netbet sports betting app

Using CRISPR as a research tool to develop cancer treatments

KSQ Therapeutics uses technology created at MIT to study the role of every human gene in disease biology.

Zach Winn | MIT News Office
April 23, 2021

CRISPR’s potential to prevent or treat disease is widely recognized. But the gene-editing technology can also be used as a research tool to probe and understand diseases.

That’s the basic insight behind KSQ Therapeutics. The company uses CRISPR to alter genes across millions of cells. By observing the effect of turning on and off individual genes, KSQ can decipher their role in diseases like cancer. The company uses those insights to develop new treatments.

The approach allows KSQ to evaluate the function of every gene in the human genome. It was developed at MIT by co-founder Tim Wang PhD ’17 in the labs of professors Eric Lander and David Sabatini.

“Now we can look at every single gene, which you really couldn’t do before in a human cell system, and therefore there are new aspects of biology and disease to discover, and some of these have clinical value,” says Sabatini, who is also a co-founder.

KSQ’s product pipeline includes small-molecule drugs as well as cell therapies that target genetic vulnerabilities identified from their experiments with cancer and tumor cells. KSQ believes its CRISPR-based methodology gives it a more complete understanding of disease biology than other pharmaceutical companies and thus a better chance of developing effective treatments to cancer and other complex diseases.

NetBet sport

KSQ’s scientific co-founders had been studying the function of genes for years before advances in CRISPR allowed them to precisely edit genomes about 10 years ago. They immediately recognized CRISPR’s potential to help them understand the role of genes in disease biology.

During his PhD work, Wang and his collaborators developed a way to use CRISPR at scale, knocking out individual genes across millions of cells. By observing the impact of those changes over time, the researchers could tease out the functionality of each gene. If a cell died, they knew the gene they knocked out was essential. In cancer cells, the researchers could add drugs and see if knocking out any of the genes affected drug resistance. More sophisticated screening methods taught the researchers how different genes inhibit or drive tumor growth.

“It’s a tool for discovering human biology at scale that was not possible before CRISPR,” says KSQ co-founder Jonathan Weissman, a professor of biology at MIT and a member of the Whitehead Institute. “You can search for genes or mechanisms that can modulate essentially any disease process.”

Wang credits Sabatini with spearheading the commercialization efforts, speaking with investors, and working with MIT’s Technology Licensing Office. Wang also says MIT’s ecosystem helped him think about bringing the technology out of the lab.

“Being at MIT and in the Cambridge area probably made the leap to commercialization a bit easier than it would have been elsewhere,” Wang says. “A lot of the students are entrepreneurial, there’s that rich tradition, so that helped shape my mindset around commercialization.”

Weissman had developed a complementary, CRISPR-based technology that Wang and Sabatini knew would be useful for KSQ’s discovery platform. Around 2015, as the founders were starting the company, they also brought on co-founder William Hahn, a member of the Broad Institute of MIT and Harvard, a professor at Harvard Medical School, and the chief operating officer of the Dana-Farber Cancer Institute.

Since then, the company has advanced Wang’s method.

“They’re able to scale this to a degree that is not possible in any academic lab, even David’s,” Wang says. “The cell lines I used for my experiments were just what was easy to grow and what was in the lab, whereas KSQ is thinking about what therapies aren’t available in certain cancers and deciding what diseases to go after.”

KSQ’s gene evaluations include tens of millions of cells. The company says the data it collects has been predictive of past successes and failures in cancer drug development. Weissman equates the data to “a roadmap for finding cancer vulnerabilities.”

“Cancers have all these different escape routes,” Weissman says. “This is a way of mapping out those escape routes. If there are too many, it’s not a good target to go after, but if there is a small number, you can now start to develop therapies to block off the escape routes.”

From discovery to impact

KSQ’s lead drug candidate is in preclinical development. It targets a DNA-repair pathway identified using an updated version of Wang’s technique. The drug could treat multiple ovarian cancers as well as a disease called triple-negative breast cancer. KSQ is also currently developing a cell therapy to boost the immune system’s ability to fight tumors.

“I’ve always thought the best biotech companies start with information that other people don’t have,” Sabatini says. “I think biotech companies have to have some discovery to them. That’s enabled KSQ to go in different directions.”

The founders feel KSQ has already validated their approach and stimulated further interest in using CRISPR as a research tool.

“There’s a lot of interest in CRISPR as a therapeutic, and that’s an important aspect,” Weissman says. “But I’d argue equally important both in discovery and in therapeutics will be [using CRISPR] to identify the targets you want to go after to affect disease process. Your ability to engineer genomes or make drugs depends on knowing what genes you want to change.”

Five from MIT elected to American Academy of Arts and Sciences for 2021

Prestigious honor society announces more than 250 new members.

MIT News Office
April 23, 2021

Five MIT faculty members are among more than 250 leaders from academia, business, public affairs, the humanities, and the arts elected to the American Academy of Arts and Sciences, the academy announced Thursday.

One of the nation’s most prestigious honorary societies, the academy is also a leading center for independent policy research. Members contribute to academy publications, as well as studies of science and technology policy, energy and global security, social policy and American institutions, the humanities and culture, and education.

Those elected from MIT this year are:

  • Linda Griffith, the School of Engineering Professor of Teaching Innovation, Biological Engineering, and Mechanical engineering;
  • Muriel Médard, the Cecil H. Green Professor in the Department of Electrical Engineering;
  • Leona Samson, professor of biological engineering and biology;
  • Scott Sheffield, the Leighton Family Professor in the Department of Mathematics; and
  • Li-Huei Tsai, the Picower Professor in the Department of Brain and Cognitive Sciences.

“We are honoring the excellence of these individuals, celebrating what they have achieved so far, and imagining what they will continue to accomplish,” says David Oxtoby, president of the academy. “The past year has been replete with evidence of how things can get worse; this is an opportunity to illuminate the importance of art, netbet online sports bettingideas, knowledge, and leadership that can make a better world.”

Since its founding in 1780, the academy has elected leading thinkers from each generation, including George Washington and Benjamin Franklin in the 18th century, Maria Mitchell and Daniel Webster in the 19th century, and Toni Morrison and Albert Einstein in the 20th century. The current membership includes more than 250 Nobel and Pulitzer Prize winners.

These worms’ stem cells are developmental shapeshifters
Eva Frederick | Whitehead Institute
April 20, 2021

Planarians are small water-dwelling worms known for their regenerative capacity. If you chop one into ten pieces, you’ll end up with ten fully-formed worms.

While humans have pools of specialized stem cells that can create our regenerative body parts like hair and skin, these worms owe their regenerative superpowers to a special kind of stem cell called a neoblast. At least some of these cells are “pluripotent,” meaning that they can divide to create almost any cell type in a worm’s body at any time. Neoblasts are actually the only dividing cells in planarians — fully committed cells like those in the eyes or intestines cannot divide again.

“The big question for us is, how does a neoblast go from being able to make anything, to making one particular thing?” says Amelie Raz, a postdoctoral researcher at Whitehead Institute who conducted her graduate research in the lab of Whitehead Institute Member Peter Reddien. “How do they go from being able to make anything in the body to being, say, an intestine cell that’s going to stay an intestine cell until it dies?”

Now, in a paper published online April 20 in the journal Cell Stem Cell, researchers at Whitehead Institute lay out a new model for how these stem cells commit to their fates and go on to create fully differentiated cells. The process of cellular differentiation is often viewed as a hierarchy, with one special stem cell at the top which can take a number of potential paths to arrive at a specialized state. This is generally thought to take place over a series of cell divisions in which each generation’s fate is gradually restricted.

“We’re proposing something happens that is very different from the conventional view,” says senior author Reddien, who is also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute. “We think that stem cells can make broad jumps in state without going through a series of fate-restricting divisions. We call it the single-step fate model.”

In the new model, neoblasts that are on a path toward creating skin cells or intestine cells can produce progeny cells that can switch fates to create cells of other types. The work is a step in the long road to understanding these worms’ regenerative capacities, and could possibly inform regenerative medicine approaches far in the future.

“The ability of planarian stem cells to essentially switch their fate is really, really powerful,” says Raz, the first author of the paper. “Obviously this is a long way off, but theoretically the concept of stem cell fate switching could be applied to regenerative medicine, with human stem cell programming.”

Upturning the hierarchy

Neoblasts can be sorted into many “classes.” For example, one class of neoblasts contains all the materials to make skin cells, and others have the necessary toolkit to form the worms’ primitive kidneys or their intestines. According to the hierarchical model, these specialized neoblasts are intermediaries between a pluripotent cell at the top of the hierarchy, and the non-dividing body cells.

“You can imagine that the special cell at the top is a blank slate with no predisposition towards any cell type — it can make anything,” says Raz. “This is how we’ve often imagined development works.”

But Raz, Reddien and Omri Wurtzel, a former postdoc in the Reddien lab now at Tel Aviv University, started to question this assumption after noticing a few mysterious properties of planarian cells.

First of all, researchers have observed in the past that when a planarian is treated with radiation to kill all existing stem cells, a single neoblast can rescue the animal by forming a colony containing many different classes of neoblasts. If, as previous theories suggested, there was a single class of neoblast that gave rise to all these types, Raz and Reddien reasoned that that class should be a common resident in every colony that formed. After creating many of these colonies and analyzing their composition, however, the researchers saw that this was not the case. “For every class we looked at, there were plenty of colonies that lacked that class altogether,” says Reddien. “There was no unique class present in all colonies.”

Another sticking point: the researchers began to realize that, when applying the hierarchy model, the math of planarian cell divisions and potency just didn’t add up. In a prior cell transplantation study, the Reddien lab found that many of the neoblasts they tested were pluripotent —in this study they found that proportion to be larger than what they would expect if only non-specialized neoblasts were pluripotent. “When you add up all the different kinds of specialized neoblasts, it’s at least three quarters of the neoblast population, and almost certainly higher than that.” says Raz. Therefore, the researchers wondered if some specialized neoblasts could be pluripotent as well.

Another study from the Reddien lab showed that skin-specialized neoblasts did not retain skin fate through more than one cell division. Also, in about half of all cell divisions in planarians, the two daughter cells will be different from one another. This raised the possibility that specialized neoblasts can divide asymmetrically as a possible route to stem cells changing fate.

Furthermore, the timeline for regeneration was off — the rate at which planarians were able to regrow body parts didn’t allow for several rounds of fate-restricting divisions.

After conducting experiments to study these different situations, Raz, Wurtzel, and Reddien were able to create a case for their new model of cell differentiation. “What we think is happening is that planarians have a ton of plasticity in their general stem cell population, where individual cells can move in and out of different specialized stages through the process of cell division in order to give rise to what is required,” Raz says.

“This is just the beginning of exploring this process, even though we’ve been studying it for many years,” Reddien says. “Focusing on the model, we’re suggesting that the cells can choose one fate, and then through the process of a division with an asymmetric outcome, one of the daughter cells can now divide again and choose a different fate. That fate switching process might be fundamental to explaining pluripotency.”

Reddien’s lab will continue investigating the mechanisms of neoblast fate specification, including how specialization lines up with the timing of the cell cycle.

“Understanding the structure of cell lineage and how fate choices are made is fundamental to understanding adult stem cell biology, and how in the context of injury and repair, new cells can be brought about,” says Reddien. “Do they have to go through long, complex lineage trajectories? Or can they make big jumps in state from stem cells to the final state? How flexible is that? All of these things have potential implications for understanding stem cell biology broadly, and we hope that the work will highlight some of these mechanisms and provide opportunities to explore general principles in the future.”

Two heads are better than one, but two disciplines are even better

How biologists and mathematicians reached across departmental lines to solve a long-standing problem in electron microscopy

Saima Sidik | Department of Biology
April 19, 2021

MIT’s Hockfield Court is bordered on the west by the ultra-modern Stata Center, with its reflective, silver alcoves that jut off at odd angles, and on the east by Building 68, which is a simple, window-lined, cement rectangle. At first glance, Bonnie Berger’s mathematics lab in the Stata Center and Joey Davis’s biology lab in Building 68 are as different as the buildings that house them. And yet, a recent collaboration between these two labs shows how their disciplines complement each other. The partnership started when Ellen Zhong, a graduate student from the Computational and Systems Biology (CSB) Program, decided to use a computational pattern-recognition tool called a neural network to study the shapes of molecular machines. Three years later, Zhong’s project is letting scientists see patterns that run beneath the surface of their data, and deepening their understanding of the molecules that shape life.

Zhong’s work builds on a technique from the 1970s called cryo-electron microscopy (cryo-EM), which lets researchers take high-resolution images of frozen protein complexes. Over the last decade, better microscopes and cameras have led to a “resolution revolution” in cryo-EM that’s allowed scientists to see individual atoms within proteins. NetBet live casinoBut, as good as these images are, they’re still only static snapshots. In reality, many of these molecular machines are constantly changing shape and composition as cells carry out their normal functions and adjust to new situations.

Along with former Berger lab member Tristan Belper, Zhong devised software called cryoDRGN. The tool uses neural nets to combine hundreds of thousands of cryo-EM images, and shows scientists the full range of three-dimensional conformations that protein complexes can take, letting them reconstruct the proteins’ motion as they carry out cellular functions. Understanding the range of shapes that protein complexes can take helps scientists develop drugs that block viruses from entering cells, study how pests kill crops, and even design custom proteins that can cure disease. COVID-19 vaccines, for example, work partly because they include a mutated version of the virus’s spike protein that’s stuck in its active conformation, so vaccinated people produce antibodies that block the virus from entering human cells. Scientists needed to understand the variety of shapes that spike proteins can take in order to figure out how to force spike into its active conformation.

Two women standing by rock wall
Graduate student Ellen Zhong (right), and her co-advisor, Professor of Mathematics Bonnie Berger (left)

Getting off the computer and into the lab

Zhong’s interest in computational biology goes back to 2011 when, as a chemical engineering undergrad at the University of Virginia, she worked with Professor Michael Shirts to simulate how proteins fold and unfold. After college, Zhong took her skills to a company called D. E. Shaw Research, where, as a Scientific Programmer, she took a computational approach to studying how proteins interact with small molecule drugs.

“The research was very exciting,” Zhong says, “but all based on computer simulations. To really understand biological systems, you need to do experiments.”

This goal of combining computation with experimentation motivated Zhong to join MIT’s CSB PhD program, where students often work with multiple supervisors to blend computational work with bench work. Zhong “rotated” in both the Davis and Berger labs, then decided to combine the Davis lab’s goal of understanding how protein complexes form with the Berger lab’s expertise in machine learning and algorithms. Davis was interested in building up the computational side of his lab, so he welcomed the opportunity to co-supervise a student with Berger, who has a long history of collaborating with biologists.

Davis himself holds a dual bachelor’s degree in computer science and biological engineering, so he’s long believed in the power of combining complementary disciplines. “There are a lot of things you can learn about biology by looking in a microscope,” he says. “But as we start to ask more complicated questions about entire systems, we’re going to require computation to manage the high-dimensional data that come back.”

Before rotating in the Davis lab, Zhong had never performed bench work before — or even touched a pipette. She was fascinated to find how streamlined some very powerful molecular biology techniques can be. Still, Zhong realized that physical limitations mean that biology is much slower when it’s done at the bench instead of on a computer. “With computational research, you can automate experiments and run them super quickly, whereas in the wet lab, you only have two hands, so you can only do one experiment at a time,” she says.

Zhong says that synergizing the two different cultures of the Davis and Berger labs is helping her become a well-rounded, adaptable scientist. Working around experimentalists in the Davis lab has shown her how much labor goes into experimental results, and also helped her to understand the hurdles that scientists face at the bench. In the Berger lab, she enjoys having coworkers who understand the challenges of computer programming.

“The key challenge in collaborating across disciplines is understanding each other’s ‘languages’,” Berger says. “Students like Ellen are fortunate to be learning both biology and computing dialects simultaneously.”

Bringing in the community

Man smiling outside
Zhong’s second co-advisor, Professor Joey Davis

Last spring revealed another reason for biologists to learn computational skills: these tools can be used anywhere there’s a computer and an internet connection. When the COVID-19 pandemic hit, Zhong’s colleagues in the Davis lab had to wind down their bench work for a few months, and many of them filled their time at home by using cryo-EM data that’s freely available online to help Zhong test her cryoDRGN software. The difficulty of understanding another discipline’s language quickly became apparent, and Zhong spent a lot of time teaching her colleagues to be programmers. Seeing the problems that non-programmers ran into when they used cryoDRGN was very informative, Zhong says, and helped her create a more user-friendly interface.

Although the paper announcing cryoDRGN was only recently published, the tool created a stir as soon as Zhong posted her code online, many months prior. The cryoDRGN team thinks this is because leveraging knowledge from two disciplines let them visualize the full range of structures that protein complexes can have, and that’s something researchers have wanted to do for a long time. For example, the cryoDRGN team recently collaborated with researchers from Harvard and Washington University to study locomotion of the single-celled organism Chlamydomonas reinhardtii. The mechanisms they uncovered could shed light on human health conditions, like male infertility, that arise when cells lose the ability to move. The team is also using cryoDRGN to study the structure of the SARS-CoV-2 spike protein, which could help scientists design treatments and vaccines to fight coronaviruses.

Zhong, Berger, and Davis say they’re excited to continue using neural nets to improve cryo-EM analysis, and to extend their computational work to other aspects of biology. Davis cited mass spectrometry as “a ripe area to apply computation.” This technique can complement cryo-EM by showing researchers the identities of proteins, how many of them are bound together, and how cells have modified them.

“Collaborations between disciplines are the future,” Berger says. “Researchers focused on a single discipline can take it only so far with existing techniques. Shining a different lens on the problem is how advances can be made.”

Zhong says it’s not a bad way to spend a PhD, either. Asked what she’d say to incoming graduate students considering interdisciplinary projects, she says: “definitely do it.”

Undergraduate students meld biology and art to forge remote collaborations
April 14, 2021

Taught for the first time in 2013, 7.016 (Introductory Biology) introduces MIT undergraduates to fundamental principles of biochemistry, molecular biology, and genetics. While the class has historically packed over 200 students into a lecture hall, the past two iterations have been held over Zoom due to COVID-19 restrictions. In order to incite collaboration and spur creativity in a remote setting, Professor of Biology and Chemistry, Barbara Imperiali, Associate Professor of Biology, Adam Martin, and MITxBio Instructor, Monika Avello, have infused the homework assignments with some whimsey.

One bonus question on a problem set required students to work together in teams to devise a cartoon of the Statue of Liberty. Inspired by a drawing in Chemical & Engineering News that depicted Lady Liberty clad in chemistry gear, Imperiali, Martin, and Avello asked the students to re-imagine the cartoon with a biology theme instead.

“We wanted to create a light-hearted, fun, and rewarding opportunity for 7.016 students to collaborate and connect with each other in our remote class,” Avello says. “We were totally blown away by how creative and talented the students were. So many of them went above and beyond by modifying the cartoon template we provided to showcase their creativity and artistic skills.”
Below is a sampling of responses from the assignment.
Black and white sketch of the Statue of Liberty
Credit: Gary Nguyen and Sandra Tang

This biology-inspired Statue of Liberty features a crown made of deoxyribose (the 5-carbon sugar in DNA). Per lab protocol, she has also donned safety goggles and disposable gloves. She holds some DNA in one hand and a microscope inspecting a cell in the other.

Cartoon of Statue of Liberty
Credit: Cindy Jie and Dion Sukhram

A DNA sash, hydroxyl eyes, and a crown of SARS-CoV-2 spike proteins highlight some of the details that were central to class discussions this semester. With a textbook in hand and her mitochondria torch held high, this cute comic lifted students’ spirits.

Statue of Liberty and a sunset
Credit: Andrew Emmel and Yoni Haile

In one hand, Lady Liberty is holding a microscope to symbolize discovery. She is holding a petri dish in the other hand, indicating that data are absolute. Her crown is a centrifuge, because the experiment is “king.” And the sunglasses? Those are to show that biology is cool.

Cartoon of Statue of Liberty as a red blood cell
Credit: Joanna Cao and Sarah Wei

Here, Lady Liberty takes NetBet sportthe form of a red blood cell, which carries oxygen all over the body. As such, she is holding an oxygen molecule in one hand. In the other hand, she holds carbon dioxide.

Sketch of the Statue of Liberty made of molecules
Credit: Savannah Ashley, Katia Pendowski, and Malia Smith

This cartoon features Lady Liberty standing on the lipid bilayer that constitutes the membrane encircling a cell’s internal components. She is holding a DNA molecule and wearing a dress with deoxyribose molecules, which form the “backbone” of DNA. She is also sporting a crown with adenosine triphosphate (ATP) molecules — providing energy to drive cellular processes — and holding a torch of proteins.

An on-off switch for gene editing
Eva Frederick | Whitehead Institute
April 9, 2021

Now, in a paper published online in Cell on April 9, researchers describe a new gene editing technology called CRISPRoff that allows researchers to control gene expression with high specificity while leaving the sequence of the DNA unchanged. Designed by Whitehead Institute Member Jonathan Weissman, University of California San Francisco assistant professor Luke Gilbert, Weissman lab postdoc James Nuñez and collaborators, the method is stable enough to be inherited through hundreds of cell divisions, and is also fully reversible.

“The big story here is we now have a simple tool that can silence the vast majority of genes,” says Weissman, who is also a professor of biology at MIT and an investigator with the Howard Hughes Medical Institute. “We can do this for multiple genes at the same time without any DNA damage, with great deal of homogeneity, and in a way that can be reversed. It’s a great tool for controlling gene expression.”

The project was partially funded by a 2017 grant from the Defense Advanced Research Projects Agency to create a reversible gene editor. “Fast forward four years [from the initial grant], and CRISPRoff finally works as envisioned in a science fiction way,” says co-senior author Gilbert. “It’s exciting to see it work so well in practice.”

Genetic engineering 2.0

The classic CRISPR-Cas9 system uses a DNA-cutting protein called Cas9 found in bacterial immune systems. The system can be targeted to specific genes in human cells using a single guide RNA, where the Cas9 proteins create tiny breaks in the DNA strand. Then the cell’s existing repair machinery patches up the holes.

Because these methods alter the underlying DNA sequence, they are permanent. Plus, their reliance on “in-house” cellular repair mechanisms means it is hard to limit the outcome to a single desired change. “As beautiful as CRISPR-Cas9 is, it hands off the repair to natural cellular processes, which are complex and multifaceted,” Weissman says. “It’s very hard to control the outcomes.”

That’s where the researchers saw an opportunity for a different kind of gene editor — one that didn’t alter the DNA sequences themselves, but changed the way they were read in the cell.

This sort of modification is what scientists call “epigenetic” — genes may be silenced or activated based on chemical changes to the DNA strand. Problems with a cell’s epigenetics are responsible for many human diseases such as Fragile X syndrome and various cancers, and can be passed down through generations.

Epigenetic gene silencing often works through methylation — the addition of chemical tags to to certain places in the DNA strand — which causes the DNA to become inaccessible to RNA polymerase, the enzyme which reads the genetic information in the DNA sequence into messenger RNA transcripts, which can ultimately be the blueprints for proteins.

Weissman and collaborators had previously created two other epigenetic editors called CRISPRi and CRISPRa — but both of these came with a caveat. In order for them to work in cells, the cells had to be continually expressing artificial proteins to maintain the changes.

“With this new CRISPRoff technology, you can [express a protein briefly] to write a program that’s remembered and carried out indefinitely by the cell,” says Gilbert. “It changes the game so now you’re basically writing a change that is passed down through cell divisions — in some ways we can learn to create a version 2.0 of CRISPR-Cas9 that is safer and just as effective, and can do all these other things as well.”

Building the switch

To build an epigenetic editor that could mimic natural DNA methylation, the researchers created a tiny protein machine that, guided by small RNAs, can tack methyl groups onto specific spots on the strand. These methylated genes are then “silenced,” or turned off, hence the name CRISPRoff.

Because the method does not alter the sequence of the DNA strand, the researchers can reverse the silencing effect using enzymes that remove methyl groups, a method they called CRISPRon.

As they tested CRISPRoff in different conditions, the researchers discovered a few interesting features of the new system. For one thing, they could target the method to the vast majority of genes in the human genome — and it worked not just for the genes themselves, but also for other regions of DNA that control gene expression but do not code for proteins. “That was a huge shock even for us, because we thought it was only going to be applicable for a subset of genes,” says first author Nuñez.

Also, surprisingly to the researchers, CRISPRoff was even able to silence genes that did not have large methylated regions called CpG islands, which had previously been thought necessary to any DNA methylation mechanism.

“What was thought before this work was that the 30 percent of genes that do not have a CpG island were not controlled by DNA methylation,” Gilbert says. “But our work clearly shows that you don’t require a CpG island to turn genes off by methylation. That, to me, was a major surprise.”

CRISPRoff in research and therapy

To investigate the potential of CRISPRoff for practical applications, the scientists tested the method in induced pluripotent stem cells. These are cells that can turn into countless cell types in the body depending on the cocktail of molecules they are exposed to, and thus are powerful models for studying the development and function of particular cell types.

The researchers chose a gene to silence in the stem cells, and then induced them to turn into nerve cells called neurons. When they looked for the same gene in the neurons, they discovered that it had remained silenced in 90 percent of the cells, revealing that cells retain a memory of epigenetic modifications made by the CRISPRoff system even as they change cell type.

They also selected one gene to use as an example of how CRISPRoff might be applied to therapeutics: the gene that codes for Tau protein, which is implicated in Alzheimer’s disease. After testing the method in neurons, they were able to show that using CRISPRoff could be used to turn Tau expression down, although not entirely off.  “What we showed is that this is a viable strategy for silencing Tau and preventing that protein from being expressed,” Weissman says. “The question is, then, how do you deliver this to an adult? And would it really be enough to impact Alzheimer’s? Those are big open questions, especially the latter.”

Even if CRISPRoff does not lead to Alzheimer’s therapies, there are many other conditions it could potentially be applied to. And while delivery to specific tissues remains a challenge for gene editing technologies such as CRISPRoff, “we showed that you can deliver it transiently as a DNA or as an RNA, the same technology that’s the basis of the Moderna and BioNTech coronavirus vaccine,” Weissman says.

Weissman, Gilbert, and collaborators are enthusiastic about the potential of CRISPRoff for research as well.  “Since we now can sort of silence any part of the genome that we want, it’s a great tool for exploring the function of the genome,” Weissman says.

Plus, having a reliable system to alter a cell’s epigenetics could help researchers learn the mechanisms by which epigenetic modifications are passed down through cell divisions. “I think our tool really allows us to begin to study the mechanism of heritability, especially epigenetic heritability, which is a huge question in the biomedical sciences,” Nuñez says.

School of Science announces 2021 Infinite Mile awards

Thirteen staff members recognized for dedication to School of Science and to MIT.

School of Science
April 9, 2021

The MIT School of Science has recognized 13 staff members with the 2021 Infinite Mile Award.

Staff are nominated for Infinite Mile Awards, presented annually since their creation in 2001, by their peers for going above and beyond in their roles and making MIT a better place. Their support for the School of Science, and the Institute community as a whole, has been invaluable, especially as we pass NetBet live casinothe one-year mark of work-from-home and social distancing due to the Covid-19 pandemic.

The following are the 2021 School of Science Infinite Mile winners.

  • Rebecca Chamberlain, administrative officer in the Department of Biology, was nominated by Professor Stephen Bell because Chamberlain “makes things easier for everyone in the department and this has never been more true than in this trying year. Even as she has taken on so much more, she has continued to maintain a friendly, patient, and unflappable attitude that makes her all the more remarkable.”
  • Janice Chang, academic administrator in the Department of Biology, was nominated by MIT Human Resources administrator Helene Kelsey because Chang is “truly exceptional, strives for perfection, and her skills and work ethic are recognized throughout the department. Janice has embraced the associated challenges with wisdom, a common-sense approach, dedication, goodwill, and a willingness to devote endless additional hours to the tasks at hand.”
  • Emma Dunn, undergraduate programs assistant in the Department of Physics, was nominated by Academic Administrator Catherine Modica because, when campus closed, “it was Emma who came up with all the ideas we used to try to reach out to our students, […] tracking their arrivals at home to make sure they were safe, and creating and sending shipments of care packages to every undergraduate major to remind them that we were […] thinking about them and standing ready to help.”
  • Jennifer Fentress, communications officer in the Department of Earth, Atmospheric and Planetary Sciences, was nominated by professor of physics and department head Robert van der Hilst; associate professor of physics David McGee; and staff colleagues Julia Keller, Megan Jordan, Angela Ellis, Maggie Cedarstrom, Brandon Milardo, and Scott Wade because Fentress “has helped advance the work of the school and MIT more broadly. At every opportunity, she ensures that the voices of EAPS research scientists are well-represented.”
  • Laura Frawley, a lecturer in the Department of Brain and Cognitive Sciences, was nominated by Professor Michale Fee and staff colleagues Kate White and Kimberli DeMayo because Frawley “has dedicated so much time and effort into learning all the new tools and resources available to help faculty convert to remote learning. […] All in all, Laura has been a savior this year!”
  • Brittany Greenough, an events planning assistant in the Picower Institute for Learning and Memory, was nominated by Picower Institute director and professor of brain and cognitive sciences Li-Huei Tsai and Administrative Officer William Lawson because, “[i]n this new, virtual environment, Brittany has taken it upon herself to be the resident expert with transitioning events to online formats.”
  • Chhayfou Hong, a financial assistant in the Laboratory for Nuclear Science, was nominated by professors of physics Jesse Thaler, Mike Williams, Joseph Formaggio, and Philip Harris because “without Chai’s herculean efforts here, the IAIFI [NSF AI Institute for Artificial Intelligence and Fundamental Interactions] would not exist, and MIT would have missed out on housing one of the inaugural NSF AI institutes — and on $20 million in revenue over the next five years.”
  • Beverly La Marr, a test engineer in the MIT Kavli Institute for Astrophysics and Space Research, was nominated by Kavli Institute director and professor of physics Robert Simcoe and principal research scientists Marshall Bautz, Ronald Remillard, and Gregory Prigozhin because La Marr “has played an essential part in MKI’s success in space with flagships, mid-sized, and small missions; and in fact, at this moment, three missions bearing her intellectual ‘fingerprints’ are all producing exciting scientific data from space. Her contributions to her colleagues are no less significant.”
  • Brian Pretti, a facilities and operations administrator in the Department of Chemistry, was nominated by professor and department head Troy Van Voorhis and administrative officer Richard Wilk because Pretti “is someone who goes far above and beyond his usual call of duty. He is also a joy to work with, no matter the stress or difficulty of the situation. Brian exemplifies all of the qualities of someone who truly cares about the quality of his work and those individuals he supports. He has demonstrated an incredible commitment to the Department, and it is a better place because of him.”
  • Alison Salie, senior fiscal officer in the Department of Biology, was nominated by professor and department head Alan Grossman because Salie “is a top-notch employee, well-respected across the department and Institute, and valued for her knowledge and expertise, common-sense approach, willingness to provide support and guidance at every turn, persistence, and never-ending goal to keep work flowing smoothly with limited administrative burden on faculty.”
  • Amanda Trainor, a technical associate in the Department of Chemistry, was nominated by colleagues John Dolhun, Brian Pretti, Scott Ide, John Grimes, and graduate student Axel Vera because her “work on all aspects of various lab functions has been outstanding, from finishing her assigned responsibilities, to taking on unassigned work that needed to be done, [and] demonstrating a strong commitment to the well-being of the MIT community by going countless extra miles.”
  • Joshua Wolfe, a technical instructor in the Department of Physics, was nominated by postdoc Alex Shvonski and lecturer Michelle Tomasik because Wolfe “goes above and beyond his prescribed duties because he cares holistically about creating an effective learning environment in our classes.”
  • Macall Zimmerman, senior financial officer in the Department of Chemistry, was nominated by professor and department head Troy Van Voorhis and staff colleagues Richard Wilk and Tyler Brezler because Zimmerman “is someone who goes far above and beyond her usual call of duty. She is an excellent leader, manager, and mentor. She demonstrates an exceptional commitment to every aspect of her work and the staff whom she mentors. Our department is a better place with her in it.”

The 2021 Infinite Mile Award winners receive a monetary award. An in-person celebration will be held in their honor, as well as the 2021 Infinite Expansion Award winners, at a later date with their families, friends, and nominators.

Matthew Vander Heiden named director of the Koch Institute

MIT biology professor and pioneering researcher of cancer cell metabolism will succeed longtime director Tyler Jacks.

Anne Trafton | MIT News Office
April 1, 2021

Matthew Vander Heiden, an MIT professor of biology and a pioneer in the field of cancer cell metabolism, has been named the next director of MIT’s Koch Institute for Integrative Cancer Research, effective April 1.

Vander Heiden will succeed Tyler Jacks, who has served as director for more than 19 years, first for the MIT Center for Cancer Research and then for its successor, the Koch Institute.

“Matt Vander Heiden has been a part of the Koch Institute almost from the beginning,” says MIT President L. Rafael Reif. “He knows firsthand that incredible discoveries emerge when scientists and engineers come together, in one space, to collaborate and learn from each other. We are thrilled that he will be carrying forward the institute’s groundbreaking work at the frontiers of cancer research.”

The MIT Center for Cancer Research (CCR) was founded by Nobel laureate Salvador Luria in 1974, shortly after the federal government declared a “war on cancer,” with the mission of unravelling the molecular basis of cancer. Working alongside colleagues such as Associate Director Jacqueline Lees, Jacks oversaw the evolution of the CCR into the Koch Institute in 2007, as well as the construction of the institute’s new home in Building 76, completed in 2010.

“I’m very grateful for all of the wonderful things that Tyler’s leadership has led to, because I think this really positions us to build on all of those successes and move forward to do more amazing things over the next decade,” Vander Heiden says.

Vander Heiden, who became a member of the Koch Institute in 2010 and has served as an associate director since 2017, is “an excellent choice for the Koch’s next director,” Jacks says. “Matt knows the landscape of cancer research deeply. He is very well-positioned to guide our existing programs and to develop new ones that take advantage of the unique strengths at the Koch and at MIT more broadly, at the intersection of science and engineering for cancer. I am looking forward to watching him lead the Institute’s exciting next chapter.”

Over the past several decades, cancer researchers have made significant strides in their understanding of the genetic underpinnings of the disease. They’ve also identified molecular signatures that distinguish different types of tumors, leading to the development of targeted treatments for specific types of cancer.

Vander Heiden says that he sees great opportunity in the field of cancer research for making new fundamental discoveries regarding the disease, and also for translating existing knowledge into better treatments. He expects that one key area netbet sports betting appof focus in the coming years will be applying the power of machine learning and artificial intelligence to understanding cancer.

“With the MIT Schwarzman College of Computing coming online, there’s tremendous opportunity in using the rapid advances in machine learning and computer science for health care,” Vander Heiden says. “I think that’s something MIT absolutely should be a leader on, especially as it applies to cancer.”

“Matt Vander Heiden will be a wonderful director,” says Phillip Sharp, an MIT Institute Professor and a member of the Koch Institute, who chaired the search committee for the new director. “His innovative research on cancer metabolism, service as associate director, and ability to ‘think like an engineer’ has earned him deep admiration from colleagues.”

Vander Heiden, who grew up in Wisconsin, earned his bachelor’s degree, MD, and PhD from the University of Chicago. While a graduate student, he became interested in studying the abnormal metabolism seen in cancer cells, which was first discovered nearly 100 years ago by the German chemist Otto Warburg. Instead of breaking down sugar using aerobic respiration, as healthy mammalian cells do, cancer cells switch to an alternative metabolic pathway called fermentation, which is less efficient.

As a postdoc in 2008, Vander Heiden and his colleagues at Harvard Medical School made the discovery that cancer cells shift their metabolism to fermentation by activating an enzyme called PKM2. While at Harvard, Vander Heiden also worked on a paper that contributed to the eventual development of drugs that target cancer cells with a mutation in the IDH gene. These drugs, the first modern FDA-approved cancer drugs that target metabolism, shut off an alternative pathway used by cancer cells with the IDH mutation.

In 2010, Vander Heiden became one of the first new faculty members hired after the creation of the Koch Institute. The Koch Institute was formed with the mission of bringing scientists and engineers together to work on cancer problems, an experimental approach that has had great success, Vander Heiden says.

“When I look at the Koch Institute today, I don’t think of my colleagues as being scientists or engineers. I just view them as people who are asking interesting questions in cancer, trying to solve translational problems, and trying to solve basic problems,” he says. “We have broken down all these barriers, these traditional silos of fields, and I think that uniquely positions us to answer the big questions about cancer going forward.”

While serving as director, Vander Heiden plans to continue his own research program on the role of cell metabolism in the development and progression of cancer. He also plans to continue his work as a medical oncologist at Dana-Farber Cancer Institute, where he treats prostate cancer patients.

“Having a personal link to the clinic helps keep me grounded in the realities of how patients experience cancer, and hopefully that will help me be a better steward of the Koch Institute and help us have even more impact with the work that we’re doing,” he says.

Spying on enzymes while they perform chemical reactions could help treat gut ailments
Raleigh McElvery
March 26, 2021

Humans breathe oxygen, but many microbes deep within in our gut don’t have access to this precious resource. Instead, they breathe sulfur compounds, releasing hydrogen sulfide in the process. This colorless gas is best-known for its rotten stench, but inside the human colon it has been linked to a thinner mucus barrier, and ailments such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and colorectal cancer. In order to develop potential treatments, researchers are probing how microbes create hydrogen sulfide and which molecules they use.

To help further these efforts, Catherine Drennan’s lab and Heather Kulik’s lab at MIT collaborated with Emily Balskus’ lab at Harvard University to investigate the structure and mechanism of an enzyme that’s critical for hydrogen sulfide production: isethionate sulfite-lyase (IslA). The team examined IslA while it was bound to a metabolite that’s readily available in the gut — and revealed how the bacterium Bilophila wadsworthia uses this interaction to help generate the hydrogen sulfide precursor called sulfite. The researchers then compared IslA’s binding behavior to other enzymes in the same family, in order to better understand how these enzymes have evolved to perform challenging chemistry on a wide variety of molecules. Their findings were published on Mar. 26 in the journal Cell Chemical Biology.

“Although abundant, sulfide-producing bacteria are not well understood,” says Drennan, a professor of biology and chemistry and a Howard Hughes Medical Institute investigator. “By characterizing the enzymes in these bacteria that are responsible for sulfur metabolism, we can develop therapeutic strategies to limit production of hydrogen sulfide that can lead to disease.”

Although researchers have been studying bacterial sulfur respiration for decades, IslA was only recently identified. This enzyme breaks the bond between a carbon atom and a sulfur atom in a compound called isethionate, which is a prevalent metabolite in the human body. In doing so, IslA releases the sulfite that bacteria such as B. wadsworthia use to produce hydrogen sulfide.

IslA is a member of a large family of enzymes, known as glycyl radical enzyme (GREs). Scientists can learn a lot from examining the way GREs bind to other molecules, according to Christopher Dawson PhD ’20, the study’s co-first author.

GREs contain a binding site (or “active site”) where they latch onto their respective substrates to perform chemical reactions. “Understanding GREs better will aid in drug design efforts to combat the deleterious effects of some of these enzymes,” Dawson says. “It will also help to engineer enzymes that perform diverse, challenging reactions to expand the toolkit for chemical synthesis.”

To this end, Dawson wanted to compare IslA’s active site — where it binds to isethionate to break the C-S bond — to other enzymes in the GRE family. He used X-ray crystallography to visualize this interaction at the level of individual atoms. The GREs he examined shared similar “barrel-like” structures in their active sites, but used these core features in different ways, depending on the substrates they bound. For instance, isethionate bound higher in IslA’s active site compared to the way other GREs bind their respective substrates. While this aberrant binding behavior is quite unique — even among GREs — another group had found something similar when they elucidated IslA’s structure in a different bacterium. And, the Drennan lab suspects this pattern could be prevalent in other classes of enzymes as well.

Next, Dawson and his colleagues wanted to investigate how IslA goes about cleaving the C-S bond once the enzyme has bound to isethionate. Others had predicted this process would occur via a “migration” reaction. In that scenario, the sulfite leaving group first migrates to another carbon atom and then that C-S bond is cleaved to release it. However, after co-first author Stephania Irwin generated multiple IslA variants, the Kulik lab performed computational analyses, and the researchers completed structural comparisons, the team concluded that migration was not occurring. Instead, IslA appeared to be performing an “elimination” reaction that severed the C-S bond without forming another one via migration.

Now that they know more about IslA — and GREs in general — the researchers hope their insights will aid drug design.

“Understanding how pathogens use enzymes like these to extract sulfite from their hosts and fuel hydrogen sulfide production has very clear therapeutic implications,” Dawson says. “And that’s one of the things I like best about this story.”

Citation
“Molecular Basis of C-S Bond Cleavage in the Glycyl Radical Enzyme Isethionate Sulfite-Lyase”
Cell Chemical Biology, online March 26, 2021,
DOI: 10.1016/j.chembiol.2021.03.001
Christopher D. Dawson, Stephania M. Irwin, Lindsey R. F. Backman, Chip Le, Jennifer X. Wang, Vyshnavi Vennelakanti, Zhongyue Yang, Heather J. Kulik, Catherine L. Drennan, and Emily P. Balskus

Study of synapse strength focuses on ‘active zones’

With new NIH grant, team will learn how neurons build key sites that release neurotransmitters a lot, or a little, to drive nervous system communication

Picower Institute
March 16, 2021

Job descriptions for the thousands of types of neurons in the brain typically include a common function: release chemicals called neurotransmitters to communicate across circuit connections called synapses. In a new study funded by the National Institutes of Health, the lab of MIT Professor Troy Littleton will seek to understand how neurons construct synapses of different strengths, a variety that may be key to the diversity of neural communication.

Littleton, Menicon Professor of Neuroscience in The Picower Institute for Learning and Memory and the Departments of Biology and Brain and Cognitive NetBet live casinoSciences at MIT, said the findings could increase scientists’ understanding of how neural circuits develop and change to reflect learning and experience – a phenomenon called plasticity – and might also suggest ways to adjust synaptic strength when it is atypical in disorders such as autism or intellectual disability.

Video from a 2018 Littleton Lab study shows calcium flux (green) indicating the release of glutamate at synapses tagged by the presence of a glutamate receptor (red).

Using neurons that control muscles in the Drosophila fruit fly, the study will focus on “active zones” (AZs), which are tiny neural structures that enable the release of neurotransmitters across each synapse. The flies provide a simple model, Littleton said, that can help elucidate many basic factors affecting AZ strength that are also at play in the neurons of other animals, including mammals.

“Understanding the rules in a simple model like Drosophila that help to define when a synapse is strong or weak allows us to view these principles as fundamental elements of how neurons control synaptic growth and development,” he said. “Depending on which of these factors a neuron modifies or plays around with, it is likely to be able to make synapses stronger or weaker in very different patterns.”

During larval development the neurons build hundreds of AZs. In a 2018 study, Littleton’s lab found that AZs vary widely in their strength: About 10 percent release neurotransmitters as much as 50 times more often than the majority of weaker synapses. The researchers also found that the strongest AZs were typically the ones that had the most time to develop and accumulate their many protein building blocks.

In the new study, which will provide nearly $1.9 million over five years, the team will learn how those active zones get built step by step out of more than a dozen different proteins that arrive at different stages of development. Because some AZs apparently build up bigger and stronger than others, Littleton likens the process to the construction of a variety of houses in a neighborhood—from big four-bedroom homes to little townhomes. The new study, including preliminary work the team has done with the support of the Picower Institute Innovation Fund, will help explain how each kind of structure emerges, in their relative abundance, in the same cell.

In one set of experiments, for instance, his team will study whether the supply of building materials – the various proteins – is a limitation on how many AZs can mature to full strength before development ceases (i.e. maybe they don’t all get enough lumber or nails to fully frame the house in time). The scientists will test that, for instance, with genetic manipulations that change the amount of key proteins produced. By imaging the proteins as they accumulate and by looking in on the same AZs day after day, a technique the lab uses called “intravital imaging,” they can see how changing protein availability changes the construction of AZs in a neuron.

With a house blueprint background a cartoon shows two frames: a few lines and circles arranged over a horizontal bar and then a larger array of lines over the bar with the overall appearance of an erupting fountain or a sprouting plant
A model of active zone construction: Numerous proteins arrive over time during development to ultimately build a structure for releasing neurotransmitters.

In another set of experiments, the team will test whether some AZs are better than others at acquiring the available material supply and putting it to use (i.e. some may have more carpenters than others to make the best use of the available nails and lumber). And to better understand how the construction process might work in longer-lived animals like mammals, where protein materials not only need to be gathered but also maintained and replaced, they will artificially prolong the flies’ larval stage.

In a third set of tests they will examine the case of two types of neurons that each connect to the same fly muscles but exert control in different ways. Though each type works by releasing the same neurotransmitter, called glutamate, “tonic” neurons feature small but constant glutamate release, while the “phasic” cells release stronger, but more occasional, bursts. The study will examine how AZ development differs, for instance, due to differences in gene expression to promote the different function of these otherwise similar cells.

In all, their goal will be to determine how neurons build their different capacities and styles of connection and communication.

In addition to Littleton the research team includes research scientists Yulia Akbergenova and Suresh Jetti, and graduate students Karen Leopold Cunningham and Andrés Crane.