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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 & PerspectivesPeopleResearchMarch 1, 2019
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
EventsPeopleMarch 20, 2019
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.