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3 Questions: Ibrahim Cissé on using physics to decipher biology

A biophysicist employs super-resolution microscopy to peer inside living cells and witness never-before-seen phenomena.

Raleigh McElvery | Department of Biology
July 23, 2020

How do cells use physics to carry out biological processes? Biophysicist Ibrahim Cissé explores this fundamental question in his interdisciplinary laboratory, leveraging super-resolution microscopy to probe the properties of living matter. As a postdoc in 2013, he discovered that RNA polymerase II, a critical protein in gene expression, forms fleeting (“transient”) clusters with similar molecules in order to transcribe DNA into RNA. He joined the Department of Physics in 2014, and was recently granted tenure and a joint appointment in biology. He sat down to discuss how his physics training led him to rewrite the textbook on biology.

Q: How does your work revise conventional models describing how RNA polymerases carry out their cellular duties?

A: My interest in biology has always been curiosity-driven. As a physicist reading biology textbooks, I thought that transcription — the process by which DNA is made into RNA — was fully understood. It’s so basic, and the textbooks write about it with such confidence. Come to find out, most of what we know about the cell nucleus, where gene expression starts, comes from people studying these processes outside the cell, inside a test tube. I started to wonder: Do we actually know how they work in a living cell?

The textbook models say that when a specific gene is being activated, RNA polymerase and dozens of other molecules are recruited to the DNA to begin transcription. If you don’t look closely enough, the polymerases appear to be uniformly distributed and acting randomly throughout the nucleus. However, my single-molecule and “super-resolution” microscopy methods allowed me to see something different when I looked inside live cells: polymerase clusters, which are very dynamic. In the mid-’90s, people had observed similar clusters in so-called “fixed” cells that were chemically frozen. But these findings were dismissed as possible artifacts of the fixation procedure. However, when we saw these same protein clusters in living cells that were not treated with harsh chemicals, it suggested that the textbook explanation may be incomplete.

Q: How has your background in physics given you a unique perspective on the mechanics of living cells?

A: When I arrived at the University of Illinois at Urbana-Champaign to begin my PhD in physics, I hadn’t enrolled in a biology class since high school. I was really taken with the interdisciplinary work of one physics professor, Taekjip Ha, who became my PhD mentor. He had developed single-molecule fluorescence resonance energy transfer techniques, to study with unprecedented sensitivity when two biomolecules are close to each other and monitor the distance between them in real time.

Taekjip graciously accepted me into his lab despite my limited biology background, and I never looked back. His work mirrored my interest in condensed matter physics, but the material we were looking at wasn’t from the inanimate world, it was living matter.

Between 2006 and 2008, as I was working on my PhD, super-resolution microscopy really took off from the single-molecule microscopes I used in grad school. It was a natural progression, in my mind, to learn cell biology during my postdoc fellowship at École Normale Supérieure in Paris, and to try to visualize weak and transient interactions directly in living cells using single-molecule and super-resolution imaging. You could now pinpoint molecules with nanometer accuracy; you could “turn on” and “off” molecules to observe them individually and ensure there was no overlap between those that were side-by-side.

Thanks to these new techniques, we saw clusters of RNA polymerases in living cells for the first time during my postdoc, and I pushed the technique further to reveal the cluster dynamics. But the fact that you had to turn individual molecules on and off made it really hard to see these clusters assembling or disassembling. I didn’t want to trade temporal resolution for spatial resolution. So I came up with an approach called Time-Correlated Photoactivated Localization Microscopy (tcPALM). It allowed us to measure the lifetimes of these ephemeral polymerase clusters, and we found that they last just a few seconds.

Once I arrived at MIT, we wanted to test whether the clusters could be fleeting but still biologically relevant. We pushed a dual-color super-resolution technique where we correlated the clusters with gene activity. With RNA live-imaging experts at Howard Hughes Medical Institute’s Janelia Research Campus, Brian English and Tim Lionnet, and my postdoc, Wonki Cho, we found that roughly 80 to 100 polymerases form a cluster on a gene where transcription is about to start. Although the cluster is only there for a few seconds, that’s enough time to load a handful of polymerases and generate “bursts” of RNA transcription. In fact, there was a linear correlation between the clusters’ transient dynamics and the number of messenger RNAs made in each burst.

Q: What is it like to be a physicist working with biologists?

A: Even though I joined MIT as a physics hire, I was lucky enough to get lab space in Building 68 alongside amazing biologists. They were the perfect people to talk to about my crazy ideas. And it turned out that renowned researchers like Rick Young and Phil Sharp actually had similar theories. They had genomic evidence for clusters of gene regulators, which they call “super enhancers,” that we all thought could relate to what my lab was seeing. That’s led to hours of exciting discussions between our labs, and has evolved into one of my most rewarding collaborations — and revealed that clusters associate as tiny transcriptional condensates with properties of liquid droplets.

Now, students and postdocs in my lab are wondering about the clusters’ functions and mechanisms of action, and whether protein clustering extends beyond transcription. For instance, clustering could explain some aspects of neurodegeneration. One perplexing idea that came out of this work is that perhaps it gets harder for our cells to clear protein condensates as we age, leading to Parkinson’s, Alzheimer’s, and other diseases. It’s becoming clearer that physics may be just as important as biology for understanding how cells work. The physics of how condensates and droplets form in the inanimate world is increasingly helpful in determining how living cells can evolve to regulate the same process for specific biological functions like transcription. Nature uses physics in much more elaborate ways than we initially anticipated.

Proteins and labs come together to prevent Rett syndrome
Greta Friar | Whitehead Institute
July 22, 2020

New discoveries about the disruption of condensates in the neurodevelopmental disorder Rett syndrome provide insights into how cells compartmentalize chromosomes as well as new potential paths for therapies.

Scientists have, for many years, conceptualized the cell as a relatively free-flowing space, where–apart from the organization provided by specific cellular structures–molecules float freely, somehow ultimately ending up in the right place at the right time. In recent years, however, scientists have discovered that cells have much more spatial organization than previously thought thanks to a mechanism called phase separation, which occurs in cells when certain molecules form large droplet-like structures that separate what’s inside of the droplet from the rest of the cell. The droplets, called condensates, help sequester and concentrate molecules in specific locations, and appear to increase the efficiency of certain cellular functions.

Whitehead Institute Member Richard Young, also a professor of biology at Massachusetts Institute of Technology (MIT), has been exploring the previously unknown role that condensates play in gathering the molecules needed for gene transcription–the process by which DNA is read into RNA. In order to better understand when and how cells use phase separation, Charles Li, a graduate student in Young’s lab, set out to identify more proteins that can form condensates. That search led him to MeCP2, a protein associated with the severe neurodevelopmental disorder Rett syndrome, studied by Young’s colleague at Whitehead Institute, Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. No cure for Rett syndrome currently exists, and Jaenisch’s lab has been investigating the biology of the disorder in the hopes of discovering a medical therapy that can rescue neurons affected by Rett syndrome.

With the discovery of MeCP2’s condensate forming ability, Young and Jaenisch saw the opportunity for a promising collaboration between their labs. Led by co-first authors Li and Eliot Coffey, another graduate student in Young’s lab, the two labs investigated MeCP2 and whether the disruption of its condensate-forming ability contributes to Rett syndrome. During these investigations, the researchers also uncovered how cells may use condensates to help organize the active and inactive parts of chromosomes. Their findings, published in the journal Nature on June 22, report on these insights and suggest new paths for developing therapies for Rett syndrome.

PHASE SEPARATION AND RETT SYNDROME

Proteins that form condensates often contain intrinsically disordered regions (IDRs), long spaghetti-like strands that transiently stick together to form a dynamic mesh. Research has historically focused on the structured regions of proteins, which bind very specifically to other molecules, while IDRs have largely been overlooked. In this case, MeCP2’s large IDRs were exactly what drew Li to it.

“What was striking to me was that this protein has been studied for decades, and so much function has been ascribed to the protein as a whole, yet it only has one structured domain with a recognized function, the DNA binding domain. Beyond that, the entire protein is disordered, and how its parts function was largely unknown,” Li says.

The researchers found that MeCP2 used its IDRs to glom together and form condensates. Then they tested many of the mutations in the MECP2 gene that are associated with Rett syndrome and found that they all disrupt MeCP2’s ability to form condensates. Their findings suggest that therapies targeting condensates associated with the protein, rather than the protein itself, may be promising in the hunt for a Rett syndrome treatment.

“MeCP2 and Rett syndrome have been studied intensely for many years in many labs and yet not a single therapy has been developed. When the project began, I was immediately fascinated by the idea that we might find a new disease mechanism that could help us finally understand how Rett syndrome arises and how it could be treated,” Coffey says.

“Rick [Young] has shown that condensates play key roles in maintaining normal cellular function, and our latest collaboration illuminates how their disruption may drive diseases such as Rett syndrome,” Jaenisch says. “I hope the insights we have gained will prove useful both in our continued search for a treatment for Rett syndrome and more broadly in research on condensates and disease.”

COMPARTMENTALIZING CHROMOSOMES

The researchers’ investigation into MeCP2’s condensate forming behavior also shed light on how chromosomes are organized into regions of active and inactive genes. When MeCP2 is functioning normally, it helps to maintain heterochromatin, the roughly half of our chromosomes where genes are “turned off,” unable to be read into RNA or further processed to make proteins. MeCP2 binds to sequences of DNA marked with a certain type of regulatory tag that is typically found in heterochromatin. This helps crowd MeCP2 to the threshold concentration needed to form heterochromatin condensates. These condensates, in turn, help to sequester the molecules needed to maintain it apart from euchromatin, the half of our chromosomes filled with active genes. Different proteins form condensates near euchromatin, concentrating the molecular machinery needed to transcribe active genes there.

Since condensates form when proteins with large spaghetti-like IDRs stick together, one might expect that any protein containing IDRs could interact with any other IDR-containing protein to form droplets, and that is what the researchers have often seen. However, what they observed with MeCP2, which is associated with heterochromatin, is that key condensate-forming proteins associated with euchromatin refused to mix.

It’s important for the health of the cell that the genes in heterochromatin not be inadvertently turned on. The researchers reason that discrete euchromatin and heterochromatin condensates may play a key role in ensuring that transcriptional machinery localizes to euchromatin only, while repressive machinery–like MeCP2–localizes to heterochromatin. The researchers are excited to turn their attention to how proteins are able to join condensates selectively, and when and where else in the cell they do so.

“There’s a chemical grammar waiting to be deciphered that explains this difference in the ability of some proteins to move into one condensate versus another,” Young says. “Discovering that grammar can help us understand how cells maintain the crucial balance between the active and silent halves of our genome, and it could help us understand how to treat disorders such as Rett syndrome.”

***

Written by Greta Friar

Richard Young’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 professor of biology at the Massachusetts Institute of Technology.

Rudolf Jaenisch’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 professor of biology at Massachusetts Institute of Technology.

Li, C.H., Coffey, E., et al. (2020). MeCP2 links heterochromatin condensates and neurodevelopmental disease. Nature. DOI: 10.1038/s41586-020-2574-4

Ankur Jain and Pulin Li appointed to prestigious chairs
Whitehead Institute
July 13, 2020

Massachusetts Institute of Technology (MIT) provost Martin A. Schmidt has announced that two Whitehead Institute Members — Ankur Jain and Pulin Li — have been appointed to MIT career development professorships.

Jain has been named to the Thomas D. and Virginia W. Cabot Career Development Professorship. Li has been named the Eugene Bell Career Development Professor of Tissue Engineering. Both also continue to be assistant professors in the MIT department of Biology.

The Cabot and Bell chairs both recognize and support excellence in teaching and research by gifted faculty members who show exceptional promise in their professional careers. In addition to affirming Jain’s and Li’s status as emerging leaders in biomedical research, the appointment provides funding to advance their scientific initiatives — better enabling them to pursue new research directions and capitalize on new opportunities.

“The Biology Department and MIT are delighted to provide this support to Pulin and Ankur,” says Alan D. Grossman, professor and head of the MIT department of Biology, “and we are thrilled that they are engaged and active members of our community.”

“We are very proud to have accomplished, early-career researchers like Ankur and Pulin on our faculty,” says Whitehead Institute director Ruth Lehmann, “and pleased that MIT is recognizing their talents and promise for leadership with these prestigious professorships.”

Both appointments are for a three-year term beginning July 1, 2020.

How to Reopen? Tools Visualizing Covid-19 Data Provide Concrete Guidance
Kara Baskin | Slice of MIT
July 14, 2020

Where could another Covid-19 spike happen? During the next major hurricane, will residents have access to food and appropriate shelter?

Ellie Graeden PhD ’11 answers questions like these as founder and CEO of Talus Analytics, a Colorado-based research and consulting firm. She’s a scientific interpreter, deciphering natural-disaster and public-health data for decision makers who must act sensibly—and quickly.

Talus is currently focused on modeling the spread of Covid-19 to guide response efforts, working closely with academic and research partners and the US Centers for Disease Control and Prevention in a range of efforts, several of which are publicly available.“Often, those kinds of data aren’t communicated in a way that’s immediately useful,” she explains. “We translate the data and the modeling results to inform practical decisions that need to get made on a day-in, day-out basis.”

COVID Local is a data-driven decision framework that helps policymakers determine when and how to reopen during each phase. A dashboard uses clear metrics to determine the parameters for each threshold. It’s a joint initiative from the Global Biological Policy Program at the Nuclear Threat Initiative (NTI), the Center for Global Development, and the Georgetown University Center for Global Health Science and Security, where Graeden is an adjunct professor.

“COVID Local is focused on getting concrete guidance in place for those local decision makers so that they have a checklist that they can work through, driven by some of the best experts in global public health, who have managed outbreaks for Ebola in 2014 and elsewhere,” she says.

A second tool, Re:Public COVID Log, is a map-based platform that tracks communities visually, providing views of hazard risk, infrastructure, and population. It was developed with support from the US Department of Homeland Security and FEMA, and it’s simple enough for a nonexpert to use.

“A lot of the current tools are very expert focused. This is targeted for use by those without hazard-specific expertise—for example, by the communications office for a mayor,” she says.

In collaboration with Georgetown University, Talus has also built a large-scale database to track the effectiveness of various mitigation policies, helping to guide policymakers who might need to close for a second wave.

“We let them know what worked the first time,” she says.

All of this might seem like a leap for a microbiologist. Graeden earned her doctorate in cell biology at MIT, where she studied brain development in zebrafish under Professor Hazel L. Sive.

“I learned how to tell scientific stories visually, which is essentially what microscopy is. You’re telling stories with pictures,” she says.

She founded her 10-person firm in 2015 to do the same with global health issues: There was plenty of data, she felt, that nobody was looking at under a microscope and bringing to light. (Fellow MIT alum Trae Wallace MBA ’10 guides Talus’s development as its head of data.)

The company first made a name for itself during Hurricane Matthew in 2016, when Talus deployed to FEMA’s National Response Coordination Center to deduce how many people would be impacted by the storm’s wrath.

Her team harnessed data from the Department of Energy, looking at real-time power outages, and merged them with inland and coastal flood modeling to determine counties that would be hit. Next, they leveraged census data to capture the total number of people affected. While all the data from each source had been previously available, the questions being asked required real-time integration of the information for the response effort.

Since then, Talus has become a go-to for government and academic partners when “integrating different types of information and doing that storytelling,” Graeden says. “Flood modelers didn’t feel comfortable pulling in energy data or outage data or coastal modeling data. It was really a data analysis and storytelling problem,” she says.

Now, she tells these number stories from her perch in Colorado, where she moved in 2015 to be farther from what she calls “power-driven” Washington. It’s also closer to northern Idaho, where she grew up. Still, she looks back fondly on her time in Cambridge, where she jogged in the Arboretum and played competitive Ultimate Frisbee off campus, practicing up to 16 hours on the weekends. She also leaves a legacy of service to the school community as the founder of MIT BioREFS (Resource for Easing Friction and Stress), a peer mentorship program within the biology department, after a friend died by suicide.

“MIT was the first place I’d ever been where the response to an idea was routinely, ‘Well, is that the right thing to do?’ Whereas prior, the response had always been, ‘Well, can it be done right?’ At MIT, it’s not ‘Can it be done?’ but ‘What is the right way to solve it?’” she says.

As for the right thing to be doing about Covid, her assessment is stark.

“In the US, we are functionally no different from where we were three months ago. We have better treatments and a better sense for what works on the treatment side, but we have no preventative measures. We have no vaccine. We have no way to prevent people from getting sick, except social distancing measures,” she warns.

She hopes for equitable distribution of an eventual vaccine, using transparent data with demographic information layered in to target vulnerable communities.

“We need to be clear-eyed about what is happening. We need to collect data with demographic details attached. Florida, for example, decided at one point not to allow its coroners to report Covid deaths, and those limitations on data release really hamstring our ability to respond in an informed way. We have to collect the data, we need to be able to analyze it, and we need to be able to integrate data so that we can make decisions on the basis of it,” she says.

Lindsay Case

Education

  • PhD, 2014, University of North Carolina at Chapel Hill
  • BA, 2008, Biology, Franklin and Marshall College

Research Summary

We study how cells regulate the spatial organization of signaling molecules at the plasma membrane to control downstream signaling. For example, receptor clustering and higher-order assembly with cytoplasmic proteins can create compartments with unique biochemical and biophysical properties. We use quantitative experimental approaches from biochemistry, molecular biophysics, and cell biology to study transmembrane signaling pathways and how they are misregulated in diseases like cancer.

Awards

  • NSF Career Award, 2025
  • Searle Scholar, 2022
  • NIH Director’s New Innovator Award, 2022
  • AFOSR Young Investigator Award, 2021
  • Brown-Goldstein Award, 2020
  • Damon Runyon-Dale F. Frey Breakthrough Scientist, 2020
Yukiko Yamashita

Education

  • PhD, 1999, Kyoto University
  • BS, Biology, 1994, Kyoto University

Research Summary

Two remarkable feats of multicellular organisms are generation of many distinct cell types via asymmetric cell division and transmission of the germline genome to the next generation, essentially in eternity. Studying these processes using the Drosophila male germline as a model system has led us to venture into new areas of study, such as functions of satellite DNA, a ‘genomic junk,’ and how they might be involved in speciation.

Awards

  • Tsuneko and Reiji Okazaki Award, 2016
  • Howard Hughes Medical Institute, Investigator, 2014
  • MacArthur Fellow, 2011
  • Women in Cell Biology Early Career Award, American Society for Cell Biology, 2009
  • Searle Scholar, 2008
Seemingly similar, two neurons show distinct styles as they interact with the same muscle partner
Picower Institute
July 7, 2020

A new study by MIT neuroscientists into how seemingly similar neuronal subtypes drive locomotion in the fruit fly revealed an unexpected diversity as the brain’s commands were relayed to muscle fibers. A sequence of experiments revealed a dramatic difference between the two nerve cells – one neuron scrambled to adjust to different changes by the other, but received no requital in response when circumstances were reversed.

The findings published in the Journal of Neuroscience suggest that these subclasses of neurons, which are also found abundantly in people and many other animals, exhibit a previously unappreciated diversity in their propensity to respond to changes, a key property known as “synaptic plasticity.” Synaptic plasticity is considered an essential mechanism of how learning and memory occur in the brain, and aberrations in of the process are likely central to disorders such as autism.

“By seeing that these two different types of motor neurons actually show very distinct types of plasticity, that’s exciting because it means it’s not just one thing happening,” said senior author Troy Littleton, a member of The Picower Institute for Learning and Memory and Menicon Professor of Neuroscience in MIT’s Departments of Biology and of Brain and Cognitive Sciences. “There’s multiple types of things that can be altered to change connectivity within the neuromuscular system.”

Tonic and phasic neurons

Both of the neurons work in the same way, by emitting the neurotransmitter glutamate onto their connections, or synapses, with the muscles. But these two neurons do so with different styles. The “tonic” neuron, which connects only to a single muscle, emits its glutamate at a constant but low rate while the muscle is active. Meanwhile, the “phasic” neuron connects to a whole group of muscles and jumps in with a strong quick pulse of activity to spring the muscles into action.

Heading into the study Littleton and lead author Nicole Aponte-Santiago were curious to explore whether these different neurons compete or cooperate to drive the muscle fibers, and if they exhibited different plasticity when their functions were altered. To get started on what ultimately became her dissertation research, Aponte-Santiago developed the means to tailor genetic alterations specifically in each of the two neurons.

“The reason we were able to answer these questions in the first place was because we produced tools to start differentially manipulating one neuron versus the other one, or label one versus the other one,” said Aponte-Santiago, who earned her PhD in Littleton’s lab earlier this spring and is now a postdoc at the University of California at San Francisco.

With genetic access to each neuron, Aponte-Santiago distinctly labeled them to watch each one grow in fly larvae as they developed. She saw that the tonic neuron reached the muscle first and that the phasic one connected to the muscle later. She also observed that unlike in mammals, the neurons did not compete to control the muscle but remained side by side, each contributing in its characteristic way to the total electrical activity needed to drive movement.

To study the neurons’ plasticity, Aponte-Santiago employed two manipulations of each neuron. She either wiped them out completely by making them express a lethal protein called “reaper” or she substantially tamped down their glutamate activity via expression of tetanus toxin.

When she wiped out the phasic neuron with reaper, the tonic neuron quickly stepped up its signaling, attempting to compensate as much as it could. But in flies where she wiped out the tonic neuron, the phasic neuron didn’t budge at all, continuing as if nothing had changed.

Similarly when Aponte-Santiago reduced the activity of the phasic neuron with the toxin, the tonic neuron increased the number of boutons and active zone structures in its synapses to respond to the loss of its partner. But when she reduced the activity of the tonic neuron the phasic neuron again didn’t appear to respond.

In all the experiments, the muscle received less overall drive from the neurons than when everything was normal. And while the phasic neuron  apparently didn’t bother to make up for any loss on the part of the tonic neuron, the tonic neuron employed different means to compensate – either increasing its signaling or by enhancing the number of its connections on the muscle – depending on how the phasic neuron was diminished.

“It was quite intriguing that Nicole found that when the phasic input wasn’t there, there was a unique form of plasticity that the tonic neuron showed,” Littleton said, “but if the phasic neuron was there and wasn’t working, the tonic neuron behaved in a very different way.”

Another intriguing aspect of the study is the role of the muscle itself, which may be an active intermediary of the plasticity, Littleton said. The neurons may not sense when each other have been wiped out or inactivated. Instead the muscle appears to call for those changes.

“Even though a muscle has two distinct inputs, it can sort of uniquely control those two,” Littleton said. “When the muscle is getting glutamate, does it know whether it is coming from the tonic or the phasic neuron and does it care? It appears that it does care, that it really needs the tonic more than the phasic. When the phasic is gone it shifts some of the plasticity, but when the tonic is gone the phasic can’t do much about it.”

In new work, the lab is now looking at differences in gene expression between the two neurons to identify which proteins are responsible for the unique properties and plasticity of the tonic and phasic neurons. By defining the genetic underpinnings of their unique properties, the lab hopes to begin to get a handle on the molecular underpinnings of neuronal diversity in the brain.

In addition to Aponte-Santiago and Littleton, the paper’s other authors are Kiel Ormerod and Yulia Akbergenova.

The National Institutes of Health and the JPB Foundation supported the study.

Nine MIT School of Science professors receive tenure for 2020

Professors earn tenure in the departments of Brain and Cognitive Sciences, Chemistry, Mathematics, and Physics.

School of Science
July 6, 2020

Beginning July 1, nine faculty members in the MIT School of Science have been granted tenure by MIT. They are appointed in the departments of Brain and Cognitive Sciences, Chemistry, Mathematics, and Physics.

Physicist Ibrahim Cisse investigates living cells to reveal and study collective behaviors and biomolecular phase transitions at the resolution of single molecules. The results of his work help determine how disruptions in genes can cause diseases like cancer. Cisse joined the Department of Physics in 2014 and now holds a joint appointment with the Department of Biology. His education includes a bachelor’s degree in physics from North Carolina Central University, concluded in 2004, and a doctoral degree in physics from the University of Illinois at Urbana-Champaign, achieved in 2009. He followed his PhD with a postdoc at the École Normale Supérieure of Paris and a research specialist appointment at the Howard Hughes Medical Institute’s Janelia Research Campus.

Jörn Dunkel is a physical applied mathematician. His research focuses on the mathematical description of complex nonlinear phenomena in a variety of fields, especially biophysics. The models he develops help predict dynamical behaviors and structure formation processes in developmental biology, fluid dynamics, and even knot strengths for sailing, rock climbing and construction. He joined the Department of Mathematics in 2013 after completing postdoctoral appointments at Oxford University and Cambridge University. He received diplomas in physics and mathematics from Humboldt University of Berlin in 2004 and 2005, respectively. The University of Augsburg awarded Dunkel a PhD in statistical physics in 2008.

A cognitive neuroscientist, Mehrdad Jazayeri studies the neurobiological underpinnings of mental functions such as planning, inference, and learning by analyzing brain signals in the lab and using theoretical and computational models, including artificial neural networks. He joined the Department of Brain and Cognitive Sciences in 2013. He achieved a BS in electrical engineering from the Sharif University of Technology in 1994, an MS in physiology at the University of Toronto in 2001, and a PhD in neuroscience from New York University in 2007. Prior to joining MIT, he was a postdoc at the University of Washington. Jazayeri is also an investigator at the McGovern Institute for Brain Research.

Yen-Jie Lee is an experimental particle physicist in the field of proton-proton and heavy-ion physics. Utilizing the Large Hadron Colliders, Lee explores matter in extreme conditions, providing new insight into strong interactions and what might have existed and occurred at the beginning of the universe and in distant star cores. His work on jets and heavy flavor particle production in nuclei collisions improves understanding of the quark-gluon plasma, predicted by quantum chromodynamics (QCD) calculations, and the structure of heavy nuclei. He also pioneered studies of high-density QCD with electron-position annihilation data. Lee joined the Department of Physics in 2013 after a fellowship at CERN and postdoc research at the Laboratory for Nuclear Science at MIT. His bachelor’s and master’s degrees were awarded by the National Taiwan University in 2002 and 2004, respectively, and his doctoral degree by MIT in 2011. Lee is a member of the Laboratory for Nuclear Science.

Josh McDermott investigates the sense of hearing. His research addresses both human and machine audition using tools from experimental psychology, engineering, and neuroscience. McDermott hopes to better understand the neural computation underlying human hearing, to improve devices to assist hearing impaired, and to enhance machine interpretation of sounds. Prior to joining MIT’s Department of Brain and Cognitive Sciences, he was awarded a BA in 1998 in brain and cognitive sciences by Harvard University, a master’s degree in computational neuroscience in 2000 by University College London, and a PhD in brain and cognitive sciences in 2006 by MIT. Between his doctoral time at MIT and returning as a faculty member, he was a postdoc at the University of Minnesota and New York University, and a visiting scientist at Oxford University. McDermott is also an associate investigator at the McGovern Institute for Brain Research and an investigator in the Center for Brains, Minds and Machines.

Solving environmental challenges by studying and manipulating chemical reactions is the focus of Yogesh Surendranath’s research. Using chemistry, he works at the molecular level to understand how to efficiently interconvert chemical and electrical energy. His fundamental studies aim to improve energy storage technologies, such as batteries, fuel cells, and electrolyzers, that can be used to meet future energy demand with reduced carbon emissions. Surendranath joined the Department of Chemistry in 2013 after a postdoc at the University of California at Berkeley. His PhD was completed in 2011 at MIT, and BS in 2006 at the University of Virginia. Suendranath is also a collaborator in the MIT Energy Initiative.

A theoretical astrophysicist, Mark Vogelsberger is interested in large-scale structures of the universe, such as galaxy formation. He combines observational data, theoretical models, and simulations that require high-performance supercomputers to improve and develop detailed models that simulate galaxy diversity, clustering, and their properties, including a plethora of physical effects like magnetic fields, cosmic dust, and thermal conduction. Vogelsberger also uses simulations to generate scenarios involving alternative forms of dark matter. He joined the Department of Physics in 2014 after a postdoc at the Harvard-Smithsonian Center for Astrophysics. Vogelsberger is a 2006 graduate of the University of Mainz undergraduate program in physics, and a 2010 doctoral graduate of the University of Munich and the Max Plank Institute for Astrophysics. He is also a principal investigator in the MIT Kavli Institute for Astrophysics and Space Research.

Adam Willard is a theoretical chemist with research interests that fall across molecular biology, renewable energy, and material science. He uses theory, modeling, and molecular simulation to study the disorder that is inherent to systems over nanometer-length scales. His recent work has highlighted the fundamental and unexpected role that such disorder plays in phenomena such as microscopic energy transport in semiconducting plastics, ion transport in batteries, and protein hydration. Joining the Department of Chemistry in 2013, Willard was formerly a postdoc at Lawrence Berkeley National Laboratory and then the University of Texas at Austin. He holds a PhD in chemistry from the University of California at Berkeley, achieved in 2009, and a BS in chemistry and mathematics from the University of Puget Sound, granted in 2003.

Lindley Winslow seeks to understand the fundamental particles shaped the evolution of our universe. As an experimental particle and nuclear physicist, she develops novel detection technology to search for axion dark matter and a proposed nuclear decay that makes more matter than antimatter. She started her faculty position in the Department of Physics in 2015 following a postdoc at MIT and a subsequent faculty position at the University of California at Los Angeles. Winslow achieved her BA in physics and astronomy in 2001 and PhD in physics in 2008, both at the University of California at Berkeley. She is also a member of the Laboratory for Nuclear Science.

Parasite research heats up
Greta Friar | Whitehead Institute
July 7, 2020

Apicomplexan parasites infect hundreds of millions of people around the world each year. Several species of apicomplexan parasites in the Plasmodium genus cause malaria, while another apicomplexan species, Toxoplasma gondii (T. gondii), causes toxoplasmosis, a disease with flu-like symptoms that can be lethal for people with weakened immune systems. In spite of their impact, the biology of these disease-causing parasites is not very well understood and treatment options for infection are limited.

One potential approach to treat infection could be drugs that disrupt the parasites’ calcium signaling, which they rely on to spread from cell to cell in their hosts. The parasites need an influx of calcium in order to burst out of an infected host cell—a process called egress—and move through the host’s body and invade other cells. In previous work, a researcher from Whitehead Institute Member Sebastian Lourido’s lab, Saima Sidik, had tested a large collection of molecules and identified one called enhancer 1 (ENH1), which perturbed the parasites’ calcium levels and prevented egress, as a promising anti-parasitic lead. However, the original experiments did not determine how ENH1 acts. In research published in the journal ACS Chemical Biology on June 29, Alice Herneisen, a graduate student in Lourido’s lab, and Lourido, who is also an assistant professor of biology at the Massachusetts Institute of Technology, used an approach called thermal proteome profiling to discover how ENH1 prevents T. gondii parasites from egress. They identified the main target of ENH1 as a calcium-dependent molecule called CDPK1 that parasites use to prepare for egress, moving between cells, and invasion of host cells. ENH1 binds to and prevents CDPK1 from functioning.

“Advances over the past few decades have made discovering a molecule’s potentially therapeutic activity much easier, but the next step of figuring out how the molecule works is often still a challenge,” Lourido says. “By applying newer expansive approaches, we are starting to build a more holistic picture of the parasites’ cell biology.”

Understanding the biology responsible for a potential drug’s observed effects is important because most drugs require modification before they are ready for human use—they may need to be made less toxic, more potent, or more amenable to the environment of the human body—and these sorts of modifications cannot be made until the molecule and its activity are understood.

Herneisen decided to use a relatively new approach in parasites, thermal proteome profiling, to discover the targets of ENH1—the molecules it binds to, leading to its therapeutic effects. The approach works by graphing how each of the proteins inside the parasite reacts to changes in heat with and without being exposed to ENH1. One advantage of this approach is that it is unbiased, meaning that instead of researchers picking likely targets up front to test, they investigate as many molecules as possible, which can lead to unexpected findings. For example, Lourido has been investigating CDPK1 in other contexts for many years, and based on his lab’s previous understanding of its role would not have expected it to be a main target of ENH1—such surprises can direct research in exciting new directions.

Although CDPK1 is ENH1’s main target, the investigations did not uncover the target that allows ENH1 to cause oscillations in the parasites’ calcium levels. Finding this missing target is one of the lab’s next goals.

“The fact that ENH1 affects multiple aspects of calcium signaling may be what makes it such an effective antiparasitic agent,” Herneisen says. “It’s messing with the parasites on several levels.”

Translation of the research for clinical testing is a long way off, but there are multiple indicators that this is a promising direction for investigation. Not only is calcium signaling key to the parasites’ life cycle and ability to spread inside of a host, but the molecules and mechanisms that the parasites use to modulate calcium levels are very different from the ones found in mammals. This means that a drug that disrupts the parasites’ calcium signaling is unlikely to interfere with calcium signaling in human patients, and so could be deadly to the parasites without harming the patients’ cells.

Written by Greta Friar

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Sebastian Lourido’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 the Massachusetts Institute of Technology.

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Herneisen, Alice L. et al. “Identifying the target of an antiparasitic compound in Toxoplasma using thermal proteome profiling.” ACS Chemical Biology, June 29, 2020. https://doi.org/10.1021/acschembio.0c00369

Ruth Lehmann

Education

  • Dr. rer. nat., 1985, University of Tübingen
  • MS, 1981, Biology, University of Freiburg

Research Summary

We study germ cells, the only cells in the body naturally able to generate completely new organisms. In addition to the nuclear genome, cytoplasmic information is passed though the egg cell to the next generation. We analyze the organization and regulation of germ line specific RNA-protein condensates, and explore mechanisms used by endosymbionts such as mitochondria and the intracellular bacterium, Wolbachia, to propagate through the cytoplasm of the female germ line.

Awards

  • Vanderbilt Prize in Biomedical Science, 2022
  • Gruber Genetics Prize, 2022
  • Thomas Hunt Morgan Medal, Genetics Society of America, 2021
  • Francis Amory Prize in Reproductive Medicine and Reproductive Physiology, American Academy of Arts and Sciences, 2020
  • Vilcek Prize in Biomedical Science, 2020
  • Keith R. Porter Award, American Society for Cell Biology, 2018
  • Inaugural Klaus Sander Prize, German Society for Developmental Biology, 2017
  • European Molecular Biology Organization, Foreign Associate, 2012
  • Conklin Medal of the Society of Developmental Biology, 2011
  • National Academy of Sciences, Foreign Associate, 2005; Member, 2008
  • American Academy of Arts and Sciences, Member, 1998
  • Howard Hughes Medical Institute, Investigator, 1990 and 1997