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Home , Cornelia Bargmann, Gary Ruvkun, Victor Ambros, Walter Gilbert

mcgovern institute for brain research at mit Braın SCAN spring 2016 Issue no. 37

Bob Horvitz From to brain research: learning from worms from the director

I have often written in this column about the central importance of basic research, the engine of discovery that drives all of science. There is no better example than the work of my colleague Bob Horvitz, who has devoted his career to studying the microscopic worm known as C. elegans. As you can read in this issue, this tiny creature has revealed profound insights into many aspects of , from embryonic development to cancer to aging and neurodegeneration. Bob is perhaps best known for his work on cell death and its relationship to cancer, for which he shared the 2002 for Medicine, but he has also made major contributions to , including studies of brain development, synaptic function, and the control of behavioral states. Most recently, along with his collaborator and spouse Martha Constantine-Paton, he has uncovered a new gene with profound effects on synaptic signaling and a potential link to autism. All of this has emerged from genetic studies on an organism with less than a thousand Bob Horvitz approaches science with cells, including a nervous system of just 302 . patience and the confidence that he will Bob has also been an influential mentor, and last month we were delighted to host find answers to big questions if he explores one of his most prominent former trainees, Cori Bargmann, winner of this year’s Scolnick Prize. Cori’s lecture provided a remarkable important problems in tractable ways. illustration of how fundamental mechanisms of brain function can be studied in simple organisms, at a level of precision that would In Bob Horvitz’s lab, students watch be impossible in other more complex species. tiny worms as they wriggle under the microscope. Their tracks twist and turn Bob Desimone, Director in every direction, and to a casual observer Doris and Don Berkey Professor the movements appear random. There of Neuroscience is a pattern, however, and the animals’ movements change depending on their environment and recent experiences.

“A hungry worm is different from a well- fed worm,” says Horvitz, David H. Koch On the cover: Professor of Biology and a McGovern The nematode worm has provided answers to many Investigator. “If you consider worm fundamental questions in biology. psychology, it seems that the thing Image: Bob Horvitz in worms care most about is food.”

2 Bob Horvitz From cancer to brain research: learning from worms

Horvitz’s work with the nematode worm for food. When a hungry worm detects a Caenorhabditis elegans extends back to the food source, it slows almost to a standstill, mid-1970s. He was among the first to allowing it to remain close to the food. recognize the value of this microscopic Postdoctoral scientist Nick Paquin analyzed organism as a model species for asking how a mutation in a gene called vps-50, causes fundamental questions about biology worms to slow similarly even when they and human disease. are well fed. It seemed that these mutant worms were failing to transition normally The leap from worm to human might seem between the hungry and the well-fed state. great and perilous, but in fact they share many fundamental biological mechanisms, Paquin decided to study the gene further, one of which is programmed cell death, also in worms and also in mouse neurons, known as apoptosis. Horvitz shared the Nobel the latter in collaboration with Yasunobu Prize in Physiology or Medicine in 2002 Murata, a former research scientist in for his studies of cell death, which is central Martha Constantine-Paton’s lab at the to a wide variety of human diseases, including McGovern Institute. The team, later cancer and neurodegenerative disorders. He joined by postdoctoral fellow Fernando Image: Christoph Engert has continued to study the worm ever since, Bustos in the Constantine-Paton lab, found Individual cell nuclei in a developing worm. contributing to many areas of biology but that the VPS-50 protein controls the activity Horvitz helped chart the entire sequence of cell with a particular emphasis on the nervous of synapses, the junctions between nerve divisions by which a fertilized egg gives rise to system and the control of behavior. cells. VPS-50 is involved in a process that an adult animal. acidifies synaptic vesicles, microscopic In a recently published study, the Horvitz bubbles filled with neurotransmitters lab has found another fundamental that are released from nerve terminals, mechanism that likely is shared with mice sending signals to other nearby neurons. and humans. The discovery began with an If VPS-50 is missing, the vesicles do observation by former graduate student not mature properly and the signaling Beth Sawin as she watched worms searching from neurons is abnormal. VPS-50 has 3 remained relatively unchanged during evolution, and the mouse version can substitute for the missing worm gene, indicating the worm and mouse proteins are similar not only in sequence but also in function. This might seem surprising given the wide gap between the tiny nervous system of the worm and the complex brains

of mammals. But it is not surprising to Image: Bob Horvitz Horvitz, who has committed about half The nematode worm C. elegans measures of his lab resources to studying the about 1mm in length, and has 959 somatic cells. worm’s nervous system and behavior.

“Our finding underscores something it became clear that the mutation was The comment is matter-of-fact, and that I think is crucially important,” affecting worm neurons in a novel way, Horvitz is anything but pretentious. he says. “A lot of biology is conserved it was a natural decision to collaborate He thinks about both big questions and among organisms that appear superficially and study the gene in mice. They are small experimental details and is always very different, which means that the currently working to understand the role on the lookout for links between the understanding and treatment of human of VPS-50 in mammalian brain function, worm and human health. diseases can be advanced by studies and to explore further the possible link of simple organisms like worms.” to autism. “When someone in the lab finds something new, Bob is quick to ask if it relates to human disease,” says former Human Connections The Day the Worm Turned graduate student Nikhil Bhatla. “We’re not thinking about that. We’re deep in In addition to its significance for normal A latecomer to biology, Horvitz studied the nitty-gritty, but he’s directing us to synaptic function, the vps-50 gene might mathematics and economics as an potential collaborators who might help be important in autism spectrum disorder. undergraduate at MIT in the mid- us make that link.” Several autism patients have been described 1960s. During his last year, he took a few with deletions that include vps-50, and biology classes and then went on to earn This kind of mentoring, says Horvitz, other lines of evidence also suggest a link a doctoral degree in the field at Harvard has been his primary role since he to autism. “We think this is going to be University, working in the lab of James joined the MIT faculty in 1978. He has a very important molecule in mammals,” Watson (of double helix fame) and trained many of the current leaders in says Constantine-Paton. “We’re now in . In 1974, Horvitz moved the worm field, including a position to look into the function of to Cambridge, England, where he worked and , who shared the 2008 vps-50 more deeply.” with Sydney Brenner and began his , Michael Hengartner, now studies of the worm. “Remarkably, all President of the University of Zurich, Horvitz and Constantine-Paton are married, of my advisors, even my undergraduate and Cori Bargmann, who recently won and they had chatted about vps-50 long advisor in economics here at MIT, Bob the McGovern’s 2016 Scolnick Prize in before her lab began to study it. When Solow, now have Nobel Prizes,” he notes. Neuroscience. “If the science we’ve done has been successful, it’s because I’ve been lucky to have outstanding young researchers as colleagues,” Horvitz says.

Before becoming a mentor, Horvitz had to become a scientist himself. At

Photo: Justin Knight Photo: Justin Knight Harvard, he studied bacterial viruses and learned that even the simplest organisms could provide valuable insights about fundamental biological processes. Image:

The move to Brenner’s lab in Cambridge was a natural step. A pioneer in the field of , Brenner was also the driving force behind the adoption of C. elegans as a genetic model organism, which he advocated for its simplicity (adults have fewer than 1000 cells, and Horvitz and members of his lab listen as graduate student Kaitlin Driscoll presents her findings at their weekly group meeting. only 302 neurons) and short generation time (only three days). 4 mcgovern.mit.edu Working in Brenner’s lab, Horvitz Discovery Machine at Work and his collaborator John Sulston traced the lineage of every body cell from Since the Nobel Prize, Horvitz has studied fertilization to adulthood, showing that the nervous system using the same strategy the sequence of cell divisions was the that had been so successful in deciphering same in each individual animal. Their the mechanism of programmed cell landmark study provided a foundation death. His approach, he says, begins with for the entire field. “They know all the traditional . Researchers expose cells in the worm. Every single one,” worms to mutagens and observe their says Constantine-Paton. “So when they behavior. When they see an interesting make a mutation and something is change, they identify the mutation and weird, they can determine precisely try to link the gene to the nervous system Image: Nikhil Bhatla & Rita Droste which cell or set of cells are affected. to understand how it affects behavior. Electron micrograph of C. elegans head, showing We can only dream of having such “We make no assumptions,” he says. muscle fibers and nerve cells. By reconstructing an understanding of a mammal.” “We let the animal tell us the answer.” thousands of such images, researchers were able to discover the complete wiring diagram of the It is now known that the worm has While Horvitz continues to demonstrate worm nervous system. about 20,000 genes, many of which that basic research using simple organisms are conserved in mammals including produces invaluable insights about human humans. In fact, in many cases, a cloned biology and health, there are other forces feeding. The animals had provided a clue. human gene can stand in for a missing at work in his lab. Horvitz maintains Bhatla went on to discover that worms worm gene, as is the case for vps-50. As a sense of wonder about life and is respond to light by producing hydrogen a result, the worm has been a powerful undaunted by big questions. peroxide, which activates a taste receptor. discovery machine for human biology. In a sense, worms taste light, a wonder For instance, when Bhatla came to of biology no one could have predicted. In the early years, though, many doubted him wanting to look for evidence of whether worms would be relevant. Horvitz consciousness in worms, Horvitz blinked Some years ago, the Horvitz lab made persisted undeterred, and in 1992 his but didn’t say no. The science Bhatla t-shirts displaying a quote from the conviction paid off, with the discovery proposed was novel, and the question philosopher Friedrich Nietzsche: “You of ced-9, a worm gene that regulates was intriguing. Bhatla pursued it. have made your way from worm to man, programmed cell death. A graduate student But, he says, “It didn’t work.” and much within you is still worm.” in Horvitz’ lab cloned ced-9 and saw that The words have become an informal lab it resembled a human cancer gene called So Bhatla went back to the drawing board. motto, “truer than Nietzsche could ever Bcl-2. They also showed that human Bcl-2 During his earlier experiments, he had have imagined,” says Horvitz. “There’s could substitute for a mutant ced-9 gene observed that worms would avoid light, still so much mystery, particularly about in the worm and concluded that the two a previously known behavior. But he also the brain, and we are still learning from genes have similar functions: ced-9 in noticed that they immediately stopped the worm.” worms protects healthy cells from death, and Bcl-2 in cancer patients protects cancerous cells from death, allowing them to multiply. “This was the moment we knew that the studies we’d been doing with C. elegans were going to be relevant to understanding human biology and disease,” says Horvitz. Photo: Horvitz Lab, MIT

Ten years later, in 2002, he was in the French Alps with Constantine-Paton and their daughter Alex attending a wedding, when they heard the news on the radio: He’d won a Nobel Prize, along with Brenner and Sulston. On the return trip, Alex, then 9 years old but never shy, asked for first-class upgrades at the airport; the agent compromised and gave them all upgrades to business class instead.

Horvitz and lab members, with the skyline beyond.

5 institute news

McGovern Welcomes First Lundbeck Fellow

Thorvald Andreassen joined Guoping Feng’s lab in April 2016 as the McGovern Institute’s first Lundbeck Postdoctoral Photo: JackSeeds, Flickr Fellow. Thorvald received his PhD from Shenzhen Bay Bridge, China. the University of Copenhagen in 2016 where he studied the pre- and post-synaptic to model in rodents. Recent advances such processes involved in dopamine signaling. China Symposium as CRISPR are now making it possible on Primate Research to apply genetic approaches in primates, The Lundbeck Fellows Program has been allowing the development of new disease created by the Lundbeck Foundation and In March, the McGovern Institute models. China has emerged as a leader Lundbeck Pharmaceuticals to provide co-organized an international in this area, and the McGovern Institute young Danish neuroscientists with training symposium at the Shenzhen Institute is collaborating with SIAT to establish a new fellowships at the world’s top neuroscience for Advanced Technology (SIAT), to primate facility in Shenzhen and to develop institutions. The McGovern Institute is discuss new opportunities in primate methods for applying new genetic methods most grateful to Lundbeck for the creation neuroscience. The meeting drew many in primate models. To fully realize the of this program. leading neuroscientists from the US, benefits from this and other similar projects, China, Europe and Japan, for two days a large collaborative effort will be needed, of discussion on how the field can take involving labs in many countries, and the advantage of recent technical advances main goal of this meeting was to launch a in areas such as genome editing. discussion on how this can best be achieved.

Although ethical considerations point The meeting was organized by Bob to the use of rodents or other simpler Desimone, Guoping Feng and Feng Zhang organisms wherever possible, certain at the McGovern Institute, along with questions about brain function can only Liping Wang and Huihui Zhou at SIAT. be studied in primates. In particular, We are grateful to SIAT for hosting the many psychiatric diseases involve meeting, and to the Ministry of Science Photo: Justin Knight disruption of higher cognitive functions and Technology of China and the Chinese or social behaviors that are very difficult Academy of Sciences for their support. Lundbeck Fellow Thorvald Andreassen.

awards & honors

Feng Zhang, an investigator at the promoted to tenure at MIT, will share McGovern Institute, a core institute the Gairdner Award with , member of the Broad Institute, and W. , Phillipe Horvath M. Keck Career Development Associate and Rodolphe Barrangou. Professor in MIT’s Department of Brain and Cognitive Sciences, has been named John Gabrieli has been elected to the Photo:Bryce Vickmark a recipient of the 2016 Canada Gairdner American Academy of Arts and Sciences, International Award — Canada’s most one of the country’s oldest learned societies. prestigious scientific prize — for his role Gabrieli and the other members of the in developing the CRISPR-Cas9 gene- class of 2016 will be inducted at a ceremony editing system. Zhang, who was recently on October 8th in Cambridge, MA.

McGovern Investigator Feng Zhang. 6 mcgovern.mit.edu research news

signals used by neurons to communicate with other cells. Neuropeptides are also important in controlling human physiology and behavior. Several lines of evidence led the researchers to propose that the Image: Gloria Choi human counterpart of vps-50 might be linked to autism.

In 2010, a large study in Denmark found that pregnant women who suffered

Image: Jenny Chai & Susan Whitfield-Gabrieli an infection severe enough to require hospitalization were much more likely Children at heightened risk for depression Inflammation during pregnancy to have a child with autism. Now research show hyperconnectivity of subgenual anterior can affect the developing mouse brain. cingulate cortex (shown in orange). from Gloria Choi’s lab reveals a possible mechanism for how this may occur. In a study of mice, the researchers found A new brain imaging study from The findings suggest that drugs that immune cells activated in the mother the McGovern Institute and Harvard boosting TRN activity could improve during severe inflammation produce Medical School may lead to a screen that ADHD symptoms and possibly help treat a molecule called IL-17 that appears could identify children at high risk of other disorders that affect attention. to interfere with brain development. developing depression later in life. In the The researchers also found that blocking study, the researchers found distinctive MIT neuroscientists led by Bob Horvitz this signal could restore normal behavior brain differences in children known to and Martha Constantine-Paton have and brain structure in the offspring. be at high risk because of family history discovered a gene that plays a critical role of depression. The finding suggests in controlling nerve cell communication We can easily recognize objects that this type of scan could be used to and the switch between alternative independent of their size or viewing identify children whose risk was previously behavioral states (see pg 2). Their study angle, but we also perceive these variables unknown, allowing intervention before was conducted using both nematode and use them to interpret complex visual they develop depression, says John worms and mice. In humans, transitions scenes. Jim DiCarlo and colleagues have Gabrieli, one of the study’s authors. between behavioral states include hunger- developed a computational model that satiety and sleep-wakefulness, for example. mimics the brain’svisual recognition Guoping Feng has previously developed The worm gene, which the researchers capabilities and explains how the visual a mouse model of autism based on dubbed vps-50, affects the processing system can achieve both of these tasks a mutation in the Shank3 gene, which and release of neuropeptides — chemical in parallel. is linked to autism in humans. His team has now shown that many of the mutation’s effects on brain and behavior can be reversed by restoring Shank3 gene activity in adult mice. The findings offer hope that it will eventually be possible to reverse some of the effects of autism in human patients.

In a separate study, Guoping Feng and collaborators at New York University have linked ADHD and other attention difficulties to the brain’s thalamic reticular nucleus (TRN), which is responsible for blocking out distracting sensory input. In a study of mice, the researchers discovered that a gene mutation found in some patients with ADHD produces a defect in the TRN that leads to attention impairments. Image: Bob Horvitz

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Design: Director ofDevelopment: Writer: Editors: Sametz BlackstoneAssociates,Boston Elizabeth Dougherty Charles Jennings,JuliePryor Kara Flyg

Photo: Justin Knight