scott and her team set out to identify genes involved in taste. Remarkably, these neurons began firing when flies drank water. The They first compared genes expressed in the feeding appendages of findings were published May 6, 2010, in Nature. flies that lacked taste neurons with those in normal flies. When they Because the class of proteins is found in many organisms, Scott narrowed in on ion channels that were enriched in taste tissue, they believes ppk28 plays a role found the ppk28 gene. in water consumption in The researchers then measured the activity of neurons stimu- other animals, perhaps even lated with taste compounds by imaging changes in a fluorescently humans. In future studies, labeled calcium-sensitive ion channel and by inserting tiny elec- she plans to investigate how trodes into the flies’ taste-sensing bristles. They found that neurons water activates ion channels expressing ppk28 activated strongly when flies tasted water, but their and how internal drives, activity diminished when flies tasted other substances, such as sug- such as hunger and thirst, ars, bitter compounds, salts, and acids. affect the detection and con- Moreover, neurons did not respond when flies withoutppk28 A fruit ﬂy sucks up water with its sumption of water and sugar. narrow feeding appendage. drank water. And whereas normal flies drank water for about 10 sec- W –JANELLE WEAVER

IN BRIEF

ANXIOUS MICE Rafii and his collaborators found that samples for hundreds of pollutants, infec- Turning off a gene in mice makes them slitrk5-deficient mice have structural tious agents, nutrients, and compounds, anxious, skittish, and obsessive about defects in the striatum, a brain region including blood sugar. High blood sugar grooming, HHMI scientists have dis- associated with a decrease in the num- levels signal diabetes. covered. The engineered animals could ber of glutamate receptors. These unique Butte and his collaborators analyzed become an ideal model for studying abnormalities are strikingly similar to those the relationship between blood sugar lev- obsessive-compulsive disorder (OCD), found in the brains of people with OCD. els and 266 environmental factors in four characterized in humans by repetitive The results were published in the May 2010 sets of CDC data, spanning 1999 through behaviors and anxiety. issue of Nature Medicine. They hope fur- 2006. They controlled for the effects of The researchers, led by HHMI investi- ther research will illuminate just how the age, body mass index, gender, ethnic- gator Shahin Rafii of Weill Cornell Medical gene relates to the extreme behaviors and ity, and socioeconomic status, which are College, weren’t originally studying OCD. may give scientists hints about the molecu- already linked to type 2 diabetes. They set out to find genes involved in the lar causes of OCD in humans. The researchers were left with four fac- interplay between blood stem cells and tors that are statistically linked to one’s blood vessel cells. Their hunt led them to COMPLEX CAUSES OF DIABETES risk for diabetes. High blood levels of a gene called slitrk5, which is expressed in It’s not just genes, diet, and exercise but polychlorinated biphenyls (PCBs)—an blood stem cells and vascular cells but is perhaps also environmental pollutants and industrial pollutant—or heptachlor epox- most active in the brain. vitamins that are associated with a per- ide—a breakdown product of heptachlor, To probe slitrk5’s function, the research- son’s risk of type 2 diabetes, according to which was used to kill termites in the 1960s ers engineered mice without the gene. a new study. Led by Atul Butte, an HHMI and 1970s but has since been banned for While the mice appeared normal at birth, physician-scientist early career awardee most uses—were also linked to greater after three months they exhibited signs at the Stanford University School of Medi- chances of high blood sugar. In addition, of anxiety: they avoided open and high cine, the large-scale analysis used records they found a connection between high spaces, preferring corners and enclosed from the Centers for Disease Control and blood sugar and high levels of the most areas. Moreover, the altered mice jumped Prevention (CDC) to make the links. common form of vitamin E in the Ameri- at any touch and had bald batches on their Every two years, the CDC takes a can diet, gamma-tocopherol. Last, they faces from persistent grooming, which was snapshot of the nation’s health, using confirmed previous studies showing that relieved with Prozac, a standard drug used questionnaires and blood and urine high amounts of beta-carotene, a form of

to treat patients with OCD. samples from individuals. They test the vitamin A, are protective against type 2 Scott Lab

42 HHMI BULLETIN | August 2o1o Mustard’s Mini-Me A WAY TO SWITCH PLANTS’ REPRODUCTIVE PROGRAMS COULD HELP FARMERS.

The shipments of seeds that farms rely on at the beginning of each structures, or ovules, of the plant. growing season could soon be a relic of the past. Scientists have One gene jumped out: Argonaute 9, discovered how to coax plants to clone themselves by altering their one of ten Argonaute genes in the reproductive methods. mustard plant. While Argonaute Most plants—including major food crops like corn—create seeds proteins control gene expression by mixing genetic material from male and female cells. Offspring are across the whole plant, Argonaute 9 unique, an unfortunate fact for farmers who want every generation is only found in the ovules, the re- of plants to have the same optimized characteristics. To ensure that searchers found. sameness, farmers buy quality-controlled seeds rather than rely on the When they turned off the gene, plants’ hit-or-miss approach. But many wild plants reproduce in a dif- the researchers were in for a sur- Arabidopsis ovules show multiple reproductive precursor ferent way, called apomixis. They produce seeds that, instead of having prise. The Arabidopsis ovules started cells when one gene is blocked. a random mix of genes, contain an exact copy of their own genome. producing cells that are precursors HHMI international research scholar Jean-Philippe Vielle- to seeds and usually contain a mix of genes. But these instead had Calzada wanted to know which genes and molecules distinguished clones of their own genetic material—just as apomictic plants do. apomictic plants from their sexually-reproducing relatives, and “For the first time, we have a hint of where to look to induce this whether one type of plant could be coaxed to behave like the other. phenomenon in sexual plants,” says Vielle-Calzada. He focused his research on Arabidopsis thaliana, a flowering mus- The scientists hypothesize that turning off Argonaute 9 in other tard plant that reproduces sexually. plants will have the same effect. They continue to study why this gene Vielle-Calzada’s lab group, at the Center for Research and so drastically changes the reproduction program of Arabidopsis and Advanced Studies of the National Polytechnic Institute in Mexico, they want to know what other molecules are involved—for example, screened Arabidopsis for genes with high activity in the reproductive what genes Argonaute 9 helps to repress. W –SARAH C.P. WILLIAMS

IN BRIEF

diabetes. The results appear in the May 20, to form in the injured heart, as would hap- the team reported May 7, 2010, in Science . 2010, issue of PLoS One. pen in a damaged human heart. After the Of those varying proteins, it’s not yet regenerative block was released, new heart known whether any of the sequence differ- BROKEN-HEARTED FISH muscle built up around the scar. The results ences leads to changes in function. Zebrafish have the unusual ability to repair could help scientists studying human heart In the same issue of Science, a large their own hearts, something doctors treat- damage develop new treatments. international team including HHMI inves- ing humans would love to harness. New tigator Evan Eichler, at the University research brings that goal one step closer NEANDERTAL NUCLEOTIDES of Washington, published the complete to reality, with cellular details revealing The heavily built hominids that roamed 3-billion-base-pair genome of a different just how zebrafish manage to regenerate the planet until 30,000 years ago are Neandertal individual from bones found heart muscle. more human—when it comes to their ge- in Croatia. That study also found that rela- HHMI early career scientist Kenneth nomes—than scientists once thought. To tively few changes have been incorporated Poss of Duke University Medical Center come to this conclusion, HHMI investigator into the human genome since humans stimulated zebrafish heart regeneration by Gregory J. Hannon of Cold Spring Harbor diverged from the Neandertals. cutting off part of the animal’s ventricle— Laboratory used a new genetic sequenc- one chamber of the heart. Then Poss and ing technology to analyze DNA from a TARGETING BRAIN TUMORS his collaborators tracked the activity of 49,000-year-old Neandertal bone flake Researchers have revealed a weak spot in cells over time. found in a Spanish cave. one of the deadliest forms of brain can- They discovered that some heart mus- Since the ancient bone material was cer. Turning off a pathway that’s active in cle cells near the injury began expressing crawling with bacterial and fungal con- many glioblastoma tumor cells triggers the a gene called gata4. When this gene is taminants from the cave, Hannon and his cells to die. turned on, heart cells begin to divide, build- collaborators relied on a novel technol- In 2002, the University of Massachu- ing a new wall of heart muscle. Within two ogy called “DNA capture and resequenc- setts lab group, led by HHMI investigator to four weeks, the researchers observed ing,” which allowed them to isolate only Michael R. Green, discovered a cellular that new wall was functioning in sync with DNA that encodes proteins. They focused survival factor called ATF5 that’s overly the rest of the heart. on 14,000 genes and compared their activated in many cancerous cells. The The results, published March 25, 2010, sequences with the same genes in humans. protein is an attractive drug target for glio- in Nature, were similar even after they Only 88 genes produced proteins that dif- blastomas, because it is often abundant in

Vielle-Calzada Lab Vielle-Calzada blocked regeneration to allow scar tissue fered between Neandertals and humans, brain tumors but is not produced in healthy

August 2o1o | HHMI BULLETIN 43 lab book

Double-Checking Doublesex FRUIT FLY CELLS DON’T ALL KNOW WHAT SEX THEY ARE.

Scientists who spend hours each day poring over fruit fly biology They observed that, beginning 12 hours after fertilization, only can easily distinguish a male fruit fly from a female under the some cells in the embryos express doublesex. Expression of the gene microscope. But place an individual cell from a fly under the scope varies among cells and tissues throughout development. By the time and ask whether it is male or female, and you’ll surely stump them. the fly is an adult, only a portion of the fly’s tissues have doublesex HHMI scientists have now found that many cells in male and turned on—including all regions of the fly with obvious sex differ- female fruit flies not only look the same, they are more identical at ences, like the genitalia. However, many cells, they found, turn off a molecular level than was previously thought. doublesex permanently. Thus, in fruit flies both males and females “It’s been a widely accepted paradigm that all cells know their are sexual mosaics, in that some sex,” says Bruce Baker, a group leader at HHMI’s Janelia Farm cells know their sex, whereas Research Campus and an author of the new study. Researchers other cells do not. The research believed that all somatic cells in a fruit fly expresseddoublesex , was published on May 4, 2010, a gene known to control sex determination in flies. Females and in PLoS Biology. males differed as a consequence of the expression of sex-specific Since doublesex is a con- Doublesex proteins. served sex determination gene “This was a good model. It worked fine for explaining what we in many animal species, includ- knew. But it had never been rigorously tested,” says Baker. Now it has. ing humans, Baker and his Baker and his colleagues genetically engineered fruit flies so that coauthors suggest their results when a cell made protein from the doublesex gene, the cell lit up. may foreshadow similar findings The researchers then tracked the development of these fruit flies Only some cells in a ﬂy’s leg express in other animal species. W the doublesex gene (red). from embryos onward, watching which cells lit up. –SARAH C.P. WILLIAMS

IN BRIEF

neurons. But the protein is a transcription The human disease, achalasia, strikes strains of influenza spread from country to factor, binding to certain genes to turn 2,000 people a year in the United States country during each flu season. Just how them on—a type of protein that is notori- and the cause has never been identified. complex these viral migration patterns are ously difficult to block with drugs. When someone is afflicted with the con- has now been revealed. In their most recent work, Green’s team dition, the muscles of the esophagus Working in the lab of Mercedes Pascual, surveyed mice cells for other proteins that can’t relax and therefore can’t push food an HHMI investigator at the University of are in the same pathway as ATF5 and or liquid toward the stomach with normal Michigan, Trevor Bedford and Sarah Cobey might be better targets. They developed wave-like contractions. applied a computer algorithm to publicly a system in which only cells where ATF5 Proventricular dilation disorder (PPD) in available genetic sequences of 2,165 flu was turned off survived infection by a domesticated birds has many of the same viruses. Each sequence, from viruses col- diphtheria toxin. Then they shut off, in a symptoms: tissue in the birds’ proven- lected between 1998 and 2007, was paired high-throughput fashion using small snip- triculus, similar to the human esophagus, with a location and date, so the research- pets of RNA, each of the mouse’s nearly becomes diseased and its wave-like con- ers could trace how variants moved around 30,000 genes. tractions are disrupted. The scientists, led the globe. Twelve genes when turned off shut by HHMI investigators Don Ganem and While it’s long been presumed that down ATF5 activity, the scientists reported Joseph DeRisi of the University of Califor- most seasonal flu variants begin in China in the June 2010 issue of Nature Medi- nia, San Francisco, identified the virus as an and Southwest Asia, the analysis showed cine. Analysis of human brain tissue from avian bornavirus. that successful influenza strains origi- glioblastoma patients revealed that these Their recent work, published May 26, nated in the United States 24 percent genes are expressed in many tumor sam- 2010, in Science Translational Medicine, of the time. Moreover, in 1999 a strain of ples. In addition, using a mouse model of documents the similarities between PPD influenza that evolved in the United States glioblastoma, the researchers tested a and achalasia. While the avian bornavi- spread worldwide and was so successful drug—already on the market to treat other rus is not the cause of human achalasia, that all seasonal flu strains that exist today cancers—that blocks a protein in the ATF5 the research has inspired the scientists to descend from it. pathway. The results were encouraging. look for a viral cause of the human disease. The findings, Pascual says, offer impor- They’re now employing the same high- tant lessons for global influenza control. LEARNING FROM A BIRD VIRUS throughput viral screening methods that For example, the strains that circulate in A disease that’s been killing parrots and led them to the PPD virus to try to pinpoint South America during the winter almost macaws worldwide has now been found the cause of achalasia. always originated in North America the to have strong parallels with a swallow- previous season. This kind of knowledge ing disorder in humans. In 2008, a team GLOBAL MIGRATION OF THE FLU offers a way to predict which vaccines will of HHMI scientists identified a virus as the With airplanes zipping around the globe be effective. The research was published

cause of the bird disease. every day of the year, it’s no surprise that May 27, 2010, in PLoS Pathogens. Baker Lab

44 HHMI BULLETIN | August 2o1o ask a scientist

Q A How can Jellyfish are mysterious and amazing like muscle tissues. By contracting these creatures. Many people are entranced as sheets of cells, jellies move by pushing jellyﬁsh of the they watch these beautiful animals dance water out from under their bodies. Some gracefully through the water. Although of them can coordinate more sophisti- same kind they appear simplistic at first, jellyfish cated body movements and even switch gather in a participate in many complex behaviors. direction while swimming. The explanation behind this feat lies in Occasionally, jellyfish congregate group if they their fascinating biology and their rela- in large groups or clusters in oceans don’t have tionship with their environment. and lakes. In some cases, this gather- Although jellies have no brain or ing is a sensory response to changes in brains? complex organs, specialized cells and the way their food—tiny plants called structures allow them to thrive in their phytoplankton and animals called asked by Liz from Indiana dynamic environments. Jellyfish possess zooplankton—moves, is caught, or is an intricate network of nerves covering produced. Environmental changes such their body. This diffuse nerve net allows as shifting currents and temperature may them to sense and respond to stimuli affect this activity. Moon jellies (Aurelia) coming from any direction, without the and other jellyfish (Cyanea, Pelagia) use of a centralized brain. While human come together in areas in the sea where neurons send information in only one a shift in temperature or salinity occurs. direction, jellyfish neurons can fire in This location coincides with the home either direction, helping transfer infor- of their zooplankton food. Others, mation rapidly across their entire bodies. including the hydromedusae and stauro- Jellyfish do not have brains, but some medusae, gather near sea grasses or algae possess centralized sensory structures, to be near those food sources. called “nerve rings.” These rings, made Reproduction may also be part of up of condensed areas of the nerve net, jellyfish group activities. Mass spawn- help initiate movement by triggering ing sometimes occurs when they gather; contractions in the body. They connect however, it is unknown whether it is additional sensory structures to the nerve a cause or effect of congregation. In net, including simple eyes that detect Hawaii, the box jellyfish appear to arrive light changes in the environment, chemo- on the shore to spawn at a precise time receptor cells, and statocysts—organs that during the lunar cycle. Many jellies help sense balance and relative position release their sperm and eggs into the in the water. water, while others release only sperm With all these sensory structures, and fertilize internally. In either case, jellyfish are very aware of their surround- the group dynamic increases their odds ings and this information influences of successful reproduction. their behavior. They may appear to drift effortlessly along with the cur- ANSWER RESEARCHED BY DANIELLE FURTHER READING rent, but many jellies regularly move LIUBICICH, an assistant professor of Brusca and Brusca, 2003. Invertebrates. 2nd Edition. Sinauer Associates, USA between deeper and shallower waters. biology at Los Medanos College and a former doctoral student in the lab of University of California Museum of Paleontology Their nerves act in conjunction with http://www.ucmp.berkeley.edu/cnidaria/cnidaria.html sheets of specialized cells that function HHMI investigator Nipam Patel.

Science is all about asking questions, exploring the problems that confound or intrigue us. But answers can’t always be found in a classroom or textbook. At HHMI’s Ask a Scientist website, working scientists tackle your tough questions about human biology, diseases, evolution, animals, and genetics. Visit www.hhmi.org/askascientist to browse an archive of questions and answers, ﬁnd helpful Web links, or toss your question into the mix. What’s been puzzling you lately?

August 2o1o | HHMI BULLETIN 45 nota bene

SPOTLIGHT

Twelve Elected to National Academy of Sciences

TOP ROW: ANGELIKA AMON, VANN BENNETT, NANCY CRAIG, DON GANEM, ERIC GOUAUX, WILLIAM KAELIN BOTTOM ROW: DOUGLAS KOSHLAND, RUSLAN MEDZHITOV, ROELAND NUSSE, CHARLES SAWYERS, TERRENCE SEJNOWSKI, LYNN RIDDIFORD

Eleven HHMI investigators and one Janelia Farm fellow were elected to the National Academy of Sciences. They are Angelika Amon, Massachusetts Institute of Technology; Vann Bennett, Duke University; Nancy L. Craig, The Johns Hopkins University School of Medicine; Don Ganem, University of California, San Francisco; Eric Gouaux, Oregon Health & Science University; William G. Kaelin, Jr., Dana-Farber Cancer Institute; Douglas E. Koshland, University of California, Berkeley; Ruslan M. Medzhitov, Yale School of Medicine; Roeland Nusse, Stanford University School of Medicine; Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center; and Terrence J. Sejnowski, Salk Institute for Biological Studies. The senior fellow at Janelia Farm Research Campus is Lynn M. Riddiford. d: Paul Fetters Bertozzi: Barbara Ries Fetters d: Paul

HHMI program director at the Univer- Research Center. Bieniasz studies how hosts ogy and its importance in biology, education, Courtesy of Douglas Koshland: Fetters sity of California, San Francisco, BRUCE defend themselves against viruses and how and everyday life. ALBERTS, was named a 2010 recipient of pathogens take advantage of this process. the National Science Board’s Vannevar Bush PETER CRESSWELL, an HHMI investiga- Award, which honors lifelong leaders in sci- SEAN B. CARROLL, an HHMI investigator tor at Yale School of Medicine, won the 2010 ence and technology. at the University of Wisconsin–Madison who Buchanan Medal from The Royal Society, the was recently named HHMI’s next vice presi- UK’s national academy of science. The prize SARA BERMAN, an HHMI interdisciplinary dent for science education, won the 2010 is given biennially in recognition of medical undergraduate scholar at Haverford Col- Stephen Jay Gould Prize from the Society research. Cresswell studies the major histo- lege, received a Fulbright Research Grant for the Study of Evolution. The prize recog- compatibility complex, a family of cell surface to join a research team at the Max-Planck nizes individuals who have helped advance proteins involved in the immune response. Institute of Neurobiology’s Axonal Guid- public understanding of evolutionary biol- ance and Neural Connectivity Laboratory in Martinsried, Germany. She will study retinal SPOTLIGHT axons and how neuronal circuits facilitate vision. VIDYA R. RAGHAVAN, an HHMI- funded undergraduate at Mount Holyoke Bertozzi Wins Lemelson-MIT Prize

College, received a Fulbright Research Carolyn R. Bertozzi, an HHMI investigator at the Grant to work in Lausanne, Switzerland, at University of California, Berkeley, is the 2010 the École Polytechnique Fédérale. Her re- recipient of the prestigious Lemelson-MIT Prize. search will focus on interactions between the Bertozzi is among the youngest, and the first female, to win since the prize was established in immune system and tumor development. 1994 by Jerome H. Lemelson, one of the most pro- liﬁc inventors in U.S. history, and his wife, Dorothy. The American Society for Microbiology gave Bertozzi studies glycosylation—the normal pro- the 2010 Eli Lilly and Company Research cess in cells by which sugars are added to proteins Award to PAUL D. BIENIASZ, an HHMI CAROLYN BERTOZZI and other molecules—and its links to diseases.

investigator at the Aaron Diamond AIDS Kaelin: Paul Fetters Ganem: Lenny Gonzalez Gouaux: Paul Fetters McCullough Craig: Paul Bennett: Jeffrey Fetters Amon: Paul Riddifor Fetters Sawyers: Liz Baylen / PR Newswire, ©HHMI Sejnowski: Paul Fetters Medzhitov: Amy Etra Nusse: Paul Koshland

46 HHMI BULLETIN | August 2o1o SPOTLIGHT their Outstanding Investigators of 2010 for his research on how necrosis—one form of 2010 Gairdner Award Goes to Kaelin cell death—relates to heart disease.

William G. Kaelin, an HHMI investigator at Dana- BARBARA J. SPEZIALE, an HHMI program Farber Cancer Institute, was one of ﬁve scientists director at Clemson University, received the awarded 2010 Canada Gairdner International South Carolina Governor’s Award for Scien- Awards from the Gairdner Foundation. These annual awards recognize leading medical tific Awareness for her contributions to state researchers around the world. Kaelin shares his science education and outreach for K–12 award with Peter J. Ratcliffe of the University students, teachers, undergraduate students, of Oxford and Gregg L. Semenza of the Johns and the public. Hopkins University School of Medicine for their

WILLIAM KAELIN studies on how cells sense oxygen levels. HHMI investigator THOMAS C. SÜDHOF, of Stanford University School of Medicine, won a 2010 Kavli Prize in neuroscience. The HHMI investigators PETER CRESSWELL, KATHERINE A. HIGH, an HHMI investigator awards are given annually in neuroscience, Yale School of Medicine; ROY R. PARKER, at the Children’s Hospital of Philadelphia, astrophysics, and nanoscience by the Kavli University of Arizona; THOMAS C. SÜDHOF, received an Outstanding Achievement Foundation. Südhof shares the award with Stanford University School of Medicine; and Award from the American Society of Gene Richard Scheller of Genentech and James BRUCE D. WALKER, Massachusetts General & Cell Therapy for her development of gene E. Rothman of Yale University for their dis- Hospital, were named fellows of the American therapies to treat genetically inherited discoveries of how neurotransmitter release Academy of Arts and Sciences. The academy’s eases, including hemophilia and a form of passes signals between neurons. elected members are leaders in academics, hereditary blindness. the arts, business, and public affairs. HHMI early career scientist JOSEPH W. HHMI investigator A. JAMES HUDSPETH, of THORNTON, of the University of Oregon, The Human Frontier Science Program Orga- the Rockefeller University, received the John won the Oregon Medical Research Founda- nization named HHMI early career scientist and Samuel Bard Award in Medicine and Sci- tion’s 2010 Richard T. Jones New Investigator KARL DEISSEROTH, of Stanford University, ence from Bard College. The award is named Award. Each year, this statewide award rec- the first winner of the HFSP Nakasone Award. for two 18th century physicians, father and ognizes a young scientist with exceptional Named for former Prime Minister Nakasone son, whose descendant founded Bard Col- promise in a career in biomedical research. of Japan for his creation of the HFSP organi- lege. Hudspeth studies the biophysical and zation, the award honors key breakthroughs molecular basis of hearing and equilibrium. HHMI investigator WILFRED A. VAN DER in the life sciences. Deisseroth was chosen for DONK, of the University of Illinois at Urbana– his pioneering work in optogenetics. THOMAS M. JESSELL, an HHMI inves- Champaign, was awarded the 2010 Jeremy tigator at Columbia University College of Knowles Award from the Royal Society of HHMI investigator DAVID GINSBURG, of Physicians and Surgeons, won the 2009 Chemistry. Van der Donk’s research focuses on the University of Michigan Medical School, Perl-UNC Neuroscience Prize from the the discovery and development of antibiotics. received the 2010 Robert J. and Claire Pasa- University of North Carolina School of row Foundation Annual Medical Research Medicine. Jessell studies the function and LESLIE B. VOSSHALL, an HHMI investiga- Award in Cardiovascular Disease for his organization of motor neurons and the tor at the Rockefeller University, won the 2010 research on blood clotting. behaviors that their neural circuits encode. Dart/NYU Biotechnology Achievement Award for her discoveries of odor-sensing pathways in HHMI professor JO HANDELSMAN, of Yale HHMI investigator KAROLIN LUGER, of insects. The Dart/NYU Awards recognize the University, won the 2010 Education Award Colorado State University, was chosen to serve role of pure science in the development of phar- from the American Institute of Biological on the National Advisory General Medical maceuticals by honoring innovative research in Sciences. The award recognizes individuals Sciences Council, a group of leaders in the bio- biotechnology and molecular biology. or groups that have made significant con- logical and medical sciences, education, health tributions to biology education at any level. care, and public affairs who help guide the Na- RICHARD N. ZARE, an HHMI professor Handelsman is a cochair of the National tional Institute of General Medical Sciences. at Stanford University, received the 2009 Academies Summer Institute program, which BBVA Frontiers of Knowledge Award in the works with university faculty on teaching The International Society for Heart Fail- Basic Sciences. He shares the award with strategies. She also cofounded the Women in ure Research named HHMI investigator Michael E. Fisher of the University of Mary- Science and Engineering Leadership Insti- JEFFERY D. MOLKENTIN, of Cincinnati land. Zare plans to use his portion of the award

Paul Fetters Paul tute at the University of Wisconsin–Madison. Children’s Hospital Medical Center, one of to set up a graduate fellowship at Stanford.

August 2o1o | HHMI BULLETIN 47 CONTINUED FROM PAGE 23 have suggested that malaria can be eliminated, and more than two (TWO ROADS TO AN END) dozen countries have launched efforts that they hope will stamp out part in a research project, he says, requiring approval by an ethics the disease, with some progress reported. panel and village elders as well as cooperation with traditional Plowe and Djimdé support the ambitious goal. “The malaria healers. “You have to respect the customs and the organization of research world has been transformed by the call for eradication,” the community. You have to find a way to explain what you plan to Plowe says. But the two say it will take years of research to stop ma- do, what risks are involved, and the likely benefits for the commu- laria in nations where the disease is now endemic and widespread. nity and perhaps for mankind in general.” “I think eradication is possible, but not in the near future,” says In one project, Djimdé’s group, in collaboration with Wellems’ Djimdé. “The tools we have today—notably, the artemisinin-based NIAID lab, is examining the parasite’s resistance to quinine, the combination therapies and mosquito nets, with the possibility of an time-tested drug derived from tree bark that is often used to treat efficacious vaccine against malaria—can be very effective if they the most severe cases of malaria. (Quinine is a natural product are available and are deployed. In specific communities, they can that differs markedly from chloroquine, which was synthesized lessen malaria to the extent that it is no longer a serious public by German scientists and refined as an antimalarial drug by U.S. health problem. researchers during World War II.) He is also trying to determine the “I don’t think we have the tools to [eradicate malaria] yet. This safety of, and whether resistance is emerging to, the newest genera- will require sustained funding and decades of research,” he adds. tion of ACTs. Both Djimdé and Plowe will continue to lead the way. “Djimdé The fight against malaria has continued for centuries—and is now one of the best-known researchers in all of Africa,” says Plowe. intensified in recent years with the advent of the World Health Although they’re using different approaches to tackle malaria, the Organization Global Malaria Programme and related efforts two scientists remain friends after nearly 20 years—sometimes men- sponsored by major aid organizations. In recent years, optimistic toring the same students and discussing their separate projects. Even funding agencies, such as the Bill & Melinda Gates Foundation, their families are close. “It’s been a great friendship.” W

CONTINUED FROM PAGE 33 says Reddien. He says this study captivates translating what you find in planarians to (MASTER OF REGENERATION) him because it hammers home the idea actual human stem cell function is going tug-of-war with itself, a century earlier. But that choices are being made at the sites of to be much shorter,” he notes. Petersen and Reddien were in a better posi- wounds. He wants to uncover how those Sánchez Alvarado speaks fondly of his tion; they knew which silenced gene had decisions happen. quirky, but potentially powerful, pet organ- caused the oddity. It was beta-catenin, a “We could not ask these questions in ism: “What model system isn’t funky? key molecule in the Wnt signaling pathway Drosophila or C. elegans. Planarians’ biol- C. elegans has such a defined cell lineage, that controls body plan polarity in many ogy is very different and they enable a whole it’s uncanny. Morgan chose Drosophila animals during embryonic development. suite of questions that couldn’t be addressed because they were such prodigious egg lay- Beta-catenin transmits the Wnt signal into in existing model systems that do not regen- ers. All model organisms got chosen because the cell’s nucleus, where it directs changes erate robustly,” notes Reddien. they exaggerate a particular biology.” to a set of other genes’ expression levels. Brenton Graveley, one of a handful of Sánchez Alvarado remembers the flight The two showed that, normally, beta- scientists starting to use planarians in bio- home after the fountain-foraging expe- catenin turns on genes that suppress head medical research, gives Sánchez Alvarado, dition in Barcelona. He and Newmark formation and promote tail formation. How- Newmark, and Reddien all the credit. “The camouflaged the cooler of live worms with ever, when beta-catenin is absent, the default three of them brought planarians into the cardboard and duct tape. “It looked so sus- is to produce a head at any wound site, accord- molecular era,” says Graveley, a molecu- picious, but they let us through.” ing to their 2008 Science paper. At the same lar biologist at University of Connecticut The journey into planarian self-renewal time and also published in Science in 2008, Health Center in Farmington. has been both adventurous and arduous. Sánchez Alvarado’s group created an animal The early genome work by Sánchez “It was hard,” he admits. “But when you with boosted levels of beta-catenin; when its Alvarado and Newmark that showed pla- look at the animal, and the wild type is head was amputated, a tail grew back instead. narian genes were closely related to human already unbelievable—I mean, the guillo- “This is the type of science you dream genes “propelled planarians to the fore- tine would not work on this guy—I thought, about as a kid. We are studying processes front,” he adds. “If you are not going to work ‘If we can actually go in and perturb these that are dramatic and broadly important,” on human or mouse cells, then the leap in things, how amazing it would be.’” W

This paper is certiﬁed by SmartWood for FSC standards, which promote environmentally appropriate, socially beneﬁcial, and economically viable management of the world’s forests.

48 HHMI BULLETIN | August 2o1o