Author: mantulin

New drug combo shows early potential for treating pancreatic cancer

Researchers find three immunotherapy drugs given together can eliminate pancreatic tumors in mice.

Anne Trafton | MIT News Office
August 5, 2021

Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years.

While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer Cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

The power of two

Graduate student Ellen Zhong helped biologists and mathematicians reach across departmental lines to address a longstanding problem in electron microscopy.

Saima Sidik | Department of Biology
July 1, 2021

MIT’s Hockfield Court is bordered on the west by the ultramodern 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 past decade, better microscopes and cameras have led to a “resolution revolution” in cryo-EM that’s allowed scientists to see individual atoms within proteins. But, 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.

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

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 nonprogrammers 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 just published in February, 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 universities 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.”

Engineered yeast could expand biofuels’ reach

By making the microbes more tolerant to toxic byproducts, researchers show they can use a wider range of feedstocks, beyond corn.

Anne Trafton | MIT News Office
June 28, 2021

Boosting production of biofuels such as ethanol could be an important step toward reducing global consumption of fossil fuels. However, ethanol production is limited in large part by its reliance on corn, which isn’t grown in large enough quantities to make up a significant portion of U.S. fuel needs.

To try to expand biofuels’ potential impact, a team of MIT engineers has now found a way to expand the use of a wider range of nonfood feedstocks to produce such fuels. At the moment, feedstocks such as straw and woody plants are difficult to use for biofuel production  because they first need to be broken down to fermentable sugars, a process that releases numerous byproducts that are toxic to yeast, the microbes most commonly used to produce biofuels.

The MIT researchers developed a way to circumvent that toxicity, making it feasible to use those sources, which are much more plentiful, to produce biofuels. They also showed that this tolerance can be engineered into strains of yeast used to manufacture other chemicals, potentially making it possible to use “cellulosic” woody plant material as a source to make biodiesel or bioplastics.

“What we really want to do is open cellulose feedstocks to almost any product and take advantage of the sheer abundance that cellulose offers,” says Felix Lam, an MIT research associate and the lead author of the new study.

Gregory Stephanopoulos, the Willard Henry Dow Professor in Chemical Engineering, and Gerald Fink, the Margaret and Herman Sokol Professor at the Whitehead Institute of Biomedical Research and the American Cancer Society Professor of Genetics in MIT’s Department of Biology, are the senior authors of the paper, which appears today in Science Advances.

Boosting tolerance

Currently, around 40 percent of the U.S. corn harvest goes into ethanol. Corn is primarily a food crop that requires a great deal of water and fertilizer, so plant material known as cellulosic biomass is considered an attractive, noncompeting source for renewable fuels and chemicals. This biomass, which includes many types of straw, and parts of the corn plant that typically go unused, could amount to more than 1 billion tons of material per year, according to a U.S. Department of Energy study — enough to substitute for 30 to 50 percent of the petroleum used for transportation.

However, two major obstacles to using cellulosic biomass are that cellulose first needs to be liberated from the woody lignin, and the cellulose then needs to be further broken down into simple sugars that yeast can use. The particularly aggressive preprocessing needed generates compounds called aldehydes, which are very reactive and can kill yeast cells.

To overcome this, the MIT team built on a technique they had developed several years ago to improve yeast cells’ tolerance to a wide range of alcohols, which are also toxic to yeast in large quantities. In that study, they showed that spiking the bioreactor with specific compounds that strengthen the membrane of the yeast helped yeast to survive much longer in high concentrations of ethanol. Using this approach, they were able to improve the traditional fuel ethanol yield of a high-performing strain of yeast by about 80 percent.

In their new study, the researchers engineered yeast so that they could convert the cellulosic byproduct aldehydes into alcohols, allowing them to take advantage of the alcohol tolerance strategy they had already developed. They tested several naturally occurring enzymes that perform this reaction, from several species of yeast, and identified one that worked the best. Then, they used directed evolution to further improve it.

“This enzyme converts aldehydes into alcohols, and we have shown that yeast can be made a lot more tolerant of alcohols as a class than it is of aldehydes, using the other methods we have developed,” Stephanopoulos says.

Yeast are generally not very efficient at producing ethanol from toxic cellulosic feedstocks; however, when the researchers expressed this top-performing enzyme and spiked the reactor with the membrane-strengthening additives, the strain more than tripled its cellulosic ethanol production, to levels matching traditional corn ethanol.

Abundant feedstocks

The researchers demonstrated that they could achieve high yields of ethanol with five different types of cellulosic feedstocks, including switchgrass, wheat straw, and corn stover (the leaves, stalks, and husks left behind after the corn is harvested).

“With our engineered strain, you can essentially get maximum cellulosic fermentation from all these feedstocks that are usually very toxic,” Lam says. “The great thing about this is it doesn’t matter if maybe one season your corn residues aren’t that great. You can switch to energy straws, or if you don’t have high availability of straws, you can switch to some sort of pulpy, woody residue.”
The researchers also engineered their aldehyde-to-ethanol enzyme into a strain of yeast that has been engineered to produce lactic acid, a precursor to bioplastics. As it did with ethanol, this strain was able to produce the same yield of lactic acid from cellulosic materials as it does from corn.

This demonstration suggests that it could be feasible to engineer aldehyde tolerance into strains of yeast that generate other products such as diesel. Biodiesels could potentially have a big impact on industries such as heavy trucking, shipping, or aviation, which lack an emission-free alternative like electrification and require huge amounts of fossil fuel.

“Now we have a tolerance module that you can bolt on to almost any sort of production pathway,” Stephanopoulos says. “Our goal is to extend this technology to other organisms that are better suited for the production of these heavy fuels, like oils, diesel, and jet fuel.”

The research was funded by the U.S. Department of Energy and the National Institutes of Health.

MIT J-WAFS awards eight grants in seventh round of seed funding

Ten principal investigators from seven MIT departments and labs will receive up to $150,000 for two years, overhead-free, for innovative research on global food and water challenges.

Andi Sutton | Abdul Latif Jameel Water and Food Systems Lab
June 9, 2021

The Abdul Latif Jameel Water and Food Systems Lab (J-WAFS) at MIT has announced its seventh round of seed grant funding to the MIT community. J-WAFS is MIT’s Institute-wide initiative to promote, coordinate, and lead research related to water and food that will have a measurable and international impact as humankind adapts to a rapidly expanding population on a changing planet. The seed grant program is J-WAFS’ flagship funding initiative, aimed at catalyzing innovative research across the Institute that solves the challenges facing the world’s water and food systems.

This year, eight new projects will be funded, led by nine faculty principal investigators (PIs) across six MIT departments. The winning projects address challenges that range from climate-resilient crops, food safety technologies and innovations that can remove contaminants from water, research supporting smallholder farmers’ productivity and resilience, and more.

Many of the projects that were selected for funding this year are focused on agriculture and food systems challenges, and these innovations could not be more timely. “Agriculture and food production are responsible for more than 30 percent of the world’s greenhouse gas emissions. Even if we could completely shut down fossil fuel emissions today, agricultural emissions would prevent us from meeting the targets of the Paris accords. Simply fixing energy systems will not be enough,” says J-WAFS Director John H. Lienhard V. “It will take researchers working in all sectors and disciplines working together to address these challenges to meet the needs of current and future populations despite the challenges posted by climate change. The innovations that are being developed at MIT, such as those that we selected for funding this year, are truly inspiring and can lead the way toward a food-secure future.”

Water and food systems challenges are inspiring a growing number of faculty across the Institute to pursue solutions-oriented research. Over 190 MIT faculty members from across all five schools at MIT as well as the MIT Stephen A. Schwarzman College of Computing have submitted proposals to J-WAFS’ grant programs since its launch in 2015. In 2021 alone, 37 principal investigators from 17 departments across all five schools proposed to the J-WAFS seed grant program. Competing for funding were established experts in water and food-related research areas as well as professors who are only recently applying their disciplinary expertise to the world’s water and food challenges. Engineering faculty from four departments were funded, including the Departments of Civil and Environmental Engineering, Chemical Engineering, Materials Science and Engineering, and Mechanical Engineering. Additional funded principal investigators are from the Department of Biology in the School of Science, the Sloan School of Management, and the MIT Media Lab in the School of Architecture and Planning.

The eight projects selected for J-WAFS seed grant funding and detailed below will receive $150,000, overhead-free, for two years.

Ensuring climate resilience in agriculture and crop production

Climate change poses a grave risk to water availability and rain-fed agriculture, especially in sub-Saharan Africa. “Impact of Near-term Climate Change on Water Availability and Food Productivity in Africa,” a project led by Elfatih A. B. Eltahir, the Breene M. Kerr Professor in the Department of Civil and Environmental Engineering, aims to better understand the projected near-term effects of the climate crisis on agricultural production at the southern edge of the Sahara Desert. Eltahir’s research will focus on integrating regional climate modeling with an analysis of archived observations on rainfall, temperature, and yield. His goal is to better understand how impacts of climate change on crop yields vary at the regional level. His team will work closely with other scientists and the policymakers in Africa who are in charge of planning climate change adaptation in the water and agriculture sectors to support a transition to resilient agriculture planning.

The climate crisis is projected to affect agricultural productivity worldwide. In nature, species adapt to environmental changes through the natural genetic variation that exists within a specific population. However, the time frame for this process is long and cannot meet the urgent need for food crops that are adaptable in a changing climate. With her project, “A New Approach to Enhance Genetic Diversity to Improve Crop Breeding,” Mary Gehring, an associate professor in the Department of Biology, is re-imagining the future of plant breeding beyond current practices that rely on natural variation. Supported by a J-WAFS seed grant, she will develop methods that rapidly produce genetic variations in order to increase the genetic diversity of food crop species. Using pigeon pea, a legume that is widely grown as a food, they will then test these variations against environmental stresses such as heat and drought in order to identify strains that could be more adapted to climate change.

Food loss and waste, which accounted for 32 percent of all food produced in the world in 2009, presents grand societal, economic, and environmental challenges, especially when climate change threatens current and future food supplies. In developing countries where food security is still a great concern, food loss is largely due to lack of adequate refrigeration for post-harvest food. Technologies exist for crop storage that use evaporative cooling, but they are less effective in hot and humid climates. Jeffrey C. Grossman, the Morton and Claire Goulder and Family Professor in Environmental Systems in the Department of Materials Science and Engineering, has teamed up with Evelyn N. Wang, the Gail E. Kendall Professor in the Department of Mechanical Engineering, to find a solution. With their project, “Hybrid Evaporative and Radiative Cooling as a Passive Low-cost High-performance Solution for Food Shelf-life Extension,” they are developing a low-cost device using an innovative combination of two methods of cooling: evaporative and radiative technologies. Their structure will use solar-reflecting materials and highly porous insulation to double the shelf life of perishable foods in remote and rural settings, without the need for electricity.

Addressing pathogens and pesticide contamination with novel technology

Food-borne illness represents a major source of both human morbidity and economic loss; however, current pathogen detection methods used across the United States are time- and labor-intensive. This means that food contamination is often not detected until it is already in the hands of consumers, requiring costly recalls. While rapid tests have emerged to address this challenge, they are do not have the sensitivity to detect a wide variety of contaminants. Rohit Karnik, a professor in the Department of Mechanical Engineering, has teamed up with Pratik Shah, a principal research scientist at the MIT Media Lab, to develop a food safety test that is rapid, sensitive, and easy to use. The device that they are developing with their project, “On-site Analysis of Foodborne Pathogens Using Density-Shift Immunomagnetic Separation and Culture,” will use a novel technology called density-shift immunomagnetic separation (DIMS) to detect a wide variety of pathogens on-site within a matter of hours to enable on-site testing at food processing plants.

Pesticide ingestion by humans poses another health challenge. A class of chemicals called organophosphates (OPs) — commonly used for pesticides — is particularly toxic. Though some OPs have been discontinued, many of these toxic chemicals remain widely available and continue to be used for weed control in agriculture and to reduce mosquito populations. Currently, OP can only be detected in blood or urine after a person has been exposed, and the methods for detection are costly. With her project, “Engineered Microbial Co-Cultures to Detect and Degrade Organophosphates,” Ariel L. Furst, an assistant professor in the Department of Chemical Engineering, is developing a technology to more quickly and effectively detect and remove this chemical. She is engineering specific strains of bacteria to work together to both detect and degrade OPs. These bacteria will be deployed using a single electronic device, which will provide a modular, adaptable strategy to detect and degrade these harmful toxins before they are ingested.

Aquaculture is widely recognized as an efficient system that can enable the production of healthy protein for human consumption with a minimal impact on the environment. With 85 percent of the world’s marine stocks fully exploited, it plays a pivotal role in current and future food production. However, the industry is challenged by the spread of preventable infectious diseases that cripple farmed fish populations and can cause substantial economic losses. Fish vaccines are in use for certain diseases, but effective delivery is challenging and costly, and can lead to adverse effects to the fish. Benedetto Marelli, the Paul M. Cook Career Development Assistant Professor in the Department of Civil and Environmental Engineering, is developing a solution. With his project, “Precise Fish Vaccine Injection Using Silk-based Microneedles for Sustainable Aquaculture,” he is creating a microneedle for fish vaccination that is made of silk. This novel technology will enable controlled drug release in fish and will also naturally degrade in water, which will support the health of fish populations and reduce losses for aquaculture farms.

Improving the resilience of rural populations and smallholder farmers

Regions around the world that don’t have access to safe or abundant supplies of freshwater often rely on small-scale, decentralized groundwater desalination devices that use reverse osmosis. Unfortunately, these systems are extremely energy-intensive, and therefore are both expensive to operate and environmentally unsustainable. Amos G. Winter V, an associate professor in the Department of Mechanical Engineering, is working on a new design for desalination devices for settings such as these that has the potential to make reverse osmosis water treatment more affordable and better able to be powered by renewable energy. With his project, “A Sliding Vane Energy Recovery Device (ERD) for Photovoltaic-Powered Brackish Water Reverse Osmosis Desalination (PV-BWRO),” Winter and his research team will focus on affordability, energy efficiency, and ease of use in their design to ensure that the resulting technology is accessible to poor and rural communities around the world.

Agricultural supply chains in developing countries are highly fragmented and opaque. Millions of smallholder farmers worldwide are the main producers, and often sell through a complex network of traders and intermediaries. Due to the highly fragmented nature of this system, these farmers persistently struggle with low productivity and high poverty. In an effort to find a solution, many countries have invested in mobile technologies that are intended to improve farmers’ market and information access. However, there remains a disconnect between the data that are collected and distributed via these mobile platforms and their effective use by smallholders. Yanchong Zheng, associate professor of operations management at the Sloan School of Management, aims to fill this gap with her project, “Improving Smallholder Farmers’ Welfare with AI-driven Technologies,” by developing AI-driven market tools that can sift through the data to develop unbiased weather, crop planning, and pricing information. Additionally, she and her research team will develop recommendations based on these data that can more effectively inform farmers’ investments. The team will work in close collaboration with public and private sector organizations on the ground in order to ensure that their solutions are informed by the specific needs of the smallholder farmers that they seek to support.

With the addition of these eight newly funded projects, J-WAFS will have supported 53 seed grant research projects since the program launched in 2014. The J-WAFS seed funding catalyzes new solutions-oriented research at MIT and supports MIT researchers who bring a wide variety of disciplinary tools and knowledge from working in other sectors to apply their expertise to water and food systems challenges. The results of this investment are already evident: to date, J-WAFS’ seed grant PIs have brought in nearly $15 million in follow-on funding, have published numerous papers in internationally recognized journals and publications, obtained patents, and launched spinout companies. Each project yields fresh insights and engages J-WAFS with new partners and thought leaders who drive the development of solutions at and beyond MIT.

2021 MITx Prize winners build community on campus and across the globe

MIT instructors honored for creating multidimensional, multidisciplinary online courses that help learners everywhere address real-world problems.

MIT Open Learning
June 7, 2021

On May 14, six MIT instructors were honored with the 2021 MITx Prize for Teaching and Learning in MOOCs. The prize, established in 2016, honors excellence in creating Massive Open Online Courses (MOOCs) for MITx on edX. Anyone in the MIT community can submit nominations, including MITx MOOC creators, and awardees are selected by the MITx Faculty Advisory Committee.

The award was given to two courses this year, honoring faculty and instructors from four disciplines. Jonathan Gruber, Ford Professor of Economics, was honored for his 14.01x (AP Microeconomics) course, which uses MIT materials geared toward high school learners to help them prepare for the College Board exam. The other course recognized, 15.480x (The Science and Business of Biotechnology), was created by professors Andrew Lo of the MIT Sloan School of Management and Harvey Lodish of the Department of Biology, along with graduate students Zied Ben Chaouch of the Department of Electrical Engineering and Computer Science (EECS) and Kate Koch of the Department of Biology, as well as Shomesh Chaudhuri ’14, PhD ’18, an EECS graduate.

The MITx Faculty Advisory Committee assesses prize nominees on four criteria: effective and engaging teaching methods, learner-focused innovation, residential impact and reuse, and global reach and impact. It is that last criterion that has drawn the most focus over the past year; in the wake of the Covid-19 crisis, demand for the established, high-quality resources offered by MIT Open Learning has been higher than ever.

“Now more than ever, by opening MIT teaching and learning to the world, our MITx courses are making a global impact,” says Dean for Digital Learning Krishna Rajagopal. “The courses honored with this award are exemplars of the best of MITx, and of MIT. They reach quite different audiences; high school students in one case, current and future leaders in biotechnology in the other. In both cases, they are doing so in ways that are sparking new curiosity and interest and opening new opportunities for their learners worldwide.”

Gruber’s Microeconomics course is a perfect example of a learning resource that has grown beyond its original purpose to reach a diverse international audience. Gruber first designed the course in 2017 to fill the void of preparatory materials available to U.S. students planning to take the AP Microeconomics exam; he notes that few high schools offer any kind of support or formal training for the test. The MOOC is structured around the exam curriculum, to serve either as standalone training or as a supplement to instructor-led courses. But perhaps in part because of its wide-ranging, pop-culture savvy appeal (Gruber uses LeBron James’ basketball career, Kim Kardashian’s Instagram account, and the pros and cons of attending university as just a few of his real-world economics examples) the course has found a truly global audience with learners from 180 countries.

Gruber has also used the course to develop and implement a very practical economic policy of his own. He has done away with assigning a required — and costly — textbook for his students in his residential MIT version of the course, instead assigning materials from the MOOC and other free, open source MIT learning materials as a supplement to class lectures and notes. David Autor, Ford Professor of Economics, in support of the course’s nomination, commended the “labor of love” that is Gruber’s course, and how with each new iteration of the MOOC, his colleague builds bridges for high school students, “[opening] pathways that were previously cloudy or just invisible.” Over time, says Autor, the course will “foster diversity and inclusion by seeding opportunity where it was absent.”

The Science and Business of Biotechnology course team was no less ambitious in creating their multidisciplinary exploration of the industry, setting up the course based on the comprehensive, research-led approach they’d like to see companies adopt. Like Gruber, course leaders Andrew Lo and Harvey Lodish have personal connections to their subject: Lo was moved to make change in the sector after experiencing disillusionment with biotech during loved ones’ battles with cancer. Lodish has witnessed the enormous impact of the biotech industry on both personal and professional levels: years after he co-founded Genzyme, his daughter gave birth to a son who depends on one of the company’s medicines for treatment of a chronic health condition.

The team’s dedication and well-balanced approach to a multifaceted industry has been a smashing success. Calling Lo and Lodish “superstars” in his letter of support, Institute Professor Robert Langer lauded the course’s comprehensive approach to the subject matter, finding it essential for those who would seek to make a real impact on the biotech industry. Heidi Pickett, assistant dean for the MIT Sloan Master of Finance Program, also praised the combination of subject areas explored throughout the course, citing its ability to redress weaknesses in individual learners’ skill sets; those coming from a finance background, for example, would benefit from a deeper engagement with the science of biotech, while still gaining knowledge in their primary field. She also spoke to the course’s wide appeal: “Considering the importance of topics discussed presented in 15.480x, it is no wonder the course attracted learners from around the world bringing different backgrounds and perspectives,” she says, adding that lively exchanges between users on the course’s discussion boards greatly enhanced the learning experience.

After a year when so many learners struggled to adapt to a sudden shift to remote education, MITx Director Dana Doyle finds ample reason to celebrate the power of intentional online teaching and learning. “In a time when people everywhere have felt both increasingly isolated and increasingly connected by the experience of the pandemic, it’s so heartening to witness how these courses have brought learners together to dive into important, complex global issues.”

Lessons from teaching about the pandemic in real-time

Covid-19 class taps experts to help students and the public avoid misinformation as the crisis evolves.

Raleigh McElvery | Department of Biology
May 21, 2021

Just a few months after the Covid-19 pandemic took hold, Alan Grossman was already mulling over an idea for a new class to help people make sense of the virus. As head of MIT’s Department of Biology, he was aware of the key role fundamental research would play in the coming months. From RNA viruses and genomic sequencing to antibodies and vaccines, MIT students and the general public would need reliable scientific information to understand the evolving situation — and discern fact from fiction.

Not long after, the thoughts he’d feverishly scribbled on paper scraps scattered around his house began to take shape. With the support of the MIT School of Science, Accessibility Office, MIT Video Productions, and others around the institute, the Department of Biology added a new fall subject to the course catalog: 7.00 (Covid-19, SARS-CoV-2 and the Pandemic). Undergraduates could take the class for credit, as notable researchers stepped up to the virtual podium to share their expertise in front of a public livestream.

Grossman brought his nascent plans to associate department head and Whitehead Institute for Biomedical Research Member Peter Reddien, and together the two brainstormed individuals who might be willing to lead the class and queue speakers. They reached out to professor of biology and Whitehead Institute Member Richard Young, who served as an advisor to the World Health Organization and National Institutes of Health when a different virus of unknown origins was spreading — HIV. Young was also quick to mount a collaborative research campaign against SARS-CoV-2, the virus that causes Covid-19.

“I give Alan a lot of credit,” Young says. “He thought that it was the responsibility of the department to take the lead in filling the Covid-19 knowledge niche, and asked me if I would take this on and find a partner.”

Young contacted Ragon Institute Associate Director Facundo Batista, a world-class expert in immunology and infectious disease. Batista recalls being hesitant at first to co-lead the class; he couldn’t fathom condensing the global emergency into a single course. “But then I realized that the onslaught of information was the very reason we needed to organize this class — to help students and the public avoid misinformation,” he says. “We were filling a gap that the whole world was experiencing.”

Together, Batista and Young generated a list of 14 experts in an array of pandemic-related areas, including Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, David Baltimore of Caltech, and Kizzmekia Corbett of the National Institutes of Health. Each geared their lecture toward MIT undergraduates with a minimal biology background, and defined key terms and concepts so non-biologists watching the livestream could follow along as well.

Although Batista and Young agree that remote learning pales in comparison to in-person classes, the livestream format opened the talks up to thousands more viewers, and allowed the speakers to present their work without the need for travel. The recordings of each Tuesday lecture were posted on the Department of Biology’s website shortly thereafter, permitting asynchronous viewing for people around the world. The livestream audience regularly exceeded 1,000, and the YouTube views for each recording ranged from 4,000-97,000 and climbing. In many cases, the week’s topic fortuitously coincided with current events. For instance, Corbett spoke about vaccine development just days after the results of Pfizer-BioNTech’s first clinical trial were announced. As one of the NIH scientists who collaborated with Moderna to design another important mRNA-based vaccine, Corbett was able to discuss her reaction to the news and her expectations for Moderna’s imminent clinical trial results.

In addition to the livestream audience, each week roughly 300 MIT undergraduates would enter the Zoom room and get the opportunity to ask questions during the Q&A. Participation was unusually high, Young and Batista recall, thanks to the recitation sessions led by graduate student and teaching assistant Lena Afeyan. Afeyan would walk the students through the fundamentals of molecular biology, virology, and any other topics slated to feature heavily in the upcoming lecture. She also invited trainees and medical residents from various institutions to attend, in order to introduce students to the next generation of scientists and health-care professionals. The supplementary reading materials from these sessions are still available online, so biology teachers and other members of the public can access them.

“When I heard that this class was being put together, I hoped I could help make the content more accessible for the students and anyone else joining us,” Afeyan says. “The responses we got were overwhelming. It was incredible to hear from so many teachers, researchers, and alums across the world who watched the course every week.”

Even today, Afeyan, Young, and Batista continue to receive international kudos from scientists and non-scientists alike. At one point, Young was even interviewed by a radio station in Tasmania about the course.

“I learned a lot from 7.00 — not only about Covid-19, but about immunology and biology in general,” says Lucas Marden, a first-year undergraduate who enrolled in the class. “I particularly enjoyed the focus on the real-world response to the pandemic. We learned about everything from designing and developing different tests, treatments, and vaccines, to the scale-up of these technologies. The scientific community’s response to Covid-19 has been incredibly impressive, and I loved learning about it from the people at the forefront of their fields.”

Now, Grossman says, the department is planning to offer the class again this coming fall. “The initial idea stemmed from the need to share clear and reliable information about the pandemic as it began spreading,” he explains. “Although we’ve been living with Covid-19 for over a year now, that need is still present today — perhaps more so as we continue to learn what it will take to tame the virus.”

The next iteration of 7.00 will begin in September, and likely feature some of the same speakers and topics, along with new experts in areas that have recently emerged, such as the evolving viral variants. By arming the MIT community and the public with information from leading experts, Grossman, Batista, Young, and Afeyan hope to help the world navigate this pandemic — and prevent the next one.

Biologists discover a trigger for cell extrusion

Study suggests this process for eliminating unneeded cells may also protect against cancer.

Anne Trafton | MIT News Office
May 5, 2021

For all animals, eliminating some cells is a necessary part of embryonic development. Living cells are also naturally sloughed off in mature tissues; for example, the lining of the intestine turns over every few days.

One way that organisms get rid of unneeded cells is through a process called extrusion, which allows cells to be squeezed out of a layer of tissue without disrupting the layer of cells left behind. MIT biologists have now discovered that this process is triggered when cells are unable to replicate their DNA during cell division.

The researchers discovered this mechanism in the worm C. elegans, and they showed that the same process can be driven by mammalian cells; they believe extrusion may serve as a way for the body to eliminate cancerous or precancerous cells.

“Cell extrusion is a mechanism of cell elimination used by organisms as diverse as sponges, insects, and humans,” says H. Robert Horvitz, the David H. Koch Professor of Biology at MIT, a member of the McGovern Institute for Brain Research and the Koch Institute for Integrative Cancer Research, a Howard Hughes Medical Institute investigator, and the senior author of the study. “The discovery that extrusion is driven by a failure in DNA replication was unexpected and offers a new way to think about and possibly intervene in certain diseases, particularly cancer.”

MIT postdoc Vivek Dwivedi is the lead author of the paper, which appears today in Nature. Other authors of the paper are King’s College London research fellow Carlos Pardo-Pastor, MIT research specialist Rita Droste, MIT postdoc Ji Na Kong, MIT graduate student Nolan Tucker, Novartis scientist and former MIT postdoc Daniel Denning, and King’s College London professor of biology Jody Rosenblatt.

Stuck in the cell cycle

In the 1980s, Horvitz was one of the first scientists to analyze a type of programmed cell suicide called apoptosis, which organisms use to eliminate cells that are no longer needed. He made his discoveries using C. elegans, a tiny nematode that contains exactly 959 cells. The developmental lineage of each cell is known, and embryonic development follows the same pattern every time. Throughout this developmental process, 1,090 cells are generated, and 131 cells undergo programmed cell suicide by apoptosis.

Horvitz’s lab later showed that if the worms were genetically mutated so that they could not eliminate cells by apoptosis, a few of those 131 cells would instead be eliminated by cell extrusion, which appears to be able to serve as a backup mechanism to apoptosis. How this extrusion process gets triggered, however, remained a mystery.

To unravel this mystery, Dwivedi performed a large-scale screen of more than 11,000 C. elegans genes. One by one, he and his colleagues knocked down the expression of each gene in worms that could not perform apoptosis. This screen allowed them to identify genes that are critical for turning on cell extrusion during development.

To the researchers’ surprise, many of the genes that turned up as necessary for extrusion were involved in the cell division cycle. These genes were primarily active during first steps of the cell cycle, which involve initiating the cell division cycle and copying the cell’s DNA.

Further experiments revealed that cells that are eventually extruded do initially enter the cell cycle and begin to replicate their DNA. However, they appear to get stuck in this phase, leading them to be extruded.

Most of the cells that end up getting extruded are unusually small, and are produced from an unequal cell division that results in one large daughter cell and one much smaller one. The researchers showed that if they interfered with the genes that control this process, so that the two daughter cells were closer to the same size, the cells that normally would have been extruded were able to successfully complete the cell cycle and were not extruded.

The researchers also showed that the failure of the very small cells to complete the cell cycle stems from a shortage of the proteins and DNA building blocks needed to copy DNA. Among other key proteins, the cells likely don’t have enough of an enzyme called LRR-1, which is critical for DNA replication. When DNA replication stalls, proteins that are responsible for detecting replication stress quickly halt cell division by inactivating a protein called CDK1. CDK1 also controls cell adhesion, so the researchers hypothesize that when CDK1 is turned off, cells lose their stickiness and detach, leading to extrusion.

Cancer protection

Horvitz’s lab then teamed up with researchers at King’s College London, led by Rosenblatt, to investigate whether the same mechanism might be used by mammalian cells. In mammals, cell extrusion plays an important role in replacing the lining of the intestines, lungs, and other organs.

The researchers used a chemical called hydroxyurea to induce DNA replication stress in canine kidney cells grown in cell culture. The treatment quadrupled the rate of extrusion, and the researchers found that the extruded cells made it into the phase of the cell cycle where DNA is replicated before being extruded. They also showed that in mammalian cells, the well-known cancer suppressor p53 is involved in initiating extrusion of cells experiencing replication stress.

That suggests that in addition to its other cancer-protective roles, p53 may help to eliminate cancerous or precancerous cells by forcing them to extrude, Dwivedi says.

“Replication stress is one of the characteristic features of cells that are precancerous or cancerous. And what this finding suggests is that the extrusion of cells that are experiencing replication stress is potentially a tumor suppressor mechanism,” he says.

The fact that cell extrusion is seen in so many animals, from sponges to mammals, led the researchers to hypothesize that it may have evolved as a very early form of cell elimination that was later supplanted by programmed cell suicide involving apoptosis.

“This cell elimination mechanism depends only on the cell cycle,” Dwivedi says. “It doesn’t require any specialized machinery like that needed for apoptosis to eliminate these cells, so what we’ve proposed is that this could be a primordial form of cell elimination. This means it may have been one of the first ways of cell elimination to come into existence, because it depends on the same process that an organism uses to generate many more cells.”

Dwivedi, who earned his PhD at MIT, was a Khorana scholar before entering MIT for graduate school. This research was supported by the Howard Hughes Medical Institute and the National Institutes of Health.

3 Questions: Sheena Vasquez and Mandana Sassanfar on building an outreach initiative from scratch

Graduate student and outreach director discuss efforts by the Department of Biology’s faculty, students, and staff to engage local community college students in scientific research.

Raleigh McElvery | Department of Biology
May 4, 2021

On June 10 of last year, MIT’s Department of Biology took the day to engage in open conversations about racial bias, diversity, and inclusion in support of the #ShutDownSTEM national initiative. These discussions spurred students, faculty, and staff to come together and form their own initiative. Known as the Community College Partnership, this program hopes to develop strong ties with local community colleges that are within commuting distance and serve diverse, nontraditional students — in order to increase access to MIT’s on-site and online resources. 

The department’s existing outreach programs — including the MIT Summer Research Program in Biology (MSRP-Bio), Quantitative Methods Workshop (QMW), and LEAH Knox Scholars Program — engage local high school students and non-MIT undergraduates from historically underrepresented groups in science. However, as of last year, the department had no research training opportunities geared toward community college students. The Community College Partnership is filling this gap by organizing virtual career panels, workshops, and seminars for students from Bunker Hill Community College and Roxbury Community College. In doing so, the initiative aims to encourage community college students from the Boston area to participate in additional MIT research opportunities, such as MSRP-Bio and QMW. Graduate student Sheena Vasquez, who spearheaded this initiative, and Mandana Sassanfar, the department’s director of outreach, sat down to discuss building a new program from scratch and how to plan for long-term success.

Q: What was your impetus for creating a program geared toward community college outreach?

Vasquez: I consider community college outreach very important for personal reasons. Back when I was applying to college, I couldn’t afford to attend a traditional four-year institution. I was also unsure what I wanted to major in, and I needed to stay close to home to take care of my family. I attended Georgia Perimeter College — a two-year community college — before transferring to the University of Georgia to finish my bachelor’s degree. I was able to participate in programs funded by the National Science Foundation, which led me to MIT for several summers as part of MSRP-Bio.

Looking back, I don’t think I would be a biology graduate student today if I hadn’t attended a community college. It also allowed me to see firsthand the talent, drive, and diversity at community colleges. And yet, at times these students are overlooked and underestimated by the general public. After our #ShutDownSTEM event last summer, it seemed like an ideal time to start engaging local community colleges in MIT’s biology research.

Sassanfar: I agree. It was by admitting bright students like Sheena to programs like MSRP that I realized the lack of initiatives aimed at community colleges. #ShutDownSTEM generated the energy and interest we needed to finally catalyze something like this. It was the missing link.

Q: What are the goals of the program, and how will you measure success?

Sassanfar: Our goals are twofold. First, we want to ensure that these students go far and reach their career goals — and possibly discover new goals that they didn’t realize were possible. Second, we hope to educate our own MIT community about the community college population, and build long-lasting relationships. This way, everyone will benefit.

Vasquez: We’ll be able to gauge the strength of these budding relationships by tracking how many students go on to participate in MSRP-Bio, QMW, and other rigorous research opportunities after attending our events. We also hope to create a team of graduate student mentors who can offer their expertise in grant writing and applying to graduate or other post-secondary schools.

Q: What challenges have you had to overcome in order to launch an outreach program aimed at a new community? How have you surmounted these difficulties?

Vasquez: The first challenge we faced was figuring out which community colleges to reach out to, and establishing points of contact there. We connected with Bunker Hill Community College first because of the diversity of students that attend. In addition, they had an active diversity, equity, and inclusion office, but no formal relationship with MIT Biology yet.

The next challenge was figuring out how to teach lab techniques virtually during our four-day workshop. We experimented with several different platforms before settling on Zoom. We also ended up sharing video recordings of ourselves in lab, and included tutorials on open-source software such as SnapGene and PyMOL — which allowed students to try their hand at procedures like DNA cloning, PCR, and interpreting protein structures. We asked everyone to fill out a survey at the very end, and 82 percent said they enjoyed the workshop and gained new skills. Ninety-six percent said they’d be interested in learning more about applying to graduate school, and some students have even reached out to us individually to continue the discussion.

Sassanfar: As Sheena alluded to, we’ve learned over the years that the secret to success is finding at least one faculty member or administrator at the other institution who is equally passionate about forming a partnership. In the case of Roxbury Community College, it took one meeting with a handful of faculty members to identify a professor who was willing to help make things happen. We do our part and they do their part; there has to be seamless communication.

My last piece of advice is that it’s vital for an outreach initiative to be focused. Go for depth, not breadth. It would be impossible to engage all community colleges in the greater Boston area. Instead, we are working hard to form strong relationships with a few in particular. That’s essential to creating something that’s long-lasting.

Up for a challenge in the lab and on the mat

While exploring a variety of research opportunities, senior Jose Aceves-Salvador has also thrown himself into mentoring, teaching, and cheerleading.

Hannah Meiseles | MIT News Office
April 28, 2021

At 5:30 a.m., his alarm would start blaring. Reluctant to get up, Jose Aceves-Salvador would hear his parents outside his door, bustling to get ready for work. “Ponte las pilas!” they would shout, using a Spanish idiom expressing encouragement to work hard.

The expression would stick with Aceves-Salvador throughout high school as he dreamed of going to college. Although neither of his parents had college degrees, they were both huge supporters of his decision. As Mexican immigrants who had moved to Los Angeles in their youth, their goal was to see their son achieve a better future.

“They didn’t know much about applying to college, but they knew that when you go, you’re set up for life,” explains Aceves-Salvador. “Whenever I’d hit a low, I’d think of how they’d tell me to work hard and keep going.”

To get a first taste of campus life, Aceves-Salvador attended a program at MIT called Minority Introduction to Engineering and Science (MITES) during the summer before his junior year of high school. MITES allowed Aceves-Salvador to take a genomics class at the Broad Institute of MIT and Harvard. The experience exposed him to the exciting and ever-changing world of scientific research.

“After MITES was over, I knew I wanted to go back to MIT. There was so much I still wanted to learn and explore,” Aceves-Salvador says. “In my mind, MIT was a huge reach school. But I couldn’t let go of the goal and figured I’d apply anyway.”

Aceves-Salvador was admitted and is now a senior studying biology with a concentration in education. “I love the learning process, and in biology there’s a never-ending cycle of questions to explore,” he says enthusiastically. “There are also so many opportunities to learn from failures and successes along the way.”

Aceves-Salvador wanted to do research the moment he arrived on campus, but struggled to get a lab position without any prior experience. Fortunately, in his sophomore year an interview with Xun Gong, a postdoc with the Strano Research Group, led to an opportunity. The lab had recently observed a new phenomenon in single-walled carbon nanotubes and wanted to investigate further. Aceves-Salvador joined the group and led the side project with Gong’s mentorship. “The project, and the fact that we were going into the unknown and exploring a new phenomenon perfectly fit my mentality, so I immediately said yes,” says Aceves-Salvador. “I eventually got my first taste of real science and have been hooked ever since.”

Since his first project, Aceves-Salvador has continued to do research, in multiple MIT labs and at the University of California at Los Angeles one summer. He has enjoyed working on everything from modeling protein behavior to developing a gut microphysical system. “As a college student, you come in barely knowing what’s out there to explore. I’ve tried to use my undergraduate degree to learn more about biology as a field before committing to something,” he says.

Across his different lab experiences, Aceves-Salvador has noted the lack of Latinx representation in science. He is devoted to encouraging greater minority representation in STEM and has served as a teaching assistant and mentor for MITES and the MIT Leadership Training Institute. These roles have allowed him to share his empowering story and love for education by teaching others. “I really wouldn’t be here if it weren’t for programs like MITES. I’m so grateful I can give back and be part of its legacy,” Aceves-Salvador says.

For an afterschool program he led in Los Angeles, Aceves-Salvador shaped the science curriculum he teaches to be more exciting to young learners. Students were challenged through hands-on activities, like creating chemical reactions, to make their own observations. “At a young age you’re so curious and curiosity is what science is all about,” says Aceves-Salvador. “But oftentimes, this curiosity gets stifled through outside pressures. In the hands-on activities I help lead, I try to create an open environment that encourages students to feel comfortable asking questions.”

Aceves-Salvador noticed the same approaches being used abroad during his international teaching experiences. Through MISTI Global Teaching Labs, he has traveled to Spain and Mexico to teach biology, math, health sciences, and chemistry. In Spain, Aceves-Salvador got to lead a discussion with local teachers on how to approach and encourage STEM education. “At least in the school I was placed in, I saw greater opportunities for students to explore different corners of science in their projects,” he notes. “The community-centric classrooms were also more focused on discussion among the students and less lecture.”

Outside of teaching and research, Aceves-Salvador enjoys channeling his passionate energy into dance and cheer. He has been part of MIT Cheerleading and DanceTroupe. These activities have pushed him physically, for example training him to lift cheerleaders on his shoulders and throw them into the air. He credits the intense nature of workout routines for creating a deep communal bond between members. “You share a connection with people after they’ve seen you fall on your face,” he jokes. “You can’t really hide anything at that point.”

This fall, Aceves-Salvador will be attending Harvard Medical School to pursue a PhD through the Biological and Biomedical Sciences program. He looks forward to continuing to explore different realms in science, as well as encouraging other young minority students to do the same. “Growing up, I never expected myself to be here in this position today. Even when I actually got into MIT, I faced a lot of pushback. People questioned my abilities and attributed my successes to luck,” Aceves-Salvador explains.

“It took me four years to leave that mentality. Now, I want to be a driving force to change that stigma. I want people to know that the reason we’re here is because we deserve to be here. And we’re going to do big things just like anyone else.”

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.

A tool for discovery

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.”