News Article | May 17, 2017
Most research institutions are essentially collections of independent laboratories, each run by principal investigators who head a team of trainees. This scheme has ancient roots and a track record of success. But it is not the only way to do science. Indeed, for much of modern biomedical research, the traditional organization has become limiting. A different model is thriving at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, where I work. In the 1990s, the Whitehead Institute for Biomedical Research, a self-governing organization in Cambridge affiliated with the Massachusetts Institute of Technology (MIT), became the academic leader in the Human Genome Project. This meant inventing and applying methods to generate highly accurate DNA sequences, characterize errors precisely and analyse the outpouring of data. These project types do not fit neatly into individual doctoral theses. Hence, the institute created a central role for staff scientists — individuals charged with accomplishing large, creative and ambitious projects, including inventing the means to do so. These non-faculty scientists work alongside faculty members and their teams in collaborative groups. When leaders from the Whitehead helped to launch the Broad Institute in 2004, they continued this model. Today, our work at the Broad would be unthinkable without professional staff scientists — biologists, chemists, data scientists, statisticians and engineers. These researchers are not pursuing a tenured academic post and do not supervise graduate students, but do cooperate on and lead projects that could not be accomplished by a single academic laboratory. Physics long ago saw the need to expand into different organizational models. The Manhattan Project, which during the Second World War harnessed nuclear energy for the atomic bomb, was not powered by graduate students. Europe's particle-physics laboratory, CERN, does not operate as atomized labs with each investigator pursuing his or her own questions. And the Jet Propulsion Laboratory at the California Institute of Technology in Pasadena relies on professional scientists to get spacecraft to Mars. In biology, many institutes in addition to the Broad are experimenting with new organizational principles. The Mechanobiology Institute in Singapore pushes its scientists to use tools from other disciplines by discouraging individual laboratories from owning expensive equipment unless it is shared by all. The Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Virginia, the Salk Institute of Biological Sciences in La Jolla, California, and the Allen Institute for Brain Science in Seattle, Washington, effectively mix the work of faculty members and staff scientists. Disease-advocacy organizations, such as the ALS Therapy Development Institute in Cambridge, do their own research without any faculty members at all. Each of these institutes has a unique mandate, and many are fortunate in having deep resources. They also had to be willing to break with tradition and overcome cultural barriers. At famed research facilities of yore, such as Bell Labs and IBM Laboratories, the title 'staff scientist' was a badge of honour. Yet to some biologists the term suggests a permanent postdoc or senior technician — someone with no opportunities for advancement who works solely in a supervisor's laboratory, or who runs a core facility providing straightforward services. That characterization sells short the potential of professional scientists. The approximately 430 staff scientists at the Broad Institute develop cutting-edge computational methods, invent and incorporate new processes into research pipelines and pilot and optimize methodologies. They also transform initial hits from drug screens into promising chemical compounds and advance techniques to analyse huge data sets. In summary, they chart the path to answering complex scientific questions. Although the work of staff scientists at the Broad Institute is sometimes covered by charging fees to its other labs, our faculty members would never just drop samples off with a billing code and wait for data to be delivered. Instead, they sit down with staff scientists to discuss whether there is an interesting collaboration to be had and to seek advice on project design. Indeed, staff scientists often initiate collaborations. Naturally, tensions still arise. They can play out in many ways, from concerns over how fees are structured, to questions about authorship. Resolving these requires effort, and it is a task that will never definitively be finished. In my view, however, the staff-scientist model is a win for all involved. Complex scientific projects advance more surely and swiftly, and faculty members can address questions that would otherwise be out of reach. This model empowers non-faculty scientists to make independent, creative contributions, such as pioneering new algorithms or advancing technologies. There is still much to do, however. We are working to ensure that staff scientists can continue to advance their careers, mentor others and help to guide the scientific direction of the institute. As the traditional barriers break down, science benefits. Technologies that originate in a faculty member's lab sometimes attract more collaborations than one laboratory could sustain. Platforms run by staff scientists can incorporate, disseminate and advance these technologies to capture more of their potential. For example, the Broad Institute's Genetic Perturbation Platform, run by physical chemist David Root, has honed high-throughput methods for RNA interference and CRISPR screens so that they can be used across the genome in diverse biological contexts. Staff scientists make the faculty more productive through expert support, creativity, added capacity and even mentoring in such matters as the best use of new technologies. The reverse is also true: faculty members help staff scientists to gain impact. Our staff scientists regularly win scientific prizes and are invited to give keynote lectures. They apply for grants as both collaborators and independent investigators, and publish regularly. Since 2011, staff scientists have led 36% of all the federal grants awarded for research projects at the Broad Institute (see ‘Staff-led grants’). One of our staff scientists, genomicist Stacey Gabriel, topped Thomson Reuters' citation analysis of the World's Most Influential Scientific Minds in 2016. She co-authored 25 of the most highly cited papers in 2015 — a fact that illustrates both how collaborative the Broad is and how central genome-analysis technologies are to answering key biological questions. At the Broad Institute's Stanley Center for Psychiatric Research, which I direct, staff scientists built and operate HAIL, a powerful open-source tool for analysis of massive genetics data sets. By decreasing computational time, HAIL has made many tasks 10 times faster, and some 100 times faster. Staff scientist Joshua Levin has developed and perfected RNA-sequencing methods used by many colleagues to analyse models of autism spectrum disorders and much else. Nick Patterson, a mathematician and computational biologist at the Stanley Center, began his career by cracking codes for the British government during the cold war. Today, he uses DNA to trace past migrations of entire civilizations, helps to solve difficult computational problems and is a highly valued support for many biologists. Why haven't more research institutions expanded the roles of staff scientists? One reason is that they can be hard to pay for, especially by conventional means. Some funding agencies look askance at supporting this class of professionals; after all, graduate students and postdocs are paid much less. In my years leading the US National Institute of Mental Health, I encountered people in funding bodies across the world who saw a rising ratio of staff to faculty members or of staff to students as evidence of fat in the system. That said, there are signs of flexibility. In 2015, the US National Cancer Institute began awarding 'research specialist' grants — a limited, tentative effort designed in part to provide opportunities for staff scientists. Sceptical funders should remember that trainees often take years to become productive. More importantly, institutions' misuse of graduates and postdocs as cheap labour is coming under increasing criticism (see, for example, et al. Proc. Natl Acad. Sci. USA 111, 5773–5777; 2014). Faculty resistance is also a factor. I served as Harvard University's provost (or chief academic officer) for a decade. Several years in, I launched discussions aimed at expanding roles for staff scientists. Several faculty members worried openly about competition for space and other scarce resources, especially if staff scientists were awarded grants but had no teaching responsibilities. Many recoiled from any trappings of corporatism or from changes that felt like an encroachment on their decision-making. Some were explicitly concerned about a loss of access and control, and were not aware of the degree to which staff scientists' technological expertise and cross-disciplinary training could help to answer their research questions. Institutional leaders can mitigate these concerns by ensuring that staff positions match the shared goals of the faculty — for scientific output, education and training. They must explain how staff-scientist positions create synergies rather than silos. Above all, hiring plans must be developed collaboratively with faculty members, not by administrators alone. The Broad Institute attracts world-class scientists, as both faculty members and staff. Its appeal has much to do with how staff scientists enable access to advanced technology, and a collaborative culture that makes possible large-scale projects rarely found in academia. The Broad is unusual — all faculty members also have appointments at Harvard University, MIT or Harvard-affiliated hospitals. The institute has also benefited from generous philanthropy from individuals and foundations that share our values and believe in our scientific mission. Although traditional academic labs have been and continue to be very productive, research institutions should look critically and creatively at their staffing. Creating a structure like that of the Broad Institute would be challenging in a conventional university. Still, I believe any institution that is near an academic health centre or that has significant needs for advanced technology could benefit from and sustain the careers of staff scientists. If adopted judiciously, these positions would enable institutions to take on projects of unprecedented scope and scale. It would also create a much-needed set of highly rewarding jobs for the rising crop of talented researchers, particularly people who love science and technology but who do not want to pursue increasingly scarce faculty positions. A scientific organization should be moulded to the needs of science, rather than constrained by organizational traditions.
News Article | April 25, 2017
A large new study from the Psychiatric Genomics Consortium provides the first molecular genetic evidence that genetic influences play a role in the risk of getting Posttraumatic Stress Disorder (PTSD) after trauma. The report extends previous findings that showed that there is some shared genetic overlap between PTSD and other mental disorders such as schizophrenia. It also finds that genetic risk for PTSD is strongest among women. The study will be published April 25, 2017 in Molecular Psychiatry. "We know from lots of data -- from prisoners of war, people who have been in combat, and from rape victims -- that many people exposed to even extreme traumatic events do not develop PTSD. Why is that? We believe that genetic variation is an important factor contributing to this risk or resilience," said senior author Karestan Koenen, professor of psychiatric epidemiology at Harvard T.H. Chan School of Public Health who leads the Global Neuropsychiatric Genomics Initiative of the Stanley Center for Psychiatric Research at Broad Institute. PTSD is a common and debilitating mental disorder that occurs after a traumatic event. Symptoms include re-experiencing the traumatic event, avoiding event-related stimuli, and chronic hyperarousal. In the U.S., one in nine women and one in twenty men will meet the criteria for a PTSD diagnosis at some point in their lives. The societal impact is large, including increased rates of suicide, hospitalization, and substance use. The new study -- by bringing together data from more than 20,000 people participating in 11 multi-ethnic studies around the world -- builds a strong case for the role of genetics in PTSD, which had been previously documented on a smaller scale in studies of twins. Using genome-wide genomic data, the researchers found that, among European American females, 29% of the risk for developing PTSD is influenced by genetic factors, which is comparable to that of other psychiatric disorders. In contrast, men's genetic risk for PTSD was substantially lower. The researchers found strong evidence that people with higher genetic risk for several mental disorders -- including schizophrenia, and to a lesser extent bipolar and major depressive disorder -- are also at higher genetic risk for developing PTSD after a traumatic event. "PTSD may be one of the most preventable of psychiatric disorders," said first author Laramie Duncan, who did part of the research while at the Broad Institute and is now at Stanford University. "There are interventions effective in preventing PTSD shortly after a person experiences a traumatic event. But they are too resource-intensive to give to everyone. Knowing more about people's genetic risk for PTSD may help clinicians target interventions more effectively and it helps us understand the underlying biological mechanisms."
News Article | April 27, 2017
Regenerative medicine using human pluripotent stem cells to grow transplantable tissue outside the body carries the promise to treat a range of intractable disorders, such as diabetes and Parkinson’s disease. However, as stem cell lines grow in a lab dish, they often acquire mutations in the TP53 (p53) gene, an important tumor suppressor responsible for controlling cell growth and division, according to new research from a team at the Harvard Stem Cell Institute, Harvard Medical School and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The findings suggest that genetic sequencing technologies should be used to screen stem cell cultures so that those with mutated cells can be excluded from scientific experiments and clinical therapies. If such methods are not employed, the researchers said, it could lead to an elevated cancer risk in patients receiving transplants. The paper, published online in the journal Nature on April 26, comes at just the right time, the researchers said, as experimental treatments using human pluripotent stem cells are ramping up across the country. “Our results underscore the need for the field of regenerative medicine to proceed with care,” said the study’s co-corresponding author, Kevin Eggan, a principal faculty member at HSCI and director of stem cell biology at the Stanley Center. The team said that the new research should not discourage the pursuit of experimental treatments, but instead should be heeded as a call to rigorously screen all cell lines for mutations at various stages of development as well as immediately before transplantation. “Fortunately,” said Eggan, this additional series of genetic quality-control checks “can be readily performed with precise, sensitive and increasingly inexpensive sequencing methods.” Researchers can use human stem cells to recreate human tissue in the lab. Eggan’s lab in Harvard University’s Department of Stem Cell and Regenerative Biology uses human stem cells to study the mechanisms of brain disorders, including amyotrophic lateral sclerosis, intellectual disability and schizophrenia. Eggan has also been working with Steve McCarroll, associate professor of genetics at HMS and director of genetics at the Stanley Center, to study how genes shape the biology of neurons, which can be derived from human stem cells. McCarroll’s lab recently discovered a common precancerous condition in which a blood stem cell in the body acquires a so-called pro-growth mutation and then outcompetes a person’s normal stem cells, becoming the dominant generator of that person’s blood cells. People with this condition are 12 times more likely to develop blood cancer later in life. The current study’s lead authors, Florian Merkle and Sulagna Ghosh, collaborated with Eggan and McCarroll to test whether laboratory-grown stem cells might be vulnerable to an analogous process. “Cells in the lab, like cells in the body, acquire mutations all the time,” said McCarroll, co-corresponding author of the study. “Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous and ‘take over’ a tissue.” “We found that this process of clonal selection—the basis of cancer formation in the body—is also routinely happening in laboratories.” To find acquired mutations, the researchers performed genetic analyses on 140 stem cell lines. Twenty-six lines had been developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 were listed on the NIH registry of human pluripotent stem cells. “While we expected to find some mutations, we were surprised to find that about 5 percent of the stem cell lines we analyzed had acquired mutations in a tumor-suppressing gene called p53,” said Merkle. Nicknamed the “guardian of the genome,” p53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni syndrome, which confers a near 100 percent risk of developing cancer in a wide range of tissue types. The specific mutations that the researchers observed are dominant negative mutations, meaning that when present on even one copy of p53, they compromise the function of the normal protein. The same dominant negative mutations are among the most commonly observed mutations in human cancers. “They are among the worst p53 mutations to have,” said co-lead author Ghosh. The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the scientists found that p53 mutant cells outperformed and outcompeted nonmutant cells in the lab dish. In other words, a culture with a million healthy cells and one p53 mutant cell, said Eggan, could quickly become a culture of only mutant cells. “The spectrum of tissues at risk for transformation when harboring a p53 mutation includes many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells,” said Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver and lungs. However, Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with concerning mutations that might prove dangerous after transplantation. The researchers point out in their paper that screening approaches already exist to identify these p53 mutations and others that confer cancer risk. Such techniques are being used in cancer diagnostics. In fact, an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells (iPSCs) is using gene sequencing to ensure the transplanted cell products are free of dangerous mutations.
News Article | April 26, 2017
Regenerative medicine using human pluripotent stem cells to grow transplantable tissue outside the body carries the promise to treat a range of intractable disorders, such as diabetes and Parkinson's disease. However, a research team from the Harvard Stem Cell Institute (HSCI), Harvard Medical School (HMS), and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard has found that as stem cell lines grow in a lab dish, they often acquire mutations in the TP53 (p53) gene, an important tumor suppressor responsible for controlling cell growth and division. Their research suggests that genetic sequencing technologies should be used to screen for mutated cells in stem cell cultures, so that cultures with mutated cells can be excluded from scientific experiments and clinical therapies. If such methods are not employed it could lead to an elevated cancer risk in those receiving transplants. The paper, published online in the journal Nature on April, 26, comes at just the right time, the researchers said, as experimental treatments using human pluripotent stem cells are ramping up across the country. "Our results underscore the need for the field of regenerative medicine to proceed with care," said the study's co-corresponding author Kevin Eggan, an HSCI Principal Faculty member and the director of stem cell biology for the Stanley Center. Eggan's lab in Harvard University's Department of Stem Cell and Regenerative Biology uses human stem cells to study the mechanisms of brain disorders, including amyotrophic lateral sclerosis, intellectual disability, and schizophrenia. The research, the team said, should not discourage the pursuit of experimental treatments but instead be heeded as a call to screen rigorously all cell lines for mutations at various stages of development as well as immediately before transplantation. "Our findings indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies," Eggan said. "Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods." With human stem cells, researchers can recreate human tissue in the lab. This enables them to study the mechanisms by which certain genes can predispose an individual to a particular disease. Eggan has been working with Steve McCarroll, associate professor of genetics at Harvard Medical School and director of genetics at the Stanley Center, to study how genes shape the biology of neurons, which can be derived from these stem cells. McCarroll's lab recently discovered a common, precancerous condition in which a blood stem cell in the body acquires a pro-growth mutation and then outcompetes a person's normal stem cells, becoming the dominant generator of his or her blood cells. People in whom this condition has appeared are 12 times more likely to develop blood cancer later in life. The study's lead authors, Florian Merkle and Sulagna Ghosh, collaborated with Eggan and McCarroll to test whether laboratory-grown stem cells might be vulnerable to an analogous process. "Cells in the lab, like cells in the body, acquire mutations all the time," said McCarroll, co-corresponding author. "Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous, and 'take over' a tissue. We found that this process of clonal selection - the basis of cancer formation in the body - is also routinely happening in laboratories." To find acquired mutations, the researchers performed genetic analyses on 140 stem cell lines--26 of which were developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 were listed on the NIH registry of human pluripotent stem cells. "While we expected to find some mutations in stem cell lines, we were surprised to find that about five percent of the stem cell lines we analyzed had acquired mutations in a tumor-suppressing gene called p53," said Merkle. Nicknamed the "guardian of the genome," p53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni Syndrome, which confers a near 100 percent risk of developing cancer in a wide range of tissue types. The specific mutations that the researchers observed are "dominant negative" mutations, meaning, when present on even one copy of P53, they are able to compromise the function of the normal protein, whose components are made from both gene copies. The exact same dominant-negative mutations are among the most commonly observed mutations in human cancers. "These precise mutations are very familiar to cancer scientists. They are among the worst P53 mutations to have," said Sulagna Ghosh, a co-lead author of the study. The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the Harvard scientists found that p53 mutant cells outperformed and outcompeted non-mutant cells in the lab dish. In other words, a culture with a million healthy cells and one p53 mutant cell, said Eggan, could quickly become a culture of only mutant cells. "The spectrum of tissues at risk for transformation when harboring a p53 mutation include many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells," said Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver and lungs. However, Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with concerning mutations that might prove dangerous after transplantation. The researchers point out in their paper that screening approaches to identify these p53 mutations and others that confer cancer risk already exist and are used in cancer diagnostics. In fact, in an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells (iPSCs), gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations. This work was supported by the Harvard Stem Cell Institute, the Stanley Center for Psychiatric Research, The Rosetrees Trust and The Azrieli Foundation, Howard Hughes Medical Institute, the Wellcome Trust, the Medical Research Council, and the Academy of Medical Sciences, and by grants from the NIH (HL109525, 5P01GM099117, 5K99NS08371, HG006855, MH105641).
News Article | April 25, 2017
Boston, MA - A large new study from the Psychiatric Genomics Consortium provides the first molecular genetic evidence that genetic influences play a role in the risk of getting Posttraumatic Stress Disorder (PTSD) after trauma. The report extends previous findings that showed that there is some shared genetic overlap between PTSD and other mental disorders such as schizophrenia. It also finds that genetic risk for PTSD is strongest among women. The study will be published April 25, 2017 in Molecular Psychiatry. After the embargo lifts, the paper can be found at this link: http://dx. "We know from lots of data--from prisoners of war, people who have been in combat, and from rape victims--that many people exposed to even extreme traumatic events do not develop PTSD. Why is that? We believe that genetic variation is an important factor contributing to this risk or resilience," said senior author Karestan Koenen, professor of psychiatric epidemiology at Harvard T.H. Chan School of Public Health who leads the Global Neuropsychiatric Genomics Initiative of the Stanley Center for Psychiatric Research at Broad Institute. PTSD is a common and debilitating mental disorder that occurs after a traumatic event. Symptoms include re-experiencing the traumatic event, avoiding event-related stimuli, and chronic hyperarousal. In the U.S., one in nine women and one in twenty men will meet the criteria for a PTSD diagnosis at some point in their lives. The societal impact is large, including increased rates of suicide, hospitalization, and substance use. The new study--by bringing together data from more than 20,000 people participating in 11 multi-ethnic studies around the world--builds a strong case for the role of genetics in PTSD, which had been previously documented on a smaller scale in studies of twins. Using genome-wide genomic data, the researchers found that, among European American females, 29% of the risk for developing PTSD is influenced by genetic factors, which is comparable to that of other psychiatric disorders. In contrast, men's genetic risk for PTSD was substantially lower. The researchers found strong evidence that people with higher genetic risk for several mental disorders--including schizophrenia, and to a lesser extent bipolar and major depressive disorder--are also at higher genetic risk for developing PTSD after a traumatic event. "PTSD may be one of the most preventable of psychiatric disorders," said first author Laramie Duncan, who did part of the research while at the Broad Institute and is now at Stanford University. "There are interventions effective in preventing PTSD shortly after a person experiences a traumatic event. But they are too resource-intensive to give to everyone. Knowing more about people's genetic risk for PTSD may help clinicians target interventions more effectively and it helps us understand the underlying biological mechanisms." Harvard Chan School's Andrea Roberts, research associate in the Department of Social and Behavioral Sciences, was also a co-author. This study was conducted by the Psychiatric Genomics Consortium PTSD Working Group and was supported by the National Institute of Mental Health (U01MH094432; U01MH094432), Cohen Veterans Bioscience, One Mind, and the Stanley Center for Psychiatric Research. "Largest GWAS of PTSD (N=20,070) Yields Genetic Overlap with Schizophrenia and Sex Differences in Heritability," Laramie E. Duncan, Andrew Ratanatharathorn, Allison E. Aiello, Lynn M. Almli, Ananda B. Amstadter, Allison E. Ashley-Koch, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan Bisson, Bekh Bradley, Chia-Yen Chen, Shareefa Dalvie, Lindsay A. Farrer, Sandro Galea, Melanie E. Garrett, Joel E. Gelernter, Guia Guffanti, Michael A. Hauser, Eric O. Johnson, Ronald C. Kessler, Nathan A. Kimbrel, Anthony King, Nastassja Koen, Henry R. Kranzler, Mark W. Logue, Adam X. Maihofer, Alicia R. Martin, Mark W. Miller, Rajendra A. Morey, Nicole R. Nugent, John P. Rice, Stephan Ripke, Andrea L. Roberts, Nancy L. Saccone, Jordan W. Smoller, Dan J. Stein, Murray B. Stein, Jennifer A. Sumner, Monica Uddin, Robert J. Ursano, Derek E. Wildman, Rachel Yehuda, Hongyu Zhao, Mark J. Daly, Israel Liberzon, Kerry J. Ressler, Caroline M. Nievergelt, Karestan C. Koenen, Molecular Psychiatry, online April 25, 2017, doi: 10.1038/MP.2017.77 Visit the Harvard Chan School website for the latest news, press releases, and multimedia offerings. Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives--not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America's oldest professional training program in public health.
News Article | March 24, 2016
More than 3 million Americans suffer from attention deficit hyperactivity disorder (ADHD), a condition that usually emerges in childhood and can lead to difficulties at school or work. A new study from MIT and New York University links ADHD and other attention difficulties to the brain’s thalamic reticular nucleus (TRN), which is responsible for blocking out distracting sensory input. In a study of mice, the researchers discovered that a gene mutation found in some patients with ADHD produces a defect in the TRN that leads to attention impairments. The findings suggest that drugs boosting TRN activity could improve ADHD symptoms and possibly help treat other disorders that affect attention, including autism. “Understanding these circuits may help explain the converging mechanisms across these disorders. For autism, schizophrenia, and other neurodevelopmental disorders, it seems like TRN dysfunction may be involved in some patients,” said Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research and the Stanley Center for Psychiatric Research at the Broad Institute. Feng and Michael Halassa, an assistant professor of psychiatry, neuroscience, and physiology at New York University, are the senior authors of the study, which appears in the March 23 online edition of Nature. The paper’s lead authors are MIT graduate student Michael Wells and NYU postdoc Ralf Wimmer. Feng, Halassa, and their colleagues set out to study a gene called Ptchd1, whose loss can produce attention deficits, hyperactivity, intellectual disability, aggression, and autism spectrum disorders. Because the gene is carried on the X chromosome, most individuals with these Ptchd1-related effects are male. In mice, the researchers found that the part of the brain most affected by the loss of Ptchd1 is the TRN, which is a group of inhibitory nerve cells in the thalamus. It essentially acts as a gatekeeper, preventing unnecessary information from being relayed to the brain’s cortex, where higher cognitive functions such as thought and planning occur. “We receive all kinds of information from different sensory regions, and it all goes into the thalamus,” Feng said. “All this information has to be filtered. Not everything we sense goes through.” If this gatekeeper is not functioning properly, too much information gets through, allowing the person to become easily distracted or overwhelmed. This can lead to problems with attention and difficulty in learning. The researchers found that when the Ptchd1 gene was knocked out in mice, the animals showed many of the same behavioral defects seen in human patients, including aggression, hyperactivity, attention deficit, and motor impairments. When the Ptchd1 gene was knocked out only in the TRN, the mice showed only hyperactivity and attention deficits. At the cellular level, the researchers found that the Ptchd1 mutation disrupts channels that carry potassium ions, which prevents TRN neurons from being able to sufficiently inhibit thalamic output to the cortex. The researchers were also able restore the neurons’ normal function with a compound that boosts activity of the potassium channel. This intervention reversed the TRN-related symptoms but not any of the symptoms that appear to be caused by deficits of some other circuit. “The authors convincingly demonstrate that specific behavioral consequences of the Ptchd1 mutation — attention and sleep — arise from an alteration of a specific protein in a specific brain region, the thalamic reticular nucleus. These findings provide a clear and straightforward pathway from gene to behavior and suggest a pathway toward novel treatments for neurodevelopmental disorders such as autism,” said Joshua Gordon, an associate professor of psychiatry at Columbia University, who was not involved in the research. Most people with ADHD are now treated with psychostimulants such as Ritalin, which are effective in about 70 percent of patients. Feng and Halassa are now working on identifying genes that are specifically expressed in the TRN in hopes of developing drug targets that would modulate TRN activity. Such drugs may also help patients who don’t have the Ptchd1 mutation, because their symptoms are also likely caused by TRN impairments, Feng said. The researchers are also investigating when Ptchd1-related problems in the TRN arise and at what point they can be reversed. And, they hope to discover how and where in the brain Ptchd1 mutations produce other abnormalities, such as aggression. The research was funded by the Simons Foundation Autism Research Initiative, the National Institutes of Health, the Poitras Center for Affective Disorders Research, and the Stanley Center for Psychiatric Research at the Broad Institute.
News Article | January 28, 2016
Researchers have identified a gene that increases the risk of schizophrenia, and they say they have a plausible theory as to how this gene may cause the devastating mental illness. After conducting studies in both humans and mice, the researchers said this new schizophrenia risk gene, called C4, appears to be involved in eliminating the connections between neurons — a process called "synaptic pruning," which, in humans, happens naturally in the teen years. It's possible that excessive or inappropriate "pruning" of neural connections could lead to the development of schizophrenia, the researchers speculated. This would explain why schizophrenia symptoms often first appear during the teen years, the researchers said. Further research is needed to validate the findings, but if the theory holds true, the study would mark one of the first times that researchers have found a biological explanation for the link between certain genes and schizophrenia. It's possible that one day, a new treatment for schizophrenia could be developed based on these findings that would target an underlying cause of the disease, instead of just the symptoms, as current treatments do, the researchers said. "We're far from having a treatment based on this, but it's exciting to think that one day, we might be able to turn down the pruning process in some individuals and decrease their risk" of developing the condition, Beth Stevens, a neuroscientist who worked on the new study, and an assistant professor of neurology at Boston Children's Hospital, said in a statement. The study, which also involved researchers at the Broad Institute's Stanley Center for Psychiatric Research at Harvard Medical School, is published today (Jan. 27) in the journal Nature. [Top 10 Mysteries of the Mind] From previous studies, the researchers knew that one of the strongest genetic predictors of people's risk of schizophrenia was found within a region of DNA located on chromosome 6. In the new study, the researchers focused on one of the genes in this region, called complement component 4, or C4, which is known to be involved in the immune system. Using postmortem human brain samples, the researchers found that variations in the number of copies of the C4 gene that people had, and the length of their gene, could predict how active the gene was in the brain. The researchers then turned to a genome database, and pulled information about the C4 gene in 28,800 people with schizophrenia, and 36,000 people without the disease, from 22 countries. From the genome data, they estimated people's C4 gene activity. They found that the higher the levels of C4 activity were, the greater a person's risk of developing schizophrenia was. The researchers also did experiments in mice, and found that the more C4 activity there was, the more synapses were pruned during brain development. Previous studies found that people with schizophrenia have fewer synapses in certain brain areas than people without the condition. But the new findings "are the first clear evidence for a molecular and cellular mechanism of synaptic loss in schizophrenia," said Jonathan Sebat, chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego, who was not involved in the study. Still, Sebat said that the studies in mice are preliminary. These experiments looked for signs of synaptic pruning in the mice but weren't able to directly observe the process occurring. More detailed studies of brain maturation are now needed to validate the findings, Sebat said. In addition, it remains to be seen whether synaptic pruning could be a target for antipsychotic drugs, but "it's promising," Sebat said. There are drugs in development to activate the part of the immune system in which C4 is involved, Sebat noted. Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
News Article | April 6, 2016
CAMBRIDGE, MA — Intel and the Broad Institute of MIT and Harvard announced at the Bio-IT World Conference & Expo that they are co-developing new tools, and advancing fundamental capabilities, so large genomic workflows can run at cloud scale. Broad Institute also announced collaborations with cloud providers to enable cloud-based access to its Genome Analysis Toolkit (GATK) software package. This is expected to expand access to the GATK Best Practices pipeline. The new tools Broad is developing with Intel aim to simplify the execution of large genomic workflows such as GATK, and to improve the storage, scalability, and processing of genomic data. This has the potential to not only speed variant detection and biomarker discovery, but enable discoveries that would not have been detected with smaller cohorts. Broad’s workflow execution engine, called “Cromwell,” is designed to launch genomic pipelines on private or public clouds in a portable and reproducible manner. Broad is working with Intel to extend Cromwell’s capabilities to support multiple input languages and execute on multiple back ends simultaneously, enabling researchers to run jobs anywhere. This integrated workflow engine has built-in intelligence capable of finding the optimal way to execute tasks, the most appropriate hardware resources to run those tasks on, and methods to avoid redundant steps. “Orchestrating genomic workflows at cloud scale is complex,” said Dr. Eric Banks, Senior Director of Data Sciences and Data Engineering at Broad and a creator of the GATK software package. “We wanted to simplify the execution of common genomic data types like reads and variants and to create an environment that allows any researcher to do this at scale in an easy-to-use way.” Another area of joint innovation is in the processing and storing of genomic variant datasets, which often consist of large, sparse data matrices. Gene sequence variation data is commonly stored as text files for bioinformatics. The declining cost of DNA sequencing has driven an increase in the volume of genomic data sets that researchers want to incorporate, making it increasingly difficult to jointly analyze large volumes of data from text files. Large scale reads and writes of variant call data, joint genotyping, or variant recalibration require next-generation databases that are built and optimized for genomic data. Broad and Intel are collaborating on a faster, more flexible, and scalable solution. ‘GenomicsDB’ is a novel way to store vast amounts of patient variant data and to perform fast processing with unprecedented scalability. Built and optimized for the management of genomic variant data, GenomicsDB runs on top of an array database system optimized for sparse data called ‘TileDB.’ TileDB was developed by MIT and Intel researchers working at the Intel Science and Technology Center for Big Data, which is based at MIT's Computer Science and Artificial Intelligence Lab. GenomicsDB is now used in the Broad’s production pipeline running on an Intel Xeon processor based cloud environment to perform joint genotyping. “The time it now takes to perform the variant discovery process went from eight days to 18 hours,” Banks said. “However, that’s with 100 whole genomes. We routinely process projects with thousands of samples, so that speedup itself is truly transformative. We recently needed to abandon our attempt to run variant discovery on an eight thousand sample project, because we estimated it would take 90 days without GenomicsDB. With GenomicsDB, however, it should take under a week. This means we can say ‘yes’ to our researchers far more often, on far more ambitious projects.” “With the integration of these two tools into the genomic pipeline that we are running on a cloud environment, the orchestration and execution of the workflow is not only simplified but significantly accelerated,” said Ben Neale, an institute member at the Broad Institute’s Stanley Center for Psychiatric Research and the Broad’s Program in Medical and Population Genetics. “We are excited that the research community will be able to start testing GenomicsDB and Cromwell.” Intel is releasing TileDB and GenomicsDB as open source tools. Engineers building the ‘Collaborative Cancer Cloud,’ a precision medicine network including Oregon Health Sciences University (OHSU), Dana-Farber Cancer Institute (DFCI), and Ontario Institute for Cancer Research (OICR) are already using these tools across their collective data sets. Long-term goals are to expand upon these tools to enable joint genotyping with other large genomic research centers in a federated and secure model, regardless of the location of data. Broad will continue to work with Intel on next-generation computing technologies that address the size, speed, security and scalability challenges associated with large scale genomic sequencing data and analytics. “The progress that we’re seeing in our development work with Broad represents another step in the moonshot goal of taming cancer and other maladies,” said Eric Dishman, Intel Vice President, Health and Life Sciences. “Harnessing and analyzing massive amounts of genomic data may eventually be a key factor in enabling people around the world to live longer, healthier lives.”
News Article | September 14, 2016
In an unprecedented move, the group that selects the winners of the Nobel Prize in Physiology or Medicine — the Nobel Assembly — has asked two of its members to resign following a scandal at the institute that supplies the assembly’s members. But scientists around the world don’t see the events at the Karolinska Institute (KI) in Stockholm as a threat to the reputation of the medical prize. They say that the assembly is sufficiently separate to the KI and has handled the affair well so far. “Everything is exploding now, but the long-term credibility won’t be affected,” says cancer researcher Julio Celis, associate scientific director of the Danish Cancer Society Research Center in Copenhagen. The scandal involves the surgeon Paolo Macchiarini. Multiple inquiries have alleged that he committed scientific misconduct and subjected patients to unethical, experimental tracheal transplant operations, three of which occurred at the affiliated Karolinska University Hospital. Two of the patients have since died, and the third has required continuous hospital care since the transplant. In June, Swedish public prosecutors opened investigations following preliminary charges against Macchiarini of involuntary manslaughter and causing grievous bodily harm. Macchiarini has denied the allegations. On 5 September, an independent report that revealed institutional problems at the KI mentioned Nobel Assembly members Harriet Wallberg-Henriksson and Anders Hamsten — both former KI vice-chancellors — for their roles in hiring Macchiarini in 2010 and subsequently extending his contracts. (Hamsten resigned as vice-chancellor in February after acknowledging that he had misjudged Macchiarini; the KI dismissed Macchiarini in March.) The call for Wallberg-Henriksson and Hamsten to resign came a day after the report and is a first for the 115-year-old panel, says neuroscientist Thomas Perlmann, secretary of the Nobel Committee, whose fixed-term members are elected from the more permanent assembly. “The professionalism of some of the faculty at the Karolinska Institute has been called into question, and this won’t go away,” says Erwin Neher of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, who won the medicine prize in 1991. “But I don’t think this discredits the Nobel prize — they are two different things.” When Alfred Nobel died in 1896, he left the bulk of his fortune — amassed from his explosives businesses — to the Nobel prizes. His will specified which institutions would select each prize, and declared the KI in charge of medicine. The first prizes were awarded in 1901. At first, the entire KI faculty selected the medicine winners, but by the 1970s it had grown too large for this to be practical — and a new law made all documents at state institutions accessible to the public, ruling out secret deliberations. So in 1977, the Nobel Assembly was created, comprising 50 KI professors; the Nobel Foundation pays for its operations. The Nobel Committee has also done a good job of separating itself from the Macchiarini affair since it began, says neuroscientist Eero Castrén at the University of Helsinki. KI geneticist Urban Lendahl, who participated in the decision to hire Macchiarini, resigned his position as secretary-general of the Nobel Committee in February, notes Castrén. (Lendahl stepped down because he anticipated that he would be involved in the investigation.) Two other assembly members — clinical immunologist Katarina Le Blanc, who co-authored a paper with Macchiarini that is under investigation by the Central Ethical Review Board, and Hans-Gustaf Ljunggren, who was dean of research at the KI from 2013 until February — have not been asked to resign because there is still “uncertainty over their roles” in the Macchiarini affair, says Perlmann. “To protect the brand”, he adds, none of the three, nor Wallberg-Henriksson, nor Hamsten, has participated in assembly activities since February. Perlmann says that the Nobel Committee is not taking further action, but will monitor perceptions of the prize to see whether it needs to do more. “It is important that institutions deal in a fair way with those whose judgement or moral probity has been called into question,” says Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute in Boston, Massachusetts, who has nominated prize candidates to the Nobel Committee. “The Nobel Assembly seems to be doing this.” He adds: “There is no benefit to the world, or to patients who have been harmed, by using a very serious incident to undercut a globally important institute.” The assembly has survived other challenges, usually relating to complaints about its choices. In 1994, it encountered accusations — quickly discredited — that it had allowed a drug company to buy the 1986 medicine prize for Italian neuroscientist Rita Levi-Montalcini. Just as the Swedish king never comments on politics, the Nobel Assembly never comments on such complaints. But during its 100th anniversary celebrations, it acknowledged some regrets — such as awarding a share of the 1923 prize for the discovery of insulin to John Macleod, whose role is now questioned, and the failure to recognize Oswald Avery, who identified DNA as the genetic material in the 1940s. “The prize has survived many things,” says cell biologist Måns Ehrenberg of Uppsala University, who has served on the committee that selects the Nobel Prize in Chemistry. “The standard of evaluation no one can criticize.”
News Article | December 2, 2016
Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops. Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now, scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs. The scientists demonstrated that Zika infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus. "Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells," said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University, and co-corresponding author on a paper reporting the research in Cell Stem Cell. "It's very important for the research community to learn that targeting the AXL protein alone will not defend against Zika," agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for BioMedical Research (NIBR). Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain. "We were thinking that the knocked-out NPCs devoid of AXL wouldn't get infected," said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. "But we saw these cells getting infected just as much as normal cells." Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain "organoids" containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice. "We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect," said Kaykas. "For the first few months, the organoids do a really good job in recapitulating normal brain development." Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish. The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika. The Harvard/NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika's global challenge, as the virus has spread to more than 70 countries and territories. "At the genesis of the project, my wife was pregnant," Eggan remarked. "One can't read the newspapers without being concerned." The collaboration grew out of interactions at the Broad Institute of MIT and Harvard's Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders. "Zika seemed to be a big issue where we could have an impact, and we all shared that interest," Eggan said. "It's been great to have this public, private collaboration." The researchers are studying other receptor proteins that may be open to Zika infection, in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus.