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."