Genetics and your health. The Jackson Laboratory Annual Report 2009

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1 Genetics and your health The Jackson Laboratory Annual Report 2009

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3 Table of contents From the President and CEO: Genetics and your health...3 Departments JAX Mice & Services...5 Genetic Resource Science...6 Research...7 Education/Courses and Conferences...8 Advancement...9 Features Neurodegeneration...10 Genetic variability...14 Cancer...18 FY 2009 financial summary...22 Donors...26 Funding agencies/sponsors...33 Board of Trustees/Senior Management Team...34 Mission We discover the genetic basis for preventing, treating and curing human disease, and we enable research and education for the global biomedical community. Vision Our mouse models and genetics research lead the world to solutions for cancer and other complex and intractable diseases. Cover: Rebecca O Donnell (front) and family ride triumphantly to the Atlantic coast of Mount Desert Island, Maine, at the conclusion of a 4,400-mile, cross-country bike trip. Rebecca has type 1 diabetes, and the journey named Rebecca s Ride raised awareness for the disease as well as thousands of dollars for type 1 diabetes research at The Jackson Laboratory. Joining Rebecca are her mother Deb, a facilities engineer at the Laboratory, brother James and father Mike. 1

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5 Genetics and your health C.C. Little founded The Jackson Laboratory on the then bold idea of investigating the genetic basis of cancer. Study the genetics and you learn about cancer. Little was right. The Laboratory s genetic research is now contributing both to understanding how to stay healthy and what happens when we develop disorders such as cancer, diabetes, Alzheimer s and heart disease. Our own genomes hold many keys to our health. Now that we can sequence them, we can begin to decode them. Piece by piece, we are learning how our genetic variability influences many things about us, including how we respond to drugs and how susceptible we are to different diseases. This information holds huge promise for improving medical care. Only a short time ago, decoding genomes was impossible and assessing susceptibilities to disease hopelessly complex. Much remains to be done, but personalized medicine care that treats everyone based on their unique individual genomes is already gaining a foothold in medical practice, with more clinical applications on the way. The Laboratory s role, as always, is one of providing answers to important basic questions. Where do we look first in our genomes to address our most serious diseases? How can we model human genetic diversity in drug testing and preclinical trials? How do we unravel the complexity of genetic disease networks? The research into these and many other questions will help enable this exciting new era of medicine in which the treatment of patients is more precise, predictive and personal. Richard P. Woychik, Ph.D. President and CEO 3

6 Visitors queue up for guided tours of the new JAX West facility in Sacramento, Calif., on May 6, 2009.

7 Francine Kaufman, M.D., addresses the crowd at the JAX West Grand Opening. JMS GRS Research Education/Courses Advancement New, expanded JAX West facility opens The Jackson Laboratory has expanded its footprint in California, home to the world s greatest concentration of biomedical researchers. The newly renovated, 85,000-square-foot facility in Sacramento is twice the size of JAX West s previous space in West Sacramento. The grand opening and an accompanying symposium took place on May 5-6, The West Coast biomedical research community is an exciting community, and we re becoming a bigger part of it, notes Jackson President and CEO Richard Woychik, Ph.D. Jackson scientists have developed unparalleled expertise in monitoring mouse models for a wide range of physiological characteristics, including disease symptoms. The new JAX West space will enable more extensive in vivo service offerings, including cancer and stem cell research collaborations. The in vivo approach promotes better understanding of human disease processes, says Jackson Vice President and COO Charles Hewett, Ph.D., and enables the development of new treatments. JAX Mice & Services offers outstanding quality and efficiency For biomedical researchers, working with large mouse populations can be an expensive logistical nightmare. For example, I-Ming Wang, Ph.D., of Merck Research Laboratory, needed to work with mice to identify gene networks involved with inflammation. Enter the In Vivo Services group from The Jackson Laboratory. Wang used the group to maintain the mouse populations and gather data according to an agreed-upon study design and timeline. The result, what Wang characterizes as an inflammatome, identified a set of genes that plays a key role in inflammation-related diseases. It s hoped that the discoveries will reveal new targets for treating diseases associated with inflammation, such as asthma, atherosclerosis, rheumatoid arthritis and others. We were very pleased with JAX s efficiency, speed, on-time delivery and quality of the samples collected, says Wang. It was a very pleasant experience to work with the highly professional staff. 5

8 JMS GRS Research Education/Courses Advancement Michael J. Fox Foundation supports the Laboratory to improve Parkinson s disease research The Jackson Laboratory s Parkinson s Disease Mouse Model Repository is teaming with the Michael J. Fox Foundation (MJFF) to expand the selection of specialized mouse models useful for Parkinson s disease research. Parkinson s disease is a chronic degenerative disease of the brain characterized by impaired motor skills and speech. The root cause is damage to cells in the brain that produce dopamine, which is essential to the muscles ability to function smoothly. While available therapies improve symptoms, none stop disease progression. MJFF funding will allow the Laboratory s repository to import and characterize new mouse models that will be made available to the Parkinson s disease research community. The mice will be used to discover the cellular mechanisms involved in the disease and to investigate how genetic factors interact with environmental factors, with an ultimate goal of developing improved treatments and perhaps a cure for Parkinson s disease. Cathy Lutz, Ph.D., works to improve SMA research. The Laboratory provides essential resources for SMA breakthroughs The primary cause of spinal muscular atrophy (SMA), the most prevalent lethal genetic disease in young children, is a well-known mutation in a single gene, SMN1. Unfortunately, knowing the cause hasn t led to a simple cure. But The Jackson Laboratory, in an effort spearheaded by Genetic Resource Science Repository Assistant Director Cathy Lutz, Ph.D., is playing a vital role in research that offers tremendous hope for the future. 6 The Laboratory imports, develops and distributes mice that model SMA for research. Recent collaborations include work with Johns Hopkins University and Columbia University. Last year Lutz also began work on a project with the SMA Foundation with an important new mouse model capable of switching on the SMN1 gene at different developmental time points. Surprisingly, the disease in these mice could be reversed later after birth than originally anticipated, a very encouraging discovery for SMA children and their parents.

9 New faculty members Matthew Hibbs, Ph.D. (left), and Chengkai Dai, Ph.D. JMS GRS Research Education/Courses Advancement Two new principal investigators join the Laboratory Cancer researcher Chengkai Dai, Ph.D., and computational biologist Matthew Hibbs, Ph.D., joined The Jackson Laboratory faculty during the winter of Dai came to the Laboratory from a postdoctoral appointment at the Whitehead Institute for Biomedical Research. He studies heat shock proteins, which normally protect healthy cells from environmental stress. In cancer, however, their beneficial effect can backfire, protecting the cancer cells from the stress of growing and dividing very rapidly. Hibbs served as a postdoctoral research assistant at Princeton University prior to his arrival in Bar Harbor. Applying machine learning and artificial intelligence to available data, Hibbs seeks to predict the behavior of genes and proteins. The predictions can then be tested and help guide future experiments in the laboratory. In the end, says Hibbs, it s about finding ways to make these data more accessible and more useful to the biomedical research community. Research discoveries improve disease prospects Work by Jackson Laboratory researchers both past and present attracted notice in recent months. Professor Derry Roopenian, Ph.D., reported on how mice that normally develop lupus exhibited none of the symptoms of the disease when a particular immune protein was blocked (PNAS, January 2009). Adjunct Professor Shaoguang Li, M.D., Ph.D., discovered a pathway crucial to chronic myeloid leukemia and was able to prevent the disease in mice with a commonly used asthma drug (Nature Genetics, June 2009). And Professor David Harrison, Ph.D., led a group that demonstrated the first significant increase in mammalian life span using a pharmacological agent, in this case rapamycin, a drug used to suppress the immune response (Nature, July 2009). Finally, Professor Emeritus Douglas Coleman, Ph.D., whose work in the 1970s helped lay the groundwork for today s obesity and type 2 diabetes research, won the prestigious 2009 Shaw Prize. The prize is widely regarded as the Nobel of the East. 7

10 JMS GRS Research Education/Courses Advancement Joe Palca, Ph.D. (left), of NPR leads a discussion with symposium presenters. 50th Short Course and symposium 8 Personalized medicine. Genetics and health. While these have only recently become hot topics in laboratories, clinics and the media around the world, the concept of merging genetics with medicine has been the focus of attention in Bar Harbor, Maine, for two weeks every summer for 50 years. The landmark 50th Short Course on Medical and Experimental Mammalian Genetics was celebrated on July 31, 2009, with a daylong symposium looking to the future. Luminaries in the field including Nobel Laureates Richard Axel and Mario Capecchi, former National Institutes of Health Director Elias Zerhouni, Eric Lander, Rudolf Jaenisch, Janet Rowley and more provided insight into Biomedical Science and Medicine in the Next 50 Years. The agenda also included panel discussions on the future of genetics research and trends in policy and ethics moderated by Joe Palca, National Public Radio science correspondent. The Jackson Laboratory named one of the Best Places for postdocs The Jackson Laboratory garnered significant attention as a great place to work in the past year. Of particular note was The Scientist s March 2009 list of top institutions for postdoctoral associates, which ranked the Laboratory #2 in the United States. After completing their Ph.D.s, most scientists find a postdoctoral research position under the mentorship of a principal investigator, a kind of apprenticeship before setting up their own laboratories. Jackson postdocs participating in the survey cited training and mentoring and funding as the institution s greatest workplace strengths. The postdoc ranking came on the heels of another survey, Best Places to Work in Academia, which was presented in the November 2008 issue of The Scientist. The Laboratory ranked 19th overall among U.S. academic research institutions. Respondents cited job satisfaction and pay as the key workplace strengths.

11 Attendee Bob Moore chats with friends at the 2009 Discovery Day Awards Dinner. JMS GRS Research Education/Courses Advancement Gift offers $1 million challenge Launching the career of a young scientist with innovative ideas takes a lot of both time and money. Geneticist and author Weslie Janeway has made a significant contribution to the process at The Jackson Laboratory. Janeway made a challenge gift of $1 million to the Laboratory for the recruitment and support of new scientists working to understand the genetic basis of human disease. The challenge is for other donors to make $1 million in matching gifts, which will be used to help pay for faculty starting salaries, lab equipment and experiments. A secure funding base is necessary to attract outstanding researchers, Janeway, a member of the Laboratory s Board of Trustees, says. This represents the best possible investment in the future of The Jackson Laboratory and its work in the basic science that makes it possible to advance human health. JAX enews delivers monthly Laboratory highlights There has always been a lot going on at the Laboratory, but the pace of work is quickening and the scope of possibilities and capabilities is expanding in the genomic era. The near-constant buzz includes research discoveries, significant new funding, new collaborations, new faculty hires, and other events and highlights. Now there s a convenient, single-source way to keep up-todate: JAX enews. JAX enews delivers an overview of Laboratory happenings and progress via each month to subscribers. It doesn t replace the many press releases, journal articles and publications the Laboratory produces and broadcasts but instead highlights the top stories in a format that s simple and quick to read. To learn more about the work being done at the Laboratory and the amazing people who do it, visit and sign up for JAX enews. 9

12 Neurodegeneration Each of the estimated 1 trillion cells in the human body is genetically programmed to undertake a specific biomechanical task. Each cell is also programmed, sooner or later, to die. New, younger cells that perform the same task often replace dead cells. Researchers at The Jackson Laboratory are taking a hard look at why this natural progression sometimes goes wrong. Premature cell death is the mechanism underlying an array of neurological diseases, including glaucoma, Alzheimer s, Parkinson s, Huntington s and amyotrophic lateral sclerosis (ALS), which is more commonly known as Lou Gehrig s disease. Many of these and other less common but equally life-threatening diseases are rooted in the premature death of motor neurons, the brain cells that control voluntary and involuntary muscle movement. Motor neuron death is a part of aging, says Associate Professor Gregory Cox, Ph.D., whose research team is studying genetic susceptibility to ALS, an always-fatal disease that claims the lives of most who have it within five years of diagnosis. In ALS, motor neuron death is accelerated. When you age, you lose a motor neuron here and there, but you have hundreds and hundreds within a muscle, so, if you lose one, it s not that big a deal. You lose another one next year, still no big deal. But, with ALS, when you lose 50 at a time, and they all start dropping out, that s a very big deal. ALS researchers at The Jackson Laboratory and elsewhere have found that fewer than 10 percent of the 5,600 new ALS cases diagnosed in the United States each year can be directly attributed to family genetics. With at least 90 percent of ALS cases appearing to be random, this disease can potentially surface in anyone, Cox says. This disorder is so devastating, and our knowledge base is still so incomplete, that I m the first to admit that there are many more questions than answers. That is especially true with the sporadic cases. We re all still scratching our heads. We really don t know what triggers these sporadic cases or why an obscure group like an Italian soccer team of unrelated players would have huge susceptibility. We re hopeful that what we learn from the handful of genetic cases might apply to the sporadic cases, but that s a big might. We have no idea if it will or not, but it s the only handle we have. The mouse models for ALS created at The Jackson Laboratory are widely used in ongoing motor neuron disease research worldwide. They were engineered to include multiple copies of a mutated gene associated with some inherited ALS cases. With insights gleaned through in-house research and work at other labs, new ALS models are continuously under development. 10

13 Cox s ongoing research is enhanced through collaboration with other principal investigators. Through a Laboratory-wide study into the genetics of aging, these front-line researchers share their insights, techniques and technologies in exploring the complexities of motor neuron biomechanics and the roles they play in a wide range of diseases. Colleagues such as Assistant Professor Kevin Mills, Ph.D., are using carefully bred strains of mice to study the effects of aging on chromosome instability, chromosome susceptibility to DNA damage and the biomechanics of DNA repair. Professor Beverly Paigen, Ph.D. s, and her research team are using other strains to glean insight into the genetic basis of longevity. We are heavily involved in The Jackson Laboratory s institutional commitment to better understanding the genetics of aging, she says. We are surveying a large set of mouse model strains for differences in longevity. Every six months, we measure their health and well-being in a number of ways. Through this and many other projects in the 37 other laboratories within The Jackson Laboratory, we hope to gain insights into the genetic basis of longevity. A research team headed by Professor and Howard Hughes Medical Institute Investigator Simon John, Ph.D., is using genetics, genomics, cell biology and physiology to understand the fundamental biologic processes that cause disease, with a focus on how neurodegeneration contributes to glaucoma, which affects 70 million people worldwide. In glaucoma, retinal ganglion cell death and optic nerve degeneration lead to blindness, John says. Harmfully high intraocular pressure is an important contributing factor in many cases. The genetic factors that determine it and susceptibility to pressure-induced damage are largely unknown. Dr. Gregory Cox and Dr. Simon John 11

14 For 25 years, Professor Susan Ackerman, Ph.D., has been doing breakthrough research at The Jackson Laboratory into the basic mechanisms that underlie neurodegenerative disorders such as Alzheimer s and Parkinson s diseases. A Howard Hughes Medical Institute investigator, she has spent years working with a variety of mouse models that exhibit progressive movement problems, or ataxia, as they age, a symptom of impaired brain function. These mouse models are proving crucial to discoveries related to her ongoing efforts to better understand the molecular mechanisms that underlie the development and maintenance of motor neurons in the brain. These mice are proving essential to our research into the underlying neuron loss in the aging mammalian brain, she says. Ackerman s research team also is also using ataxic mouse models in studying the genetic basis for the formation of misfolded proteins that are common to many forms of neurodegenerative diseases. It is a signature process in Alzheimer s disease, clogging brain neurons with a toxic protein sludge that triggers cell death. Some of these misfolded proteins are due to mutations directly within disease-related proteins, which is common in some forms of inherited Alzheimer s disease, she says. The mechanisms underlying protein misfolding in Alzheimer s and many other neurodegenerative diseases remain unknown. We think that fully understanding this process could lead to treatment, to stopping or slowing the progression of neurodegenerative diseases in people that are caused by protein misfolding. We re seeing that the mechanisms underlying protein misfolding in Alzheimer s and many other neurodegenerative diseases remain unknown. 12 Dr. Susan Ackerman

15 Other ongoing research at The Jackson Laboratory is focusing on the mechanisms that underlie the formation and maintenance of neuronal circuits and connections. Associate Professor Robert Burgess, Ph.D., is overseeing a research team that is analyzing how nerve cells within the retina of the eye are interconnected, and how abnormal connections impact the normal circuitry of these cells. I m interested in how the nervous system wires itself up, and how the proper connections within circuits of the central nervous system are established and maintained, Burgess says. There are probably 50 different types of neurons in the retina, defined by differences in gene expression, and subsequently differences in function. Changing the way these cell types connect with each other changes the function of the circuit, just like rewiring the plugs and switches and light bulbs can change the function of an electrical circuit. What we are discovering about the mechanisms of circuit formation in the retina will certainly extrapolate to other parts of the brain. The research is a collaborative effort involving researchers at Massachusetts General Hospital, Northwestern University, University of Aberdeen (Scotland), University of Antwerp (Belgium), The Scripps Research Institute, and University of California research teams in Santa Barbara, Santa Cruz and Berkeley. Burgess fascination with neural wiring extends beyond the retina and the brain to the neuromuscular system. I m interested in the connections between motor neurons and muscles, the neuromuscular junction, as another example of a circuit connection. Understanding the normal state will likely contribute to better understanding of disease states that involve improper circuit formation in everything from neuromuscular diseases to autism, Down syndrome and schizophrenia. We are coming at this from a basic science point of view. What are the normal rules for wiring the nervous system? What my research team has already shown is that there s a lot left to learn. Dr. Robert Burgess 13

16 Genetic variability Human beings have almost infinite genetic variability. Our genomes, the 3 billion letters of DNA code that make us human, are very similar from person to person. Nonetheless, there are millions of small differences. These variations are why we have different eye color, hair color, height and so on. These variations make each one of us an individual. But what makes us unique also makes us difficult for our doctors to treat. We respond differently to drugs and other therapies indeed, what works great for one might actually harm someone else so the best medical care is not one size fits all. It s personalized for each of us based on our genetics. Progress in genome sequencing learning all the letters of our DNA is providing the tools needed to overcome this medical challenge. Learning our own complete sequence and understanding what it means is only part of the story, however. We need to test and verify drugs and treatments before we try them in patients. Enter The Jackson Laboratory. Through learning the complete genetic sequences of mice, it s becoming possible to effectively use them to model human genetic diversity. Traditional research involving a single inbred strain of mouse, in which all the individuals are genetically identical, uncovers genetic pathways and processes. Unfortunately, it often does not translate well to genetically diverse human populations. Just as the same drug or therapy can have different effects in different people, it can have different effects in different strains of mice. Carefully selecting multiple strains of mice allows researchers to observe different responses across the strains. When the mice have known genomic sequences, researchers can then analyze the different effects of the drugs and therapies and identify which genes contribute to them. So by the time they are tested in human patients, researchers and doctors have a much better idea of how they work and, of particular importance, who should try them and who should not. 14 Dr. Kenneth Paigen

17 The Jackson Laboratory is at the forefront of these efforts, with work by the Center for Genome Dynamics of particular note. The Laboratory, led by Professor Kenneth Paigen, Ph.D., contributed significantly to a recent paper reporting success in screening for genetic susceptibility to liver toxicity from acetaminophen. Professor Gary Churchill, Ph.D., is spearheading the production of a more comprehensive genetic diversity tool using inbred strains of mice, dubbed the Collaborative Cross, which promises to provide a powerful tool for gene discovery and systems genetics inquiries. Churchill is also developing a robust system of outbred (genetically diverse) mice to mimic the genetic population of humans for research. A patient s response to medication or his or her susceptibility to disease is determined by genetics, and each patient will respond differently due to his or her unique genetic makeup, says Research Programs Manager Imogen Hurley, Ph.D., of the Center for Genome Dynamics. As the Laboratory s researchers examine a wider range of mouse strains, as in the acetaminophen study, or strains that contain a greater depth of genetic variation, like the Collaborative Cross, the mice they study more accurately reflect the genetic diversity seen in humans. For the acetaminophen experiment, David Threadgill, Ph.D., of the University of North Carolina at Chapel Hill, Paigen and their collaborators employed inbred mice. But instead of a single strain, which is analogous to testing a drug in a single individual over and over again, they used three dozen strains. Furthermore, they selected the strains to represent the widest possible genetic diversity. The advantage of using inbred mice is that in any one strain, all the mice are uniform, says Paigen. But if we go across an array of strains in this case we used over 30 and they re picked to represent the maximum amount of diversity that we know about in mouse populations, then we can mimic that very, very broad range of genetic variation that humans have, and we can do it in a reproducible way. So that s really the power of this system. For their test compound they used one of the most familiar drugs on the market, acetaminophen, commonly sold under the brand name Tylenol. Despite its over-the-counter convenience and presence on the shelf of practically every store that sells medications, acetaminophen carries a risk of liver toxicity for certain people. And sure enough, the researchers found a wide variation in acetaminophen toxicity between their mouse strains. Using data about known genetic differences between the strains, they were able to identify the genes that played a significant role in the variable responses. 15

18 Of course, the key to using mice effectively in this role is being able to translate the results to human patients. The experiment succeeded in this regard as well. Variations in the equivalent of one of the mouse genes identified, called CD44 in humans, proved to be an important marker of sensitivity to liver toxicity in two groups of human subjects. Identifying such markers allows patients to be screened to assess potential for both efficacy and adverse side effects before a drug is actually administered. Modeling human genetic diversity is also vital to understanding complex diseases involving multiple genes and gene-gene interactions. But better tools are needed to study these complex traits and diseases. The Collaborative Cross arose from an idea first proposed at a conference eight years ago, when forward-thinking researchers, including Gary Churchill, saw that the single-strain, single-gene focus of mammalian genetics research needed to be expanded in the post-genomic era. I was worried that mouse genetics would fall behind, says Churchill. Human disease studies were providing a picture of genetic causality that wasn t simple or linear. Mice provide the best experimental system, but even here at The Jackson Laboratory, with access to the richest mouse resources in the world, what we had to work with was inadequate for complex disease studies involving many genes. The first step was to select eight primary strains of mice, all of which were obtained from The Jackson Laboratory. From the original eight, careful breeding would yield hundreds of genetically diverse, yet precisely characterized inbred strains. The effort is ongoing, and Churchill expects to have several hundred strains available within the next three to five years. The Collaborative Cross promises to be an exceptional resource, allowing researchers to map genes quickly to small regions of the genome based on differences between the carefully characterized strains. Still, Churchill and some colleagues were concerned with some limitations encountered when using inbred strains to model human genetic diversity. So last year, to further But with high-throughput genetic tools, we can completely sequence the progenitor strains and track exactly what the resulting mouse population is made of. And, unlike human studies, we can control the environment. 16

19 solidify mouse genetics as a crucial component of biomedical research into the future, they developed a new initiative, the diversity outcross mouse project. Churchill hopes it will be ready in about a year, but a pilot project is already being launched, and outside cancer and toxicology researchers have registered strong interest. It s a new way of thinking at the Laboratory, to move away from inbred strains, says Churchill. But with high-throughput genetic tools, we can completely sequence the progenitor strains and track exactly what the resulting mouse population is made of. And, unlike human studies, we can control the environment. Modeling genetic diversity is complex and arduous. The potential impact on clinical care is tremendous, however. It will allow for far more efficient and effective preclinical drug and treatment trials. Lowoccurrence side effects and their genetic components will be characterized, making clinical trials much safer. Efficacy will be better measured across a wide sample, allowing for drugs and treatments to be targeted to those who can benefit the most. And genetic markers will be readily identified, making it possible to develop genetic screening protocols for human patients. In the end, bringing better drugs and treatments to patients will be faster, safer and more efficient. Dr. Gary Churchill and Dr. Imogen Hurley 17

20 Cancer Cancer. It s still synonymous with dread, and for good reason. About half of all American men and a third of the women will receive a diagnosis of cancer during their lives. And nearly half of those diagnosed will die of the disease. Researchers at The Jackson Laboratory have amassed many insights into the biomolecular complexities of human cancers over the years. What they ve learned is now driving strategies for controlling the explosive cell growth that is common to all forms of human cancer. Established as a cancer research center in 1929, the Laboratory was designated a National Cancer Institute Cancer Center in Through aggressive recruiting, it has recently increased the cadre of cancer researchers on its scientific staff. Today, many of the Laboratory s 38 principal investigators are examining cancer in a variety of ways and are on the front lines of cancer research. Of course, the researchers can t perform their experiments in humans, so they work with mice to learn the complexities of cancer. With genetics that are 95 percent identical to the genetics of humans, mice are the ideal model for exploring ways to prevent, control and cure human cancers. And part of the challenge embraced by Laboratory scientists is finding ever-better ways to work with mice and translate research results into medical progress. Among researchers exciting new tools is a mouse model genetically engineered in Bar Harbor to host living cancer cells once found only in humans. Professor Leonard Shultz, Ph.D., and his research team spent years engineering what s known to colleagues as Lenny s mouse. 18 Dr. Kevin Mills

21 Because its immune system has been altered, the mouse can tolerate a variety of human cells blood, immune, cancer, etc. This allows researchers to experiment with human cells in new ways and to have the results contribute much more directly to human medicine. This humanized mouse provides insights into living human biology that aren t otherwise possible, Shultz says. The challenge was creating a mouse model with an immune system that was not so robust that it would reject human tissue and cells and not so weak that it offered the mouse insufficient protection from infection and premature death. With both a low immunity and a relatively long life span of more than 90 weeks, this strain allows the long-term efficacy, as well as safety, of different therapies to be determined. Lenny s mouse also plays a key role in a recently opened cancer services laboratory at the Sacramento, Calif., facility. The cancer services laboratory provides research services to both academic and commercial researchers to speed the development of cancer therapeutic treatments. Using human tumor samples and humanized mice, researchers can explore which therapeutic approaches will be most effective for a particular human tumor and why. In Bar Harbor, many of the Laboratory s principal investigators explore different aspects of the biomolecular mechanics of cancer cells and tumor formation. Much of its ongoing cancer research involves the cooperative efforts of motivated faculty such as Professor Carol Bult, Ph.D., Assistant Professor Casey Fox, Ph.D., Assistant Professor Kevin Mills, Ph.D., Assistant Professor Lindsay Shopland, Ph.D., and Assistant Professor Kyuson Yun, Ph.D. This cancer research brain trust continued to grow this past year with the addition of Assistant Professor Richard Maser, Ph.D., and Assistant Professor Chengkai Dai, M.D., Ph.D. Dr. Carol Bult 19

22 Collectively, their work is helping to explain how and why human cancers are so variable and difficult to treat, focusing on two separate perspectives. First, how does the structure and variation within our genomes determine our individual susceptibility to cancer? Mills and Shopland address the physical nature of our genomes and how it can contribute to cancer onset. Second, what mechanisms drive cancer initiation and progression, and what can be done to disrupt those mechanisms? Modern cancer research is extending its focus beyond specific organ systems brain cancer, lung cancer, liver cancer, etc. to a detailed understanding of the molecular anatomy, physiology and biochemistry of cancer as a genetic disease. Such understanding is essential to developing therapies that address cancers based on specific tumor characteristics, not where in the body they might arise. Jackson researchers are approaching the problem from many perspectives. Dai and Fox are looking at particular cellular pathways that cancer cells use to proliferate and might offer therapeutic targets. Maser investigates how the ends of chromosomes, called telomeres, can contribute to both cancer and normal aging. (Note: The Nobel Prize in Physiology or Medicine was recently awarded to three researchers for their work with telomeres.) Bult is Dai and Fox are looking at particular cellular pathways that cancer cells use to proliferate and might offer therapeutic targets. 20 Dr. Chengkai Dai

23 investigating how the genetics of normal development differs from that of cancer initiation in lung tissue. And Yun researches a special kind of cancer cell called a cancer stem cell that is now implicated in the ability of many cancers to recur following initial treatment. Discoveries that lead to genetics-based, personalized clinical therapies are especially critical in cancer research and care. Expanding our knowledge and improving the ability to tailor therapies to specific tumors and individuals will allow for better diagnoses, safer and more effective approaches to prescribing drugs, and targeted treatments. For example, on average, any given prescription drug now on the market works for only half of those who take it. Among cancer patients, the rate of effectiveness is only 25 percent. Understanding the myriad cancer pathways and the genetics behind them lays the groundwork for more effective and personalized cancer therapy. The emergence of personalized medicine is of particular importance for cancer patients. A recent pilot study demonstrated that treatments designed around an individual s genetic profile already improve prognoses for patients whose cancers had spread and stopped responding to their previous drug regimens. A Jackson Laboratory research report published in June in the journal Nature Genetics points the way to new genetic approaches to addressing cancers. The researchers identified a gene involved with the inflammatory response that could hold the key to treating or even preventing chronic myeloid leukemia, a lethal cancer. They reported that the gene, Alox 5, is vital to the development and maintenance of cancer stem cells slowdividing cells thought to generate and maintain a variety of cancers, including leukemia. What s more, the group found that the gene s activity could be squelched using an asthma medication already on the market. Discoveries like this will make patient-by-patient, genome-based assessments an essential component of cancer treatment. Testing for specific mutations will supersede the historical trial-anderror paradigm that increases costs and delays effective disease management. But cancer is a complex foe, and there is far more to learn. Research at The Jackson Laboratory will contribute to better outcomes for cancer patients in the future. Dr. Casey Fox and Dr. Lindsay Shopland 21

24 FY 2009 financial summary Statement of Activity Revenue and Expenses (in millions) FY 2009 FY 2008 Operating Revenue Government Support Private Gifts and Grants JAX Mice & Services Other Revenue Subtotal Operating Revenue Operating Expenses* Research JAX Mice & Services Training and Education Institutional Support Subtotal Operating Expenses Increase in Net Assets From Operating Activities Non-Operating Financial Support (Expense) Construction Grants Contributions for Plant and Endowment Long-Term Investments Return, Net of Amount Utilized (21.3) (0.3) Realized and Unrealized Loss on Interest Rate Swaps (3.3) (5.9) Expenses Related to Curtailment of Post-Retirement Plan (2.8) Changes in Actuarial Assumptions Related to Retirement Benefit Plans (3.1) (0.9) Increase (Decrease) in Net Assets From Non-Operating Activities (26.4) (7.9) Increase (Decrease) in Net Assets (25.0) (6.2) *Please note the program operating expenses for FY 2008 have been reclassified to be consistent with the FY 2009 allocation basis. 22

25 Operating Revenue FY % 1.3% JAX Mice & Services Government Support 32.7% Private Gifts and Grants Other Revenue 6.6% Operating Expenses FY % JAX Mice & Services 2.5% Research Institutional Support 38.2% 20.2% Training and Education 23

26 FY 2009 financial summary Statement of Financial Position FY 2009 FY 2008 Assets Land, Buildings and Equipment (Net) Current Assets Other Assets Funds Held by Bond Trustee Endowment Fund Contributions Receivable Total Assets Liabilities and Fund Balances Current Liabilities Bonds Payable, Net Fund Balances Total Liabilities and Fund Balances The Jackson Laboratory receives operating revenue from several sources including public sector support in the form of federal grants, private sector support in the form of private foundation grants and philanthropic contributions, and resource revenue in the form of cost and fees collected for JAX Mice & Services. Federal grants are typically awarded competitively for multiple years and cover direct costs and a portion of indirect costs for research and education efforts. State grants are typically restricted to purchasing equipment or supporting efforts to expand research. Other operating revenue includes conference fees, interest income, endowment income dedicated to operating costs and miscellaneous fees. 2. The Laboratory s operating expense is shown by major program and shared services costs. Direct personnel, facility, scientific services, animal health and other direct costs are shown under the program costs. Indirect costs of services that support all of the programs such as administrative support, Human Resources, Information Technology, Advancement and Fiscal Services are shown as institutional support costs. 3. Non-operating activity includes grants and gifts restricted to construction costs or endowment, earnings on the endowment above the amount stipulated to be used to support research and education each year, unrealized changes in the value of interest rate hedges, and non-recurring costs. 24

27 (in millions) Operating Revenue Operating Expense 0 FY2005 FY2006 FY2007 FY2008 FY Value of the Endowment (in millions) FY2005 FY2006 FY2007 FY2008 FY

28 Donors $1,000,000 Lifetime Contributors Anonymous Weslie R. Janeway Mr. and Mrs. Winthrop Knowlton Daniel R. and Sheryl C. Tishman Donors June 1, 2008-May 31, 2009 National Council Members June 1, 2008-May 31, 2009 The National Council is The Jackson Laboratory s most influential group of friends, supporters and advocates. National Council members are those individuals who give most generously, $1,000 per year or more. The National Council works to expand the reach of The Jackson Laboratory, carrying the message of hope to current and future supporters. Leading the Search Club $250,000+ Mr. and Mrs. Walter M. Cabot Mrs. William H. Janeway Roscoe B. Jackson Club $25,000+ Anonymous (3) Mr. Robert Alvine* Richard and Susan Bingham Joseph M. Cohen* Anthony B. Evnin, Ph.D., and Judith P. Evnin James Fitzgerald, LEED AP Mr. Peter F. Gerrity* Mr. Richard J. Mack Tom P. Maniatis, Ph.D.* Pam and David Moser Mr. and Mrs. Scott Relf Mr.* and Mrs. Daniel R. Tishman Mr.* Brian F. Wruble and Ms. Kathleen W. Bratton Clarence C. Little Club $10,000+ Dr. and Mrs. Noubar Afeyan Mr. and Mrs. Paul M. Anderson Bob Beck* David* and Susan Cabot John K. Castle Mr. Charles I. Clough Jr. Joette and John Cook Mr. and Mrs. Alvin Dworman Ross Dworman* The Honorable and Mrs. Stephen Evans-Freke Mr. George J. Gillespie III* Mr. Richard Grace Mr.* and Mrs. Richard S. Gurin The Harwood*/Leeson Family Peter M. Hecht, Ph.D. Abigail M. Hirschhorn 82* and Mr. Andreas Beroutsos Mr. Leo A. Holt* Mr.* and Mrs. Edwin T. Johnson Ed and Ann Kania Kate and Rick* Lannamann Mr. Dwight E. Lee* Martin L. Leibowitz, Ph.D. Mrs. Louis C. Madeira Dr. and Mrs. Leslie C. Norins Mr. and Mrs. Steven Roth Mr.* and Mrs. William M. Rudolf Edward* and Marthann Samek Mr.* and Mrs. Leonard Shaykin Christine and Brian* Sherwin Dr. Willys K. Silvers 49, 50* Donald* 71 and Antje Stern Mary Sulzer Mr. Donald Sussman Mr. S. Tucker Taft 69* Ms. Pamela M. Thye* Tom* and Beth Volpe Mr. and Mrs. William R. Wister, Jr. Benefactor $5,000+ Anonymous (1) Mr.* and Mrs. Robert Adelman Mr. and Mrs. Robert M. Bass Helena and Peter Bienstock Ms. Catherine Dickey Brown Martin and Helen Chooljian Mr. and Mrs. Peter O. Crisp Ms. Lizabeth B. Cronenberg Dr. Luke B. Evnin and Ms. Deann K. Wright Mrs. Ruth M. Gerrity Mr. and Mrs. David R. Hathaway Stewart J. Hen, M.B.A. Mrs. Gerry H. Hodes Dr. Bob Holtzman 56 Richard W. Jackson Stefanie S. Jeffrey, M.D. 69 Mrs. Christine Kiernan Samantha Knowlton, M.D.* Mr. Sam R. Little* Mr. and Mrs. Ted H. McCourtney Jr. Mr. Edward M. Miller John T. Potts, Jr., M.D.* Mr. and Mrs. Sanford R. Robertson Mr. David Rockefeller Dr. and Mrs. Richard G. Rockefeller Mr. and Mrs. Alan B. Rummelsburg Mr. and Mrs. Winthrop A. Short Peter Skaperdas* Mrs. Ann H. Symington Ms. Rosalind Whitehead Janice and Rick* Woychik 26

29 Donors Friend $1,000+ Anonymous (4) Dr. Karen Artzt Mr. and Mrs. David J. Backer Mr. Robert L. Barbanell Mrs. Lydia Barnes Mr. Thomas Barry Mr. Richard M. Bass and Ms. Linda Grossman Joanne and Paul Bean Cathy and Stan Bernstein Mr. C. Graham Berwind, Jr. Robert S. Birch Mrs. William M. Blackwell Edward McC. Blair Mr. and Mrs. James C. Blair Ms. Juanita Blumberg Mr. Jeremiah M. Bogert Sr. Mr. Garen G. Bohlin Mr. and Mrs. Earle K. Borman Jr. Mr. and Mrs. Earle K. Borman III Mr. and Mrs. Nathaniel R. Bowditch Madeleine and Bob Braun Mrs. Jennifer Brooker Mr. Michael C. Brooks Pamela Brown 71 Mrs. Alan G. Carr Cheryl M. Coffin, M.D. 74 and Ralph E. Topham Doug Coleman Mr. and Mrs. Tristram C. Colket Jr. Mary S. Consalvi and Dr. Anthony F. Alario Mr. J. Taylor Crandall Mrs. Edith LaC. Dabney Ms. Josephine Detmer Charley and Rogie Dickey Mrs. Elizabeth H. Dickinson G. Morris Dorrance, Jr. Alexandra and William Dove Mr. and Mrs. Wolcott B. Dunham, Jr. Mr. and Mrs. Robert J. Easton Dr. William L. Elkins 51 Dr. and Mrs. Ervin H. Epstein Mrs. Albert P. Everts Jr. Don and Diane Fischer Martha and Robert Forrester Mr. Colin J. Foster Mr. and Mrs. William G. Foulke Jr. Jean L. Fourcroy, M.D., Ph.D., M.P.H. Marta Frank and Robert Frank Hope L. and John L. Furth Howard and Sue Goldman Mr. and Mrs. Jay S. Goldsmith John R. and Kiendl Dauphinot Gordon Paul Greengard, Ph.D. Mr. Andrew F. Gurley Denise Hall Mrs. Margaret B. Harding Lieutenant Colonel and Mrs. Bartlett Harwood III Charles E. and Jacqueline K. Hewett Mr. Benjamin R. Heywood Mr. James Heywood Dr. Colin C. Hill Karen and Andrew Hirschberg Mrs. Linda B. Hirschson Ken Hollander Anders D. Hove, M.D. Mr. and Mrs. Mike Hyde David Ingall, M.D. Ms. Paula Jelly Bob and Lynn Johnston Thomas P. Jones Mrs. Jacquelynn Kaufman Mr. and Mrs. Kevin H. Kerchner Margaret V. and E. Robert Kinney Allan and Joan Kleinman Dr. and Mrs. Julius R. Krevans Ms. Marie J. Langlois Dr. and Mrs. Norman W. Lavy Ms. Judith A. Lese Ms. Donna Levy Roxanne Wruble Levy Mrs. Eleanor Clough Linton Leo X. Liu, M.D. Joan and Fred Mansfield M. Louise Markert 70 Barbara A. Marroccoli, M.D. 77 Mr. and Mrs. John C. Maxwell Jr. Dr. and Mrs. Allan McAllister Bob and Lois McKown Anne B. McKusick Ms. Elizabeth McMullan and Mr. Kaveh Haghkerdar Mrs. Phoebe Milliken Peter H. Model, Ph.D. Mrs. Carolyn H. Montgomery 55, 56 Mrs. Caroline Morong Mr. and Mrs. Benjamin R. Neilson Mrs. Harry R. Neilson Jr. Mr. and Mrs. George D. O Neill Mr. and Mrs. David Ott Mr. and Mrs. Jon Parks Dr. Lee Pearce Mr. and Mrs.* Robert Peck Dr. Christopher Penta Mitzi Perdue Mr. and Mrs. Daniel Pierce Drs. Deborah Plachta 71 and Alan Diner Ms. Charlotte W. Price Nancy and George Putnam Dr. and Mrs. William H. Rastetter Frances J. and George B. Rathmann Tom 76 and Mariluz Reynolds Patricia B. Rice Bryan E. Roberts, Ph.D. Mr. David Rockefeller Jr. Mrs. Carol S. Rush Allene and Paul Russell Ms. Elaine B. Sargent Frank and Lolita Savage Elizabeth C. Schermerhorn Lynda Schubert, Ph.D. Valerie E. Scott Mr. Dennis Sherwin Irving I. Silverman Charles A. Simmons, Esq. Randy Slifka Mr. and Mrs. Stockton Smith Drs. Samuel Solish and Jo Linder Ms. Martha Stewart Natasha and Richard Stowe Mr. Robert D. Stuart Jr. Mr. Anthony Sun Kathleen M. Sutton Raymond H. Taylor Mr. Carter Thacher Mr. William R. Thomas Mr. and Mrs. Raymond S. Troubh 27

30 Donors Mr. Michael F. Tyrrell Adam Usdan and Andrea Pollack Mr. and Mrs. Hans P. Utsch Dr. P. Roy Vagelos Mr. Carlo Vittorini Drs. Thomas Vogt 79 and Dr. Gwen Guglielmi Drs. Candace and Edward Walworth Mr. Caspar Weinberger Jr. Mr. and Mrs. Andrew J. Weisenfeld L. John Wilkerson, Ph.D. Mr. Mayer Wolf Mr. Michael I. Wolfson and Dr. Ellen N. Wolfson Jason C. Yeung, C.F.A. Mr. and Mrs. Stephen Younger Jane S. Zirnkilton Supporter $250+ Anonymous (7) Ms. Martha Abbott Dr. Gary R. Agisim 67 Patty Bacon Ms. Delores Bailey LuAnn and Michael Ballesteros Mrs. Charlotte Barry Ms. Susan Belanger Dr. 57 and Mrs. Thomas Peter Bennett Ms. Susan Blaisdell Patricia Bolz 54 Dr. Calhoun Bond, Jr. 74 Florence Borda Ms. Audrey A. Boughton Stuart Brown 57 Marie and Paul Bubier Dr. Carol Bult Dr. 53 and Mrs. Howard Franklin Bunn Reg and Sandra Buxton Pete and Ruth Calas Mrs. Zechariah Chafee III E. H. Marcelle Coffin Joan Conway Debbie Richards Cooper, Ph.D. 76 Mr. Chris E. Corrie Mrs. Caroline Cushman Emily L. Danforth Dr. Peggy Danneman Mr. Alan C. Davis Closey and Whit Dickey Mr. and Mrs. Charles W. H. Dodge Dorothea Donio Mr. and Mrs. John J. Donnelly Drs. Linda and Jeffrey Dunn Constance A. Eastburn John M. and Carolyn B. Eckert Howard J. Eisen, M.D., and Judith E. Wolf, M.D. Charles and Sylvia Erhart Jacqueline Fawcett, Ph.D., R.N., F.A.A.N. Mr. and Mrs. Nathaniel R. Fenton Georgina Munson Ducey Field Heidi and David Fitz Mrs. Charles Fleischmann Jon and Cynthia Floria Bob and Maggie Flynn Christopher and Erin Fogg Mr. Eugene Forsyth Philip Fox II Dorothy G. Frie Wendy Gamble and Carl Kuehn Anne and Murray Gartner Shirley C. Gegenheimer Fred Gehris, M.D. 59 Peter and Susan Geiger Thomas Gelehrter 54 Mr. and Mrs. Chandler Gifford, Jr. Dr. Robert 60 and Mrs. Linda Gordon John T. Graham Dr. Douglas Grahn Mr. and Mrs. Philip Grier Mr. and Mrs. Rick Guyer Morton I. and Joan F. Hamburg Mrs. Ida Hammatt Dr. Peter J. Hamre 50 Dr. Mary Ann T. Handel Mrs. Katharine D. Ducey Hardy Ms. Monika Haseloff Charles and Nancy Hatfield Dermot and Mary Ellen Healey Gerald Hertz 75 Dr. and Mrs. Joseph J. Hiebel Richard and Nancy Higgerson Ann M. Hirschhorn, M.D. 53 Mr. and Mrs. Matthew R. Horton Mr. and Mrs. Thomas F. Houston Jane Goodrich Hurst 42 Gay Lynn and Mel Jackson E. Thomas Johnson, Jr. Mrs. Jo Anne Wells Keller 63 Ellie and Victor Kelmenson Dr. Donna A. King 75 Mr. and Mrs. John H. Knowles, Jr. Rhoda Krasner Stephen A. Landaw, M.D. Ms. Angela N. Latigona Jeffrey Laurence 68 Carol Leininger, Ph.D., M.P.H 70 Gary R. Login, D.M.D. Leo and Emily Loiselle Ms. Louise Lopez Ms. Nicole M. Luecke Mr. and Mrs. Lawrence F. Lunt Dr. John Macauley Larry F. Martin 71 Jan and Bob Marville Mr. and Mrs. Finlay B. Matheson Mrs. D. H. Mauran Mr. Michael M. McFarland Mike and Norma McInnis Mr. and Mrs. Robert J. McWilliams Jr. Jay and Jacqueline Montfort David and Ann Montgomery Dennis and Jean Moore 56 Gregory E. Moore Robert and Lynn Moore Dr. Aurobindo Nair Rosemary G. O Brien and Joanne Schindelheim Dr. John R. O Meara Ms. Melissa Osborne Joyce Peterson R. Anderson Pew Susanne Phippen Laurence A. Pierce David and Susanna Place Mrs. Mary Haskell Pyles 50 Dr. Kathryn L. Radke 70 Tony and Ann Marie Ramos Mr. James E. Richardson Jeanne Riggs Mrs. Lois Rinck 28