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More than 15 million colonoscopies are performed in the United States every year, and in at least 20 percent of those, gastroenterologists end up removing precancerous growths from the colon. Eliminating these early-stage lesions, known as polyps, is the best way to prevent colon cancer from developing.
To reduce the risk of tearing the colon during this procedure, doctors often inject a saline solution into the space below the lesion, forming a “cushion” that lifts the polyp so that it’s easier to remove safely. However, this cushion doesn’t last long.
MIT researchers have now devised an alternative — a solution that can be injected as a liquid but turns into a solid gel once it reaches the tissue, creating a more stable and longer-lasting cushion.
“That really makes a huge difference to the gastroenterologist who is performing the procedure, to ensure that there’s a stable area that they can then resect using endoscopic tools,” says Giovanni Traverso, an assistant professor in MIT’s Department of Mechanical Engineering and a gastroenterologist at Brigham and Women’s Hospital.
Traverso is the senior author of the study, which appears in the July 30 issue of Advanced Science. The lead authors of the study are former MIT postdocs Yan Pang and Jinyao Liu. Other authors include MIT undergraduate Zaina Moussa, technical associate Joy Collins, former technician Shane McDonnell, Division of Comparative Medicine veterinarian Alison Hayward, Brigham and Women’s Hospital gastroenterologist Kunal Jajoo, and David H. Koch Institute Professor Robert Langer.
A stable cushion
While many colon polyps are harmless, some can eventually become cancerous if not removed. Gastroenterologists often perform this procedure during a routine colonoscopy, using a lasso-like tool to snare the tissue before cutting it off.
This procedure carries some risk of tearing the lining of the colon, which is why doctors usually inject saline into the area just below the lining, called the submucosal space, to lift the polyp away from the surface of the colon.
“What that does is separate those tissue layers briefly, and it gives one a little bit of a raised area so it’s easier to snare the lesion,” Traverso says. “The challenge is that saline dissipates very quickly, so we don’t always have enough time to go in and intervene, and may need to reinject saline.”
Complex lesions can take 10 to 20 minutes to remove, or even longer, but the saline cushion only lasts for a few minutes. Researchers have tried to make the cushions longer-lived by adding thickening agents such as gelatin and cellulose, but those are very difficult to inject through the narrow needle that is used for the procedure.
To overcome that, the MIT team decided to create a shear-thinning gel. These materials are semisolid gels under normal conditions, but when force is applied to them, their viscosity decreases and they flow more easily. This means that the material can be easily injected through a narrow needle, then turn back into a solid gel once it exits into the colon tissue.
Shear-thinning gels can be made from many different types of materials. For this purpose, the researchers decided on a combination of two biocompatible materials that can form gels — Laponite, a powdery clay used in cosmetics and other products, and alginate, a polysaccharide derived from algae.
“We chose these materials because they are biocompatible and they allow us to tune the flowing behavior of the resulting gels,” Pang says.
Using these materials, the researchers created a shear-thinning gel that could be injected and form a stable cushion for more than an hour, in pigs. This would give gastroenterologists much more time to remove any polyps.
“Otherwise, you inject the saline, then you change tools, and by the time you’re ready the tissue is kind of flat again. It becomes really difficult to resect things safely,” Traverso says.
This approach could offer “an elegant solution” to the problem of keeping lesions elevated during a surgical removal, says Jay Pasricha, a professor of medicine and neuroscience at Johns Hopkins School of Medicine.
“It’s a growing unmet need,” says Pasricha, who was not involved in the research. “In the last decade, we’ve shifted toward trying to resect more complex tumors from the colon endoscopically, rather than through traditional forms of surgery. It would be great to have a material that can last throughout the duration of the procedure.”
By varying the composition of the gel components, the researchers can control features such as the viscosity, which influences how long the cushion remains stable. If made to last longer, this kind of injectable gel could be useful for applications such as narrowing the GI tract, which could be used to prevent acid reflux or to help with weight loss by making people feel full. It could also potentially be used to deliver drugs to the intestinal tract, Traverso says.
The researchers also found that the material had no harmful side effects in pigs, and they hope to begin trials in human patients within the next three to five years.
“This is something we think can get into patients fairly quickly,” Traverso says. “We’re really excited about moving it forward.”
The research was funded by the National Institutes of Health, the Alexander von Humboldt Foundation, the Division of Gastroenterology at Brigham and Women’s Hospital and the MIT Department of Mechanical Engineering.
Improved air quality can be a major bonus of climate mitigation policies aimed at reducing greenhouse gas emissions. By cutting air pollution levels in the country where emissions are produced, such policies can avoid significant numbers of premature deaths. But other nations downwind from the host country may also benefit.
A new MIT study in the journal Environmental Research Letters shows that if the world’s top emitter of greenhouse gas emissions, China, fulfills its climate pledge to peak carbon dioxide emissions in 2030, the positive effects would extend all the way to the United States, where improved air quality would result in nearly 2,000 fewer premature deaths.
The study estimates China’s climate policy air quality and health co-benefits resulting from reduced atmospheric concentrations of ozone, as well as co-benefits from reduced ozone and particulate air pollution (PM2.5) in three downwind and populous countries: South Korea, Japan, and the United States. As ozone and PM2.5 give a well-rounded picture of air quality and can be transported over long distances, accounting for both pollutants enables a more accurate projection of associated health co-benefits in the country of origin and those downwind.
Using a modeling framework that couples an energy-economic model with an atmospheric chemistry model, and assuming a climate policy consistent with China’s pledge to peak CO2 emissions in 2030, the researchers found that atmospheric ozone concentrations in China would fall by 1.6 parts per billion in 2030 compared to a no-policy scenario, and thus avoid 54,300 premature deaths — nearly 60 percent of those resulting from PM2.5. Total avoided premature deaths in South Korea and Japan are 1,200 and 3,500, respectively, primarily due to PM2.5; for the U.S. total, 1,900 premature deaths, ozone is the main contributor, due to its longer lifetime in the atmosphere.
Total avoided deaths in these countries amount to about 4 percent of those in China. The researchers also found that a more stringent climate policy would lead to even more avoided premature deaths in the three downwind countries, as well as in China.
The study breaks new ground in showing that co-benefits of climate policy from reducing ozone-related premature deaths in China are comparable to those from PM2.5, and that co-benefits from reduced ozone and PM2.5 levels are not insignificant beyond China’s borders.
“The results show that climate policy in China can influence air quality even as far away as the U.S.,” says Noelle Eckley Selin, an associate professor in MIT’s Institute for Data, Systems, and Society and Department of Earth, Atmospheric and Planetary Sciences (EAPS), who co-led the study. “This shows that policy action on climate is indeed in everyone’s interest, in the near term as well as in the longer term.”
The other co-leader of the study is Valerie Karplus, the assistant professor of global economics and management in MIT’s Sloan School of Management. Both co-leaders are faculty affiliates of the MIT Joint Program on the Science and Policy of Global Change. Their co-authors include former EAPS graduate student and lead author Mingwei Li, former Joint Program research scientist Da Zhang, and former MIT postdoc Chiao-Ting Li.
Reducing carbon dioxide (CO2) emissions from power plants is widely considered an essential component of any climate change mitigation plan. Many research efforts focus on developing and deploying carbon capture and sequestration (CCS) systems to keep CO2 emissions from power plants out of the atmosphere. But separating the captured CO2 and converting it back into a gas that can be stored can consume up to 25 percent of a plant’s power-generating capacity. In addition, the CO2 gas is generally injected into underground geological formations for long-term storage — a disposal method whose safety and reliability remain unproven.
A better approach would be to convert the captured CO2 into useful products such as value-added fuels or chemicals. To that end, attention has focused on electrochemical processes — in this case, a process in which chemical reactions release electrical energy, as in the discharge of a battery. The ideal medium in which to conduct electrochemical conversion of CO2 would appear to be water. Water can provide the protons (positively charged particles) needed to make fuels such as methane. But running such “aqueous” (water-based) systems requires large energy inputs, and only a small fraction of the products formed are typically those of interest.
Betar Gallant, an assistant professor of mechanical engineering, and her group at MIT have therefore been focusing on non-aqueous (water-free) electrochemical reactions — in particular, those that occur inside lithium-CO2 batteries.
Research into lithium-CO2 batteries is in its very early stages, according to Gallant, but interest in them is growing because CO2 is used up in the chemical reactions that occur on one of the electrodes as the battery is being discharged. However, CO2 isn’t very reactive. Researchers have tried to speed things up by using different electrolytes and electrode materials. Despite such efforts, the need to use expensive metal catalysts to elicit electrochemical activity has persisted.
Given the lack of progress, Gallant wanted to try something different. “We were interested in trying to bring a new chemistry to bear on the problem,” she says. And enlisting the help of the sorbent molecules that so effectively capture CO2 in CCS seemed like a promising way to go.
The sorbent molecule used in CCS is an amine, a derivative of ammonia. In CCS, exhaust is bubbled through an amine-containing solution, and the amine chemically binds the CO2, removing it from the exhaust gases. The CO2 — now in liquid form — is then separated from the amine and converted back to a gas for disposal.
In CCS, those last steps require high temperatures, which are attained using some of the electrical output of the power plant. Gallant wondered whether her team could instead use electrochemical reactions to separate the CO2 from the amine — and then continue the reaction to make a solid, CO2-containing product. If so, the disposal process would be simpler than it is for gaseous CO2. The CO2 would be more densely packed, so it would take up less space, and it couldn’t escape, so it would be safer. Better still, additional electrical energy could be extracted from the device as it discharges and forms the solid material. “The vision was to put a battery-like device into the power plant waste stream to sequester the captured CO2 in a stable solid, while harvesting the energy released in the process,” says Gallant.
Research on CCS technology has generated a good understanding of the carbon-capture process that takes place inside a CCS system. When CO2 is added to an amine solution, molecules of the two species spontaneously combine to form an “adduct,” a new chemical species in which the original molecules remain largely intact. In this case, the adduct forms when a carbon atom in a CO2 molecule chemically bonds with a nitrogen atom in an amine molecule. As they combine, the CO2 molecule is reconfigured: It changes from its original, highly stable, linear form to a “bent” shape with a negative charge — a highly reactive form that’s ready for further reaction.
In her scheme, Gallant proposed using electrochemistry to break apart the CO2-amine adduct — right at the carbon-nitrogen bond. Cleaving the adduct at that bond would separate the two pieces: the amine in its original, unreacted state, ready to capture more CO2, and the bent, chemically reactive form of CO2, which might then react with the electrons and positively charged lithium ions that flow during battery discharge. The outcome of that reaction could be the formation of lithium carbonate (Li2CO3), which would deposit on the carbon electrode.
At the same time, the reactions on the carbon electrode should promote the flow of electrons during battery discharge — even without a metal catalyst. “The discharge of the battery would occur spontaneously,” Gallant says. “And we’d break the adduct in a way that allows us to renew our CO2 absorber while taking CO2 to a stable, solid form.”
A process of discovery
In 2016, Gallant and mechanical engineering doctoral student Aliza Khurram began to explore that idea.
Their first challenge was to develop a novel electrolyte. A lithium-CO2 battery consists of two electrodes — an anode made of lithium and a cathode made of carbon — and an electrolyte, a solution that helps carry charged particles back and forth between the electrodes as the battery is charged and discharged. For their system, they needed an electrolyte made of amine plus captured CO2 dissolved in a solvent — and it needed to promote chemical reactions on the carbon cathode as the battery discharged.
They started by testing possible solvents. They mixed their CO2-absorbing amine with a series of solvents frequently used in batteries and then bubbled CO2 through the resulting solution to see if CO2 could be dissolved at high concentrations in this unconventional chemical environment. None of the amine-solvent solutions exhibited observable changes when the CO2 was introduced, suggesting that they might all be viable solvent candidates.
However, for any electrochemical device to work, the electrolyte must be spiked with a salt to provide positively charged ions. Because it’s a lithium battery, the researchers started by adding a lithium-based salt — and the experimental results changed dramatically. With most of the solvent candidates, adding the salt instantly caused the mixture either to form solid precipitates or to become highly viscous — outcomes that ruled them out as viable solvents. The sole exception was the solvent dimethyl sulfoxide, or DMSO. Even when the lithium salt was present, the DMSO could dissolve the amine and CO2.
“We found that — fortuitously — the lithium-based salt was important in enabling the reaction to proceed,” says Gallant. “There’s something about the positively charged lithium ion that chemically coordinates with the amine-CO2 adduct, and together those species make the electrochemically reactive species.”
Exploring battery behavior during discharge
To examine the discharge behavior of their system, the researchers set up an electrochemical cell consisting of a lithium anode, a carbon cathode, and their special electrolyte — for simplicity, already loaded with CO2. They then tracked discharge behavior at the carbon cathode.
As they had hoped, their special electrolyte actually promoted discharge reaction in the test cell. “With the amine incorporated into the DMSO-based electrolyte along with the lithium salt and the CO2, we see very high capacities and significant discharge voltages — almost three volts,” says Gallant. Based on those results, they concluded that their system functions as a lithium-CO2 battery with capacities and discharge voltages competitive with those of state-of-the-art lithium-gas batteries.
The next step was to confirm that the reactions were indeed separating the amine from the CO2 and further continuing the reaction to make CO2-derived products. To find out, the researchers used a variety of tools to examine the products that formed on the carbon cathode.
In one test, they produced images of the post-reaction cathode surface using a scanning electron microscope (SEM). Immediately evident were spherical formations with a characteristic size of 500 nanometers, regularly distributed on the surface of the cathode. According to Gallant, the observed spherical structure of the discharge product was similar to the shape of Li2CO3 observed in other lithium-based batteries. Those spheres were not evident in SEM images of the “pristine” carbon cathode taken before the reactions occurred.
Other analyses confirmed that the solid deposited on the cathode was Li2CO3. It included only CO2-derived materials; no amine molecules or products derived from them were present. Taken together, those data provide strong evidence that the electrochemical reduction of the CO2-loaded amine occurs through the selective cleavage of the carbon-nitrogen bond.
“The amine can be thought of as effectively switching on the reactivity of the CO2,” says Gallant. “That’s exciting because the amine commonly used in CO2 capture can then perform two critical functions. It can serve as the absorber, spontaneously retrieving CO2 from combustion gases and incorporating it into the electrolyte solution. And it can activate the CO2 for further reactions that wouldn’t be possible if the amine were not there.”
Gallant stresses that the work to date represents just a proof-of-concept study. “There’s a lot of fundamental science still to understand,” she says, before the researchers can optimize their system.
She and her team are continuing to investigate the chemical reactions that take place in the electrolyte as well as the chemical makeup of the adduct that forms — the “reactant state” on which the subsequent electrochemistry is performed. They are also examining the detailed role of the salt composition.
In addition, there are practical concerns to consider as they think about device design. One persistent problem is that the solid deposit quickly clogs up the carbon cathode, so further chemical reactions can’t occur. In one configuration they’re investigating — a rechargeable battery design — the cathode is uncovered during each discharge-charge cycle. Reactions during discharge deposit the solid Li2CO3, and reactions during charging lift it off, putting the lithium ions and CO2 back into the electrolyte, ready to react and generate more electricity. However, the captured CO2 is then back in its original gaseous form in the electrolyte. Sealing the battery would lock that CO2 inside, away from the atmosphere — but only so much CO2 can be stored in a given battery, so the overall impact of using batteries to capture CO2 emissions would be limited in this scenario.
The second configuration the researchers are investigating — a discharge-only setup — addresses that problem by never allowing the gaseous CO2 to re-form. “We’re mechanical engineers, so what we’re really keen on doing is developing an industrial process where you can somehow mechanically or chemically harvest the solid as it forms,” Gallant says. “Imagine if by mechanical vibration you could gently remove the solid from the cathode, keeping it clear for sustained reaction.” Placed within an exhaust stream, such a system could continuously remove CO2 emissions, generating electricity and perhaps producing valuable solid materials at the same time.
Gallant and her team are now working on both configurations of their system. “We don’t know which is better for applications yet,” she says. While she believes that practical lithium-CO2 batteries are still years away, she’s excited by the early results, which suggest that developing novel electrolytes to pre-activate CO2 could lead to alternative CO2 reaction pathways. And she and her group are already working on some.
One goal is to replace the lithium with a metal that’s less costly and more earth-abundant, such as sodium or calcium. With seed funding from the MIT Energy Initiative, the team has already begun looking at a system based on calcium, a material that’s not yet well-developed for battery applications. If the calcium-CO2 setup works as they predict, the solid that forms would be calcium carbonate — a type of rock now widely used in the construction industry.
In the meantime, Gallant and her colleagues are pleased that they have found what appears to be a new class of reactions for capturing and sequestering CO2. “CO2 conversion has been widely studied over many decades,” she says, “so we’re excited to think we may have found something that’s different and provides us with a new window for exploring this topic.”
This research was supported by startup funding from the MIT Department of Mechanical Engineering. Mingfu He, a postdoc in mechanical engineering, also contributed to the research. Work on a calcium-based battery is being supported by the MIT Energy Initiative Seed Fund Program.
This article appears in the Spring 2019 issue of Energy Futures, the magazine of the MIT Energy Initiative.
NASA’s Transiting Exoplanet Survey Satellite, or TESS, has discovered three new worlds that are among the smallest, nearest exoplanets known to date. The planets orbit a star just 73 light-years away and include a small, rocky super-Earth and two sub-Neptunes — planets about half the size of our own icy giant.
The sub-Neptune furthest out from the star appears to be within a “temperate” zone, meaning that the very top of the planet’s atmosphere is within a temperature range that could support some forms of life. However, scientists say the planet’s atmosphere is likely a thick, ultradense heat trap that renders the planet’s surface too hot to host water or life.
Nevertheless, this new planetary system, which astronomers have dubbed TOI-270, is proving to have other curious qualities. For instance, all three planets appear to be relatively close in size. In contrast, our own solar system is populated with planetary extremes, from the small, rocky worlds of Mercury, Venus, Earth, and Mars, to the much more massive Jupiter and Saturn, and the more remote ice giants of Neptune and Uranus.
There’s nothing in our solar system that resembles an intermediate planet, with a size and composition somewhere in the middle of Earth and Neptune. But TOI-270 appears to host two such planets: both sub-Neptunes are smaller than our own Neptune and not much larger than the rocky planet in the system.
Astronomers believe TOI-270’s sub-Neptunes may be a “missing link” in planetary formation, as they are of an intermediate size and could help researchers determine whether small, rocky planets like Earth and more massive, icy worlds like Neptune follow the same formation path or evolve separately.
TOI-270 is an ideal system for answering such questions, because the star itself is nearby and therefore bright, and also unusually quiet. The star is an M-dwarf, a type of star that is normally extremely active, with frequent flares and solar storms. TOI-270 appears to be an older M-dwarf that has since quieted down, giving off a steady brightness, against which scientists can measure many properties of the orbiting planets, such as their mass and atmospheric composition.
“There are a lot of little pieces of the puzzle that we can solve with this system,” says Maximilian Günther, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research and lead author of a study published today in Nature Astronomy that details the discovery. “You can really do all the things you want to do in exoplanet science, with this system.”
Compare and contrast worlds in the TOI 270 system with these illustrations. Temperatures given for TOI 270 planets are equilibrium temperatures, calculated without the warming effects of any possible atmospheres. Credit: NASA’s Goddard Space Flight Center
A planetary pattern
Günther and his colleagues detected the three new planets after looking through measurements of stellar brightness taken by TESS. The MIT-developed satellite stares at patches of the sky for 27 days at a time, monitoring thousands of stars for possible transits — characteristic dips in brightness that could signal a planet temporarily blocking the star’s light as it passes in front of it.
The team isolated several such signals from a nearby star, located 73 light years away in the southern sky. They named the star TOI-270, for the 270th “TESS Object of Interest” identified to date. The researchers used ground-based instruments to follow up on the star’s activity, and confirmed that the signals are the result of three orbiting exoplanets: planet b, a rocky super-Earth with a roughly three-day orbit; planet c, a sub-Neptune with a five-day orbit; and planet d, another sub-Neptune slightly further out, with an 11-day orbit.
Günther notes that the planets seem to line up in what astronomers refer to as a “resonant chain,” meaning that the ratio of their orbits are close to whole integers — in this case, 3:5 for the inner pair, and 2:1 for the outer pair — and that the planets are therefore in “resonance” with each other. Astronomers have discovered other small stars with similarly resonant planetary formations. And in our own solar system, the moons of Jupiter also happen to line up in resonance with each other.
“For TOI-270, these planets line up like pearls on a string,” Günther says. “That’s a very interesting thing, because it lets us study their dynamical behavior. And you can almost expect, if there are more planets, the next one would be somewhere further out, at another integer ratio.”
“An exceptional laboratory”
TOI-270’s discovery initially caused a stir of excitement within the TESS science team, as it seemed, in the first analysis, that planet d might lie in the star’s habitable zone, a region that would be cool enough for the planet’s surface to support water, and possibly life. But the researchers soon realized that the planet’s atmosphere was probably extremely thick, and would therefore generate an intense greenhouse effect, causing the planet’s surface to be too hot to be habitable.
But Günther says there is a good possibility that the system hosts other planets, further out from planet d, that might well lie within the habitable zone. Planet d, with an 11-day orbit, is about 10 million kilometers out from the star. Günther says that, given that the star is small and relatively cool — about half as hot as the sun — its habitable zone could potentially begin at around 15 million kilometers. But whether a planet exists within this zone, and whether it is habitable, depends on a host of other parameters, such as its size, mass, and atmospheric conditions.
Fortunately, the team writes in their paper that “the host star, TOI-270, is remarkably well-suited for future habitability searches, as it is particularly quiet.” The researchers plan to focus other instruments, including the upcoming James Webb Space Telescope, on TOI-270, to pin down various properties of the three planets, as well as search for additional planets in the star’s habitable zone.
“TOI-270 is a true Disneyland for exoplanet science, and one of the prime systems TESS was set out to discover,” Günther says. “It is an exceptional laboratory for not one, but many reasons — it really ticks all the boxes.”
This research was funded, in part, by NASA.
Wei Zhang’s breakthrough happened on the train. He was riding home to New York after visiting a friend in Boston, during the last year of his PhD studies in mathematics at Columbia University, where he was focusing on L-functions, an important area of number theory.
“All of a sudden, things were linked together,” he recalls, about the flash of insight that allowed him to finish a key project related to his dissertation. “Definitely it was an ‘Aha!’ moment.”
But that moment emerged from years of patient study and encounters with other mathematicians’ ideas. For example, he had attended talks by a certain faculty member in his first and third years at Columbia, but each time he thought the ideas presented in those lectures wouldn’t be relevant for his own work.
“And then two years later, I found this was exactly what I needed to finish a piece of the project!” says Zhang, who joined MIT two years ago as a professor of mathematics.
As Zhang recalls, during that pivotal train ride his mind had been free to wander around the problem and consider it from different angles. With this mindset, “I can have a more panoramic way of putting everything into one piece. It’s like a puzzle — when you close your eyes maybe you can see more. And when the mind is trying to organize different parts of a story, you see this missing part.”
Allowing time for this panoramic view to come into focus has been critical throughout Zhang’s career. His breakthrough on the train 11 years ago led him to propose a set of conjectures that he has just now solved in a recent paper.
“Patience is important for our subject,” he says. “You’re always making infinitesimal progress. All discovery seems to be made in one moment. But without the preparation and long-time accumulation of knowledge, it wouldn’t be possible.”
An early and evolving love for math
Zhang traces his interest in math back to the fourth grade in his village school in a remote part of China’s Sichuan Province. “It was just pure curiosity,” he says. “Some of the questions were so beautifully set up.”
He started participating in math competitions. Seeing his potential, a fifth-grade math teacher let Zhang pore over an extracurricular book of problems. “Those questions made me wonder how such simple solutions to seemingly very complicated questions could be possible,” he says.
Zhang left home to attend a high school 300 miles away in Chengdu, the capital city of Sichuan. By the time he applied to study at Peking University in Beijing, he knew he wanted to study mathematics. And by his final year there, he had decided to pursue a career as a mathematician.
He credits one of his professors with awakening him to some exciting frontiers and more advanced areas of study, during his first year. At that time, around 2000, the successful proof of Fermat’s Last Theorem by Andrew Wiles five years earlier was still relatively fresh, and reverberating through the world of mathematics. “This teacher really liked to chat,” Zhang says, “and he explained the contents of some of those big events and results in a way that was accessible to first-year students.”
“Later on, I read those texts by myself, and I found it was something I liked,” he says. “The tools being developed to prove Fermat’s Last Theorem were a starting point for me.”
Today, Zhang gets to cultivate his own students’ passion for math, even as his teaching informs his own research. “It has happened more than once for me, that while teaching I got inspired,” he says. “For mathematicians, we may understand some sort of result, but that doesn’t mean we actually we know how to prove them. By teaching a course, it really helps us go through the whole process. This definitely helps, especially with very talented students like those at MIT.”
From local to global information
Zhang’s core area of research and expertise is number theory, which is devoted to the study of integers and their properties. Broadly speaking, Zhang explores how to solve equations in integers or in rational numbers. A familiar example is a Pythagorean triple (a2+b2=c2).
“One simple idea is try to solve equations with modular arithmetic,” he says. The most common example of modular arithmetic is a 12-hour clock, which counts time by starting over and repeating after it reaches 12. With modular arithmetic, one can compile a set of data, indexed, for example, by prime numbers.
“But after that, how do you return to the initial question?” he says. “Can you tell an equation has an integer solution by collecting data from modular arithmetic?” Zhang investigates whether and how an equation can be solved by restoring this local data to a global piece of information — like finding a Pythagorean triple.
His research is relevant to an important facet of the Langlands Program — a set of conjectures proposed by mathematician Robert Langlands for connecting number theory and geometry, which some have likened to a kind of “grand unified theory” of mathematics.
Conversations and patience
Bridging other branches of math with number theory has become one of Zhang’s specialties.
In 2018, he won the New Horizons in Mathematics Breakthroughs Prize, a prestigious award for researchers early in their careers. He shared the prize with his old friend and undergraduate classmate, and current MIT colleague, Zhiwei Yun, for their joint work on the Taylor expansion of L-functions, which was hailed as a major advance in a key area of number theory in the past few decades.
Their project grew directly out of his dissertation research. And that work, in turn, opened up new directions in his current research, related to the arithmetic of elliptic curves. But Zhang says the way forward wasn’t clear until five years — and many conversations with Yun — later.
“Conversation is important in mathematics,” Zhang says. “Very often mathematical questions can be solved, or at least progress can be made, by bringing together people with different skills and backgrounds, with new interpretations of the same set of facts. In our case, this is a perfect example. His geometrical way of thinking about the question was exactly complementary to my own perspective, which is more number arithmetic.”
Lately, Zhang’s work has taken place on fewer train rides and more flights. He travels back to China at least once a year, to visit family and colleagues in Beijing. And when he feels stuck on a problem, he likes to take long walks, play tennis, or simply spend time with his young children, to clear his mind.
His recent solution of his own conjecture has led him to contemplate unexplored terrain. “This opened up a new direction,” he says. “I think it’s possible to finally get some higher-dimensional solutions. It opens up new conjectures.”
Tiny “Russian doll-like” particles that deliver multiple drugs to brain tumors, developed by researchers at MIT and funded by Cancer Research UK, are at the center of a new international collaboration.
Professor Paula Hammond from the Department of Chemical Engineering developed the nanoparticle technology, which will be used in an effort to treat glioblastoma — the most aggressive and deadly type of brain tumor.
Hammond will be working with Professor Michael Yaffe from the Department of Biological Engineering to determine the combinations of drugs placed within the particles, and the order and timing in which the drugs are released.
The nanoparticles — 1,000 times smaller than a human hair — are coated in a protein called transferrin, which helps them cross the blood-brain barrier. This is a membrane that keeps a tight check on anything trying to get in to the brain, including drugs.
Not only are the nanoparticles able to access hard-to-reach areas of the brain, they have also been designed to carry multiple cancer drugs at once by holding them inside layers, similarly to the way Russian dolls fit inside one another.
To make the nanoparticles even more effective, they will carry signals on their surface so that they are only taken up by brain tumor cells. This means that healthy cells should be left untouched, which will minimize the side effects of treatment.
The researchers, who are based at the Koch Institute for Integrative Cancer Research, are also working with Professor Forest White from the Department of Biological Engineering. The group are one of three international teams to have been given Cancer Research UK Brain Tumor Awards — in partnership with The Brain Tumour Charity — receiving $7.9 million of funding. The awards are designed to accelerate the pace of brain tumor research. Altogether, teams were awarded a total of $23 million.
Just last year, around 24,200 people in the United States were diagnosed with brain tumors. With around 17,500 deaths from brain tumors in the same year, survival remains tragically low.
Brain tumors represent one of the hardest types of cancer to treat because not enough is known about what starts and drives the disease, and current treatments are not effective enough.
The researchers from MIT will now work with teams in the U.K. and Europe to use the nanoparticles to carry multiple drug therapies to treat glioblastoma.
Early research carried out in the lab has already shown that nanoparticles loaded with two different drugs were able to shrink glioblastomas in mice. The team has also demonstrated that the nanoparticles can kill lymphoma cells grown in the lab, and they are also exploring their use in ovarian cancer.
The Cancer Research UK Brain Tumor Award will now allow the researchers and their collaborators to use different drug combinations to find the best parameters to tackle glioblastomas.
Drugs that have already been approved, as well as experimental drugs that have passed initial safety testing in people, will be used. Because of this, if an effective drug combination is found, the team won’t have to navigate the initial regulatory hurdles needed to get them into clinical testing, which could help get promising treatments to patients faster.
“Glioblastoma is particularly challenging because we want to get highly effective but toxic drug combinations safely across the blood-brain barrier, but also want our nanoparticles to avoid healthy brain cells and only target the cancer cells," Hammond says. "We are very excited about this alliance between the MIT Koch Institute and our colleagues in Edinburgh to address these critical challenges.”
Cell therapies, in which cellular material is injected, grafted, or implanted into a patient to treat a range of illnesses and medical conditions, are a vital and integral component of medicine today — promising treatment of tissue degenerative diseases, cancer, and autoimmune disorders.
However, significant challenges currently exist to prevent its widespread adoption, including problems such as safety, potency, efficacy, and costs. To overcome these challenges, the Singapore-MIT Alliance for Research and Technology (SMART), together with A*STAR Institutes and supported by the National Research Foundation (NRF), has launched a new national initiative in Singapore that deploys MIT’s globally renowned applied innovation methodology combined with Singapore’s dynamic and growing biopharmaceutical manufacturing industry.
As part of the national initiative in cell manufacturing, Critical Analytics for Manufacturing Personalized-Medicine (CAMP) is a new interdisciplinary research group within SMART that will focus on ways to produce living cells as medicine delivered to humans, leading to improved health outcomes. The National Research Foundation will support this multimillion-dollar, multiyear project that will bring together 35 MIT and Singapore investigators. They will be recruited from researchers working in SMART and Singapore institutes including A*STAR, KK Women’s and Children’s Hospital, the National University Hospital, and local universities. Investigators from MIT in Cambridge, Massachusetts, will also be recruited to support the program.
“This is a field that is ripe for innovation, and one which we believe will benefit from both MIT’s and Singapore’s strengths,” says Eugene Fitzgerald, CEO and director of SMART and the Merton C. Flemings-Singapore MIT Alliance Professor of Materials Engineering at MIT. “By applying our problem-solving research methodology, coupled with Singapore’s well-established biopharmaceutical manufacturing ecosystem, we are confident that we will be able to achieve market-ready breakthroughs.”
Since its inception in Singapore in 2007, SMART has pioneered innovations that have transformed and are transforming fields such as autonomous driving, agriculture, microelectronics, mechanics and microfluidics platforms for biology and medical diagnostics, and antimicrobial resistance.
SMART CAMP will be helmed by professors Krystyn Van Vliet of MIT and Hanry Yu of NUS and A*STAR. Van Vliet is an engineer with expertise at the interface of materials, mechanics, and biological systems and is an experienced leader, currently serving as the associate provost and the director of manufacturing innovation at MIT. Her current research, stemming from earlier SMART collaborations, is in clinical trials at the Singapore General Hospital, and the prior SMART team that she led has spun off several medical-technical companies in Singapore.
Van Vliet explains, “By addressing critical technology bottlenecks in how the next generation of personalised medicines is made, SMART CAMP researchers will help set the standards for innovating on quality by design. Imagine providing just the right living cells — the most sophisticated drug factories we know — to each patient, as quickly and safely as possible. Delivering on that promise requires exciting changes in the way we understand, engineer, measure, and select cells that offer a safe and effective medicine for that person’s ailment. And that goal, in turn, benefits from this investment in the research and researchers that can transform the manufacturing and analytics of biopharma products.”
Yu is a physiologist with expertise interface between mechanobiology, biomaterials, imaging, and AI-based data analytics. He is also a serial entrepreneur, recently forming six companies, and the founding member of the Mechanobiology Institute Research Centre of Excellence in Singapore.
“This program integrates experts from various disciplines, training staff and students who can think through the translational pipelines from basic knowledge and technology into commercially viable and clinically relevant solutions,” says Yu.
“There is a global need for safe and cost-effective cell therapies,” says Khiang Wee Lim, executive director of CREATE, NRF. “We believe that it is an area in which Singapore can provide innovation space and bring these transformational technologies to millions around the world. Advances in this area will also boost Singapore’s biopharmaceutical industry, bringing innovations and helping gain a lead in this promising market that is estimated to be worth billions.”
Singapore-MIT Alliance for Research and Technology (SMART) is MIT’s research enterprise in Singapore, established in partnership with the National Research Foundation (NRF) of Singapore since 2007. SMART is the first entity in the Campus for Research Excellence and Technological Enterprise (CREATE) developed by NRF. SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore. Cutting-edge research projects in areas of interest to both Singapore and MIT are undertaken at SMART. SMART currently comprises an Innovation Centre and six interdisciplinary research groups: Antimicrobial Resistance, BioSystems and Micromechanics, CAMP, Disruptive & Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems.
SMART research is funded by the NRF Singapore under the CREATE program.
As NASA gears up to send humans back to the moon or even to Mars, they'll need to figure out how to keep these humans healthy and safe, far away from the resource-abundant Earth.
It won't be feasible to pack everything they may need over the course of the mission, and resupply missions like those that keep the International Space Station (ISS) stocked will be prohibitively expensive and lengthy.
What these astronauts can pack are Earth's unique renewable resource: cells. Cells of fungi and bacteria, for example, can be reprogrammed with synthetic DNA to produce specific materials, like bioplastics. These materials can then be fed into 3-D printers to manufacture things the astronauts may need during spaceflight — everything from hardware and medical devices to medicine and food.
In an opinion piece published online in Trends in Biotechnology, researchers from the Universities Space Research Association (USRA), MIT Lincoln Laboratory, and NASA outline ways that synthetic biology and 3-D printing can support life during deep-space human missions. But to make these ideas a reality, NASA is seeking help.
"Our opinion piece is a call to action to get DIY [do-it-yourself] biology and makerspace communities involved," says Peter Carr, who works in Lincoln Laboratory's Bioengineering Systems and Technologies Group. The DIY biology community makes it possible for anyone in the public with an interest to conduct biological engineering. The community operates outside the traditional academic or industry settings and spreads knowledge through open sourcing. Many DIY biologist groups operate makerspaces that provide equipment and supplies for members to do experiments on their own.
"These separate, eclectic communities do bio in unconventional settings all the time and are pioneers at rapid prototyping and developing technologies with limited resources. There are parallels here with space and the needs of NASA crews," Carr says. "But this also requires organizations like ours and NASA to connect more deeply with them in a two-way process, so there's a real pathway to getting people's work into space. We're just getting started."
3-D printers are common staples of makerspaces. Experiments done on the ISS with 3-D printers have proven their utility for manufacturing on-demand items, like replacement hardware. But if 3-D printing is to be a reliable tool for long-duration missions in space, a new problem crops up: the need to supply the ship with the feedstock for the printers.
To meet this need, the authors envision using synthetic biology to produce custom biological "ink" to 3-D print whatever may be needed over the course of a mission. Such a process would give scientists "the autonomy to design for the unknown," says Jessica Snyder, a USRA researcher who leads the synthetic biology task for the NASA Academic Mission Services.
Living organisms can convert sunlight, nitrogen, and water into finished products. Bioengineers can reprogram the inner logic of these organisms' cells to produce target compounds. The building blocks to edit these cells can be digitized and sent to the space crew in the form of a DNA sequence, which can be synthesized, assembled, and inserted into an organism on ship. "The idea is what we call a 'bits-to-biology' converter," says David Walsh, a bioengineer at Lincoln Laboratory.
Here's one example of how this vision could be implemented: Say that astronauts faced a situation that occurred on the ISS in 2007 — a solar panel has torn and needs a repair strap. On Earth, synthetic biologists, whether of the DIY type or not, design and test genetic programs instructing bacteria to produce the polymer feedstock for 3-D printing. (This work could also take place well before the need arises during the space mission.) The maker community works out the design of a strap from those materials. These genetic instructions and 3-D printing instructions are sent digitally from Earth to the space crew. The crew reproduces the genetic program, and the bacteria reproduce and synthesize the raw materials, which are used to 3-D print the strap. At the end of the product's life cycle, the part is recovered and digested, and a new one can be made.
"We have the power of digital information. We can design and work out all of the kinks on Earth and simply send the instructions to space," Walsh says.
The same principles can be used to insert DNA into organisms in space to make target compounds for food or pharmaceuticals, which if brought directly from Earth would degrade over time from radiation in space.
Astronauts would be able to conduct these complex biology experiments by using 3-D-printed microfluidic devices. These tiny "lab-on-a-chip" devices automatically control the flow and mixture of fluids through microchannels and use only trace amounts of chemicals to run hundreds of bioreactions in parallel in seconds. Genetic instructions would be sent directly to electronics controlling these microfluidic devices, enabling them to precisely follow the digital "recipe" to synthetize molecules of DNA.
Earlier this year, Lynn Rothschild, a scientist at the NASA Ames Research Center who co-authored the opinion piece, led a team that ran the first synthetic biology experiments in space. The experiments aimed to test how well bacteria in space take in synthetic DNA inserted into their genome and how well the bacteria produce proteins, while being spun to simulate microgravity (what astronauts in the ISS encounter), lunar gravity, and Martian gravity levels. The experiments took place on the PowerCell payload aboard the German satellite mission Eu:CROPIS (Euglena and Combined Regenerative Organic-Food Production in Space).
There is still a long way to go, however, both in experimenting with synthetic biology and figuring out all of the parameters that would make 3-D printing with biomaterials possible in space. "For example, bacteria will need water and will take up space; they need the right environment to live; and they'll produce waste. We still need to put these ideas up against the real-world constraints," Carr says.
But there's urgency in developing the concepts now. If synthetic biology and 3-D printing techniques can be proven and practiced in time for missions close to Earth, from which supplies can still be sent relatively quickly, then they can be counted on for a long-term mission to Mars.
"Flexible manufacturing techniques provide an excellent complement to Earth-based supply chains for destinations days away, like the International Space Station and possible lunar infrastructure, for examples. Let's take advantage of this redundancy to build an in-space manufacturing capacity to take us further into space more safely," Snyder says. Do-it-yourself biologists and makers can help today by publishing their designs for 3-D-printed products, microfluidic devices, or synthetic DNA on open-source repositories and by testing and editing published designs. "If DIY bio communities use, iteratively improve, and ultimately approve of a technique, then that technique has been optimized more robustly than most individuals or team could offer without great effort. Partnering with these communities is an invaluable asset," Snyder adds. People who are interested can also see NASA's Centennial Challenges, which outline problems that NASA is seeking the public's help to solve.
"We often hear about the engineer who was inspired by NASA in their youth and works there now. But what about the bio people who are inspired by these grand ideas? How can they contribute? Now is a chance to transition their ideas to space," Carr says. "There is so much opportunity to innovate."
Although psychiatric disorders can be linked to particular genes, the brain regions and mechanisms underlying particular disorders are not well-understood. Mutations or deletions of the SHANK3 gene are strongly associated with autism spectrum disorder (ASD) and a related rare disorder called Phelan-McDermid syndrome. Mice with SHANK3 mutations also display some of the traits associated with autism, including avoidance of social interactions, but the brain regions responsible for this behavior have not been identified.
A new study by neuroscientists at MIT and colleagues in China provides clues to the neural circuits underlying social deficits associated with ASD. The paper, published in Nature Neuroscience, found that structural and functional impairments in the anterior cingulate cortex (ACC) of SHANK3 mutant mice are linked to altered social interactions.
“Neurobiological mechanisms of social deficits are very complex and involve many brain regions, even in a mouse model,” explains Guoping Feng, the James W. and Patricia T. Poitras Professor at MIT and one of the senior authors of the study. “These findings add another piece of the puzzle to mapping the neural circuits responsible for this social deficit in ASD models.”
The Nature Neuroscience paper is the result of a collaboration between Feng, who is also an investigator at MIT’s McGovern Institute and a senior scientist in the Broad Institute’s Stanley Center for Psychiatric Research, and Wenting Wang and Shengxi Wu at the Fourth Military Medical University, Xi’an, China.
A number of brain regions have been implicated in social interactions, including the prefrontal cortex (PFC) and its projections to brain regions including the nucleus accumbens and habenula, but these studies failed to definitively link the PFC to altered social interactions seen in SHANK3 knockout mice.
In the new study, the authors instead focused on the ACC, a brain region noted for its role in social functions in humans and animal models. The ACC is also known to play a role in fundamental cognitive processes, including cost-benefit calculation, motivation, and decision making.
In mice lacking SHANK3, the researchers found structural and functional disruptions at the synapses, or connections, between excitatory neurons in the ACC. The researchers went on to show that the loss of SHANK3 in excitatory ACC neurons alone was enough to disrupt communication between these neurons and led to unusually reduced activity of these neurons during behavioral tasks reflecting social interaction.
Having implicated these ACC neurons in social preferences and interactions in SHANK3 knockout mice, the authors then tested whether activating these same neurons could rescue these behaviors. Using optogenetics and specfic drugs, the researchers activated the ACC neurons and found improved social behavior in the SHANK3 mutant mice.
“Next, we are planning to explore brain regions downstream of the ACC that modulate social behavior in normal mice and models of autism,” explains Wenting Wang, co-corresponding author on the study. “This will help us to better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders.”
Previous clinical studies reported that anatomical structures in the ACC were altered and/or dysfunctional in people with ASD, an initial indication that the findings from SHANK3 mice may also hold true in these individuals.
The research was funded, in part, by the Natural Science Foundation of China. Guoping Feng was supported by NIMH grant no. MH097104, the Poitras Center for Psychiatric Disorders Research at the McGovern Institute at MIT, and the Hock E. Tan and K. Lisa Yang Center for Autism Research at the McGovern Institute at MIT.
When two protons collide, they release pyrotechnic jets of particles, the details of which can tell scientists something about the nature of physics and the fundamental forces that govern the universe.
Enormous particle accelerators such as the Large Hadron Collider can generate billions of such collisions per minute by smashing together beams of protons at close to the speed of light. Scientists then search through measurements of these collisions in hopes of unearthing weird, unpredictable behavior beyond the established playbook of physics known as the Standard Model.
Now MIT physicists have found a way to automate the search for strange and potentially new physics, with a technique that determines the degree of similarity between pairs of collision events. In this way, they can estimate the relationships among hundreds of thousands of collisions in a proton beam smashup, and create a geometric map of events according to their degree of similarity.
The researchers say their new technique is the first to relate multitudes of particle collisions to each other, similar to a social network.
“Maps of social networks are based on the degree of connectivity between people, and for example, how many neighbors you need before you get from one friend to another,” says Jesse Thaler, associate professor of physics at MIT. “It’s the same idea here.”
Thaler says this social networking of particle collisions can give researchers a sense of the more connected, and therefore more typical, events that occur when protons collide. They can also quickly spot the dissimilar events, on the outskirts of a collision network, which they can further investigate for potentially new physics. He and his collaborators, graduate students Patrick Komiske and Eric Metodiev, carried out the research at the MIT Center for Theoretical Physics and the MIT Laboratory for Nuclear Science. They detail their new technique this week in the journal Physical Review Letters.
Seeing the data agnostically
Thaler’s group focuses, in part, on developing techniques to analyze open data from the LHC and other particle collider facilities in hopes of digging up interesting physics that others might have initially missed.
“Having access to this public data has been wonderful,” Thaler says. “But it’s daunting to sift through this mountain of data to figure out what’s going on.”
Physicists normally look through collider data for specific patterns or energies of collisions that they believe to be of interest based on theoretical predictions. Such was the case for the discovery of the Higgs boson, the elusive elementary particle that was predicted by the Standard Model. The particle’s properties were theoretically outlined in detail but had not been observed until 2012, when physicists, knowing approximately what to look for, found signatures of the Higgs boson hidden amid trillions of proton collisions.
But what if particles exhibit behavior beyond what the Standard Model predicts, that physicists have no theory to anticipate?
Thaler, Komiske, and Metodiev have landed on a novel way to sift through collider data without knowing ahead of time what to look for. Rather than consider a single collision event at a time, they looked for ways to compare multiple events with each other, with the idea that perhaps by determining which events are more typical and which are less so, they might pick out outliers with potentially interesting, unexpected behavior.
“What we’re trying to do is to be agnostic about what we think is new physics or not,” says Metodiev. “We want to let the data speak for itself.”
Particle collider data are jam-packed with billions of proton collisions, each of which comprises individual sprays of particles. The team realized these sprays are essentially point clouds — collections of dots, similar to the point clouds that represent scenes and objects in computer vision. Researchers in that field have developed an arsenal of techniques to compare point clouds, for example to enable robots to accurately identify objects and obstacles in their environment.
Metodiev and Komiske utilized similar techniques to compare point clouds between pairs of collisions in particle collider data. In particular, they adapted an existing algorithm that is designed to calculate the optimal amount of energy, or “work” that is needed to transform one point cloud into another. The crux of the algorithm is based on an abstract idea known as the “earth’s mover’s distance.”
“You can imagine deposits of energy as being dirt, and you’re the earth mover who has to move that dirt from one place to another,” Thaler explains. “The amount of sweat that you expend getting from one configuration to another is the notion of distance that we’re calculating.”
In other words, the more energy it takes to rearrange one point cloud to resemble another, the farther apart they are in terms of their similarity. Applying this idea to particle collider data, the team was able to calculate the optimal energy it would take to transform a given point cloud into another, one pair at a time. For each pair, they assigned a number, based on the “distance,” or degree of similarity they calculated between the two. They then considered each point cloud as a single point and arranged these points in a social network of sorts.
Three particle collision events, in the form of jets, obtained from the CMS Open Data, form a triangle to represent an abstract "space of events." The animation depicts how one jet can be optimally rearranged into another.
The team has been able to construct a social network of 100,000 pairs of collision events, from open data provided by the LHC, using their technique. The researchers hope that by looking at collision datasets as networks, scientists may be able to quickly flag potentially interesting events at the edges of a given network.
“We’d like to have an Instagram page for all the craziest events, or point clouds, recorded by the LHC on a given day,” says Komiske. “This technique is an ideal way to determine that image. Because you just find the thing that’s farthest away from everything else.”
Typical collider datasets that are made publicly available normally include several million events, which have been preselected from an original chaos of billions of collisions that occurred at any given moment in a particle accelerator. Thaler says the team is working on ways to scale up their technique to construct larger networks, to potentially visualize the “shape,” or general relationships within an entire dataset of particle collisions.
In the near future, he envisions testing the technique on historical data that physicists now know contain milestone discoveries, such as the first detection in 1995 of the top quark, the most massive of all known elementary particles.
“The top quark is an object that gives rise to these funny, three-pronged sprays of radiation, which are very dissimilar from typical sprays of one or two prongs,” Thaler says. “If we could rediscover the top quark in this archival data, with this technique that doesn’t need to know what new physics it is looking for, it would be very exciting and could give us confidence in applying this to current datasets, to find more exotic objects.”
This research was funded, in part, by the U.S. Department of Energy, the Simons Foundation, and the MIT Quest for Intelligence.
The Media Lab has always been a place for students and researchers to work on building the future they want to live in. As such, many innovative companies have spun out of its multidisciplinary working spaces. Since 2013, however, the lab has taken a more deliberate approach to helping entrepreneurs create successful companies, with the E14 Fund.
The fund is designed to supercharge the Media Lab’s impact in the world by supporting the imaginative people that have walked its hallways. That support can come in the form of early-stage investments and fellowships that give students, alumni, and researchers a “runway” to turn their ideas into businesses. But E14 — named after the location of the Media Lab building — is much more than an investment fund.
“Even though the E14 Fund has the word ‘fund’ at the end of it, first and foremost we’re a community-builder,” Managing Partner Habib Haddad says. “When you put that first, you actually become a stronger venture fund by being an authentic community supporter.”
Haddad, fellow Managing Partner Calvin Chin, and their team of venture partners and advisors believe their efforts help turn the innovative ideas of the Media Lab’s community into companies that benefit society.
“I helped launch [E14] because I felt it addressed an important need in offering a runway to graduating students who wanted to deploy their research through a new company, and it's been successful at doing that,” Media Lab Director Joi Ito says. “But it's also become a really good community and a networking hub for Media Lab students, researchers, and alumni — not just ones working on building a company.”
A bold founding mission
The Media Lab is known for fostering a culture that blends future-focused research with current problems to inspire creative solutions. The lab’s community has also developed a reputation for pursuing bold, new ideas at rapid — some might say entrepreneurial — speed.
Throughout 2013, Ito was looking for a way to help students continue following the Media Lab’s “deploy” mantra after graduation. Ito believed a venture fund, if structured correctly, could increase the Media Lab’s impact on the world while also furthering its academic mission, by helping students focus on their coursework without worrying about losing support when they graduate.
In keeping with the lab’s experimental ethos, E14 began as what Haddad calls a “prototype fund” of $2 million in 2013. The money was used to provide both equity and nonequity funding and mentoring to recent graduates in the early stages of starting companies. Some of the carried interest from the fund would be donated back to MIT to support more research at the Media Lab (a practice that carries on today).
A handful of the earliest investments went on to raise much larger funding rounds and find commercial success, including the manufacturing app platform Tulip, robotic furniture company Ori, and urban technology company Soofa. With an eye toward building a community, E14 also provided slightly later-stage funding to Media Lab spinouts Formlabs and Affectiva.
Even as the early investments had success, it became clear the Media Lab would benefit from an even more involved investment team. E14’s next fund, launched at the end of 2017, raised $37 million.
“As that prototype fund was evolving, it turned out some of these companies needed much more capital and support,” Haddad recalls. “We said, ‘These are all great companies, but for each one, there’s a few others that could have been great spinoffs that didn’t have the right funding or support.’”
Since then, the E14 Fund has been advising everyone from Media Lab alumni starting their fourth company to current students nearing graduation. It’s also helped the lab’s member companies connect with researchers and created a more active community overall.
A pillar in the community
Today the E14 team regularly hosts events and gatherings for members of the Media Lab. The lab’s semiannual member week now includes a startup showcase, and alumni are becoming a more common sight in the hallways.
E14 also works with the other entrepreneurial resources on campus, giving students advice on what programs are worth exploring depending on what stage their idea is in.
The E14’s average funding is between $500,000 and $1 million, while its fellowship program offers a lower-risk way of pursuing the commercialization of an idea. Some of E14’s latest investments include ThruWave, a company using millimeter wave sensors to see through packaging; Figur8, which has developed a system that captures three-dimensional skeletal movement and muscle output; Wise Systems, which uses fleet dispatch and routing software to optimize deliveries; Canopy, which uses machine learning to preserve privacy on the internet; and Kiwi, which offers a robotic cropdusting system for distributing chemicals and seeds on precise plots of land.
By investing exclusively in Media Lab founders with a new technology, the E14 team spends far more time with founders — sometimes years, as students work toward graduation or alumni consider starting companies — compared to traditional investment funds, and helps researchers and scientists develop a more entrepreneurial mindset over time.
“We like to say we don’t have all the answers, but we ask a lot of questions,” Chin says. “It’s really just brainstorming and thinking about the kind of company they’re going to build, the way they’re going to build it, and the market they’re going to address. A lot of times in that process we’ll be making introductions. We’re trying to add value even if we’re not invested.”
In fact, beyond making investments, the E14 Fund bears little resemblance to other venture capital funds, in which partners typically guard their time like gold and focus on narrow areas of industries. The members of E14, conversely, say their areas of investment are entirely dependent on the interests of members of the Media Lab.
“Our model is serving the community, and then finding companies as a subset of that community,” Chin says. “We just always want to be listening to the community. If the community’s research interests or business interests go a certain way, we want to be there with the resources the community needs. That’s what we’re excited about going forward.”
As embryos develop, they follow predetermined patterns of tissue folding, so that individuals of the same species end up with nearly identically shaped organs and very similar body shapes.
MIT scientists have now discovered a key feature of embryonic tissue that helps explain how this process is carried out so faithfully each time. In a study of fruit flies, they found that the reproducibility of tissue folding is generated by a network of proteins that connect like a fishing net, creating many alternative pathways that tissues can use to fold the right way.
“What we found is that there’s a lot of redundancy in the network,” says Adam Martin, an MIT associate professor of biology and the senior author of the study. “The cells are interacting and connecting with each other mechanically, but you don’t see individual cells taking on an all-important role. This means that if one cell gets damaged, other cells can still connect to disparate parts of the tissue.”
To uncover these network features, Martin worked with Jörn Dunkel, an MIT associate professor of physical applied mathematics and an author of the paper, to apply an algorithm normally used by astronomers to study the structure of galaxies.
Hannah Yevick, an MIT postdoc, is the lead author of the study, which appears today in Developmental Cell. Graduate student Pearson Miller is also an author of the paper.
A safety net
During embryonic development, tissues change their shape through a process known as morphogenesis. One important way tissues change shape is to fold, which allows flat sheets of embryonic cells to become tubes and other important shapes for organs and other body parts. Previous studies in fruit flies have shown that even when some of these embryonic cells are damaged, sheets can still fold into their correct shapes.
“This is a process that’s fairly reproducible, and so we wanted to know what makes it so robust,” Martin says.
In this study, the researchers focused on the process of gastrulation, during which the embryo is reorganized from a single-layered sphere to a more complex structure with multiple layers. This process, and other morphogenetic processes similar to fruit fly tissue folding, also occur in human embryos. The embryonic cells involved in gastrulation contain in their cytoplasm proteins called myosin and actin, which form cables and connect at junctions between cells to form a network across the tissue. Martin and Yevick had hypothesized that the network of cell connectivity might play a role in the robustness of the tissue folding, but until now, there was no good way to trace the connections of the network.
To achieve that, Martin’s lab joined forces with Dunkel, who studies the physics of soft surfaces and flowing matter — for example, wrinkle formation and patterns of bacterial streaming. For this study, Dunkel had the idea to apply a mathematical procedure that can identify topological features of a three-dimensional structure, analogous to ridges and valleys in a landscape. Astronomers use this algorithm to identify galaxies, and in this case, the researchers used it to trace the actomyosin networks across and between the cells in a sheet of tissue.
“Once you have the network, you can apply standard methods from network analysis — the same kind of analysis that you would apply to streets or other transport networks, or the blood circulation network, or any other form of network,” Dunkel says.
Among other things, this kind of analysis can reveal the structure of the network and how efficiently information flows along it. One important question is how well a network adapts if part of it gets damaged or blocked. The MIT team found that the actomyosin network contains a great deal of redundancy — that is, most of the “nodes” of the network are connected to many other nodes.
This built-in redundancy is analogous to a good public transit system, where if one bus or train line goes down, you can still get to your destination. Because cells can generate mechanical tension along many different pathways, they can fold the right way even if many of the cells in the network are damaged.
“If you and I are holding a single rope, and then we cut it in the middle, it would come apart. But if you have a net, and cut it in some places, it still stays globally connected and can transmit forces, as long as you don’t cut all of it,” Dunkel says.
The researchers also found that the connections between cells preferentially organize themselves to run in the same direction as the furrow that forms in the early stages of folding.
“We think this is setting up a frame around which the tissue will adopt its shape,” Martin says. “If you prevent the directionality of the connections, then what happens is you can still get folding but it will fold along the wrong axis.”
Although this study was done in fruit flies, similar folding occurs in vertebrates (including humans) during the formation of the neural tube, which is the precursor to the brain and spinal cord. Martin now plans to apply the techniques he used in fruit flies to see if the actomyosin network is organized the same way in the neural tube of mice. Defects in the closure of the neural tube can lead to birth defects such as spina bifida.
“We would like to understand how it goes wrong,” Martin says. “It’s still not clear whether it’s the sealing up of the tube that’s problematic or whether there are defects in the folding process.”
The research was funded by the National Institute of General Medical Sciences and the James S. McDonnell Foundation.
Years before he set foot on the MIT campus, Kieran P. Dolan participated in studies conducted at MIT's Nuclear Reactor Laboratory (NRL). As an undergraduate student majoring in nuclear engineering at the University of Wisconsin at Madison, Dolan worked on components and sensors for MIT Reactor (MITR)-based experiments integral to designing fluoride-salt-cooled high-temperature nuclear reactors, known as FHRs.
Today, as a second-year doctoral student in MIT's Department of Nuclear Science and Engineering, Dolan is a hands-on investigator at the NRL, deepening his research engagement with this type of next-generation reactor.
"I've been interested in advanced reactors for a long time, so it's been really nice to stay with this project and learn from people working here on-site," says Dolan.
This series of studies on FHRs is part of a multiyear collaboration among MIT, the University of Wisconsin at Madison, and the University of California at Berkeley, funded by an Integrated Research Project (IRP) Grant from the U.S. Department of Energy (DOE). The nuclear energy community sees great promise in the FHR concept because molten salt transfers heat very efficiently, enabling such advanced reactors to run at higher temperatures and with several unique safety features compared to the current fleet of water-cooled commercial reactors.
"Molten salt reactors offer an approach to nuclear energy that is both economically viable and safe," says Dolan.
For the purposes of the FHR project, the MITR reactor simulates the likely operating environment of a working advanced reactor, complete with high temperatures in the experimental capsules. The FHR concept Dolan has been testing envisions billiard-ball-sized composites of fuel particles suspended within a circulating flow of molten salt — a special blend of lithium fluoride and beryllium fluoride called flibe. This salt river constantly absorbs and distributes the heat produced by the fuel's fission reactions.
But there is a formidable technical challenge to the salt coolants used in FHRs. "The salt reacts with the neutrons released during fission, and produces tritium," explains Dolan. "Tritium is one of hydrogen’s isotopes, which are notorious for permeating metal." Tritium is a potential hazard if it gets into water or air. "The worry is that tritium might escape as a gas through an FHR's heat exchanger or other metal components."
There is a potential workaround to this problem: graphite, which can trap fission products and suck up tritium before it escapes the confines of a reactor. "While people have determined that graphite can absorb a significant quantity of hydrogen, no one knows with certainty where the tritium is going to end up in the reactor,” says Dolan. So, he is focusing his doctoral research on MITR experiments to determine how effectively graphite performs as a sponge for tritium — a critical element required to model tritium transport in the complete reactor system.
"We want to predict where the tritium goes and find the best solution for containing it and extracting it safely, so we can achieve optimal performance in flibe-based reactors," he says.
While it's early, Dolan has been analyzing the results of three MITR experiments subjecting various types of specialized graphite samples to neutron irradiation in the presence of molten salt. "Our measurements so far indicate a significant amount of tritium retention by graphite," he says. "We're in the right ballpark."
Dolan never expected to be immersed in the electrochemistry of salts, but it quickly became central to his research portfolio. Enthused by math and physics during high school in Brookfield, Wisconsin, he swiftly oriented toward nuclear engineering in college. "I liked the idea of making useful devices, and I was especially interested in nuclear physics with practical applications, such as power plants and energy," he says.
At UW Madison, he earned a spot in an engineering physics material research group engaged in the FHR project, and he assisted in purifying flibe coolants, designing and constructing probes for measuring salt's corrosive effect on reactor parts, and experimenting on the electrochemical properties of molten fluoride salts. Working with Exelon Generation as a reactor engineer after college convinced him he was more suited for research in next-generation projects than in the day-to-day maintenance and operation of a commercial nuclear plant.
"I was interested in innovation and improving things," he says. "I liked being part of the FHR IRP, and while I didn't have a passion for electrochemistry, I knew it would be fun working on a solution that could advance a new type of reactor."
Familiar with the goals of the FHR project, MIT facilities, and personnel, Dolan was able to jump rapidly into studies analyzing MITR's irradiated graphite samples. Under the supervision of Lin-wen Hu, his advisor and NRL research director, as well as MITR engineers David Carpenter and Gordon Kohse, Dolan came up to speed in reactor protocol. He's found on-site participation in experiments thrilling.
"Standing at the top of the reactor as it starts and the salt heats up, anticipating when the tritium comes out, manipulating the system to look at different areas, and then watching the measurements come in — being involved with that is really interesting in a hands-on way," he says.
For the immediate future, "the main focus is getting data," says Dolan. But eventually "the data will predict what happens to tritium in different conditions, which should be the main driving force determining what to do in actual commercial FHR reactor designs."
For Dolan, contributing to this next phase of advanced reactor development would prove the ideal next step following his doctoral work. This past summer, Dolan interned at Kairos Power, a nuclear startup company formed by the UC Berkeley collaborators on two DOE-funded FHR IRPs. Kairos Power continues to develop FHR technology by leveraging major strategic investments that the DOE has made at universities and national laboratories, and has recently started collaborating with MIT.
"I've built up a lot of experience in FHRs so far, and there's a lot of interest at MIT and beyond in reactors using molten salt concepts," he says. "I will be happy to apply what I've learned to help accelerate a new generation of safe and efficient reactors."
For patients with kidney failure who need dialysis, removing fluid at the correct rate and stopping at the right time is critical. This typically requires guessing how much water to remove and carefully monitoring the patient for sudden drops in blood pressure.
Currently there is no reliable, easy way to measure hydration levels in these patients, who number around half a million in the United States. However, researchers from MIT and Massachusetts General Hospital have now developed a portable sensor that can accurately measure patients’ hydration levels using a technique known as nuclear magnetic resonance (NMR) relaxometry.
Such a device could be useful for not only dialysis patients but also people with congestive heart failure, as well as athletes and elderly people who may be in danger of becoming dehydrated, says Michael Cima, the David H. Koch Professor of Engineering in MIT’s Department of Materials Science and Engineering.
“There’s a tremendous need across many different patient populations to know whether they have too much water or too little water,” says Cima, who is the senior author of the study and a member of MIT’s Koch Institute for Integrative Cancer Research. “This is a way we could measure directly, in every patient, how close they are to a normal hydration state.”
The portable device is based on the same technology as magnetic resonance imaging (MRI) scanners but can obtain measurements at a fraction of the cost of MRI, and in much less time, because there is no imaging involved.
Lina Colucci, a former graduate student in health sciences and technology, is the lead author of the paper, which appears in the July 24 issue of Science Translational Medicine. Other authors of the paper include MIT graduate student Matthew Li; MGH nephrologists Kristin Corapi, Andrew Allegretti, and Herbert Lin; MGH research fellow Xavier Vela Parada; MGH Chief of Medicine Dennis Ausiello; and Harvard Medical School assistant professor in radiology Matthew Rosen.
Cima began working on this project about 10 years ago, after realizing that there was a critical need for an accurate, noninvasive way to measure hydration. Currently, the available methods are either invasive, subjective, or unreliable. Doctors most frequently assess overload (hypervolemia) by a few physical signs such as examining the size of the jugular vein, pressing on the skin, or examining the ankles where water might pool.
The MIT team decided to try a different approach, based on NMR. Cima had previously launched a company called T2 Biosystems that uses small NMR devices to diagnose bacterial infections by analyzing patient blood samples. One day, he had the idea to use the devices to try to measure water content in tissue, and a few years ago, the researchers got a grant from the MIT-MGH Strategic Partnership to do a small clinical trial for monitoring hydration. They studied both healthy controls and patients with end-stage renal disease who regularly underwent dialysis.
One of the main goals of dialysis is to remove fluid in order bring patients to their “dry weight,” which is the weight at which their fluid levels are optimized. Determining a patient’s dry weight is extremely challenging, however. Doctors currently estimate dry weight based on physical signs as well as through trial-and-error over multiple dialysis sessions.
The MIT/MGH team showed that quantitative NMR, which works by measuring a property of hydrogen atoms called T2 relaxation time, can provide much more accurate measurements. The T2 signal measures both the environment and quantity of hydrogen atoms (or water molecules) present.
“The beauty of magnetic resonance compared to other modalities for assessing hydration is that the magnetic resonance signal comes exclusively from hydrogen atoms. And most of the hydrogen atoms in the human body are found in water molecules,” Colucci says.
The researchers used their device to measure fluid volume in patients before and after they underwent dialysis. The results showed that this technique could distinguish healthy patients from those needing dialysis with just the first measurement. In addition, the measurement correctly showed dialysis patients moving closer to a normal hydration state over the course of their treatment.
Furthermore, the NMR measurements were able to detect the presence of excess fluid in the body before traditional clinical signs — such as visible fluid accumulation below the skin — were present. The sensor could be used by physicians to determine when a patient has reached their true dry weight, and this determination could be personalized at each dialysis treatment.
The researchers are now planning additional clinical trials with dialysis patients. They expect that dialysis, which currently costs the United States more than $40 billion per year, would be one of the biggest applications for this technology. This kind of monitoring could also be useful for patients with congestive heart failure, which affects about 5 million people in the United States.
“The water retention issues of congestive heart failure patients are very significant,” Cima says. “Our sensor may offer the possibility of a direct measure of how close they are to a normal fluid state. This is important because identifying fluid accumulation early has been shown to reduce hospitalization, but right now there are no ways to quantify low-level fluid accumulation in the body. Our technology could potentially be used at home as a way for the care team to get that early warning.”
Sahir Kalim, a nephrologist and assistant professor of medicine at Massachusetts General Hospital, described the MIT approach as “highly novel.”
“The development of a bedside device that can accurately inform providers about how much fluid a patient should ideally have removed during their dialysis treatment would likely be one of the most significant developments in dialysis care in many years,” says Kalim, who was not involved in the study. “Colucci and colleagues have made a promising innovation that may one day yield this impact.”
In their study of the healthy control subjects, the researchers also incidentally discovered that they could detect dehydration. This could make the device useful for monitoring elderly people, who often become dehydrated because their sense of thirst lessens with age, or athletes taking part in marathons or other endurance events. The researchers are planning future clinical trials to test the potential of their technology to detect dehydration.
The research was funded by the MGH-MIT Strategic Partnership Grand Challenge, the Air Force Medical Services/Institute of Soldier Nanotechnologies, the National Science Foundation Graduate Research Fellowships Program, the National Institute of Biomedical Imaging and Bioengineering, the Koch Institute Support (core) Grant from the National Cancer Institute, and Harvard University.
Following their graduation in 2016, two dual-degree students from the MIT Center for Real Estate (CRE) and the Department of Architecture — Kun Qian MSRED '16, MArch ’16 and Marwan Aboudib MSRED '16, MArch ’16 — asked Professor Dennis Frenchman if he would join with their firm, Tekuma, to create an international design practice.
“They came to me and said, ‘Look, we have this project opportunity in Jinan, [China],’” says Frenchman, the Class of ’22 Professor of Urban Design and Planning and now CRE director. “Would you like to join us?”
Frenchman said yes. The resulting urban design and innovation studio, Tekuma Frenchman, practices worldwide, applying Frenchman’s research at MIT to many scales of intervention — from planning cities for millions in China to art and cultural installations in the Middle East and Boston, Massachusetts. In addition to Qian, Aboudib, and Frenchman, the partnership includes urban designer Naomi Hebert and a staff of 10 working in Cambridge, Massachusetts; Dubai; and Beijing.
The firm’s projects include design of Seoul Digital Media City in South Korea; the Digital Mile in Zaragoza, Spain; Ciudad Creativa Digital, Guadalajara, Mexico; Media City: UK in England; Twofour54 in Abu Dhabi; Jinan North New District and Chanqing University City in China; and, more recently, projects in cities across the Middle East.
In 2018, Tekuma Frenchman won the Shenzhen New Marine City International Design Competition in China. Their design, titled “Ocean Edge,” will be home to 50,000 people on 5.5 square kilometers of reclaimed land.
The competition was part of China’s 13th Five-Year Plan for the Development of the National Marine Economy, which aims to advance manufacturing industry along China’s southern coast.
Shenzhen is a city of more than 12 million in the Guangdong province of southern China, where Hong Kong links to China’s mainland. Shenzhen was the first special economic zone in China that encouraged outside investment and is the home to high-tech industries in computer science, robotics, artificial intelligence, and data storage.
The urban design competition for Shenzhen New Marine City received over 140 design submissions from international firms. A jury of nine design professionals and senior academics selected Tekuma Frenchman’s proposal. The organizers wanted a scheme that would be both innovative and operable, and become a world-class demonstration site for the future of marine economy and sustainability.
Frenchman’s winning scheme integrates marine ecology, marine industry, marine culture, and coastal landscape, providing the design framework for a visionary development. Land reclamation for Ocean Edge has already begun, and key aspects of the development will be in place by 2022. It is expected that the project will take about 20 years to complete.
Piers and mangroves as a solution
The waterfront site poses many challenges. To minimize the use of fill and disruption of water flow, Tekuma Frenchman decided to put parts of the city on piers, islands, and autonomous floating structures.
A 1-kilometer central entertainment pier will connect Shenzhen’s convention center with the ocean and anchor recreation areas along the waterfront. This pier and boardwalk area includes a ferry terminal, port offices, deep-sea aquarium, theater, cinemas, clubs, water sports, seafood restaurants, and specialty retail shops.
Tekuma Frenchman’s design will regenerate an indigenous mangrove forest to protect the shoreline from waves, retain soil, support biodiversity, and help clean the water. The design also provides a habitat for fish. The growth of the forest will be monitored by sensors controlling the mix of freshwater runoff with salt water, ensuring an ideal habitat for optimum growth of marine fauna and flora. In this way, Ocean Edge both senses and responds to the natural environment.
Sea-level rise and storm surge from the South China Sea is a concern in Shenzhen. Ocean Edge helps prevent flooding by using the regenerated mangrove forest as a natural protection from storm surge. “There’s a sustainable matrix into which this contemporary city is built,” Frenchman says.
Promoting ocean industry
The heartbeat of the city is a new industry cluster dedicated to deep-sea exploration and resource extraction, using autonomous undersea vehicles.
Robotic vehicles will be researched, developed, and deployed from Ocean Edge to, for example, scavenge manganese nodules from the ocean floor or to manage fish and agricultural production. A spine of development, accessible directly to the water, will house private labs, academic research institutions, and public agencies devoted to understanding and exploiting the resources of the South China Sea.
Production and manufacturing for this industry cluster are woven in with housing and entertainment.
“Most of the new cities out there are built as places to consume — shopping, eating, culture,” Frenchman says. “What’s interesting about the Ocean Edge design in Shenzhen is its focus on making a productive city with emerging 21st century industries and lifestyles at its heart. Ocean Edge will become a key link in the chain of manufacturing cities which make up the Guangzhou-Shenzhen Innovation Corridor.”
“Over the years we have been researching and implementing a new methodology to design cities that celebrate production, making places that are human-centric and productive,” says Kun Qian. “We believe that the future is moving toward a productive urbanism, where companies from all economic sectors also participate in the shaping of our public realm and creating unique experiences for people. The Ocean Edge proposal is a great testimony to this approach.”
“What differentiates our firm is that our work goes beyond design,” says partner Marwan Aboudib. “The key is our integration of design with real estate economics and technology. Our understanding and ability to bring those domains together enables us to create more vibrant cities in which people can excel. We make it possible for cities to thrive, which creates stronger returns for businesses and residents.”
For a video of Tekuma Frenchman’s winning design, see Vimeo.
MIT professors David Sontag and Peter Szolovits don’t assign a textbook for their class, 6.S897HST.956 (Machine Learning for Healthcare), because there isn’t one. Instead, students read scientific papers, solve problem sets based on current topics like opioid addiction and infant mortality, and meet the doctors and engineers paving the way for a more data-driven approach to health care. Jointly offered by MIT’s Department of Electrical Engineering and Computer Science (EECS) and the Harvard-MIT program in Health Sciences Technology, the class is one of just a handful offered across the country.
“Because it’s a new field, what we teach will help shape how AI is used to diagnose and treat patients,” says Irene Chen, an EECS graduate student who helped design and teach the course. “We tried to give students the freedom to be creative and explore the many ways machine learning is being applied to health care.”
Two-thirds of the syllabus this spring was new. Students were introduced to the latest machine-learning algorithms for analyzing doctors’ clinical notes, patient medical scans, and electronic health records, among other data. Students also explored the risks of using automated methods to explore large, often messy observational datasets, from confusing correlation with causation to understanding how AI models can make bad decisions based on biased data or faulty assumptions.
With all of the hype around AI, the course had more takers than seats. After 100 students showed up on the first day, students were assigned a quiz to test their knowledge of statistics and other prerequisites. That helped whittle the class down to 70. Michiel Bakker, a graduate student at the MIT Media Lab, made the cut and says the course gave him medical concepts that most engineering courses don’t provide.
“In machine learning, the data are either images or text,” he says. “Here we learned the importance of combining genetic data with medical images with electronic health records. To use machine learning in health care you have to understand the problems, how to combine techniques and anticipate where things could go wrong.”
Most lectures and homework problems focused on real world scenarios, drawing from MIT’s MIMIC critical care database and a subset of the IBM MarketScan Research Databases focused on insurance claims. The course also featured regular guest lectures by Boston-area clinicians. In a reversal of roles, students held office hours for doctors interested in integrating AI into their practice.
“There are so many people in academia working on machine learning, and so many doctors at hospitals in Boston,” says Willie Boag, an EECS graduate student who helped design and teach the course. “There’s so much opportunity in fostering conversation between these groups.”
In health care, as in other fields where AI has made inroads, regulators are discussing what rules should be put in place to protect the public. The U.S. Federal Drug Administration recently released a draft framework for regulating AI products, which students got to review and comment on, in class and in feedback published online in the Federal Register.
Andy Coravos, a former entrepreneur in residence at the FDA, now CEO of ElektraLabs in Boston, helped lead the discussion and was impressed by the quality of the comments. “Many students identified test cases relevant to the current white paper, and used those examples to draft public comments for what to keep, add, and change in future iterations,” she says.
The course culminated in a final project in which teams of students used the MIMIC and IBM datasets to explore a timely question in the field. One team analyzed insurance claims to explore regional variation in screening patients for early-stage kidney disease. Many patients with hypertension and diabetes are never tested for chronic kidney disease, even though both conditions put them at high risk. The students found that they could predict fairly well who would be screened, and that screening rates diverged most between the southern and northeastern United States.
“If this work were to continue, the next step would be to share the results with a doctor and get their perspective,” says team member Matt Groh, a PhD student at the MIT Media Lab. “You need that cross-disciplinary feedback.”
The MIT-IBM Watson AI Lab took the trouble of making the anonymized data available and providing cloud computing support to students on the IBM cloud out of an interest in helping to educate the next generation of scientists and engineers, says Kush Varshney, principal research staff member and manager at IBM Research. “Health care is messy and complex, which is why there are no substitutes for working with real-world data,” he says.
Szolovits agrees. Using synthetic data would have been easier but far less meaningful. “It’s important for students to grapple with the complexities of real data,” he says. “Any researcher developing automated techniques and tools to improve patient care needs to be sensitive to its many nuances.”
In a recent recap on Twitter, Chen gave shout-outs to the students, guest lecturers, professors, and her fellow teaching assistant. She also reflected on the joys of teaching. “Research is rewarding and often fun, but helping someone see your field with fresh eyes is insanely cool.”
Marine protected areas are large swaths of coastal seas or open ocean that are protected by governments from activities such as commercial fishing and mining. Such marine sanctuaries have had rehabilitating effects on at-risk species living within their borders. But it’s been less clear how they benefit highly migratory species such as tuna.
Now researchers at MIT and the Woods Hole Oceanographic Institution have found evidence that tuna are spawning in the Phoenix Islands Protected Area (PIPA), one of the largest marine protected areas in the world, covering an area of the central Pacific as large as Argentina.
The researchers observed multiple species of tuna larvae throughout this protected expanse, suggesting that several migratory species are using these protected waters as a reproductive stopover, over several consecutive years, and even during a particularly strong El Niño season, where PIPA may have provided a critical refuge.
The results, published this week in the journal Scientific Reports, suggest that marine protected areas may be ocean oases for migratory fish, with plentiful nutrients and clean, clear waters that encourage tuna and other migratory species to linger, and spawn often. The study supports the notion that marine protected areas can provide protection to adult fish during spawning, and in this way, help to bolster fish populations — particularly those that, outside protected areas, are in danger of overfishing.
“We have proven that tuna are spawning in this protected area, and that it’s worth protecting,” says Christina Hernández, a graduate student in MIT’s Department of Earth, Atmospheric, and Planetary Sciences. “There are various types of protection for marine areas around the world, and all those measures allow us to preserve populations better, and in some cases protect highly migratory species.”
Sea change in conservation
The Phoenix Islands Protected Area is part of the territorial waters of the Republic of Kiribati (pronounced Keer-ee-bahs), a sovereign state in Micronesia made up of three island chains in the central Pacific. The islands, if stitched together, would amount to no more than the land area of Cape Cod. However, Kiribati’s ocean territory is vast, extending 200 nautical miles from each of its 32 atolls. The people of Kiribati rely heavily on revenue from tuna licenses that they mete out to commercial fishers. In 2008, however, the republic designated 11 percent of its waters as a mixed-use marine protected area, with limited fishing. Officials ultimately banned all fishing activities in the region starting in 2015, in a conservation effort that — among other things — protected many endangered species, such as giant clams and coconut crab, along with birds, mammals, and sea turtles living within its boundaries.
While fishing vessels have respected the protected territory, keeping their activities outside PIPA’s boundaries, legal fishing efforts surrounding PIPA caused the researchers to wonder whether PIPA might eventually provide an economic gain in the form of “spillover effects.” In other words, if an ecological region is preserved over long periods of time, it might produce more fish that, once full-grown, might cross the territory’s boundaries, benefiting both Kiribati and the regional fishing community.
Hernández’ colleague, Randi Rotjan of Boston University, had been working with the Republic of Kiribati on ways to scientifically monitor PIPA, and wanted to assess whether the protected region might also serve as protected spawning grounds for migratory tuna.
In 2014, the team began yearly expeditions to the central Pacific, to sample within PIPA for tuna larvae, fish younger than 4 weeks old, that would suggest recent spawning activity in the region. The researchers embarked on a 140-foot-long student sailing vessel, owned and operated by Sea Education Association, which also collaborated on this study. Sailing from Hawaii, the ship reached the edges of PIPA after about a 10-day journey. Once within the protected area, the team began sampling the waters for tiny fish, using three different nets, each designed to collect at 100 meters, 50 meters, and skimming the surface.
The team pulled up nets teeming with ocean plankton, including tuna larvae, along with tiny crustaceans, jellyfish, pelagic worms, and anchovies, all of which they preserved and transported back to Massachusetts, where they carried out analyses to extract and identify the number and type of tuna larvae amid the rest of the catch.
From 2015 to 2017, the three years included in the current paper, the researchers analyzed samples from over 175 net tows, and identified more than 600 tuna larvae, covering a distance within PIPA of more than 650 nautical miles, or 1,200 kilometers. Compared with a handful of previous studies on tuna larvae populations, Hernández says the number and density of larvae they found is “pretty on track for what we expect for this part of the Pacific.”
“Larval populations can’t really control how they move, and they get mixed around by ocean currents and dispersed away from each other,” Hernández explains. “As they continue to grow, they start to school and are in denser aggregations. But as larvae, they live at low densities.”
The tuna larvae appeared in about similar abundances over all three years, and even in 2015, when a strong El Niño season dramatically altered ocean conditions.
“That’s something that’s relatively good news, that the protected area seems to be pretty good habitat across environmental conditions,” Hernández says.
The team identified tuna larvae in their samples as species of skipjack, big-eye, and yellowfin.
“These particular fish are not so picky about where they spawn, and they can spawn every two to three days, for a couple of months,” Hernández says. “If they’re thinking the food is pretty good in PIPA, they may stay inside its boundaries for a few weeks, and might have additional spawning events that they wouldn’t have if they were outside the protected area, where they could get caught before they spawn.”
The results are the first evidence that highly migratory species spawn in marine protected areas. But whether such regions encourage species to reproduce more than in other, unprotected waters will require studies over a longer period of time.
“We have to protect these areas long enough to figure out if they are causing an increase in tuna populations,” Hernández says. “The amount of information we have about the Pacific tuna is paltry. And it’s critically important that we study the early life stages of fishes, and that we monitor protected areas, and populations of tuna, as the ocean changes.”
This work was supported in part by the PIPA Trust, Sea Education Association, the Prince Albert of Monaco Foundation II, New England Aquarium, and Boston University.
One of Babak Manouchehrifar’s favorite places in Cambridge, Massachusetts, is a city block on Prospect Street that hosts residences, a mosque, a synagogue, and a church. This is unsurprising considering that the fourth-year PhD candidate’s research centers around the relationships between urban planning, secularism, and religion.
“I’m interested in the peaceful coexistence of communities with differing views on religion and secularism through urban planning initiatives,” says Manouchehrifar, who left his home country of Iran to study at MIT’s Department of Urban Studies and Planning (DUSP). “This interest comes from my professional as well as social experiences, before and after coming to the U.S. To me, this is part of what MIT calls ‘building a better world.’”
According to Manouchehrifar, planners deal with various aspects of religion and secularism in their daily practices considerably more often than they do in their academic training. On the job, planners work with communities of differing viewpoints, such as when a host community opposes certain secular proposals or practices of different faith groups, or when a group of citizens requests religious exemption from zoning laws.
At the same time, these planners must work within the legal and political structures that authorize their work, such as the Religious Land Use and Institutionalized Person Act of 2000, which bars planners from burdening a person’s free exercise of religion.
“My research aims to spur further discussion on what I see as a practical dilemma, namely, how should planners deal with religious differences when their professional code of conduct calls for a particularly ‘indifferent’ approach,” Manouchehrifar says.
In his research, including a paper recently published in the journal “Planning Theory and Practice,” which was selected as one of the five best papers published in the field of planning in 2018, Manouchehrifar critiques the conventional view that there is a clear, simple distinction between religion and secularism in the practice of urban planning.
“My goal is to transcend the secular-religious dichotomy through the planning perspective. I aim to show that these two categories are in fact inextricably linked and deeply entangled in planning practice; they depend on each other for meaning,” he says.
Early constraints and the passion for a better world
Through his work, Manouchehrifar hopes to promote a better understanding of the religious differences of global communities away from the adversarial rhetoric of war or conflict. This hope is rooted in his childhood experiences.
Born in Iran at the brink of the Iranian Revolution and right before the Iran-Iraq War, Manouchehrifar’s childhood took place in a world in conflict. He recalls thinking war was normal because he didn’t have another frame of reference with which to compare his environment. But he and his family did imagine a different world, one in which he would run outdoors to soccer fields instead of bomb shelters.
“It was quite a difficult time, but I was part of a lucky generation because when I became a teenager, things began to be more stable,” he recalls. The war ended when Manouchehrifar was almost 10, but his wartime experience sparked his passion for contributing to a more peaceful world.
Before coming to MIT, Manouchehrifar received a bachelor’s degree in civil engineering and surveying from Isfahan University and a master’s degree in urban and regional planning from Shahid Beheshti University (SBU), both in Iran. His first job after college was as a surveying engineer in Isfahan, where he worked on a highway project that was cutting through a low-income neighborhood.
He was presented with an ethical dilemma when he was told that homes would have to be demolished and their residents be displaced in order to clear the way for the construction of the highway. When he brought his concerns to his project manager, he was told that it wasn’t his job as an engineer to worry about the social impact of the work. This led Manouchehrifar to quit his job and pursue a career in urban planning, believing that it would allow him more knowledge and power to consider the social impacts of urban projects.
After working as a planner and teaching at SBU for seven years, Manouchehrifar and his wife, Pegah, moved to Cambridge in 2013 so he could pursue a master’s degree in urban planning and international development at MIT. He completed the program in 2015 (their daughter, Danna, was also born at MIT at this time) and has since been working on his PhD. Studying in the U.S., and at the Institute in particular, has been a highly positive experience for Manouchehrifar, but it hasn’t been without its difficulties.
New constraints — and new possibilities
Manouchehrifar was halfway through his PhD when the White House imposed its travel ban in 2017. His initial research centered around the relationship between religion and planning in Iran, meaning that he had to do his fieldwork there. But Manouchehrifar was unsure as to whether or when he would be able to come back to the States and finish his studies if he left.
Although it wasn’t easy, he redirected his research project to focus on the U.S. instead. “I was rather forced to change course, but the results have also been fruitful for my research because it has enriched my understanding of the topic and given me a more nuanced comparative lens,” he says. On a personal level, the impact of the travel ban has been much harder for Manouchehrifar and his family to handle: “The disruption of research is something that we can manage one way or another. The disruption of family life, on the other hand, is quite unsettling and oftentimes paralyzing.”
Manouchehrifar says such constraints have motivated him to work harder in his studies.
“I think [these experiences] have reinforced my passion for building a better world through planning and international development initiatives. What I decided to do, following a period of contemplation and consultation especially with my advisor, Professor Bish Sanyal, was to try to transform such constraints into an intellectual energy to conduct research on a topic that is meaningful both for myself and for my field of study,” he says.
Manouchehrifar has served as an instructor for 11.005 (Introduction to International Development Planning) and has been a teaching assistant for four other courses. Sanyal says that Manouchehrifar’s students have praised him for creating “an atmosphere where everyone could get their thoughts out and learn, and be challenged by each other.”
When he isn’t working, Manouchehrifar spends as much time as he can with his wife and daughter. The family particularly enjoys going to parks and museums together. Manouchehrifar says he is grateful for everything his family has done for him: “I couldn’t have done my studies without their support and sacrifices, and it is really like the entire family is a getting a PhD.”
This fall, the School of Science will welcome four new members joining the faculty in the departments of Biology, Brain and Cognitive Sciences, and Chemistry.
Evelina Fedorenko investigates how our brains process language. She has developed novel analytic approaches for functional magnetic resonance imaging (fMRI) and other brain imaging techniques to help answer the questions of how the language processing network functions and how it relates to other networks in the brain. She works with both neurotypical individuals and individuals with brain disorders. Fedorenko joins the Department of Brain and Cognitive Sciences as an assistant professor. She received her BA from Harvard University in linguistics and psychology and then completed her doctoral studies at MIT in 2007. After graduating from MIT, Fedorenko worked as a postdoc and then as a research scientist at the McGovern Institute for Brain Research. In 2014, she joined the faculty at Massachusetts General Hospital and Harvard Medical School, where she was an associate researcher and an assistant professor, respectively. She is also a member of the McGovern Institute.
Morgan Sheng focuses on the structure, function, and turnover of synapses, the junctions that allow communication between brain cells. His discoveries have improved our understanding of the molecular basis of cognitive function and diseases of the nervous system, such as autism, Alzheimer’s disease, and dementia. Being both a physician and a scientist, he incorporates genetic as well as biological insights to aid the study and treatment of mental illnesses and neurodegenerative diseases. He rejoins the Department of Brain and Cognitive Sciences (BCS), returning as a professor of neuroscience, a position he also held from 2001 to 2008. At that time, he was a member of the Picower Institute for Learning and Memory, a joint appointee in the Department of Biology, and an investigator of the Howard Hughes Medical Institute. Sheng earned his PhD from Harvard University in 1990, completed a postdoc at the University of California at San Francisco in 1994, and finished his medical training with a residency in London in 1986. From 1994 to 2001, he researched molecular and cellular neuroscience at Massachusetts General Hospital and Harvard Medical School. From 2008 to 2019 he was vice president of neuroscience at Genentech, a leading biotech company. In addition to his faculty appointment in BCS, Sheng is core institute member and co-director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, as well as an affiliate member of the McGovern Institute and the Picower Institute.
Seychelle Vos studies genome organization and its effect on gene expression at the intersection of biochemistry and genetics. Vos uses X-ray crystallography, cryo-electron microscopy, and biophysical approaches to understand how transcription is physically coupled to the genome’s organization and structure. She joins the Department of Biology as an assistant professor after completing a postdoc at the Max Plank Institute for Biophysical Chemistry. Vos received her BS in genetics in 2008 from the University of Georgia and her PhD in molecular and cell biology in 2013 from the University of California at Berkeley.
Xiao Wang is a chemist and molecular engineer working to improve our understanding of biology and human health. She focuses on brain function and dysfunction, producing and applying new chemical, biophysical, and genomic tools at the molecular level. Previously, she focused on RNA modifications and how they impact cellular function. Wang is joining MIT as an assistant professor in the Department of Chemistry. She was previously a postdoc of the Life Science Research Foundation at Stanford University. Wang received her BS in chemistry and molecular engineering from Peking University in 2010 and her PhD in chemistry from the University of Chicago in 2015. She is also a core member of the Broad Institute of MIT and Harvard.
Kava (Piper methysticum) is a plant native to the Polynesian islands that people there have used in a calming drink of the same name in religious and cultural rituals for thousands of years. The tradition of cultivating kava and drinking it during important gatherings is a cultural cornerstone shared throughout much of Polynesia, although the specific customs — and the strains of kava — vary from island to island. Over the past few decades, kava has been gaining interest outside of the islands for its pain-relief and anti-anxiety properties as a potentially attractive alternative to drugs like opioids and benzodiazepines because kavalactones, the molecules of medicinal interest in kava, use slightly different mechanisms to affect the central nervous system and appear to be non-addictive. Kava bars have been springing up around the United States, kava supplements and teas lining the shelves at stores like Walmart, and sports figures in need of safe pain relief are touting its benefits.
This growing usage suggests that there would be a sizeable market for kavalactone-based medical therapies, but there are roadblocks to development: for one, kava is hard to cultivate, especially outside of the tropics. Kava takes years to reach maturity and, as a domesticated species that no longer produces seeds, it can only be propagated using cuttings. This can make it difficult for researchers to get a large enough quantity of kavalactones for investigations or clinical trials.
Now, research from Whitehead Institute member and MIT associate professor of biology Jing-Ke Weng and postdoc Tomáš Pluskal, published online in Nature Plants July 22, describes a way to solve that problem, as well as to create kavalactone variants not found in nature that may be more effective or safer as therapeutics.
“We’re combining historical knowledge of this plant’s medicinal properties, established through centuries of traditional usage, with modern research tools in order to potentially develop new drugs,” Pluskal says.
Weng’s lab has shown that if researchers figure out the genes behind a desirable natural molecule — in this case, kavalactones — they can clone those genes, insert them into species like yeast or bacteria that grow quickly and are easier to maintain in a variety of environments than a temperamental tropical plant, and then get these microbial bio-factories to mass produce the molecule. In order to achieve this, first Weng and Pluskal had to solve a complicated puzzle: How does kava produce kavalactones? There is no direct kavalactone gene; complex metabolites like kavalactones are created through a series of steps using intermediate molecules. Cells can combine these intermediates, snip out parts of them, and add bits onto them to create the final molecule — most of which is done with the help of enzymes, cells’ chemical reaction catalysts. So, in order to recreate kavalactone production, the researchers had to identify the complete pathway plants use to synthesize it, including the genes for all of the enzymes involved.
The researchers could not use genetic sequencing or common gene editing tools to identify the enzymes because the kava genome is huge; it has 130 chromosomes compared to humans’ 46. Instead they turned to other methods, including sequencing the plant’s RNA to survey the genes expressed, to identify the biosynthetic pathway for kavalactones.
“It’s like you have a lot of Lego pieces scattered on the floor,” Weng says, “and you have to find the ones that fit together to build a certain object.”
Weng and Pluskal had a good starting point: They recognized that kavalactones had a similar structural backbone to chalcones, metabolites shared by all land plants. They hypothesized that one of the enzymes involved in producing kavalactones must be related to the one involved in producing chalcones, chalcone synthase (CHS). They looked for genes encoding similar enzymes and found two synthases that had evolved from an older CHS gene. These synthases, which they call PmSPS1 and PmSPS2, help to shape the basic scaffolding of kavalactones molecules.
Then, with some trial and error, Pluskal found the genes encoding a number of the tailoring enzymes that modify and add to the molecules’ backbone to create a variety of specific kavalactones. In order to test that he had identified the right enzymes, Pluskal cloned the relevant genes and confirmed that the enzymes they encode produced the expected molecules. The team also identified key enzymes in the biosynthetic pathway of flavokavains, molecules in kava that are structurally related to kavalactones and have been shown in studies to have anti-cancer properties.
Once the researchers had their kavalactone genes, they inserted them into bacteria and yeast to begin producing the molecules. This proof of concept for their microbial bio-factory model demonstrated that using microbes could provide a more efficient and scalable production vehicle for kavalactones. The model could also allow for the production of novel molecules engineered by combining kava genes with other genes so the microbes would produce modified kavalactones. This could allow researchers to optimize the molecules for efficiency and safety as therapeutics.
“There’s a very urgent need for therapies to treat mental disorders, and for safer pain relief options,” Weng says. “Our model eliminates several of the bottlenecks in drug development from plants by increasing access to natural medicinal molecules and allowing for the creation of new-to-nature molecules.”
Kava is only one of many plants around the world containing unique molecules that could be of great medicinal value. Weng and Pluskal hope that their model — combining the use of drug discovery from plants used in traditional medicine, genomics, synthetic biology, and microbial mass production — will be used to better harness the great diversity of plant chemistry around the world in order to help patients in need.
This work was supported by grants from the Smith Family Foundation, Edward N. and Della L. Thome Memorial Foundation, the Family Larsson-Rosenquist Foundation, and the National Science Foundation. Tomáš Pluskal is a Simons Foundation Fellow of the Helen Hay Whitney Foundation. Jing-Ke Weng is supported by the Beckman Young Investigator Program, Pew Scholars Program in the Biomedical Sciences, and the Searle Scholars Program.