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Genetic body/brain connection identified in genomic region linked to autism
October 6, 2017

CAMBRIDGE, Mass. – For the first time, Whitehead Institute scientists have documented a direct link between deletions in two genes—fam57ba and doc2a—in zebrafish and certain brain and body traits, such as seizures, hyperactivity, enlarged head size, and obesity.

“Finding the molecular connections between a brain and a body phenotype is indeed really paradigm shifting,” says Whitehead Institute Member Hazel Sive, who is also a professor of biology at MIT. “It lets us think about the common control of these two aspects of phenotype, which is very interesting and could be useful for developing therapies for these phenotypes.”

Both genes reside in the 16p11.2 region of human chromosome 16. About 1 in 2000, or around 4 million people worldwide, have deletions in this region, and these deletions are associated with multiple brain and body symptoms, including autism spectrum disorders, developmental delay, intellectual disability, seizures, and obesity.

Scientists have had difficulty teasing apart the relationship between specific traits and deletions in this region, because it includes at least 25 genes, and because there is not a one-to-one mapping of gene to phenotype. Instead, multiple genes seem to create a web of interactions that produce a variety of characteristics.

To solve such a complex puzzle, Jasmine McCammon, a postdoctoral researcher in Sive’s lab, enlisted the zebrafish as a “living test tube”.  The Sive group uses zebrafish to study the genetic/phenotype connections associated with human disorders. Like the human genome, the zebrafish genome has two copies of each gene, and scientists can remove the function of multiple genes to produce phenotypes that are reminiscent of human symptoms.

The results from McCammon’s initial screen with zebrafish indicate that two genes in the 16p11.2 region could be key for brain development: fam57ba and doc2a. (fam57b encodes a ‘ceramide synthase’ that makes a kind of lipid, and doc2a encodes a regulator of secretion.) McCammon investigated further by deleting one copy of fam57ba and doc2a individually; the effect was minimal. However, simultaneously removing a copy of both genes revealed significant synergy between them. Compared with controls, fish with only one copy of each gene exhibit hyperactivity, increased propensity for seizures, increased body and head size, and fat content. When both copies of only fam57ba are removed, the fish are much larger and with a higher fat content. All of the study’s results are published in the journal Human Molecular Genetics.

Although her findings use zebrafish and are far from the clinic, McCammon was struck by how much people affected by deletions in this genome identified with her results.

“When I spoke with the parents of some kids with neurodevelopmental disorders, I was surprised how much the brain/body connection that we described resonated with them,” she says. “They said that yes, their child has autism, but he also has really weak muscle tone. Or she has a gastrointestinal problem and that’s been more problematic than her behavior issues. For me, it’s been really revealing to talk to people who’ve actually experienced this as opposed to reading about statistics in journals.”

The mechanisms underlying this brain/body connection are still not well understood. One of the identified genes, fam57ba, provides some intriguing hints as to how metabolism and brain function could be intertwined, because it produces an enzyme that plays a role in lipid production and is believed to be a metabolic regulator.  The lipid type, ceramide, also has a functional role in various signaling pathways and affects synaptic function, although its primary role is not in the synapse, but providing structure in cell membranes.

For Sive, the two identified genes could be just the beginning. “Our data suggest that there may be metabolic genes involved in human neurodevelopmental disorders,” she says.  “This is a nascent field, that we’re very interested in going forward.”

This work was supported by Jim and Pat Poitras, Len and Ellen Polaner, and the Markell-Balkin-Weinberg Postdoctoral Fellowship.

Written by Nicole Giese Rura
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Hazel Sive’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a professor of biology at Massachusetts Institute of Technology.
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Full Citation:
“The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes”
Human Molecular Genetics, Volume 26, Issue 19, 1 October 2017.
Jasmine M. McCammon(1), Alicia Blaker-Lee(1), Xiao Chen(2), and Hazel Sive (1,2).
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Department of Biology hosts its first Science Slam

Eight biology trainees had just three minutes to explain their research and earn favor with the judges and audience in new yearly event.

Raleigh McElvery | Department of Biology
October 5, 2017

Nearly 300 spectators crowded into a lecture hall at the Ray and Maria Stata Center on a recent Tuesday to witness the first annual Science Slam, hosted by MIT’s Department of Biology.

A science slam features a series of short presentations where researchers explain their work in a compelling manner and — as the name suggests — make an impact. The presentations aren’t just talks, they’re performances geared towards a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges.

The jury included Ellen Clegg, editorial page editor of The Boston Globe and co-author of two award-winning books, “ChemoBrain” and “The Alzheimer’s Solution;” Emilie Marcus, CEO of Cell Press and editor-in-chief of the flagship journal, Cell; and Ari Daniel, an independent science reporter who produces digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were five graduate students and three postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, the Broad Institute, the Koch Institute for Integrative Cancer Research, and the Picower Institute for Learning and Memory. The storytellers were:

  • Sahin Naqvi, from David Page’s lab, who spoke about the evolution of genetic sex differences in mammals, as well as how these differences impact the likelihood of developing certain diseases based on gender;
  • Sudha Kumari, from Darrell Irvine’s lab, who spoke about her work investigating immune cell interactions — specifically how T cells communicate using physical contact;
  • Deniz Atabay, from Peter Reddien’s lab, who spoke about the ways cells in flatworms self-organize during regeneration to re-form organs, tissues, and even neural circuits;
  • Emma Kowal, from Christopher Burge’s lab, who spoke about her goals to demystify the ways in which certain noncoding regions of genetic sequence, known as introns, contribute to protein production;
  • Xin Tang, from Rudolf Jaenisch’s lab, who spoke about a technique to illuminate the seemingly invisible changes in brain cells that trigger disease, using a glowing enzyme from a firefly;
  • Nicole Aponte, from Troy Littleton’s lab, who spoke about her ability to manipulate brain cell activity in the fruit fly, and study how defects in neuronal connections contribute to developmental disorders;
  • Karthik Shekhar, from Aviv Regev’s lab, who spoke about his efforts to identify and manipulate different types of brain cells, understanding how they assemble into complex networks to facilitate learning, memory, and — in some cases — disease; and
  • Monika Avello, from Alan Grossman’s lab, who spoke about “bacterial sexology,” that is, how and why these organisms choose to block unwanted sexual advances from fellow bacteria.

Vivian Siegel, who oversees the department’s communications efforts, moderated the event. Siegel and the Building 68 communications team joined forces with three members of the Building 68 MIT Postdoctoral Association — Ana Fiszbein, Isabel Nocedal, and Peter Sudmant — to publicize the event and to host two pre-slam workshops, as well as one-on-one training sessions with individual participants.

“Participating in a Science Slam seemed like a great way for our trainees to learn how to communicate to a nonspecialized audience, which is something they will need to be able to do throughout their careers,” Siegel said. “We really wanted to develop a camaraderie among the participants, and bring trainees together from across the department to help each other tell compelling stories about their science.”

Kowal — whose talk was titled “Gone but Not Forgotten: How Do Introns Enhance Gene Expression?”  — ultimately took home both the audience and jury cash prizes. Kowal completed her undergraduate degree in chemical and physical biology at Harvard before coming to MIT for graduate school. Her dream is to write science fiction, so she decided she’d better study science so she’d know what to write about.

“I really enjoyed seeing people get stoked about introns, and the fact that they enhance gene expression,” she said. “It’s a great way to get comfortable explaining your project in a compelling way to a broad audience. Since you’ll probably be telling people about your work for a while, I think it’s a very good use of time to practice doing that.”

New target for treating “undruggable” lung cancer

Drug already in clinical trials may be effective on some aggressive adenocarcinomas.

Becky Ham | MIT News correspondent
October 2, 2017

Mutations in the KEAP1 gene could point the way to treating an aggressive form of lung cancer that is driven by “undruggable” mutations in the KRAS gene, according to a new study by MIT researchers.

KEAP1 mutations occur alongside KRAS mutations in about 17 percent of lung adenocarcinoma cases. Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and co-senior author of the study, and his colleagues found that cancer cells with nonfunctioning KEAP1 genes are hungry for glutamine, an amino acid essential for protein synthesis and energy use. Starving these cells of glutamine may thus offer a way to treat cancers with both KRAS and KEAP1 mutations.

Indeed, small-molecule-based inhibitors of glutaminase, an enzyme crucial to glutamine metabolism, slowed cancer cell growth and led to smaller tumors overall in human lung adenocarcinoma cell lines and in tumors in mice with KEAP1 mutations, the researchers found.

The study offers a way to identify lung cancer patients who might respond well to drugs that block the work of glutaminase, says MIT graduate student Rodrigo Romero, a first author on the paper that appears in the Oct. 2 online edition of Nature Medicine.

“All cell lines that we have currently tested that are KEAP1-mutant — independent of their KRAS status — appear to be exquisitely sensitive to glutaminase inhibitors,” says Romero, a graduate student in Jacks’ lab, who participated in the MIT Summer Research Program (MSRP) as an undergraduate.

Hyperactivating the antioxidant response

Lung adenocarcinoma accounts for about 40 percent of U.S. lung cancers, and 15 to 30 percent of those cases contain a KRAS mutation. KRAS has been “notoriously difficult to inhibit” because the usual ways of blocking the KRAS protein’s interactions or interfering with the protein’s targets have fallen short, says Romero.

Lung cancers containing KRAS mutations often harbor other mutations, including KEAP1, which is the third most frequently mutated gene in lung adenocarcinoma. To find out more about how these co-mutations affect lung cancer progression, the MIT research team created KEAP1 mutations in mouse models of lung adenocarcinoma, using the CRISPR/Cas9 gene-editing system to target the gene.

The KEAP1 protein normally represses another protein called NRF2, which controls the activation of an antioxidant response that removes toxic, reactive oxygen species from cells. When the researchers disabled KEAP1 with loss-of-function mutations, NRF2 was able to accumulate and contribute to a “hyperactivation” of the antioxidant response.

Lung adenocarcinomas bearing the KEAP1 mutation may “take advantage of this [hyper-activation] to promote cellular growth or detoxify intracellular damaging agents,” Romero says.

In fact, when the researchers examined genes targeted by NRF2 across a sample of human lung adenocarcinoma tumors, they concluded that the expression of these genes was greater in advanced stage IV tumors, and that patients with such “up-regulated” NRF2 tumors had significantly worse survival rates than other lung adenocarcinoma patients.

Tumors hungry for glutamine

Romero and colleagues used CRISPR/Cas9 to learn more about other genetic interactions with KEAP1 mutants. Their screening demonstrated that lung cancer cells with KRAS and KEAP1 loss-of function mutations were more dependent than other cells on increased amounts of glutamine.

To learn whether this glutamine hunger could be a therapeutic vulnerability, the researchers tested two glutaminase inhibitors against the cancer cells, including one compound called CB-839 that is in phase I clinical trials for KRAS-mutant lung cancer. CB-839 slowed growth and kept tumors smaller than normal in lung adenocarcinoma with KEAP1 mutations, the researchers found.

Phase I clinical trials that treat KEAP1-mutant lung adenocarcinoma patients with a combination of CB-839 and the cancer immunotherapy drug nivolumab (Opdivo) are also underway, says Romero, who notes the MIT study might help identify patients who would be good candidates for these trials.

“There are also many clinical trials testing the efficacy of glutaminase inhibition in a variety of cancer types, independent of KRAS status. However, the results from these studies are still unclear,” Romero says.

Jacks emphasizes that his laboratory has and will continue to study several mutations beyond KEAP1 that may cooperate with KRAS in their mouse models of human lung adenocarcinoma. “The complexity of human cancer can be quite daunting,” he notes. “The genetic tools that we have assembled allow us to create models of many individual subtypes of the disease and in this way begin to define the exploitable vulnerabilities of each. The observed sensitivity of KEAP1 mutant tumors to glutaminase inhibitors is an important example of this approach. There will be more.”

Co-authors on the Nature Medicine paper include former Koch Institute postdoc Thales Papagiannakopoulos, now at New York University, and MIT professor of biology Matthew Vander Heiden. The research was funded by the Laura and Isaac Perlmutter Cancer Support Grant, the National Institutes of Health, and the Koch Institute Support Grant from the National Cancer Institute.