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

Blending complementary expertise, Tsai and Kellis labs tackle brain diseases

Pair brings a team science approach to Down syndrome, Alzheimer's and other conditions
An illustration of a brain in profile overlaid with binary code

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.”

Alana Gift to MIT Launches Down Syndrome Research Center

Alana Down Syndrome Center will fund Down Syndrome biology research, technology program for disabilities
Ana Lucia Villela stands in front of a ADSC sign
Alana Foundation President Ana Lucia Villela speaks at the Alana Down Syndrome Center launch event

As part of MIT’s continued mission to help build a better world, the Institute announced the creation of the Alana Down Syndrome Center, an innovative new research endeavor, technology development initiative, and fellowship program launched with a $28.6 million gift from Alana Foundation, a nonprofit organization started by Ana Lucia Villela of São Paulo, Brazil.

In addition to multidisciplinary research across neuroscience, biology, engineering, and computer science labs, the gift will fund a four-year program with MIT’s Deshpande Center for Technological Innovation called “Technology to Improve Ability,” in which creative minds around MIT will be encouraged and supported in designing and developing technologies that can improve life for people with different intellectual abilities or other challenges.

The Alana Down Syndrome Center, hosted out of MIT’s Picower Institute for Learning and Memory, will engage the expertise of scientists and engineers in a research effort to increase understanding of the biology and neuroscience of Down syndrome. The center will also provide new training and educational opportunities for early career scientists and students to become involved in Down syndrome research. Together, the center and technology program will work to accelerate the generation, development, and clinical testing of novel interventions and technologies to improve the quality of life for people with Down syndrome.

“At MIT, we value frontier research, particularly when it is aimed at making a better world,” says MIT President L. Rafael Reif.  “The Alana Foundation’s inspiring gift will position MIT’s researchers to investigate new pathways to enhance and extend the lives of those with Down syndrome. We are grateful to the Foundation’s leadership — President Ana Lucia Villela and Co-President Marcos Nisti — for entrusting our community with this critical challenge.”

With a $1.7 million gift to MIT in 2015, Alana funded studies to create new laboratory models of Down syndrome and to improve understanding of the mechanisms of the disorder and potential therapies. In creating the new center, MIT and the Alana Foundation officials said they are building on that partnership to promote discovery and technology development aimed at helping people with different abilities gain greater social and practical skills to enhance their participation in the educational system, in the workforce, and in community life.

“We couldn’t be happier and more hopeful as to the size of the impact this Center can generate,” Villela said. “It’s an innovative approach that doesn’t focus on the disability but, instead, focuses on the barriers that can prevent people with Down Syndrome from thriving in life in their own way.”

Marcos Nisti, CEO & Vice-President of Alana, added, “This gift represents all the trust we have in MIT especially because the values our family hold are so aligned with MIT’s own values and its mission.”

Villela and Nisti have two daughters, one with Down syndrome. MIT Executive Vice President and Treasurer Israel Ruiz has had a personal connection to the Foundation.

“It is an extraordinary day,” Ruiz said. “It has been a pleasure getting to know Ana Lucia, Marcos and their family over the past few years. Their work to advance the needs of the Down Syndrome community is truly exemplary, and I look forward to future collaborations. Today, MIT celebrates their generosity in recognizing all abilities and working to provide opportunities to all.”

Down syndrome, also known as trisomy 21, is characterized by extra genetic material from some or all of chromosome 21 in many or all of an individual’s cells and occurs in one out of every 700 babies in the United States. Though the chromosomal hallmark of Down syndrome has been well known for decades, and advances in research, health care and social services have doubled lifespans over the past 25 years, significant challenges remain for individuals with different abilities and their families because the underlying neurobiology of the disorder is complex.

The center will be co-directed by Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research, and Li-Huei Tsai, the Picower Professor of Neuroscience. Amon is an expert in understanding the health impacts of chromosomal instability and aneuploidy, the presence of an abnormal chromosome number, while Tsai is renowned for her work in the field of neurodegenerative disorders, including Alzheimer’s disease, which shares important underlying similarities with Down syndrome. In the first four years, the new center will employ cutting-edge techniques to study Down syndrome in the brain with two main focuses: systems and circuits as well as genes and cells.

With the support of the previous Alana Foundation gift, Hiruy Meharena, senior fellow in Tsai’s neuroscience lab, has already been deeply engaged in studying Down syndrome’s impact in the brain at the cellular and genomic level, examining key differences in gene expression in cultures of neurons and glia created from patient-derived induced pluripotent stem cells.

At the molecular and cellular level, Professor Manolis Kellis, director of MIT’s Computational Biology Group and a leader in big-data integration and analysis of genomic, epigenomic, and gene expression data will collaborate with Tsai for single-cell profiling of brain samples to understand the genes, molecular pathways, and cellular states that play causal roles in cognitive differences in Down syndrome.

At the systems and circuits level, Ed Boyden, the Y. Eva Tan Professor in Neurotechnology will lead efforts to conduct high-resolution 3D brain mapping and will collaborate with Tsai to examine the potential of using her emerging non-invasive, sensory-based therapy for Alzheimer’s in Down syndrome.

Amon’s lab will bring its deep expertise from their study of cancer to the new center. They have made important discoveries about how aneuploidy may undermine overall health, for instance by causing stresses within cells. It is their hope that identifying genetic alterations that suppress the stresses associated with trisomy 21 could lead to the development of therapeutics that improve cell function in individuals with Down syndrome.

To further support these research endeavors and to increase the long-term global pipeline of scientists trained in the study of Down syndrome, the Alana Down Syndrome Center will fund postdoctoral Alana Fellowships and graduate fellowships.

The Alana Center will also convene an annual symposium on Down syndrome research, the first of which is tentatively scheduled for this fall.

The Alana Foundation gift supports the MIT Campaign for a Better World, which was publicly launched in 2016 with a mission to advance MIT’s work in education, research, and innovation to address humanity’s urgent challenges. A joint statement guiding the gift’s purpose is available here.