The Simons Foundation 2008 Annual Report

Annual Report 2008

The figures on the cover are projections into the plane of n-dimensional hypercubes (aka n-cubes), as n varies from zero to eight – eight to coincide with the year of the annual report, 2008. The projections are orthogonal projections chosen in such a way that the convex hull of the n-cube projection is a regular 2n-gon in the plane, called the Petrie polygon of the projection. Since the n-cube is a face of the (n+1)-cube, the projections are linked in a natural way: the vertices that make up each projection's convex hull can be seen in the projection of the next higher-dimensional cube. Thus, the red polygon highlighted in each figure is the image of the Petrie polygon of the next lower-dimensional cube, helping the viewer to grasp the relationships between the n-cubes.

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President’s Message Math & Science SFARI Financials Simons Staff Simons Grants

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Simons Foundation Annual Report 2008 { President's Message }

Letter from the President “Collaboration can lead to new ways of looking at old problems; partnerships can lead to a synthesis of ideas; teamwork can help us build something greater than ourselves.” In today’s complex, deeply specialized, and vast world of research possibilities, how does the Simons Foundation envision having an impact? We see our potential to advance research through grantmaking that encourages collaborations, makes connections, and builds bridges. We seek to fund studies that will heighten interchanges between institutions, across fields, and among scientists to facilitate the exchange of new ideas. A few examples of grants made this fiscal year will illustrate our funding strategies and goals. Modern theoretical physics and the geometric aspects of mathematics have had increasingly fruitful interactions in the past 30 years, illuminating and advancing both fields. We have every reason to expect that this approach will continue to be productive. To this end, the Simons Foundation is funding the Simons Center for Geometry and Physics in order to bring together mathematicians and physicists investigating the fundamental shape and structure of the universe. The application of quantitative methods to biology has been progressively more productive over the past several decades. The use of statistical methods and largescale data analyses, for example, is in the process of revolutionizing modern genetics. The applications of both math and physics have been critical to neurobiology. Bringing together mathematicians and biologists, the Simons Foundation supports a Biology Colloquium at the Mathematical Sciences Research Institute (MSRI), a systems biology program at the Institute for Advanced Study (IAS), and a newly established biology program at the Institut des Hautes Études Scientifiques (IHÉS). Through these interdisciplinary programs, the foundation hopes to stimulate collaborations that will further advance research in the life sciences.

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Connecting investigators and facilitating their joint efforts to build a repository of blood samples and a collection of psychological assessment data is the goal of the Simons Simplex Collection (SSC). This project, involving over 100 people working in research teams at 13 outstanding institutions, is compiling a large sample of genotypic and phenotypic information to be made available for research worldwide. By coming together to assure a uniform standard of excellence, it is hoped that scientists will further our understanding of the fundamental roots of autism. These grants are important representatives of our key strategy of building bridges. Collaboration can lead to new ways of looking at old problems; partnerships can lead to a synthesis of ideas; teamwork can help us build something greater than ourselves. By working together we anticipate exciting developments in the years ahead. The Foundation is pleased to support many excellent projects. I hope you will enjoy reading about our work. Sincerely,

Marilyn Simons President Simons Foundation

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Simons Foundation Annual Report 2008 { Math & Science }

Progress through Math and Science

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The Flower of Maths What is a mathematician? Not a scientist Not an artist But caught between the two In a world of structures and truths Creating the seeds But proving the flowers And vaguely hoping That their scent will save the world – Wendy Lowen

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Simons Foundation Annual Report 2008 { Math & Science }

Simons Center for Geometry and Physics “The Simons Center will give mathematicians and physicists the opportunity to work in an environment and architecture designed to enhance collaboration.” – Jim Simons From the work of Archimedes on the center of mass to present mathematicians with a remarkable opportuthat of Einstein on the shape of the universe, there has nity to develop new mathematics. Environments that been crucial interdependence between theoretical phys- encourage younger generations of mathematicians to ics and the geometric side of mathematics. Recent devel- become aware of this physical intuition and these potenopments in cosmology, string theory and quantum field tial worlds of mathematics are welcome and timely.” theory, together with important progress in topology and differential geometry, have caused these fields to become The Simons Center will give mathematicians and increasingly intertwined, as developments on each side physicists the opportunity to work in an environment stimulate and inform developments on the other. and architecture designed to enhance collaboration. In addition to providing an attractive facility, the gift will be At the Simons Center for Geometry and Physics at used to recruit and retain permanent faculty, provide Stony Brook University, researchers will explore these enhanced training and support for graduate students, interactions, hopefully deepening their understanding attract visiting scholars and post-docs – up to 30 at a of each field in its own right and continuing to unravel time – and sponsor workshops and conferences. their remarkable relationship to each other. The building housing the center is scheduled to open in 2010. John Morgan, known for his contributions to topology and geometry, and formerly chair of the Mathematics “Mathematicians often develop their mathematical con- Department at Columbia University, will be the center’s cepts based on internal consistency, elegance and first director. Among the permanent faculty members of appropriate generality, independent of these physical the center will be internationally renowned string theorist connections,” said Dennis Sullivan, professor of mathe- Michael R. Douglas. Dr. Douglas was instrumental in the matics at Stony Brook, National Medal of Science recipi- development of the first solvable models of string theory ent, and trustee of the new center. “Physical models and its relations to particle physics and mathematics. Left: Rendering of the new Simons Center for Geometry and Physics. Right: Dr. Morgan, a mathematician known for his contributions to topology and geometry, is the Simons Center's first director. www.scgp.stonybrook.edu

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Interview with John Morgan Director of the Simons Center for Geometry and Physics

“What we are attempting to do here is to create an environment in which geometers and physicists can exchange ideas in a way that enriches both disciplines.” Why is it important to have a center for both geometry and physics under the same roof?

level, we will be running workshops where the topics will be of interest to both geometers and physicists.

Around the world there are many centers for geometry What are some areas of research interest that the and centers for physics. Sometimes, like for example center will focus on? at the Institute for Advanced Study, they exist side by side in the same place, but even when they exist in There are many topics that I could list, but I will list the same place there is usually little organized interac- the topics of this year’s workshops. The titles of the tion between the groups. What we are attempting to three workshops planned for the spring are ‘Derived do here is to create an environment in which geom- Geometry’, ‘Kahler Geometry and Extemal Metrics’, eters and physicists can exchange ideas in a way that and ‘String Field Theory’. As the first two names indienriches both disciplines. The recent interaction has its cate, these topics fit squarely in the area of geometry, origin in conversations between Jim Simons and C.N. but there is a modern twist in the topic inspired by Yang, here at Stony Brook in the 1960s, concerning the physics, and in particular by string theory, which is latest developments in physics, gauge theories, and the one of the most active areas in theoretic high-energy corresponding mathematical context. But as physics of physics. In the study of string theory, the appropriate gauge theories developed and string theory came along, geometry is not the classical geometry of Gauss and the developments in physics outstripped the available Riemann alluded to before, but rather a more abstract geometry. While these developments give hints about form of geometry ‘derived’ from these classical forms. the nature of the geometry that would be needed, what Ideas from string theory have led to new insights into is needed is far too vast, new and different to be devel- and new questions about these derived geometries and oped full-blown out of the hints so far provided by phys- their relation to classical geometry. These insights have ics. What the nature of this geometry is and how it will already produced a revolution in how we think about be useful in physics are fundamental mysteries in both ‘classical geometry’, and there promises to be much subjects. Progress toward their resolution will surely more to come. This geometric revolution is providing have major impacts, some indication of which we can new impetus for progress in physics. The topic of the already see. Studying these mysteries – from the math- last workshop this year is one that belongs more purely ematical perspective, the physical perspective and the to physics: the study of modern string theory. joint perspective – is the focus of the Simons Center for Geometry and Physics. For interviews with John Morgan and Dennis Sullivan visit www.simonsfoundation.org. How will the center create an atmosphere where scientists from both disciplines can collaborate? We hope to create the collaborative atmosphere in several ways. First of all, the building will have much open, common space with blackboards, chairs and tables to facilitate spontaneous, scientific conversations. As we search for permanent members, post-docs and visitors, we will put real emphasis on a desire for collaboration across the math-physics divide. On the programmatic

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Simons Foundation Annual Report 2008 { Math & Science }

Math for America The program has recruited, trained and retained more than 200 skilled mathematicians to work as teachers. Zach Korzyk’s biggest challenge teaching math at a New York City public school is keeping his students motivated.

MƒA. After joining the program, MƒA sent him to Bard College for a master’s degree in teaching with a concentration in secondary mathematics.

“Some students don't like that I won't let them be pas- Korzyk is about halfway through his five-year commitsive in class and do poorly,” said Korzyk. “I make them ment to MƒA, and while it’s a tough job, he said he take notes and answer questions. The upper-level loves his work. students are grateful for challenging problems and engaging conversations.” “I really enjoy coming up with interesting activities that pleasantly surprise my students,” Korzyk said. “I like to Korzyk, 24, has been teaching math since 2007 as encourage them and see them grow mathematically.” a fellow in the Math for America (MƒA) program. He’s one of about 200 teachers MƒA has recruited to help MƒA was launched in 2004 to address the deficit in address a critical shortage of qualified math teachers. math education. To date, the program has recruited, Nearly 40 percent of all public high-school math teach- trained and retained more than 200 skilled mathematiers do not have a degree in math or a related field, cians to work as teachers in New York City’s public according to one study. schools. As an undergraduate at Boston College, Korzyk majored in theatre arts and computer science, with a minor in mathematics. He wanted to teach math but wasn’t sure how he could get a job without a degree in teaching. Then, he spotted an advertisement for

Building on this success, MƒA is expanding to other cities around the country. The nonprofit has created a national office while starting new programs in San Diego, Los Angeles and Washington, DC.

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“The ultimate goal of MƒA programs is to convince people that our approach to recruit and retain outstanding teachers works and our underlying principles can dramatically improve mathematics education across the country.” – John Ewing To further its expansion, MƒA seeks partnerships with state governments, educational institutions and foundations. Leading the expansion is MƒA’s new president, John Ewing, the former head of the American Mathematical Society.

Exceptional high-school math teachers currently working in public schools are recruited into the four-year Master Teacher program. Teachers receive annual stipends and participate in professional development and leadership opportunities.

“The ultimate goal of MƒA programs is to convince people that our approach to recruit and retain outstanding teachers works and our underlying principles can dramatically improve mathematics education across the country,” Ewing said.

For Korzyk, the experience of teaching with MƒA and being part of a corps of other math-savvy individuals has taught him lessons that he applies every day on the job.

“I’ve learned to maintain high but clear expectations for For gifted mathematicians who are new to teaching, my students,” he said. “I am getting better at explaining MƒA offers its five-year fellowship. Following a rigor- assignments in different ways so my students at every ous selection process, fellows spend a year earning learning level know what to do.” a master’s degree in mathematics education with a partner college or university. Fellows then teach for four www.mathforamerica.org years in New York City’s public schools. The fellowship includes a full tuition scholarship with a stipend of $100,000 over five years to supplement their teacher’s salary. The program includes mentoring, leadership opportunities and professional development services.

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Simons Foundation Annual Report 2008 { Math & Science }

Institut des Hautes Études Scientifiques Gromov’s team hopes that the knowledge they will gain through their investigation could help in discovering ways to prevent heart attacks. Heart attacks, known to doctors as myocardial infarctions, are a leading cause of death around the world. At the Institut des Hautes Études Scientifiques (IHÉS), a research team led by Mikhail Gromov is seeking to use mathematics to better understand the cause of heart attacks. The Simons Foundation supports Gromov’s investigation of the heart as part of its 11-year record of contributions to IHÉS. Half of a recent contribution from the Simons Foundation will fund the Institute’s activities at the interface of biology and mathematics. The investigation into the electrophysiological geometry of the heart by Gromov continues the Institute’s tradition of fundamental research in the sciences. Gromov’s team hopes that the knowledge they will gain through their investigation will help in discovering ways to prevent heart attacks.The objective is to identify a metric that governs the propagation of electromagnetic waves in the heart. The metric may prove useful in characterizing normal and abnormal heart functions.

IHÉS is one of the world’s premiere research institutions. Located in Bures-sur-Yvette, France, IHÉS is dedicated to fostering fundamental advances in mathematics, physics and other related theory-based disciplines. Founded in 1958, IHÉS has a small number of permanent professors, appointed for life, and invites about 200 visitors a year for varying terms averaging three months. It also has a small number of long-term visitors. Research is not contracted or directed: it is left to each individual researcher to pursue their own goals. Permanent professors are only required to be in residence six months a year. www.ihes.fr

Left: Mikhail Gromov. Right: Dennis Sullivan and Mikhail Gromov.

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Top: Image of an electrocardiogram. Left: Maxim Kontsevich. Right: Alain Connes.

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Simons Foundation Annual Report 2008 { Math & Science }

American University of Beirut “In the broad light of day mathematicians check their equations and their proofs, leaving no stone unturned in their search for rigour. But, at night, under the full moon, they dream, they float among the stars...” Michael Atiyah is sometimes described as one of the greatest living mathematicians. He was the corecipient, along with Isadore Singer, of the Abel Prize, an award that is compared to the Nobel Prize. The prize was awarded for their development of the Atiyah-Singer Index Theorem that is used to count the number of independent solutions of many important differential equations. In honor of Atiyah’s achievements, the Simons Foundation has established the Michael Atiyah Chair in Mathematical Sciences at the American University of Beirut (AUB).

mathematical modeling will be greatly enhanced with leadership in this chair in the mathematical sciences,” Bitar said. Atiyah has spoken passionately about the importance of mathematics. During a speech at AUB, he described mathematics as “an essential component of our world. In all the sciences, physical, biological or social, mathematics is increasingly important, and in recent years the business and financial community has also woken up to this fact.” When he was awarded an honorary doctorate from AUB in 2004, Atiyah described himself as “a firm believer in the fundamental and central role that mathematics plays in our modern technological society, where it underpins everything from science and engineering to finance and economics.”

The gift will be used to attract top researchers and professors to the university. AUB’s Faculty of Arts and Sciences Dean Khalil Bitar noted that the endowment would bring new possibilities to the study of mathemat- The Simons Foundation hopes that the gift will help the ics at the university. university excel in both academic research and outstanding pedagogy. “The recent surge in the use of mathematical techniques via computer simulations in fields that tradition- “For many years AUB has been a beacon of scholarship ally have not made use of mathematical analysis and/or and tolerance in an embattled part of the world,” said Jim Simons. “We are pleased to think that our contribution will help and strengthen the university in continuing to fulfill this important mission.” www.aub.edu.lb

College Hall, the main building at the American University of Beirut.

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Memorial Sloan-Kettering Cancer Center Scientists are trying to create therapies that target cancer cells and the abnormal signaling pathways needed to maintain them. Of the hundred of types of cancers that can afflict the to kill cancer cells, specifically block cell proliferation, human body, brain cancer poses some of the toughest inhibit development of specific stem cells and prevent treatment challenges. Getting drugs into the brain can cancer cell survival. be difficult because a barrier physically shields the brain from chemicals circulating in the body. Medications that “These machines can screen compounds thousands of do enter the brain may cause serious side effects. times faster than we could in the past,” said Hakim Djaballah, the director of the high-throughput screening Memorial Sloan-Kettering Cancer Center’s new Brain core facility. Tumor Center (BTC) is working to overcome these obstacles using recently revealed insights into the BTC director Dr. Eric Holland has developed a prommolecular and cellular properties of tumors. Scientists ising new system for glioma modeling. Holland’s colare trying to create therapies that target cancer cells league, neurosurgeon Philip Gutin, and Shahin Rafii, and the abnormal signaling pathways needed to main- a hematologist at Weill Cornell Medical College, are tain them. seeking to treat tumors by cutting off their blood supply. The team is studying the use of blood supply-producThe Simons Foundation supports this important work ing cells derived from bone marrow. by underwriting preclinical studies of new therapies for the type of tumors called gliomas to confirm that they Research into brain tumors may also be useful in produce their desired effect in animal models. There understanding autism. Of the several candidate genes currently exists no drug pipeline developed specifically that enhance the risk for autism uncovered so far, for gliomas, and such preclinical work is an essential three – PTEN, TSC1 and TSC2 – are part of biochemistep in the design of new therapies for use in humans. cal pathways that suppress the formation of tumors. Disabling these genes in mice produces signs and The BTC is undertaking both basic scientific investiga- symptoms that are relevant to autism in humans. tions into brain tumors and translational research in which potential new targets and therapies make the “Putting Memorial Sloan-Kettering’s basic science peotransition from animal experiments to humans. ple together with neurosurgeons and medical oncologists and radiation oncologists – everyone who treats One major goal at BTC is to find chemicals that can brain tumors – facilitates the exchange of ideas among be used in glioma treatment. In a gleaming room in investigators with conjoined interests,” said Dr. Holland. Memorial Sloan-Kettering’s new research tower on Manhattan’s Upper East Side, the arms of a robotic www.mskcc.org laboratory click and whirr. Machines are testing 250,000 compounds to see if they might be useful in killing tumor cells. The screening machines have found several compounds that enhance the ability of radiation

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Simons Foundation Annual Report 2008 { SFARI }

SFARI: Simons Foundation Autism Research Initiative

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“We are not alone in the effort to understand autism. This effort goes to the core of the human condition, so one can expect that real advances will take the combined efforts of a world wide community of scientists of all stripes.” – Gerald D. Fischbach

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Simons Foundation Annual Report 2008 { SFARI }

From the SFARI Director “To deal with the massive amounts of phenotypic and genetic data, we have created an interactive database called SFARI Base that will allow sophisticated queries of the data, and hopefully uncover new correlations.”

An important goal of SFARI is to create tools that scientists can use to enhance our understanding of autism. Last fall, we released the first set of phenotype data and DNA from the SFARI Simplex Collection (SSC). The SSC is a tool of fundamental importance that will facilitate the identification of autism genetic risk factors. Studying alterations in gene structure and function is a crucial first step toward understanding underlying molecular mechanisms. This information will, in turn, lead us to new therapeutics and to a better understanding of environmental influences on the developing nervous system. The SSC aims to establish a repository of genetic samples and phenotypic data from simplex families, where one child is diagnosed with an Autism Spectrum Disorder while both parents and other siblings are unaffected. Our initial goal is to identify de novo copy number variants (chromosomal deletions or duplications) in probands from 2,000 families. To deal with the massive amounts of phenotypic and genetic data, we have created an interactive database called SFARI Base that will allow sophisticated queries of the data, and hopefully uncover new correlations. We recently unveiled SFARI Gene, a new online autism gene database that appears on our website at http://gene.sfari.org. SFARI Gene collects information on genes linked to Autism Spectrum Disorders from the published scientific literature. This publicly available database will be expanded by addition of new, interactive modules that incorporate genetic structural alterations as well as biochemical, physiological and anatomic data.

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 critically important “tool” is an interactive community of scholars dedicated to sharA ing information, research reagents, animals, and most important, ideas to enhance autism research. To build this community, we have organized a series of workshops at the Simons Foundation and many discussions with individuals and small groups, and we are looking forward to our first Annual Science Meeting in New Orleans in April 2009. We will expand the number of workshops in the coming year as collaborations expand and questions become better defined. Our website will serve as an important resource for Simons Investigators and for all other scientists with interests in related areas. At the present time, we fund research in three areas: gene discovery, molecular mechanisms, and cognition and behavior. Our hope is to blur the distinctions, technical hurdles and strategic barriers that keep these approaches too far apart. A list of Simons Investigators can be found at http://sfari.org/simons-investigators.  e are not alone in the effort to understand autism. This effort goes to the core of W the human condition, so one can expect that real advances will take the combined efforts of a worldwide community of scientists of all stripes. We look forward to building partnerships in the coming years.

Gerald D. Fischbach SFARI Director

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Simons Foundation Annual Report 2008 { SFARI }

John Constantino

“ How is it that you can have part of the syndrome, but not all of it?”

From the very beginning of his medical training, John Constantino has coupled rigorous clinical research with teaching social workers, educators and parents about children’s mental health.

iors – are not independent of each other. “It seems that they’re very tightly connected to each other and that some underlying cause may produce symptoms in all three domains of autism at the same time,” he says.

In 1999, he helped develop the first scale of traits of people on the autism spectrum that is quick and easy enough for general practitioners and school teachers to use.

The SRS has also allowed Constantino to quantitatively study the ‘broader autism phenotype’ – milder behavioral, neurobiological or anatomical traits in the siblings and parents of children with autism – and to increase the statistical power of traditional linkage studies.

Since its commercial release in 2005, the test, the Social Responsiveness Scale (SRS), has been published in “How is it that some individuals have subtle autistic seven languages and is set to be available in eight more. social impairments that fall below the level of severity Clinicians say it’s one of the most reliable measures of seen in fully affected children?” he asks. “Understanding autism, and has a 70% correlation with scores on the this can provide insight into the confluence of factors ADI-R – the gold standard of autism diagnoses. that give rise to the full autistic syndrome.” The SRS’s 65-item questionnaire focuses on reciprocal social behavior, such as the ability to understand and respond to emotional cues from others, and takes just 15 to 20 minutes to complete. On the basis of the first sets of SRS data, Constantino found that the three domains of autism – social impairment, language impairment and repetitive behav-

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Guoping Feng

“Our goal now is to look at how the genes [causing] synaptic   defects in the striatum are related to autism.” People on the autism spectrum tend to exhibit repeti- “Many steps can affect circuitry function, but the syntive behaviors – a characteristic that’s also seen in those apse is definitely one of the key places where somewith obsessive-compulsive disorder (OCD). thing can go wrong,” Feng says. Neurobiologist Guoping Feng is searching for the genetic basis of repetitive behaviors by unraveling the mechanisms at work in OCD.

The synapse is likely to prove equally important in autism, Feng says. SAPAP3 interacts directly with another synaptic protein, SHANK3, mutations in which have been associated with autism.

In August 2007, Feng and his colleagues at the Duke University Medical Center published the first well- SAPAP3 and SHANK3 are expressed highly in syndescribed mouse model of OCD, a disorder defined apses located in the striatum – the deep, central brain by recurrent, unwanted thoughts and aimless rituals. region that is known to undergo changes in people with The researchers focused on SAPAP3, a protein that OCD. Some studies have also found abnormally large provides scaffolding at the synapse, the junction at striatal volumes in people on the autism spectrum. which nerve cells communicate. By deleting the gene for SAPAP3, the researchers were able to turn healthy “We think that compulsive behavior in OCD and autism mice into compulsive, round-the-clock groomers that may have a common circuitry mechanism,” Feng says. scratched the hair right off their faces. “Our goal now is to look at how the genes [causing] synaptic defects in the striatum are related to autism.” Using up to 400 samples from the Simons Simplex Collection, a gene bank of children on the autism spectrum and their families, Feng’s team plans to look for mutations in SAPAP3 and about 20 other genes that encode synaptic proteins. Feng’s team reported in a January 2009 paper that they had found rare mutations in the SAPAP3 gene in 4.2 percent of people with OCD, compared with 1.1 percent in a control group without OCD.

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Simons Foundation Annual Report 2008 { SFARI }

Dan Geschwind

“ Nowhere has there been more progress in genetics in any   complex disease than in autism.” In August 2001, neurogeneticist Daniel Geschwind and other researchers affiliated with the nonprofit Cure Autism Now created the Autism Genetic Resource Exchange (AGRE), a gene bank of more than 4,500 samples from families in which at least two children have autism.

males. In November 2008, the researchers linked CNTNAP2 to families with specific language impairment, another childhood development disorder. Geschwind, whose first career was strategic business consulting, says “you’d need a crystal ball” to know where the rapidly growing autism field is headed, particularly because it comprises such a diverse spectrum of behavioral and genetic characteristics.

Since then, using the AGRE samples, Geschwind has led many of the largest high-resolution genome scans intended to pinpoint the chromosomal anomalies in people on the autism spectrum. “What we’ve learned most is that autism is far more heterogeneous than any of us expected,” he says. At the University of California, Los Angeles, Geschwind’s “But on the other hand, nowhere has there been more lab studies brain asymmetry, fronto-temporal dementia progress in genetics in any complex neuropsychiatric and other neurological diseases. But its main focus is the disease than in autism.” genetics of autism. In particular, Geschwind is seeking genetic similarities among people with autism who share endophenotypes – quantifiable markers of disease – such as sex, language ability and social impairment. For instance, his team found in January 2008 that a gene thought to be involved in nerve cell communication, contactin-associated protein-like 2 or CNTNAP2, is associated with autism and language deficits in

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Rebecca Saxe

“ The answers are not going to be at the level of the biology,   the answers are going to be at the level of the systems.” ‘Theory of mind’ – the ability to sense what other people Saxe plans other autism-related experiments, including want, believe or intend – has fascinated philosophers brain scans of people on the spectrum making moral and psychologists for centuries. But it wasn’t until judgments, and a comprehensive survey of how spe2003 that Rebecca Saxe, then a graduate student, cific brain regions develop in babies at risk of developidentified a precise region in the brain, a part of the ing autism and in healthy controls. temporo-parietal junction, that's active when we try to divine others’ thoughts. “My gut instinct about the mind – and I don’t know about autism, but I’m trying what I know – is that the answers Now an assistant professor at the Massachusetts are not going to be at the level of the biology,” she Institute of Technology’s Department of Brain and says. “The answers are going to be at the level of the Cognitive Sciences, Saxe is using functional magnetic systems.” resonance imaging to study social cognition in people on the autism spectrum, who often have trouble grasping what others are thinking. In one experiment, for instance, Saxe uses a new procedure in which live video displays brain activity during real-time, back-and-forth social interaction – a measure that she predicts will be strikingly different in people with autism.

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Simons Foundation Annual Report 2008 { SFARI }

Michael Wigler Q&A “We were discovering new mutations – things that occur spontaneously in the parental germ line.”

The Simons Simplex Collection (SSC) aims to collect DNA and phenotypic information from 2,000 ‘simplex’ families, in which one child has autism but siblings and parents are unaffected. The SSC is a collaboration of 13 university-affiliated research clinics across the United States and Canada, under the guidance of the University of Michigan Autism & Communication Disorders Center. The clinics follow meticulous phenotype protocols, and this information is paired with genetic data from the blood samples. Using different technologies, groups led by Michael Wigler, of Cold Spring Harbor Laboratory, and Matthew State, of Yale University, are analyzing the samples to detect copy number variations – chunks of DNA that are duplicated or deleted.

rate in kids with autism than in unaffected children, but we only saw this as a significant difference in the socalled ‘simplex’ families, families with only one child on the spectrum. This effect was not significant in families with multiple children on the spectrum (the ‘multiplex’ families). We were discovering new mutations – things that occur spontaneously in the parental germ line. So you wouldn’t expect two kids in the multiplex family to have them. Previous autism collections were devoted to multiplex families. We decided that it would be very useful to have a collection devoted to the simplex families. What's the status of the collection?

Here, Dr. Wigler discusses the evolution of the SSC.

We’ve been getting samples since March 2008, and we’ve only [genotyped] the first 250 families. But the results that we saw previously are holding up. There’s also a strong genomic asymmetry in boys and girls.

How did the idea for the SSC come about?

Why use two methods to genotype the data?

We had preliminary results that de novo (spontaneous or new) copy number variations are present at a higher

Why do you have two lungs? In case one of them fails. There’s a little bit more information of one type that Left: Close-up of a syringe injecting buffer fluid into a sequencer gel. The gel will then be loaded into a sequencer, which will automatically analyze the DNA molecules. Right: Dr. Michael Wigler, a researcher at Cold Spring Harbor Laboratory.

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“The real goal is to find the genes that are causing autism, so that we can formulate a neurophysiologic hypothesis for why a child is on the spectrum.”

you can get from the Yale method, and a little bit more resolution that you can get from our method. The two platforms search for copy number variations using different strategies. What are your genotyping goals for the end of 2009? We’d like to identify several hundred loci [the area on a chromosome where a particular gene is located]. Hopefully some of these will be recurrent. That is, they will be independently occurring events that tell us this region is important. The real goal is to find the genes that are causing autism, so that we can formulate a neurophysiologic hypothesis for why a child is on the spectrum. We should be further along in 2009, by at least threefold more families than we have now.

Left: Electrophoresis gel. Right: Fluorescence microscopy of chromosomes.

Another goal is to see if there are common polymorphisms [common genetic variations in the general population] that are associated with autism. So far, there’s no evidence that these things exist. They would be very important to find. For instance, why are girls less likely to be on the spectrum? It’s got to be something genetic ultimately. It would be an enormously useful clue if we could see something like that.

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Simons Foundation Annual Report 2008 { SFARI }

How the SSC Works The primary goal of the Simons Simplex Collection is to establish a permanent repository of genetic samples from 2,000 families, each of which has one child affected with an autism spectrum disorder (ASD) and parents unaffected with ASD. Each genetic sample will have an associated collection of data that provides a precise characterization of the individual (phenotype). Rigorous phenotyping will maximize the value of the resource for a wide variety of future research into the causes and mechanisms of autism. Visit http://sfari.org/ssc

Families recruited

Phenotype data and blood samples collected

Families with one child on the spectrum are recruited into the collection at 13 sites across North America. Site staff members screen each family to ensure they meet study criteria. Participating family members complete an extensive testing protocol, including questionnaires, behavioral assessment, cognitive testing, physical exam and blood sample collection.

Blood samples sent to central repository

Blood from each family member is sent to the Rutgers University Cell and DNA Repository (RUCDR) for processing. The RUCDR runs screening tests, whole-blood DNA extraction and cell line creation.

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Centralized review of key phenotype data

Final phenotype data published in SFARI Base data repository

Data are reviewed and validated by a panel. The review includes diagnoses, behavioral assessment and medical history. Data are made anonymous.

Researchers request access and submit findings

Approved researchers can access phenotype data directly from SFARI Base. Shipments of biological samples are coordinated through the RUCDR. Data from researchers is submitted to SFARI Base, continuing to add to the richness of the information.

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Simons Foundation Annual Report 2008 { Financials }

Financials

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Desintegration d'un kaon positif (meson K+) en vol. © CERN Copyright This image is taken from one of CERN's bubble chambers and shows the decay of a positive kaon in flight. The decay products of this kaon can be seen spiraling in the magnetic field of the chamber. The invention of bubble chambers in 1952 revolutionized the field of particle physics, allowing real tracks left by particles to be seen and photographed by expanding liquid that has been heated to boiling point.

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Simons Foundation Annual Report 2008 { Financials }

Balance Sheet June 30, 2008

June 30, 2007

$27,861,666

$815,022

1,064,269,117

693,764,890

16,094,323

514,561

182,146

0

Other

93,749

886,350

Total

1,108,501,001

695,980,823

129,546,444

76,690,635

0

2,245,374

8,659,983

7,071,983

Other

0

265,548

Total

138,206,427

86,273,540

$970,294,574

$609,707,283

ASSETS Cash and Cash Equivalents Investment Portfolio Property and Equipment, Net Prepaid Excise Taxes

LIABILITIES Grants Payable Taxes Payable Deferred Excise Tax Liability

NET ASSETS UNRESTRICTED NET ASSETS

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Income Statement REVENUE

June 30, 2008

June 30, 2007

Contributions

$180,480,577

$70,923,570

Investment Income

290,467,232

182,565,644

Total

470,947,809

253,489,214

Grants Paid

47,660,532

32,607,522

Change in Grants Payable

52,855,809

47,349,034

General and Administrative

1,649,880

817,816

Program

5,287,127

1,102,637

222,199

164,939

2,908,800

3,633,092

Other

0

89,000

Total

110,584,347

85,764,040

$360,363,462

$167,725,174

EXPENSES

Depreciation and Amortization Federal Excise Taxes

NET INCOME

Proportions of Expenses

($’s in Thousands)

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Simons Foundation Annual Report 2008 { Simons Staff }

Trustees Marilyn H. Simons, Ph.D. President Marilyn Hawrys Simons has worked primarily in the nonprofit sector as a volunteer for the past 20 years, focusing on education. She has served as president of the Simons Foundation since 1994. Ms. Simons is currently president of the board of LearningSpring School, a school for children diagnosed with autism spectrum disorders, and is a member of the board of trustees of the East Harlem Tutorial Program. Ms. Simons is also a trustee of the Cold Spring Harbor Laboratory. She received a B.A. and a Ph.D. in economics from the State University of New York at Stony Brook.

Mark Silber, J.D., M.B.A. Vice President Mark Silber, J.D., M.B.A., is vice president and general counsel at Renaissance Technologies, where he has held responsibility for finance, administration and compliance since joining the firm in 1983. Prior to joining Renaissance, he was a Certified Public Accountant with the accounting firm of Seidman & Seidman, now BDO Seidman. Mr. Silber holds a bachelor’s degree from Brooklyn College, a J.D. and L.L.M. in tax law from the New York University School of Law, and an M.B.A. in finance from the New York University Graduate School of Business Administration.

James H. Simons, Ph.D. Secretary and Treasurer James H. Simons, Ph.D., is secretary and treasurer of the Simons Foundation. Dr. Simons is president and founder of Renaissance Technologies. Prior to his financial career, Dr. Simons served as chairman of the Mathematics Department at the State University of New York at Stony Brook, taught mathematics at Massachusetts Institute of Technology and Harvard University, and was a cryptanalyst at the Institute of Defense Analyses in Princeton, N.J. Dr. Simons’ scientific work was in the area of geometry and topology, and his most influential work involved the discovery and application of certain measurements, now called Chern-Simons invariants, which have had wide use, particularly in theoretical physics. Dr. Simons holds a B.S. from the Massachusetts Institute of Technology and a Ph.D. from the University of California, Berkeley, and won the American Mathematical Society’s Veblen Prize for his work in geometry in 1975. He is a former chairman of the Stony Brook Foundation and is currently a trustee of Rockefeller University, Massachusetts Institute of Technology, Brookhaven National Laboratory, the Mathematical Sciences Research Institute and the Institute for Advanced Study.

31

Simons Foundation Staff Marilyn Simons, Ph.D. President

Adrienne Greenberg, B.S. Business Manager

James H. Simons, Ph.D. Secretary and Treasurer

Marion Greenup, M.P.H., M.Ed. Vice President, Administration

Maria Adler, M.B.A. Vice President, Finance

Stephen Johnson, Ph.D. Informatics Director

Marta Benedetti, Ph.D. Associate Director for Research

Apoorva Mandavilli, M.S., M.A. Executive Editor

Sascha Brodsky, M.S., M.I.A. Director of Communications

Alan Packer, Ph.D. Associate Director for Research (not pictured)

Meghan Criswell Administrative Assistant

Amy Pasquariello, B.A. Project Manager, SFARI

Gerald D. Fischbach, M.D. Scientific Director

Lauren Rath, B.A. Grants Associate

Chris Fleisch, B.S. Programmer/Analyst

John Spiro, Ph.D. Senior Associate Director for Research

Andrea Gallego, B.A. Executive Assistant

Patricia Weisenfeld, M.P.A. Director of Family Giving

32

Simons Foundation Annual Report 2008 { Simons Grants }

Connect and Collaborate

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Simons Foundation Annual Report 2008 { Simons Grants }

The Simons Foundation supports outstanding individual researchers and institutions seeking funding for advanced work in the basic sciences and mathematics, with a focus on innovative scientific projects where our involvement will play an essential role. In the course of this support, the foundation is interested in partnering with other entities, or providing matching support where appropriate. Historically, the Simons Foundation has accepted only solicited grant proposals. All grant decisions are made by the trustees of the foundation and the foundation staff. The foundation does not make awards to individuals, except through their institutions. Simons Investigators Ralph Adolphs California Institute of Technology

Michael D. Ehlers Duke University

John M. Allman California Institute of Technology

Guoping Feng Duke University

Mark Bear Massachusetts Institute of Technology

Gordon J. Fishell New York University School of Medicine

Arthur Beaudet Baylor College of Medicine

Eric Fombonne McGill University

Raphael Bernier University of Washington

John Gabrieli Massachusetts Institute of Technology

Joseph Buxbaum Mount Sinai School of Medicine

Daniel Geschwind University of California, Los Angeles

Brian Chait The Rockefeller University

Jay Gingrich Research Foundation for Mental Hygiene, Inc., New York State Psychiatric Institute

Aravinda Chakravarti Johns Hopkins University School of Medicine Andrew Chess Massachusetts General Hospital John Constantino Washington University Edwin Cook, Jr. University of Illinois at Chicago Eric Courchesne University of California, San Diego Mark Daly Massachusetts General Hospital Ted M. Dawson Johns Hopkins University School of Medicine Curtis Deutsch University of Massachusetts Medical School

Joseph Gogos Columbia University Ann Graybiel Massachusetts Institute of Technology Paul Greengard The Rockefeller University James F. Gusella Massachusetts General Hospital Nathaniel Heintz The Rockefeller University Barbara Hempstead Weill Medical College of Cornell University Z. Josh Huang Cold Spring Harbor Laboratory

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Eric R. Kandel Columbia University

Vijaya Ramesh Massachusetts General Hospital

Ami Klin Yale University

Louis Reichardt University of California, San Francisco

Richard Krauzlis Salk Institute for Biological Studies

Bernardo Sabatini Harvard Medical School

Abba Krieger University of Pennsylvania

Joshua Sanes Harvard University

Louis Kunkel Children's Hospital Boston

Rebecca Saxe Massachusetts Institute of Technology

David Ledbetter Emory University

Morgan Sheng Massachusetts Institute of Technology

Arnold J. Levine Institute for Advanced Study

Maggie Shiffrar Rutgers, The State University of New Jersey

Pat Levitt Vanderbilt University

Pawan Sinha Massachusetts Institute of Technology

Dan Littman New York University School of Medicine

Hazel Sive Whitehead Institute for Biomedical Research

Catherine Lord University of Michigan

Matthew State Yale University

Christa Lese Martin Emory University

Thomas Südhof Stanford University

Steven McKnight University of Texas Southwestern Medical Center

David Sulzer Columbia University

Judith Miles University of Missouri

Mriganka Sur Massachusetts Institute of Technology

Alea Mills Cold Spring Harbor Laboratory

James Sutcliffe Vanderbilt University

Anthony Monaco University of Oxford

Susumu Tonegawa Massachusetts Institute of Technology

Daniel Notterman Princeton University

Li-Huei Tsai Massachusetts Institute of Technology

Opal Ousley Emory University

Richard Tsien Stanford University

Luis Parada University of Texas Southwestern Medical Center

Michael Ullman Georgetown University

Karen Parker Stanford University

Christopher Walsh Beth Israel Deaconess Medical Center

Paul Patterson California Institute of Technology

Stephen Warren Emory University

Kevin Pelphrey Yale University

Zachary Warren Vanderbilt University

Bradley Peterson Columbia University

Michael Wigler Cold Spring Harbor Laboratory

Judith Piggot University of California, Los Angeles

Huda Zoghbi Baylor College of Medicine

Joseph Piven University of North Carolina at Chapel Hill

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Simons Foundation Annual Report 2008 { Simons Grants }

Grants to Institutions Math and Physical Science American University of Beirut Beirut, Lebanon Friends of the Institut des Hautes Études Scientifiques New York, New York Harvard University Cambridge, Massachusetts Massachusetts Institute of Technology Cambridge, Massachusetts Mathematical Sciences Research Institute Berkeley, California Science Festival Foundation New York, New York S. S. Chern Foundation for Mathematical Research Beijing, China Stony Brook University Stony Brook, New York Tsinghua Education Foundation Beijing, China University of California, Berkeley Berkeley, California

Math and Science Education Aquarium of the Pacific Long Beach, California Fannie & John Hertz Foundation Livermore, California Math for America New York, New York New England Aquarium Boston, Massachusetts Ohio State University Columbus, Ohio

Memorial Sloan-Kettering Cancer Center New York, New York The Rockefeller University New York, New York Autism Baylor College of Medicine Houston, Texas Beth Israel Deaconess Medical Center Boston, Massachusetts California Institute of Technology Pasadena, California Children’s Hospital Boston Boston, Massachusetts Children’s Hospital Philadelphia Philadelphia, Pennsylvania Cold Spring Harbor Laboratory Cold Spring Harbor, New York Columbia University New York, New York Cornell University New York, New York Duke University Durham, North Carolina Emory University Atlanta, Georgia Georgetown University Washington, District of Columbia Harvard Medical School Boston, Massachusetts Johns Hopkins University Baltimore, Maryland Massachusetts General Hospital Boston, Massachusetts

Life Sciences

Massachusetts Institute of Technology Cambridge, Massachusetts

Beth Israel Deaconess Medical Center Boston, Massachusetts

McGill University Montreal, Canada

Cold Spring Harbor Laboratory Cold Spring Harbor, New York

Mount Sinai School of Medicine New York, New York

Institute for Advanced Study Princeton, New Jersey

New York University School of Medicine New York, New York

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Princeton University Princeton, New Jersey

University of Missouri Columbia, Missouri

Research Foundation for Mental Hygiene, Inc., at New York State Psychiatric Institute New York, New York

University of North Carolina at Chapel Hill Chapel Hill, North Carolina

Rockefeller University New York, New York Rutgers, The State University of New Jersey New Brunswick, New Jersey Salk Institute for Biological Studies La Jolla, California Stanford University Menlo Park, California University of California, Los Angeles Los Angeles, California University of California, San Diego San Diego, California University of California, San Francisco San Francisco, California University of Illinois at Chicago Chicago, Illinois

University of Oxford Oxford, England University of Pennsylvania Philadelphia, Pennsylvania University of Texas Southwestern Medical Center Dallas, Texas University of Washington Seattle, Washington Vanderbilt University Nashville, Tennessee Washington University in St. Louis St. Louis, Missouri Whitehead Institute for Biomedical Research Cambridge, Massachusetts Yale University New Haven, Connecticut

University of Massachusetts Medical School Worcester, Massachusetts University of Michigan Ann Arbor, Michigan

SFARI Scientific Advisory Board Dennis W. Choi, M.D., Ph.D. Emory University

Richard P. Lifton, M.D., Ph.D. Yale University

Wendy Chung, M.D., Ph.D. Columbia University Medical Center

Catherine E. Lord, Ph.D. University of Michigan Autism and Communication Disorders Center

Thomas M. Jessell, Ph.D. Columbia University Nancy Kanwisher, Ph.D. Massachusetts Institute of Technology

J. Anthony Movshon, Ph.D. New York University School of Medicine Martin Raff, M.D. University College London

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Simons Foundation Annual Report 2008 { Contact }

For more information on the Simons Foundation and SFARI, please visit our websites: simonsfoundation.org sfari.org

The Flower of Maths was quoted on page 5 with permission from “The Unravelers: Mathematical Snapshots,” AK Peters Ltd, 2008. All photos on the bottom of pages 10 and 11 are courtesy of IHÉS and appear in the book, “The Unravelers: Mathematical Snapshots,” © Copyright Jean-François Dars, AK Peters Ltd, 2008. Michael Atiyah was quoted on page 12 with permission from “The Unravelers: Mathematical Snapshots,” AK Peters Ltd, 2008.

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