Mixing mitochondrial biology, mentoring — and doughnuts

Breann Brown works to be honest about the Black experience in academia without scaring talented students away from science.

Leia Dwyer | ASBMB
October 28, 2020

The phrase “the mitochondria is the powerhouse of the cell” has a jokey reputation in American education as a hallmark of middle school memorization-based learning. Breann Brown researches the structural biology of protein complexes regulating mitochondrial physiology, and she harks back to that well-worn phrase when she describes herself as, like the mitochondria, “small but mighty.”

As Breann Brown launches her lab during a period of international momentum for the Black Lives Matter movement, she considers the career implications of her identity as a Black woman.

Now an assistant professor in the biochemistry department at Vanderbilt University, Brown states with calm self-assurance, “I’ve always known a career in academia was for me.”

She does not remember a time when she wavered from her goal. She credits both a stubborn streak and the exceptional support of her family and academic mentors along her journey to a career she describes as “vocational.”

Encouraged by her parents, Brown attended an engineering program in high school, which helped kick-start her interest in science. She gained research lab experience during an internship before college, and she says now that such academic experiences and a commitment by colleges and universities to giving back to their local communities through educational opportunities are important because they expose school-age children, especially girls, to careers they might want to explore.

Before landing in Nashville, Brown steadily traveled the East Coast in her academic trajectory. Born and raised in the Washington, D.C., metro area, she attended Duke University as an undergraduate in chemistry and then earned her Ph.D. in molecular pharmacology and physiology in Rebecca Page’s lab at Brown University. Continuing north, she did her postdoctoral training in biology at the Massachusetts Institute of Technology with Tania Baker. Though she’s excited about her new lab at Vanderbilt, Brown said she misses one thing about the East Coast: the sports culture.

Building a basic research lab

For Brown, athletics and team dynamics translate from the field and court to her vision for building her research lab. She grew up playing team sports, including volleyball and softball, and she takes the same approach to learning skills in sports and research. “Mentorship is coaching,” she said. “I’ll show you how to do it, you’ll practice, you’ll get better and do it on your own.”

Brown arrived at Vanderbilt in 2019, so her lab is still young and growing, as is her role in mentoring her students. She took on her first graduate student in spring 2019 and a research assistant shortly thereafter. “I’m … a first-base coach right now,” she said. “I’ll be more like a third-base coach as my students start getting nearer to graduating.”

Brown describes the theme of her research in structural biology as “proper macromolecular protein complex assembly is critical for maintaining human health” through a variety of cellular processes. Her current focus is on mitochondrial biology and metabolism, an area so complex that “there are lots of avenues to pursue and a lot that we don’t know.”

Brown sees applications of her current work in mitochondrial encephalopathy, lactic acidosis and strokelike episodes, or MELAS, syndrome, a rare genetic disorder caused by mutations in the mitochondrial DNA. Her lab resides in the division of basic sciences, and she notes that Vanderbilt supports mechanistic and basic science–driven research with the understanding that strong fundamentals must precede developments in downstream applications. Her lab website states that other areas of interest include “assembly mechanisms responsible for regulation of heme biosynthesis, which is altered in several blood diseases, and maintenance of mitochondrial DNA copy number, which has direct implication in proper neuronal development.”

‘A Black woman first’

As Brown launches her lab during a period of international momentum for the Black Lives Matter movement, she actively considers the implications of her identity in her career. “I identify as a Black woman first and foremost,” she said, “and everything else comes after that.”

As many institutions in the U.S. prioritize creating a space for talking about race, Brown believes it is crucial to bring diverse perspectives to these conversations in academia and to move forward with the aim of making concrete changes. She wants to communicate her experience as best she can, she said, and she has reached a point in her career where she is comfortable speaking her mind. She feels a responsibility to represent herself as a Black woman to the next generation of scientists because, she said, “Being a Black woman in science is not easy.”

Brown works to stay true to herself as she develops her voice at Vanderbilt. Her aim is to balance mentoring students, teaching classes, building a lab, representing herself as a Black woman and all the other challenges of academic life in a way that doesn’t turn people off science. “I never walk into lab in a power suit,” she said. “I joke around, and I don’t want to lose that.”

Doing hands-on lab work and troubleshooting is part of what originally drew her to science, and today she goes into the lab as often as she can. She likes the freedom and flexibility she has as an academic to structure her schedule and follow her own path.

Another passion for Brown is finding ways to satisfy her sweet tooth, and she fuels her lab with Nashville’s finest local bakery fare. She searches the city for new bakeries and coffee shops and flexes her chemistry muscles in the kitchen, experimenting with her own pies and cakes. In the race to satisfy her craving, she said, one sweet is leading at the bench: “Our lab is a doughnut lab.”

Amaris Torres-Delgado: biochemist, process development scientist, and salsa dancer

How an MIT Biology alum from Puerto Rico came to love living in Boston

Saima Sidik
October 27, 2020

Even as a kid, Amaris Torres-Delgado PhD ’16 was analytical. “I wanted to be fact-based,” she says. “Once I had the facts, I’d speak with conviction.” As a result, her family wasn’t surprised that she decided to earn a PhD from MIT Biology, then apply for jobs in the pharmaceutical industry. Now, she works as a process development scientist at Amgen, where she uses her analytical skills to optimize drug production.

Torres-Delgado grew up in Puerto Rico, and the people, mindsets — and even the food — that she encountered in Cambridge, Massachusetts were unfamiliar at first. But after a decade of living in the Boston area, Torres-Delgado has come to love her new home, and she embraces the diversity of people and scientific problems she encounters.

Young child sitting on stairs
Even as a young child, Torres-Delgado was curious and analytical. Here she is at age three, on her first day of school. Credit: Escuela Josefita Monserrate de Selles

In high school, Torres-Delgado considered becoming either a medical doctor or a lawyer. But because Torres-Delgado loves problem solving, her mother suggested that she consider becoming a scientist instead. This advice led her to earn a bachelor’s degree in industrial biotechnology from the University of Puerto Rico at Mayaguez. The drug company Amgen helped create this degree program in order to train future employees for its Puerto Rican branch. Torres-Delgado found the program to be an exciting opportunity to learn a combination of biology, chemistry, and chemical engineering, as well as a doorway into a meaningful career in the pharmaceutical industry.

During college, Torres-Delgado spent a summer working in Tania Baker’s lab as part of the MIT Summer Research Program in Biology (MSRP-Bio). “The mentorship I received was wonderful,” she says, and so when she was accepted to the MIT Biology Graduate Program, she didn’t hesitate to return, and she opted to stay in the Baker lab.

Being more than a thousand miles from home left Torres-Delgado feeling lonely, but fortunately, another Puerto Rican graduate student introduced her to a new hobby: salsa dancing. “We’d go to socials at the different salsa schools around Boston,” Torres-Delgado says. With this new community, she started to feel less homesick.

In the lab, Torres-Delgado became captivated by a protein degradation machine that others in the Baker lab were studying. Cells use these wood-chipper-like machines to regulate protein levels, and a component of this machine called ClpS carries proteins to the site where they’re destroyed. Strikingly, ClpS speeds up the degradation of some kinds of proteins and slows down the degradation of others, but no one had been able to figure out why. Although other Baker lab members told Torres-Delgado that the ClpS mystery would be tricky to solve, she was determined to crack this cold case.

By the end of her PhD, she’d discovered that, in addition to delivering proteins to the degradation machine, ClpS sits on the same machine and makes it work less efficiently. Carrying certain proteins to the machine speeds up their degradation, but sitting on the machine slows down degradation of incoming proteins.

Although she enjoyed learning biochemistry in the Baker lab, Torres-Delgado says, “I’ve always been excited about pharmaceutical work that goes on close to the patient.” Her original plan was to return to Puerto Rico after earning her doctorate in order to work as an industry scientist there, but when she finished her PhD, she felt like she wasn’t done exploring Boston.

Torres-Delgado and her PhD advisor, Tania Baker. Credit: Juan E. Parra

She took a job at Vertex Pharmaceuticals with a group that oversaw manufacturing of the company’s first drug based on a biological molecule. While many drugs are produced through chemical reactions, this drug was produced in living cells, and Torres-Delgado was part of the team that supervised this new area of drug production. The biochemistry she’d learned during her PhD gave her the scientific background to provide valuable insight, but Torres-Delgado had a lot to learn about the process of efficiently producing a high-quality drug, and her industry colleagues helped her pick up the new skills she needed.

“I learned these skills on the job, from my peers, and this way of learning is something that’s available and encouraged,” she says. “You don’t have to be super focused on your long-term career goals during your training.” She’s since moved to Amgen’s Cambridge branch, where she works in process development as part of their oncology division.

Ten years after leaving her childhood home in Puerto Rico, Torres-Delgado still doesn’t feel like she’s finished living in Boston. She moved north at an impressionable point in her life, at a time when minority rights were gaining traction, and the people and philosophies she found in Boston have impacted her world view substantially.

“As a young adult, I wanted to experience a way of living that differed from how I grew up,” she says. “I didn’t realize how much more there is to the world until I moved to Boston. Here, I’ve had the opportunity to learn about other religions, other cultures, people from the whole gender spectrum — even understanding that there is a gender spectrum was a new experience.”

Torres-Delgado also finds diversity in her job, which includes a variety of tasks like figuring out how to optimize a manufacturing process, making sure Amgen meets regulatory standards, and mentoring other scientists. Underlying all these skills is the same analytical mindset that she started developing back in Puerto Rico and built on at MIT — it’s all about leveraging the facts.

Posted 10.22.20
Top photo: Amaris Torres-Delgado/Ammar Arsiwala
Bench, bath and beyond

Transform your apartment into a yeast lab, and have fun doing it!

Grad Admissions Blog | Veda K.
October 22, 2020
One of the very first lessons you learn in microbiology is that while countless things can – and will – go wrong, you can almost always count on your microbes to grow. There is some strange comfort in knowing that what looks like clear liquid today will reveal countless gleaming colonies smiling up at you from your petri dish tomorrow. This radical assurance of growth transforms the many tedious tasks of lab work into an almost meditative experience. Pouring, plating, streaking — these could easily be yoga poses in the clinically sterile studio of a BSL-2 lab[1].

When the pandemic-that-shall-not-be-named abruptly separated me from my work this March, I threatened to bring the lab home. Unsurprisingly, my roommates were far from enthused at the idea of me culturing human pathogens in our garage. Somewhere in-between trying to bribe them with beer and baked goods I realized I could turn my scientific focus on an organism far more delicious than MRSA[2]: yeast!

Yeast, the tiny organism so miraculous that it was known as “godisgoode” in the days before microscopes were invented, is behind the magical transformations that give us beer, wine, sourdough, doughnuts, kombucha — you name it. In our technological times, it is tempting to relegate the study of microbes to sterile, fluorescently-lit, strictly controlled labs where the genetically engineered organisms you order off the internet live pampered lives. In quarantine in my own home, I re-discovered a centuries-old truth: yeast will appear and grow anywhere. Like any good pet, yeast are largely well-behaved and will sit, stand, and shake your hand on command. Disclaimer: they may also bubble over and stain your carpet in unsavory ways.

With a bit of intuition and a lot of patience, you too can transform any apartment into a lab to grow your pet yeast in!

The kitchen: your new bench

Sourdough: needy but delicious

Growing your own sourdough starter is a relatively low-effort process that is not only ridiculously easy, it also lends you serious kitchen clout. All you need to get started are flour, water, and the right temperature. Combine the flour and water in equal quantities in a container with quite a bit of headspace. “Feed” your starter once a day by replacing half of it by weight with a fresh water-flour mixture. Grow your starter at 68-75F. In the cold of the winter, yeast will take longer to grow and consume the complex nutrients in flour. In the summer, your starter may be so active it requires “feeding” twice a day!

 A young starter with “hooch” on top

As the complex community develops in your starter, it will go from being watery (the liquid on top is actually called “hooch”, if that is any indication of its actual nature) and frankly pretty stinky to bubbly and aromatic. Your nose and eyes are your best tools for judging what bugs are living in your starter (move over, Illumina[3]!). Fuzzy and white? Probably mould! Orange and cheesey? Serratia marcescens is likely the culprit. Simply use a clean spoon to remove these offending species. The wonderful magic of your starter is that, as a living community of wild yeasts and bacteria, it will eventually fend off nastier invaders and reach a set-point of well-behaved yeast. Patience is crucial! Keep feeding, and believe in “godisgoode”.

As a microbiologist, I must admit that the process of developing a working starter far outweighed the actual bread-baking process. For those of you who are excited about baking – the starter can be used for pancakes, doughnuts, muffins, cake, almost any dessert that uses dry active yeast. When you need a break from your prolific baking streak, simply pop your starter in the freezer and it’ll be ready for the next time you get hungry!

Beer: hurry up and wait

Over our many weeks in confinement, my roommates and I have been refining our beer-tasting palates by attending Lamplighter Brewery’s virtual tasting events. The wonderful folks at lamp gave me my first introduction to how beer is made and, eager to fill my weekends with more than just existential dread, I decided to venture into brewing.

To be completely honest, I’d also been missing those $6 pitchers of High Life at the Muddy (the Muddy Charles Pub, a campus highlight).

Like baking, brewing is a process that has engendered a cult-following. Homebrewers take their craft seriously, and you can find countless blog posts and youtube videos describing everything from sanitization techniques to pitch rates (how much yeast goes in) to heated debates on hop flavor profiles. To an MIT grad student, drinking from this “firehose” of information should feel almost comfortable, if you can withstand the flashbacks to 7.51 (principles of biochemical analysis). The trick, I’ve learned, is to dive in headfirst and take in specific pieces of information only as needed.

Brewing requires a little more investment than baking. The equipment you need will likely not be lying around the house, and unfortunately cannot be repurposed for much if you find that brewing isn’t quite your thing. The good news is that there are several companies selling pre-assembled “kits” to get you started on your boozy journey. After doing some research of my own, and soliciting advice from my homebrewer friends, I went with an IPA kit that included most of the hardware I’d need.

My first (and only, so far) brew day was a 6-hour process. Like any experiment in the lab, I anxiously sanitized, scrubbed, stirred, heated and cooled alternately. The day after, I realized my hyper-aware level of caution had been superfluous – my yeast were happily bubbling away in their preferred temperature range of 68F-75F. Little did I know that they’d still be bubbling away two weeks later at 91F (!!), thanks to the heat of a Boston summer and a failed condenser in our central AC.

The garage: your new incubator / engineering lab

Once your beer has been brewed, it needs to ferment in a cool, dark place for two weeks. The only cool, dark place in our now very hot apartment is our garage, which has been taken over by my MechE roomie (hey Annie!) Annie, not constrained by a study of deadly bacteria, was uninhibited in her assembly of a mini-engineering lab in our garage, even having equipment sent directly to our apartment! My yeast and fermenting beer join her assorted selection of wires in filling the void in our hearts normally filled by our labs.

Sourdough starter fed and beer bottled, all that is left to do is wait. In between waiting for bread and booze, I like to sneak in some studying for my upcoming qualifying exams!

As we become ever more intimately acquainted with our homes and the yeast that inhabit them, I highly encourage you to experience the magic of micro-organismal life for yourself. Biting into that first slice of bread or taking your first sip of home-brewed beer is a fulfilling reminder that, but for the pardoning mercy of an only 99.99% effective clorox wipe, our sterile world would be dull and flat. Grant yourself a moment to breathe and celebrate the 0.01% of microbes that make our world wonderful — you’ll be back in the lab in no time!

[1] Biosafety level 2 (BSL-2)refers to  laboratories that work with biological agents that pose a moderate health hazard

[2] Methicillin-Resistant Staphylococcus Aureus (MRSA) is a form of antibiotic resistant bacteria that causes infections

[3] Illumina is a DNA sequencing company that is well known for its technology

Course 7 Alums Named to 2020 Fortune 40 Under 40 List
Julie Fox | Slice of MIT
October 21, 2020

To mark a year of “monumental change,” the editors of Fortune say they decided to upend the publication’s annual “40 Under 40” feature, forgoing a single list and instead highlighting 40 influential people in each of five categories: finance, technology, health care, government and politics, and media and entertainment.

Read on to meet the six MIT alumni who made this year’s list. And learn more about them and the other honorees on the Fortune 40 Under 40 website. (All images via Fortune.)

Fortune 2020 “40 Under 40”: MIT Alumni

Amir Barsoum MBA ’20 (Health Care)

Founder and CEO, Vezeeta

“A Zocdoc-like platform…to empower people with information about health providers that has been traditionally hard to find in the region.” Read more: Fortune.

Suelin Chen ’03, SM ’07, PhD ’10 (Health Care)

CEO, Cake

“A web-based service that helps users plan for their end-of-life goals and wishes.” Read more: Fortune.

Jason Kelly ’03, PhD ’08 (Health Care)

Cofounder and CEO, Ginkgo Bioworks

“The company’s early investment in automation made it uniquely well equipped to tackle Covid-19…building a facility capable of testing 100,000 samples a day.” More: Fortune.

Akshay Naheta SM ’04 (Finance)

Senior vice president of investments, SoftBank Group

“Helping implement the [Japanese telecom] company’s multibillion-dollar plan to win back shareholder confidence.” More: Fortune.

Kartik Ramamoorthi PhD ’14 (Health Care)

Cofounder and CEO, Encoded Therapeutics

“An inventor and provisional patent holder with more than a dash of scientist and entrepreneurial spirit.” More: Fortune.

Rebecca Elizabeth Lipon Weekly ’03 (Technology)

Senior director of cloud business strategy and platform enabling, Intel Corporation

“Helps craft products and features to appeal to Intel’s cloud provider customers amid fierce competition from AMD and Nvidia.” More: Fortune.

Type 1 diabetes from a beta cell’s perspective
Eva Frederick | Whitehead Institute
September 24, 2020

Type 1 diabetes is an autoimmune disease that occurs when T-cells in the immune system attack the body’s own insulin-producing cells, called beta cells, in the pancreas. Usually diagnosed in children and young adults, type 1 diabetes accounts for around five percent of all diabetes cases.

The underlying biology of type 1 diabetes is tricky to study for a number of reasons. For one thing, by the time a person begins to show symptoms, their T-cells have already been destroying beta cells for a long period — months or even years. Also, the initial trigger for the disease is often unclear; a number of beta cell proteins can set off the immune response.

In a study published Sept. 22 in Cell Reports Medicine, researchers in the lab of Whitehead Institute Founding Member Rudolf Jaenisch demonstrate a new experimental system for more precisely studying the mechanisms of type 1 diabetes, focusing on how a person’s beta cells respond to an attack from their own immune system. In doing so, they reveal features of the disease that could be targets for future therapeutics.

“Here our question was, let’s say the T cells get activated; what happens next from the perspective of beta cells? Could we find some potential intervention opportunities?” said Haiting Ma, a postdoctoral associate in Jaenisch’s lab and the first author of the study.

Ma, working with Jaenisch, also a professor of biology at MIT, and Jacob Jeppesen, Novo Nordisk’s Head of Diabetes and Metabolism Biology, took a synthetic biology approach to achieve this goal.

The researchers engineered a system by inducing human pluripotent stem cells to differentiate into functional pancreatic beta cells, and added a model antigen called CD19 to these cells using CRISPR techniques. They established that these cells functioned as insulin-producing beta cells by implanting them in diabetic mice; upon receiving the cells, the mice experienced an improvement in glucose levels.

They then replicated the autoimmune components of the disease using engineered immune cells called CAR-T cells. CAR-T cells are T-cells tailor-made to attack a certain type of cell; for example, they can be targeted to tumor cells to treat certain types of cancer. For the diabetes model, the researchers engineered the cells to contain receptors for the model antigen CD19.

When the researchers cocultured the synthetic beta cells and CAR-T cells, they found the system worked well to mimic a simplified version of type 1 diabetes: the CAR-T cells attacked the beta cells and caused them to enter the process of cell death. The researchers were also able to implement the strategy in humanized mice.

Using their new experimental system, the researchers were able to identify some interesting factors involved in the beta cells’ response to diabetic conditions. For one thing, they found that the beta cells cranked up production of protective mechanisms such as the protein PDL1. PDL1 is a protein found on non-harmful cells in the body that, in normal circumstances, prevents the immune system from attacking them.

Changes in PDL1 levels had been associated with type 1 diabetes in previous studies. Now, Ma wondered if it was possible to rescue the beta cells from the immune onslaught by inducing the expression of even more of the helpful protein. “We found that we can help beta cells by giving them a higher expression of PDL1,” he said. “When we do this, they can do better in the model.” If validated in human cells, increasing expression of PDL1 could be evaluated as a potential therapeutic method, Ma said.

Another finding concerned the way the cells died after T-cell attack. Ma found that the genes that were being upregulated as the beta cells were under attack were associated not with the usual form of cell death, apoptosis, but with a more inflammatory and violent kind of cell death called pyroptosis.

“The interesting thing about pyroptosis is that it causes the cells to release their contents,” Ma said. “This is in contrast to apoptosis, which is considered to be the main mechanism for autoimmune response. We think that pyroptosis could play a role in propelling this autoimmune reaction, because the contents from beta cells include multiple potential antigens. If these are released, they can be picked out by antigen presenting cells and start to crank up this autoimmunity.”

The process of pyroptosis in the context of beta cell autoimmunity could be linked to ER stress in beta cells, a highly secretory cell type. Indeed, an ER stress inducing chemical increased the marker of pyroptosis.

If researchers could find a way to inhibit the process of pyroptosis safely in humans, it could potentially lessen the severity of the autoimmune reaction that is the hallmark of type 1 diabetes. Pyroptosis is mediated by a protein called caspase-4, which can be inhibited in the lab. “If that can be validated in patient beta cells, that could indicate that modulating caspases could also be [a therapeutic mechanism],” Ma said.

Going forward, Ma and Jaenisch plan to investigate the immune mechanisms underlying autoimmunity in humans by using induced pluripotent stem cells from patients with type 1 diabetes. “These cells could be differentiated into immune cells such as T, B, macrophage, and dendritic cells, and we can investigate how they interact with beta cells,” Ma said.

They also plan to keep improving their new experimental system. “This system provides a very robust and tractable synthetic immune response that we can use to study type 1 diabetes,” said Jaenisch. “In the future it could be used to study other autoimmune diseases.”

This study was supported by a generous gift from Liliana and Hillel Bachrach, a collaborative research agreement from Novo Nordisk, and NIH grant 1R01-NS088538 (to R.J.).

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Written by Eva Frederick

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Citation:

Ma, H., Jeppesen, J, and Jaenisch, R. “Human T-cells expressing a CD19 CAR-T receptor provide insights into mechanisms of human CD19 positive cell destruction.” Cell Reports Medicine. Sept 22. https://doi.org/10.1016/j.xcrm.2020.100097