Placement: Promote to Homepage

Alan D. Grossman

Education

  • PhD, 1984, University of Wisconsin, Madison
  • BS, 1979, Biochemistry, Brown University

Research Summary

We use a variety of approaches to investigate several of the fundamental and conserved processes used by bacteria for propagation and growth, adaptation to stresses, and acquisition of new genes and traits via horizontal gene transfer. Our long term goals are to understand many of the molecular mechanisms and regulation underlying basic cellular processes in bacteria. Our organism of choice for these studies is usually the Gram positive bacterium Bacillus subtilis.

Our current efforts are focused in two important areas of biology: 1) The control of horizontal gene transfer, specifically the lifecycle, function, and control of integrative and conjugative elements (ICEs). These elements are widespread in bacteria and contribute greatly to the spread of antibiotic resistances between organisms. 2) Regulation of the initiation of DNA replication and the connections between replication and gene expression, with particular focus on the conserved replication initiator and transcription factor DnaA. This work is directly related to mechanisms controlling bacterial growth, survival, and stress responses.

Awards

  • National Academy of Sciences, 2014
  • American Academy of Arts and Sciences, 2008
  • American Academy of Microbiology 1998
  • Eli Lilly Company Research Award, 1997
A scientific approach to writing fiction

Megan Miranda '02 graduated from MIT intent on pursuing a career in biotechnology. Instead, she became a New York Times best-selling author.

Jay London | MIT Alumni Association
November 15, 2017

Megan Colpitts Miranda ’02, who graduated from MIT with a degree in biology, intended to pursue a career in biotechnology. Instead, she became a successful fiction author whose book, “All the Missing Girls,” is a New York Times best-seller. Both careers share a trial-and-error approach to achieving success, she believes.

“There are a lot of similarities in the process,” Miranda says. “Each book draft is an experiment where I can assess what’s working and what’s not. You start with a blank slate; then each step gets you closer to a solution.”

Miranda worked in biotech in Boston for two years after graduation before moving with her husband, Luis Miranda ’01, to North Carolina, where she spent two years as a high school science teacher.

“Teaching put me back in touch with the elements that made me initially fall in love with science,” she says. “That love of science kind of funneled into writing my first books, which all contained weird scientific elements in their plots.”

Miranda began writing full time after the birth of her two children. After a few years of proposals, rewrites, and revisions, her first book, the young-adult thriller “Fracture,” was released in 2012. Six other books quickly followed, including “Hysteria,” “Vengeance,” “Soulprint,” and “The Safest Lies.” But the one to make the biggest impact has been “All the Missing Girls,” a story about the disappearance of two young women that was named editors’ choice by The New York Times Book Review and one of The Wall Street Journal’s “5 Killer Books for 2016.”

Miranda’s most recent work, “The Perfect Stranger,” was published by Simon and Schuster this year. And her next young-adult book, “Fragments of the Lost,” is due out in early 2018.

Miranda credits the thematic elements of her young-adult books, in part, to her coursework at MIT, where she mixed bioengineering with a steady dose of anthropology and literature.

“My first books combined biology and anthropology,” she says. “They are different sides of the same interests. Biology is the science element, confirmed by process of experiment, while anthropology is the human element.”

MIT’s “fail-forward” mentality also helped lay the groundwork for her literary career. “At MIT, I learned not to fear failure,” Miranda says. “MIT is the type of place where you need self-discipline and a willingness to take risks and try a different approach. Writing is no different.”

Miranda lives near Charlotte with her husband, a senior manager at Accenture, and their 11-year-old daughter and nine-year-old son. She enjoys connecting with readers through school and library visits, and she offers Skype Q&A sessions to book clubs and classes.

This article originally appeared in the September/October 2017 issue of MIT Technology Review.

Mary Clare Beytagh: Finding poetry in medicine

MIT senior and aspiring physician aims to tell stories that humanize the patients behind medical statistics.

Fatima Husain | MIT News correspondent
November 12, 2017

When MIT senior Mary Clare Beytagh isn’t performing research at the Koch Institute for Integrative Cancer Research or writing poetry, she can be found in ballet class at the Harvard Dance Center, continuing her 15 years of intensive dance training.

For Beytagh, ballet provides a reprieve from the hustle and bustle of academics and research. Her twice-a-week classes are “a nice way to de-stress and think about things,” including flashbacks to exciting moments on stage as a preprofessional ballerina, and fond memories with friends.

On days without dance class, Beytagh goes running. The two activities are “sort of antithetical to each other,” she notes. However, she makes it work. Beytagh is majoring in biology and literature at MIT — two fields that, like running and ballet, rarely intersect. But Beytagh aims to change that.

Running start on research

The summer before Beytagh’s senior year in high school, her teachers encouraged her to apply to a research program at the University of Texas Southwestern Medical Center.

The eight-week program took Beytagh out of the the classroom and into to the lab of Kathryn O’Donnell-Mendell, a cancer researcher studying B-cell lymphoma. The program was Beytagh’s first experience with scientific and medical research, and she was hooked.

She continued the research into her senior year of high school and submitted a paper to the prestigious Siemens Competition in Math, Science, and Technology.

While working in the lab, she met an MD-PhD student who opened Beytagh’s eyes to the possibility of pursuing medicine and cancer research simultaneously. When Beytagh applied to college, she looked for schools that emphasized undergraduate research. MIT topped her list.

“MIT rises above everyone else in that aspect,” she says. During an on-campus visit, she took part in a tour that allowed her to learn about the different types of research performed at the Institute. By the end of the tour, Beytagh knew MIT was the right fit. “These are my people,” she recalls thinking.

Upon the advice of her research advisor at UT Southwestern, after Beytagh arrived at MIT she sought out Tyler Jacks, professor of biology and director of the Koch Institute.

Beytagh has worked in the Jacks Lab since her second semester at the Institute. She and the other researchers are developing mouse models for cancer that recapitulate more aspects of the human disease. One goal, for example, is to have the tumors grow in the same locations in the animals as they do in humans.

Last year, Beytagh was invited to speak at the American Association for Cancer Research meeting. There, she presented her research alongside postdocs and early-career cancer biologists.

“That was a cool experience,” she says, “But then, it was back to the lab immediately!”

Documenting experiences

Outside of the lab, Beytagh enjoys expressing herself through her writing as a literature major.

During her sophomore Independent Activities Period (IAP), she traveled to Madrid to study Spanish literature. Her class was taught by MIT professors Stephen Tapscott and Margery Resnick. It examined post-Spanish Civil War novels and poetry — and captivated Beytagh.

After IAP ended, Beytagh continued studying poetry in Tapscott’s course 21L.487 (Modern Poetry). During the class, distinguished American poet Martha Collins visited and performed a poetry reading.

The visit had such an impact on Beytagh that she embarked upon an exercise inspired by one of Collins’ poetry series. The experiment lasted 21 days, during which Beytagh wrote poetic snapshots of each day within a set of predetermined rules.

“I’m a person who likes rules, but within those rules finds creativity,” Beytagh says.

On the 21st day, poetry morphed from hobby to emotional necessity. She found out her good friend had been diagnosed with Hodgkin’s lymphoma. At that moment, her poetry “became catharsis.”

She decided to declare literature as her second major.

“I had been flirting with the idea, but I had never committed,” she says, “Then, at the end of [sophomore] year, I committed.”

“This is it,” she says, recounting her reasoning, “These professors are amazing. I’m having a great time. It’s enriching me as a person.”

Bringing backstories to the forefront

Beytagh often integrates her research and other undergraduate experiences into her writing.

During her junior year IAP, she did an externship in the Yale School of Medicine’s emergency medicine department, with Charles Wira, III. She worked on developing a new risk score system for patients experiencing sepsis, but it was what she witnessed while shadowing in the emergency room that transformed her outlook.

“The most timely and impactful thing I saw there was the nature of the opioid epidemic,” she says, “You can read all you want in The New York Times and look at graphs — but that’s just statistics.”

That winter, she witnessed two to three patients coming into the emergency room for opioid overdoses each day she was there.

“What you don’t get in a graph,” she points out, “are the backstories of all these people.”

After that experience, she began to write about patients she saw and interacted with, in her poetry. In the long term, Beytagh hopes to become a science writer as well as a physician-scientist, telling stories that humanize patients and focus on the social and economic determinants of health.

Though she plans to study cancer biology in an MD-PhD program, she hopes to end up at an institution that allows her to take on other projects such as epidemiological research on opioid addiction.

Facilitating leadership

After a recommendation from her roomates freshman year, Beytagh joined the Leadership Training Institute, an organization which provides leadership training and mentorship to underprivileged Boston area high school students. The institute runs a 12-week program for 50 students each spring.

As the director of the program, Beytagh aims to reach students who are shy but passionate about community service and leadership, and works to provide them with transformative experiences.

“It’s always very gratifying when the students [graduate from the program],” she says. “They say, ‘You guys have made me realize that I not only want to keep service as a part of high school, but as a part of my career and onward.’”

“That gives you chills,” Beytagh says. “If you can spark that in someone and make them realize having an others-focused heart is the way to live life, it can only be good for our world.”

New player in cellular signaling

Researchers have identified a key nutrient sensor in the mTOR pathway that links nutrient availability to cell growth.

Nicole Giese Rura | Whitehead Institute
November 9, 2017

To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.

The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.

Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.

Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.

“There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”

Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.

“People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”

The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.

“It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”

This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.

Retinoic acid regulates transitions in mouse sperm production
November 7, 2017

CAMBRIDGE, MA – Sperm production requires progression through a well-orchestrated series of transitions in the testes that move diploid spermatogonia cells, with two complete sets of chromosomes, through a series of transitions to produce haploid sperm, with one copy of each chromosome, poised to swim and fertilize an available egg. There are four major transitions in sperm production, or spermatogenesis. The first is spermatogonial differentiation, during which spermatogonia differentiate, losing their stem-cell like qualities. The resulting spermatocytes then initiate meiosis and undergo two rounds of cell division to generate haploid spermatids. The spermatids undergo elongation and then the resulting sperm are released.

The signals that control progression through these transitions were poorly understood until 2015, when David Page, Member and Director of Whitehead Institute, professor of biology at Massachusetts Institute of Technology, and investigator with Howard Hughes Medical Institute and colleagues determined that retinoic acid (RA), a derivative of vitamin A that has been shown to play a key role in a number of developmental processes, was responsible for coordinating the first two stages of spermatogenesis-differentiation and meiosis. Now, in a paper published this week in the journal Proceedings of the National Academy of Sciences, Page, first author Tsutomu Endo, and colleagues extend those findings to show that RA signaling in mice coordinates the second two transitions as well.

Diagram of model by which retinoic acid coordinates spermatogenesisThe researchers used chemical manipulation of RA levels to determine that RA controlled the second two transitions, spermatid elongation and sperm release, in addition to the first two. With this knowledge in hand, the researchers were then able to drill down and get a better picture of how RA regulates male gamete production. One outstanding question has been how males are able to continually produce sperm throughout their lifetime, in contrast with females whose egg production and maturation is limited. Page and colleagues measured RA levels in the testes and discovered that it is cyclically produced, driving production of sperm during the male lifetime. In addition to the timing of RA production, the researchers also examined its source. From which cells was the RA signal coming? During the first two transitions, they determined that the RA was coming from the somatic Sertoli cells, the support cells of the testes, and in the second two transitions they determined that it was being released by the germ cells themselves-the meiotic (pachytene-stage) spermatocytes were found to be secreting RA to other germ cells in the testes.

These findings not only contribute to our fundamental understanding of male gamete formation, they also provide important clues for the field of reproductive technology. For years, scientists have been working on making gametes in the laboratory, but have had difficulty making functional sperm. This discovery of the role of RA in spermatogenesis adds important tools to the toolbox of assisted reproduction. The work shows that RA is required in both the early and late transitions of spermatogenesis and sheds light on an important component of laboratory efforts for sperm production.

Other researchers involved include Elizaveta Freinkman and Dirk G. de Rooij.

This research was supported by Howard Hughes Medical Institute (HHMI) and the United States Department of Defense (DoD W81XWH-15-1-0337)

Written by Lisa Girard
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David Page’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and a Professor of Biology at the Massachusetts Institute of Technology.
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Paper cited: Endo, T et al.  Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis. Proc Natl Acad Sci. DOI: 10.1073/pnas.1710837114. Epub 2017 Nov 6.
Other work cited: Endo T et al. Periodic retinoic acid-STRA8 signaling intersects with periodic germ-cell competencies to regulate spermatogenesis. Proc Natl Acad Sci. DOI: 10.1073/pnas.1505683112. Epub 2015 Apr 20.
A new workflow for natural product characterization comes ashore with red algae
October 30, 2017

CAMBRIDGE, Mass. – A few years ago while paddling off the coast near La Jolla, California, avid surfer Roland Kersten noticed a piece of red algae (Laurenica pacifica) bobbing alongside his surfboard. Kersten, whose background is in natural product chemistry, was intrigued.

Natural products—chemicals from living organisms such as plants and algae—represent a rich source of potential therapeutics. A majority of anti-cancer drugs are natural product-based or inspired. One such well-known natural product—the potent anti-cancer drug Taxol—was identified in the bark of a yew tree.

Marine algae, like the red algae Kersten found, are often rich in compounds called sesquiterpenes, some of which have been shown to have potential medicinal attributes. Since the 1970s, scientists identified many sesquiterpenes produced by Laurencia species with anti-cancer properties. The identification techniques usually required about tens of milligrams of purified compounds, which were obtained from more than a kilogram of algae. Because Laurencia and the reef ecosystems in which it thrives are protected, and such large-scale harvesting for scientific or medicinal purposes is no longer tenable, Kersten had to devise a different approach to analyze its sesquiterpenes.

Kersten received a collection permit to clamber over the rocky shore at deep low tide to collect a hand-sized sample of the red algae. Now a postdoctoral fellow in the lab of Whitehead Member and Massachusetts Institute of Technology assistant professor of biology Jing-Ke Weng, Kersten’s first task was to search the RNA sequences of all genes expressed in his red algae sample to find those whose product seemed likely to be enzymes that make sesquiterpenes.  In order to determine the product generated by these enzymes, he engineered them in yeast and isolated its sesquiterpene products.

In order to define the first step in the biogenesis of sesquiterpenes in red algae, Kersten wanted to see the precise 3-D structure of the isolated sesquiterpene. But the small handful of algae he had obtained produced only a fraction of the amount required for x-ray crystallography, the established method for determining a compound’s absolute structure. So Kersten tried a method recently developed by collaborator Makoto Fujita at the University of Tokyo that requires only a few nanograms of material: soaking extracted compounds into a special crystalline sponge, which supports the sample’s molecular shape while it is bombarded with x-rays to accurately determine the 3-D conformation of a molecule. A new combination of the crystalline sponge method and nuclear magnetic resonance spectroscopy by the Fujita group revealed the structure of prespatane.

With the compound’s structure in hand, Kersten is closer to understanding how Laurenciabiosynthesizes its sesquiterpenes and how to engineer yeast to produce the same molecules for medicinal research at scale—without touching the red algae flourishing on protected reefs. And the novel workflow—spanning genomics, metabolomics, synthetic biology, and x-ray crystallography with crystalline sponges—established by Weng, Kersten, and their collaborators may expedite the identification of other promising compounds produced by organisms from both land and sea.

Other contributors to this work include Shoukou Lee of Tokyo University, Daishi Fujita of Tokyo University and Whitehead Institute, Tomáš Pluskal of Whitehead Institute.  The team also collaborated with researchers from Scripps Institution of Oceanography and Salk Institute of Biological Sciences.

This work was supported by Howard Hughes Medical Institute, the Simons Foundation, the Helen Hay Whitney Foundation, the Pew Scholars Program in the Biomedical Sciences, the Searle Scholars Program, and the Japan Science and Technology Agency.

 Written by Nicole Giese Rura
* * *
Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.
* * *
Full Citation:
“A Red Algal Bourbonane Sesquiterpene Synthase Defined by Microgram-scale NMR-coupled Crystalline Sponge XRD Analysis”
Journal of the American Chemical Society, online October 30, 2017.
Roland D. Kersten (1,6), Shoukou Lee (2,6) , Daishi Fujita (1,2) , Tomáš Pluskal (1) , Susan Kram (3), Jennifer E. Smith (3) , Takahiro Iwai (2) , Joseph P. Noel (4) , Makoto Fujita (2), Jing-Ke Weng (1,5).
1. Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA, United States
2. Graduate School of Engineering, The University of Tokyo, JST-ACCEL, Tokyo, Japan
3. Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, United States
4. Howard Hughes Medical Institute, Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA, United States
5. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
6. These authors contributed equally
Department of Biology hosts 2017 Massachusetts Junior Academy of Science Symposium

High school students present research projects to build communication skills while earning membership to the American Junior Academy of Science.

Raleigh McElvery | Department of Biology
October 24, 2017

On Oct. 14, 22 school students from across the state presented their research projects at the annual Massachusetts Junior Academy of Science (MassJAS) Symposium.

The talks were split into two concurrent sessions based on subject: biological and environmental sciences; and engineering, chemistry, mathematics, and physics. Participants were selected based on merit and ranking in this year’s Massachusetts State Science and Engineering Fair.

Judges nominated three students from the biology session and four from physics and engineering as American Junior Academy of Science (AJAS) delegates. Delegates are invited to attend the AJAS Convention, which will be held in Austin, Texas this coming February. The AJAS is a national honor society that meets annually in conjunction with the American Association for the Advancement of Science — the world’s largest science organization and the publisher of Science. All participants were inducted as AJAS fellows.

The sessions took place in adjacent lecture rooms in Building 68. The event was organized by Mandana Sassanfar, director of diversity and science outreach for MIT’s Department of Biology and Department of Brain and Cognitive Sciences, as well as the director of MassJAS. During the event, delegates toured local research institutions, shared their projects with others in the field, and attended conference sessions.

At this year’s MassJAS symposium, the jury for the biological and environmental science session was composed of three graduate students and postdoc from the MIT Department of Biology.

“I really enjoyed hearing how these projects came to be, and what inspired students to ask their respective research questions,” said Sora Kim, a third year graduate student in Tania Baker’s lab and a returning judge. “Some students did these projects at home, while others had collaborations with researchers at local universities. In many cases, these were their first science projects, so being able to understand their own projects and also convey their ideas to a more general audience is really important.”

First-time judge Summer Morrill, a third year graduate student in Angelika Amon’s lab, agreed that learning to present ideas clearly in ways that inspire others is key to the scientific process. “I was excited to hear what people at the high school level think is important in science, because they’re the next generation of scientists,” she said.

Each participant had ten minutes to present, followed by an audience question-and-answer session. The biology-related talks ranged from antimicrobial resistance to gene editing techniques to the effects of wifi router radiation.

Joshua Powers and Natalia Huynh, both juniors at the Everett High School STEM Academy, presented first, describing the results of their summer research project at MIT as part of the LEAH Knox Scholars pilot program. Powers and Huynh pooled their findings, isolating and characterizing bacterial specimens from the Charles River.

“We’re friends and we both go to the same high school, so it was easy to collaborate with both our ideas and our data,” said Powers. “The LEAH Knox Scholars program was intense in that we had the chance to perform more advanced procedures with equipment we’ve never used before in school.”

Huynh also enjoyed tackling larger research questions with more refined tools, adding, “We practiced explaining our results this summer, so today’s presentation was similar to what we’d already done — but a little more intense because it was a competition.”

Nancy Cianchetta, who teaches biotechnology at Everett High School and serves as the coordinator for the STEM Academy, said Powers and Huynh will be part of the very first class to graduate from the Academy. She and many of her students have participated in MIT biology outreach programs over the years.

“I’ve taken my classes here for field trips and career exploration days, and many of my students come for the spring lecture series at the Whitehead Institute,” she said. “The kids get so excited to come to MIT.”

While some participants shared data they’d only just begun to analyze, others had been tackling the same research question for over a year.

Evan Mizerak, a returning MassJAS Symposium winner and senior at Wachusett Regional High School, has spent the past two-and-a-half years collaborating with researchers at the University of Massachusetts Medical School on his project related to heritable infertility in fruit flies.

Mizerak attended last year’s AJAS Convention in Boston, as well as the MIT-sponsored Breakfast with Scientists. This year, delegates met with esteemed faculty, including Institute Professor Phillip Sharp, the winner of the 1993 Nobel Prize in physiology or medicine and a member of the Department of Biology and the Koch Institute for Integrative Cancer Research.

“The AJAS Convention was incredible last year, because we had the chance to meet researchers from around the country — not just in and around Massachusetts,” he said. “At the Breakfast with Scientists, we met with Nobel Prize winners. Being introduced to people I consider celebrities was just amazing.”

“You wouldn’t expect anyone that famous to be interested in our work,” added Emma Kelly, a junior from Newton Country Day School and also a returning presenter. “But these professionals were genuinely curious, and often gave us ideas for new projects and things like that. It was such an incredible opportunity.”

MIT neuroscientists build case for new theory of memory formation

Existence of “silent engrams” suggests that existing models of memory formation should be revised.

Anne Trafton | MIT News Office
October 23, 2017

Learning and memory are generally thought to be composed of three major steps: encoding events into the brain network, storing the encoded information, and later retrieving it for recall.

Two years ago, MIT neuroscientists discovered that under certain types of retrograde amnesia, memories of a particular event could be stored in the brain even though they could not be retrieved through natural recall cues. This phenomenon suggests that existing models of memory formation need to be revised, as the researchers propose in a new paper in which they further detail how these “silent engrams” are formed and re-activated.

The researchers believe their findings offer evidence that memory storage does not rely on the strengthening of connections, or “synapses,” between memory cells, as has long been thought. Instead, a pattern of connections that form between these cells during the first few minutes after an event occurs are sufficient to store a memory.

“One of our main conclusions in this study is that a specific memory is stored in a specific pattern of connectivity between engram cell ensembles that lie along an anatomical pathway. This conclusion is provocative because the dogma has been that a memory is instead stored by synaptic strength,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, the director of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, and the study’s senior author.

The researchers also showed that even though memories held by silent engrams cannot be naturally recalled, the memories persist for at least a week and can be “awakened” days later by treating cells with a protein that stimulates synapse formation.

Dheeraj Roy, a recent MIT PhD recipient, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Oct. 23. Other authors are MIT postdoc Shruti Muralidhar and technical associate Lillian Smith.

Silent memories

Neuroscientists have long believed that memories of events are stored when synaptic connections, which allow neurons to communicate with each other, are strengthened. Previous studies have found that if synthesis of certain cellular proteins is blocked in mice immediately after an event occurs, the mice will have no long-term memory of the event.

However, in a 2015 paper, Tonegawa and his colleagues showed for the first time that memories could be stored even when synthesis of the cellular proteins is blocked. They found that while the mice could not recall those memories in response to natural cues, such as being placed in the cage where a fearful event took place, the memories were still there and could be artificially retrieved using a technique known as optogenetics.

The researchers have dubbed these memory cells “silent engrams,” and they have since found that these engrams can also be formed in other situations. In a study of mice with symptoms that mimic early Alzheimer’s disease, the researchers found that while the mice had trouble recalling memories, those memories still existed and could be optogenetically retrieved.

In a more recent study of a process called systems consolidation of memory, the researchers found engrams in the hippocampus and the prefrontal cortex that encoded the same memory. However, the prefrontal cortex engrams were silent for about two weeks after the memory was initially encoded, while the hippocampal engrams were active right away. Over time, the memory in the prefrontal cortex became active, while the hippocampal engram slowly became silent.

In their new PNAS study, the researchers investigated further how these silent engrams are formed, how long they last, and how they can be re-activated.

Similar to their original 2015 study, they trained mice to fear being placed in a certain cage, by delivering a mild foot shock. After this training, the mice freeze when placed back in that cage. As the mice were trained, their memory cells were labeled with a light-sensitive protein that allows the cells to be re-activated with light. The researchers also inhibited the synthesis of cellular proteins immediately after the training occurred.

They found that after the training, the mice did not react when placed back in the cage where the training took place. However, the mice did freeze when the memory cells were activated with laser light while the animals were in a cage that should not have had any fearful associations. These silent memories could be activated by laser light for up to eight days after the original training.

Making connections

The findings offer support for Tonegawa’s new hypothesis that the strengthening of synaptic connections, while necessary for a memory to be initially encoded, is not necessary for its subsequent long-term storage. Instead, he proposes that memories are stored in the specific pattern of connections formed between engram cell ensembles. These connections, which form very rapidly during encoding, are distinct from the synaptic strengthening that occurs later (within a few hours of the event) with the help of protein synthesis.

“What we are saying is that even without new cellular protein synthesis, once a new connection is made, or a pre-existing connection is strengthened during encoding, that new pattern of connections is maintained,” Tonegawa says. “Even if you cannot induce natural memory recall, the memory information is still there.”

This raised a question about the purpose of the post-encoding protein synthesis. Considering that silent engrams are not retrieved by natural cues, the researchers believe the primary purpose of the protein synthesis is to enable natural recall cues to do their job efficiently.

The researchers also tried to reactivate the silent engrams by treating the mice with a protein called PAK1, which promotes the formation of synapses. They found that this treatment, given two days after the original event took place, was enough to grow new synapses between engram cells. A few days after the treatment, mice whose ability to recall the memory had been blocked initially would freeze after being placed in the cage where the training took place. Furthermore, their reaction was just as strong as that of mice whose memories had been formed with no interference.

Sheena Josselyn, an associate professor of psychology and physiology at the University of Toronto, said the findings run counter to the longstanding idea that memory formation involves strengthening of synapses between neurons and that this process requires protein synthesis.

“They showed that a memory formed during protein-synthesis inhibition may be artificially (but not naturally) recalled. That is, the memory is still retained in the brain without protein synthesis, but this memory cannot be accessed under normal conditions, suggesting that spines may not be the key keepers of information,” says Josselyn, who was not involved in the research. “The findings are controversial, but many paradigm-shifting papers are.”

Along with the researchers’ previous findings on silent engrams in early Alzheimer’s disease, this study suggests that re-activating certain synapses could help restore some memory recall function in patients with early stage Alzheimer’s disease, Roy says.

The research was funded by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation.

Stuck on the membrane

A pro-metastatic transcription factor’s journey from anonymity to a promising target for breast cancer therapy

October 20, 2017

An overwhelming majority of deaths from cancer are associated not with the primary tumor, but instead with its metastases to other sites in the body. For this reason, understanding the properties of cancer cells that give them a high metastatic potential, and identifying molecular strategies to intervene, is critical for improving clinical outcomes.

One of the hallmarks of cancer cells with high metastatic potential is an epithelial to mesenchymal transition (EMT). This shift in their gene expression landscape is a harbinger for both invasive behavior and anti-cancer drug resistance. One signaling pathway active in cells that have undergone EMT transition, the PERK pathway, has been of particular interest to Whitehead Institute Member and Massachusetts Institute of Technology associate professor of biology Piyush Gupta and postdoctoral researchers in Gupta’s lab, Yu-Xiong Feng and Dexter Jin. The PERK signaling pathway has been a sought-after target for a number of types of cancer, including breast cancer. Drug companies had largely given up on the PERK signaling pathway as a target, however, because when it is inhibited, it also has the unintended consequence of affecting glucose regulation to the degree that mice given PERK inhibitors typically develop diabetes within a few weeks. Gupta and colleagues hypothesized that downstream elements of the pathway could include targets with more specific effects on metastatic behavior, potentially enabling the development of therapies that do not result in the unintended consequences associated with inhibiting PERK. 

In a recent article in Nature Communications, Gupta, Feng, Jin, and colleagues describe CREB3L1, a factor downstream of the PERK pathway that is active in the subset of triple negative breast cancer cells and tumor cells that have undergone an EMT transition. CREB3L1 expression is associated with distant metastasis and is important for the transformed cell’s invasive and drug resistant properties. While factors like CREB3L1, called transcription factors, are usually difficult to target with small molecules, Gupta and his team zeroed in on a unique property it shares with only a small handful of other factors-it is normally stuck to the membrane of a cellular compartment called the endoplasmic reticulum and, in order for it to be active, it need to be cut free by factors called proteases. Gupta and colleagues show that certain protease inhibitors can actually stop the activation of CREB3L1 in its tracks, along with the invasive and drug resistance properties its activation confers. 

While the PERK signaling pathway has been an attractive target for anticancer therapy, its more general cellular role made it an intractable target. The downstream factor of the pathway  CREB3L1 is a potential new target for breast cancer therapy whose specificity of action makes it an attractive option for targeting metastatic behavior.

By Lisa Girard
Citation:
Feng Y-X, Jin DX, et al. “Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1.” Nature Communications DOI:10.1038/s41467-017-01052-y
School of Science welcomes new faculty members

This fall brings 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

School of Science
October 10, 2017

This fall, the MIT School of Science has welcomed 14 new professors in the departments of Biology, Chemistry, Mathematics, and Physics.

Ian J. M. Crossfield focuses on the atmospheric characterization of exoplanets through all possible methods — transits, eclipses, phase curves, and direct imaging — from the ground and from space, with an additional interest in the discovery of new exoplanets, especially those whose atmospheres that can be studied in more detail. He joins the MIT Department of Physics as an assistant professor.

Joey Davis, an assistant professor in the Department of Biology, studies the molecular mechanisms underpinning autophagy using biochemical, biophysical, and structural biology techniques such as mass spectrometry and cryo-electron microscopy. This pathway is responsible for protein and organelle degradation and has been linked to a variety of aging associated disorders including neurodegeneration and cancer.

Daniel Harlow works on black holes and cosmology, viewed through the lens of quantum gravity and quantum field theory. He has joined the Department of Physics as assistant professor.

Philip Harris, a new assistant professor in the Department of Physics, searches for dark matter, seeking a deeper understanding of the petabytes of data collected at the Large Hadron Collider. Much of his research exploits new techniques to resolve the structure of quark and gluon decays, known as jet substructure.

Or Hen studies quantum chromodynamics effects in the nuclear medium, and the interplay between partonic and nucleonic degrees of freedom in nuclei, conducting experiments at the Thomas Jefferson and Fermi National Accelerator Laboratories, as well as other accelerators around the world. He has joined the faculty as an assistant professor in the Department of Physics and the Laboratory of Nuclear Science.

Laura Kiessling investigates how carbohydrates are assembled, recognized, and function in living cells, which is crucial to understanding key biological processes such as bacterial cell wall biogenesis, bacteria chemotaxis, enzyme catalysis and inhibition, immunity, and stem cell propagation and differentiation. She is the new Novartis Professor of Chemistry.

Rebecca Lamason investigates how intracellular bacterial pathogens hijack host cell processes to promote infection. In particular, she studies how Rickettsia parkeri and Listeria monocytogenes move through tissues via a process called cell-to-cell spread. She has joined the Department of Biology as an assistant professor.

Sebastian Lourido studies the molecular events that enable parasites in the phylum Apicomplexa to remain widespread and deadly infectious agents. Lourido uses Toxoplasma gondii to model processes conserved throughout the phylum, in order to expand our understanding of eukaryotic diversity and identify specific features that can be targeted to treat parasite infections. He has been welcomed into the Department of Biology as an assistant professor.

Ronald T. Raines, who has joined the faculty as the Firmenich Professor of Chemistry, uses techniques that range from synthetic chemistry to cell biology to illuminate in atomic detail both the chemical basis and the biological purpose for protein structure and protein function. He seeks insights into the relationship between amino-acid sequence and protein function (or dysfunction), as well as to the creation of novel proteins with desirable properties.

Giulia Saccà is an algebraic geometer with a focus on hyperkähler and Calabi-Yau manifolds, K3 surfaces, moduli spaces of sheaves, families of abelian varieties and their degenerations, and symplectic resolutions. She is now an assistant professor in the Department of Mathematics.

Stefani Spranger studies the interactions between cancer and the immune system, with the goal of improving existing immunotherapies or developing novel therapeutic approaches. Spranger seeks to understand how CD8 T cells, otherwise known as killer T cells, are excluded from the tumor microenvironment, with a focus on lung and pancreatic cancers. She has joined the Department of Biology as an assistant professor.

Daniel Suess works at the intersection of inorganic and biological chemistry, studying redox reactions that underpin global biogeochemical cycles, metabolism, and energy conversion. He develops chemical strategies for attaining precise, molecular-level control over the structures of complex active sites. In doing so, his research yields detailed mechanistic insight and enables the preparation of catalysts with improved function. Suess is an assistant professor in the Department of Chemistry.

Wei Zhang is a number theorist who works in arithmetic geometry, with special interest in fundamental objects such as L-functions, which appear in the Riemann hypothesis and its generalizations, and are central to the Langlands program. Zhang has joined the Department of Mathematics as a full professor.

Yufei Zhao, who has joined the Department of Mathematics as an assistant professor, works in combinatorics and graph theory, and is especially interested in problems with extremal, probabilistic, and additive flavors.