contributions to JAX Weslie Janeway’s many Geneticist/philanthropist cancer therapies Novel ways toimprove PDX &avatars Where diseaseresearch starts immunology Understanding underpinnings oflupus Seeking thegenetic The Jackson Laboratory Willys Silversand mice &miracles Of medicine,

THE SEARCH SPRING 2014 • VOL.7 • NO.1 • THE JACKSON LABORATORY THE JACKSON LABORATORY THE JACKSON Contents Features A PUBLICATION OF A PUBLICATION 8 Of medicine, mice & miracles Willys Silvers and The Jackson Laboratory SEARCH

14 Seeking the genetic underpinnings of lupus

16 Understanding immunology Where disease research starts THE 20 PDX & avatars Novel ways to improve cancer therapies

24 Geneticist/philanthropist Weslie Janeway’s many contributions to JAX LEFT RNA used to be seen as having limited functions, mostly carrying out the process of converting DNA code to working proteins. Researchers now know RNA plays far more roles in each cell, and RNA research is growing in importance. Unfortunately, the RNA Departments molecules themselves are difficult to work with and tend to degrade quickly. Here, RNA samples awaiting analysis News & notes ...... 5 are kept stable in Eppendorf tubes on ice. Photograph by Françoise Gervais 5 questions...... 28

Cover photograph by Jennifer Torrance Beyond the news...... 30 2 :: THE SEARCH :: The Jackson Laboratory The Search

Editor Mark Wanner

Art direction, design Jennifer Torrance JAX awarded Korean grant for cancer genomics project Sametz Blackstone Associates President’s message The Jackson Laboratory, in collaboration will work with principal investigator Copy editor with Seoul National University, will receive Jong‑Il Kim, M.D., Ph.D., of the Seoul Carol Lamb Our bodies are made up of a lot of cells. The latest estimates a five-year, $7.5 million grant from the National University College of Medicine put the number at around 100 trillion, give or take a few. South Korean government for a large‑scale and other academic collaborators in Web editor Large as that number sounds, our own cells are vastly cancer genomics project employing Seoul. During the first phase of the Joseph Blanchette outnumbered by fellow organisms we carry within and on us: the the latest sequencing technology and grant (2013‑15), Kim and colleagues will microorganisms that make up what is now called the microbiome. special JAX mouse models that can host collect and store tumors from patients Contributors For every cell that’s ours, there are approximately 10 microbial cells, human tumors. with gastric, breast, colon, lung and rare Meg Haskell, Jacqueline Mitchell, Joyce Peterson, for a total of 1 quadrillion additional cells. We have long known the “This is a wonderful example of the cancers, and sequence and determine Mark Wanner consequence of having too many of the nastier varieties—infectious international collaborations that JAX is the genomic signatures of those disease. But only recently has the nuanced interplay between ourselves building to rapidly advance its research cancers. Lee will lead the development of Gareth Howell wins Photographers and our microbiomes become better known and appreciated, and there mission,” says Charles Lee, Ph.D., scientific hundreds of new mouse model systems Rudin Glaucoma Prize Janine Gelineau, Françoise Gervais, Jim Graham, is growing evidence that microorganisms contribute to our wellness as director of The Jackson Laboratory for for gastric, breast and other cancers that Meg Haskell, Stanton Short, Jennifer Torrance, well as to disease. Genomic Medicine and leader of the JAX will be made available to the worldwide Assistant Professor Gareth Howell, Ph.D., Rogier van Bakel The Jackson Laboratory has been investigating the genetic component of the project. scientific community. is one of two winners of the prestigious material contained within each and every mammalian cell for more Lee, who is also a distinguished visiting 2013 Lewis Rudin Glaucoma Prize from than 80 years. How does it function, and what happens when proper professor at Seoul National University, The New York Academy of Medicine (NYAM). The Jackson Laboratory function is somehow disrupted? The answers gained while working The prize recognizes the most significant to answer those simple questions have contributed greatly to medical scholarly article on glaucoma published President and Chief Executive Officer progress and promise much more to come. But now JAX is expanding Jeffrey Chuang receives grant for RNA-protein research in a peer-reviewed journal in the prior Edison Liu, M.D. its research to embrace our quadrillion fellow travelers and how they calendar year. influence human health, both for better and for worse. Jackson Laboratory Associate Professor and many of the most common learning “For the first time in the history of Vice President, Development Having George Weinstock, Ph.D., join our faculty was a terrific step Jeffrey Chuang, Ph.D., has been awarded a disabilities. Advances in understanding the the Rudin Glaucoma Prize, two prizes and Communications forward. George helped lead the human microbiome project, which two-year grant totaling $519,750 from the underlying mechanisms of RNA-protein will be awarded. Each is a truly novel Kristen Rozansky gathered essential data about the microbiome at various sites in and National Human Genome Research Institute interaction have great value for improving and transformative paper and the on our bodies. Building on this foundation, scientists can investigate for his studies into how genes are regulated health.” culmination of years of research that Director of Communications how the microbiome varies between sites and between individuals and and expressed. DNA provides the blueprint for building was done despite the universal feeling Barry Teater how those variations contribute to health and disease. Chuang researches the regulatory and running a living organism, but some that neither could ever be accomplished,” Another new faculty member, Jacques Banchereau, Ph.D. effects of RNA-protein interactions. proteins in the cell act like change said Dr. David Abramson, chair of the Research programs (profiled on page 16), looks at the microbiome from a different “Gene regulation at the RNA level is central orders in a construction plan. Binding Lewis Rudin Prize selection committee Cancer angle—how the body responds immunologically when things go to many human diseases,” says Chuang, to DNA molecules, these proteins can and chief of ophthalmic oncology at Computational biology and bioinformatics awry. And while immunology encompasses a far wider scope, “including cancer, muscular dystrophy, change how genes are expressed. While Memorial Sloan‑Kettering Cancer Center. Developmental and reproductive biology including autoimmune disease, and much DNA‑protein interactions for hundreds of Howell’s paper, “Radiation treatment Immunology more, infectious disease response is an important component of the proteins have been cataloged and studied, inhibits monocyte entry into the optic Metabolic disease expanding immunology program. protein interactions with RNA, molecules nerve head and prevents neuronal Neurobiology Overall, JAX research still focuses on mammalian genetics and transcribed from the DNA template that damage in a mouse model of glaucoma,” genomics. But bringing our microbial community into the picture perform a variety of functions, are less was published in the Journal of Clinical Locations expands our knowledge of how our bodies work and increases our well known. Investigation. The study was performed Bar Harbor, Maine ability to improve human health. “Scientific understanding of RNA‑level while Howell was a research scientist Farmington, Connecticut gene regulation is rudimentary, despite working with Howard Hughes Medical Sacramento, California the fact that this type of regulation Institute Investigator Simon John, Ph.D. probably influences the function of most Howell is now an assistant professor Printed April 2014 genes,” Chuang says. “Excitingly, several at the Laboratory and is using genetic groups around the world, notably our and genomic approaches to understand collaborators in the Brenton Graveley lab at neurodegenerative diseases including Edison Liu, M.D. the University of Connecticut, have started glaucoma, dementia and traumatic President and CEO, The Jackson Laboratory to generate new types of experimental data brain injury. on RNA-protein interactions.”

www.jax.org :: Leading the search for tomorrow’s cures :: 5 Zhengqing Ouyang and Michael Stitzel

JAX researchers show that acarbose extends life span

A research team led by Professor of complex carbohydrates. It diminishes David Harrison, Ph.D., reported in the release of glucose into the bloodstream December 2013 that acarbose, a drug that from the food you’re digesting, preventing is frequently prescribed in Europe for type insulin spikes.” 2 diabetes, extends the life span of mice. In 2009, under the Interventions Interestingly, male mice show a more Testing Program of the National Institute pronounced effect than the females. The on Aging that also funded this research, study, prepared in collaboration with groups the Harrison lab reported that rapamycin at the University of Texas Health Science significantly extends the life span of mice, Center at San Antonio, the University of the first demonstration of a pharmaceutical Michigan and other institutions, appears intervention to do so in mammals. Edison Liu named in the journal Aging Cell. In related research, also reported in 2014 Chen Award recipient Though the mechanisms behind the Aging Cell, the researchers at the three JAX, UC Davis extend, Three JAX faculty among GenomeWeb life-span-extending effects of acarbose participating institutions also showed The international Human Genome expand partnership top young genomics researchers have yet to be determined, reducing recently that the life span-extending effects Organisation (HUGO) has named insulin levels could be a factor, says of rapamycin vary with both dosage of the Jackson Laboratory President and CEO The Jackson Laboratory and the Every year GenomeWeb, an influential Stitzel joined JAX Genomic Medicine Jackson Laboratory Senior Research drug and gender of the mice, with greater Edison Liu, M.D., as the recipient of University of California, Davis are online site that focuses on genomics in September 2013 after completing a Scientist Kevin Flurkey, Ph.D., a co-author effect in females than males. the 2014 Chen Award for Distinguished expanding their 15-year collaboration research, identifies and profiles 20 of postdoctoral appointment at the NIH in of the study. “Acarbose inhibits digestion Academic Achievement in Human Genetic to provide mutual support in research the most promising up-and-coming the lab of NIH Director Francis Collins, and Genomic Research infrastructure and educational programs. researchers. This past year’s list, released Ph.D. He investigates the genomics In 2010, Yuan-Tsong Chen, M.D., The new agreement will enable UC in late December, includes three JAX underlying type 2 diabetes. Early genomics A. Karolina Palucka joins and Alice Der-Shan Chen established Davis to fully utilize JAX’s Sacramento- researchers—Zhengqing Ouyang, Ph.D., studies have turned up many associations JAX Genomic Medicine the Chen Award to celebrate research based infrastructure to reduce long‑term Michael Stitzel, Ph.D., and Haoyi Wang, between the disease and genetic variants, accomplishments in human genetics capital and operating expenses, while Ph.D.—who are just beginning their careers but the signals are weak. Stitzel is Internationally recognized clinical and genomics, and to recognize the providing flexibility to the UC Davis as principal investigators. looking at pancreatic islet cells (which oncologist and cancer immunologist tremendous impact that genetics and investigators and administration in pursuit “Having three investigators on this list secrete insulin), identifying variations in A. Karolina Palucka, M.D., Ph.D., genomics have had on the improvement of their research results. of 20 really speaks to the exceptional talent gene regulation and expression found joined The Jackson Laboratory for of health and treatment of diseases. The “This new memorandum of of the scientists we have recruited to our in diabetes patients. In particular he Genomic Medicine faculty on March 1 annual award honors the achievements understanding between JAX and research team,” says JAX President and is looking at the effects of epigenetic as professor and associate director of of a biomedical scientist who has made UC Davis not only stretches research CEO Edison Liu, M.D. changes (modifications to the genome that cancer immunology. significant contributions to genetics and dollars through collaboration, but also All three came to JAX after postdoctoral don’t alter the DNA sequence), such as Science magazine recognized cancer genomics. As the 2014 awardee, Liu will enables two nonprofit organizations appointments with pioneering genomics changes in chromatin structure and DNA immunotherapy as the “Breakthrough of receive a $10,000 award and plaque, and with similar missions to recruit researchers. Their work moving forward methylation, on gene expression. the Year” in 2013, and Palucka is one of the will present a plenary lecture at HUGO’s world‑class scientists and contribute to will explore important yet very different Wang, who will ultimately divide leaders in this field. Her research exploits annual meeting in Geneva, Switzerland, the Sacramento region’s life sciences areas of genomics investigation. his research time between JAX’s dendritic cells, which control the body’s on April 30. momentum,” said Auro Nair, Ph.D., In December 2012, Ouyang began Bar Harbor, Maine, campus and China, immune response to tumors, as the basis HUGO is an international organization general manager of JAX® Mice, Clinical and work at JAX Genomic Medicine as is currently finishing his postdoc work for new vaccines against melanomas and dedicated to coordinating research in the Research Services. “UC Davis has been a one of its first faculty members after with Rudolf Jaenisch, Ph.D., at the other human cancers. “The diagnostic aspect of genomic human genome and fostering collaboration key ally over the last decade as we grew completing a postdoctoral appointment Whitehead Institute. He will work to In a recent interview in the journal medicine is very important, but so among scientists through meetings and from 50 employees in 2008 to nearly 200 with Michael Snyder, Ph.D., at Stanford develop innovative new gene-targeting Nature, Palucka described how is the therapy component,” says educational programs. Part of HUGO’s employees at our Sacramento facility.” University. He uses computational methods technologies, and he has expertise with she used this approach to treat the Charles Lee, Ph.D., scientific director of mission is to encourage public debate Harris Lewin, Ph.D., UC Davis vice to explore non-coding RNA, which is TALENs and CRISPR/cas, the leading pancreatic cancer of Nobel Prize winner JAX Genomic Medicine. “We need to keep and provide information and advice on chancellor of research, said, “As UC Davis transcribed from DNA but doesn’t code tools for actually editing genes within Ralph M. Steinman using dendritic cells— coming up with creative ways to utilize a the scientific, ethical, social, legal and grows to meet its strategic imperatives, for proteins. Long considered “junk” in the the genome. His long-term goal is to the very cells Steinman and colleagues had person’s genetic information to develop commercial implications of human The Jackson Laboratory’s world-class genome, recent research has indicated better understand diseases and defects discovered. “Although we can’t say for sure novel and effective therapies to human genome projects. mouse infrastructure and scale in that such RNA is very important for proper associated with the Y chromosome. that this treatment was responsible, Ralph diseases. Dr. Palucka has had amazing Sacramento can provide a measure of genomic and cellular function. Ouyang survived for 4.5 years after his diagnosis— success in this area and I am absolutely capital and operating flexibility for the is using statistical and computational something that only around 5 percent of delighted to have her join our team here University, which should result in more methods to identify non-coding RNA and patients with this disease achieve,” she in Connecticut.” innovative, efficient and scientifically tease out its function on a genomic scale. told the interviewer. substantive collaborations in the future.”

6 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 7 Willys Silvers, seen here with his toy poodle Gigi, began collecting Pennsylvania Impressionist paintings with his wife Abigail in the 1980s. Their gallery is now displayed in the house of Silvers’ daughter and son-in-law. ofmedicine,

mice miraclesBY JOYCE PETERSON PHOTOGRAPHY BY JIM GRAHAM

WILLYS SILVERS AND THE JACKSON LABORATORY

“I’ve had one of the most fabulous lives of “Seeing that flyer was the first miracle!” anybody,” says Willys Kent Silvers, Sr., Ph.D. he exclaims. “And when you get down to it, it’s all due to Silvers spent the summer of 1949 as my association with The Jackson Laboratory.” a Jackson Laboratory intern, assisting In that case, The Jackson Laboratory has psychologist Joseph Royce with his a lot of which to be proud. Silvers has had a behavioral studies of dogs. The following distinguished career in biomedical research summer he won a scholarship for another and academic leadership, including 31 years summer at JAX, “not because of the at the University of Pennsylvania and decades outstanding research I had done,” Silvers of service to the Laboratory. One of his books says with a chuckle, “but because I was is still a go-to classic of scientific literature. always willing to volunteer to help wash Silvers likes to point out that he was born the dishes in the central dining hall!” in 1929, the year of The Jackson Laboratory’s During his time at The Jackson Laboratory, founding. He graduated from high school Silvers says, “I met two of my best, lifelong in 1946, “right when all the veterans from friends,” Henry J. Winn, Ph.D., and World War II returned,” he says, so when he Lloyd Guth, M.D. Guth is an eminent enrolled at Johns Hopkins University as a neuroscientist and a pioneer in the study of pre-med student, most of his classmates were spinal cord injuries at the NIH, University of older men attending on the G.I. bill. “College Maryland and College of William and Mary; was not a joyful experience,” he says. Winn, an immunologist, was on the JAX One day during his junior year, on his faculty before joining the surgery department I’VE HAD ONE OF THE MOST way out of the biology building for the at Massachusetts General Hospital. day, Silvers noticed a flyer promoting Silvers got to know Jackson Laboratory FABULOUS LIVES OF ANYBODY... The Jackson Laboratory’s Summer Student founder and then‑director C.C. Little. “I Program. “I thought, gee whiz, this sounds adored ‘Prexy,’ as everyone called him. He WHEN YOU GET DOWN TO IT, like a nice way to spend the summer,” he was definitely a very positive figure in my reminisces, “and it will probably help me get life. Indeed, he told me I reminded him of IT’S ALL DUE TO MY ASSOCIATION into med school, so why not look into it? himself when he was younger. He was an WITH THE JACKSON LABORATORY.”

8 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 9 LEFT The history of mammalian genetics through the 1950s is captured in this extraordinary photograph of four generations of scientists. William Castle, far left, pioneered the field of mammalian genetics, beginning his research soon after the rediscovery of Mendel’s laws of inheritance in 1900. Among his students were JAX founder C.C. Little and Sewall Wright, second from left, who is one of three scientists credited with developing a mathematical basis for modern evolutionary theory. Longtime and renowned JAX researcher Elizabeth “Tibby” Russell, second from right, worked with Wright at the University of Chicago in the 1930s as a Ph.D. student. Silvers, far right, worked in Russell’s lab during his time at JAX.

BELOW LEFT Silvers met his wife-to-be Abigail Adams at JAX, and their wedding cake had a mouse decoration on top. Abigail Silvers went on to graduate from the University of Pennsylvania Medical School and her successful medical career included an appointment as medical director of cancer programs at The Bryn Mawr Hospital.

exceedingly charming individual and always at the University of Chicago, where she had “Tibby asked me to supervise David, but was soon obvious to me that my bride was willing to spend time with me.” received her graduate degree. And somehow he was so bright he didn’t need any help,” exceedingly unhappy in giving up medical C.C. Little’s grandson, Philadelphia she was able to get me accepted!” Silvers recalls. school.” Soon Silvers accepted a staff architect and Jackson Laboratory Trustee Silvers became a student of Sewall Wright, Silvers’ association with Russell was position at The Jackson Laboratory, again in Sam R. Little, has known Silvers for many Russell’s mentor. Together with C.C. Little, also responsible for the next step in his Russell’s lab, and his wife was accepted at the years. “When I first became involved with Wright had been a student of William Castle’s career: an NIH postdoctoral fellowship at University of Vermont School of Medicine, the Laboratory, Willys cared that I should at Harvard’s Bussey Institute—a veritable Brown University with Herman B. Chase, the young couple resigning themselves to a know what made the place so special. “who’s who” of 20th century American one of Russell’s former University of Chicago long‑distance relationship. With his very personal recollections of the mammalian geneticists. classmates under Sewall Wright. But in the spring of 1957, right close‑knit scientists, the excitement of the Silvers earned his Ph.D. from the Next came what Silvers calls “another on schedule, yet “another miracle.” work they were doing, and how it changed University of Chicago, conducting his thesis miracle.” In the summer of 1956, he returned Rupert Billingham, whom Silvers had his life, Willys made the earlier days come research at JAX in Russell’s laboratory. While to Bar Harbor to finish his postdoctoral first met during his postdoc years, offered alive for me. It also speaks of the legacy Russell’s research at the time was primarily training in Russell’s lab. “A young woman Silvers a position at The Wistar Institute which now helps give the Laboratory its in hematology and germ cell genesis, she named Abigail Adams, who had just in Philadelphia, and Abigail Silvers was promise for the future.” continued her early work in pigment cell graduated from Mount Holyoke, was accepted at the UPenn Medical School That second summer Silvers worked with genetics as a kind of “hobby.” And, Silvers spending her second summer as Tibby’s right across the street from Wistar. She, the legendary Elizabeth “Tibby” Russell, says, “although my research eventually student,” he recounts fondly. “Towards the who was one of only six women in a class whose contributions include the first became more focused in transplantation end of the summer, I asked her out for a date, of 125, excelled in her studies, completing successful bone marrow transplantations in immunology, I too had a lifelong interest and a few weeks later I proposed to her.” her internship at The Bryn Mawr Hospital mice to cure anemia. But it was at the end of in pigment cell genetics, starting with However, Adams had been accepted and becoming board certified in internal that summer that Russell’s mentoring really my dissertation.” at the University of Pennsylvania Medical medicine, hematology and oncology. kicked in. During that time Russell had a summer School, and in the 1950s med school and While building their careers in “I had not been accepted to medical student named David Baltimore, who along marriage didn’t generally mix, especially for Pennsylvania, the couple also had two school, and I really didn’t know what I with another JAX student that summer, female students. Silvers finally persuaded her children, daughter Deborah and son Kent. was going to do,” he recounts. “And Tibby Howard Temin, would go on to win the to choose marriage just a few weeks before In 1965 the University of Pennsylvania suggested I apply to the zoology department 1975 Nobel Prize in Physiology or Medicine. she was due to start her first classes. “But it started one of the first departments of

10 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 11 Silvers first came to JAX in 1949 as a summer intern looking to improve his transcript for med school. He poses with his fellow students (back row, third from right) in front of the old Lodge, an iconic Laboratory building that served many functions over the years.

medical genetics, and recruited Silvers as manuscript to scientific publisher Springer In 2004 Silvers terminated his research different species of mice, rats and other small an associate professor in the department. As Verlag. The publisher in turn sent the book efforts when his wife was diagnosed with mammals—to JAX, where they now grace this department subsequently became the to the top expert in the field for review: none lung cancer. Despite her own illness, she the library and North Research Building department of human genetics and finally other than Elizabeth Russell. “She gave it a was active as medical director of hospice, of the Bar Harbor campus. The Silvers the department of genetics, Silvers served as great review!” Silvers says. Silvers’ Coat Colors counseling other cancer patients. She died have also been philanthropic supporters of acting chair for nine years. of Mice was so successful that after 35 years in 2005. the Laboratory, including establishing the “In my three decades at Penn,” Silvers says, it is still in demand and is now available on Abigail Silvers had a distinguished career Elizabeth Russell Scholarship Fund. “what I enjoyed most was my association The Jackson Laboratory’s website. as an oncologist and hematologist in private In reminiscing about his lifelong with students, and I was chair of the genetics “My primary research interests have been practice and in academic and leadership connection to Bar Harbor, Silvers says, graduate program for 12 years.” It’s not pigment cell biology and transplantation posts, including medical director of cancer “from summer student to the chairman of the hard to imagine the extroverted Silvers biology, and I’m proud to have written books programs at The Bryn Mawr Hospital and Board of Scientific Overseers, I don’t think as an outstanding teacher; he won the on both subjects,” Silvers says. clinical assistant professor of medicine at anyone else has been in as many different university’s Mary F. Lindback Award for Throughout the 1980s, Silvers served on Thomas Jefferson University. positions at The Jackson Laboratory. Distinguished Teaching, and a Dean’s Award The Jackson Laboratory’s Board of Scientific Silvers now lives in Gladwyne, Pa., “And it all started when I saw that in Graduate Teaching. Overseers (now the Board of Scientific with his daughter and son-in-law (and summer student notice when I was a junior Silvers published The Immunobiology Counselors), chairing it from 1986 to 1989. his 13-year-old toy poodle, Gigi). Their at Hopkins. A notice that, because it luckily of Transplantation with Rupert Billingham, Silvers retired from the University house includes a gallery exhibiting the caught my eye, resulted in a graduate degree, in 1971. Around 1975, Silvers was asked of Pennsylvania in 1996, but continued collection of Pennsylvania (New Hope a productive research program, a wonderful to compile a list of genes affecting coat to do research at the Fox Chase Cancer School) Impressionist paintings that Will wife, two wonderful ‘F-1s’ [genetics-speak for color in mice, his lifelong research “hobby.” Center, also in Philadelphia, as a visiting and Abigail Silvers assembled starting in offspring] and wonderful friends. A fabulous “I realized it had been years since anybody scientist. There he collaborated with the 1980s. life indeed!” had written a review article on the subject, Beatrice Mintz, Ph.D., whom he had met In his younger years, Silvers, like many and that was ‘The Coat Color Genes in at The Jackson Laboratory when she was a mouse genetics researchers, collected Rodents and Carnivores’ by C.C. Little.” summer investigator in Tibby Russell’s lab. pictures of mice. He and his wife donated Once Silvers wrote the review article and Silvers’ work with Mintz focused on the his first art collection—including original compiled the list of genes, he realized he development and treatment of melanomas. prints by John James Audubon depicting had a book’s worth of material. He sent the

12 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 13 Elisabeth Adkins is the first student in the “JAX track,” a joint mammalian genetics graduate program between Tufts University by Jacqueline Mitchell and the Laboratory. Photography by Jennifer Torrance Butterflies are a symbol SEEKING for lupus, the focus of her research. the genetic underpinnings of LUPUS

Lupus is one of the most enigmatic models,” says Adkins, who received a 2013 undergoing an active immune response. of diseases. It can take years to diagnose, Gina M. Finzi Memorial Student Summer “That was a surprise. No one would have marked as it is by a laundry list of seemingly Fellowship from the Lupus Foundation to expected that,” says Roopenian. unrelated symptoms: fever, fatigue, rashes, support her research. “We see a lot of the Next, the scientists want to figure out hair loss, sensitivity to light, seizures and same indicators [in these mice] that human how those cells develop in normal mice, even psychosis. Nearly 2 million Americans lupus patients have.” information that could illuminate what have some form of lupus, an autoimmune One such indicator is kidney failure, exactly goes wrong when lupus occurs. disorder in which the immune system wages something that human lupus patients often That would not only open the door to new war on the body’s own cells and tissues. More died of before steroids were used to manage therapies; it could have diagnostic value, too. than 90 percent of those who suffer from it the disease. Adkins’ mutant mice die of “Historically, lupus has been extremely are women, and there is no cure. kidney failure before they are eight months hard to diagnose. A lot of our effort is to Elisabeth Adkins, a doctoral student at old. The normal life span of mice is two to understand the mechanisms much better so the Sackler School of Graduate Biomedical three years. it will be easier to predict when people are Sciences at Tufts University, is trying to With Roopenian as her mentor, Adkins showing early signs of it,” says Roopenian. decode the genetic underpinnings of the is studying these doomed mutant mice to It was serendipity that put Adkins, who disease, a crucial step in combating it. She’s figure out the mechanisms behind the onset has been interested in science and medicine working in the lab of Derry Roopenian, a of disease. The mutation causes the mice since high school, on the JAX track in 2011. clinical professor at Tufts School of Medicine to produce too much of a protein called After studying genetics as an undergraduate and a professor at The Jackson Laboratory, 21, or IL21. Roopenian’s team at Central Connecticut State University, and is the first student to take advantage of has known for awhile that this protein she knew she wanted pursue a Ph.D., but the mammalian genetics “JAX track,” a joint has something to do with lupus. Normally, she wasn’t sure if she wanted to focus on program of the Sackler School and JAX. The it helps the immune system respond to genetics or immunity. The mammalian program, launched in 2011, offers students in infections. But the scientists found that, genetics program allowed her to marry her Tufts’ genetics program—which emphasizes when produced in excess as it is in their two interests. The JAX track, she says, also human disease—in-depth training in strain of mutant mice, IL21 leads to the gives her access to the breadth of research mammalian genetics, an increasingly symptoms of lupus. at Tufts and the depth of genetic expertise at recognized need in biomedical research. “It turned out that it wasn’t just lupus, but The Jackson Laboratory. Established as a cancer research center in many other autoimmune disorders, too,” says “It’s nice to have the two names together,” 1929, The Jackson Laboratory is famous for Roopenian. “We focus on lupus so we aren’t she says of the new program. “It adds more its mice. It maintains a “library” of special going in 20 different directions at a time.” weight to what I’m doing.” strains of mice that make it easy to study Now Adkins is studying the specific “Liz has an innate drive to think certain diseases in humans. The type of immunity cells (a subset of T helper cells) scientifically and to come up with answers,” mice that Adkins and Roopenian use that produce the protein. Her goal is to Roopenian says of Adkins. “As the first [JAX arose accidentally, through mutation; figure out exactly how IL21 contributes track] student, she is really setting a high bar they begin to exhibit lupus-like to lupus, how it’s produced and how it for everyone else.” symptoms by the time they are four functions. Her work has already led to one weeks old. It’s a lesser-known strain significant finding. Originally published in Tufts Now of mice, but a potentially promising Adkins found that these cells exist in http://medicalxpress.com/news/2014-01- one. “We think it’s one of the better healthy mice, even when they are not genetic-underpinnings-lupus.html

14 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 15 Understanding IMMUNOLOG Where disease research starts

BY MARK WANNER • PHOTOGRAPHY BY JENNIFER TORRANCE

“Understanding immunology provides insight researchers. He envisions the program as into all human disease.” a triangle that will provide the potential to It’s a bold statement from someone understand diseases better than ever before. working at a genetics laboratory, but “At one corner you have human patients Jacques Banchereau, Ph.D., is bold as well as with disease and samples from those confident. He has spent his career pushing patients,” says Banchereau. “Then you have the envelope with his research, always research expertise and technology to work seeking to translate discoveries to clinical with the samples and data. Finally, you progress. He now brings his perspective have the mice, which are the best models and experience to The Jackson Laboratory. for human disease and allow discovery that In his role as director of immunological you can take back to the patients. JAX has sciences, he will begin a human immunology a unique situation, which completes the program at the The Jackson Laboratory for triangle with the absolute best personnel, Genomic Medicine facility in Farmington, experimental models and resources available. Conn. He will also lead a significant It is a winning combination.” expansion of immunology research across all JAX campuses. RESEARCH HEYDAY Banchereau comes to JAX after a stint at Banchereau’s use of a geometric figure to Roche Pharmaceuticals, and he knows the capture how the pieces fit together at JAX is research landscape from both academic and fitting. As a child growing up in the French corporate perspectives. “Jacques Banchereau town of Angers, he first became interested in is a distinguished and world-renowned science via mineralogy when he was only 8 immunologist,” says Jackson Laboratory or 9 years old. He was, and still is, “absolutely President and CEO Edison Liu, M.D. “We mesmerized” by crystals, and he still collects look forward to the exciting opportunities them as well as fossils five decades later. for partnerships between JAX campuses Angers (pronounced Ahn-zhay) is in and other institutes afforded to us by his the middle of the Loire Valley, a region extensive network of colleagues. He is a renowned for its wine. Banchereau retains tremendous addition to our faculty.” his love of French culture, including good Banchereau sees unprecedented food and wine, but his early career path opportunities at JAX, built upon its brought him to the United States, if only Jacques Banchereau views formidable history and its current core temporarily. While training in clinical dendritic cells, which function of highly accomplished immunology pathology, he traveled to New York City as intermediaries in the immune system, directing the response to external materials and pathogens. 16 :: THE SEARCH :: The Jackson Laboratory 17 See more photographs at www.jax.org/thesearch/immunology.

JAX HAS A WINNING COMBINATION THAT WILL ALLOW US TO PURSUE ANSWERS TO THE BIG QUESTIONS IN IMMUNOLOGY. IT’S A PERFECT STORM IN THE RIGHT SENSE.

to perform research in a laboratory at “It was an extraordinary adventure,” he with systemic onset juvenile arthritis, done In addition, immunologist and JAX ’s College of Physicians says. “A really, really exciting and exceptional with collaborator Virginia Pascual, Ph.D. Professor Leonard Shultz, Ph.D., developed and Surgeons. It was only for a year, but it time. The work was divided between Genomics studies revealed that the disease the NSG mouse that provides the had a major impact on his moving forward. California and France, working with both might be caused by interleukin 1 (IL-1), and cornerstone for much of the upcoming “I learned good English and ‘learned’ mouse models and human immunology. Pascual used an approved but rarely used mouse modeling work in cancer and New York City,” says Banchereau. “Most of We discovered many exciting things, drug—an IL-1 receptor antagonist—to treat infectious diseases (see page 30). Shultz all, I confirmed that I really wanted to do including human IL (interleukin) 4, 5, 10 two patients resistant to every previous is particularly intrigued by the potential research. I looked at clinical pathology as a and 13. My lab cloned and characterized therapy. Within two days their chronic fevers for tumor immunology research as the good fallback position though.” human IL-17. It was the heyday of biotech.” disappeared, and within weeks that arthritis program evolves. CYTOKINE BIOLOGY Banchereau’s tenure in that “fallback” subsided. There is now an IL-1 antibody “At JAX we have a unique resource, these career lasted exactly one day in October 1981. STARTING ANEW therapy approved, and about 70 percent of mice and the knowledge of how to use them,” The very same day he started a professorship The work evolved over the years, however, patients have a nearly complete response for says Shultz. “Moving forward, we’ll need Even scratching the surface of cytokine biology is in clinical pathology in Paris, he quit in order and after a decade Banchereau’s priorities a disease that less than 10 years ago had no to focus on specific disciplines like cancer daunting. For example, an exciting research area right to accept an offer to join a startup institution began to diverge from those of his company. effective treatment. immunotherapy and integrating the new now involves the family of cytokines and funded by the pharmaceutical company Desire to take his research closer to patient principal investigators into the group.” Schering Plough. interaction and benefit drew him back to PERFECT STORM The recent recruitment of JAX Professor their corresponding receptors. They are known to play a The startup had a very specific goal: work academia, this time launching another Banchereau has a broad view of the Karolina Palucka, Ph.D. (see News & Notes) key regulatory role in host defense (immune response to with human cytokines, the cell-signaling startup institution for the Baylor Healthcare work to be done at JAX. “Yes, we want to from Baylor immediately strengthens external infectious microbes) and inflammatory disease proteins vital to immunological function. System based in Dallas. While the move study cancer immunology, but we also the cancer immunology effort, an area The chain reaction that leads to immune away from industry may not have been have priorities for autoimmunity and that is sure to grow. She and Banchereau processes, but important details of their function remain response—antibody production, macrophage surprising to his friends and colleagues, the inflammation, infectious disease, the previously developed a dendritic cell-based unclear. What is known is that IL-17s alone constitute an (killer cell) activation, and so on—has many geographical destination certainly was. importance of the microbiome in the vaccine to treat patients with metastatic elaborate and nuanced system of signaling and response. components, and the roles of cytokines were “Many people in France had this idea development of diseases and more. We have melanoma and HIV. Some patients have seen only beginning to be discovered. about Texas, that it’s awful, full of burning a lot of collaborators excited to work together, spectacular remission of the melanoma, but According to a review published last year in the Nature In the early 1980s, cytokines were oil wells,” says Banchereau with a chuckle. and we want to leverage our strengths and in Banchereau’s words, “not enough yet.” He journal Emerging Microbes & Infections: not only an exciting research area, but “Fortunately I’d had the privilege of doing a use mouse models to precisely reproduce plans to continue studies to improve the knowledge of them was quite new. two-month sabbatical at the University of human disease and immune response.” clinical vaccine outcomes by combining Banchereau, who had done his dissertation Texas Southwestern in Dallas, so I knew the Of course, JAX has a long and them with selected anti-cancer agents. Functional receptors for IL-17 family cytokines often exist in research on lymphokines (a particular reality was totally different. In those days illustrious history of immunology research. “I’m very excited to work with colleagues the form of heterodimers, with IL-17RA as a common subunit. class of cytokine), jumped at the chance Baylor had a vision to create a program in George Snell won the Nobel Prize for his who bring an array of expertise to bear, For example, the receptor complex consisting of IL-17RA and to continue working with them when he human immunology that was a bit ahead of work on the major histocompatibility and to have everyone working together,” received the offer. He soon found himself its time and recruited me to lead it.” complex, a key component of the immune says Banchereau. “JAX has a winning IL-17RC recognizes IL-17A and IL-17F, whereas IL-17RA pairs directing the new institute near Lyon, What started as a chair and an office response to foreign substances. And JAX’s combination that will allow us to pursue with IL-17RB, followed by binding to IL-25. advised by two Nobel laureates (Paul Berg grew steadily to a well-funded institution current immunology program includes answers to the big questions in immunology. and Arthur Kornberg) and other high-level employing 125 people when Banchereau left award-winning research into type 1 diabetes It’s a perfect storm in the right sense.” scientists and administrators. The excitement in 2010. One of his significant achievements and lupus. Got that? What’s more, IL-17 is only one of many echoes in Banchereau’s voice 30 years later. while at Baylor was a study of children families of cytokines, and the complexity has made immune response research both challenging and exciting. www.jax.org :: Leading the search for tomorrow’s cures :: 19 PDXand avatars: Novel ways to improve cancer therapies

BY MARK WANNER & MEG HASKELL • PHOTOGRAPHY BY JENNIFER TORRANCE

In 2012, after a routine mammogram to study cancer, and they have launched the revealed a suspicious spot in her left breast, Maine Triple-Negative Breast Cancer Study. Trish Ropp of Bar Harbor, Maine, learned Despite significant advances in science she had cancer. and medicine, breast cancer remains Although important progress has been the most frequent cancer diagnosis for made in identifying and treating some women throughout the world, and the common forms of breast cancer, the second‑highest cause of cancer deaths disease remains a scary diagnosis. Ropp’s among women in the United States. One was especially so. Her cancer is classified in every eight women born in the U.S. as “triple-negative” breast cancer—TNBC— today will be diagnosed with breast cancer and it is impervious to the most advanced, at some point in her life. Only about 20 targeted cancer therapies. percent of breast cancer cases in the U.S. fall “I generally feel most things in life can into the TNBC category, according to the be dealt with,” Ropp says, “but I know this National Cancer Institute. But because of its disease could come back anytime, anywhere aggressive behavior and because no effective in my body, and be stage 3 or stage 4 before drug targets have been identified, it has a we know it’s there.” higher mortality rate than other forms of breast cancer. In the TNBC study, breast tumor tissue The TNBC study from patients like Trish Ropp will be shipped to the Laboratory, where a portion of each Cancer is a highly complex disease, tumor will undergo genome sequencing. The and what works to stop it in the laboratory remainder will be implanted into specialized often doesn’t work in patients. Efforts mice with a suppressed immune response Trish Ropp, who was are under way to bridge the gap from that enables them to host human tissues. THIS DISEASE COULD COME BACK ANYTIME, diagnosed with cancer research to medicine, however, and These recipient mice will then be tested in 2012, is taking on The Jackson Laboratory is spearheading with drugs that match the treatment of the ANYWHERE IN MY BODY, AND BE STAGE 3 OR new challenges, such an important one with the Maine Cancer tumor donor. The goal is to demonstrate if as lobstering with a Initiative. Researchers at the Laboratory are response to treatment in the mice mirrors STAGE 4 BEFORE WE KNOW IT’S THERE. citizen’s license. teaming with Maine’s top clinical centers that observed in individual patients.

www.jax.org :: Leading the search for tomorrow’s cures :: 21 LEFT Work on the PDX resource at JAX’s Sacramento facility involves the intake of human tumors and implantation of them in specially bred mice. The resulting data will improve understanding of tumor growth and help identify therapeutic targets. The background image shows the structure of a ductal cell carcinoma of the breast from the tumor of an 89-year-old patient.

RIGHT A Circos plot shows gene interactions in the tumor pictured to the left.

Visit www.jax.org/thesearch/pdx for more images and information.

“This is a study with a vision,” says genome sequencing, data analysis and drug Cancer Risk and Prevention Program at more deeply and be better informed, with Professor Carol Bult, Ph.D., who heads studies to advance the development of new, Maine Medical Center in Portland. enormous benefits for the patients and the project at the Laboratory. “The targeted cancer therapies. The Laboratory “The goal is to start building bridges clinicians in our practice and for the people Triple‑Negative Breast Cancer Study brings has implanted human tumors from a wide between basic research scientists and of Maine.” together expertise in cancer genetics and range of cancers into NSG mice to create clinicians caring for women with clinical oncology from across the state to what are called patient-derived xenografts, or triple‑negative breast cancer,” she says. “We work collaboratively, using the power of PDX. PDX tumors are grown and expanded have never done a project like this. We’re all Hope for the future emerging genome technologies and animal in the mice, yielding information about how incredibly busy clinically, but now we have models to develop precise, individualized the cancers change over time as well as a The Jackson Laboratory as a scientific partner For Trish Ropp, that future is unknown. therapies for Maine cancer patients.” hugely valuable data and research resource to help ground the project. This pilot project Still, she remains philosophical about her for studying human cancer. will really help to establish and build the cancer and its treatment. It’s a challenging process, and not all infrastructure for the future.” “It could be years before they crack Building the PDX resource tumors “take” and grow in mice. Nonetheless, whatever code there is,” she says. “And JAX has established more than 300 PDX this cancer of mine could come back Like most research initiatives at JAX, the models from patient tumors so far, including Progress toward patient avatars anywhere—my brain, my liver, my lungs. TNBC Study uses mice as models for human bladder, brain, breast, colon, kidney, lung, And if it comes back, the chemo I had this disease. In this case, the mice are a launching ovarian, pancreatic, skin and other cancers. While the PDX program provides a solid time won’t be much use to me. So what I point for exciting projects that quickly mesh The Laboratory is now targeting high-risk, foundation of knowledge and resources, really have to fight with now is my own good biomedical research with human patients metastatic tumors for the PDX program, the benefits to patients are indirect. The health and my commitment to exercise, diet and human medicine. including those that have or acquire next step in the cancer xenograft story is and serenity.” The mouse in question is known as NSG, resistance to targeted therapies. to use a similar platform to create “avatars,” She credits scientific research for having short for NOD scid gamma, developed by “The PDX program is a great place for us mouse stand-ins for specific human patients improved the outlook for breast cancer JAX Professor Leonard Shultz, Ph.D., after to start,” says Thomas Openshaw, M.D., a in which therapeutics can be tested and patients in the past, and takes inspiration years of advanced immunology work. NSG medical oncologist who heads up cancer treatments refined. Eventually, researchers from patients who have tried out new mice have immune system deficiencies that research at Eastern Maine Medical Center’s expect to be able to assign a team of mouse drugs and procedures as they have become allow them to accept xenografts—implanted Cancer Care of Maine in Brewer. “It allows avatars to a specific patient, so testing available. She has told her physicians that she tissues from other species, such as human us to identify different drugs that can be of second-line drug therapies can take would be honored to have her cancer tissue tumor tissue—and can even be engrafted used on the xenograft, to zero in on what a place while the patient undergoes initial used in the new pilot study. with functional human immune cells. They particular patient’s tumor might respond to.” standard of care treatment. Although a “I understand there is no gain to me therefore provide an advanced, realistic A focused outgrowth of the PDX program, full-blown clinical trial of this patient- directly,” she says. “But in a small way, maybe research platform for a number of human the Maine TNBC study may be small in specific avatar model may take a few years, I can help grow our understanding of what diseases that can be hard to recreate in mice, scope, but it establishes critical infrastructure the Maine TNBC study will pave the way, makes triple-negative breast cancer what it including cancer. for growth in the emerging field of genomic Openshaw says. is. We’re very lucky that most breast cancers Over the last four years, the Laboratory medicine, says Susan Miesfeldt, M.D., a “Clinical research is a rising tide that are very treatable now. It would be nice if has built a comprehensive platform for medical oncologist and director of the lifts all boats,” he says. “It allows us to think triple‑negative were treatable, too.”

22 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 23 Weslie Janeway studied by Meg Haskell genetics in England and Photography by Stanton Short & Rogier van Bakel spent the summer of 2009 at JAX studying GENETICIST chromosomal alterations. HILANTHROPIST We cannot just sit back and wait P for the government to fully fund science. Weslie Janeway’s many contributions to JAX

Scientist, investment professional, author Janeway is originally from Rhode Island, research. Given her growing interest in the At JAX, we regressed those stem cells to and philanthropist: Weslie Janeway is all of but her family has summered in coastal work taking place at The Jackson Laboratory, determine how meaningful the chromosomal these, and, since 2002, a thoughtful trustee Maine for decades. Like many seasonal she said, a science education “just seemed alterations were. We learned that the cell and supporter of The Jackson Laboratory. residents, she was aware of the Laboratory’s like the right thing to do.” Janeway’s earlier lines were still viable despite the changes.” With the evolution of The Jackson Laboratory presence in the area but knew little about it. education includes a bachelor’s degree in That summer, Janeway’s respect for for Genomic Medicine in Connecticut, she “I had heard The Jackson Laboratory was political science from Barnard College and a The Jackson Laboratory deepened. She says, personal philanthropy, unrestricted in an economic engine for Hancock County, but master’s degree from Brown University, also especially enjoyed her working relationship its use, must play an increasingly important I didn’t know much more than that, except in political science. with cytogenic technologist Ellen Akeson, role in supporting the Laboratory’s mission. about the mouse-production business that In Cambridge, she first joined the lab of whom she calls “one of the many people at At a recent board meeting, Janeway, the so many people think of,” she said. But in renowned American stem cell researcher the Laboratory who is doing amazing work— vice chair, was everywhere—checking 2002, Dr. Ann Hirschhorn—a longtime Roger Pederson at the Cambridge Stem Cell she is really a national treasure.” in with organizers in the lobby, debating friend, JAX board member and alumna of Institute, conducting classic research using Denegre, now program manager of the one-on-one between sessions in the main the JAX Summer Student Program—brought both mouse and human cell lines to study Knock-Out Mouse Project (KOMP) at JAX, meeting room, taking part in an animated her to visit the Bar Harbor campus, where post-conception differentiation. With remembers well Janeway’s summer in his lab. lunch-table discussion. she learned about the important genetic Pederson’s impending retirement, Janeway “I was asked if I would take her on as an “Weslie Janeway is a remarkable discoveries taking place there. moved to the lab of Mark Kotter, M.D., Ph.D., intern,” he says. “All I knew was that she was individual—simply one-of-a-kind,” says “It became apparent to me right away that to study neural cell repair following damage a trustee with some scientific background. President and CEO Edison Liu, M.D. “She if you’re going to be part of Hancock County, due to trauma or neurological diseases. Then I learned she had been studying with is a philanthropist-turned-scientist, and her you should really be part of the Laboratory,” Later, in 2009, Janeway spent an Roger Pederson, and my respect notched way contributions to JAX have been enormous. she says. “I wish more people felt that way.” absorbing summer at JAX, studying up. She has a very inquisitive mind, and she As CEO, I have relied on her keen sense of She has served on the JAX Board of cytogenetics with James Denegre, Ph.D., was committed to completing her study.” observation and her sage advice on many Trustees since that time, and her generous who at the time was the senior manager Janeway, a dedicated supporter of science matters related to Laboratory management. giving has supported essential growth at for imaging sciences and worked in the and culture, believes public support for Her intellect, her generosity and her sense the Laboratory, including a 2009 leadership windowless lower levels of the Bar Harbor scientific research is essential, the way it is of style leave a lasting impression.” donation to fund new research positions. campus. Janeway refers to it as “the summer for schools, highways and healthcare. At the end of a long day of providing After joining the board, Janeway made of the basement” and recalls it as a deeply “There are things a just society should and processing information at the board it her business to learn more about the rewarding experience. provide for people,” she says. “Privatization meeting, Janeway shared her views on world of research. In 2006, when she and “I learned a great deal,” she says. “In and entrepreneurship are often held up as science, philanthropy and the future of her husband, economist William Janeway, Cambridge, we had developed stem cell lines panaceas for financing our institutions, but The Jackson Laboratory. moved to England, she entered genetics with somewhat damaged chromosomes. they’re not always the answer.”

www.jax.org :: Leading the search for tomorrow’s cures :: 25 Janeway received the 2009 Chairman’s Award at the Laboratory’s Annual Meeting for her many contributions to JAX.

Janeway has contributed greatly to the Laboratory’s recent growth. However, she adds, “We cannot just sit the founder. When that person moves on or She was joined by Maine’s leading politicians for the ribbon cutting back and wait for the government to fully changes focus, the funding is lost.” for the East Research Building (above left, third from the right) and fund science. Government agencies are, by Even in tough economic times, she notes, broke ground with then-President and CEO Richard Woychik, Ph.D., their nature, risk-averse. We need private wealth changes hands from one generation for the new importation and cryopreservation facility (above right). philanthropy to support more promising to the next, and many aging philanthropists young investigators and to fund our elect to channel some of their resources overhead costs.” to causes that inspire them rather than to While commercialization of some JAX their families. discoveries may yield important revenues, “There is really a lot of opportunity now, Janeway says philanthropy will remain an some of it from unlikely sources,” she says. essential funding source as the Laboratory The challenge, Janeway says, is to attract Weslie Janeway is a remarkable heads into a future that includes expansion high-level giving that supports not only the into clinical genomics. She recognizes that exciting new work of clinical genomics, but there are steep philanthropic challenges also the basic research that has been the JAX individual—simply one-of-a-kind. ahead, especially with recent fluctuations in hallmark for eight decades. the national and world economies. “It’s easy to get focused on clinical research “People who serve on charitable at the expense of basic science,” she says. Her intellect, generosity and sense boards are there to forward the mission “There’s no doubt that translational science of their institutions,” she says. “But with is the future of genetics, but it’s important changing economic times come changing to maintain our leadership in basic research, of style leave a lasting impression. pressures and competing interests for too. Our move into clinical genomics philanthropic dollars.” presents us with great challenges and great For example, she says, “A lot of younger opportunities. But for basic research or EDISON LIU PRESIDENT & CEO philanthropists really like the idea of direct, translational science, there will always be an grassroots investment in specific disease important place for quality institutions like areas of research. But the institutions The Jackson Laboratory.” backing those operations are only as stable as

26 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 27 Visit www.jax.org/thesearch/5-questions for bonus content from the interview. questions

What did you do What does scientific before coming to JAX? computing do?

I grew up in southern Maine—Kittery Point— Our job is to be faculty focused. We build tools and graduated from the University of Maine that help faculty do their research, developing and with a computer science degree and math programming the kinds of applications and databases minor. During my education I gravitated toward that you can’t buy off the shelf. scientific applications, not business, and after working at the University of Southern Maine for a couple of years in data processing, I came to the Laboratory in 1992 when an opportunity What are some opened to write database applications. I became very interested in the research and specific examples? took the Genetics course here, then moved to Mouse Genome Informatics (MGI), the online We are optimizing command line programs that run database and bioinformatics resource hosted by on high performance computing clusters to help JAX, for the first time after a couple of years and faculty work with massive data sets, developing small helped design our first web interface. databases and web interfaces, developing image analysis tools, helping researchers visualize data, and a lot more. I lead a group of six now, and we work on a Did you work with MGI wide variety of projects. until you moved to How did you get into that scientific computing? kind of work? No, in 1996 I moved to Boston to work for a startup company. That began a time when I You might say I lucked into it, but I ended up where worked for five companies in about eight years. I want to be. I enjoyed working in MGI, but then Startups folded, I was at Nortel when they computational sciences saw the need to automate closed a facility and laid off the entire staff… data analysis and sharing for faculty, and I was hired to it became pretty difficult. It was good to come do that. It grew from there, and I find the work very fun Dave Walton back and rejoin MGI. and interesting. There are new projects all the time, I get to meet new faculty and solve different problems. Maybe it’s that I have the right job for someone with a Manager, Software Engineering short attention span! The Jackson Laboratory

28 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 29 beyond the news

Cancers are heterogeneous.

That short sentence explains a lot mutations that activate a particular able to express genes in the NOTCH1 about why cancers are so difficult to treat. gene, NOTCH1, that can play a key role pathway, showing that the difference is It means that cancers are not the same— in the disease. It followed, therefore, that not in the DNA sequence itself. Instead, between types of cancers, between cancers inhibiting it should stop the disease, which it’s epigenetic, meaning that chemical in different individuals, even between it does. Briefly. Clinical tests of inhibitors modifications are made to the DNA rather cancer cells within the same person. showed that the response was much more than to the DNA sequence itself, as in So how do you figure out what’s transient than hoped, indicating that at genetic mutations. different in cancers so you can develop new least some cancer cells had escaped the Essentially, persister cells, which make therapies in the face of those differences? treatment. But how? Researchers couldn’t up well under 10 percent of the total cell Experiments can’t be done ethically within investigate further within the human population, survive NOTCH1 inhibition the patients, who need the best available patients, so one group turned to cell line through epigenetic adjustments. But what if their ability to make epigenetic changes was also shut down? After identifying the likely mechanism Progress toward better therapies for leukemia through which persister cells make their epigenetic modifications, the researchers theorized that a treatment treatment, and fast. Using human cancer investigations to learn more about what that combines inhibition of both NOTCH1 cell lines helps, but the crucial interplay was happening in the patients’ cancer and the epigenetic changes might improve between the cancers and their host cells. They then worked with NSG mice to outcomes. Using NSG mice implanted with environments is absent. Animal models test what they had learned, and the results human patient leukemia cells to test their also help, but cancers in research animals are encouraging. idea, the researchers confirmed that the such as mice are different from those A paper published in Nature Genetics on combination therapy is far more effective in humans. March 2, titled “An epigenetic mechanism than either inhibitor administered alone. Enter the NSG mouse, developed of resistance to targeted therapy in Given that therapeutic resistance by Jackson Laboratory Professor T cell acute lymphoblastic leukemia,” remains a major challenge in cancer Leonard Shultz, Ph.D. NSG mice have shows their findings. The group, led by treatment overall, the findings provide impaired immune systems, so they can scientists at Harvard Medical School important insight into an epigenetic accept and grow human cancer cells like and including Shultz, found a small mechanism for drug resistance and how it those grown in glass dishes. But the cells population of leukemia cells that survive might be overcome. Using the NSG mouse can be studied within a living system, treatment, which they called “persister” for confirmation is a vital step to bringing a better modeling the patient environment. cells. Apparently persister cells don’t need more effective combination therapy to the Take recent research into T cell acute NOTCH1 to proliferate, relying instead clinic for the benefit of leukemia patients. lymphoblastic leukemia, an aggressive on a different mechanism. But when the blood cancer. Scientists discovered inhibitor was removed, they were quickly

Knoechel B, et al. 2014. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nature Genetics doi:10.1038/ng.2913. Leonard Shultz

30 :: THE SEARCH :: The Jackson Laboratory www.jax.org :: Leading the search for tomorrow’s cures :: 31 600 Main Street Bar Harbor, ME 04609-1523

Sandy Daigle, high-throughput sequencing specialist, prepares an automated process in the clinical genomics and translational technology laboratory.

Photograph by Françoise Gervais