Tsai presents 40Hz stimulation study at Mass. Down Syndrome Congress

Alana Down Syndrome Center team recruiting volunteers to test whether 40Hz light and sound benefits cognition

At the 40th Anniversary Conference of the Massachusetts Down Syndrome Congress, Director Li-Huei Tsai described a new study. Scientists will test whether a potential therapy using flickering light and clicking sound can enhance cognition in people with Down syndrome.

With early studies indicating that non-invasive sensory stimulation of a gamma frequency brain rhythm may improve cognition in Alzheimer’s disease, researchers in the Alana Down Syndrome Center and The Picower Institute for Learning and Memory at MIT are beginning to also test it with volunteers from the Down syndrome community.

At a presentation March 23 in Worcester, Mass., at the Massachusetts Down Syndrome Congress 40^th Anniversary Conference, Alana Center and Picower Institute Director Li-Huei Tsai said her research team is recruiting volunteers to try out the potential therapy, which involves flickering light and clicking sound at 40Hz, a gamma band frequency of the brain associated with processing sensory information and also memory and cognition.

Finding a safe and accessible way to enhance cognition is one of the goals of the team of researchers at the Alana Center, founded in 2019 at MIT with a gift from the Alana Foundation, Tsai said.

“The mission is to conduct research and develop technologies that help give people with disabilities the skills to participate in education, the workforce and in other community settings,” she said.

Addressing Alzheimer’s

In several studies, Tsai’s team and others have tested forms of non-invasive 40Hz stimulation in mice modeling Alzheimer’s disease and with human volunteers with the condition. Mouse studies at MIT have shown significant reductions in disease pathology, including in levels of amyloid and tau proteins, and important health-promoting changes in brain cells including neurons, astrocytes and the brain’s vasculature. One of the lab’s most recent studies showed that 40Hz stimulation appears to clear amyloid by improving how well it can be flushed out by the brain fluids that flow through the glymphatic system. Importantly mice treated with 40Hz light, sound or vibration have also shown cognitive improvements.

In human volunteers, early-stage clinical studies at MIT and by a company that licenses MIT’s technology, have reported that the treatment is safe and produced some clinical improvements as well. Volunteers with Alzheimer’s disease exposed to 40Hz light and sound experienced benefits including a slower loss of brain volume and, in the company’s recently published phase 2 clinical trial results, also exhibited significantly slower declines on scores of mental functioning.

New Down syndrome study

Decades ago the life expectancy of people with Down syndrome was very low but today, many speakers at the MDSC conference noted, it extends past 60 years. But after the age of 40 the prevalence of Alzheimer’s disease among people with Down syndrome becomes very high. Many researchers believe that a major reason is that the amyloid precursor protein gene, a risk factor for Alzheimer’s, resides on chromosome 21, which is the chromosome that has an extra copy in Down syndrome.

Given the importance of Alzheimer’s disease and the overlap in disease pathology for people with Down syndrome, Tsai’s team at the Alana Center recently began to test whether 40Hz sensory stimulation could help.

As in the Alzheimer’s experiments, Tsai’s team started with mice. The data so far is preliminary—it has not yet been peer-reviewed and published—but Down syndrome model mice treated with 40Hz stimulation appear to show improved cognition.

The team has also begun a clinical study of people with Down syndrome. Testing so far is finding that light or light and sound combined increases the strength of the 40Hz gamma rhythm in the brain, as it does in Alzheimer’s patients and mouse models. With more volunteers, the team hopes to determine if the stimulation produces cognitive or functional benefits, Tsai said. The team is especially looking to include people in their 20s and 30s before the onset of Alzheimer’s disease symptoms.

Time, and testing, will tell if non-invasive gamma rhythm stimulation can benefit people with Down syndrome.

In Down syndrome cells, genome-wide disruptions mimic cell aging

Extra chromosome alters conformation and DNA accessibility across the whole genome

ResearchJanuary 6, 2022

Neural progenitor cells

The presence of a third copy of chromosome 21 causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. The main effects of this are more genetic interactions within each chromosome and less interactions among them. These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development.

In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. The resulting disruption of gene transcription and cell function are so similar to those seen in cellular aging, or senescence, that the scientists leading the study found they could use anti-senescence drugs to correct them in cell cultures.

The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for future treatment of Down syndrome, said Hiruy Meharena, a new assistant professor at the University of California San Diego who led the work as a Senior Alana Fellow in the Alana Down Syndrome Center at MIT.

“There is a cell-type specific genome-wide disruption that is independent of the gene dosage response,” Meharena said. “It’s a very similar phenomenon to what’s observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.”

The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain including neurons, have a senescent character is remarkable and novel, said senior author Li-Huei Tsai, but it is substantiated by the team’s extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneupoloidy, within the nucleus of the cells.

“This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders,” said Tsai, Picower Professor of Neuroscience, director of the Alana Center, and of The Picower Institute for Learning and Memory at MIT. “We didn’t begin this work expecting to see senescence as a translationally relevant feature of Down syndrome, but the data emerged from asking how the presence of an extra chromosome affects the architecture of all of a cell’s chromosomes during development.”

Genomewide changes

Meharena and co-authors spent years measuring distinctions between human cell cultures that differed only by whether they had a third copy of chromosome 21. Stem cells derived from volunteers were cultured to turn into NPCs. In both the stem cells and the NPCs, the team examined 3D chromosome architecture, several metrics of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also looked at the consequences of the gene expression differences on important functions of these developmental cells, such as how well they proliferated and migrated in 3D brain tissue cultures. Stem cells were not particularly different, but NPCs were substantially affected by the third copy of chromosome 21.

Overall, the picture that emerged in NPCs was that the presence of a third copy causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. The main effects of this “chromosomal introversion,” meticulously quantified in the study, are more genetic interactions within each chromosome and less interactions among them. These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development.

Treated as senescence

For the first couple of years as these data emerged, Meharena said, the full significance of the genomic changes were not apparent, but then he read a paper showing very similar genomic rearrangement and transcriptional alterations in senescent cells.

After validating that the Down syndrome cells indeed bore such a similar signature of transcriptional differences, the team decided to test whether anti-senescence drugs could undo the effects. They tested a combination of two: dasatinib and quercetin. The medications improved not only gene accessibility and transcription, but also the migration and proliferation of cells.

That said, the drugs have very significant side effects—dasatinib is only given to cancer patients when other treatments have not done enough—so they are not appropriate for attempting to intervene in brain development amid Down syndrome, Meharena said. Instead an outcome of the study could be to inspire a search for medications that could have anti-senolytic effects with a safer profile.

Senescence is a stress response of cells. At the same time, years of research by former MIT biology professor Angelika Amon, who co-directed the Alana Center with Tsai, has shown that aneuploidy is a source of considerable stress for cells. A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome NPCs is indeed the result of an aneuploidy induced stress and if so, exactly what that stress is.

Another implication of the findings is how excessive senescence among brain cells might affect people with Down syndrome later in life. The risk of Alzheimer’s disease is much higher at a substantially earlier age in the Down syndrome population than among people in general. In large part this is believed to be because a key Alzheimer’s risk gene, APP, is on chromosome 21, but the newly identified inclination for senescence may also accelerate Alzheimer’s development.

In addition to Meharena and Tsai, the paper’s other authors are Asaf Marco, Vishnu Dileep, Elana Lockshin, Grace Akatsu, James Mullahoo, Ashley Watson, Tak Ko, Lindsey Guerin, Fatema Abdurrob, Shruti Rengarajan, Malvina Papanastasiou and Jacob Jaffe.

The Alana Foundation, the LuMind Foundation, Burroughs Wellcome Fund, UNCF-Merck and the National Institutes of Health funded the research.

Down syndrome symposium highlights clinical, fundamental progress

Speakers describe studies to address Alzheimer’s disease, sleep apnea and to advance fundamental discoveries

Events ResearchNovember 20, 2020

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

PeopleOctober 30, 2020

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

EventsOctober 1, 2020

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

Human Models for Neuroscience

Stem cell, genetic technologies enable sophisticated studies of human brain cells and brain "organoids"

ResearchJanuary 21, 2020

An organoid, or "minibrain," labeled to show neurons and glial cells (credit: Kwanghun Chung lab)

Scientists cannot perform many experiments directly on people’s brains, but with new technologies, they can create human brain tissue models and ask important questions via experiments on those. Their findings could help them find new ways to improve brain health.

For decades, neuroscientists seeking to better understand human neurological conditions and develop new therapies have worked with the obvious limitation that a living patient’s brain is not open for investigation or experimentation at the genetic, molecular or cellular scale where many of the brain’s mysteries hide. Nonetheless, they’ve made extraordinary progress with studies in animal models and post-mortem human tissue.

But now neuroscientists are in a whole new era. Three technological breakthroughs over the past 12 years have given them a revolutionary way to study human brain disease: They can create cultures of brain cells derived from individual patients, and even engineer complex, three-dimensional “organoids” that mimic key aspects brain tissue. Scientists are only beginning to harness the potential of these new human cell and tissue models, and Picower Institute labs are helping lead the way. ADSC Director Li-Huei Tsai, and Professors Mriganka Sur and Kwanghun Chung are among a global vanguard that is making and analyzing these new patient-derived testbeds and applying them to study conditions such as Down syndrome, Alzheimer’s disease, Rett syndrome, and Zika virus infection.

While the whole field’s progress with these new capabilities has been rapid, so has been the recognition of their limits. That’s why rather than replacing animal models and other research methods, these new models are becoming integrated as powerful tools to complement broader research programs where findings from multiple methods often enhance each other’s value.

The new wave of breakthroughs began in 2007 when scientists showed how to take a cell from an individual’s body (often a skin cell) and to “reprogram” it to become an “induced pluripotent stem cell” (iPSC) that can then be biochemically guided to become any other cell, like a neuron or a supporting astrocyte or microglia. This development allowed scientists to make the brain cells that they of course would never directly extract from patients. By 2013, scientists began using iPSCs to grow 3D cultures of multiple brain cell types, or “organoids,” that can reproduce key aspects of brain development and intercellular interactions. That same year, scientists demonstrated that a technique called CRISPR/Cas9, could be used for precise genetic editing. Scientists quickly began using that to manipulate the genes in their iPSC-grown cultures and organoids, creating “isogenic pairs” where two otherwise identical stem cells contain a disease-causing or healthy version of a gene.

Tsai and lab members Jay Penney and William Ralvenius summarized and celebrated the significance of these breakthroughs for Alzheimer’s disease research in an August 2019 paper in Molecular Psychiatry.

“In little more than a decade since the advent of human iPSC technologies we have developed the ability to generate all the main brain cell types from pluripotent cells,” they wrote. “Increasingly complex 3D co-culture systems are also emerging that allow us to reconstitute many of the key interactions between brain cells. These technologies have already contributed greatly to our understanding of human development and human disease.”

Sur agreed, “It is perhaps the only way one can study a direct human model – it’s astonishing to be able to grow brain cells from a patient with a disease, derived from that person’s genetic material.”

Abundant applications

Picower labs have embarked on numerous studies using the models. In 2018, Tsai’s lab, led by Yuan-Ta Lin and Jinsoo Seo, published a paper in Neuron in which they used 2D single-cell-type iPSC cultures and 3D mixed-cell-type organoids to study the differences made by two versions of the leading risk gene for Alzheimer’s disease, APOE. People with the APOE4 variant are at much higher risk for the disease than APOE3 carriers but scientists haven’t been sure why. Tsai and Lin’s team used CRISPR/Cas9 to make isogenic pairs of neurons, astrocytes and microglia and spotted several key differences that likely help explain how APOE4 raises disease risk. For instance, APOE4 neurons secreted more potentially harmful amyloid proteins, APOE4 astrocytes showed dysregulated cholesterol metabolism and cleared less amyloid. APOE4 microglia, too, did a poorer job of getting rid of amyloid buildup. Using CRISPR to change APOE4 to APOE3, meanwhile, improved cell activity.

Elsewhere in the the Tsai lab, Joel Blanchard is using iPSCs to model the blood-brain barrier, which stringently filters what comes into and goes out of the brain through the blood stream, so he can see how APOE variants affect that. Researchers are also looking at how myelination – the process of wrapping neurons in a fatty sheath to improve their electrical conductivity – may differ in Alzheimer’s.

As part of the work in the Alana Down Syndrome Center, Tsai’s lab is also using iPSC-based cultures to study the difference that having a third copy of chromosome 21 makes in gene expression in a variety of brain cells and in the development of organoids. At October’s Society for Neuroscience (SfN) annual meeting, the team presented some initial results. Hiruy Meharena observed significant physical changes within chromosomes in various brain cell types with the syndrome’s three copies of chromosome 21 (trisomy) vs. when they have two copies (disomy). These changes, which appear especially prevalent in neural progenitor cells, occur genomewide and result in substantial differences in gene expression that are associated with brain development. Meanwhile, Lin showed how organoids grown from trisomy iPSCs vs. disomy ones have smaller diameters after 30 days of growth and show gene expression differences that may hinder development. Elana Lockshin focused on differences in glial cells, finding, for instance, that trisomy astrocytes don’t migrate during development as readily as in disomy ones.

A woman stands with a research poster at a neuroscience conference — Elana Lockshin, a member of the lab of Li-Huei Tsai, presents research on how neural support cells, or glia, are affected in trisomy 21.

Sur’s lab has been able to make important findings by using iPSCs as part of its studies of Rett syndrome, an autism-like disorder. In a study published in 2017 in Molecular Psychiatry, a team led by Nikolaos Mellios used isogenic 2D iPSC cultures to find that the disease-causing mutation in the gene MeCP2 led to misregulated forms of RNA that alter a key molecular pathway in early neural and brain development. They also used organoids to show that if they corrected regulation of those RNAs, they could restore healthier development. The study helped to show that Rett syndrome may begin to affect health even earlier than the onset of systems in toddlerhood.

Both the Tsai and Sur labs frequently collaborate with Kwanghun Chung, whose research group is dedicated to developing tools and technologies to help fellow scientists better visualize and quantitatively analyze tissues from the scale of whole human brains down to subcellular components like the synaptic connections between neurons. Chung has not only aided the Sur’ lab’s Rett syndrome studies but has also been working with MIT Health Sciences and Technology Professor Lee Gehrke in his lab’s efforts to quantify differences that may help explain what hinders the growth of organoids – and brains – with Zika infection.

“Organoids were pivotal in helping scientists discover how Zika causes microcephaly,” said Chung lab postdoc Alex Albanese. “We are taking a more in depth look at how Zika is actually modifying the structure and cell populations inside the organoids.”

Innovating past limits

A large part of the work in Chung’s lab, which is led by Albanese and Justin Swaney, aims to overcome some key fundamental limits of organoids. Though they are sometimes called “minibrains,” they really aren’t lab replicas of the real thing. A human brain, while extraordinarily complex, has a well-defined geography. Even though organoids are much simpler – with thousands of cells rather than about 100 billion – they are much more variable in how they turn out. While a real brain will develop highly distinct regions and exactly the right number of ventricles in the right places, organoids will recapitulate only an approximation of, say, cortical structure and may have enough ventricles to look more like Swiss cheese than a brain. Albanese calls this the “snowflake” problem, alluding to how organoids can differ so widely.

So how can they still be valuable models? One has to know how to assess them. Chung’s lab has developed advanced tissue processing technologies that can clarify, preserve, label and enlarge tissues, including organoids, so that properties like physiology and cellular function can be highlighted at all scales. Moreover, his lab has developed an imaging pipeline using light-sheet microscopy that is capable of capturing enormous amounts of data quickly (15 minutes per organoid), so that technicians can thoroughly image many organoids in a day.

Another limitation of organoids is that they aren’t actually that small. A millimeter or two of diameter may seem tiny, but that’s still big enough to present challenges. Traditional microscopes can’t image far enough into them to resolve what’s going on with deeper cells. Chung’s technologies overcome that problem both by clarifying tissue and labeling cells and proteins, but that requires chemically fixing the organoids. Yildirim’s “three photon” microscope technology doesn’t label cells as richly, but it can image all the way through organoids while they are alive and active. That’s how Sur’s lab was able to witness the erratic migration of new neurons. They’ve developed microfluidic multiple-well housings for organoids and devised methods for holding them perfectly steady for long-term imaging while still allowing nutrients and oxygen to circulate around them.

A roundish organoid sits very still within concentric circles. — Mriganka Sur’s lab has developed a system for holding an organoid very stably while nutrients circulate around.

Indeed a significant problem associated with large size is that with no blood vessels to carry oxygen and nutrients in or to take waste out, the innermost cells can die. Keeping either the nutrients and oxygen, or the organoid, in motion helps keep them healthier than just growing them in dishes, research has shown. The Tsai lab recently began growing organoids by the thousands using a clever bioreactor device that keeps them spinning in the incubator. Postdoc Ping-Chieh Pao said the system saves space and uses less growth media, while yielding higher quality organoids with more mature neurons and less cell death.

Blood vessels are also integral to brain function. For instance, dysfunction in the blood-brain barrier plays a potentially pivotal role in Alzheimer’s. To build a human model of Alzheimer’s that explicitly accounts for vasculature in sickness and in health, Tsai and Blanchard recently secured a grant from the National Institutes of Health to build a “brain on a chip” that will engineer connections to unify their blood-brain barrier model with a co-culture of many brain cell types. The addition of vasculature and cell types like the oligodendrocytes that produce myelination will simulate a richer degree of Alzheimer’s complexity than human iPSC-based models have to date.

Yet another limitation of organoids has been that they don’t mimic multiple brain regions all that clearly, though they can be chemically coaxed to trend toward one or another. For that reason, organoids don’t provide much of a testbed for understanding the functional significance of inter-regional circuits. Delepine said the Sur lab is interested in experimenting with growing multiple organoids of different regional character on a chip and then nurturing connections between them to see if they can replicate such circuits.

Multiple models together

While Picower researchers and colleagues elsewhere work to make the most of human disease models, there are some limits that seem sure to endure, both for technical and ethical reasons. That means that traditional models, including animals, will remain integral to neuroscience research.

After all, organoids don’t think, behave or remember. They can’t gather any sensory input and do not exhibit consciousness. Lacking all these basic capabilities, they naturally can’t provide any data about how disease affects those vital functions of daily existence. In a recent study where Sur collaborated with MIT biologist Rudolf Jaenisch to test new drugs with the potential to treat Rett syndrome, Jaenisch’s lab screened the compounds on stem-cell derived human neurons, but Sur’s lab tested the most promising ones in mouse models, because that was the only way to see if they improved cognition and behavior.

“The question was, were they valid in a much more functional system,” Sur said.

Mellios’s study, too, drew upon and also utilized findings in Rett model mice.

“Our work in these two studies shows how mouse work can complement human work,” he said.

Especially when fighting disease, researchers will always draw upon whatever systems they can to help them find answers.

Blending complementary expertise, Tsai and Kellis labs tackle brain diseases

Pair brings a team science approach to Down syndrome, Alzheimer's and other conditions

Ideas & Perspectives People ResearchMarch 1, 2019

Li-Huei Tsai is a neuroscientist and Manolis Kellis is a computer scientist, so by working together, their research teams are able to ask questions about the big data of the brain that neither one could alone.

In their collaboration to help elucidate and mitigate Alzheimer’s disease and other neurological conditions, the labs of neuroscientist Li-Huei Tsai and computer scientist Manolis Kellis are two sides of the same coin on two sides of Vassar Street.

Bringing complementary skills to a shared mission as part of MIT’s Aging Brain Initiative and Alana Down Syndrome Center, the team seamlessly blends and advances some of the hottest and most powerful methods in science – statistical genetics, computational genomics, epigenomics, machine learning, single-cell profiling, “big data” integration, induced stem-cell reprogramming, mini-brain organoids, tissue engineering, and CRISPR-Cas9 genetic manipulation.This allows their teams to study genetic and molecular differences between healthy and diseased samples from multiple brain regions of humans and mice, integrate and analyze the resulting data to identify significant disease-driver genes and the cell types where they act, and engineer cells, tissues and mouse models to test their hypotheses and discover therapeutic interventions.

“Working together, we have the opportunity to garner big data from a large number of human subjects to elucidate the driver genes and pathways that are novel but key to the disease,” said Tsai, Picower Professor and director of the Picower Institute for Learning and Memory. “We can then test these genes/pathways in the induced pluripotent stem cells (iPSC) system coupled with CRISPR-Cas9 to manipulate the genome. We can induce the iPS cells into all major brain cell types, and dissect the contributions of each of these cell types to disease.”

It’s a joint research venture that’s as close, cutting-edge, and multidisciplinary as any at MIT, and fits squarely within the Schwarzman College of Computing’s emphasis on integrating artificial intelligence with the sciences. Kellis recalls it all getting started back in 2012 via the connection of postdocs, Elizabeth Gjoneska of the Tsai Lab and Andreas Pfenning from the Kellis Lab, who had met at a seminar on campus. With similarly overlapping interests in how gene regulation, and specifically epigenomic differences, affect the workings and health of the brain, they and other members of the two labs kindled dialogues that soon brought the professors together.

“The collaboration kind of happened organically,” said Kellis, professor of computer science and head of MIT’s Computational Biology Group. “We found kindred spirits – folks who thought similarly but were extremely complementary in their expertise.”

Within two years, the labs had jointly published two major papers. One in Nature, part of a sweeping set of reports on epigenomics that Kellis helped lead, showed that highly analogous sets of gene misregulation signals in the hippocampus of mice and humans each revealed a strong role for the brain’s immune cells and processes in allowing Alzheimer’s disease to progress. The other paper, in Cell, showed that in order to rapidly express genes critical for experience to affect synaptic connections, neurons naturally employ double-strand breaks of their DNA. The team hypothesized that failure to repair these breaks increases with age and may also contribute to neurodegeneration.

Each paper demonstrated the power of their combined approach. Since then, the collaboration has grown significantly to encompass about half a dozen projects. In 2016, for instance, they earned a National Institutes of Health grant to determine the significant epigenomic differences afoot in major brain cell types in Alzheimer’s disease.

In the last year, Kellis and Tsai received an influx of several new NIH grants and philanthropic gifts, such as the one establishing the Alana Down Syndrome Center, enabling them to substantially expand their efforts in Alzheimer’s, tackle new disorders, bring in new collaborators, include new types of experiments, and expand their mechanistic studies. Their new directions include Schizophrenia, Bipolar Disorder, Psychosis in Alzheimer’s Disease, Frontotemporal Dementia, Lewy Body Dementia, and healthy aging.

Importantly, each experiment is designed together, Kellis says. Knowing that the team combines the capabilities of each lab, the team can be more ambitious.

“We think in a different way than any one lab would think by itself,” Kellis said. “For instance, I wouldn’t have the guts to ask many of these things that we are asking, if it wasn’t for our close collaboration with Li-Huei’s lab.”

In the Alana Center, they will apply their team science approach to modeling and analyzing Down syndrome, looking to identify and dissect the unique genetic and molecular signals that explain how the presence of an extra chromosome 21 affects the brain.

And with the new NIH grants, they will ask a litany of questions such as why many people with Alzheimer’s develop psychotic symptoms as well, what are the unique molecular signatures that distinguish Alzheimer’s and other dementias, and how do specific genetic variations in non-coding DNA elevate risk for a number of neurodegenerative and neuropsychiatric disorders.

“How privileged I feel to work with the world’s best computational team,” Tsai said. “This is only possible at MIT.”