Watch: Technology to Improve Ability Webinar

MIT innovators present their inventions to improve quality of life for individuals with Down Syndrome
a woman with down syndrome works on a laptop

The ADSC hosted an exciting webinar showcasing two projects funded by the Innovation to Improve Ability program at the Deshpande Center for Technical Innovation at MIT.

Watch the full Webinar below!

Upcoming Webinar: Technology to Improve Ability

Join us Wednesday, June 16 at 12:00pm ET
a woman with down syndrome works on a laptop

The ADSC presents an update on our Technology to Improve Ability Grant program. These talks will be accessible to the general public.

Featured Talks:

A Novel Device For Obstructive Sleep Apnea In Down Syndrome

(Ravi Rasalingam and Tarsha Ward of the Ellen Roche group)

&

Commalla: Augmentative Communication Tech using Naturalistic Data and Machine Learning

​(Kristina Johnson and Jaya Narain of the Pattie Maes and Rosalind Picard groups)

 

Registration is free, but required: https://mit.zoom.us/webinar/register/WN_MhEkEpxzQnyXqJ55OFnx0g

Down syndrome symposium highlights clinical, fundamental progress

Speakers describe studies to address Alzheimer’s disease, sleep apnea and to advance fundamental discoveries
Li-Huei Tsai stands at an MIT podium with the Alana Center logo in the background
Alana Center co-director Li-Huei Tsai, speaking at a previous center event.

Whether they are working with patients in clinical trials or with chromosomes in cell cultures, scientists and physicians in the Boston area and beyond are testing a wide variety of new ways help people with Down syndrome. At the New England Down Syndrome Symposium, presented by the Alana Down Syndrome Center on Nov. 10, a virtual audience of hundreds of people learned about the research progress of a dozen research teams. The Alana Center at MIT partnered with the Massachusetts Down Syndrome Congress and the LuMind IDSC Foundation to organize the daylong program of online talks.

“I am hopeful that the research being done today will improve medical care and the quality of life of people with Down syndrome,” said Kate Bartlett, a member of the Self-Advocate Advisory Council of the MDSC. “Your work is important for me and my peers. Together we can make a better world for all people to lead active, healthy, fulfilling lives.”

Clinical studies

One of the specific health concerns Bartlett, who is 35, called out in her remarks is that the age of onset for Alzheimer’s disease among people with Down syndrome can be as early as 40. Finding ways to address the community’s elevated risk of Alzheimer’s was one of the four main themes of the symposium, along with new potential therapies for sleep apnea, and fundamental research on developmental biology and on chromosome number and dosage.

Li-Huei Tsai presents two mouse brain scans side by side. One has more white spots than the other.
Alana Center co-director Li-Huei Tsai presents research showing that 40Hz light and sound stimulation reduces amyloid plaques, a hallmark of Alzheimer’s pathology. The research team hopes this can help people with Down syndrome, who have an elevated risk of the disease.

MIT is poised to launch a clinical study of a potential Alzheimer’s therapy among people with Down syndrome, said Alana center co-director Li-Huei Tsai, Picower Professor of Neuroscience at MIT. About five years ago her lab discovered that in Alzheimer’s brain wave power and connectivity at a specific frequency, 40Hz, is notably lessened. They discovered that by exposing lab mice to light flickering and sound buzzing at 40Hz they could restore the rhythm, leading to many benefits including improved learning and memory, reduced neuron death and reductions in the level of toxic tau and amyloid proteins considered hallmarks of Alzheimer’s pathology.

More recently the team has begun clinical studies of the potential therapy, called Gamma ENtrainment Using Sensory Stimuli (GENUS), in humans to test its safety and efficacy in healthy people and in people with Alzheimer’s. Picower Clinical Fellow Diane Chan, the neurologist leading the human studies, said that so far the data indicate that exposure to 40Hz light and sound is safe and may be contributing to improved sleep and a preservation of brain volume in patients with mild Alzheimer’s disease. As soon as conditions related to the Covid-19 pandemic allow, she said, the team will invite people with Down syndrome to enroll in a study to test safety, tolerability and efficacy specifically for them.

Two speakers from Massachusetts General Hospital tackled the important related issue of diagnosing and tracking the progression of Alzheimer’s specifically in people with Down syndrome. Stephanie Santoro, a clinical geneticist with the hospital’s Down syndrome program, described the nationwide LIFE-DSR study, which counts Bartlett among its participants. The study has rigorously developed a suite of assessments to track changes in cognition, behavior, function and health in 270 adults of various ages with Down syndrome over a course of more than 30 months, Santoro said. The results will offer doctors and patients new insights into how aging and Alzheimer’s affect life over time, which may help in screening for Alzheimer’s risk.

Diana Rosas, an MGH neurologist, is one of the researchers helping to run the LIFE-DSR study. In her talk she focused on another study, the National Institute of Health’s ABC-DS study, in which she is developing biomarkers that may indicate the onset of mild cognitive impairment and Alzheimer’s in Down syndrome including data from brain scans, molecule and protein levels measured in blood, and genetic screens. She noted that these markers seeking to track changes over time need to be specific for Down syndrome patients, for instance because they have characteristic differences in brain anatomy compared to people who don’t have the condition.

Diana Rosas shows a slide comparing two brain scans made up of color coded lines
MGH neurologist Diana Rosas recently published a study showing differences in brain connectivity among Down syndrome patients with (right) and without Alzheimer’s disease (left).

Another challenge that can hinder learning, memory and cognition in people with Down syndrome is loss of sleep due to breathing trouble. Two symposium speakers discussed new approaches to treating the problem, called sleep apnea, which is very common in people with Down syndrome because of characteristics such as decreased muscle tone, differences in facial anatomy, and larger tongue size. Daniel Combs, a pediatrician at the University of Arizona, described a trial he recently began to test a combination of drugs to treat sleep apnea in children with Down syndrome. The medicines he’s testing have been studied for sleep apnea in non-Down syndrome adults and appear to be helping by increasing airway muscle tone, he said.

Massachusetts Eye and Ear Infirmary otolayrngologist Christopher Hartnick, meanwhile, discussed a surgical approach he is testing for difficult sleep apnea cases. Called hypoglossal nerve stimulation, the procedure involves implanting a breathing sensor on a rib that leads to a processor further up the chest. The processor then stimulates electrodes on muscles of the tongue.  When the patient is drawing a breath (sensed at the rib) the processor stimulates the tongue muscles to move the tongue out of the way to improve air flow. This approach has been successful in adults with DS and sleep apnea. So far, Hartnick said, 33 children have been implanted and results look promising.

Fundamental research

At the same time that all of these clinical trials have been progressing, other researchers have been working in the lab to advance more fundamental understanding of the biology going on in cells of people with Down syndrome, often also called trisomy 21 because it is caused by having a third copy of chromosome 21.

Some researchers have forged ahead by working to develop better mouse models of Down syndrome that can more closely reproduce the biology of the condition in the lab. Tarik Haydar of the Center for Neuroscience Research at Children’s National Hospital in Washington DC described his lab’s recent study showing how variations in a predominant mouse model called Ts65dn have led to differing and sometimes contradictory research conclusions that need to be recognized and accounted for.

While important nuances about the Ts65dn model are becoming better understood, Elizabeth Fisher of University College London shared that new mouse models are emerging. In mice the genes that are on human chromosome 21 are spread out over three chromosomes. That has given researchers the challenge of engineering mice to express genes in the same way that people with Down syndrome do. Fisher’s lab has led advances in doing so, and she reported that recently another group managed to directly inserting human chromosome 21 into mice to develop a new model, the TcMAC21 mouse.

Mouse models are crucial because they are whole living organisms that can demonstrate how health and behavior change with an extra chromosome. But another way to model Down syndrome in the lab is by engineering human cell cultures from cells taken from patients. Skin cells, for instance, can be turned into stem cells, which in turn can grow into neurons or heart cells.

MIT biology Professor Laurie Boyer, for instance, has begun studying gene expression in heart muscle cells derived from Down syndrome (DS) persons. The development of the heart is a very intricate and sensitive process and faulty regulation leads to congenital heart defects (CHD). Her goal is to learn how an extra copy of chromosome 21 in DS contributes to the high incidence of CHD that will hopefully fuel potential new therapies for these heart defects.

In other experiments with patient-derived cells—in this case, neurons—Lindy Barrett of the Broad Institute of MIT and Harvard is finding intriguing overlaps between Down syndrome and a form of autism called Fragile X syndrome. Her lab is finding that the protein missing in Fragile X, called FMRP, normally regulates some genes that are also expressed too much in Down syndrome. The findings, she said, raise the question of whether manipulating levels of FMRP could help Down syndrome patients.

While individual genes, or groups of them, could present new targets for therapies, another goal of the field remains finding a way to repress the activity of the third chromosome 21 as a whole. Speakers Jeanine Lee and Mitzi Kuroda, each of Harvard Medical School, described mechanisms by which various organisms, including humans, naturally suppress or enhance whole-chromosome activity. Females have two X chromosomes but males have an X and a Y. To remedy that imbalance, insects like fruit flies doubly express the X chromosome in males but mammals, like people, suppress or “silence” the activity of one of the X chromosomes in females.

This unusual degree of whole-chromosome up- or down-regulation offers intriguing scientific opportunities. Lee discussed how she hopes to address an autism-like disorder called Rett Syndrome in which girls develop abnormally because a mutant copy of the gene MeCP2 happens to be on one X chromosome they express. Her strategy is to selectively subvert X-chromosome silencing to express the healthy copy of MeCP2 on the inactivated X chromosome. Meanwhile speaker Stefan Pinter of the University of Connecticut discussed how his lab is using the X-chromosome’s silencing machinery to silence the extra chromosome 21 in Down syndrome. Pinter said that by silencing the third copy in developing brain cells in the lab his research group is developing a dynamic model for lab studies in which they can now control chromosome 21 dosage in developing brain cells.

In wrapping up the symposium, Alana Center faculty member Ed Boyden, Y. Eva Tan Professor of Neurotechnology at MIT, said the day provided many individual examples of progress that taken together are even more encouraging.

“Today we have seen many individual examples of research and advocacy from which we can draw inspiration and hope,” he said. “But there is another source of those same feelings as well: the way this community came together today to share and to learn from each other. Even if our interaction was virtual, the growth in our understanding and our interconnection was real.”

Angelika Amon, research pioneer and ADSC founding member, dies at 53

Amon was co-director of the Alana Down Syndrome Center
Angelika Amon
Angelika Amon, 1967-2020

MIT is mourning the passing of biologist Angelika Amon, co-director of the Alana Down Syndrome Center. She died of cancer after living with the disease for two-and-a-half years. “Angelika’s intellect and research were as astonishing as her bravery and her spirit,” said her Alana colleague Li-Huei Tsai.

Angelika Amon, professor of biology and a member of the Koch Institute for Integrative Cancer Research, died on Oct. 29 at age 53, following a two-and-a-half-year battle with ovarian cancer.

“Known for her piercing scientific insight and infectious enthusiasm for the deepest questions of science, Professor Amon built an extraordinary career – and in the process, a devoted community of colleagues, students and friends,” MIT President L. Rafael Reif wrote in a letter to the MIT community.

“Angelika was a force of nature and a highly valued member of our community,” reflects Tyler Jacks, the David H. Koch Professor of Biology at MIT and director of the Koch Institute. “Her intellect and wit were equally sharp, and she brought unmatched passion to everything she did. Through her groundbreaking research, her mentorship of so many, her teaching, and a host of other contributions, Angelika has made an incredible impact on the world — one that will last long into the future.”

A pioneer in cell biology

From the earliest stages of her career, Amon made profound contributions to our understanding of the fundamental biology of the cell, deciphering the regulatory networks that govern cell division and proliferation in yeast, mice, and mammalian organoids, and shedding light on the causes of chromosome mis-segregation and its consequences for human diseases.

Human cells have 23 pairs of chromosomes, but as they divide they can make errors that lead to too many or too few chromosomes, resulting in aneuploidy. Amon’s meticulous and rigorous experiments, first in yeast and then in mammalian cells, helped to uncover the biological consequences of having too many chromosomes. Her studies determined that extra chromosomes significantly impact the composition of the cell, causing stress in important processes such as protein folding and metabolism, and leading to additional mistakes that could drive cancer. Although stress resulting from aneuploidy affects cells’ ability to survive and proliferate, cancer cells — which are nearly universally aneuploid — can grow uncontrollably. Amon showed that aneuploidy disrupts cells’ usual error-repair systems, allowing genetic mutations to quickly accumulate.

Aneuploidy is usually fatal, but in some instances extra copies of specific chromosomes can lead to conditions such as Down syndrome and developmental disorders including those known as Patau and Edwards syndromes. This led Amon to work to understand how these negative effects result in some of the health problems associated specifically with Down syndrome, such as acute lymphoblastic leukemia. Her expertise in this area led her to be named co-director of the recently established Alana Down Syndrome Center at MIT.

“Angelika’s intellect and research were as astonishing as her bravery and her spirit. Her lab’s fundamental work on aneuploidy was integral to our establishment of the center,” say Li-Huei Tsai, the Picower Professor of Neuroscience and co-director of the Alana Down Syndrome Center. “Her exploration of the myriad consequences of aneuploidy for human health was vitally important and will continue to guide scientific and medical research.”

Another major focus of research in the Amon lab has been on the relationship between how cells grow, divide, and age. Among other insights, this work has revealed that once cells reach a certain large size, they lose the ability to proliferate and are unable to reenter the cell cycle. Further, this growth contributes to senescence, an irreversible cell cycle arrest, and tissue aging. In related work, Amon has investigated the relationships between stem cell size, stem cell function, and tissue age. Her lab’s studies have found that in hematopoetic stem cells, small size is important to cells’ ability to function and proliferate — in fact, she posted recent findings on bioRxiv earlier this week — and have been examining the same questions in epithelial cells as well.

Amon lab experiments delved deep into the mechanics of the biology, trying to understand the mechanisms behind their observations. To support this work, she established research collaborations to leverage approaches and technologies developed by her colleagues at the Koch Institute, including sophisticated intestinal organoid and mouse models developed by the Yilmaz Laboratory, and a microfluidic device developed by the Manalis Laboratory for measuring physical characteristics of single cells.

The thrill of discovery

Born in 1967, Amon grew up in Vienna, Austria, in a family of six. Playing outside all day with her three younger siblings, she developed an early love of biology and animals. She could not remember a time when she was not interested in biology, initially wanting to become a zoologist. But in high school, she saw an old black-and-white film from the 1950s about chromosome segregation, and found the moment that the sister chromatids split apart breathtaking. She knew then that she wanted to study the inner workings of the cell and decided to focus on genetics at the University of Vienna in Austria.

After receiving her BS, Amon continued her doctoral work there under Professor Kim Nasmyth at the Research Institute of Molecular Pathology, earning her PhD in 1993. From the outset, she made important contributions to the field of cell cycle dynamics. Her work on yeast genetics in the Nasmyth laboratory led to major discoveries about how one stage of the cell cycle sets up for the next, revealing that cyclins, proteins that accumulate within cells as they enter mitosis, must be broken down before cells pass from mitosis to G1, a period of cell growth.

Towards the end of her doctorate, Amon became interested in fruitfly genetics and read the work of Ruth Lehmann, then a faculty member at MIT and a member of the Whitehead Institute. Impressed by the elegance of Lehmann’s genetic approach, she applied and was accepted to her lab. In 1994, Amon arrived in the United States, not knowing that it would become her permanent home or that she would eventually become a professor.

While Amon’s love affair with  fruitfly genetics would prove short, her promise was immediately apparent to Lehmann, now director of the Whitehead Institute. “I will never forget picking Angelika up from the airport when she was flying in from Vienna to join my lab. Despite the long trip, she was just so full of energy, ready to talk science,” says Lehmann. “She had read all the papers in the new field and cut through the results to hit equally on the main points.”

But as Amon frequently was fond of saying, “yeast will spoil you.” Lehmann explains that “because they grow so fast and there are so many tools, ‘your brain is the only limitation.’ I tried to convince her of the beauty and advantages of my slower-growing favorite organism. But in the end, yeast won and Angelika went on to establish a remarkable body of work, starting with her many contributions to how cells divide and more recently to discover a cellular aneuploidy program.”

In 1996, after Lehmann had left for New York University’s Skirball Institute, Amon was invited to become a Whitehead Fellow, a prestigious program that offers recent PhDs resources and mentorship to undertake their own investigations. Her work on the question of how yeast cells progress through the cell cycle and partition their chromosomes would be instrumental in establishing her as one of the world’s leading geneticists. While at Whitehead, her lab made key findings centered around the role of an enzyme called Cdc14 in prompting cells to exit mitosis, including that the enzyme is sequestered in a cellular compartment called the nucleolus and must be released before the cell can exit.

“I was one of those blessed to share with her a ‘eureka moment,’ as she would call it,” says Rosella Visintin, a postdoc in Amon’s lab at the time of the discovery and now an assistant professor at the European School of Molecular Medicine in Milan. “She had so many. Most of us are lucky to get just one, and I was one of the lucky ones. I’ll never forget her smile and scream — neither will the entire Whitehead Institute — when she saw for the first time Cdc14 localization: ‘You did it, you did it, you figured it out!’ Passion, excitement, joy — everything was in that scream.”

In 1999, Amon’s work as a Whitehead Fellow earned her a faculty position in the MIT Department of Biology and the MIT Center for Cancer Research, the predecessor to the Koch Institute. A full professor since 2007, she also became the Kathleen and Curtis Marble Professor in Cancer Research, associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT, a member of the Ludwig Center for Molecular Oncology at MIT, and an investigator of the Howard Hughes Medical Institute.

Her pathbreaking research was recognized by several awards and honors, including the 2003 National Science Foundation Alan T. Waterman Award, the 2007 Paul Marks Prize for Cancer Research, the 2008 National Academy of Sciences (NAS) Award in Molecular Biology, and the 2013 Ernst Jung Prize for Medicine. In 2019, she won the Breakthrough Prize in Life Sciences and the Vilcek Prize in Biomedical Science, and was named to the Carnegie Corporation of New York’s annual list of Great Immigrants, Great Americans. This year, she was given the Human Frontier Science Program Nakasone Award. She was also a member of the NAS and the American Academy of Arts and Sciences.

Lighting the way forward

Amon’s perseverance, deep curiosity, and enthusiasm for discovery served her well in her roles as teacher, mentor, and colleague. She has worked with many labs across the world and developed a deep network of scientific collaboration and friendships. She was a sought-after speaker for seminars and the many conferences she attended. In over 20 years as a professor at MIT, she has mentored more than 80 postdocs, graduate students, and undergraduates, and received the School of Science’s undergraduate teaching prize.

“Angelika was an amazing, energetic, passionate, and creative scientist, an outstanding mentor to many, and an excellent teacher,” says Alan Grossman, the Praecis Professor of Biology and head of MIT’s Department of Biology. “Her impact and legacy will live on and be perpetuated by all those she touched.”

“Angelika existed in a league of her own,” explains Kristin Knouse, one of Amon’s former graduate students and a current Whitehead Fellow. “She had the energy and excitement of someone who picked up a pipette for the first time, but the brilliance and wisdom of someone who had been doing it for decades. Her infectious energy and brilliant mind were matched by a boundless heart and tenacious grit. She could glance at any data and immediately deliver a sharp insight that would never have crossed any other mind. Her positive attributes were infectious, and any interaction with her, no matter how transient, assuredly left you feeling better about yourself and your science.”

Taking great delight in helping young scientists find their own “eureka moments,” Amon was a fearless advocate for science and the rights of women and minorities and inspired others to fight as well. She was not afraid to speak out in support of the research and causes she believed strongly in. She was a role model for young female scientists and spent countless hours mentoring and guiding them in a male-dominated field. While she graciously accepted awards for women in science, including the Vanderbilt Prize and the Women in Cell Biology Senior Award, she questioned the value of prizes focused on women as women, rather than on their scientific contributions.

“Angelika Amon was an inspiring leader,” notes Lehmann, “not only by her trailblazing science but also by her fearlessness to call out sexism and other -isms in our community. Her captivating laugh and unwavering mentorship and guidance will be missed by students and faculty alike. MIT and the science community have lost an exemplary leader, mentor, friend, and mensch.”

Amon’s wide-ranging curiosity led her to consider new ideas beyond her own field. In recent years, she has developed a love for dinosaurs and fossils, and often mentioned that she would like to study terraforming, which she considered essential for a human success to life on other planets.

“It was always amazing to talk with Angelika about science, because her interests were so deep and so broad, her intellect so sharp, and her enthusiasm so infectious,” remembers Vivian Siegel, a lecturer in the Department of Biology and friend since Amon’s postdoctoral days. “Beyond her own work in the lab, she was fascinated by so many things, including dinosaurs — dreaming of taking her daughters on a dig — lichen, and even life on Mars.”

“Angelika was brilliant; she illuminated science and scientists,” says Frank Solomon, professor of biology and member of the Koch Institute. “And she was intense; she warmed the people around her, and expanded what it means to be a friend.”

Amon is survived by her husband Johannes Weis, and her daughters Theresa and Clara Weis, and her three siblings and their families.

–From MIT News

The Alana Center Presents: The New England Down Syndrome Symposium

Symposium Nov. 10 features a day of presentations on the latest research
Li-Huei Tsai stands at an MIT podium with the Alana Center logo in the background

On November 10, 8:45 a.m. to 4 p.m., join us for a series of stimulating talks addressing some of the latest research in New England and beyond.

This event will be held online. Registration is free but required. Click here to register.

If you have registered, click here to view the symposium.

A poster for the New England Down Syndrome Symposium showing speaker names and logos of the organizers

This event was co-organized by The Alana Down Syndrome Center, The Massachusetts Down Syndrome Congress and The Lumind IDSC Foundation

Schedule:

8:45 – 9:00am Introduction (featuring remarks from Kate Barlett, MDSC Self-Advocate Advisory Council)

Session 1: Developmental biology

9:00 – 9:40am Elizabeth Fisher (keynote), University College London : Working with mouse models to understand Down syndrome

9:40 – 10:05am Laurie Boyer, MIT, Getting to the Heart of Down Syndrome

10:05 -10:30am Tarik Haydar, Center for Neuroscience Research, Children’s National Hospital, Variation in phenotypic presentation of mouse models of Down syndrome, findings and implications

10:30 -10:55am Lindy Barrett, Broad Institute, MIT and Harvard, Probing molecular convergence between Down syndrome and Fragile X syndrome

10:55 – 11:10am Break

Session 2: Alzheimer’s Disease in Down Syndrome – Recent Advances

11:10 -11:35am Diana Rosas, Massachusetts General Hospital Neurology

11:35am – 12:00pm Stephanie Santoro Massachusetts General Hospital Down Syndrome Program, LIFE-DSR study and assessment scales for AD in DS

12:00 -12:25pm Li-Huei Tsai and Diane Chan, Alana Down Syndrome Center at MIT, Leveraging Brain Rhythms As A Therapeutic Intervention For Alzheimer’s Disease

12:25 – 12:45pm Tribute to Angelika Amon (featuring remarks from Li-Huei Tsai, Claudia Moreira, Manolis Kellis, Laurie Boyer, Brian Skotko, Ed Boyden, and Emily Niederst)

12:45 – 1:30pm Lunch

Session 3: Dosage compensation/aneuploidy

1:30 -2:10pm Jeannie Lee (keynote), Harvard Medical School, Manipulating X-chromosome dosage to treat human disorders

2:10 – 2:35pm Stefan Pinter , University of Connecticut, Trisomy 21 silencing: Towards a dynamic in vitro model of Down Syndrome

2:35 – 3:00pm Mitzi Kuroda, Harvard Medical School , X chromosome dosage compensation in Drosophila

3:00 – 3:15pm Break

Session 4: Sleep Apnea in Down Syndrome

3:15 – 3:40pm Daniel Combs, University of Arizona, Medications for Obstructive Sleep Apnea in Children with Down Syndrome

3:40 – 4:05pm Christopher Hartnick, Harvard Medical School, HGN Implant for Severe Sleep Apnea: Where are we now?

4:05 pm Closing Remarks and Angelika Amon Tribute Video

Tsai lab webinar at Mass Down Syndrome Congress

3 members of ADSC to give webinar for virtual Annual Conference
A young man gestures while holding a microphone and speaking

Translating Down Syndrome Neuroscience Research

Tuesday, July 28, 2020 10-11am EST

As people with Down syndrome age, the risk of developing Alzheimer’s disease (AD) increases significantly. The Tsai Lab discovered that by boosting gamma power, we could reverse AD related pathology and improve memory in mouse models of AD & DS. We developed a device that boosts gamma power in people using light and sound to improve memory in AD patients and individuals with Ds. In addition, the lab is using human pluripotent stem cells to generate the different types of cells in the brain, to study the mechanisms of how Trisomy 21 has such a large impact on brain function.

This webinar will not be recorded, so please plan to join live.

Diane Chan, MD PhD, Neurologist, Massachusetts Institute of Technology/Massachusetts General Hospital; Brennan Jackson, BS, Doctoral Student, Massachusetts Institute of Technology; Hiruy Meharena, PhD, Alana Senior Fellow, Massachusetts Institute of Technology

https://attendee.gotowebinar.com/register/5669979562576345359

Logos for MDSC and MIT

 

Down Syndrome symposium presents bench-to-bedside research

First annual symposium brings together local Down Syndrome research community
Angelika Amon speaks at a podium
ADSC co-director Angelika Amon speaks about her work

At its first ever symposium Nov. 6, the Alana Down Syndrome Center demonstrated ways, from the scale of chromosomes to that of caregiving communities, that scientists and physicians in Massachusetts and around the country are working to help people with Down syndrome live their healthiest, fullest lives.

Founded at MIT in March 2019, the ADSC brings together neuroscience, biology, engineering and computer science research labs together with the Desphande Center for Technological Innovation to deepen knowledge about Down syndrome and to improve health, autonomy and inclusion of people with the genetic condition characterized by an extra copy of chromosome 21.

The symposium, “Translational Research in Down Syndrome,” brought together experts working across a spectrum of fundamental biology to clinical care.  In her opening remarks, ADSC co-director Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory, said the event represented a chance for conversation and collaboration among researchers with the common goal of helping people with Down syndrome.

“Informed and inspired by their remarks we can all engage today in learning from each other,” she said. Tsai also thanked Ana Lucia Villela, whose Alana Foundation gift established the center and who had returned to MIT from Brazil to attend the symposium.

‘Aneuploidy’ advances

Throughout the afternoon, speakers shared some of their latest insights into how “aneuploidy,” having an atypical number of chromosomes, alters the biology of cells, the body and the brain.

One consequence appears to be that with an extra chromosome, cells make too many copies of the protein subunits that the chromosome encodes. Normally these subunits would become bound with partners encoded elsewhere into larger protein complexes, said ADSC Co-Director Angelika Amon, Kathleen and Curtis Marble Professor of Cancer Research in MIT’s biology department and the Koch Center for Integrative Cancer Research. But there aren’t as many of those partners, so the excess, unbound proteins become prone to clumping together, creating a major clean-up job for the cells that causes ”proteotoxic” stress. In Down syndrome, she said, that stress can hinder growth and proper function. Aneuploidy, she added, might also lead to a greater incidence of DNA damage.

Professors Reeves, Espinosa, Torres, Amon & Tsai pose for the camera
Professors Reeves, Espinosa, Torres, Amon & Tsai enjoy the meeting

Former Amon lab postdoc Eduardo Torres, who is now at the University of Massachusetts Medical School, said his lab has found that aneuploidy also disrupts the very shape and structure of the nucleus in a variety of cells, making them more sensitive to mechanical stress. The lab looked deeper to find the genetic and molecular pathway responsible and identified one related to the lipid composition of the nucleus. That insight allowed them to discover that administering certain drugs to cells with aneuploidy of chromosome 21 (or 13 or 18) can help shore up the nuclear structure and help cells grow.

To gain more insight into how aneuploidy affects neurological development many scientists have begun using techniques to grow brain cells from stem cells derived from Down syndrome patients. They can manipulate these cultures in the lab so that the only genetic difference is the extra copy of chromosome 21. Jeanne Lawrence, also of UMass, said use of such advanced models will help her understand whether a technique her lab has developed to silence extra copies of a chromosome will be effective in cells such as those in the brain or blood. Her work shows promise for a potential gene therapy to mitigate the effects of the extra copy of chromosome 21.

Another vital model of Down syndrome is the mouse. In one of the day’s two keynote addresses, Roger Reeves of the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins University described what researchers have learned from the widely used T65dn mouse model, as well as what they hope to learn from a newly developed model, that uses human chromosome 21 genes to replicate chromosome duplication. He also described their studies of the developmental anomalies in Down syndrome model mouse brains, and have found that a crucial signaling pathway for development is less responsive in these mice. He reported the results of a screen to look for the specific contributors this pathway in DS, as they may be viable targets for drug development, and his lab has also identified some of these same genes to be involved in congenital heart defects.

Clinical care

In the symposium’s other keynote, Joaquin Espinosa of the Linda Crnic Institute for Down Syndrome at the University of Colorado, discussed how a fast-emerging raft of insights including discoveries about the immune system in Down syndrome has led to a new clinical trial. Fundamental research at the institute has found that patients with Down syndrome have an increased sensitivity to interferons, proteins emitted by immune cells as they fight infections. The research led scientists to test medicines to calm the immune system. He described their current work on a clinical trial that aims to investigate a drug, Xeljanz, already used for auto-immune disease, to see if the drug not only improves autoimmune skin diseases, but possibly a wider range of symptoms associated with Down syndrome.

Another clinical trial is getting underway at Boston Children’s Hospital, said Nicole Baumer, a researcher there who said there are real opportunities for interventions to improve cognition in Down syndrome patients, but who also cautioned that researchers must always consult patients and their caregivers about what they want from clinical trials and care, rather than assuming what’s best for them. After surveying to learn more about patient and family wishes, her group has designed a study in which they will try to predict the neurodevelopmental outcomes in babies with Down syndrome, and test whether behavioral therapy interventions designed for certain autism populations might also augment intellectual development in children with Down syndrome.

Dr. Brian Skotko presents a new program from his clinic

As researchers strive in the lab and clinic to make new discoveries and improve care, Brian Skotko of Massachusetts General Hospital and Harvard Medical School has also been considering how to ensure that state-of-the-art information reaches doctors and family caregivers everywhere it’s needed. Skotko noted that among approximately 212,000 people with Down syndrome in the United States, less than five percent have access to one of the 71 specialty clinics around the country like the one he directs at MGH. Instead, they typically depend on primary care physicians. That’s why he and a diverse team have spent the last two years developing an Internet-based platform, “Down Syndrome Clinic to You (DSC2U)” in which a physician or other caregiver can enter information about a patient and learn richly linked, expert-curated information and recommendations about medical care and wellness customized for the entered patient profile. The clinical team at MGH reviews the underlying database regularly to keep it up to date. With new data showing that the system positively influences care and has been valued by users, it’s ready for a wider launch next year, he said.

Taken together, the symposium talks illustrated many routes to potential progress, from the cell to the clinic.

ADSC researchers at Society for Neuroscience 2019

ADSC lab members will present exciting neuroscience findings at the 2019 conference in Chicago
Hiruy Meharena, wearing a conference visitor badge, stands in front of a scientific poster

Special Lecture by ADSC co-Director Dr. Li-Huei Tsai

“Leveraging Brain Rhythms as a Therapeutic Intervention for Neurodegenerative Diseases”

Session 443: Oct 22, 12 – 1:10pm, Hall B

Posters

Oct 20:

Hiruy Meharena Tsai lab
Altered 3D-Genome Architecture of Neural Progenitor Cells as a Consequence of Down Syndrome
 Session 113.26 8 AM- 12 PM

Oct 21:

Y.-T. Lin Tsai lab
Engineered human cerebral organoids as a model for studying Down Syndrome
Session 278.19 8 AM- 12 PM

Oct 22:

C. Addaikkan Tsai lab
Identifying neural circuits underlying visually evoked entrainment
 Session 577.08 1 PM- 5 PM
A. Payne Boyden lab
 Genome-wide in situ sequencing
Session 611.05 1 PM- 5 PM
A. Sinha Boyden lab
Targeted and untargeted in situ sequencing in thick, physically magnified brain tissue
Session 611.06 1 PM- 5 PM

Oct 23:

E.R. Lockshin Tsai lab
Glial cell dysfunction as a result of 3D genome architecture changes in risomy-21 iPSC and ts65DN mouse models
Session 729.08 1 PM- 5 PM
B. Jackson Tsai & Boyden labs
Extended gamma sensory stimulation in cognitively normal individuals
Session 771.06 1 PM- 5 PM
D. Sarkar Boyden lab
Iterative direct expansion microscopy
Session 794.08 1 PM- 5 PM