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3 Questions: Michael Yaffe on treating Covid-19 patients with acute respiratory distress

MIT professor and intensivist/trauma surgeon explains the new challenges that Covid-19 brings to treating patients in acute respiratory distress.

Bendta Schroeder | Koch Institute
April 30, 2020

During the Covid-19 pandemic, frontline health care workers have had to adapt rapidly to treating patients with lung failure, not only because of shortages of equipment such as ventilators often used to treat severe cases, but also because such approaches are not always effective due to the unique and still imperfectly understood pathology of Covid-19 infections.

Michael Yaffe, the David H. Koch Professor in Science, normally divides his time among his roles as a researcher and professor of biology and biological engineering at MIT, an intensivist/trauma surgeon at Beth Israel Deaconess Medical Center (BIDMC), and a colonel in the U.S. Army Reserve Medical Corps. Currently, he is developing treatments for Covid-19 infections in his laboratory at the Koch Institute for Integrative Cancer Research at MIT. Additionally, he runs one of the Covid-19 Intensive Care Units at BIDMC and serves as co-director of the acute care and ICU section of Boston Hope, the 500-bed pop-up hospital organized by the City of Boston, Massachusetts in the Boston Convention and Exposition Center. Yaffe shares how he is working to improve outcomes for Covid-19 patients and offers his perspective on how emergency care for acute respiratory distress will need to evolve during this crisis and beyond.

Q: What are the special considerations for Covid-19 patients receiving treatment for respiratory failure?

A: We have known about acute respiratory distress syndrome (ARDS) for decades. It was first recognized in battlefield casualties during the Vietnam War, and was initially called “Da-Nang Lung,” but later was understood to be the result of many different diseases. In ARDS, fluid builds up in the tiny air sacs, or alveoli, preventing the lungs from filling up with enough air, and in severe cases is treated by putting patients on ventilators or other devices that support breathing.

The type of lung injury we are seeing in Covid-19 patients behaves very differently from the traditional type of ARDS, and seems to involve early damage to the cells that line the lungs, followed by intense inflammation. The inflammation leads to a massive increase in blood clotting that affects all of the blood vessels in the body, but particularly the blood vessels in the lungs. As a consequence, even if we can force air into the lungs, it does not get delivered very efficiently into the bloodstream.

In ICUs in Boston, New York, and Colorado, we have started a clinical trial using a clot-busting drug called tPA that we think will help rescue patients whose lungs are failing despite maximal support with a mechanical ventilator. This approach has gathered a lot of attention from other hospitals, both nationally and internationally, who are also trying this approach. The work has now led to FDA approval for this drug as an Investigational New Drug, meaning that it is now approved for use in Covid-19 ARDS in the setting of clinical trials.

Q: How has your wide-ranging expertise equipped you to address new challenges that you face in the ICU?

A: I have been very fortunate to be well-prepared to help out in this crisis. First, my training as an intensive care physician and trauma surgeon makes me comfortable in a crisis situation. The clinical problems that we are dealing with here  — ARDS, kidney failure, etc. — are exactly within the scope of my regular clinical practice. Second, my Army deployment experience as a surgeon and critical care doctor in Afghanistan and in Central America has made me very comfortable having to make decisions in resource-limited situations. Finally, it has been incredibly fortuitous that much of my lab’s work has been in the area of cell injury, particularly cancer treatment-related cell injury, but also in the setting of a condition called systemic inflammatory response syndrome, which is essentially exactly what Covid-19 is. In this area, my lab has been studying the link between inflammation and blood clotting for over a decade, and the basic science insights from that work have now become central to our understanding of Covid-19 lung failure, which no one could have foreseen when we first started that research.

Q: What implications do you think the Covid-19 pandemic will have for emergency care after it is over?

A: I think the implications of Covid-19 for the future are immense. First, I hope the lessons learned from this pandemic lead to a complete re-thinking of our national public health policy (or lack of one, really) and a re-engagement with World Health Organization officials for monitoring the outbreak of emerging diseases.

Second, I think that this crisis may fuel additional research funding in the area of critical care medicine. Before the Covid-19 crisis, very few people had heard of ARDS, or even critical care as a field of medicine, since it does not have the glamour of conditions like cancer medicine or cardiovascular disease. Historically, research in this area has been underfunded, but now that ARDS has taken the spotlight in the news, I am hopeful that the recognition that some patients with Covid-19 are dying because of critical illness and lung failure will lead to new efforts to better understand the link between inflammation, lung function, and innate immunity, including blood coagulation. The Covid-19 crisis will not end when this first wave subsides, but will re-visit us again in the fall. Additionally, other coronavirus diseases as well as viral epidemics are likely to continue to plague us in the future.

One final lesson we are learning from this terrible pandemic is how important it is to treat all of the different parts of the body as a complex interacting unit, and to apply what we know from systems biology and other fields of study to understand how those parts are integrated into one coherent system. The lung failure, kidney failure, and inflammation of the heart that are the hallmarks of Covid-19 critical illness directly reflect how different inflammatory molecules in the blood alter the function of each of these different organ systems. Our traditional medical approach of having separate specialists in infectious disease, pulmonary medicine, renal medicine, and hematology does not work well when all the organ systems are cross-talking to each other. The job of the intensive care physician is to integrate all of the relevant basic biology and pathology of these organs into a comprehensive holistic treatment approach for the patient. Covid-19 has made that need to think across multiple disciplines and connect basic science to clinical care even more apparent.

Engineers develop precision injection system for plants

Microneedles made of silk-based material can target plant tissues for delivery of micronutrients, hormones, or genes.

David L. Chandler | MIT News Office
April 27, 2020

While the human world is reeling from one pandemic, there are several ongoing epidemics that affect crops and put global food production at risk. Oranges, olives, and bananas are already under threat in many areas due to diseases that affect plants’ circulatory systems and that cannot be treated by applying pesticides.

A new method developed by engineers at MIT may offer a starting point for delivering life-saving treatments to plants ravaged by such diseases.

These diseases are difficult to detect early and to treat, given the lack of precision tools to access plant vasculature to treat pathogens and to sample biomarkers. The MIT team decided to take some of the principles involved in precision medicine for humans and adapt them to develop plant-specific biomaterials and drug-delivery devices.

The method uses an array of microneedles made of a silk-based biomaterial to deliver nutrients, drugs, or other molecules to specific parts of the plant. The findings are described in the journal Advanced Science, in a paper by MIT professors Benedetto Marelli and Jing-Ke-Weng, graduate student Yunteng Cao, postdoc Eugene Lim at MIT, and postdoc Menglong Xu at the Whitehead Institute for Biomedical Research.

The microneedles, which the researchers call phytoinjectors, can be made in a variety of sizes and shapes, and can deliver material specifically to a plant’s roots, stems, or leaves, or into its xylem (the vascular tissue involved in water transportation from roots to canopy) or phloem (the vascular tissue that circulates metabolites throughout the plant). In lab tests, the team used tomato and tobacco plants, but the system could be adapted to almost any crop, they say. The microneedles can not only deliver targeted payloads of molecules into the plant, but they can also be used to take samples from the plants for lab analysis.

The work started in response to a request from the U.S. Department of Agriculture for ideas on how to address the citrus greening crisis, which is threatening the collapse of a $9 billion industry, Marelli says. The disease is spread by an insect called the Asian citrus psyllid that carries a bacterium into the plant. There is as yet no cure for it, and millions of acres of U.S. orchards have already been devastated. In response, Marelli’s lab swung into gear to develop the novel microneedle technology, led by Cao as his thesis project.

The disease infects the phloem of the whole plant, including roots, which are very difficult to reach with any conventional treatment, Marelli explains. Most pesticides are simply sprayed or painted onto a plant’s leaves or stems, and little if any penetrates to the root system. Such treatments may appear to work for a short while, but then the bacteria bounce back and do their damage. What is needed is something that can target the phloem circulating through a plant’s tissues, which could carry an antibacterial compound down into the roots. That’s just what some version of the new microneedles could potentially accomplish, he says.

“We wanted to solve the technical problem of how you can have a precise access to the plant vasculature,” Cao adds. This would allow researchers to inject pesticides, for example, that would be transported between the root system and the leaves. Present approaches use “needles that are very large and very invasive, and that results in damaging the plant,” he says. To find a substitute, they built on previous work that had produced microneedles using silk-based material for injecting human vaccines.

“We found that adaptations of a material designed for drug delivery in humans to plants was not straightforward, due to differences not only in tissue vasculature, but also in fluid composition,” Lim says. The microneedles designed for human use were intended to biodegrade naturally in the body’s moisture, but plants have far less available water, so the material didn’t dissolve and was not useful for delivering the pesticide or other macromolecules into the phloem. The researchers had to design a new material, but they decided to stick with silk as its basis. That’s because of silk’s strength, its inertness in plants (preventing undesirable side effects), and the fact that it degrades into tiny particles that don’t risk clogging the plant’s internal vasculature systems.

They used biotechnology tools to increase silk’s hydrophilicity (making it attract water), while keeping the material strong enough to penetrate the plant’s epidermis and degradable enough to then get out of the way.

Sure enough, they tested the material on their lab tomato and tobacco plants, and were able to observe injected materials, in this case fluorescent molecules, moving all they way through the plant, from roots to leaves.

“We think this is a new tool that can be used by plant biologists and bioengineers to better understand transport phenomena in plants,” Cao says. In addition, it can be used “to deliver payloads into plants, and this can solve several problems. For example, you can think about delivering micronutrients, or you can think about delivering genes, to change the gene expression of the plant or to basically engineer a plant.”

“Now, the interests of the lab for the phytoinjectors have expanded beyond antibiotic delivery to genetic engineering and point-of-care diagnostics,” Lim adds.

For example, in their experiments with tobacco plants, they were able to inject an organism called Agrobacterium to alter the plant’s DNA – a typical bioengineering tool, but delivered in a new and precise way.

So far, this is a lab technique using precision equipment, so in its present form it would not be useful for agricultural-scale applications, but the hope is that it can be used, for example, to bioengineer disease-resistant varieties of important crop plants. The team has also done tests using a modified toy dart gun mounted to a small drone, which was able to fire microneedles into plants in the field. Ultimately, such a process might be automated using autonomous vehicles, Marelli says, for agricultural-scale use.

Meanwhile, the team continues to work on adapting the system to the varied needs and conditions of different kinds of plants and their tissues. “There’s a lot of variation among them, really,” Marelli says, so you need to think about having devices that are plant-specific. For the future, our research interests will go beyond antibiotic delivery to genetic engineering and point-of-care diagnostics based on metabolite sampling.”

The work was supported by the Office of Naval Research, the National Science Foundation, and the Keck Foundation.

Life and learning find a way

Despite the COVID-19 pandemic, the Department of Biology has come together while being apart.

Raleigh McElvery
April 24, 2020

On Mar. 12, 2020, Iain Cheeseman held his final in-person lecture for 7.06 (Cell Biology), before the COVID-19 pandemic prompted MIT to abruptly transition to online learning. A professor of biology and Whitehead Institute member, Cheeseman was five minutes from the end of his talk on actin binding proteins when the fire alarm unexpectedly sounded, and the entire class was forced to evacuate.

“To me, that was a metaphor for the entire semester,” he says. “You have the best-laid plans, and then an alarm sounds, everyone is suddenly forced to flee, and all you can do is hope that they stay safe. I didn’t even get to say goodbye.”

Like many universities, MIT recently emptied its physical campus and established a virtual one, instructing students to return home and community members to work remotely if possible. Despite the short notice and continually-evolving circumstances, the Department of Biology is finding ways to come together while being apart.

Cheeseman and his co-instructor, Becky Lamason, were in a better position than most to move their class online. In the fall, long before the pandemic, Cheeseman and Lamason began working with the department’s digital learning team, MITxBio, to create an online version of 7.06.

Each year, in addition to conducting award-winning educational research, MITxBio teams up with several instructors to devise massive open online courses. These “MOOCs” are replete with recorded lectures, online assessments, discussion forums, and detailed animations. Anyone can take an MITxBio MOOC for free, or pay a small fee to receive a certificate post-completion. MIT students can also use these digital resources through their class websites.

MITxBio’s list of responsibilities expanded almost immediately after MIT announced its plans to go remote. The team became the department’s go-to resource for online learning, and they began meeting with instructors to demonstrate how to record lectures, run recitations via Zoom, hold online office hours, administer exams, and determine a general workflow for the new normal. They also compiled recommendations and instructions for the transition. In addition to 7.06, MITxBio is also assisting with 7.014 (Introductory Biology), 7.05 (General Biochemistry), and 7.28/7.58 (Molecular Biology).

“Normally, it would take us about six months to develop the online resources for a MOOC,” says Mary Ellen Wiltrout, lecturer and MITx digital learning scientist. “But in this case, we didn’t have much advance notice and that really compressed our timeline.” She’s pleased to report that remote learning thus far hasn’t been very exciting, which is a “major success” because it means things are running smoothly — although there were some kinks early on.

Simple tasks that were no-brainers during in-person classes became conundrums in the virtual realm for instructors. Should they hold live lectures at the regularly scheduled time, or record their lectures for easy viewing in multiple time zones? What’s the best way to administer and grade a remote exam? How should teaching assistants conduct their recitations? Even noticing when a student raised their hand in a virtual classroom became a quandary. But perhaps the biggest predicament of all was determining how to proceed with lab classes, which revolve around hands-on experiences.

An experimental overview from 7.003.

Technical instructors like Vanessa Cheung and Eric Chu have continued to hold their labs, 7.002 (Fundamentals of Experimental Molecular Biology) and 7.003 (Applied Molecular Biology Laboratory). Cheung and Chu had just three days after students departed before Building 68 was closed to non-essential personnel. They wrapped up as many experiments as they could, and combined those results with data from previous classes for their students to analyze. Cheung and Chu documented many of the techniques through pictures, videos, and diagrams, and then supplemented their own instruction with online content from other sources. Each week, the instructors, students, and teaching assistants gather in a Zoom chat room to discuss additional material and announcements, before breaking into smaller discussion groups.

Luckily, Cheung says, the students had already learned the key lab techniques, and the remaining protocols merely required “pipetting things into tubes, which they already know how to do.” Thanks to all the online supplemental materials, she suspects the students may be getting exposed to more information than they normally would if they were still on campus. “In some ways, they may actually have the opportunity to get more out of the class,” she says.

“The lab instructors have done a phenomenal job transitioning to remote learning,” adds Adam Martin, associate professor of biology and undergraduate officer. “The students may not get to experience the joy of loading a gel for themselves, but they’ll still get the chance to analyze and write about real experimental data.”

Martin oversees his own lab of undergraduates, graduate students, postdocs, and technicians, who evacuated Building 68 shortly after the students left campus. His group studies embryonic development in fruit flies, and has put wet lab experiments on hold in favor of learning computational techniques, conducting literature searches, and composing papers from home.

“We’ve stayed pretty busy,” he says. “The biggest challenge is maintaining our fly stocks.” Some of the flies have remained in Building 68 under the supervision of designated caretakers, while a back-up collection resides safe and sound in Martin’s basement.

As an undergraduate officer, Martin has remained in touch with undergraduates outside his lab as well by setting up one-on-one meetings. “I’ve been trying to be proactive about keeping in touch, and regularly engaging with them to make sure no one is falling through the cracks,” he says.

In addition to continuing existing student services, MIT has also aggregated online teaching and learning resources, and organized a Student Success Team that pairs undergraduates with coaches who provide support.

“MIT is stressful enough in-person,” Cheung says, “but add to that distractions at home, spotty Wi-Fi, and the stress of a pandemic, and it’s a lot for students to manage.”

Through virtual check-ins, online surveys, and unintentional guest appearances by family, members of the MIT Biology community have gotten to know each other in new and different ways.

“All the students are realizing that we have lives,” Martin says. “Managing family and work responsibilities has been a balancing act, to say the least.”

Back in 7.06, Cheeseman was preparing for the first online exam by sending a practice quiz with light-hearted questions. In one question, he asked his students for silly social distancing stories. He was touched to receive tales of family bonding, online orders gone awry, and lots of recipes.

“It gave me such a perspective on the undergrads here,” he says. “I really miss them. There’s no way we can pretend this is life as normal, but I respect how the students are doing their best and have continued to have a good attitude.”

Cheung and Martin have been impressed with the high participation rate they’ve witnessed. “It’s heartwarming to see that MIT students genuinely care about learning,” Cheung says, “even when they’re scattered across the globe.”

Even after everyone eventually returns to campus, Wiltrout predicts teaching and learning at MIT will never be the same — and perhaps that’s a good thing.

“Many people were initially hesitant to adopt online learning technology,” she says. “But now they’re realizing that these online tools can really enhance in-person learning, or make some TA duties more efficient.”

While MIT weathers the pandemic, students, instructors, and staff in the department will do their best to continue as normal. “In my case, that means entertaining my students and keeping the dad jokes going,” Cheeseman says. “It isn’t the situation any of us would have wanted, but we’re coping better than we ever thought we could.”

Top image: A screenshot of a video by Vanessa Cheung explaining a cDNA synthesis procedure.
Posted: 4.24.20
Catherine Drennan elected to American Academy of Arts and Sciences
April 23, 2020

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

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

Those elected from MIT this year are:

  • Robert C. Armstrong, Chevron Professor in Chemical Engineering;
  • Dave L. Donaldson, professor of economics;
  • Catherine L. Drennan, professor of biology and chemistry;
  • Ronitt Rubinfeld, professor of electrical engineering and computer science;
  • Joshua B. Tenenbaum, professor of brain and cognitive sciences; and
  • Craig Steven Wilder, Barton L. Weller Professor of History.

“The members of the class of 2020 have excelled in laboratories and lecture halls, they have amazed on concert stages and in surgical suites, and they have led in board rooms and courtrooms,” said academy President David W. Oxtoby. “With today’s election announcement, these new members are united by a place in history and by an opportunity to shape the future through the academy’s work to advance the public good.”

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

From bedside to bench, and back again
Eva Frederick | Whitehead Institute
April 22, 2020

In 2018, a 31-year-old woman checked into Massachusetts General Hospital (MGH) in Boston with a respiratory infection so bad she had to be placed on oxygen. A trip to the hospital for lung trouble was nothing new for her — several times in the past, recurrent infections required her to stay under a doctor’s supervision for days until they blew over. Now, however, it seemed that she would not be leaving the hospital until she received two entirely new lungs.

The woman had had respiratory issues since she was a baby. Her flare-ups usually presented like pneumonia — a nasty, phlegm-y cough accompanied by a fever. After years of this the pathways between the trachea and the alveoli, called bronchi, were swollen and inflamed. Her physicians suspected that these frequent respiratory bouts had something to do with the mucus produced in her airways.

Mucus is the body’s first line of defense against the dirt and pathogens we inhale when we breathe. The sticky substance, composed mostly of water, salts, and sugar-laden proteins called mucins, traps the incoming material on its sticky surface. From there, cilia — tiny finger-like protrusions from cells that can look like small eyelashes — push the mucus up through the airways where it is eventually swallowed or coughed out.

Conditions such as cystic fibrosis can cause the mucus that lines the lung pathways to become so thick that the cilia can’t push it out, leading to bronchiectasis — the swelling of the bronchi. When physicians tested the woman for such likely causes, however, the results came back negative. Her case was a total mystery.

CRACKING THE CASE STUDY

As she awaited her double lung transplant, the woman met Dr. Raghu Chivukula, at the time a pulmonary and critical care medicine fellow at MGH interested in rare and unusual lung diseases as a consequence of his PhD training in human genetics. During his time spent working with these often critically ill patients, “it became clear that there were lots of unanswered questions in lung biology and the basis of lung diseases,” he said. Chivukula soon realized that the woman’s condition was one of these unanswered questions.

Often, when doctors are unable to come to a diagnosis, they end up referring a patient to another hospital or to see a specialist. MGH, with its reputation as one of the top hospitals in America, sees quite a lot of these mysterious cases. They saw so many, in fact, that in 2016 the hospital created a program called the Pathways Consult Service, where scientists could evaluate these unusual patients to see whether their maladies might be something entirely new to science.  The program helps connect physicians with researchers in the Boston area to help come up with the technology and resources to dive deep into the biology of the patients’ undiagnosed conditions.

After his initial conversations with the woman with the lung condition, Chivukula reached out to the Pathways program to see whether they could help him further investigate her disease.

“We were so excited when Raghu, who is an incredible physician and scientist, came to us with this opportunity to learn about biology from this patient that he was seeing,” says Dr. Katrina Armstrong, the Physician-in-Chief of the Department of Medicine at MGH who works with the Pathways program.

As the woman waited for her lung transplant, Chivukula interviewed her about her medical history. He also talked to two of her siblings, who were in town to help their sister in the run-up to her operation. Talking to the three of them offered Chivukula a clue: respiratory infections ran in the woman’s family. Her two siblings showed similar, if milder, symptoms.

This finding led Chivukula, with help from the Pathways program, to send the genetic material of the woman, her parents, and her two siblings to Fowzan S. Alkuraya, a geneticist at King Faisal Specialist Hospital and Research Centre (KFSHRC), in Riyadh, Saudi Arabia. When the results came in, Alkuraya sifted through the data looking for mutations that could be playing a role in the family’s lung issues. Across all three genomes, one common difference stood out: a mutation in a gene called NEK10. “I wrote back to Raghu to tell him how excited I was for having identified this novel gene,” Alkuraya says.

Scientists weren’t sure what this gene did, although they knew it coded for a kinase — a type of protein involved in signalling by modifying other proteins with a phosphate group. Previous studies suggested the NEK10 protein might play a role in how cancer cells respond to DNA damage in humans and the formation of the nervous system in certain kinds of fish, but no research had ever linked its activity to any kind of human disease, or to the respiratory system.

Once he realized the woman’s mutation was affecting a kinase, Chivukula decided to take on the project as part of his postdoctoral research in David Sabatini’s lab at Whitehead Institute. Chivukula had initially begun working with Sabatini on a project about the role of lysosomes in the development of pulmonary fibrosis. Since Sabatini’s previous research has included a focus on understanding important protein kinases in cells, the new mutation seemed like a perfect additional project. “I was hopeful that the combination of my own interests in lung biology with David’s lab’s world-class cell biology expertise and specialized toolkit would allow us to figure out this disease,” Chivukula says.

THE MYSTERY MUTATION

To determine whether this mutation could be to blame for the woman’s condition, Chivukula and Sabatini took a closer look at the mutation itself; the changes in the woman’s DNA sequence didn’t make her cells express less NEK10, they found. Instead, the alteration caused the insertion of 7 additional amino acids in the NEK10 protein, which Chivukula hypothesized might render the protein unstable and not able to perform some key job in the woman’s lung cells.

Still, she was only one patient, and it was possible this specific mutation that appeared in the DNA of her and her siblings was unrelated to her condition. Was this just a fluke, the scientists wondered, or could NEK10 mutations be to blame in other cases of unexplained respiratory problems?

Chivukula started sending out feelers to other hospitals and research centers around the world. He hoped to find other patients with unexplained lung conditions that shared the mutations the woman and her siblings had in their NEK10 genes. Slowly, other accounts trickled in. Other hospitals had registered similar changes in patients’ DNA coding for the NEK10 protein, but didn’t have enough evidence to tie the gene to their conditions.

Chivukula’s search eventually turned up six additional patients. All of them — including several under the age of 25 — had different mutations in the NEK10 gene, but overall the effects were the same: changes in the amino acid sequence of the NEK10 protein, and a condition similar to the woman’s, marked by pneumonia-like flares and swollen, enlarged airways. Whatever NEK10 was doing, the scientists could now assume it was associated with keeping the pathways to and from the lungs healthy.

Armed with the evidence that this mutation was associated with these patients’ conditions, Chivukula went back to the lab to find out what exactly NEK10 was doing in cells. First, he needed to find where it was being used. To do this, he turned to mRNA, or messenger RNA, the intermediate step between DNA and proteins. When a cell needs to express a certain gene, it creates an mRNA transcript. That transcript carries the genetic information to the ribosomes, where it is made into a protein.

Chivukula and his colleagues obtained airway tissue from the woman — her transplant meant they had good access to tissues to study — as well as from a few from people with normal lungs. They used a kind of genetic testing that allowed them to see what RNA was being expressed in the cells, offering a clue to where the protein was used: there were large quantities of NEK10 mRNA in specialized airway tissue, but hardly any in undifferentiated lung stem cells.

To see if they could induce these undifferentiated cells to produce NEK10, the researchers cultured them in the laboratory, using a trick to mimic the lining of a human airway. By allowing the stem cells to grow on a thin film where liquid medium meets the air, the researchers coaxed the cells to slowly mature and differentiate into airway cells in the lab. When the researchers looked at this lab-grown tissue carefully, they found much higher expression of NEK10 mRNA. This meant that whatever the protein was doing, it was most active in the cells that lined the airways.

Next they wondered whether the protein might be functioning specifically within one type of airway cell, of which there are many varieties with different roles. To test this, they used a fluorescent protein to mark the cells expressing NEK10, making these cells glow green. When they allowed the cells to differentiate, the brightest glowing cells were those that were covered in cilia. This suggested to the researchers that the woman’s condition was a kind of ciliopathy, or disorder associated with cilia. Nearly all vertebrate cells have some kind of cilia, and mutations that affect their structures can have consequences such as polycystic kidney disease, retinal disease, and conditions such as obesity and cerebral anomalies.

In the lungs, cilia move mucus by wiggling back and forth in tandem with their neighbors. Moreover, previous studies had found that disruption of airway cilia could cause a disease akin to that seen in NEK10 patients. When Chivukula took a closer look at the woman’s airway cilia, he found that they still wiggled at the same speed, but something was off; while normal cilia could transport polystyrene beads on a slithery wave of mucus, her mutated cilia could barely move mucus at all.

Under a microscope, the cilia were strangely clumpy and underdeveloped. The mutation, it turned out, had caused the cilia to be too short to effectively move mucus, leading to a build-up in her airways. This mucus build-up increased her likelihood of respiratory infections and, with each infection, her bronchi grew more enlarged and swollen until she could barely breathe on her own.

A NEW DISEASE

Chivukula, Sabatini, and coauthors published their findings on the new disease in Nature Medicine in February. From what they’ve observed in the seven patients they studied, the condition follows an autosomal recessive inheritance pattern — the gene must be knocked out in both copies for airway cilia to be affected — much like cystic fibrosis and most forms of ciliopathy that affect the lungs or other tissues.

Further research will determine how variable the condition can be depending on the type of mutation in the NEK10 gene. “It’s entirely possible that there are milder or subtler variants of this gene that are not, on their own, causing this sort of end-stage lung disease,” Chivukula says.

That might mean a mutation in the NEK10 gene that led to a protein that was deformed rather than completely unstable, he says, although at this point it is impossible to know for sure. “What we do know is that this double knockout of the gene sort of phenotype is quite rare,” he says. “But like for many genetic diseases, once you understand the severe ones, you can use that information to really dig into the more common forms.”

As for the woman who received the double lung transplant, “She’s doing pretty well,” says Chivukula. “She doesn’t need oxygen and can finally walk around without becoming short of breath. Being sick for 20 years takes its toll like it would for anyone, but she’s in a much better state than she was before her transplant.”

Dr. Armstrong and others at MGH are excited by the potential applications of Chivukula’s findings. “It’s pretty unusual [for a Pathways case] to have quite as beautiful a story as Raghu was able to put together that quickly,” she says.

Maybe in the future, Chivukula says, other patients in the woman’s position will be able to be treated before their condition becomes severe enough to need a transplant in the first place. Although much research remains to be done before the condition could be cured, Chivukula believes the potential is there. Cilia, he points out, have been shown to change slightly due to external causes. For example, smokers can have cilia that are a tiny bit shorter than those of non-smokers.

“We’ve shown that delivering extra active NEK10 protein actually causes cilia function to be improved, so that does suggest that this condition could be druggable in the future,” he says. “We just need to understand the biology a little bit better.”

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By Eva Frederick

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Chivukula, R. et al. A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance. Nature Medicine. 2020 Feb. doi: 10.1038/s41591-019-0730-x.

Troy Littleton earns Award for Excellence in Undergraduate Advising
April 21, 2020

The Department of Brain and Cognitive Sciences is honored to announce this year’s awards for faculty, graduate students, and undergraduates. These individuals have contributed exceptionally to the academic and intellectual life of our department.

Faculty Awards

BCS Award for Excellence in Undergraduate Advising: Troy Littleton

As one nominator said:

“He is my go-to faculty member for academic and career support, and his door is always open when you need it the most…There have been challenges that I’ve faced here that feel insurmountable, but whenever those times hit, I could talk it through with Professor Littleton. With his guidance, we would work towards a solution… And when I did pull through, when I succeeded beyond my own imaginable expectations, his office was the first place I went to for celebration.”

BCS Award for Excellence in Undergraduate Teaching: Myriam Heiman

This award is based on student evaluations and nominations. Myriam co-teaches 9.09, Cellular and Molecular Neurobiology, and 9.18, Developmental Neurobiology. Some comments from her evaluations show why she is so admired as a teacher:

“Myriam was a great professor. She went through the material at a perfect pace, and really emphasized general understanding of the topics we were learning about. She was also very welcoming to questions.”

“Professor Heiman is thorough, passionate, and insightful. The devil is always in the details and she does an excellent job highlighting the significant points in the context of the course.”

BCS Award for Excellence in Graduate Teaching: Sasha Rakhlin

Sasha teaches 9.521, Mathematical Statistics—an Asymptotic Approach, and co-teaches 9.520, Statistical Learning Theory and Applications. As with the undergraduate teaching award, this recognition is based on both course evaluations and student input. Some comments from Sasha’s evaluations were:

“Very high-quality teaching, with good explanations of difficult ideas and methods.”

“The material by nature requires you to get dirty, and I think he went through the details at the correct level.”

“One of the best lecturers I’ve had at MIT.”

BCS Award for Excellence in Graduate Mentoring: Mark Harnett

This award is based on student nominations. As one of them said of Mark:

“He has been exceptional in supporting the students with their projects and making sure they have all they need to succeed in their experiments, both technically and conceptually. He also always made sure we are prepared for important steps in grad school (qualifying exams and committee meetings) and can deliver excellent presentations. He has always dedicated time to teach fundamental aspects of patch clamp electrophysiology to all rotating students, and is always available, and happy, to answer questions.”

BCS Postdoc Award to an Outstanding Postdoctoral Mentor: Roger Levy

Roger was nominated by one of his postdocs and endorsed by the Building 46 Postdoctoral Association.  His nominator wrote:

“Roger is a brilliant leader and role-model. Roger is compassionate and understanding of the academic and social issues that postdocs face and is someone whose guidance I seek and respect. He has supported me as I try to decide whether or not to pursue an academic career, really proving to me that he has no stake in the outcome besides my wellbeing. He also has [a] tremendously strong moral ethic that reflects science at its best: from issues ranging from conflicts of interest to open access and funding transparency.”

Finally, we have added a special recognition this year:

BCS Award for Excellence in Teaching: Robert Ajemian

Robert is a research scientist in the McGovern Institute who teaches 9.53, Emergent Computations Within Distributed Neural Circuits. Students in this course give exceptionally strong evaluations. For example:

“Robert’s biggest strength is his enthusiasm for the material and for the field in general … The course setup, with Daniel and Karthik sharing some of the instructor responsibility, was a really great feature of the course – the nature of our discussions always benefited from having a variety of expert perspectives.”

“I appreciated the fervor with which the material was presented, which made the class all the more engaging, as well as the emphasis on critical thinking and debate, which is an important but often overlooked aspect of good scientific thinking.”

Robert’s instructor scores support these comments— a 6.4 in his first year, 2018, and a 6.6 in 2019. With scores and comments such as these, it was clear that we should recognize his contributions, and we are pleased to do so.

Graduate Student Awards

Angus MacDonald Award for Excellence in Undergraduate Teaching by a Graduate Student

This award is named for an MIT alum and Corporation Member who was a key supporter of our department and particularly our undergraduate educational mission. This year we are recognizing three graduate students for exemplary teaching of undergrads based on subject evaluations and faculty nominations:

  • Maddie Cusimano
  • Mark Saddler
  • Lupe Cruz

The next two awards named for Walle Nauta, a pioneering neuroanatomist, a founding member of this department, an Institute Professor, and one of the founders of the field of neuroscience.

Walle Nauta Award for Excellence in Graduate Teaching by a Graduate Student, recognizing exemplary teaching of their fellow graduate students based on subject evaluations and faculty nominations.

  • Mahdi Ramadan
  • Victoria Beja-Glasser

Walle Nauta Award for Continuing Dedication to Teaching by a Graduate Student, a special honor for someone who has already received a teaching award from our department and has continued to be exemplary.

  • Mika Braginsky
  • Tobias Kaiser
  • Halie Olson

Undergraduate Awards

Academic Awards (cumulative GPA of 4.9 or greater)

Course 9, Year 4:

  • Katherine Collins
  • Apolonia Gardner
  • Seungweon Pak
  • Ashti Shah
  • Aaditya Singh
  • Yotaro Sueoka
  • Lena Zhu
  • Merryn Daniel
  • Jingxuan Fan
  • Stephanie Hu
  • Ohyoon Kwon
  • Habiba Noamany
  • Raimundo Rodriguez
  • Lauren Schexnayder
  • Sarah Wu
  • Irene Zhou

Course 9, Year 3:

  • Ayesha Ng
  • Albert Gerovitch
  • Kristine Hocker

Course 6-9, Year 4:

  • Alice Zhang

Course 6-9, Year 3:

  • Keith Murray
  • Michelle Yakubek
  • Jasmine Zou

Research Awards (nominated by PI)

  • Keith Skaggs (Course 9, Year 3)
  • Michelle Hung (Course 9, Year 3)
  • Ohyoon Kwon (Course 9, Year 4)

Congratulations once again to all award recipients!

Harnessing the moonseed plant’s chemical know-how
Eva Frederick | Whitehead Institute
April 20, 2020

In overgrown areas from Canada to China, a lush, woody vine with crescent-shaped seeds holds the secret to making a cancer-fighting chemical. Now, Whitehead Institute researchers in Member Jing-Ke Weng’s lab have discovered how the plants do it.

Plants in the family Menispermaceae, from the Greek words “mene” meaning “crescent moon,” and “sperma,” or seed, have been used in the past for a variety of medicinal purposes. Native Americans used the plants to treat skin diseases, and would ingest them as a laxative. Moonseed was also used as an ingredient in curare, a muscle relaxant used on the tips of poison arrows.

But the plants also may have a use in modern-day medicine: a compound called acutumine shown to have anti-cancer properties (although not tested specifically against cancer cells, the chemical has been shown to kill human T-cells, an important quality for leukemia and lymphoma treatments). Acutumine is a halogenated product, which means the molecule is capped on one end by a halogen atom — a group that includes fluorine, chlorine and iodine, among others. In this case, the halogen is chlorine.

Halogenated compounds like acutumine can be useful in medicinal chemistry — their unusual chemical appendages mean they react in interesting ways with other biomolecules, and drug designers can put them to use in creating compounds to complete specific tasks in the body. Today, 20% of pharmaceutical compounds are halogenated. “However, chemists’ ability to efficiently install halogen atoms to desirable positions of starting compounds has been quite limited,” Weng says.

Most natural halogenated products come from microorganisms such as algae or bacteria, and acutumine is one of the only halogenated products made by plants. Chemists finally succeeded in synthesizing the compound in 2009, although the reaction is time-consuming and expensive (10 mg of synthesized acutumine can cost around $2,000).

Colin Kim, a graduate student in the Weng lab at Whitehead Institute, wanted to know how these plants were completing this tricky reaction using only their own genetic material. “We thought, why don’t we ask how the plants make it and then upscale the reaction [to produce it more efficiently]?” Kim says.

“By understanding how living organisms such as the moonseed plant perform chemically challenging halogenation chemistry, we could devise new biochemical approaches to produce novel halogenated compounds for drug discovery,” Weng says.

Kim knew that for every halogenated molecule in an organism, there is an enzyme called a halogenase that catalyzes the reaction that sticks on that halogen. Halogenases are useful in creating pharmaceuticals – a well-placed halogen can help fine-tune the bioactivities of various drugs. So Weng, who is also an associate professor of biology at Massachusetts Institute of Technology, and Kim, who spearheaded the project, began working to identify the helper molecule responsible for creating acutumine in moonseed plants.

First, the scientists obtained three species of Menispermaceae plants. Two of them, common moonseed (Menispermum canadense) and Chinese moonseed (Sinomenium acutum), were known to produce acutumine. They also procured one plant in the same family called snake vine (Stephania japonica) which did not produce the compound.

They began their investigation by using mass spectrometry to look for acutumine in all three plants, and then find out exactly where in the plants it was located. They found the chemical all throughout the first two — and some extra in the roots of common moonseed. As expected, the third plant, snake vine, had none, and could therefore be used as a reference species, since presumably it would not ever express the gene for the halogenase enzyme that could stick on the chlorine molecule.

Next, the researchers started searching for the gene. They began by sequencing the RNA that was being expressed in the plants (RNA serves as a messenger between genomic DNA and functional proteins), and created a huge database of RNA sorted by what tissue it had been identified in.

At this point, the extra acutumine in the roots of common moonseed came in handy. The researchers had some idea of what the enzyme might look like – past research on other halogenases in bacteria suggested that one specific family of enzyme, called Fe(II)/2-oxoglutarate-dependent halogenases, or 2ODHs, for short, was capable of site-specifically adding a halogen in the same way that the moonseed’s mystery enzyme did. Although no 2ODHs had yet been found in plants, the researchers thought this lead was worth a look. So they searched specifically for transcripts similar to 2ODH sequences that were more highly expressed in the roots of common moonseed than in the leaves and stems.

After analyzing the RNA transcripts, Kim and Weng were pretty sure they had found what they were looking for: one gene in particular (which they named McDAH, short for M. canadense dechloroacutumine halogenase) was highly expressed in the roots of common moonseed. Then, in Chinese moonseed, they identified another protein that shared 99.1 percent of McDAH’s sequence, called SaDAH. No similar protein was found in snakevine, suggesting that this protein was likely the enzyme they wanted.

To be sure, the researchers tested the enzyme in the lab, and found that it was indeed the first-ever plant 2ODH, able to stick on the chlorine molecule to the alkaloid molecule dechloroacutumine to form acutumine. Interestingly, the enzyme was pretty picky; when they gave it other alkaloids like codeine and berberine to see if it would install a halogen on those as well, the enzyme ignored them, suggesting it was highly specific toward its preferred substrate, dechloroacutumine, the precursor of acutumine. They compared the enzyme’s activity to other similar enzymes, and found the key to its ability lay in the substitution of one specific amino acid in the active site– aspartic acid — for a glycine.

Now that they had identified the enzyme responsible for the moonseed’s halogenation reactions, Kim and Weng wanted to see what else it could do. A chemical capable of catalyzing such a complex reaction might be useful for chemists trying to synthesize other compounds, they hypothesized.

So they presented the enzyme with some dechloroacutumine and a whole buffet of alternative anions to see whether it might catalyze a reaction with any of these molecules in lieu of chlorine. Of the selection of anions, including bromide, azide, and nitrogen dioxide, the enzyme catalyzed a reaction only with azide, a construct of 3 nitrogen atoms.

“That is super cool, because there isn’t any other naturally occurring azidating enzyme that we know of,” Kim says. The enzyme could be used in click chemistry, a nature-inspired method to create a desired product through a series of simple, easy reactions.

In future studies, Weng and Kim hope to use what they’ve learned about the McDAH and SaDAH enzymes as a starting point to create enzymes that can be used as tools in drug development. They’re also interested in using the enzyme on other plant products to see what happens. “Plant natural products, even without chlorines, are pretty effective and bioactive, so it would be cool to see if you can take those plant natural products and then install chlorines to see what kind of changes and bioactivity it has, whether it develops new-to-nature functions or retain its original bioactivity with enhanced properties,” Kim says. “It expands the biocatalytic toolbox we have for natural product biosynthesis and its derivatization.”

***

Written by Eva Frederick

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Citation: Kim, Colin Y. et al. The chloroalkaloid (−)-acutumine is biosynthesized via a Fe(II)- and 2-oxoglutarate-dependent halogenase in Menispermaceae plants. Nature Communications. April 20, 2020. DOI: 10.1038/s41467-020-15777-w

Stretch and relax
Lucy Jakub
April 13, 2020

Consider the fruit fly, Drosophila melanogaster. Though it’s only a couple of millimeters long, its body is intricately complex. But it began, as most animals do, as an amorphous blastula—a hollow ball of dividing cells. During embryonic development, the structures of the body emerge as cells multiply and change shape, sculpting tissues into the mature forms dictated by the genetic code. One of the first structural changes is gastrulation, during which the blastula becomes multilayered with an ectoderm, mesoderm, and endoderm. In the developing fly, this occurs through a tissue folding mechanism. The first fold is the invagination of the mesoderm, when cells fated to become muscles contract and curl inward, leaving the cells fated to become skin on the exterior.

Biologists have traditionally focused on how cells generate force to understand cell and tissue shape change. But researchers at MIT have found that there’s another important, though often overlooked, player in tissue folding: cell division, or mitosis. By combining live-imaging with genetic mutations of developing Drosophila embryos, they observed that cell constriction and division can act together to promote folding, and that mitosis interferes with the accumulation of motor proteins that allows cells to generate force.

“What the results tell us is that the cell cycle and cell division might need to be tightly regulated relative to other shape changes that are happening in the tissue,” says Adam Martin, the senior author of the study published on March 13 in Molecular Biology of the Cell. “They present a new paradigm for thinking about how tissue shape might be regulated during development, and provide insight into what might cause birth defects in humans.” Clint Ko PhD ’20, a former graduate student in the Martin lab, was lead author of the study.

In 2000, three different labs identified a genetic mutation that caused premature cell division in developing Drosophila embryos. They found that the gene tribbles, named for the fuzzy, rapidly-reproducing animals in Star Trek, regulates cell division in the mesoderm of the fly, ensuring that cells only divide at the appropriate time. When that gene is deleted, cell division occurs before the mesoderm can properly internalize. What was notable about this mutant was that the blastula never folded, and remained a ball of cells instead of an envelope of tissue with an inside and an outside. This observation led researchers to believe that cell cycle regulation somehow regulates tissue folding. But, at the time, there was no live-imaging technology to visualize how cells changed in the developing embryo.

By using a fluorescent protein to visualize chromosome condensation, which marks the start of mitosis and the cell’s preparation for division, the researchers were able to use live-cell imaging to see how premature division might be interfering with cell constriction. When a cell prepares to divide, it expands and becomes rounded, before elongating—shape changes that exert force on neighboring cells. But something else was going on, too.Specifically, researchers in the Martin lab wanted to see what was happening to networks of the motor protein myosin, which allows cells to contract, in the tribbles mutant. Myosin is the same protein that allows our muscle tissue to contract when we flex. To facilitate tissue folding in the developing fly, myosin is concentrated at the top of the cells in the mesoderm, where they form the surface of the blastula. As this myosin constricts, the outer surface of the tissue shrinks and contracts inward.

“We noticed that when the cells are dividing, the apical myosin networks that are present disappear,” says Ko. Cells that had already begun to contract relaxed when they entered mitosis, indicating that it’s a loss of contractility in the tribbles mutant that prevents folding. The researchers suspect that this reversal occurs because mitosis disrupts signaling from the gene RhoA, which regulates contractility and cell shape changes during development. An undergraduate researcher in the lab, Prateek Kalakuntla, showed that regulation of RhoA changes at the start of mitosis.

“Initially we were just curious about the tribbles mutant,” says Ko. “But then we started exploring other ways of looking at how cell divisions affect myosin accumulation in cells.” They utilized a mutation in which the gene fog, which is located upstream of myosin activation on the genome, was overexpressed. (Fog is short for “folded gastrulation.”) Cells in the Drosophila ectoderm don’t normally contract, but with ectopic fog overexpression, those cells activated myosin, too. With live-cell imaging, the researchers observed furrows develop across the ectoderm.

“It was a bit unexpected to see these tissues folding when they shouldn’t be folding,” says Ko. Specifically, the folds occurred along the boundaries of mitotic domains, regions of spatiotemporally patterned cell divisions that occur in coordinated pulses. “That led to this sort of novel idea that cell divisions—particularly when they’re in this pattern where they’re interspersed between contractile cells—can actually promote tissue folding.”

Understanding the genetic basis for tissue folding, and how our genes control the development of specific bodily features, can help determine how birth defects arise during development. “If cell cycle control is misregulated during development, it could actually alter the shape of that tissue,” says Martin. The study paves the way for further research into how exactly the location of myosin in the cell is regulated, and how it is affected at the molecular level by cell division.

“We observed that when these cells enter mitosis, the localization of myosin activators changes. But we don’t really know how it changes,” says Ko. “That would be a pretty interesting research problem, especially considering that it’s such an integral part of force generation in cells.” Kalakuntla has begun investigating what controls these regulators, which will be an avenue of future research for the lab.

Top image: Myosin networks, in green, contract cell membranes in the mesoderm of a developing Drosophila embryo. Credit: Martin lab.

Citation:
“Apical Constriction Reversal upon Mitotic Entry Underlies Different Morphogenetic Outcomes of Cell Division”
Molecular Biology of the Cell, online March 4, 2020, DOI: 10.1091/mbc.E19-12-0673
Clint S. Ko, Prateek Kalakuntla, and Adam C. Martin

Katie Collins, Vaishnavi Phadnis, and Vaibhavi Shah named 2020-21 Goldwater Scholars

Three MIT undergraduates who use computer science to explore human biology and health honored for their academic achievements.

Fernanda Ferreira | School of Science
April 10, 2020

MIT students Katie Collins, Vaishnavi Phadnis, and Vaibhavi Shah have  been selected to receive a Barry Goldwater Scholarship for the 2020-21 academic year. Over 5,000 college students from across the United States were nominated for the scholarships, from which only 396 recipients were selected based on academic merit.

The Goldwater scholarships have been conferred since 1989 by the Barry Goldwater Scholarship and Excellence in Education Foundation. These scholarships have supported undergraduates who go on to become leading scientists, engineers, and mathematicians in their respective fields. All of the 2020-21 Goldwater Scholars intend to obtain a doctorate in their area of research, including the three MIT recipients.

Katie Collins, a third-year majoring in brain and cognitive sciences with minors in computer science and biomedical engineering, got involved with research in high school, when she worked on computational models of metabolic networks and synthetic gene networks in the lab of Department of Electrical Engineering and Computer Science Professor Timothy Lu at MIT. It was this project that led her to realize how challenging it is to model and analyze complex biological networks. She also learned that machine learning can provide a path for exploring these networks and understanding human diseases. This realization has coursed a scientific path for Collins that is equally steeped in computer science and human biology.

Over the past few years, Collins has become increasingly interested in the human brain, particularly what machine learning can learn from human common-sense reasoning and the way brains process sparse, noisy data. “I aim to develop novel computational algorithms to analyze complex, high-dimensional data in biomedicine, as well as advance modelling paradigms to improve our understanding of human cognition,” explains Collins. In his letter of recommendation, Professor Tomaso Poggio, the Eugene McDermott Professor in the Department of Brain and Cognitive Sciences and one of Collins’ mentors, wrote, “It is very difficult to imagine a better candidate for the Goldwater fellowship.” Collins plans to pursue a PhD studying machine learning or computational neuroscience and to one day run her own lab. “I hope to become a professor, leading a research program at the interface of computer science and cognitive neuroscience.”

Vaishnavi Phadnis, a second-year majoring in computer science and molecular biology, sees molecular and cellular biology as the bridge between chemistry and life, and she’s been enthralled with understanding that bridge since 7th grade, when she learned about the chemical basis of the cell. Phadnis spent two years working in a cancer research lab while still in high school, an experience which convinced her that research was not just her passion but also her future. “In my first week at MIT, I approached Professor Robert Weinberg, and I’ve been grateful to do research in his lab ever since,” she says.

“Vaishnavi’s exuberance makes her a joy to have in the lab,” wrote Weinberg, who is the Daniel Ludwig Professor in the Department of Biology. Phadnis is investigating ferroptosis, a recently discovered, iron-dependent form of cell death that may be relevant in neurodegeneration and also a potential strategy for targeting highly aggressive cancer cells. “She is a phenomenon who has vastly exceeded our expectations of the powers of someone her age,” Weinberg says. Phadnis is thankful to Weinberg and all the scientific mentors, both past and present, that have inspired her along her research path. Deciphering the mechanisms behind fundamental cellular processes and exploring their application in human diseases is something Phadnis plans to continue doing in her future as a physician-scientist after pursuing an MD/PhD. “I hope to devote most of my time to leading my own research group, while also practicing medicine,” she says.

Vaibhavi Shah, a third-year studying biological engineering with a minor in science, technology and society, spent a lot of time in high school theorizing ways to tackle major shortcomings in medicine and science with the help of technology. “When I came to college, I was able to bring some of these ideas to fruition,” she says, working with both the Big Data in Radiology Group at the University of California at San Francisco and the lab of Professor Mriganka Sur, the Newton Professor of Neuroscience in the Department of Brain and Cognitive Sciences.

Shah is particularly interested in integrating innovative research findings with traditional clinical practices. According to her, technology, like computer vision algorithms, can be adopted to diagnose diseases such as Alzheimer’s, allowing patients to start appropriate treatments earlier. “This is often harder to do at smaller, rural institutions that may not always have a specialist present,” says Shah, and algorithms can help fill that gap. One of aims of Shah’s research is to improve the efficiency and equitability of physician decision-making. “My ultimate goal is to improve patient outcomes, and I aim to do this by tackling emerging scientific questions in machine learning and artificial intelligence at the forefront of neurology,” she says. The clinic is a place Shah expects to be in the future after obtaining her physician-scientist training, saying, “I hope to a practicing neurosurgeon and clinical investigator.”

The Barry Goldwater Scholarship and Excellence in Education Program was established by Congress in 1986 to honor Senator Barry Goldwater, a soldier and statesman who served the country for 56 years. Awardees receive scholarships of up to $7,500 a year to cover costs related to tuition, room and board, fees, and books.