NewYork-Presbyterian, Weill Cornell Medicine and Columbia University College of Physicians and Surgeons have helped launch the Simons Foundation Powering Autism Research for Knowledge (SPARK), an online research initiative designed to become the largest autism study ever undertaken in the United States. Sponsored by the Simons Foundation Autism Research Initiative (SFARI), SPARK will collect information and DNA for genetic analysis from 50,000 people with autism and their families to advance scientific understanding of the causes of the condition and to hasten the discovery of supports and treatments.

Dr. Catherine Lord, a professor of psychology in psychiatry and of psychology in pediatrics at Weill Cornell Medicine and founding director of the Center for Autism and the Developing Brain (CADB) at NewYork-Presbyterian, Weill Cornell Medicine and Columbia University College of Physicians and Surgeons, will lead the effort locally. For more information about SPARK or if interested in participating, please visit www.SPARKforAutism.org.

Dr. Lord is a co-author of The Autism Diagnostic Observation Schedule (ADOS-2) and receives royalty income from the sales of those kits.

Imagine that a psychiatrist sees two new patients. The first says she's having trouble sleeping, isn't interested in eating, and can't find joy in activities she once loved. The second also reports that he doesn't enjoy the things he once did, but his other symptoms are the opposite of the first patient's: he's having a hard time getting out of bed, can't stop eating, and has gained weight. Eventually, both are diagnosed with depression and started on similar courses of treatment.

Like patients with depression, people who have autism spectrum disorder can also experience varying symptoms that fall under the same diagnosis. While one person with autism might be nonverbal and have an IQ of 30, another might have an IQ 100 points higher and speak cogently — but repeat a lot of what he or she says, obsess about specialized topics like trains or the weather and have trouble connecting with peers. What unites them are deficits in their social interactions, sensory processing, learning and memory, and verbal and non-verbal communication.

This variability in clinical presentation isn't the only similarity between autism and depression. Some of the root causes of both may be similar, says Dr. Conor Liston'08, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute — and understanding what drives each condition is key to developing targeted therapies. "For both depression and autism, our long-term goal is to customize treatments rather than taking a one-size-fits-all approach," says Dr. Liston. "We're at the basic science level today, but in the not so distant future, the work we're doing might lead to personalized medicine for neuropsychiatric conditions."

For years, Dr. Liston has focused his studies on how nerve cells within the prefrontal cortex — an area that supports cognition, socialization and emotion recognition — communicate with each other and ultimately drive behavior. He theorizes that when there are misfires within these pathways and neural circuits subsequently fail to reconnect — especially during the transition from adolescence to adulthood — depression and other psychiatric conditions may result. Although autism is often diagnosed in childhood rather than adolescence, it too may link back to problems with connections within communication circuits in the brain, Dr. Liston says.

To test this hypothesis, Dr. Liston will revisit an approach he earlier used to identify subtypes of depression. For that work, which is currently in journal review, he studied more than 700 fMRI brain scans of depressed patients gathered from labs at Cornell, Stanford and Emory universities, and discovered distinct patterns. "We found that patients with depression have abnormal connectivity in circuits throughout different regions of the brain," he says. "Basically, in the depressed brain, the wiring is off." He grouped the scans that looked alike, and noted that they corresponded to patients with similar clinical symptoms. The result is what's called a biomarker: a measurable variable — in this case abnormal brain circuitry — that's tied to the same disease process. Ultimately, doctors might be able to discern from a brain scan whether a patient suffers from depression, what sub-type it is, how it might present clinically — and the optimal way to treat it. "Right now, some antidepressants only work in one-third of the people who take them," Dr. Liston notes. "We can do better."

Dr. Liston points out that this work is so challenging — and so important — in part because science still knows relatively little about how the brain works. But new technologies are giving researchers unprecedented insights into its processes, potentially offering great leaps in understanding about neuropsychiatric diseases and how to treat them. To describe the current state of knowledge, Dr. Liston offers an analogy to a computer. The brain's physical structure is the hardware, and when something goes wrong — like the development of a tumor — it's easily detectible on an MRI. But "software" problems are a different matter. "In a person with depression, you can't look at their brain and see anything structurally abnormal about it," Dr. Liston says. "There's something about the software — or the computations being performed by the brain — that is causing a problem."

For his new work on autism, Dr. Liston will use funding from his recent Hartwell Foundation Individual Biomedical Research Award, a grant of $300,000 over three years. His data set: brain scans and clinical information from 1,000 kids with autism, which affects an estimated one in 68 children in the United States. Because he typically studies adolescence and young adulthood, he'll focus on scans from patients aged 10 to 16, scrutinizing them for atypical patterns in neural connectivity within the prefrontal cortex. From there, as in the depression study, he'll try to link the atypical connectivity patterns to specific symptoms. Given the diversity of how autism presents, it's no small task; Dr. Liston predicts the project will require the entire three-year Hartwell Award term. "Once we've identified subtypes of these disorders, we can try to figure out what's going wrong in patients' brain circuits, what molecules are causing these wiring mistakes, and what drugs might be used to rewire them in a more functional way," Dr. Liston says. "With better tools, drugs and interventions, we'll hopefully reach the end goal: to improve each patient's quality of life."

— Anne Machalinski

This story first appeared in Weill Cornell Medicine, Vol. 14, No.3.

Dr. Conor Liston, an assistant professor in the Feil Family Brain and Mind Research Institute at Weill Cornell Medical College, has received a 2014 Hartwell Individual Biomedical Research Award from The Hartwell Foundation.

The award is for $100,000 direct cost per year for three years and will support Dr. Liston's research to develop and test biomarkers in children diagnosed with autism spectrum disorder, a neurodevelopmental syndrome characterized by a variety of deficits in social interaction and communication. Dr. Liston and his research team have previously developed neuroimaging biomarkers for subtypes of depression and other mood disorders and with support from The Hartwell Foundation will seek to extend their approach to autism.

"My research team has lots of preliminary data suggesting this is going to be successful, but it's really only through the generosity of The Hartwell Foundation that I can lead this early stage work and extend it in a new direction to help children," said Dr. Liston, who was recently featured in Episode 2 of the online video series Inside Medicine at Weill Cornell. "This award provides critical support and without it, this important research likely would not happen."

The Hartwell Foundation's mission is to fund early-stage, innovative and cutting-edge biomedical research to benefit children in the United States. This year, awards went to 12 researchers, representing 10 institutions. In addition, for each nominee selected for the Individual Biomedical Research Award, the sponsoring participating institution received a Hartwell Fellowship to fund one postdoctoral candidate of his or her choice who exemplifies the foundation's values. Weill Cornell will receive funding for one postdoctoral candidate for two years, at $50,000 direct cost per year. The fellowship supports scientists and biomedical engineers who have completed a Ph.D. or equivalent doctorate and are still in the early stages of career development.

An estimated one in 68 children in the United States are affected by autism spectrum disorder, and despite extensive research on the condition, its causes and underlying functional changes in the brain that accompany it, remain unclear. Dr. Liston's research seeks to answer some of the outstanding questions about how autism works and presents in the brain. He plans to start the project by developing neuroimaging biomarkers of autism spectrum disorder using an existing dataset that includes brain scans and information about specific types of clinical symptoms in children with autism. Using only scans from patients who are 10 to 16 years old, Dr. Liston and his team will look for abnormal connections in circuits within the prefrontal cortex, which supports cognition, social behavior and emotion recognition, and identify atypical patterns of connectivity associated with specific symptoms of autism within this population.

"It's just like how you can have a cough and I can have a cough and a third person can have a cough, and all of these coughs can be caused by very different things, like an allergy, a cold virus, or bacterial pneumonia," Dr. Liston said. "It's probably the same for patients with autism. We just don't know yet what those causes are, so what we're trying to do in the lab is first identify subgroups of people who have similarities in their symptoms and root causes."

After defining autism subgroups, Dr. Liston's group will work to identify corresponding neuroimaging biomarkers. He will then test the predicted biomarkers against a new data set using brain scans from 75 children and adolescents with autism. This phase of the research will be in close collaboration with Dr. Catherine Lord, an internationally renowned autism expert and founding director of the Center for Autism and the Developing Brain, a collaboration between Weill Cornell Medical College, NewYork-Presbyterian Hospital and Columbia University College of Physicians and Surgeons.

The second part of the project will also involve examining animal models of established autism subtypes. This part of the project will test how changes in brain circuit connectivity will affect autism-related behaviors. If successful, it may lead to targeted treatment approaches that might normalize the affected brain circuits.

"Our long-term goal is to develop personalized medicine for neuropsychiatric conditions," Dr. Liston said, referring to the goal of customizing treatments for each patient rather than taking a one-size-fits-all approach.

"If Conor is successful identifying neuroimaging biomarkers of ASD subtypes, it has the potential to transform clinical care by informing difficult diagnostic questions, like distinguishing moderate and high functioning ASD from healthy children," said Fred Dombrose, president of The Hartwell Foundation. "Such biomarkers may also satisfy the need to correctly identify affected children most likely to benefit from specific strategies for early intervention."

The first steps of identifying biomarkers will likely take the entire three-year Hartwell Award term. Dr. Liston and his team hope to later apply their findings long-term to a larger clinical population, where they will seek to develop targeted treatments in specific individuals.

NEW YORK (December 4, 2014) — Weill Cornell Medical College announced today that it has received a $25 million gift from Gale and Ira Drukier to establish a premier, cross-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. Its goal will be to rapidly translate basic research breakthroughs into the most advanced therapies for patients.

The extraordinary gift names the Gale and Ira Drukier Institute for Children's Health and will enable the medical college to recruit a team of leading scientists, including a renowned expert who will serve as the Gale and Ira Drukier Director, to pursue innovative research that improves treatments and therapies for the littlest patients. The Drukier Institute, a marquee program that will be headquartered on the 12th floor of Weill Cornell's new Belfer Research Building, will also expand and enhance the medical college's already-distinguished research and clinical care programs that strive to end diseases and disorders that affect children and adolescents, including asthma, autism, cancer, cardiovascular disease, infectious diseases and schizophrenia."We couldn't be more grateful to Gale and Ira, whose generous gift exemplifies their commitment to advancing human health and their steadfast support of Weill Cornell Medical College," said Sanford I. Weill, chairman of the Weill Cornell Board of Overseers. "The Drukiers' investment will better the lives of children in New York and beyond, and will leave a lasting mark on our next generation."

"We are greatly appreciative of Gale and Ira Drukier, whose remarkable gift will enable Weill Cornell to expand its world-class research and clinical care programs for children, who can't be treated like little adults," said Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. "The Drukiers' generosity is critical in allowing us to attract the best and brightest minds in pediatric research, who will lead the way as we pursue innovative treatments and therapies that will ensure the health of children now and in the future."

"As parents and grandparents, Gale and I appreciate the tremendous impact medicine can have on growing children," said Dr. Ira Drukier, a member of the Weill Cornell Board of Overseers. "When you cure children, you give them their entire life back. It's with immense pride that we are able to make this investment, which will empower Weill Cornell Medical College to focus and direct all of its outstanding pediatric research under the auspices of one institute and provide vital resources to develop tomorrow's treatments and cures."

"It gives us great joy to be able to support Weill Cornell Medical College and make such a tremendous difference in children's lives," Dr. Gale Drukier said. "This gift also continues our enduring relationship with Cornell University, with which we have been connected for 40 years."

The Drukiers have a legacy of philanthropy at Cornell University, having provided generous support to its Herbert F. Johnson Art Museum and College of Architecture, Art and Planning.

"We at Cornell are immensely grateful to Gale and Ira Drukier for their extraordinary leadership and generosity, which has already been felt across the university," President David Skorton said. "With this spectacular new gift, the Drukiers are enabling us to achieve an unprecedented level of excellence in pediatric research. The bench-to-bedside approach of the Drukier Institute will have a lasting impact on children and their families, giving hope when they need it most."

"The gift from Gale and Ira Drukier establishing the Drukier Institute for Children's Health makes a powerful statement about the importance of focusing the energies of a major research institution on improving the health and wellbeing of children," said Dr. Gerald M. Loughlin, the Nancy C. Paduano Professor of Pediatrics and chairman of the Department of Pediatrics at Weill Cornell Medical College and pediatrician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. "It is a wonderful legacy for these visionary philanthropists."

Caring for children is particularly challenging because their bodies are constantly changing as they grow, and their metabolisms and immune systems are vastly different than those of adults. Understanding the factors that spur growth in children can present possible lines of inquiry into other diseases, such as cancer, because tumors are also programmed to grow. There are also many genetic and developmental diseases that arise in childhood and pose serious health risks during adulthood. But treating these conditions can be arduous for pediatric patients. Many of the common treatments and therapies available to adults have toxic effects on children, making it critical to devise new and better interventions.

Using genomics and other cutting-edge research approaches, the cross-disciplinary Drukier Institute will drive excellence and innovation in pediatrics, seeking to rapidly and seamlessly catalyze research breakthroughs into the most advanced, safe and effective patient care. The Drukiers' generosity will empower the medical college to recruit five top-flight investigators — including a faculty member who conducts clinical research in pediatric genetics — to augment the distinguished team of physician-scientists already at Weill Cornell, as well as train the next generation of researchers in the field.

To help realize this vision, the Drukiers' gift will enable Weill Cornell to secure the latest research equipment, such as sequencing and informatics technology, as well as develop an infrastructure to establish a biobank. Investigators at the institute will work in close collaboration with clinicians in Weill Cornell's Department of Pediatrics to ensure that children immediately benefit from the latest research advances.

To encourage and support faculty development, research and education, the gift will endow the Drukier Lectureship, an annual lecture at Weill Cornell on a research or clinical topic in the field of children's health. It will also establish the Drukier Prize, which will be awarded once a year to a junior faculty member in the United States or abroad for excellence and achievement in advancing research on childhood diseases or disorders.

About Gale and Ira Drukier

A Cornell University graduate, Ira Drukier is co-owner of BD Hotels, LLC, a real estate development company that owns and operates more than two-dozen hotel properties in New York City, including the Mercer, Hotel Elysee and the Maritime.

Dr. Drukier graduated from Cornell in 1966 with a Bachelor of Science in Engineering with a focus on solid-state physics and in 1967 with a Master in Engineering, earning a doctorate in electrical engineering in 1973 from the Polytechnic Institute of Brooklyn. Upon graduation, he joined RCA Corporation's David Sarnoff Research Center, conducting research in the field of microwave semiconductors, which culminated in his development of the first high-power compound semiconductor field effect transistor. In 1976, he joined Microwave Semiconductor Corporation (MSC) and established a division to develop and manufacture high-power microwave transistors for commercial and military use. Siemens Corporation acquired MSC in 1981, and Dr. Drukier stayed on as corporate vice president until 1983, when he ventured into a career in real estate.

Dr. Drukier has served on the Weill Cornell Board of Overseers since 2012, sat on Cornell University's Board of Trustees for eight years and was a member of the Cornell Tech Task Force to help develop the Cornell NYC Tech campus on Roosevelt Island. He is chair of the council for the Johnson Art Museum at Cornell, chair of the board of trustees building committee of the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is vice-chair of the American Society for Yad Vashem and is a member of the Museum of Jewish Heritage's Board of Overseers. He has also published numerous papers and given lectures in the field of microwave electronics and has contributed a chapter to a book on Gallium Arsenide Field Effect Transistors.

Gale Drukier graduated from New York University's Steinhardt School of Culture, Education and Human Development in 1972 with a degree in speech pathology and audiology, later earning a Master of Science ('73) and a Doctor of Education degree ('79) in audiology from Teacher's College at Columbia University. Dr. Drukier began her career as an audiologist at Bellevue Hospital and at Veterans Affairs hospitals in metropolitan New York, later joining Trenton State University — now the College of New Jersey — as a professor. During her 17-year tenure there, Dr. Drukier conducted research, taught and developed the college's nationally accredited graduate program in audiology. She was consistently recognized by her students as the "Best Teacher." After retiring from teaching, Dr. Drukier joined her family's business, BD Hotels, and has managed and renovated properties on Manhattan's West Side for more than 12 years.

Dr. Drukier has continued to serve NYU since her graduation. She has been a member of the Steinhardt Dean's Council since 2005 as a supporter of the educational and fundraising initiatives of the school. In 2007, Dr. Drukier joined the NYU Board of Trustees and presently chairs its Academic Affairs Committee. In 2010, Dr. Drukier endowed and named the deanship of NYU's Steinhardt School of Education. She was awarded the Meritorious Service Award by NYU in 2013.

Dr. Drukier has also been active at Cornell University, chairing the Herbert F. Johnson Museum of Art's Program Committee and is a member of the Plantations Council. Dr. Drukier and her husband endowed the deanship at Cornell's College of Architecture, Art and Planning, endowed the curator of prints and drawings at the Herbert F. Johnson Museum and created a garden at Plantations at Cornell University. The couple is also active in the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is an animal lover, particularly of felines, and is on the board of directors of the Animal Rescue Fund of the Hamptons. The Drukiers have one daughter and four grandchildren.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

This release was updated on Dec. 16, 2014.

Toddlers with autism demonstrated significant improvement after intensive intervention by parents rather than clinicians, according to a new study published online in the journal Pediatrics.

"The treatment model shows that parents can learn to support their child's learning in everyday activities, and that this can result in improvements in the child's overall development and specifically in social communication and autism symptoms," said senior author Dr. Catherine Lord, director of the Center for Autism and the Developing Brain, a collaboration between Weill Cornell Medical College, NewYork-Presbyterian Hospital, and Columbia University College of Physicians and Surgeons. "The study supports the importance of including parents in their children's treatment."

Social communication includes eye gaze, facial expressions, gestures, sounds, sharing of emotion, listening, learning to understand words, discovering how to use objects — things that children with autism have difficulty learning.

"The findings are important because this treatment is viable in many communities," said Dr. Amy Wetherby, director of the Autism Institute at Florida State University’s College of Medicine and lead author of the study. "We have early intervention that's federally and state funded. Now we’ve tested a model that any early intervention system should be able to offer to all families of toddlers with autism. It’s affordable, and it’s efficient in terms of clinicians’ time."

Most children are not diagnosed with autism spectrum disorder (ASD) until age 4 — and even later in lower-income, rural and minority families. By contrast, the American Academy of Pediatrics wants every child to be screened at 18 and 24 months of age. Early diagnosis, however, does little good without early intervention.

In recent years, some intervention trials had achieved improved outcomes for children but required an inaccessible amount of time from clinicians. Others that focused on teaching parents found that the parents learned, but the children didn’t show significant gains from the treatment.

The new study outlines the results of a seven-year, randomized controlled trial, in which families of 82 toddlers with ASD who were 18 months old were assigned to one of two nine-month interventions.

The researchers compared the effects of teaching parents in a group once a week and teaching them individually in their homes three times a week for six months, and then twice a week for three more months. Children in both groups improved in their use of words and autism symptoms. But children in the second group improved more on measures of understanding and social communication.

The investigators also taught families to work with their children in their everyday activities, such as meals and snacks, caregiving and family chores, including how to bring their children into a given activity. They taught parents how to take their children to places in their communities such as playgrounds, grocery stores and restaurants.

"We tried to help parents make interactions fun and fruitful learning moments. But we also taught the parents how to push their child — because their child has autism, and we are finding these children at this very critical moment when their brain is more able to learn," Dr. Wetherby said. "If the parent can start early, then we are more likely to change the child’s trajectory of learning for the rest of their life."

Dr. Lord was involved in the development of some of the instruments used in this research and receives royalty income from the sale of those instruments.

A version of this story ran on the Florida State University website.

It is possible to recover from autism, say researchers from Weill Cornell Medical College and the University of Denver, who followed 85 children from the time they were diagnosed as toddlers until they were in their late teens.

Their study, reported online May 30 in the Journal of Child Psychology and Psychiatry, finds that 9 percent of the group improved to the point that they no longer met the diagnostic criteria for autism. Another 28 percent retained features of autism spectrum disorder (ASD), such as impaired social functioning, but were doing very well in several areas, particularly cognitive and academic functioning, the researchers report. Many in both groups were enrolled in college.

"This rate of improvement is much higher than has been reported before, and that fact offers some very good news," says the study's senior investigator, Dr. Catherine Lord, founding director of the Center for Autism and the Developing Brain, a collaboration between Weill Cornell Medical College, NewYork-Presbyterian Hospital, and Columbia University College of Physicians and Surgeons.

The children who recovered from autism were not misdiagnosed with the disorder as toddlers, Dr. Lord says. At the time of their diagnoses, these children exhibited telltale ASD symptoms such as repetitive behaviors and social dysfunction.

The majority of the mostly male study population, however, did not substantially outgrow their symptoms over the 17 years scientists followed them. In fact, the researchers predicted, with 85 percent success, poorer outcome in this group when the 2-year-olds were first tested. The tests they used were based on cognitive tests, including nonverbal IQs. The most powerful predictor at age 2 for poor outcome was a nonverbal IQ score of less than 70, the researchers say.

"But there is good news in this group, as well: Even children who clearly have significant language disability can become more independent and can continue to make progress in their teens and as young adults if people give them the opportunity to do so," says Dr. Lord, who is also the DeWitt Wallace Senior Scholar and a professor of psychology in psychiatry and in pediatrics at Weill Cornell.

Although the study was not designed to look at interventions for the children & the majority of the young children received help but the treatment each child received varied — Dr. Lord said a mixture of intervention and family support and assistance was invaluable to them. 

For example, she says that youths who outgrew their diagnosis were more likely to have participated in treatment, such as interventions to reduce social dysfunction, and had a greater reduction in repetitive behaviors between ages 2 and 3. Their IQs also increased dramatically during that year.

This suggests the "possibility of greater initial flexibility in brain development and receptivity to environmental stimuli in some children diagnosed with ASD, which then potentially accelerates cognitive growth and behavioral improvements over time," Dr. Lord says.

The study is the first to follow a large number of children from age 2 over two decades. Although diagnosis at that age is common today, it wasn't when her study began, Dr. Lord says. "The families included in this research are quite special, because they knew pretty early that something was wrong with their children, and they sought help and were willing to get involved."

They did the right thing, she adds.

"It is not a good idea for parents of very young children to wait and hope that signs of autism will just go away," she says. "Doing something for the child — getting a youngster involved in activities, starting treatments, beginning preschool or other social activities — seemed to be related to better outcomes in the children that we have followed."

The study provides a road map, of sorts, for following the path of young children diagnosed with ASD, Dr. Lord adds. "We can use our findings to monitor the trajectories of these children — how they are changing in cognitive skills, language, social skills, repetitive behavior, hyperactivity and so on," she says. "Then we can build on the success we see in each child, and perhaps suggest interventions for behaviors that have not improved. For example, we noted that children who did best were the kids that did not seem to be hyperactive — so this may be an area that can be targeted."

Dr. Lord has published about 40 research studies on these children to date. 

"The children were so young when we met them. We have spent much time with them, and now we really want to know how they are doing out on their own, whether they were in college or not," she says.  

Study co-authors include Dr. Deborah K. Anderson from Weill Cornell Medical College (now at the University of Michigan) and Jessie W. Liang from the University of Denver.

This work was supported by grants from the National Institute of Mental Health (MH081873), the National Institute of Child Health and Human Development (U 19 HD 035482), and Autism Speaks. Dr. Lord was involved in the development of some of the instruments used in the research and receives royalty income from Western Psychological Services from the sale of those instruments

Researchers now recognize that older age in a father can increase the risk that his children will develop a variety of disorders, including autism, schizophrenia, even a common form of dwarfism. The question is, how?

Now, in Stem Cell Reports, a research team has solved the problem for one such disease, Apert syndrome, and says its findings may extend to other paternal age-associated disorders. It is testing those disorders to see if that is true.

Scientists have for some time believed that the mutation for Apert syndrome — in which children are born with a disfigured skull, face, hands and feet — first occurs in the healthy fathers' spermatogonial stem cells, the male germ stem cells that produce sperm. Building on that hypothesis, the Weill Cornell investigators provide evidence to support the idea that as a man ages, the number of germ stem cells with this mutation increases, crowding out normal stem cells in the testicle. Their increasing proportion leads to a greater chance of a mutated sperm fertilizing an egg than in a younger man with relatively fewer mutated cells.

Although Apert syndrome is a rare disease, risk "increases considerably when a man is in his late 30s and exponentially thereafter due to production of a greater proportion of mutated sperm," says the study's senior investigator Dr. Marco Seandel, assistant professor of cell and developmental biology in surgery at Weill Cornell.

The findings prove that at least in this disorder, there is truth to the "selfish selection" hypothesis that proposes that when mutated stem cells compete with normal stem cells, the abnormal cells prevail, Dr. Seandel says. Scientists have proposed the theory to explain the effects of paternal age on children's health.

"There had been no experimental proof for this hypothesis, but here we show that the Apert syndrome mutation makes male germ stem cells more competitive, and they go about replacing their normal counterparts," he says. "They seem to be turning on growth pathways that preferentially produce new stem cells with this mutation. The balance of stem cells shifts from normal to mutated."

Scientists have only recently understood that as men age, they produce more genetic abnormalities that can be passed on to their children, Dr. Seandel says. One example is the type of mutation in genes in which a single nucleotide — a "letter" in the genetic code — has been changed. These "point mutations" can lead to disorders or can contribute to susceptibility to disease, he says.

"The older the father is when a child is conceived, the more point mutations he passes on to that child. By contrast, the number of point mutations a child inherits from the mother appears to be relatively fixed — it does not change no matter how old the mother is," Dr. Seandel says. Older women, however, contribute other kinds of genetic defects, such as chromosomal abnormalities, he adds.

As more is known about the paternal age effect, a question arises as to what a man should do to protect his future children, Dr. Seandel says.

"The number of children born to older fathers is rising rapidly, and if the paternal age effect is as widespread as we think it might be, one solution for men who plan to delay having children is to consider banking their sperm," he says.

Finding May Explain Many Brain Disorders, Lead to Prevention and Treatment

NEW YORK (February 27, 2014) — A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.

A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak

Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren't sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.

Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene's DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.

"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient's lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene's DNA, shutting down the gene — which was not known before.

"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."

The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)

The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.

"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."

Hope for treatment — and other disorders

Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.

"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."

So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. "These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development," says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey's laboratory and the first author of the study.

The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo's brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.

The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene's RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.

That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. "If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients," he says.

The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington's disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich's ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.

"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."

Co-authors include Michael S. Cohen from Weill Cornell Medical College; Dr. Wang-Yong Yang from The Scripps Research Institute; and Dr. Jeannine Gerhardt from Albert Einstein College of Medicine.

This work was supported by the Tri-Institutional Stem Cell Initiative (Tri-I SCI) Grant 2008-019, New York Stem Cell Foundation-Druckenmiller Fellowship, Life Sciences Research Foundation Fellowship and Tri-I SCI postdoctoral fellowship, and a FRAXA postdoctoral fellowship. Portions of this project not involving non-NIH registry stem cells were supported by NIH R01 MH80420 and NIH R01 GM079235.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

Weill Cornell Study Sheds Light on Origin of Wide Range of Brain Disorders

NEW YORK (June 6, 2013) — Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain — gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation.

In the journal Cell, the researchers describe, for the first time, that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell. So, for example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions.

The scientists say that there may be a way to use this new knowledge to fix the circuits.

"Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study's senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology.

"The brain is quite 'plastic' and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring," he says.

Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others.

In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known — and thus more prone to error.

Proteins Sense the Environment to Steer the Axon

During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another. Ultimately, these neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed. In this study, researchers investigated neurons that travel up the spinal cord into the brain. "It is very critical that axons are precisely positioned in the spinal cord," Dr. Jaffrey says. "If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain."

The way that an axon guides and finds its proper target is through so-called growth cones located at the tips of axons. "These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them. The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?" Dr. Jaffrey says. The team found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs are translated in growth cones to produce antenna-like proteins that steer the axon like a self-guided missile.

"As a circuit is being built, RNAs in the neuron's growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears," he says.

"If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty," Dr. Jaffrey says.

RNAs have Tremendous Power over Brain Development

The research finding answers a long-standing puzzle in the quest to understand brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey's laboratory.

"There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, you can have spasticity or other movement disorders," Dr. Colak says. "That has raised a major question — why would RNA degradation pathways be so critical for properly creating brain circuits?

"What we show here is that not only does RNA need to be present in growth cones to give instructions, it then also needs to be removed from the growth cones to take away those instructions at the right time," she says. "Both those processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation."

"The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn't anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it."

Other authors of the study are Dr. Sheng-Jian from the Department of Pharmacology at Weill Cornell Medical College and Dr. Bo T. Porse from the Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Denmark.

This work was supported by NIH grant NS56306 to Dr. Jaffrey and a European Molecular Biology Organization (EMBO) postdoctoral fellowship to Dr. Colak.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

Researchers and clinicians are facing watershed moments in the field of autism, manifested in basic science studies and new clinical therapies that may pave the way for greater understanding of autism spectrum disorders, and improved care for children with these disorders.

That was the major takeaway from Growing Up with Autism: Life Transitions, a symposium sponsored by the Weill Cornell Autism Research Program (WCARP) in participation with The Clinical and Translational Science Center (CTSC), on May 11 at Weill Cornell Medical College. The program offered families and health care providers the latest information about and insight into autism research and clinical treatments and therapies, focusing on autism patients' transition from childhood into adulthood.

"The sun is shining in New York City today, and I think the sun is shining in the field of autism," said Dr. Barry Kosofsky, who is the Horace W. Goldsmith Foundation Professor of Pediatrics as well as professor of pediatrics in radiology, professor of neurology and neuroscience and the principal investigator of the Weill Cornell Autism Research Program. "We are in the midst of a revolution in our thinking regarding the diagnosis, therapies and understanding of autism spectrum disorders."

Two panels of experts discussed just that during the day-long symposium, attended by nearly 200 people at Uris Auditorium and Griffis Faculty Club. The first panel, focused on research, featured Dr. John Walkup, vice chair of the Department of Psychiatry and director of the Division of Child and Adolescent Psychiatry; Dr. B.J. Casey, director of Sackler Institute for Developmental Psychobiology; Dr. Francis Lee, professor and vice chair for research in the Department of Psychiatry; and Dr. Anjali Rajadhyaksha, associate professor of neuroscience in pediatrics and associate professor of neuroscience. The panelists relayed information about novel research into autism spectrum disorders and brain development.

The second panel focused on clinical treatment and featured Dr. Catherine Lord, assistant professor of psychology in psychiatry and director of the Center for Autism and the Developing Brain at NewYork-Presbyterian Hospital's campus in Westchester; Dr. John Brown, director of training and programs in applied behavior analysis at Hunter College; Dr. Michael Siller, an assistant professor in the Psychology Department at Hunter College and co-director of the Hunter College Autism Center; and Linda Meyer, executive director of Autism New Jersey and a consultant in private practice. The panelists shared the real-world applications of that basic science research.

The symposium also featured the insights of Dr. Martha Herbert, an assistant professor of neurology at Harvard Medical School and a pediatric neurologist at the Massachusetts General Hospital in Boston who recently published a new book, "The Autism Revolution: Whole Body Strategies for Making Life All It Can Be." In addition, the event included breakout groups as well as a tabling session featuring local community organizations which provide services for autistic children in the region.

"The goal of the symposium is to communicate advances in research to service providers as well as families to try to give them a sense of current thinking," said Dr. Kosofsky, also chief of the Division of Child Neurology at Weill Cornell and an attending physician at NewYork-Presbyterian's Phyllis and David Komansky Center for Children's Health. "We're trying to make it as practical as possible."

The autism symposium began last year as a byproduct of the Weill Cornell Autism Research Program, Dr. Kosofsky said. Established four years ago with the support of the Clinical and Translational Science Center, the program and its multidisciplinary scientists engage in research to improve the understanding behind the genetics and brain chemistry of autism spectrum disorders.

The investigators seek to better identify the physical and behavioral features demonstrated by patients with autism as a starting point in detecting the contributing genetic factors of autism, and potentially any related brain imaging changes. To accomplish this, the investigators enrolled more than 50 families affected by autism in a clinical study that includes clinical evaluations comprised of neuropsychological testing and the drawing of blood to see if they can identify any genetic basis for autism. The investigators sent the first batch of donated blood for testing a month ago, and will use a newly created database with four different sets of clinical information to look for patterns in the genes that may contribute to autism.

The symposium is one way to provide these families with some return on their personal investment, Dr. Kosofsky said. The first, co-hosted last spring at Hunter College, focused on autistic children from birth to five years of age and provided information on signs and symptoms, diagnoses and evaluations. This year's symposium picked up at the transition from childhood to adulthood.

Helping patients, parents and institutions (schools and hospitals) cope with the challenge of the transitions from adolescence to adulthood is one of our greatest challenges in pediatrics," said Dr. Gerald Loughlin, Nancy C. Paduano Professor and chairman of the Department of Pediatrics at Weill Cornell Medical College and pediatrician-in-chief of the NewYork-Presbyterian Phyllis and David Komansky Center for Children's Health. "It's a good problem to have because it means that children are living longer and are interested and able to engage in typical activities of daily living, but it's also our greatest challenge."