Four from MIT receive NIH New Innovator Awards for 2022

The National Institutes of Health (NIH) has awarded grants to four MIT faculty members as part of its High-Risk, High-Reward Research program.

The program supports unconventional approaches to challenges in biomedical, behavioral, and social sciences. Each year, NIH Director’s Awards are granted to program applicants who propose high-risk, high-impact research in areas relevant to the NIH’s mission. In doing so, the NIH encourages innovative proposals that, due to their inherent risk, might struggle in the traditional peer-review process.

This year, Lindsay Case, Siniša Hrvatin, Deblina Sarkar, and Caroline Uhler have been chosen to receive the New Innovator Award, which funds exceptionally creative research from early-career investigators. The award, which was established in 2007, supports researchers who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Lindsay Case, the Irwin and Helen Sizer Department of Biology Career Development Professor and an extramural member of the Koch Institute for Integrative Cancer Research, uses biochemistry and cell biology to study the spatial organization of signal transduction. Her work focuses on understanding how signaling molecules assemble into compartments with unique biochemical and biophysical properties to enable cells to sense and respond to information in their environment. Earlier this year, Case was one of two MIT assistant professors named as Searle Scholars.

Siniša Hrvatin, who joined the School of Science faculty this past winter, is an assistant professor in the Department of Biology and a core member at the Whitehead Institute for Biomedical Research. He studies how animals and cells enter, regulate, and survive states of dormancy such as torpor and hibernation, aiming to harness the potential of these states therapeutically.

Deblina Sarkar is an assistant professor and AT&T Career Development Chair Professor at the MIT Media Lab​. Her research combines the interdisciplinary fields of nanoelectronics, applied physics, and biology to invent disruptive technologies for energy-efficient nanoelectronics and merge such next-generation technologies with living matter to create a new paradigm for life-machine symbiosis. Her high-risk, high-reward proposal received the rare perfect impact score of 10, which is the highest score awarded by NIH.

Caroline Uhler is a professor in the Department of Electrical Engineering and Computer Science and the Institute for Data, Systems, and Society. In addition, she is a core institute member at the Broad Institute of MIT and Harvard, where she co-directs the Eric and Wendy Schmidt Center. By combining machine learning, statistics, and genomics, she develops representation learning and causal inference methods to elucidate gene regulation in health and disease.

The High-Risk, High-Reward Research program is supported by the NIH Common Fund, which oversees programs that pursue major opportunities and gaps in biomedical research that require collaboration across NIH Institutes and Centers. In addition to the New Innovator Award, the NIH also issues three other awards each year: the Pioneer Award, which supports bold and innovative research projects with unusually broad scientific impact; the Transformative Research Award, which supports risky and untested projects with transformative potential; and the Early Independence Award, which allows especially impressive junior scientists to skip the traditional postdoctoral training program to launch independent research careers.

This year, the High-Risk, High-Reward Research program is awarding 103 awards, including eight Pioneer Awards, 72 New Innovator Awards, nine Transformative Research Awards, and 14 Early Independence Awards. These 103 awards total approximately $285 million in support from the institutes, centers, and offices across NIH over five years. “The science advanced by these researchers is poised to blaze new paths of discovery in human health,” says Lawrence A. Tabak DDS, PhD, who is performing the duties of the director of NIH. “This unique cohort of scientists will transform what is known in the biological and behavioral world. We are privileged to support this innovative science.”

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With fractured genomes, Alzheimer’s neurons call for help

A new study by researchers in The Picower Institute for Learning and Memory at MIT provides evidence from both mouse models and postmortem human tissue of a direct link between two problems that emerge in Alzheimer’s disease: a buildup of double-stranded breaks (DSBs) in the DNA of neurons and the inflammatory behavior of microglia, the brain’s immune cells.

A key new finding is that neurons actively trigger an inflammatory response to their genomic damage. Neurons have not been known to signal the brain’s immune system in Alzheimer’s disease, says study lead author Gwyneth Welch PhD ’22, a former MIT Department of Brain and Cognitive Sciences graduate student in the lab of senior author Li-Huei Tsai.

“This is a novel concept in neuroscience: the idea that neurons can be activating inflammatory activity in response to DNA damage,” Welch says. “The general idea was that neurons have a more passive relationship with microglia regarding age-associated neuroinflammation.”

Instead, what Welch, Tsai, and co-authors report in Science Advances is that neurons coping with mounting DSBs go through stages of first trying to fix their fractured DNA and then, when it apparently fails, sending out via molecular signals to microglia, which responded by taking on a more inflammatory state. In experiments where the scientists interrupted the immune signaling, they prevented microglia from entering that state and degrading neural circuit connections, or synapses.

Members of Tsai’s lab have been studying DSBs in the context of Alzheimer’s for more than a decade. Tsai said the new findings add to the emerging understanding of the role they play in Alzheimer’s.

“We have a long-standing interest in understanding DNA breaks in neurons,” says Tsai, Picower Professor of Neuroscience and a founder of MIT’s Aging Brain Initiative. “We previously showed that DNA double-stranded breaks are necessary for the induction of activity-regulated gene expression in neurons, but we also observed profound DNA damage in neurons in the early stages of neurodegeneration.

“We now know that DNA-damaged neurons exhibit senescent phenotypes and play an active role in eliciting an immune response from microglia and perhaps astrocytes,” Tsai adds. “This is mediated by the activation of the NFkappaB transcription factor. Moreover, we identified two cytokines secreted by damaged neurons to recruit microglia and elicit microglial response. Importantly, we show that inhibition of NFkappaB rescued synaptic loss in neurodegeneration, further elucidating of impact of neuroimmune response on synaptic integrity and cognitive function.”

In her thesis research, Welch used the lab’s “CK-p25” mouse model of Alzheimer’s, in which disease pathology can be induced. She observed a timeline in which neurons with DSBs appeared within a week, peaked in number after two weeks, and then tapered off, becoming notably reduced by six weeks. Meanwhile, those neurons also lost their ability to express a standard marker of neuronal identity. Welch realized there seemed to be stages to the process of coping with DSBs. First neurons have few DSBs and strong identity (baseline), then high DSBs with no loss of identity (stage 1), then high DSBs and a loss of neuronal identity (stage 2).

Transcripts tell the tale

To understand what cells were doing differently in each stage, Welch and the team used multiple “transcriptomics” technologies, which tracks differences in gene expression. Her analyses revealed that neuronal identity genes were most strongly expressed at baseline, DNA repair genes were strong during stage 1, and immune signaling genes were particularly prominent during stage 2.

Among the immune signaling genes were ones governed by the master transcription regulator NFkappaB. These included the cytokines Ccl2 and Cxcl10.

To see if these changes were due specifically to DSBs, Welch treated neurons in the absence of any induced pathology with a chemical called etoposide that causes DSBs. Similar gene expression patterns evident in the induced mice were recapitulated in the ones treated with etoposide. And when Welch also looked at gene expression in the brains of people with DSBs and with Alzheimer’s she also found many significant overlaps.

“We found that stage 1 and stage 2 gene signatures were active in human DSB-bearing neurons,” she and her co-authors wrote. “This neuronal immune signature was further amplified in the context of AD pathology, suggesting that it may serve a functional role in disease-associated neuroinflammation.”

A big role for microglia

Having established that DSB-afflicted neurons employ NFkappaB to send out immune signals such as Ccl2 and Cxcl10, Welch and the team then asked what the effect was. Given that the lab in 2017 had characterized a late-stage inflammatory response on the part of microglia in Alzheimer’s, they hypothesized that neurons might be responsible.

For this analysis Welch used spatial transcriptomics. She divided up both uninduced and induced mouse brains into many areas, and rated each area based on the strength of their DSB signal. Then she analyzed gene transcription in each area and found that locations with high DSBs also had many more microglia in an inflammatory state than locations with low DSBs. They were also able to directly image this relationship, yielding the observation that inflammatory microglia (evidenced by abnormally large cell bodies) were co-located with high-DSB neurons.

To further test the hypothesis, they disrupted NFkappaB regulated transcription in neurons by interfering with a key molecular cog in that machinery called p65. That step resulted in reduced proliferation of microglia and reduced microglia cell body size. It also induced beneficial changes in microglia gene expression, making them more consistent with their normal “homeostatic” state. 

In other experiments they found that etoposide-treated neurons expressed Cxcl10 and Ccl2 but that disrupting NFkappaB reduced that expression. They also saw that depleting the two molecules from the brains also prevented microglia from becoming reactive.

And looking back at the neurons, they saw that while knocking down NFkappaB activity didn’t prevent them from dying, it did preserve circuit connections, or synapses, on the neurons that remained alive. That’s important because those circuit connections underlie brain function and microglia are known to prune those.

Because NFkappaB is known to help prevent cell death (which may be why knocking it down didn’t prevent neurons from dying), Welch said knocking it down is not likely to be a therapeutic strategy.

“Its more a proof-of-principle that if you turn off a major switch for inflammation, that will change how microglia and neurons interact,” she says. “If your goal is to target inflammatory pathways, focusing on specific signaling molecules might be the more precise way to intervene.”

In addition to Welch and Tsai, the paper’s other authors are Carles Boix, Eloi Schmauch, Jose Davila-Velderrain, Matheus Victor, Vishnu Dileep, P. Lorenzo Bozzelli, Qiao Su, Jemmie D. Cheng, Audrey Lee, Noelle S. Leary, Andreas R. Pfenning, and Manolis Kellis.

The National Institutes of Health, CureAlz, the Glenn Foundation, and the JPB Foundation provided funding for the research.

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Scientists chart how exercise affects the body

Exercise is well-known to help people lose weight and avoid gaining it. However, identifying the cellular mechanisms that underlie this process has proven difficult because so many cells and tissues are involved.

In a new study in mice that expands researchers’ understanding of how exercise and diet affect the body, MIT and Harvard Medical School researchers have mapped out many of the cells, genes, and cellular pathways that are modified by exercise or high-fat diet. The findings could offer potential targets for drugs that could help to enhance or mimic the benefits of exercise, the researchers say.

“It is extremely important to understand the molecular mechanisms that are drivers of the beneficial effects of exercise and the detrimental effects of a high-fat diet, so that we can understand how we can intervene, and develop drugs that mimic the impact of exercise across multiple tissues,” says Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard.

The researchers studied mice with high-fat or normal diets, who were either sedentary or given the opportunity to exercise whenever they wanted. Using single-cell RNA sequencing, the researchers cataloged the responses of 53 types of cells found in skeletal muscle and two types of fatty tissue.

“One of the general points that we found in our study, which is overwhelmingly clear, is how high-fat diets push all of these cells and systems in one way, and exercise seems to be pushing them nearly all in the opposite way,” Kellis says. “It says that exercise can really have a major effect throughout the body.”

Kellis and Laurie Goodyear, a professor of medicine at Harvard Medical School and senior investigator at the Joslin Diabetes Center, are the senior authors of the study, which appears today in the journal Cell Metabolism. Jiekun Yang, a research scientist in MIT CSAIL; Maria Vamvini, an instructor of medicine at the Joslin Diabetes Center; and Pasquale Nigro, an instructor of medicine at the Joslin Diabetes Center, are the lead authors of the paper.

The risks of obesity

Obesity is a growing health problem around the world. In the United States, more than 40 percent of the population is considered obese, and nearly 75 percent is overweight. Being overweight is a risk factor for many diseases, including heart disease, cancer, Alzheimer’s disease, and even infectious diseases such as Covid-19.

“Obesity, along with aging, is a global factor that contributes to every aspect of human health,” Kellis says.

Several years ago, his lab performed a study on the FTO gene region, which has been strongly linked to obesity risk. In that 2015 study, the research team found that genes in this region control a pathway that prompts immature fat cells called progenitor adipocytes to either become fat-burning cells or fat-storing cells.

That finding, which demonstrated a clear genetic component to obesity, motivated Kellis to begin looking at how exercise, a well-known behavioral intervention that can prevent obesity, might act on progenitor adipocytes at the cellular level.

To explore that question, Kellis and his colleagues decided to perform single-cell RNA sequencing of three types of tissue — skeletal muscle, visceral white adipose tissue (found packed around internal organs, where it stores fat), and subcutaneous white adipose tissue (which is found under the skin and primarily burns fat).

These tissues came from mice from four different experimental groups. For three weeks, two groups of mice were fed either a normal diet or a high-fat diet. For the next three weeks, each of those two groups were further divided into a sedentary group and an exercise group, which had continuous access to a treadmill.

By analyzing tissues from those mice, the researchers were able to comprehensively catalog the genes that were activated or suppressed by exercise in 53 different cell types.

The researchers found that in all three tissue types, mesenchymal stem cells (MSCs) appeared to control many of the diet and exercise-induced effects that they observed. MSCs are stem cells that can differentiate into other cell types, including fat cells and fibroblasts. In adipose tissue, the researchers found that a high-fat diet modulated MSCs’ capacity to differentiate into fat-storing cells, while exercise reversed this effect.

In addition to promoting fat storage, the researchers found that a high-fat diet also stimulated MSCs to secrete factors that remodel the extracellular matrix (ECM) — a network of proteins and other molecules that surround and support cells and tissues in the body. This ECM remodeling helps provide structure for enlarged fat-storing cells and also creates a more inflammatory environment.

“As the adipocytes become overloaded with lipids, there’s an extreme amount of stress, and that causes low-grade inflammation, which is systemic and preserved for a long time,” Kellis says. “That is one of the factors that is contributing to many of the adverse effects of obesity.”

Circadian effects

The researchers also found that high-fat diets and exercise had opposing effects on cellular pathways that control circadian rhythms — the 24-hour cycles that govern many functions, from sleep to body temperature, hormone release, and digestion. The study revealed that exercise boosts the expression of genes that regulate these rhythms, while a high-fat diet suppresses them.

“There have been a lot of studies showing that when you eat during the day is extremely important in how you absorb the calories,” Kellis says. “The circadian rhythm connection is a very important one, and shows how obesity and exercise are in fact directly impacting that circadian rhythm in peripheral organs, which could act systemically on distal clocks and regulate stem cell functions and immunity.”

The researchers then compared their results to a database of human genes that have been linked with metabolic traits. They found that two of the circadian rhythm genes they identified in this study, known as DBP and CDKN1A, have genetic variants that have been associated with a higher risk of obesity in humans.

“These results help us see the translational values of these targets, and how we could potentially target specific biological processes in specific cell types,” Yang says.

The researchers are now analyzing samples of small intestine, liver, and brain tissue from the mice in this study, to explore the effects of exercise and high-fat diets on those tissues. They are also conducting work with human volunteers to sample blood and biopsies and study similarities and differences between human and mouse physiology. They hope that their findings will help guide drug developers in designing drugs that might mimic some of the beneficial effects of exercise.

“The message for everyone should be, eat a healthy diet and exercise if possible,” Kellis says. “For those for whom this is not possible, due to low access to healthy foods, or due to disabilities or other factors that prevent exercise, or simply lack of time to have a healthy diet or a healthy lifestyle, what this study says is that we now have a better handle on the pathways, the specific genes, and the specific molecular and cellular processes that we should be manipulating therapeutically.”

The research was funded by the National Institutes of Health and the Novo Nordisk Research Center in Seattle.

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MIT team places 3rd in materials design competition with novel 3D printable metal

The United States might be one step closer to its goal of having half of all new vehicles sold in 2030 be zero-emissions electric vehicles. That’s thanks to a pair of MIT undergraduates and their graduate student coach in Germany, who developed a new type of steel not for the cars’ build, but for the die-casting molds that stamp them out in just a few discrete parts.

MIT junior Ian Chen and Kyle Markland ’22 placed third in ASM Materials Education Foundation’s 2022 Undergraduate Design Competition. The 3D-printable steel alloy that earned them the honor was inspired by an innovative manufacturing approach called Giga-casting, popularized by carmaker Tesla and used to assemble the all-electric Model Y.

Chen accepted the award at a ceremony in New Orleans on Sept. 12, and Chen and Markland will share the $1,000 prize. ASM Materials Education Foundation is the charitable division of materials engineering organization ASM International. Its aim is to promote applied science careers to students and teachers.

A design challenge

Chen and Markland’s project has its roots in last spring’s class 3.041 (Computational Materials Design), taught by Gregory Olson, the Thermo-Calc Professor of the Practice at MIT. Olson is one of the world’s leading scholars of computational materials science, which uses computer modeling and simulation to understand and design new materials. His methodology has been used by Apple to create the Apple Watch, and it caught the attention of Tesla CEO Elon Musk.

“To get affordable electrical cars with good range, he had to make aluminum structures affordable,” says Olson, speaking of Musk. “So he looked at the kind of die casting for little car models and said, ‘Why not scale it up? We’ll cast the whole car.’”

Tesla used Olson’s computational approach for the aluminum that could be die cast — that’s the metal casting process by which molten metal is poured into a mold to form objects. Cars are typically built using hundreds of die-cast parts — engine cylinders, brackets, and other components — that are later put together on an automated assembly line to make a vehicle. The Giga-casting process — named for the massive casting machines known as Giga Press — instead involves casting just two or three large automobile pieces, vastly reducing the complexity of the process and the associated costs.

The problem is, “when you scale up the process, the heat transfer is slower, and the cycle times are too long,” Olson says — that is, the liquid metal takes longer to cool, making the whole process less efficient and more costly.

A technique called “conformal cooling” can help. In it, narrow channels follow, or conform to, the shape of the thing being cast, and coolant or water is run through them to accelerate cooling.

So the challenge took shape. Charles Kuehmann, vice president of materials engineering at SpaceX and Tesla, and a past student of Olson’s, confirmed the need: a better die steel, also called tool steel, that’s “printable” — a material that could be loaded into a 3-D printer to print new dies with better strength and thermal properties. Conventional steels, Olson said, “are quite brittle and cracking-prone if you try to print them.”

Offshore production

For an advisor to the student team, Olson turned to Florian Hengsbach, a visiting student at MIT from Paderborn University who returned to Germany during the pandemic shutdowns in 2020.

Hengsbach’s doctoral thesis couldn’t have been more apt for the MIT project: tool steel design for additive manufacturing, a term often used synonymously with 3D printing. His supervisor is Mirko Schaper, the dean of Paderborn’s college of mechanical engineering, head of its materials science department, and an expert in additive manufacturing.

“Here at Paderborn, we print materials, characterize them down to the atomic level, and determine the process-microstructure-performance correlation,” Hengsbach says — in other words, understand how the material will behave in various 3D printing conditions.

With Hengsbach working in Europe and Chen and Markland in Cambridge, Massachusetts, the team began designing the new metal using CALPHAD, a method for calculating the properties of materials. Using thermodynamic material models, the team could predict what new materials would do in different conditions.

Hengsbach formulated the material at Paderborn’s additive manufacturing center and printed it as a test — making the new metal alloy, melting it, then atomizing it into tiny droplets that solidify, making a powder. Then the powder is layered and melted by laser into an object in a 3D printer.

“This was very successful,” Hengsbach says. “We’ve designed a very promising tool steel, with superior performance regarding thermal conductivity, hardness, and toughness, which can actually be printed.”

The new metal has other potential manufacturing uses, Hengsbach says — injection molding, used often for plastics; or press hardening, which can form high-strength steel in complex shapes; or other processes — “everywhere you want to use conformal cooling channels, this material can be used.”

Hengsbach will return to MIT in February 2023 to work as a postdoc in Olson’s research group.

“You won’t regret it”

The team filed a U.S. patent application for the new printable die steel, and the next step is testing in casting die applications. Talks with Tesla are underway.

In what might be an endorsement of the team’s novel metal, Musk tweeted on Sept. 9 to his more than 100 million followers, “Take Materials Science 101. You won’t regret it.”

For Chen, a junior majoring in materials science and engineering, designing the steel has confirmed that he wants to stay in a materials-related lane for graduate school.

“This project has pushed me toward a more computationally driven materials area,” Chen says, “where computational models are used as a critical tool for materials design and analysis.”

Markland, who graduated in May with a BS in materials science and engineering, recently started working full time at the Ford Motor Company in Dearborn, Michigan. As part of the Ford College Graduate program, he’ll work on different projects his first two years, starting with vehicle paint engineering and corrosion prevention.  

“It feels great to have our work recognized by ASM,” Markland says. “Sometimes classwork can feel abstract or removed from the real world, and it’s a refreshing reminder that the project we did has recognition beyond just a class assignment.”

First prize in the ASM competition ($2,000) went to Michigan Technological University for the material characterization, modeling, and optimization of aluminum-cerium-magnesium alloys for extrusion; and second prize ($1,500) went to the University of Tennessee at Knoxville for materials analysis in the restoration of musical organs.

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SMART researchers develop quick test to determine immunity against Covid-19

A team of scientists from the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, and Nanyang Technological University, Singapore (NTU Singapore) has developed a quick test kit that can tell if a person has immunity against Covid-19 and its variants, based on the antibodies detected in a blood sample.

Unlike ART test kits — which look for the presence of viral proteins produced during a Covid-19 infection to determine if a person is infected — this rapid point-of-care test kit is a serology test that measures antibodies made by the patient. It requires a drop of blood and takes just 10 minutes to show results, as compared to the 24 to 72 hours required for conventional laboratory testing.

The test kit detects the levels of neutralizing antibodies against SARS-CoV-2, the virus causing Covid-19, and its variants such as delta and omicron, and can be easily adapted for new variants of concern and other diseases in the future.

Using a paper-based assay that is coated with chemicals that bind to antibodies in the blood sample, the test kit is low-cost, fast and has up to 93 percent accuracy. It paves the way for personalized vaccination strategies, where people are only given vaccinations and booster shots when necessary, depending on their variance in antibody levels and immune response.

The findings were published Sept. 7 in the journal Microbiology Spectrum by the joint team led by SMART’s Antimicrobial Resistance (AMR) interdisciplinary research group and NTU’s School of Biological Sciences, in collaboration with Singapore’s National University Hospital (NUH), National Center for Infectious Diseases (NCID), and MIT.

Having an accurate and rapid serology test can enable governments and health care organizations to effectively manage limited vaccine resources, and address vaccine hesitancy, particularly concerning multiple booster doses.

Vaccination has been an integral component of public health strategies to tackle the Covid-19 pandemic, with 12.6 billion doses across 184 countries administered as of Sept. 9. Vaccines reduced the Covid-19 death toll by 63 percent within the first year of their rollout, preventing an estimated 19.8 million deaths worldwide, according to a report by the World Health Organization (WHO).

In Singapore, the Ministry of Health estimated in February 2022 that Covid-19 vaccines had prevented 8,000 deaths during the wave of the Delta variant in 2021, as well as preventing an estimated 33,000 severe cases and 112,000 hospitalizations.

However, a clinical study by the joint research team has shown that the protection offered by currently available vaccines steadily declines over three months, with varying degrees of decline across individuals. The study showed that after three months of a booster shot, the neutralizing antibody (NAb) response against wild type and Delta still remained high at medians of 91.8 percent, while medians against Beta and Gamma had dropped to 82.7, and for Omicron, a large drop to 70.7 percent, down from 92.9 percent.

The case for a personalized vaccine approach

The emergence of novel variants with much higher transmissibility than the wild-type virus — such as Delta and Omicron — has exacerbated the issue of using mRNA vaccines developed based on the wild-type virus to boost immunity, especially when some current vaccines are showing reduced protection against these novel variants of concern.

In addition, vaccine hesitancy remains among certain populations in which individuals are wary of taking the vaccine or booster shots due to fear of side effects, further compounding the difficulty in employing a widespread vaccination strategy to build herd immunity.

To address vaccine hesitancy and efficacy of vaccination against novel variants, a personalized vaccination approach could be more effective, one which offers booster doses to individuals assessed to be more at risk, such as health care workers and the elderly.

For a personalized approach to be effective, health care workers need to be able to quickly evaluate the level of NAb response against variants at the individual level, using an easy-to-use point-of-care test kit in clinics, hospitals, or vaccination centers.

Hadley Sikes, SMART AMR principal investigator, associate professor of chemical engineering at MIT, and co-corresponding author of the paper says: “Over the course of the pandemic, several large studies have shown that NAb levels against the dominant variant at the time of the study are a reliable indicator of protection from infection. Some segments of the population have low tolerance for risk of infection. The test kit we developed can provide valuable, individualized information about how quickly or how slowly a person's antibodies levels have fallen, allowing them to stay informed of their health and, whenever required, get a necessary booster dose to protect themselves.”

Peter Preiser, co-lead principal investigator at SMART AMR, an associate vice president for biomedical and life sciences at NTU Singapore, and co-corresponding author of the paper adds: “Our team’s work in the development of a rapid test kit has given us valuable insights into vaccine effectiveness and protection longevity. Our study proves that our new test kit can be a powerful tool, allowing health-care organizations to screen people and determine their vaccination needs, especially against the current and upcoming variants. This will help allay some people’s fears that they will be ‘over-vaccinated with a booster,’ since the results will inform them accurately if they are well-protected against Covid-19 or not.”

In their research paper, the team describes a clinical study of their cellulose pulled-down virus neutralization test kit (cpVNT), a neutralizing antibody blood test designed to assess an individual’s immunoprotective profile against SARS-CoV-2 and its variants.

With a drop of finger-prick blood, the test kit can evaluate an individual’s neutralizing antibody level against a specific Covid-19 variant within 10 minutes, making this an efficient, low-cost, and easy-to-use tool that will enable large-scale testing and can be widely deployed anywhere as part of a personalized vaccination strategy.

The test reveals the individual’s level of neutralizing antibodies, which can then inform a person when a booster should be taken, and how cautious they should be about potential transmission before it is taken.

It can be administered by a layperson without medical training and does not require any specialized laboratory equipment, paving the way for large-scale testing of vulnerable subsets of the population, such as the elderly.

Co-first author of the paper and former SMART AMR postdoc Hoi Lok Cheng says, “This is an exciting breakthrough for us, and a continuation of our long-running work to develop efficient, low-cost, and easy-to-use NAb tests to combat the Covid-19 pandemic. As a quantitative test that can detect NAb levels specific to key variants such as delta and omicron, the cpVNT has given us valuable insights into the effectiveness of various vaccines vis-à-vis variants of concern. This test kit will also prove integral to a more personalized vaccination approach that will benefit higher-risk individuals such as the elderly and health-care workers. Individuals from these communities can have their immunoprotective profile assessed on a regular basis via the cpVNT, allowing them to know when a booster dose may be appropriate or necessary. Furthermore, this test can be easily adapted to test for novel SARS-CoV-2 variants that may emerge in the future.”

Building on years of research

This research builds on years-long body of work by the SMART team. In a paper published in the medical and public health journal Communications Medicine, the team laid out the foundation for a cellulose-based vertical-flow test to detect neutralizing antibodies against SARS-CoV-2. A separate paper published in the chemical engineering journal Bioengineering and Translational Medicine discussed the test’s effectiveness against other methods, such as the pseudovirus-based virus neutralization test (pVNT) and surrogate virus neutralization test (sVNT), with favorable results.

Using clinical samples (including both whole blood and plasma) and the WHO International Standard and Reference Panel for anti-SARS-CoV-2 antibody, the team established that a whole-blood test such as the cpVNT could be as informative as a plasma-only test. As plasma- or serum-based tests require laboratory equipment to process the blood sample as well as higher quantities of blood samples to be taken, the cpVNT is therefore more resource-efficient and less invasive. The cpVNT’s viability also demonstrates that neutralizing antibody and point-of-care tests can be successfully performed using such a format and protocol — paving the way for further development and innovation of this platform to tackle other diseases.

Further development of the test kit is underway to meet the necessary regulatory approvals and manufacturing standards for public use. The team that has developed the tests at SMART has also spun off a biotech startup, Thrixen, which is developing the test into a commercially ready product.

Key development of the rapid test was done at SMART AMR together with NTU scientists, who helped in the design of the study, providing specific reagent supplies and clinical sample collections. NUH and NCID had provided clinical sample supplies and consultation on medical use of the test, while MIT supervised the project.

This work is funded by the National Research Foundation (NRF) Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) program. It is also supported by Singapore’s National Medical Research Council under its Covid-19 Research Fund, and National Health Innovation Centre under its Covid-19 Gap funding grant.

SMART was established by MIT and the NRF in 2007. SMART is the first entity in CREATE. SMART serves as an intellectual and innovation hub conducting cutting-edge research in areas of interest to both Singapore and MIT. SMART currently comprises an Innovation Centre and five interdisciplinary research groupa: AMR, Critical Analytics for Manufacturing Personalized-Medicine, Disruptive and Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems.

The AMR IRG is a translational research and entrepreneurship program that tackles the growing threat of antimicrobial resistance. By leveraging talent and convergent technologies across Singapore and MIT, it tackles AMR head-on by developing multiple innovative and disruptive approaches to identify, respond to, and treat drug-resistant microbial infections. Through strong scientific and clinical collaborations, it provides transformative, holistic solutions for Singapore and the world.

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L. Rafael Reif receives National Academy of Engineering’s Simon Ramo Founders Award

The National Academy of Engineering (NAE) has named MIT President L. Rafael Reif as the winner of its 2022 Simon Ramo Founders Award.

Reif, who has served at MIT’s president for more than 10 years, is being honored “for pioneering leadership to reimagine and advance higher education, university-based entrepreneurship, the future of computing, the future of work, sustainability and semiconductor technology,” according to the academy’s citation.

The Founders Award was established in 1965 by the NAE to honor an outstanding member or international member who has upheld the ideals and principles of the NAE through professional, educational, and personal achievement and accomplishment. Reif accepted the award on Sunday at the NAE annual meeting.

“I am delighted to be recognized by the National Academy of Engineering and its members because choosing to become an engineer was one of the most important decisions I ever made,” Reif said. “As a leader, one is often required to make important decisions under conditions of great uncertainty — which is exactly what engineering trains you to do.”

Reif joined MIT in 1980 as an assistant professor of electrical engineering and later served for seven years as provost, becoming MIT’s 17th president in 2012. He announced in February that he will step down from the role at the end of 2022.

As president, Reif led the Institute through a period of dynamic growth as well as novel challenges such as the Covid-19 pandemic. He oversaw the creation of an innovation ecosystem on campus and in Kendall Square, including the formation of “tough tech” accelerator The Engine; launched the MIT Schwarzman College of Computing to bring the power of computing and artificial intelligence to all fields of study; helped to reimagine the future of higher education through open-source online learning initiatives such as edX; and cleared new pathways for MIT scholars to develop solutions for addressing climate change.

Reif also promoted health and well-being among MIT students, faculty, and staff; championed MIT’s international community; and worked to revitalize the MIT campus. And, he convened MIT experts to deliver nationally significant reports on topics such the future of work and reasserting U.S. leadership in the semiconductor industry.

After he steps down as president, Reif will take a sabbatical, then return to the faculty of the Department of Electrical Engineering and Computer Science.

“We live in a moment when society is starving for principled, inspired, constructive leadership, in the face of immense global challenges,” Reif said in his acceptance remarks. “In a time of such tremendous need, I believe in the vision, potential and capacity to do good of the members of the National Academy of Engineering, and that includes all of you here tonight. And I trust you will each find many ways to contribute to move the needle in the right direction for the benefit of humankind.

“I am deeply fortunate to have been welcomed into this transformative profession so many years ago, and I am profoundly grateful for the immense honor of this truly wonderful award.”

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Wiggling toward bio-inspired machine intelligence

Juncal Arbelaiz Mugica is a native of Spain, where octopus is a common menu item. However, Arbelaiz appreciates octopus and similar creatures in a different way, with her research into soft-robotics theory. 

More than half of an octopus’ nerves are distributed through its eight arms, each of which has some degree of autonomy. This distributed sensing and information processing system intrigued Arbelaiz, who is researching how to design decentralized intelligence for human-made systems with embedded sensing and computation. At MIT, Arbelaiz is an applied math student who is working on the fundamentals of optimal distributed control and estimation in the final weeks before completing her PhD this fall.

She finds inspiration in the biological intelligence of invertebrates such as octopus and jellyfish, with the ultimate goal of designing novel control strategies for flexible “soft” robots that could be used in tight or delicate surroundings, such as a surgical tool or for search-and-rescue missions.

“The squishiness of soft robots allows them to dynamically adapt to different environments. Think of worms, snakes, or jellyfish, and compare their motion and adaptation capabilities to those of vertebrate animals,” says Arbelaiz. “It is an interesting expression of embodied intelligence — lacking a rigid skeleton gives advantages to certain applications and helps to handle uncertainty in the real world more efficiently. But this additional softness also entails new system-theoretic challenges.”

In the biological world, the “controller” is usually associated with the brain and central nervous system — it creates motor commands for the muscles to achieve movement. Jellyfish and a few other soft organisms lack a centralized nerve center, or brain. Inspired by this observation, she is now working toward a theory where soft-robotic systems could be controlled using decentralized sensory information sharing.

“When sensing and actuation are distributed in the body of the robot and onboard computational capabilities are limited, it might be difficult to implement centralized intelligence,” she says. “So, we need these sort of decentralized schemes that, despite sharing sensory information only locally, guarantee the desired global behavior. Some biological systems, such as the jellyfish, are beautiful examples of decentralized control architectures — locomotion is achieved in the absence of a (centralized) brain. This is fascinating as compared to what we can achieve with human-made machines.”

A fluid transition to MIT

Her graduate studies at the University of Navarra in San Sebastian led to her working with MIT Professor John Bush in fluid dynamics. In 2015, he invited Arbelaiz to MIT as a visiting student to investigate droplet interactions. This led to their 2018 paper in Physical Review Fluids, and her pursuit of a PhD at MIT.   

In 2018, her doctoral research shifted to the interdisciplinary Sociotechnical System Research Center (SSRC), and is now advised by Ali Jadbabaie, the JR East Professor of Engineering and head of the Department of Civil and Environmental Engineering; and School of Engineering Associate Dean Anette “Peko” Hosoi, who is the Neil and Jane Pappalardo Professor of Mechanical Engineering as well as an applied math professor. Arbelaiz also regularly works with Bassam Bamieh, associate director of the Center for Control, Dynamical Systems, and Computation at the University of California at Santa Barbara. She says that working with this team of advisors gives her the freedom to explore the multidisciplinary research projects she has been drawn to over the past five years.

For example, she uses system-theoretic approaches to design novel optimal controllers and estimators for systems with spatiotemporal dynamics, and to gain a fundamental understanding of the sensory feedback communication topologies required to optimally control these systems. For the soft-robotic applications, this amounts to ranking which sensory measurements are important to best trigger each of the “muscles” of this robot. Did the robot’s performance degrade when each actuator only has access to the closest sensory measurements? Her research characterizes such a trade-off between closed-loop performance, uncertainty, and complexity in spatially distributed systems. 

“I am determined to bridge the gap between machine autonomy, systems theory, and biological intelligence,” she says.

Next chapter

A two-year Schmidt Science Fellowship, which funds young researchers to pursue postdoctoral studies in a field different from their graduate work, will let Arbelaiz further explore the intersection of biological and machine intelligence after graduation. 

She plans to spend her postdoc time at Princeton University with Professor Naomi Leonard, and to work with researchers in systems biology, computer science, and robotics, to explore the reliability and robustness of biological and artificial ensembles. Specifically, she is interested in learning how biological systems efficiently adapt to different environments so that she can apply this knowledge to human-made systems, such as autonomous machines, whose vulnerability to noise and uncertainty creates safety issues.

“I foresee an unprecedented revolution approaching in autonomous and intelligent machines, facilitated by a fruitful symbiosis between systems theory, computation, and (neuro)biology,” she says.

Paying it forward

Arbelaiz grew up in Spain acutely aware of the privilege of having access to a better education than her parents. Her father earned a degree in economics through independent study while working to support his family. His daughter inherited his persistence. 

“The hardships my parents experienced made them cherish autodidactism, lifelong learning, and critical thinking,” she says. “They passed on these values to me, so I grew up to be a curious and persevering person, enthusiastic about science and ready to seize every educational opportunity.”  

In a desire to pass this on to others, she mentors STEM students who lack guidance or resources. “I firmly believe that we should promote talent everywhere, and mentoring could be the key driver to encourage underrepresented minorities to pursue careers in STEM,” she says.

An advocate for women in STEM, she was part of the executive committee of Graduate Women at MIT (GWAMIT) and MIT Women in Mathematics, and participates in various panels and workshops. She also runs live experiments for kids, such as at the MIT Museum’s Girls Day events.

“As scientists, we are responsible to share our knowledge, to inform the public about scientific discovery and its impact, and to raise awareness about the value of research and the need to invest in it.” 

Arbelaiz also supports MIT’s Covid-19 outreach efforts, including talks about the mathematical modeling of the virus, and translating into Basque her former mentor John Bush’s MIT Covid-19 Indoor Safety app. 

This interest in paying her STEM knowledge forward is something she credits to her MIT education. 

“MIT has been one of the best experiences of my life so far: it has brought enormous academic, professional, and personal growth,” she says. “I share MIT’s taste for collaborative and multidisciplinary research, the attraction to intellectual challenges, and the enthusiasm for advancing science and technology to benefit humankind.”

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