At the 25th anniversary kickoff event, Founding Member Robert Weinberg debuts a time capsule that will store Whitehead artifacts.
2007 Annual Report
Non-Profit Org. US Postage Whitehead Institute for Biomedical Research PAID Nine Cambridge Center Cambridge, MA Cambridge, Massachusetts 02142-1479 Permit No. 56998 Below: Taken by a deep-ultraviolet microscope, this image shows how the mass of nucleic acids is Whitehead Institute distributed in a mouse macrophage (a kind of immune cell). Image by 2007 Annual Report Benjamin Zeskind, Paul Matsudaira’s laboratory.
1 Director’s letter
3 Scientific highlights
6 Research stories
12 Principal investigators
33 25th anniversary
34 Whitehead news
Whitehead Institute for Biomedical Research 36 Public outreach is a nonprofit research and educational institution. Wholly independent in its 38 Financial summary governance, finances and research programs, Whitehead shares a teaching affiliation 40 Leadership with Massachusetts Institute of Technology (MIT). Whitehead brings together a small group of world-class biomedical researchers in a highly collaborative and supportive environment and empowers them to pursue the questions that engage them most. Whitehead Institute for Biomedical Research 9 Cambridge Center on the cover: Studying how cells regulate Cambridge, MA 02142 their growth, David Sabatini’s laboratory 617.258.5000 has shown that Rag family proteins www.whitehead.mit.edu regulate the location of a key protein complex called mTORC1 in the presence of nutrients. Here, mTOR is marked in green, DNA in blue and the Rab7 protein in red. From top to bottom in the sequence here, as the cell is stimulated with amino acids, mTOR moves to be localized in a compartment near the nucleus. Sancak et al., “The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1”, Science (2008). Reprinted with permission from AAAS. Director’s letter 1 www.whitehead.mit.edu
Challenges and celebrations
David C. Page
There was no doubt that Jack White- head, Founding Director David Baltimore and many other partners had hit upon a winning formula. In fact, in 1990, only eight years after Whitehead Institute was formed, Science Watch ranked it as the top research institu- tion in the world in genetics and molecular biology. Today, we continue to rank very highly among our peer institutions, most of which are much larger than Whitehead. The Insti- tute ranked fourth in a Science Watch analy- sis of high-impact genetics and molecular biology papers from 2002 through 2006. Even more remarkable for such a small institution, two of our Members were the In 2007, Whitehead Institute for Biomedical top-ranked authors of those high-impact Research celebrated its 25th anniversary. papers. That gave us an important opportunity not I think this is a testament to the sound- just to look back, but to pause and look at ness of our model and our mission: to recruit the Institute today, and to think about the and empower the best talent we can find. future. In addition to retaining the senior faculty Looking back, we saw once again the whose discoveries have brought such luster unforgettable figure of our founder, Edwin to the Institute, we have been successful in C. “Jack” Whitehead. Jack was passionate, attracting superb young researchers. Of our endlessly curious, stubborn, colorful, charm- 23 principal investigators, 10 have joined ing and relentlessly dedicated to creating the since 2004. world’s finest institution for basic biomedi- Three of these researchers set up their cal research. Twenty-five years later, he still labs in 2007. Among them, Whitehead inspires. Member Iain Cheeseman studies key mecha- We also recalled the stunning range nisms in cell division. His work focuses on of major scientific accomplishments that the kinetochore, a structure that helps to emerged quickly from the Institute. divide DNA molecules shortly before cells 2 Director’s letter Whitehead 2007
divide. Because many cancers may be driven Moreover, Liliana and Hillel Bachrach by errors in this process, Iain’s studies may pledged $1 million to fund novel research provide payoffs in cancer research. in the Whitehead Human Embryonic Stem New Whitehead Fellow Kate Rubins Cell Facility. studies poxviruses, which include smallpox, With generous support like this, White- monkeypox, cowpox and vaccinia (the virus head research continues to flourish, despite from which the classic smallpox vaccine is today’s challenges in federal research developed). funding. Defne Yarar, a Special Fellow of White- Throughout the past 25 years, White- head Institute and the MIT Center for Can- head has launched new scientific fields of cer Research, investigates how cells employ research and careers that have changed the a network of proteins called the actin face of biomedical research throughout the cytoskeleton to engulf large molecules from world. outside the cell. This work will have dramatic conse- We also were very fortunate in bolster- quences for our own lives and those of our ing our Board of Directors with several new children and grandchildren. Members. These include Arthur W. Brill, an We don’t know what will happen in attorney with Roberts and Holland, LLP, biology in the next 25 years—except that and the longtime Secretary of the Whitehead it will be full of important surprises, that it Corporation; Peter M. Hecht, co-founder will bring research findings with enormous and chief executive officer of Ironwood implications for human health and that we Pharmaceuticals, Inc. (formerly Microbia); at Whitehead will succeed by staying faithful and David H. Koch, executive vice president to the goals and values and search for excel- and co-owner of Koch Industries, Inc. I’d lence that brought us here. also like to give special thanks to departing We will stick by our mission, empower- Board Member John K. Castle for his major ing the exceptional individual scientists who contributions over many years to Whitehead can push back the frontiers of biology. We Institute. find the right people, and we let them define This was a banner year for private dona- the future. tions; the total for 2007 exceeded $16 million. Throughout the following pages, you’ll Most notably, Whitehead received its largest see what made 2007 so memorable at the gift since its founding as Landon and Lavinia Institute. Clay gave $10 million to endow the Clay I’d like to extend my deepest thanks to Laboratory Fund. The Clays also donated the researchers, staff and partners who made $1 million to establish the Clay Fellows this progress possible. Program. —David C. Page A $4 million bequest from the estate of Margaret Sokol allowed Whitehead to establish its first endowed chair, the Marga- ret and Herman Sokol Chair in Biomedical Research. Scientific highlights 3 www.whitehead.mit.edu
Research accomplishments
Highlights of Whitehead science reported in 2007
Cancer cause tumors to spread to distant tissues • In the past few years, cancer researchers in mice, while the Weinberg lab showed have hotly debated the potential role in that another microRNA directly regulates solid tumors of cancer stem cells, which a gene implicated in human cancers. may fuel the ability of tumors to renew (For more on microRNA research at the and spread. In 2007, the lab of Whitehead Institute, see story on page 6.) Member Robert Weinberg created a line of human breast cancer stem cells that • While heat shock proteins play a beneficial may help to clarify the role that such role in adapting to stress, they also may be cells play. After being injected with just co-opted for cancer pathways, as scientists 100 of these cells, mice develop tumors in the lab of Whitehead Member Susan that metastasize. Lindquist demonstrated. Their work suggested that the heat shock master • Researchers also elucidated the role that regulator protein HSF1 may offer a microRNAs may play in cancer. Whitehead uniquely effective target for the discovery Member David Bartel’s lab showed that of broadly active anticancer agents. (See overabundance of a single microRNA can story, page 8.)
Normal human breast cells were transformed into cancerous cells (with membranes stained green) in a culture medium created by the Weinberg lab. As many as one in ten are cancer stem cells. 4 Scientific highlights Whitehead 2007
Stem cells • Embryonic stem cells can differentiate into almost any cell of the body, but the need to use embryos in their creation creates ethical and practical issues for possible therapeutic use. The lab of Whitehead Member Rudolf Jaenisch was one of three worldwide that in June reported the ability to take cells from mice tails and reprogram them into cells that appear identical to embryonic stem cells— without using an egg. This sparked labs around the world to begin investigating such “induced pluripotent stem” (IPS) cells. In December, the Jaenisch lab followed up with the first proof of principle of therapeutic use of IPS cells, further manipulating such cells to successfully treat sickle-cell anemia in mice. (See story, page 10.) 2 Infectious disease and drug development 1 • The lab of Whitehead Member Gerald Fink demonstrated that white blood cells can recognize and respond to a particular form of sugar contained on the surface of patho- 1 Inhibition of genic fungi. The work offers hope for com- • In other stem cell work, Whitehead Member the Smed-beta- bating the growing problem of microbial Peter Reddien’s lab identified a gene that catenin-1 gene infections, which can seriously threaten regulates polarity in regenerating planarian causes planarian human health, particularly in patients with flatworms (a process that is driven by a flatworms to compromised immune systems. form of adult stem cells). When a planarian regenerate a second head is cut, inhibiting that gene resulted in the (on right) instead • Whitehead Member Harvey Lodish’s animal making a head instead of a tail at of a tail. lab worked with collaborators at MIT to the site of the wound. 2 Neutrophils, a type develop a cell culture test for assessing of white blood a compound's genetic toxicity that may • Contrary to textbook models, many genes m dicesare o cells shown in pink prove dramatically cheaper than existing t that should be “off” in embryonic stem in this illustration, animal tests of drug candidates. cells and specialized adult cells remain recognize and
primed to produce master regulatory respond to a o n : ustrati ll proteins, leaving those cells vulnerable to particular form • The lab of Whitehead Member Hidde of sugar on the identity changes, as Whitehead Member Ploegh solved the complex structure surface of patho- of a recently discovered protein that is Richard Young’s lab discovered. Under- genic fungi. standing this process could bring us a found in a wide range of herpes viruses. step closer to reprogramming cells in a The protein may be a good target for drug development. controlled fashion, which has important anarian : peter reddien ; i p l applications for regenerative medicine. Scientific highlights 5 www.whitehead.mit.edu
Scientific awards and achievements
• Iain Cheeseman and Whitehead Fellow • Whitehead Director David Page was Some recent Andreas Hochwagen received Smith named a Fellow of the American Associa- recognition Family New Investigator Awards. tion for the Advancement of Science. for principal investigators • Rudolf Jaenisch was given a Vilcek • Whitehead Member Hazel Sive was Foundation Prize. These are awarded to appointed associate dean for MIT’s foreign-born individuals for extraordinary School of Science. Sive, the first contributions to society in the U.S. associate dean in the School’s history, is focusing on educational issues and • Susan Lindquist was declared one of Har- initiatives. vard's 100 most influential alumni by 02138 magazine. • Robert Weinberg received the Otto Warburg Medal from the German Society • Whitehead Member Terry Orr-Weaver for Biochemistry and an honorary was appointed American Cancer Society doctorate from the University of Uppsala Research Professor and a trustee for the in Sweden. Genetics Society of America.
Grant awards
• Richard Young’s lab received $1,305,134 • Susan Lindquist’s lab was awarded Highlights from the National Human Genome $543,377 by the National Institute of of first-year Research Institute to study transcriptional General Medical Sciences to study funding for regulatory networks in living cells. protein-folding mechanisms. selected new federal grants • Harvey Lodish’s lab received $704,872 Also, among the gifts from foundations, in calendar from the National Institute of Diabetes Robert Weinberg’s lab was awarded year 2007 & Digestive & Kidney Diseases to study $325,000 from the Breast Cancer Research cell signaling in muscle and liver, and Foundation to investigate how epithelial $399,750 from the same agency to and stromal cells, two primary types of study the expansion of blood stem cells found in mammalian tissue, interact cell cultures. in tumors. 6 Research stories Whitehead 2007
What one microRNA can do
How scientists connected a single snippet of RNA to a cancer-causing gene
Like many Whitehead researchers, Christine Mayr is an MD. Her clinical work at Lud- wig Maximilians University of Munich led to a fascination with the genetics of leuke- mia and cancer—and then to the role of microRNAs. These tiny pieces of RNA can repress gene activity by targeting the gene’s mes- research senger RNA, which contains the DNA infor- mation needed for the process of protein production. Research in microRNAs has soared stories in recent years, and the lab of Whitehead Here are glimpses of a few research advances— Member David Bartel has helped to lead the way. in small RNAs, heat shock proteins and cells that Two years ago when Mayr joined the act just like embryonic stem cells. Bartel lab, only 250 of these tiny molecules had been discovered in various organisms— about a quarter of the current total. “MicroRNAs might regulate every physiological process and, intriguingly, they behave the same way in different species,” she says. “Investigating this gene mecha- nism, which was unknown until a few years ago, was exciting. And David’s lab was at the center of discovery within this realm.” Researchers were just starting to under- stand that microRNAs were involved in the regulation of certain cancers, but they hadn’t nailed down the specific genes that were regulated by microRNAs. An indi- vidual microRNA can target hundreds of genes, making it tricky to confirm target predictions. Mayr took an unusual approach to studying the microRNA-cancer connections. Rather than modifying the expression of Research stories 7 www.whitehead.mit.edu
About two dozen microRNAs and seeing how that affected Mayr and her colleagues published their scientists in the lab of David Bartel a model organism, she began by examin- results, the first demonstration that the (foreground) study ing data on chromosomal translocations— interaction of one microRNA with one of microRNA activities in mutations in genes that can be associated its target genes can produce a certain trait in organisms ranging with tumor initiation or progression—and mammals, in Science in February 2007. from flatworms and fruit flies to mice then linked them to microRNA regulation. “Because hundreds of human genes and humans. “Many That led her to single out the gene appear to be regulated by the let-7 microRNA, microRNAs have been Hmga2, which is defective in a wide range of we were concerned that we might not see conserved for hundreds of millions of years tumors. She then analyzed whether a muta- any difference when we changed only one of evolution,” Bartel tion in that gene could disrupt a microRNA’s of these target genes,” says Bartel. “Seeing notes. “We have so ability to regulate it. the difference encourages us to explore the much more to learn about the biological As she had predicted, it turned out that a biological importance of other examples of consequences of mutation to the non-protein-coding portion microRNA regulation.” microRNA regulation.” of the gene could be critical. She found clear “I hope to identify other ways for can- evidence, both in human cell cultures and in cer cells to escape microRNA regulation,” y mice, that the let-7 microRNA is involved in says Mayr, “using my unconventional
l d / gra regulating Hmga2. approach of starting with the appearance of In fact, disrupting let-7’s ability to repress a tumor and tracing it back to a particular furna Hmga2 leads to tumor creation. microRNA.” 8 Research stories Whitehead 2007
Chaperoning cancer Chaperone proteins are specialized mol- ecules that help other proteins in a cell to perform their functions. All proteins need Unveiling the role of heat shock to acquire and maintain the correct three- regulators may lead to a new class dimensional shapes to perform properly. If of cancer drugs a protein does not have the correct shape, it cannot do its job. The chaperones help Ten years ago, a young scientist climbed onto proteins fold into the correct shape, prevent a shuttle van from a New York City airport proteins from clumping together and escort to a conference at Cold Spring Harbor on damaged or malformed proteins to the cellu- Long Island. On the 30-mile trip, he chatted lar version of a recycling center. Heat shock with another passenger, Whitehead Member proteins are specific chaperone proteins that Susan Lindquist. perform these three vital roles under nor- “I was an assistant professor at the Uni- mal conditions and especially when a cell is versity of Arizona, and she was one of the stressed by heat, cold, toxins or other hard- speakers at the conference, but we were both ships that cause proteins to misfold. working on chaperone proteins,” recalls At the time, Lindquist was using model Luke Whitesell, now a senior research sci- organisms such as fruit flies and yeast to entist in Lindquist’s group. study how chaperone proteins work and
Min Hsf1+/+ Hsf1-/- After being stimulated with growth factors, mouse cells lacking the heat shock protein 0 HSF1 (on the right) showed less activation of a pathway that often contributes to 10 the abnormal growth of cancers, indicated by much less bright green signal than seen in cells with HSF1. 30
60
90
120 Research stories 9 www.whitehead.mit.edu
1 isms to survive. They decided to see how mouse cells that could produce normal amounts of HS90 and other chaperones, but lacked the HSF1 regulator, would deal with the introduction of another cancer-causing gene called H-RAS. Strikingly, cell cultures without HSF1 did not show any evidence of being trans- formed into cancer cells, while otherwise identical cells with normal HSF1 developed cancer-like clumps of cells. That encouraged another researcher, postdoctoral fellow Chengkai Dai, to con- how their function affected cells. As a pediat- tinue the research after Whitesell returned 1 “HSF1 could provide ric oncologist, Whitesell was more interested to Arizona. a uniquely effective in a new and intriguing anticancer target, Dai’s work with mice gave dramatic sup- target for the which had been identified as the chaperone port to the earlier cell culture work. Publish- discovery of broadly active anticancer protein heat shock protein 90 (HSP90). ing in Cell in September 2007, Dai showed agents,” says Susan Ironically, HSP90 can be too good at its that eliminating HSF1 protected the mice Lindquist. chaperone job. In some cases, mutated ver- from cancerous tumors. sions of proteins trick HSP90 into helping “HSF1 plays a dual role,” Dai says. “It them. has been shown that HSF1 is involved in One of these deviants is the cancer- protecting against neurodegeneration, in causing protein v-SRC. Without help which brain cells die slowly over time. In from HSP90, v-SRC is a long, useless cancer, the opposite is true: cancer cells don’t protein string. But instead of shuttling die. Ironically, cancer cells hijack and exploit v-SRC off to be recycled, HSP90 mistakenly this evolutionarily conserved self-protective coddles v-SRC and folds it into its mature, function of HSF1.” In fact, he says, cancer cancerous form. cells appear much more sensitive than nor- Several years after their initial con- mal cells to the loss of HSF1 function. versation on Long Island, Whitesell took “It will be interesting to see how the a six-month sabbatical from his lab at the insights gained from studies such as this one University of Arizona in Tucson to work in can be applied to develop useful therapeu- the Lindquist lab on the master regulator of tics,” says Whitesell, who is now back in the all heat shock proteins, called heat shock Lindquist lab. factor 1 (HSF1). “We propose that HSF1 could provide By then, Lindquist and Whitesell knew a uniquely effective target for the discovery that organisms need increased heat shock pro- of broadly active anticancer agents,” adds tein levels to survive in all but ideal environ- Lindquist. “It might be possible to target ments and to fend off protein-accumulating cells with altered signal pathways or metab- diseases, like Alzheimer’s or Parkinson’s. olism using entirely new therapeutics based But enough of these chaperones could be on this response.” expressed without HSF1 to allow the organ- 10 Research stories Whitehead 2007
Reprogrammed for a cure Early in 2007, researchers in the Jaenisch lab grew this A new form of stem cells gets its first proof-in-principle for therapeutic use healthy mouse from an embryo containing The race was on. success, creating headlines worldwide.) induced pluripotent When Jacob Hanna joined the lab of Hanna, who had just finished his MD cells (adult cells that had been Whitehead Member Rudolf Jaenisch in and PhD at the University of Jerusalem, reprogrammed to an March 2007, his co-workers already had instead raced ahead on a follow-up project. embryonic state). learned how to create “induced pluripotent He would combine the powerful new tech- stem” (IPS) cells in mice. nique with existing methods of reprogram- First made by Shinya Yamanaka’s lab at ming DNA in vitro to show, in principle, Tokyo University the year before, IPS cells that IPS cells could act therapeutically. are created by taking adult cells and, with- The target disease was sickle-cell ane- out using an egg, turning them back into mia, a blood disease that afflicts more than cells that seem to act just like embryonic 70,000 in the U.S. Researchers have long stem cells, including the ability to generate known the cause of the disease—the muta- almost any type of cell. tion of a single nucleotide in a key gene for Researchers in the Jaenisch lab, and making the hemoglobin protein—but there their counterparts in the labs of Yamanaka is no cure. and Harvard’s Konrad Hochedlinger (a Jae- There is, however, a mouse model of
nisch-lab alum) were working furiously to the disease, developed by the laboratory of gden
extend Yamanaka’s results with mice. (A few Tim Townes of the University of Alabama at sam o months later in June, all three would report Birmingham, that incorporates the defective Research stories 11 www.whitehead.mit.edu human version of that hemoglobin gene. Fixing sickle-cell anemia To create the IPS cells, Hanna started with cells from the skin of the diseased mice. Skin cells from a mouse modeling the blood disease were reprogrammed He modified these cells by a standard lab to an embryonic state, genetically corrected, grown into blood stem cells technique employing retroviruses custom- and then transplanted back into the mouse. ized to insert genes into the cell’s DNA. The inserted genes were Oct4, Sox2, Klf4 and Mouse with c-Myc, known to act together as master sickle cell anemia regulators to keep cells in an embryonic- Transplant stem-cell-like state. IPS cells were selected Collect skin cells based on their structure and then verified to express genes specific to embryonic stem cells. The potentially cancer-causing c-Myc blood stem cells gene then was removed by genetic manipula- tion from the IPS cells. Next, with help from Whitehead Fel- low Fernando Camargo, Hanna followed a well-established protocol for differentiat- Genetically Recovered mouse corrected IPS cells ing embryonic stem cells into precursors of Oct4, Sox2 bone marrow adult stem cells, which can be Klf4, c-Myc Reprogram retroviruses transplanted into mice to generate normal into ES-like IPS cells blood cells. Correct mutation He and his colleagues created such pre- cursor cells from the sickle-cell anemia IPS Genetically identical cells, replaced the defective blood-produc- IPS cells tion gene in the precursor cells with a nor- mal gene and injected the resulting cells back into the diseased mice. Then Hanna sent off the blood of treated Moving toward medicine mice for tests on standard hospital analytical equipment. While the work in induced pluripotent stem (IPS) cells has Good news: The results showed that the created tremendous excitement, researchers caution that major disease was corrected, with measurements of challenges must be overcome before medical applications for IPS blood and kidney functions similar to those cells can be considered, starting with a better method of gene of normal mice. manipulation for generating the cells. “Retroviruses can disrupt When these results appeared in Science genes that should not be disrupted or activate genes that should in December, they sparked great interest in not be activated,” with dangerous results, Jacob Hanna notes. the sickle-cell anemia community. Also, “we wouldn’t have known anything about IPS cells if we And Hanna already was moving ahead hadn’t worked with embryonic stem cells,” emphasizes Rudolf in another race in IPS research—working Jaenisch. “For the foreseeable future, embryonic stem cells will 17-hour days this time to reprogram white remain the crucial assessment tool for measuring the therapeutic blood cells. potential of IPS cells.” 12 Principal investigators Whitehead 2007
Whitehead Members > The Institute is fully inde- pendent, but its Members also are faculty members at Massachusetts Institute of Principal Technology. I nvestigators Whitehead Institute is home to 23 principal investigators (16 Members and 7 Fellows) and more than 300 postdoctoral fellows, graduate and undergraduate students, visiting scientists and technicians from around the world. Principal investigators 13 www.whitehead.mit.edu
# “quote here”
whitehead member
David Bartel implicated in human cancers. In some types “Over the last several of cancer cells the gene is mutated such years we’ve that the microRNA can no longer recognize discovered hundreds Focus of research and regulate the gene. This is the first of microRNAs in The Bartel lab studies the role that tiny demonstration that losing the microRNA mammalian cells snippets of RNA called microRNAs play regulation of a cancer gene helps a normal and we’ve developed in gene regulation. Researchers examine cell turn into a cancer cell. “Seeing the effect ways of accurately microRNA activity in plants, the flatworm C. of changing this single gene so that it no predicting which elegans, fruit flies, mice and human cells. In longer responds to the microRNA encourages genes the microRNAs 2005, Bartel’s lab showed that microRNAs us to explore the biological importance of are targeting for affect the expression or evolution of the other examples of microRNA regulation,” plants as well as majority of human genes. Scientists want to says Bartel. animals.” better understand how microRNAs recognize — Davi d Bartel their target genes, how these protein-coding Current trends in this field (center) gene targets are regulated and the biological Growth in such studies has been explosive. consequences that ensue when that The first microRNA was described in 1993, regulation fails. (See story, page 6.) the second in 2000. Several labs, including the Bartel lab, have found hundreds of Recent scientific accomplishments genes that produce microRNAs in fruit flies, In 2007, Bartel’s lab showed that a worms, flowering plants and other species, microRNA directly regulates a specific gene with more than 400 found in humans. 14 Principal investigators Whitehead 2007
whitehead member
Recent scientific accomplishments “It is my hope that Iain Cheeseman Cheeseman is noted for discovering multiple within five to ten new kinetochore proteins within yeast, C. years, we will have Focus of research elegans and human cells. He has focused a more detailed The Cheeseman lab investigates the role of particularly on the proteins that are required understanding of the kinetochore, a group of proteins required to generate connections with spindle microtu- kinetochore proteins for cell division and chromosome segregation. bules. He recently demonstrated a critical and during disease This core network of proteins facilitates the direct role for a protein complex called Ndc80 progression. There are attachment of chromosomes to microtubule in directly associating with microtubules. multiple tantalizing polymers—the spindle structures that attach correlations between to the ends of cells, pulling and dividing them Current trends in this field these proteins and during cell division. The kinetochore is critical “When I began graduate school, there were cancer, and this to ensuring duplication without loss or 10 total known kinetochore proteins,” says has the potential to damage to the genetic material. Researchers Cheeseman. “Now there are about 80. It’s provide information also are investigating the activities of the estimated that there are about 100 of these about tumor formation individual molecular machines that make proteins in human cells. We are working to and progression up this structure and how these proteins are identify the remaining kinetochore proteins which may lead to controlled and regulated. and their functions.” improved means of diagnosis and treatment for cancer.” — iain cheeseman Principal investigators 15 www.whitehead.mit.edu
whitehead member
recognize and respond to a particular form of Gerald Fink sugar contained on the surface of pathogenic fungi. Another is ongoing work, in conjunction Focus of research with the lab of MIT Institute Professor Robert Fink is best known for building the molecular Langer, to develop ways to coat or embed tools for analyzing simple genomes such antifungal antibiotics in prostheses as that of yeast. His lab studies infectious or catheters. disease—both the pathogen and the recognition system for the pathogen. “The Current trends in this field immune system recognizes the pathogen by “We’re seeing enormous technical advances the skin of the pathogen, the cell surface,” in gene sequencing and in gene expression says Fink. “We’re very interested in finding studies, but integrating the results into the signature molecules that say, ‘I’m a biological functions is still a major challenge,” fungus.’ And then in studying the receptors says Fink. “The theoretical issues have not on the immune system that recognize those been fully understood.” and tell the rest of the immune system that the infection is a fungal infection.” “There are moments of clarity that make us think we really understand something, and next moment, a sense of confusion and a recognition that we Recent scientific accomplishments don’t really understand as much as we thought. For experimental science, One was to demonstrate that neutrophils (the that’s an exciting situation. For problem-solvers, it truly couldn’t be better.” most prevalent kind of white blood cells) can — gerald fink 16 Principal investigators Whitehead 2007
whitehead member
without using an egg. In December, the lab “These are probably Rudolf Jaenisch followed up by further manipulating IPS cells the most exciting to successfully treat sickle-cell anemia in times in research Focus of research mice, the first proof in principle of therapeutic that I have had, “What makes a given cell a given cell—what applications of such cells. (See story, because advances makes a liver cell a liver cell versus a brain page 10.) in stem cell research cell versus an embryonic cell?” asks Jaenisch. have suddenly “We want to understand this in molecular Current trends in this field opened up so many terms, and we are using this information to Discoveries about IPS cells have tremendously possibilities for convert one cell type to the other. We want accelerated research in embryonic stem cells. studying really to understand that whole process and “This method has substantial implications important biological eventually to directly convert one adult cell for studying human diseases and treating questions that we to another without going through the detour human diseases,” says Jaenisch. “It can, in never could before. of embryonic cells.” principle, yield us embryonic stem cells from That’s absolutely specific patients, so those cells have all the fantastic. And clearly Recent scientific accomplishments genetic alterations that are probably causing this has direct rel- In June 2007 the Jaenisch lab was one of the disease. This would allow you to transfer evance to disease.” three worldwide that reported successfully complex genetic human disease into the Petri — ru dolf jaenisch taking cells from mice tails and turning them dish and study it. That could be the first step (left) into “induced pluripotent stem” (IPS) cells to analyze and to define a therapy.” that appear identical to embryonic stem cells, Principal investigators 17 www.whitehead.mit.edu
whitehead member
Recent scientific accomplishments Eric Lander Achievements include developing a method for creating whole-genome maps of the state Focus of research of DNA packaging and applying it to discover Lander and colleagues have pioneered the new forms of genetic regulation of key mapping and sequencing of the human developmental genes. genome; cataloging the vast majority of genetic variation in the human population; Current trends in this field and developing the methods to map complex “The past year has seen an explosion in diseases. “We remain stubbornly interested understanding the genes underlying in trying to understand all of the functional complex diseases,” Lander notes. information encoded in the human genome— including protein-coding genes, noncoding RNAs, regulatory elements and variants “I could not imagine doing anything in the world responsible for disease-susceptibility,” that is more satisfying than being involved in he says. human genomic research.” — eric lander ad institute o maria nemchuk / br 18 Principal investigators Whitehead 2007
whitehead member
Susan Lindquist scientists don’t understand many of the most fundamental mechanisms of how prions form, replicate and cross from one Focus of research species to another. Through studying non- The Lindquist lab investigates the mechanisms toxic yeast prions, scientists in the Lindquist of protein folding and the consequences of lab discovered small but critical regions misfolding, in research that moves back and within prions that determine much of their forth between simple and complex organisms behavior. Also in 2007, the lab reported that (yeast, fruit flies, plants, mice and human a certain transcription factor (a protein binds cells). Researchers are exploiting the to specific areas of the genome and acts to understanding of protein folding to gain switch genes on and off) aids in handling insights into neurodegenerative illnesses stresses but facilitates the survival of cancer and other diseases. The lab also has cells. (See story, page 8.) identified potentially important beneficial effects of self-perpetuating alternate protein Current trends in this field “There is, somehow or other, tremendous conformations, including evolutionary “This was once considered an abstruse and satisfaction in getting change and long-term memory. arcane subject but it is now clear that protein something to work folding and problems in protein folding are that everyone else Recent scientific accomplishments of central interest in virtually all areas of thought was crazy.” Although the infectious proteins called biology, from evolution to inheritance to prions have received a great deal of scrutiny, human disease,” says Lindquist. — susan lindquist Principal investigators 19 www.whitehead.mit.edu
whitehead member “Gerald Fink, Rudolf Recent scientific accomplishment Jaenisch, Robert Harvey Lodish Over a number of years, the lab has discovered Weinberg and I a way to multiply mouse and human blood have been working Focus of research stem cells 30-fold, an expansion that offers together at Whitehead for 25 years. It’s The Lodish lab investigates hematopoietic tremendous promise for treatments such as very rare among stem cells—cells in the bone marrow that bone marrow transplants and perhaps even institutions that the give rise to all red and white blood cells— gene therapy. “The ability to extend human Founding Members focusing on identifying the hormones that cord blood stem cells in culture could lead are actually still cause these cells to divide and make more to many clinical applications, increasing the collaborating and stem cells. Researchers also are studying efficiency of bone marrow transplantation enjoying each other’s the function of individual microRNAs in the for a number of diseases,” says Lodish. company. Now that’s development and function of fat cells, muscle an achievement!” cells and hematopoietic cells, in collaboration Current trends in this field with Whitehead Member David Bartel and “If we open the most recent edition of our — harvey lodish (second from left) other colleagues. Additionally, other scientists Molecular Cell Biology textbook, of which I are analyzing red blood cell formation and am an author, we can see that 90 percent studying adiponectin, a hormone made by of it was unknown 30 years ago,” remarks fat cells that controls fatty acid and glucose Lodish. “Every four years we completely metabolism. change 30 or 40 percent of the content of the book.” 20 Principal investigators Whitehead 2007
whitehead member
Paul Matsudaira of a cell moving in three dimensions, over- coming the limits of two-dimensional models that ignore obstacles in the cell’s way. Focus of research The Matsudaira lab studies the more complex Current trends in this field aspects of how cells move: how cells move in “Biomechanics is one of the emerging areas three dimensions and how ensembles of cells in cell biology, and it’s in a lot of the papers move together. you see at the subcellular and cellular levels,” says Matsudaira. “Now we’re down at the Recent scientific accomplishments level of how a cell generates force, or how In 2007, researchers in the lab and their molecular assemblies within a cell generate colleagues created the first fluorescent force. The challenges are so new that you sensor that measures the forces involved in have to develop the techniques in order to cell movement. Previously, researchers who ask the questions.” wanted to know how much force is exerted when cells travel needed to place the cells on an instrument that bends or flexes and then calculate the force. In contrast, the fluorescent sensor simply changes colors to show how “People typically think of how a cell works in terms of chemistry. much force is applied. In other recent work, But mechanics is just as vital. Everything in life is about movement. scientists developed a computational model If it doesn’t move, it’s probably dead.” — paul matsudaira (second from right) Principal investigators 21 www.whitehead.mit.edu
whitehead member
Terry Orr-Weaver replication at specific sites in the DNA. “Gene discovery is This has allowed researchers to decipher one of the most mechanisms governing the initiation of important post- Focus of research replication and to uncover a link between genomic fields of The Orr-Weaver lab discovers genes and proteins needed for transcription and gene research. It’s a crucial proteins crucial for cell division, focusing expression and the process of DNA replication. area of biology—to on genes and proteins important for DNA They have identified direct functions in the find out what all replication in the mother cell as well as those process of initiation of DNA replication for of these unknown critical for the division of chromosomes several proteins affected in cancer cells. genes do.” between the daughter cells. She uses the — terry orr-weaver fruit fly, which her work has shown is a Current trends in this field (center) powerful model for cell division in humans. The interface between the fields of develop- mental biology and the cell cycle has become Recent scientific accomplishments accessible as discoveries in each field have One of the most difficult aspects of studying identified key regulatory genes. This makes DNA replication is finding a way to visualize it possible to now determine how cell cycle and isolate the sites at which DNA replication regulators are subjected to developmental starts. The Orr-Weaver lab has exploited signals and how control of cell division affects particular biological contexts in the fruit fly cell differentiation into distinct cell types. that permit the scientists to analyze DNA 22 Principal investigators Whitehead 2007
whitehead member
Recent scientific accomplishments “The change David Page The Page lab found that one gene (Stra8) in thinking is needed to trigger germ cells to develop about the Y Focus of research into eggs or sperm. “Understanding the chromosome Mammalian females are born with all of their embryonic foundations of human fertility at caused by our eggs, but males can produce sperm only a molecular level is our biggest contribution research is very after puberty; the difference between the in the past year,” says Page. gratifying.” female and male embryonic development is — Davi d page practically unknown. Some researchers in Current trends in this field (center) the Page lab are deciphering at a molecular Reproductive biology was transformed fairly level how mammalian germ cells can develop late by the DNA revolution, and some areas into eggs in a female or sperm precursors in of the field are still quite sleepy, says Page, males. Other lab members are sequencing whose lab’s biggest overall contribution the Y chromosome of the chimpanzee, which “has been to bring intellectual respect to may give us new insight into the evolution the Y chromosome and to put it on the and role of the human Y chromosome. The lab map.” However, reproductive genetics and also is working on the genetic basis for male development make up an extremely dynamic infertility, which is often due to deletions in field that touches on many inherently the Y chromosome. controversial areas, including cloning and stem cell research. Principal investigators 23 www.whitehead.mit.edu
# “quote here”
whitehead member “Oftentimes, the makes it easier to add tags more precisely to use of viruses has Hidde Ploegh selected proteins. Additionally, researchers been very helpful solved the complex structure of a recently to illustrate aspects Focus of research discovered protein that is found in a wide of basic biology. For example, from our Looking at the devious methods that viruses range of herpes viruses and that may be a line of research in use to sidestep our immune responses, good target for drug development. herpes viruses stems the Ploegh lab is learning about how the a whole series of immune system functions at the cellular and Current trends in this field experiments that molecular levels. Lab members are also using Ploegh believes that progress in biology in concern protein chemistry to create new tools that more general drives progress forward in all parts quality control in precisely track protein movement in a cell. of the field. For example, certain methods to general, not The work will advance many aspects of knock down gene expression that were not necessarily within cellular research. possible 10 years ago have had a ripple effect the context of a virus on how research is conducted throughout infection, but of a Recent scientific accomplishments all of biology. “Therefore, my area of biology normal, cell biological Researchers have created a new way of marches in lockstep with the rest of biology,” principle.” attaching “tags” to proteins in the cell. These says Ploegh. — hi dde ploegh tags are small molecules that glow or add (left) color to a protein, allowing concentrations of the protein to be seen. The new method 24 Principal investigators Whitehead 2007
whitehead member
polarity in the tissues of most if not all Peter Reddien animals,” says Reddien.
Focus of research Current trends in this field Reddien investigates how the flatworm Planaria were a classic model for studying planarian Schmidtea mediterranea uses stem regeneration but had not been employed cells called neoblasts to regenerate new much in the molecular genetic era. “This heads, new tails or entire new organisms requires all sorts of innovation and trouble- from a tiny fragment of its body. Developing shooting in the lab,” says Reddien. “That’s RNA interference strategies for exploring part of the excitement.” He believes the gene function, his lab has helped establish biggest payoff will be in understanding the planaria as a viable and powerful molecular basic biology of stem cells and the general system for studying regeneration. principles of regeneration—not just in planaria but in most or all multicellular animals. Recent scientific accomplishments The lab found that the gene Smed-beta- catenin-1 is crucial in determining whether “Early in college I took a required biology class and realized that with planaria, when cut, will produce a head or a little bit of knowledge you could ask questions that were lacking in answers and were at the forefront of current research.” tail at a particular site. “Based upon obser- vations, we hypothesized that Smed-beta- — peter reddien (center) catenin-1 processes specify head-to-toe Principal investigators 25 www.whitehead.mit.edu
whitehead member “I’m proud of having the mammalian target of rapamycin (mTOR), good people in my lab and seeing them David Sabatini which senses information about the environ- succeed after they’ve ment to regulate cell growth—and turns out left Whitehead. Focus of research to be a master regulator of many fundamental Mentoring people is The Sabatini lab focuses on the mechanisms cell processes. “One of the biggest contribu- the most satisfying that regulate cell growth–controlling organ tions has been understanding the pieces of part of my career.” size, body size and even the size of different this pathway and showing that their function units within the cell. “Some of the pathways matters for diseases, in particular cancer,” — Davi d sabatini (center) that control size also are involved in diseases Sabatini says. and are important pathways for targeting cancer therapy,” Sabatini notes. To study Current trends in this field these growth pathways, he adds, “we had to The pace of these studies is dramatically invent some new technologies, which took accelerating due to new technologies including on a life of their own.” These tools include high-throughput RNA interference screens genome RNA interference libraries, high- and more sensitive mass spectrometry. Also, throughput cell-based microarrays and there has been an influx of researchers cell-analysis imaging software. studying these growth systems because of their correlation to disease. “The field has Recent scientific accomplishments become more competitive, but I’m happy The most important achievements have been because it’s generated a lot more interest,” in investigating the growth pathway called he says. 26 Principal investigators Whitehead 2007
whitehead member
these fish indicate that sfpq is necessary ”We started a new Hazel Sive for normal brain development in zebrafish field—brain and possibly other vertebrates. Additionally, morphogenesis— Focus of research using the frog model, the Sive lab described and we’re literally Looking at development in zebrafish and development of the “primary mouth”, the first rewriting the frogs, the Sive lab is deciphering how the opening between the outside and the gut of textbooks.” brain develops into its specific structure, how the embryo, that is found in all multicellular — hazel sive the very front of an animal develops organs animals and is essential for eating. (right) associated with the face, and which genes may underlie certain birth defects and Current trends in this field neurodevelopmental disorders. In the last five years, Sive and her lab have changed the way researchers look at brain Recent scientific accomplishments development. As she explains, the vertebrate Researchers documented how early brain brain starts as part of a hollow tube. structure develops, using the zebrafish as Researchers have devoted much effort to ask a model, with an emphasis on the brain how the tube forms, but no one has asked ventricular system, a kind of circulatory system why the nervous system needs to be a tube. deep within the brain. They showed that a Sive lab members hypothesize that the fluid mutation in one gene (sfpq) caused abnormal contained in the tube, the cerebrospinal fluid, midbrain and hindbrain development in is essential for normal brain development. zebrafish embryos. The problems noted in Principal investigators 27 www.whitehead.mit.edu
whitehead member
evidence that some breast cancer cells recruit Robert Weinberg normal adult stem cells from the bone marrow and force them to secrete a protein that Focus of research fosters cancer cell movement and invasion. How does cancer spread? How do epithelial Additionally, the lab demonstrated that a and stromal cells, the two primary types of single microRNA can directly regulate a gene cells found in mammalian tissue, interact in implicated in human cancers. tumors? And what’s the role of cancer stem “The conceptual cells, which may fuel the ability of many Current trends in this field foundation of cancer solid tumors to renew and spread? These are When Weinberg founded his lab 30 years ago, biology is now laid. among the questions being tackled by the “the disease of cancer was quite a mystery,” I think that almost Weinberg lab. he says. “We didn’t understand what it was, everything we believe and why cancer cells misbehaved and why now will remain true Recent scientific accomplishments tumors behaved the way they do. And now 10, 20 or 30 years In 2007, researchers in the Weinberg lab the great majority of the details have come from now. We will created a line of cancer stem cells that could into view. It’s much more founded on a build on it, but future aid breast cancer research. After being coherent logical structure rather just than discoveries will not injected with just 100 of these cells, mice a hodgepodge collection of phenomena.” obviate or nullify what develop tumors that metastasize. In another we now believe.” line of research, scientists found compelling — ro bert weinberg (left) 28 Principal investigators Whitehead 2007
whitehead member
Recent scientific accomplishments “In very innovative, Richard Young “Just within the last several years we’ve challenging areas, succeeded in creating maps of the core like trying to map Focus of research regulatory circuitry of human embryonic stem the human genome’s The Young lab is mapping the regulatory cells,” says Young. In 2005 and 2006, his regulatory circuitry, circuitry that controls cell state and differ- lab and collaborators discovered how key even incremental entiation. This is an extraordinarily complex transcription factors (proteins that act as new understanding undertaking—scanning the genomes of our master regulators for gene expression) give can have a major cells with sophisticated new technologies embryonic stem cells their unique attributes. impact across many and discovering how close to 20,000 genes scientific fields.” are coordinately controlled. Many human Current trends in this field — richar d young diseases, ranging from autoimmune condi- “This is an important new biological frontier (center) tions to obesity and cancer, are caused by that wasn’t a part of the research landscape defects in this regulatory system. One of the half a decade ago, because we didn’t have lab’s goals is to map the regulatory circuitry the key technologies to map how regulators of both healthy and diseased cells, and to control our genomes,” says Young. “Mapping use this information to reprogram cells for circuitry in embryonic stem cells and induced regenerative medicine, which offers hope that pluripotent stem cells is at the frontier of one day we could use an individual’s own regenerative medicine.” healthy cells to replace damaged or diseased cells and tissues. Principal investigators 29 www.whitehead.mit.edu
Whitehead Fellows
> Whitehead Fellows are young researchers who skip the postdoctoral stage of their training and are given the space and resources to run their own labs and pursue independent research, whitehead fellow without teaching Thijn Brummelkamp responsibilities.
Thijn Brummelkamp focuses on cancer research. He uses functional genetic approaches, such as RNA interference screens, to identify genes that affect the growth and survival of cancer cells and how they respond to therapeutics. More recently he became interested in the links among organ size, stem cells and cancer. Together with Whitehead Fellow Fernando Camargo, he showed that all can be affected by the YAP1 gene. When the gene was over-expressed for 30 days in mice, liver size quadrupled. Brummelkamp and his colleagues also have found that YAP1 is normally expressed in the stem cell compartment of the intestine and that activation of YAP1 leads to expansion of undifferentiated progenitor cells. Because YAP1 expression has such important effects, the Brummelkamp lab now is figuring out how and where in the body it is turned on and off. 30 Principal investigators Whitehead 2007
whitehead fellow whitehead fellow
Fernando Camargo Hui Ge
In molecular terms, how do blood cells and immune cells Around the world, researchers are probing how thousands develop? Fernando Camargo and his colleagues study of genes and their proteins interact during embryonic hematopoietic stem cells—the cells found in bone marrow development in the tiny worm C. elegans. Like early that give rise to mature blood cells. The lab is working explorers of a distant continent, the scientists report to identify genes that are crucial in blood stem cell back the information they uncover. Hui Ge acts like a renewal and differentiation and that also are involved in cartographer, compiling millions of snippets of the development of leukemia and lymphoma. Recently, information from the C. elegans explorers and using his lab identified a microRNA critically involved in the computational methods to map how all of the gene regulation of immune responses, which may lead to the information fits together with the protein information. development of more targeted therapies for cancers. To check the accuracy of her map, the Ge lab predicts Additionally, in collaboration with the Brummelkamp lab, how a protein or gene will act in a certain situation Camargo is studying the Hippo signaling pathway, which and then tests the prediction in live worms. This work regulates the size and growth of organs and tissues, and illuminates many previously unknown relationships influences cell regeneration and possibly cancer. between numerous proteins and genes. Principal investigators 31 www.whitehead.mit.edu
whitehead fellow whitehead fellow
Andreas Hochwagen Kate Rubins
Broken chromosomes are a hallmark of cancer progression The Rubins lab targets poxviruses, a class that includes and a variety of genetic diseases. Under some develop- smallpox, monkeypox, cowpox and vaccinia (the virus mental circumstances, however, tightly controlled break from which the classic smallpox vaccine is developed). formation in chromosomes is beneficial for the organism. Probing the strategies that these viruses employ to side- For example, during meiosis, the cell division that creates step and weaken host defenses, Rubins seeks insights eggs and sperm in humans, chromosome breaks serve about their mechanisms of pathogenesis as well as the to ensure proper chromosome transmission and increase mysterious processes of immunity they highlight. Her genetic diversity in the offspring. In 2007, the Hochwagen work investigating these pathogens balances basic lab lab developed a new method to precisely locate the sites science and clinically oriented biomedical research. In of meiotic chromosome break formation using yeast as one project, she conducts field studies of monkeypox in a model organism. The resulting break profiles provided the Democratic Republic of Congo. She also analyzes fundamental new insights into the transmission of small tissue culture models of vaccinia and works with U.S. chromosomes and showed that chromosome ends serve Army researchers to develop therapies for victims of as key regulators of this process. These findings have the Ebola virus. gden important implications for our understanding of Down syndrome, which is caused by incorrect meiotic transmission of chromosome 21. rubins : sam o 32 Principal investigators Whitehead 2007
whitehead fellow whitehead fellow
Paul Wiggins Defne Yarar
Paul Wiggins is in search of elegance, more specifically Without actin, you would be a puddle on the floor. an elegant and quantitative explanation for how gene Dynamic networks of this protein provide structure for expression is affected by the structure of chromatin your cells and allow them to move and divide. They also (the complex of DNA and protein that makes up play a key role in endocytosis—a process in which the chromosomes) and the conformation of chromosomes. cell membrane folds inward, engulfing materials from To encapsulate the human genome into the nucleus, outside the cell. Endocytosis is an important mechanism the cell tightly condenses its two meters of DNA into for the basic business of cells, including the uptake of a package tens of microns across. This dramatic nutrients, immune system function and cell regulation. condensation of the genome appears to be intimately However, endocytosis also can be subverted by pathogens connected to gene expression. Combining data describing for entry into the cell. Problems with endocytosis can the chromatin structure and the physical and genomic result in diseases such as familial hypercholesterolemia position of genes, Wiggins expects to find a few basic and certain cancers. Analyzing how actin networks rules that can predict the role of chromatin structure in perform in this process, Yarar hopes to better understand gene regulation and chromatin condensation. this fundamental pathway that allows the cell to take arar : justin knight up many kinds of nutrients and to participate in certain forms of cell regulation. gdeny ; wiggins : sam o 25th anniversary 33 www.whitehead.mit.edu
1 Celebrating Whitehead’s silver anniversary
When Edwin C. “Jack” Whitehead decided to 1 On a rainy March found a biomedical research institution, he afternoon in front of 9 Cambridge wanted this to be an act of “enlightened phi- Center, confetti lanthropy” that would start with an entirely cannons help the open mind about the institution’s goals and Institute staff kick off the birthday structure. celebrations. Jack Whitehead’s decade-long quest 2 Senator Edward ended triumphantly in 1982. Partnered with 2 Nobel laureate David Baltimore and many Kennedy, Governor Deval Patrick, Vic- other allies, he launched Whitehead Institute toria Kennedy and as an independent institution focused on David Page chat basic biomedical research and formed with at the Whitehead silver anniversary a unique teaching affiliation with MIT. gala, which was In 2007, Whitehead Institute celebrated held at the Boston its 25th birthday with events for scientists, Museum of Fine Arts in November. staff and friends. Notably, 120 of the Institute’s clos- 3 At the 25th Anniver- 3 est friends attended the 25th Anniversary sary Colloquium, Board of Associates Colloquium in Novem- Whitehead Mem- ber Harvey Lodish ber. Attendees enjoyed presentations by all (second from left) Whitehead Directors past and present, a discussed “Bio- keynote address on cancer by Whitehead pharmaceutical Companies of the Member Robert Weinberg, and informal sci- Future” with BOA entific salons with many Institute scientists members Barry and distinguished colleagues. Berkowitz, Ansbert Gadicke and Don Additionally, special projects commem- Hetzel. orated the Institute’s history, including an 4 anniversary website and an exhibit at the 4 You can find remi- MIT Museum. niscences about philanthropist extraordinaire Jack Whitehead at www.wi.mit.edu/ about/25th, along with a video about his Institute’s creation. justin knight 34 Whitehead news Whitehead 2007
New members join Board versity, and he holds a PhD in molecular biology from the University of California Three longtime members of the Whitehead at Berkeley. Hecht serves on the Leadership Board of Associates joined the Whitehead Council for the David H. Koch Institute for Board of Directors in 2007. Integrated Cancer Research at MIT. Arthur W. Brill, an attorney with Rob- David H. Koch is an executive vice presi- erts and Holland, LLP, joined the White- dent and a board member of Koch Indus- head Board of Directors in March. Brill was tries, Inc., which owns a diverse group of heavily involved in the initial formation and companies with more than $90 billion in organization of Whitehead Institute, and he revenues, 80,000 employees, and a presence represented the family and estate of Jack in nearly 60 countries. Koch also is chairman Whitehead for more than 25 years. He has of the board and chief executive officer of served as Secretary of the Whitehead Cor- Koch Chemical Technology Group, LLC, a poration since 1981 and will continue in wholly owned subsidiary of Koch Industries. that role. Koch is an extraordinary philanthropist who Peter M. Hecht, chief executive officer of has made significant gifts to a wide variety Ironwood Pharmaceuticals, Inc. (formerly of organizations and programs that further Microbia) was elected to the Board in June. cancer research, enhance medical centers Co-founding the company in 1998, Hecht and support educational institutions, as well has assembled and integrated the compa- as to programs that sustain arts and cultural ny’s growing team of industry-leading “drug institutions. He is the prime contributor to hunters,” raised $231 million and driven the the David H. Koch Institute for Integrative execution of the company’s strategy. Prior to Cancer Research at MIT, where he earned founding the firm, Hecht was a postdoctoral BS and MS degrees in chemical engineering. researcher in the lab of Whitehead Member Koch was named to the Board in December Gerald Fink. He earned a BS in mathematics 2007 and began active service in 2008. and an MS in biology from Stanford Uni-
Senior administrators appointed
Martin A. Mullins started as vice Mullins, an Irish native, held positions Patricia F. Denn has joined president at Whitehead Institute in at Eli Lilly & Co. and at the Irish Whitehead as director of development. August. In that position, he is government’s Industrial Development Denn has had 23 years of development responsible for running the Institute’s Agency. He holds a BS and an MS experience, first as director of exter- administration. in biochemistry from University nal relations at the Fletcher School Previously, Mullins held the posi- College Cork. of Law and Diplomacy at Tufts tions of vice president of technology Marianne Howard was promoted University and then as director licensing at Georgetown University; to the new position of associate of foundation relations/principal associate vice president for licensing vice president for administration. In foundation gifts at Northeastern at Case Western Reserve University; her new role, Howard has assumed University. She also taught writing and senior licensing manager and line management responsibility for and literature at several colleges and interim director of the Office of Tech- information technology, environment universities. Denn received an AB in nology Licensing & Industry Spon- health and safety, physical plant and American literature from Brown sored Research at Harvard Medical the library. She also retains her posi- University and an MA in English from School. Prior to moving to the U.S., tion as director of human resources. the University of California at Irvine. Whitehead news 35 www.whitehead.mit.edu
Landon and Lavinia Clay are sponsor- ing the work of Hidde Ploegh and other Whitehead researchers
is Gerald Fink, a Whitehead Found- ing Member. “Margaret and Herman Sokol were enormously supportive of Whitehead from the very first days,” comments Whitehead Director David Page. “This extraordinarily generous gift will allow further progress in the basic research that was so important to them.” Liliana and Hillel Bachrach have pledged $1 million to fund stem cell research at Whitehead. In recogni- tion of this gift, the Liliana and Hillel Bachrach Stem Cell Bank at White- Positive results for philanthropic gifts head Institute has been permanently designated. The fund will support Whitehead Institute benefited lows Program, which will fund three novel research in the Whitehead immensely from generous private postdoctoral researchers per year Human Embryonic Stem Cell Facility donations from longtime Board of over a three-year period, working in to isolate and propagate new embry- Associates members in 2007. the Ploegh lab and potentially with onic stem cell lines from donated Landon T. Clay, founder and collaborating labs. The Clay Fel- surplus in vitro fertilization embryos managing member of East Hill Man- lows Program will enable postdocs and from adult cells reprogrammed agement, and his wife, Lavinia, gave to develop as independent research- to be pluripotent stem cells. Liliana $10 million to establish the endowed ers while also contributing to the Bachrach is a member of the White- Clay Laboratory Fund and the Clay advancement of the principal inves- head Board of Associates Executive Chair, which currently is support- tigator’s work. Committee, the Development Com- ing the lab and the professorship of Under a $4 million bequest from mittee of the Board of Directors Whitehead Member Hidde Ploegh. the estate of Margaret Sokol, White- and Whitehead’s Stem Cell Working The gift is the largest to the Institute head Institute established its first Group. Hillel Bachrach is managing since its founding. endowed chair, the Margaret and partner of 20/20 Health Care Part- The Clays also gave $1 million Herman Sokol Chair in Biomedical ners, LLC. this year to establish the Clay Fel- Research. The first holder of the chair
Whitehead’s 9 Cambridge Center 9CC renovations building is always being reconfigured to support research. But during the 25th anniversary year of 2007, the building’s lobbies and the McGovern Auditorium were remodeled, and previously stored pieces of art from the Institute’s collection were put on display for all to enjoy. 36 Public outreach Whitehead 2007
Explaining biology at the cutting edge
One of Whitehead Institute’s core missions is to share the understanding of biomedi- cal research with other scientists, students, teachers and the public. 1 In March, the Whitehead/Museum of Science public lecture series drew hundreds of attendees to hear three talks by Whitehead Members about evolution’s cornerstone role in biomedical research. The Whitehead drama fest, a public event featuring films and skits about biology 2 plus artists talking about their creations that address scientific themes, debuted in April. Also that month, 140 students attended the high school student lecture series, learn- ing how researchers are unraveling the molecular mysteries of cancer. The event 3 included laboratory tours and lunches with young Whitehead researchers. In October, the annual scientific sym- posium, on “Regeneration in Biology and Medicine,” drew about 1,000 registrants. Speakers from Whitehead and other research organizations presented overviews of cutting-edge work in stem cells and tissue regeneration. Throughout the academic year, the high school teacher lecture program brought in biology high school and community college educators to hear world-class investigators 1 At the Whitehead 2 Duke University’s 3 Whitehead Mem- talk on “The Awesome Power of Genetics.” scientific sympo- Kenneth Poss, ber Peter Reddien The BiologyWeek newsletter (biolo- sium, MIT Institute right, another describes progress gyweek.wi.mit.edu) alerted the local bio- Professor and symposium in understanding Whitehead Board speaker, chats how planarian medical research community to scientific Member Robert about zebrafish worms regenerate presentations throughout Greater Boston. Langer discusses regeneration after they have And Whitehead spread news worldwide innovations in over lunch with been chopped up. tissue engineering. postdocs. about research advances via its external website (www.whitehead.mit.edu) and Paradigm magazine. justin knight Public outreach 37 www.whitehead.mit.edu
4
4 Postdoc Jennifer 5 Young Whitehead Gutzman displays researchers (on the some of the left) partner with zebrafish whose high school biology brain development teachers throughout is studied in the academic year. Whitehead Member Hazel Sive’s lab.
5 38 Financial summary Whitehead 2007
Revenues and support (in millions)
2007
34% Federal research...... $24.3 Financial summary 17% Whitehead Institute’s commitment to Non-federal...... $12.0 best-in-class research remains unwavering, research even in the face of a challenging federal funding environment. Drawing upon its 20% own endowment and the generous Gifts and...... $14.6 support of individuals, corporations and other revenue foundations, the Institute has been able to keep pace with the rapidly escalating costs associated with maintaining—and 29% WIBR support ...... $20.7 defining—the state of the art. Institute administration is now focusing on streamlining operations, helping to ensure that a larger proportion of every dollar will directly support Whitehead science. The future for Whitehead research is Expenditures and disbursement (in millions) extraordinarily bright, firmly supported by the Institute’s solid financial foundation. Going forward, major efforts, such as the recently launched Stem Cell and 2007 Regenerative Biology Initiative, will be underwritten by a mix of new partnerships, 53% additional funding sources and the kind Research...... $35.7 of resourcefulness that has long been a Whitehead hallmark. 36% General & ...... $24.8 administrative
11% Capitalized ...... $7.6 plant & other Financial summary 39 www.whitehead.mit.edu
2006 2005
36% 40% Federal research...... $26.6 Federal research...... $26.5
14% 12% Non-federal...... $10.4 Non-federal...... $8.1 research research
20% 23% Gifts and...... $14.5 Gifts and...... $15.2 other revenue other revenue
30% 25% WIBR support ...... $21.8 WIBR support ...... $16.6
2006 2005
53% 44% Research...... $34.4 Research...... $29.2
39% 38% General & ...... $25.4 General & ...... $24.8 administrative administrative
8% 18% Capitalized ...... $5.3 Capitalized ...... $11.5 plant & other plant & other 40 Leadership Whitehead 2007
Leadership
Board of Directors Director Alexander V. d’Arbeloff David C. Page Arthur W. Brill John K. Castle* Whitehead Members Landon T. Clay David Bartel Charles D. Ellis (Chair) Iain Cheeseman Faculty and Fellows Peter M. Hecht Gerald R. Fink Whitehead principal investigators are world- Barbara Imperiali Rudolf Jaenisch class scientists working at the frontiers of Peter S. Kim Eric S. Lander biological research. Under the Institute’s Robert S. Langer Susan L. Lindquist close affiliation with Massachusetts Institute David C. Page Harvey F. Lodish of Technology, Whitehead Members also are Ellen S. Polaner Paul T. Matsudaira members of MIT’s biology department or Phillip A. Sharp Terry L. Orr-Weaver other MIT departments. John J. Whitehead Hidde Ploegh The Whitehead Fellows program allows Peter J. Whitehead Peter Reddien exceptionally talented young scientists to Susan E. Whitehead (Vice Chair) David Sabatini set up independent research programs Hazel L. Sive without undertaking normal faculty duties. Norman Hascoe Robert A. Weinberg (Emeritus, deceased) Richard A. Young Faculty honors Paul Joskow (Emeritus) Affiliate Member: David Gifford Whitehead faculty includes the recipient Patrick J. McGovern (Emeritus) of the 1997 National Medal of Science Abraham J. Siegel (Emeritus) Whitehead Fellows (Weinberg), eight members of the National Robert J. Silbey (Emeritus) Thijn Brummelkamp Academy of Sciences (Fink, Jaenisch, Lander, Lindquist, Lodish, Orr- Weaver, * Term expired 2007 Fernando Camargo Hui Ge Page and Weinberg), seven fellows of the American Academy of Arts and Sciences Officers of the Corporation Andreas Hochwagen (Fink, Jaenisch, Lander, Lindquist, Lodish, Charles D. Ellis, Board Chair Kate Rubins Ploegh and Weinberg) and three Howard Susan E. Whitehead, Paul Wiggins Hughes Medical Institute investigators Board Vice Chair Defne Yarar (Special Fellow) (Bartel, Lindquist and Page). David C. Page, President
Martin A. Mullins, Vice President Vice President editor director John Travia, Treasurer Martin A. Mullins Eric Bender Matt Fearer Arthur W. Brill, Secretary associate editors Office of Ceal Capistrano Associate Vice President Communications Cristin Carr and Public Affairs Board of Advisory Scientists for Administration Nicole Giese Whitehead Institute for Elaine Fuchs Marianne Howard principal photographer Biomedical Research John Soares Andrew Murray 9 Cambridge Center design consultant Cambridge, MA 02142 Board of Associates Daphne Preuss Mongeon: Projects, Inc. 617.258.5183 Eric Wieschaus Ellen S. Polaner, Chair www.whitehead.mit.edu Below: Taken by a deep-ultraviolet microscope, this image shows how the mass of nucleic acids is Whitehead Institute distributed in a mouse macrophage (a kind of immune cell). Image by 2007 Annual Report Benjamin Zeskind, Paul Matsudaira’s laboratory.
1 Director’s letter
3 Scientific highlights
6 Research stories
12 Principal investigators
33 25th anniversary
34 Whitehead news
Whitehead Institute for Biomedical Research 36 Public outreach is a nonprofit research and educational institution. Wholly independent in its 38 Financial summary governance, finances and research programs, Whitehead shares a teaching affiliation 40 Leadership with Massachusetts Institute of Technology (MIT). Whitehead brings together a small group of world-class biomedical researchers in a highly collaborative and supportive environment and empowers them to pursue the questions that engage them most. Whitehead Institute for Biomedical Research 9 Cambridge Center on the cover: Studying how cells regulate Cambridge, MA 02142 their growth, David Sabatini’s laboratory 617.258.5000 has shown that Rag family proteins www.whitehead.mit.edu regulate the location of a key protein complex called mTORC1 in the presence of nutrients. Here, mTOR is marked in green, DNA in blue and the Rab7 protein in red. From left to right in the sequence here, as the cell is stimulated with amino acids, mTOR moves to be localized in a compartment near the nucleus. Sancak et al., “The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1”, Science (2008). Reprinted with permission from AAAS. At the 25th anniversary kickoff event, Founding Member Robert Weinberg debuts a time capsule that will store Whitehead artifacts.
2007 Annual Report
Non-Profit Org. US Postage Whitehead Institute for Biomedical Research PAID Nine Cambridge Center Cambridge, MA Cambridge, Massachusetts 02142-1479 Permit No. 56998