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  • richardmitnick 12:13 pm on June 17, 2017 Permalink | Reply
    Tags: , , HMS- Harvard Medical School, ,   

    From HMS: “Staving Off Stem Cell Cancer Risk” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    April 26, 2017 [Never saw this one.]
    HANNAH ROBBINS

    1
    Image: BlackJack3D/Getty Images

    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.

    As stem cell lines grow in a lab dish, however, 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 Harvard Medical School, the Harvard Stem Cell Institute 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.”

    Hidden mutations

    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.”

    A p53 problem

    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.

    Ensuring safety

    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.

    This work was supported by the Harvard Stem Cell Institute, the Stanley Center for Psychiatric Research, the Rosetrees Trust, the Azrieli Foundation, the Howard Hughes Medical Institute, the Wellcome Trust, the Medical Research Council, the Academy of Medical Sciences and grants from the National Institutes of Health (HL109525, 5P01GM099117, 5K99NS08371, HG006855, MH105641).

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 1:13 pm on May 30, 2017 Permalink | Reply
    Tags: Amping Up Antibodies, , HMS- Harvard Medical School   

    From HMS: “Amping Up Antibodies” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    May 26, 2017
    NANCY FLIESLER

    1
    Artist’s rendition of antibodies. Image: urfinguss/Getty Images

    It began with the proteins.

    Before Watson and Crick unraveled DNA’s double helix in the 1950s, biochemists snipped, ground and pulverized animal tissues to extract and study proteins, the workhorses of the body.

    Then, in 1990, the Human Genome Project launched. It promised to uncover the underpinnings of all human biology and the keys to treating disease. Funding for DNA and RNA tools and studies skyrocketed as protein science fell behind.

    While genomics unveiled a wealth of information, including the identity of genes that lead to disease when mutated, researchers still do not fully understand what all the genes really do and how mutations change their function and cause disease.

    Now proteins are promising to provide the missing link.

    Biological chemist, immunologist and structural biologist Timothy Springer is reinventing protein science with new technologies. Now Springer has launched the Institute for Protein Innovation (IPI). Currently housed at Harvard Medical School, the nonprofit aims to create a massive, openly available resource of protein technologies to accelerate drug discovery and development.

    “Proteins lag behind DNA and RNA in institutional research support and funding,” said Springer, Latham Family Professor at HMS and Boston Children’s Hospital. “Yet proteins serve as the targets of almost all drugs and in many cases as therapeutic drugs themselves.”

    Partnering with co-founder Andrew Kruse, assistant professor of biological chemistry and molecular pharmacology at HMS, Springer formally launched the IPI on May 10 with $15 million in grants and philanthropy.

    Accelerating antibodies

    Nearly half of all drugs on the market today are proteins, mostly monoclonal antibodies that home in on specific targets in the body, just as our own antibodies target proteins made by disease-causing organisms. Researchers spent decades producing antibodies in the lab that blocked or activated proteins’ function. This helped investigators figure out what genes and proteins do in the body.

    Seeing their success, drug developers began seeking to mass-produce antibodies that would target protein culprits in diseases such as cancer. However, the development of antibodies for use as therapeutics faced—and still faces—major hurdles.

    First, antibodies are traditionally produced by immunizing animals like mice with a target human protein. That process is often slow and not always effective: If the mouse and human proteins are too similar, the mouse immune system won’t recognize the human protein as foreign and won’t make an antibody. This leaves many extremely important molecules without targeting antibodies.

    Second, many antibodies used in published research studies have not been properly validated through extra testing. This makes it difficult to reproduce the results of pivotal antibody-based studies, slowing scientific progress.

    Probing for proteins

    To circumvent these problems, researchers including British biochemist Greg Winter invented robust “molecular display” technologies. They involve creating immense libraries of unique antibodies or antibody fragments.

    Researchers insert the genes for antibodies into one-celled organisms such as yeast, modified so that the antibodies made by the yeast are displayed on their surface. Billions of yeast cells, each bearing a unique antibody, are then mixed with the protein of interest. The final step is fishing out the yeast that bind to the target proteins most strongly, through a two-step process.

    Because the yeast make the antibodies as instructed by inserted genes, the organisms can be used to create antibodies to molecules that a mouse immune system wouldn’t respond to. In addition, the technique can be scaled up for the high-throughput approaches of genomics and proteomics.

    But there are other problems yet to solve. Many proteins that would be used as targets in the antibody selection process are still extremely difficult to produce. Expertise in antibody manufacture is also lacking.

    Springer believes the solution is an infrastructure to make, develop and validate synthetic antibodies and their target proteins at a scale never before attempted. The IPI’s first major effort will be to develop open-source libraries of well-validated antibodies targeting every human protein found outside cells.

    Academic entrepreneurship

    Unlike Springer’s other commercial start-ups, the IPI is an academic-entrepreneurial hybrid. By straddling the traditional divide, Springer hopes to create alliances between leaders in academic research, biotechnology, the pharmaceutical industry and biomedical investing, while providing open-source resources to the scientific community at little or no charge. The institute will publish its technical processes and share its know-how freely, equipping the next generation of protein scientists.

    Springer intends for the IPI to stay afloat through a mix of public and philanthropic investment, including $5 million from the Massachusetts Life Sciences Center and a $10 million gift from Springer himself. With the 2018 NIH budget poised to be cut 18 percent, the effort could not have come at a better time.

    Springer conducted his postdoctoral studies with Nobel laureate César Milstein, who co-invented monoclonal antibody technology in 1975. This invention has led to far more drugs than have come from genomics. Springer sees IPI as the embodiment of Milstein’s vision of using antibodies to target disease.

    “César would love this,” said Springer. “He really wanted to have the promise of antibodies fulfilled.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 9:23 am on April 21, 2017 Permalink | Reply
    Tags: , Autism studies, HMS- Harvard Medical School,   

    From HMS: “A strengths-based approach to autism” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    April 20, 2017
    Monique Tello, MD, MPH

    1
    No image caption. No image credit.

    At our son’s 18-month checkup five years ago, our pediatrician expressed concern. Gio wasn’t using any words, and would become so frustrated he would bang his head on the ground. Still, my husband and I were in denial. We dragged our feet. Meanwhile, our son grunted and screamed; people said things. Finally we started therapy with early intervention services.

    A few months later, after hundreds of pages of behavior questionnaires for us and hours of testing for Gio, we heard the words: “Your son meets criteria for a diagnosis of autism spectrum disorder…”

    Our journey has taken us through several behavioral approaches with many different providers. Today, Gio is doing very well, in an integrated first grade in public school. He can speak, read, write, and play. His speech and syntax can be hard to understand, but we are thrilled that we can communicate with him.

    The difference between typical and functional

    Longtime autism researcher Laurent Mottron wrote a recent scientific editorial in which he points out that the current approach to treating a child with autism is based on changing them, making them conform, suppressing repetitive behaviors, intervening with any “obsessive” interests. Our family experienced this firsthand. Some of our early behavioral therapists would see Gio lie on the ground to play, his face level with the cars and trucks he was rolling into long rows, and they would tell us, “Make him sit up. No lying down. Let’s rearrange the cars. Tell him, they don’t always have to be in a straight line, Gio!”

    To me, this approach seemed rigid. We don’t all have to act in the exact same way. These kids need to function, not robotically imitate “normal.”

    Why not leverage difference rather than extinguish it?

    We naturally gravitated towards Stanley Greenspan’s “DIR/Floortime” approach, in which therapists and parents follow the child’s lead, using the child’s interests to engage them, and then helping the child to progress and develop.

    Mottron’s research supports Greenspan’s approach: study the child to identify his or her areas of interest. The more intense the interest the better, because that’s what the child will find stimulating. Let them fully explore that object or theme (shiny things? purple things? wheels?) because these interests help the developing brain to figure out the world.

    Then, use that interest as a means to engage with the child, and help them make more connections. Mottron suggests that parents and teachers get on the same level with the child and engage in a similar activity — be it rolling cars and trucks, or lining them up. When the child is comfortable, add in something more. Maybe, make the cars and trucks talk to each other.

    But, don’t pressure the child to join the conversation. Let them be exposed to words, conversations, and songs, without forced social interaction. This is how early language skills can be taught in a non-stressful way, acknowledging and aligning with the autistic brain. The ongoing relationship and engagement will foster communication.

    Basically, what both Greenspan and Mottron are advocating are methods of teaching autistic children to relate, adapt, and function in the world, without “forcing the autism out of them.”

    The concept of accepting autistic kids as they are, and incorporating the natural ways they think into educational and therapeutic techniques, feels right to me. Gio is different from most kids, and really, he’s not interested in most kids. Our attempts to push him to participate in “fun” group activities like soccer, Easter egg hunts, and birthday parties have all been spectacular failures. Maybe the real failure was ours: by pushing him to “fit in,” we deny his true nature. Yes, the way he thinks is sometimes mysterious to us, but he clearly has great strengths: a remarkable ability to focus and persevere, to experiment with his ideas, and to follow his vision.

    World-renowned autism expert and animal rights activist Temple Grandin (who is herself autistic, and very open about her preference for animal rather than human companionship!) sums up Mottron’s approach perfectly: “The focus should be on teaching people with autism to adapt to the social world around them while still retaining the essence of who they are, including their autism.”

    Sources

    generallymedicine blog post: Screaming Frustration: Our Two-Year-Old Won’t Talk

    generallymedicine blog post: They Dropped the A-Bomb On Us

    generallymedicine blog post: So Our Son Is Autistic… and It’s Going to Be Okay

    generallymedicine blog post: Should we let our kid hang out by himself most of the time?

    generallymedicine blog post: Autism Awareness… and Coolness

    Greenspan, Stanley (2006). Engaging Autism. Da Capo Press. http://www.stanleygreenspan.com

    Mottron, L. Should we change targets and methods of early intervention in autism, in favor of a strengths-based education? European Child & Adolescent Psychiatry, February 2017, e-pub ahead of print.

    Related Information: The Autism Revolution

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 2:40 pm on April 3, 2017 Permalink | Reply
    Tags: , HMS- Harvard Medical School, , Taking Their Best Shot   

    From HMS: “Taking Their Best Shot’ 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    March 24, 2017
    NANCY FLIESLER

    1
    Image: Esben_H/Getty Images

    In many parts of the world, babies have just one chance to be vaccinated: when they’re born. Unfortunately, newborns’ immune systems don’t respond well to most vaccines. That’s why, in the U.S., most immunizations start at two months of age.

    Currently, only BCG (for tuberculosis), polio and hepatitis B vaccines work in newborns, and the last two require multiple doses. But new research raises the possibility of one-shot vaccinations at birth—with huge implications for reducing infant mortality.

    The trick? Specially designed additives—adjuvants—tailored to stimulate newborns’ unique immune systems.

    Two papers published today demonstrate strong vaccine responses in newborn mice, and, more importantly, in newborn monkeys, the ultimate preclinical test. Both studies used formulations designed to maximize safety.

    “Our efforts have led to adjuvant approaches that may enable earlier protection of newborns and young infants from life-threatening infectious diseases, such as pneumococcus, pertussis or even respiratory syncytial virus,” said Ofer Levy, HMS associate professor of pediatrics at Boston Children’s Hospital and a senior author of both papers.

    Dramatic response

    The first of the new studies, led by David Dowling , an HMS research fellow in pediatrics in the Division of Infectious Diseases at Boston Children’s, tested an adjuvant called 3M-052. The adjuvant was manufactured by 3M Drug Delivery Systems, which partially funded the study. It works by stimulating two specific toll-like receptors (pathogen-sensing proteins), TLR7 and TLR8.

    Newborn rhesus monkeys received a series of three shots with the existing Prevnar 13 pneumococcal vaccine—“the same as my children got,” said Levy, who directs the Precision Vaccines Program at Boston Children’s.

    The team chose pneumococcal vaccine as a test case because Streptococcus pnumoniae can cause potentially fatal pneumonia, meningitis and sepsis in infants.

    Prevnar 13 already comes with an adjuvant, Alum, but half the monkeys were randomized to also receive 3M-052. All were monitored at the Tulane National Primate Research Center.

    As reported in JCI Insight, the immune response was dramatic.

    At day 28, even before their second dose, the monkeys receiving 3M-052 were producing robust quantities of antibodies. In fact, their antibody levels were 10 to 100 times higher than those with Prevnar 13 alone—high enough to ensure protection against infection. They also showed dramatically enhanced production of CD4+ T cells and B cells specific to Streptococcus pneumoniae.

    “The protective antibody response we saw was so strong that it’s conceivable that you could get protection with one shot,” said Levy. “This is critical because in many parts of the world, birth is the most reliable point of healthcare contact. After birth, it becomes challenging to bring children in for repeated clinic visits.”

    The 3M-052 adjuvant was chemically modified to minimize side effects. An added lipid “tail,” which doesn’t mix well with water, keeps the adjuvant from getting into the bloodstream, where it could cause side effects.

    “Rather than floating all over the place causing fever and chills, it stays put in the muscle and enhances the immune response to the vaccine,” said Levy.

    Alternate approach

    The second study, published in the Journal of Allergy and Clinical Immunology, was led by Dowling and Evan Scott of Northwestern University. It tested a different adjuvant, CL075, and a different type of formulation.

    This time, vaccine and adjuvant were encapsulated in nanoparticles designed to maximize the immune response while avoiding side effects. Specifically, the particles were engineered to be taken up by antigen-presenting cells, which instruct lymphocytes to make antibodies.

    When the team added the particles to human cells in a dish or injected them into mice expressing the human TLR8 gene, immune responses were as good as or better than those induced by the BCG vaccine (one of the few vaccines that works in newborns).

    Next steps

    The team now plans to develop highly stable vaccine formulations, obtain more safety data and further characterize responses in newborns versus older infants.

    Levy intends to work with collaborators from around the world, via the Precision Vaccines Program, to work towards launching human trials.

    “There’s not a long list of vaccines that can be given at birth, and we need better vaccine formulations against a range of early-life infectious pathogens,” said Levy. “We hope to meet these challenges.”

    Jeffrey Hubbell of École Polytechnique Fédérale de Lausanne in Switzerland, now at the University of Chicago, was co-senior author on the second paper with Levy.

    The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health/NIAID, the European Research Council and Boston Children’s Hospital. The Levy Laboratory also received sponsored research support from 3M Drug Delivery Systems.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:15 am on March 20, 2017 Permalink | Reply
    Tags: Angelman’s syndrome, , , Cerebellin 1 (CBLN1), Chemogenetics, Circuit Breaker, HMS- Harvard Medical School, Isodicentric chromosome 15q, , The gene UBE3A   

    From HMS: “Circuit Breaker” Autism Studies 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    March 16, 2017
    JACQUELINE MITCHELL

    1
    ktsimage/Getty Images

    Harvard Medical School researchers at Beth Israel Deaconess Medical Center have gained new insight into the genetic and neuronal circuit mechanisms that may contribute to impaired sociability in some forms of autism spectrum disorder.

    Led by Matthew Anderson, HMS associate professor of pathology and director of neuropathology at Beth Israel Deaconess, the scientists determined how a gene linked to one common form of autism works in a specific population of brain cells to impair sociability.

    The research, published today in the journal Nature, reveals the neurobiological control of sociability and could represent important first steps toward interventions for patients with autism.

    Anderson and colleagues focused on the gene UBE3A, multiple copies of which cause a form of autism in humans (called isodicentric chromosome 15q). Conversely, the lack of this same gene in humans leads to a developmental disorder called Angelman’s syndrome, characterized by increased sociability.

    In previous work, Anderson’s team demonstrated that mice engineered with extra copies of the UBE3A gene show impaired sociability, as well as heightened repetitive self grooming and reduced vocalizations with other mice.

    “In this study, we wanted to determine where in the brain this social behavior deficit arises and where and how increases of the UBE3A gene repress it,” said Anderson, who is also director of the Autism BrainNET, Boston Node.

    “We had tools in hand that we built ourselves. We not only introduced the gene into specific brain regions of the mouse, but we could also direct it to specific cell types to test which ones played a role in regulating sociability,” Anderson said.

    When Anderson and colleagues compared the brains of the mice engineered to model autism to those of normal—or wild type—mice, they observed that the increased UBE3A gene copies interacted with nearly 600 other genes.

    After analyzing and comparing protein interactions between the UBE3A regulated gene and genes altered in human autism, the researchers noticed that increased doses of UBE3A repressed Cerebellin genes.

    Cerebellin is a family of genes that physically interact with other autism genes to form glutamatergic synapses, the junctions where neurons communicate with each other via the neurotransmitter glutamate.

    The researchers chose to focus on one of them, Cerebellin 1 (CBLN1), as the potential mediator of UBE3A’s effects. When they deleted CBLN1 in glutamate neurons, they recreated the same impaired sociability produced by increased UBE3A.

    “Selecting Cerebellin 1 out of hundreds of other potential targets was something of a leap of faith,” Anderson said. “When we deleted the gene and were able to reconstitute the social deficits, that was the moment we realized we’d hit the right target. Cerebellin 1 was the gene repressed by UBE3A that seemed to mediate its effects,” he said.

    In another series of experiments, Anderson and colleagues demonstrated an even more definitive link between UBE3A and CBLN1. Seizures are a common symptom among people with autism including this genetic form.

    Seizures themselves, when sufficiently severe, also impaired sociability.

    Anderson’s team suspected this seizure-induced impairment of sociability was the result of repressing the Cerebellin genes. Indeed, the researchers found that deleting UBE3A, upstream from Cerebellin genes, prevented the seizure-induced social impairments and blocked seizures ability to repress CBLN1.

    “If you take away UBE3A, seizures can’t repress sociability or Cerebellin,” said Anderson. “The flip side is, if you have just a little extra UBE3A—as a subset of people with autism do—and you combine that with less severe seizures, you can get a full-blown loss of social interactions.”

    The researchers next conducted a variety of brain-mapping experiments to locate where in the brain these crucial seizure-gene interactions take place.

    “We mapped this seat of sociability to a surprising location,“ Anderson explained. Most scientists would have thought they take place in the cortex—the area of the brain where sensory processing and motor commands take place—but, in fact, these interactions take place in the brain stem, in the reward system.”

    Then the researchers used their engineered mouse model to confirm the precise location as the ventral tegmental area, part of the midbrain that plays a role in the reward system and addiction.

    Anderson and colleagues used chemogenetics—an approach that makes use of modified receptors introduced into neurons that respond to drugs but not to naturally occurring neurotransmitters—to switch this specific group of neurons on or off.

    Turning these neurons on could magnify sociability and rescue seizure and UBE3A-induced sociability deficits.

    “We were able to abolish sociability by inhibiting these neurons, and we could magnify and prolong sociability by turning them on,” said Anderson. “So we have a toggle switch for sociability. It has a therapeutic flavor; someday, we might be able to translate this into a treatment that will helps patients.”

    The researchers thank Oriana DiStefano, Greg Salimando and Rebecca Broadhurst for colony work and the HMS Neurobiology Imaging Facility (NINDS P30 Core Center Grant #NS07203).

    This work was supported an American Academy of Neurology Research Training Fellowship, the National Institutes of Health (grants 1R25NS070682, 1R01NS08916, 1R21MH100868 and 1R21HD079249), the Nancy Lurie Marks Family Foundation, the Landreth Family Foundation, the Simons Foundation, Autism Speaks/National Alliance for Autism Research and the Klarman Family Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:19 am on February 14, 2017 Permalink | Reply
    Tags: , HMS- Harvard Medical School, , Stem Cells Step Forward   

    From HMS: “Stem Cells Step Forward” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    February 8, 2017
    NANCY FLIESLER

    For first time, iPS cells flag potential drug for blood disease.

    1
    Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s.

    Researchers at Harvard Medical School and Boston Children’s Hospital were able, for the first time, to use patients’ own cells to create cells similar to those in bone marrow and then use them to identify potential treatments for a blood disorder.

    The work was published Feb. 8 in Science Translational Medicine.

    The team derived the so-called blood progenitor cells from two patients with Diamond-Blackfan anemia (DBA), a rare, severe blood disorder in which the bone marrow cannot make enough oxygen-carrying red blood cells.

    The researchers first converted some of the patients’ skin cells into induced pluripotent stem (iPS) cells. They then got the iPS cells to make blood progenitor cells, which they loaded into a high-throughput drug-screening system.

    Testing a library of 1,440 chemicals, the team found several that showed promise in a dish. One compound, SMER28, was able to get live mice and zebrafish to start churning out red blood cells.

    The study marks an important advance in the stem cell field. iPS cells, theoretically capable of making virtually any cell type, were first created in the lab in 2006 from skin cells treated with genetic reprogramming factors. Specialized cells generated by iPS cells have been used to look for drugs for a variety of diseases—except for blood disorders, because of technical problems in getting iPS cells to make blood cells.

    “iPS cells have been hard to instruct when it comes to making blood,” said Sergei Doulatov, former HMS research fellow at Boston Children’s and co-first author on the paper with doctoral student Linda Vo and research fellow Elizabeth Macari. “This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

    DBA is currently treated with steroids, but these drugs help only about half of patients, and some of them eventually stop responding. When steroids fail, patients must receive lifelong blood transfusions, and quality of life for many patients is poor. The researchers believe SMER28 or a similar compound might offer another option.

    “It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond-Blackfan anemia,” said Leonard Zon, HMS Grousbeck Professor of Pediatrics and director of the Stem Cell Research Program at Boston Children’s and co-corresponding author on the paper.

    “This work illustrates a wonderful triumph,” said co-corresponding author George Q. Daley, dean of HMS and associate director of the Stem Cell Research Program.

    Making red blood cells

    As in DBA itself, the patient-derived blood progenitor cells, studied in a dish, failed to generate the precursors of red blood cells, known as erythroid cells. The same was true when the cells were transplanted into mice. But the chemical screen got several “hits”: in wells loaded with these chemicals, erythroid cells began appearing.

    Because of its especially strong effect, SMER28 was put through additional testing. When used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that in turn made red blood cells, reversing or stabilizing anemia.

    The same was true in cells from DBA patients transplanted into mice. The higher the dose of SMER28, the more red blood cells were produced, and no ill effects were found. Formal toxicity studies have not yet been conducted.

    Circumventing a roadblock

    Previous researchers have tried for years to isolate blood stem cells from patients. They have sometimes succeeded, but the cells are very rare and cannot create enough copies of themselves to be useful for research. Attempts to get iPS cells to make blood stem cells have also failed.

    The HMS and Boston Children’s researchers were able to circumvent these problems by instead transforming iPS cells into blood progenitor cells using a combination of five reprogramming factors. Blood progenitor cells share many properties with blood stem cells and are readily multiplied in a dish.

    “Drug screens are usually done in duplicate, in tens of thousands of wells, so you need a lot of cells,” said Doulatov, who now heads a lab at the University of Washington. “Although blood progenitor cells aren’t bona fide stem cells, they are multipotent and they made red cells just fine.”

    SMER28 has been tested preclinically for some neurodegenerative diseases. It activates a so-called autophagy pathway that recycles damaged cellular components. In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Doulatov plans to further explore how this interferes with red blood cell production.

    Zon and Daley have been awarded NIH funding from the National Heart, Lung and Blood Institute’s Progenitor Cell Translational Consortium to further explore several promising compounds identified through the study.

    The study was supported by grants from the National Institutes of Health (R24-DK092760, R24-DK49216, UO1-HL100001, R01HL04880, AQ42R24OD017870-01), Alex’s Lemonade Stand, the Taub Foundation Grants Program for MDS AQ43 Research and the Doris Duke Medical Foundation. Additional funding came from a National Science Foundation Graduate Research Fellowship and NHLBI grant 1F32HL124948-01.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 11:25 am on February 6, 2017 Permalink | Reply
    Tags: , , HMS- Harvard Medical School, , Mullerian Inhibiting Substance (MIS), Ovarian Chemo Shield?   

    From HMS: “Ovarian Chemo Shield?” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 30, 2017
    SUE MCGREEVEY

    A hormone that plays a role in fetal development may help protect the ovaries from chemo damage.

    1
    Scientists report that a naturally occurring hormone that plays a role in fetal development may help protect the ovaries from chemo damage. Photo credit: Magicmine/Getty Images.

    A naturally occurring hormone that plays an important role in fetal development may be the basis for a new type of reversible contraceptive that can protect ovaries from the damage caused by chemotherapy drugs.

    In their report receiving online publication in PNAS, a team from the Pediatric Surgical Research Laboratories in the Harvard-affiliated Massachusetts General Hospital (MGH) Department of Surgery describes using Mullerian Inhibiting Substance (MIS) to halt, in a mouse model, the early development of the ovarian follicles in which oocytes mature, an accomplishment that protects these primordial follicles from chemotherapy-induced damage.

    “MIS has long been suspected as an inhibitor of the initial stages of follicular development, but the complete blockade of the process was unexpected and opened up a number of new applications for the hormone,” said corresponding author David Pepin, an assistant professor of Surgery at Harvard Medical School (HMS).

    “Because most of what we know about female reproduction is focused on the late stages of follicle maturation, our current therapies – including contraceptive drugs – are all targeted at those processes.

    The ability to target earlier stages and potentially maintain the larger pool of quiescent oocytes called the ovarian reserve not only could maintain fertility during chemotherapy but also could be applied to modern fertility treatments,” he said.

    During embryonic development, MIS is secreted by the testes of male embryos to prevent the maturation of structures that would give rise to female reproductive organs.

    Patricia Donahoe, director of the Pediatric Surgical Research Laboratories and a co-author of the PNAS paper, has been investigating the potential use of MIS to treat ovarian cancer and other reproductive tumors for several years.

    As part of that continuing work, Pepin made the surprising observation that overexpression of MIS in female animals completely blocked the maturation of follicles, keeping them at the inactive, primordial stage and rendering the animals infertile.

    Chemotherapy’s anti-cancer effects depend on its ability to damage rapidly growing cells, including cells in maturing ovarian follicles. But chemotherapy is also believed to accelerate the activation of primordial follicles, essentially using up the ovarian reserve over a matter of months instead of years.

    The idea that ovarian suppression could preserve fertility in women undergoing chemotherapy is not new, but the ability to halt activation of primordial follicles during chemotherapy was not previously possible.

    Current hormonal contraceptives act at later stages, after the follicle has been committed to either grow or perish, so the unique action of MIS in maintaining follicles at the primordial stage offered intriguing new possibilities.

    In a series of experiments with female mice, the research team first showed that increasing MIS levels either by twice-daily injection of the purified protein or by gene therapy led to a gradual but significant decrease in the number of growing follicles, leading after several weeks to an almost complete lack of growing follicles but maintaining a consistent level of primordial follicles.

    Halting MIS treatment, either by discontinuing the injections or by transplanting follicle-depleted ovarian tissues from gene-therapy treated mice into untreated control animals, led to resumption of follicle development in as little as 12 days, indicating that the effect is reversible.

    Mice in which MIS levels were elevated by gene therapy gradually lost their fertility, and those with higher MIS levels were completely infertile after six weeks.

    Both methods of MIS administration were able to protect the ovarian reserve from the effects of common chemotherapy drugs, resulting in primordial follicle counts from 1.4 to nearly 3 times higher than in mice not receiving MIS during chemotherapy, with counts depending on the particular chemotherapy drug used and the route of MIS administration.

    “We have just begun to scratch the surface of the implications of MIS for reproductive and overall health,” Pepin said.

    “Its unique mechanism of action means it could be useful in treating many conditions that cause primary ovarian insufficiency or premature menopause. Long-term contraceptive use would probably require replacement of hormones such as estrogen to prevent the side effects of ovarian shutdown, which would be less of a concern for short-term treatment during chemotherapy. Gene therapy with MIS could also offer a nonsurgical alternative to veterinary sterilization procedures,” Pepin said.

    Pepin’s team is now investigating the quality of the oocytes preserved by MIS treatment after chemotherapy, along with elucidating the molecular mechanisms by which MIS inhibits follicle activation, which may lead to the development of small-molecule oral alternatives.

    The researchers have also formed a company, Provulis LLC, to develop clinical applications of MIS treatment and are planning clinical trials.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
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