netbet sports betting app

A force for health equity

Through on-site projects in developing countries and internships in the business world, Kendyll Hicks explores the political and economic drivers of global health.

Becky Ham | MIT News Office
March 1, 2020

After spending three weeks in Kenya working on water issues with Maasai women, Kendyll Hicks was ready to declare it her favorite among the international projects she’s participated in through MIT.

As a volunteer with the nonprofit Mama Maji, Hicks spoke about clean water, menstrual hygiene, and reproductive health with local women, sharing information that would enable them to become community leaders. “In rural Kenya, women are disproportionately affected by water issues,” she explains. “This is one way to give them a voice in societies that traditionally will silence them.”

The team also planned to build a rainwater harvesting tank, but climate change has transformed Kenya’s dry season into a rainy one, and it was too wet to break ground for the project. During her stay, Hicks lived in the home of the first female chief of the Masaai, Beatrice Kosiom, whom Hicks describes as “simultaneously a political animal and the most down-to-earth-person.” It was this close contact with the community that made the project especially fulfilling.

During MIT’s Independent Activities Period, Hicks also has traveled to South Africa to learn more about the cultural and biological determinants of that country’s HIV/AIDS epidemic, and to Colombia to lead an entrepreneurial initiative among small-scale coffee farmers. Hicks joined the Kenya trip after taking an MIT D-Lab class on water, sanitation, and hygiene. Each experience has been successively more hands-on, she says.

“I’ve been drawn to these experiences mainly because I love school, and I love the classroom experience,” Hicks says. “But it just can’t compare to living with people and understanding their way of life and the issues they face every day.”

Hicks, a senior majoring in computer science and molecular biology, says she has shifted her focus during her time at MIT from more incremental technical discoveries to addressing larger forces that affect how those discoveries contribute — or fail to contribute — to global health.

Her love of biology began with animals and zoology, later expanding into an interest in medicine. “Humans are these amazing machines that have been crafted by nature and evolution, and we have all these intricacies and mechanisms that I knew I wanted to study further,” Hicks says.

At the same time, she says, “I’ve always been interested in health care and medicine, and the main impetus behind that is the fact that when someone you love is sick, or if you’re sick, you’ll do whatever you can.”

As a first-year student she worked in the Lippard Lab at MIT, helping to synthesize and test anticancer compounds, but she soon decided that lab work wasn’t the right path for her. “I made the realization that health care and medicine are extremely political,” she recalls. “Health policy, health economics, law — those can be the drivers of real large-scale change.”

To learn more about those drivers, Hicks has worked two summers at the management consulting firm McKinsey and Company, and will take a full-time position with the company after graduation.

“As someone immersed in the world of science and math and tech, I had this lingering insecurity that I didn’t know that much about this entirely different but super-important area,” she says. “I thought it would be important to understand what motivates business and the private sector, since that can have a huge effect on health care and helping communities that are often disenfranchised.”

Hicks wants to steer her work at McKinsey toward their health care and hospital sector, as well as their growing global health sector. Over the long term, she is also interested in continuing fieldwork that involves science, poverty eradication, and international development.

“Being at MIT, it’s like this hub of tech, trying to venture further into novel breakthroughs and innovations, and I think it’s amazing,” Hicks says. “But as I have started to garner more of an interest in politics and economics and the highly socialized aspects of science, I would say it’s important to take a pause before venturing further and deeper into that realm, to make sure that you truly understand the downstream effects of what you are developing.”

“Those effects can be negative,” she adds, “and they oftentimes impact communities that already are systematically and institutionally oppressed.”

Hicks joined MIT’s Black Students Union as a first-year student and now serves as the BSU Social and Cultural Co-Chair. In the role, she is responsible for planning the annual Ebony Affair fly-in program, which brings more than 30 black high school students to campus each year to participate in workshops, tour labs, and join a gala celebration with BSU students, faculty, and staff. “We’re doing our best as a community to convince young bright black minds to come to a place like MIT,” she says.

It worked for Hicks: She participated in Ebony Affair as a high schooler, and the experience cemented her decision to attend. “When I saw everyone showing out and having such pride in being black and being at MIT, I was like, ‘OK, I want to be a part of that,’” she recalls.

Last year, Hicks planned BSU’s first Black Homecoming event, a barbecue that brought together current and former black MIT students — some who attended the school 50 years ago. The event was a celebration of support and a way to strengthen the BSU network. “You have to do what you can to cultivate communities wherever you are, and that’s what I’ve tried to do here at MIT,” she says.

Hicks also served as the Black Women’s Alliance alumni relations chair and GlobeMed’s campaigns co-director, and was on the Undergraduate Association Diversity and Inclusion Committee. She has discovered a love of event organizing and leadership at MIT, although it has been a change of pace from her former shy, “hyper-bookworm” self, she says.

“I have realized that in my career that I really want to do a lot of good and affect a lot of change in people’s lives, and in order to do that, you kind of have to be this way.”

Unusual labmates: Biology all-stars
Greta Friar | Whitehead Institute
February 25, 2020

NetBet sport

Zak Swartz, a postdoctoral researcher in Whitehead Institute Member Iain Cheeseman’s lab, gets an unusual delivery a few times a year. It comes in a cardboard box a few feet in length on each side with a “perishable” label on top. When the most recent box arrived, Swartz took it to a small, chilly room across from Cheeseman’s lab. He cut and tore his way through several layers of packaging, insulation, and cold packs to get to his prize: a bunch of plastic bags half-filled with water, the sort of thing that might contain a goldfish at a county fair. Instead of goldfish, these makeshift aquaria each contained two or three bat stars (Patiria miniata), a hardy species of starfish seemingly unphased by their transcontinental trip in a cardboard box.

Bat stars are so named because the thick webbing between their arms—of which they typically have five, though they can have up to nine—gives their short limbs a bat-wing-like appearance. The stars are most often some shade of red or orange, but come in a variety of colors and patterns. Each star that Swartz pulled out of the box had a unique design coating its body.

Swartz untied the plastic bags and took the bat stars out one by one. netbet online sports bettingHe gently dropped each star into an aquarium in the corner of the room, where it would sink slowly to the bottom, then crawl to the sides and inch its way up, clinging to the glass. Although their movements are barely perceptible to a human watching, within minutes bat stars coated the walls of the aquarium, the tiny tube feet on the underside of each arm sticking them firmly in place.

As the first round of bat stars settled onto their chosen perches, Swartz returned to the box. He took another bat star out of its bag and held it in his hand for a moment.

“This one’s heavy,” he said, with satisfaction; heavy stars are more likely to be full of eggs, and that’s what Swartz is interested in. He’s researching how cells, such as immature egg cells, that remain dormant or non-dividing for a long time retain their ability to divide. The proteins necessary for cell division degrade over time, like parts of a machine rusting and breaking down, and yet many cells remain able to divide long after their unused cellular machinery should have become useless. In the case of humans, precursor egg cells can spring back into action after decades of dormancy in the ovaries, and can go on to perform that most impressive feat of cell division: the creation of a whole new organism from one cell. But human eggs are not the most accessible or readily available research material, and so Swartz has turned to the bat stars, an excellent source of reproductive cells, to help answer his questions.

Fertile ground for discovery

Bats stars reproduce by spawning. The females release millions of eggs into the ocean through pores in between their arms, while at the same time males release clouds of sperm. The reproductive characteristics of bat stars make them ideal research animals for Swartz. They have a long breeding season during which they can ovulate, they produce millions of eggs at a time, and they release these eggs out into their environment, where they develop externally.

In the lab, Swartz must extract the immature egg cells before they are released, so he can study the processes that take place in the cells during their development. This is much easier than extracting cells from mammalian ovaries; all it requires is a minimally invasive procedure from which the starfish quickly recover. Once Swartz has extracted the eggs in their “hibernating” pre-spawn state, he can control and observe all of the steps of their development, from their re-activation through to fertilization and beyond.

In the wild, fertilized bat star eggs develop into embryos, which quickly become tiny, transparent larvae that swim freely and live as plankton. These larvae have strong regenerative capabilities: if a bat star larva is cut in half, each half can regrow the missing parts of its body. Some species of starfish maintain robust regenerative capacity into their adult stage.
Unlike the adult stage of the bat star, the larvae have bilateral symmetry, with mirroring left and right sides, just like humans. Bat stars develop through several stages as bilateral larva, becoming a bipinnaria and then a brachiolaria. These stages are transparent, their insides easily visible—a good feature for research subjects. Only when the stars metamorphose into their juvenile and then adult forms do they assume their familiar, five-point radially symmetric shape.
Bat stars share a common ancestor with mammals, and bat star and human embryonic development are similar enough for the former to be a useful model for the latter in research like Swartz’s. In fact, bat stars belong to the phylum Echinodermata, a group of animals also including sea urchins, sea cucumbers, sand dollars and others, that have historically proved to be important tools for research into reproduction. The first observation of sperm fertilizing an egg occurred in transparent sea urchin eggs, which helped solve the mystery of how each sex’s gametes contribute to sexual reproduction.

One reason Swartz has chosen bat stars over other starfish species is because of their hardiness. Bat stars fare well in a laboratory aquarium—they even do well being shipped in a cardboard box—whereas other species that Swartz considered using are less adaptable to these conditions. So, while it may have been more convenient to use a species from local Atlantic waters, in the interest of maintaining a healthy lab population of specimens, Swartz has had to procure his research subjects long distance. The geographical range of bat stars is the stretch of Pacific Ocean along the coast of North America.

How are the animals getting from the Pacific coast to Whitehead Institute? They are collected by a contact Swartz made several years ago in California.

Scuba diving for science

Josh Ross runs a research specimen procurement company based in San Pedro, California called South Coast Bio-Marine. Ross has been collecting starfish for Swartz since 2015, and he also collects a variety of marine animals, from sea urchins to limpets to nudibranchs, for researchers at other institutions. Specimens from South Coast Bio-Marine have been used in research on, among other topics, fertilization, memory formation, sleep, and shape changes in oocytes.

Most mornings, Ross and his employees load up a boat with scuba gear and equipment and head to their chosen dive spots, where they collect specimens for the first half of the day.

“I love the fact that I get to dive and work in the ocean every day. When Monday comes, all the weekend boaters and fishermen go back to their jobs, and we have the ocean almost all to ourselves. We are out in the wilderness with truly wild ocean creatures,” Ross says—though sometimes those wild creatures can interfere with their collection plans.

The team then take what they have collected back to Ross’ lab, where the specimens are kept in chilled seawater tanks for a few days to acclimate before Ross ships them to researchers. Ross takes care to harvest specimens with sustainability in mind. When finding starfish for Swartz, he will only take animals that have had time to grow large and spawn several times in their native habitat before being collected.

Ross searches for bat stars at dive sites in 55- to 70-foot deep water, either out in the open, on rocky shelf reefs, or on the sand near the reefs. Bat stars’ habitat ranges from the low intertidal zone, the part of the seashore that’s covered with water except at low tide, into the mild depths of the subtidal zone. They live among kelp and surf grass forest, and use the numerous tube feet lining the underside of each arm to crawl across the sandy ocean floor and cling to rocks. Instead of blood, starfish pump sea water through a water vascular system to circulate nutrients through their bodies and control their limbs. They pump water into and out of their tube feet to make them extend and contract, allowing the stars to move. The tube feet can also release glue-like chemicals that help the stars adhere to rocks even in the strong currents of the ocean—or cling to glass walls in aquariums.

Bat stars are voracious eaters—scavengers as well as predators—and Ross often finds them in the middle of a meal. Bat stars eat by extending their stomachs out of their bodies to dissolve their prey in digestive juices, then drink it up. This system allows them to eat larger prey than their small mouths would otherwise allow. A second stomach that remains inside the star further digests the food.

Ross tries to select starfish for Swartz that feel “ripe,” meaning they are ready or nearly ready to spawn. Indicators that Ross uses include ripe stars having larger “shoulders” and being puffier than unripe stars. After Ross has collected enough bat stars, he ships them from California to Cambridge, Massachusetts, where their role in Swartz’ research begins. Swartz is interested in female specimens, but there is no good way to identify a starfish’s sex on sight, so the bat stars that Ross sends to Swartz tend to be fifty-fifty female and male. Swartz must examine a small biopsy of the gonad to find out which of them contain oocytes, the immediate precursor cells to fertilizable eggs. Once identified, the animals are separated into two aquariums by sex, ready to provide oocytes for experiments. Swartz feeds the starfish a steady diet primarily consisting of raw, peeled shrimp, which keeps them developing new oocytes. When the starfish have completed their time in the lab, Swartz tries to donate them to local aquariums.

Eggs with answers: What we’ve learned from bat stars

Swartz is using the bat stars to investigate how cells divide—specifically, how cells retain the ability to divide after long periods without doing so, and how cell division processes are adapted to the context of animal reproduction and development. Whitehead Member Iain Cheeseman’s lab, where Swartz is a postdoc, investigates the cellular machinery required for cell division. In particular, Cheeseman’s team studies the kinetochore, a complex of proteins involved in orchestrating the precise segregation of chromosomes during cell division, and the centromere, the region in the middle of the chromosome where the kinetochore assembles. The centromere is not defined by its DNA sequence, but by proteins that attach there and signal the kinetochore to assemble at that location. One of the necessary proteins that marks the centromere is called CENP-A. Without CENP-A, the centromere NetBet live casinowon’t function properly, so chromosomes won’t be correctly distributed into the two new cells created during cell division. However, as with other proteins, there was an open question whether CENP-A degrades over time. Once it is lost at the centromere the cell cannot get it back, and loses the ability to divide. This fact caused Cheeseman and Swartz to wonder how cells that spend long periods of time without dividing can start up again. What sort of maintenance do cells need to do to keep their cell division machinery operational?

Eggs and oocytes, the precursor cells that will develop into eggs, are a great test case because they remain non-dividing for a very long time. Swartz harvested the bat stars’ oocytes and used a fluorescent tag to track the quantity of CENP-A inside of the cells as they progressed through their cell cycle stages. To get a close look at what happens to the CENP-A in oocytes during their dormancy, Swartz maintained the cells in a state of arrested development in petri dishes by putting them in a mixture he calls “starfish juice,” a blend of culture fluids, antibiotics, and some of the bat stars’ own natural fluids.

With the help of the fecund bat stars, Swartz and Cheeseman found the answer to their questions about CENP-A. In research published in Developmental Cell in 2019 [4], the scientists discovered that cells slowly replace their CENP-A over time, swapping out the old protein at risk of breaking down with new functional protein. This finding upended the previous understanding of CENP-A as a static protein that was placed on the centromere once and then remained as long as it could. The researchers also tested a human cell line that can enter dormancy and divide later, and found that, like the sea star oocytes, those cells gradually exchanged CENP-A. In contrast, the researchers discovered that cell types that never need to divide again, like muscle cells or other specialized cells, let most of their CENP-A degrade and so permanently lose the capacity to divide. This finding means that the presence of CENP-A may be a good indicator for use in determining whether any given cell retains the ability to divide in the future. The question of a specialized, or terminally differentiated, cell’s potential for renewed cell division is of great interest in regenerative medicine research. Indeed, this work sparked collaboration between Cheeseman, Swartz and Whitehead Institute Fellow Kristin Knouse, who studies regeneration in mouse and human cells.

The findings could also explain why tissues like muscle rarely develop cancers; the cells cannot replicate and so cannot grow tumors. Furthermore, Swartz thinks that their findings could prove valuable for assisted fertility research.

“Understanding the natural biology that keeps eggs in good shape, able to resume and finish their development after long dormancies, could provide insight into what goes wrong when eggs do not remain viable,” Swartz says.

The possibilities for future research spawning from Swartz’ work are many. The advances that may come, whether in regenerative medicine, assisted fertility, or elsewhere, will all be owed in part to a group of bat stars that travelled across a continent, from ocean to ocean, in a chilled cardboard box to help unravel the mysteries of cell division.

Researchers discover an RNA-related function for a DNA repair enzyme
Raleigh McElvery
February 26, 2020

After decades of speculation, researchers have demonstrated that a classical DNA repair enzyme also binds to RNA, affecting blood cell development.

The DNA-dependent protein kinase, otherwise known as DNA-PK, is one of the most important enzymes that binds DNA and repairs double-stranded breaks. This mode of repair is essential for generating receptors that help the immune system fight off intruders. But DNA-PK doesn’t just bind DNA; it also binds RNA. Although researchers have known this for decades, they didn’t fully understand what kinds of RNAs DNA-PK bound in mammalian cells, or the physiological consequences of this binding.

In a new study published on February 26 in Nature, researchers from MIT and Columbia University have uncovered a mechanism whereby DNA-PK binds to the RNA involved in ribosome assembly. Ribosomes — the cell’s protein synthesis machinery — ensure that stem cells give rise to enough red blood cells. The researchers found that mutating DNA-PK prevents the ribosomes from being built properly, which prevents blood cells from doing their job and leads to blood disorders.

“This is the first biochemical evidence of DNA-PK assembly and activation by RNA inside cells,” says Eliezer Calo, a co-senior author and assistant professor in MIT’s Department of Biology. “We’re still trying to determine the mechanisms that regulate protein synthesis in stem cells, and this study reveals one of them.”

Co-senior author, Shan Zha from Columbia University, had previously studied DNA-PK’s role in DNA repair by generating a mouse model that carried enzymatically-dead versions of DNA-PK. While using this model to investigate tumorigenesis, Zha’s lab found these mutant mice developed a form of blood cancer known as myeloid disease. At the same time, another research group showed that mutations in DNA-PK also led to anemia, which occurs when the body does not have enough healthy red blood cells

Neither myeloid disease nor anemia could be easily explained by DNA repair defects alone. However, the two blood disorders did share some similarities to diseases caused by ribosome defects. Because DNA-PK resides in the same organelle where ribosomes are made, the Zha and Calo labs began to wonder whether DNA-PK could bind to the RNA there and control ribosome biogenesis.

In this new study, the Zha lab found that DNA-PK mutations impaired protein translation in red blood cell progenitors, which might contribute to anemia. In parallel, the Calo lab was investigating ribosomal RNA processing and was surprised to find that DNA-PK seemed to be implicated in ribosome assembly. The Calo lab then mapped all the RNAs in cells that bind DNA-PK. The enzyme unexpectedly attached to U3, a small RNA that helps assemble one of the subunits comprising the ribosome. Once it binds U3, DNA-PK can transfer a phosphate group to several specific sites on one of its own subunits. If DNA-PK is defective and cannot transfer the phosphate group, protein synthesis in blood stem cells is impaired, eventually causing anemia.

DNA-PK is essential for cellular viability in nearly all human cell lines, including cancer cell lines, while many other proteins involved in same DNA repair pathway are dispensable. Several studies, including one published by the Zha lab, showed that DNA-PK protein levels are 50-fold higher in common human cell lines than in rodent cell lines. The researchers do not yet know why the enzyme is so critical, but they suspect it might have to do with its ability to bind RNA. “We are interested in exploring whether this new role for DNA-PK could provide clues to this puzzle,” Zha says.

Calo says their findings could also have important implications for cancer treatment, because DNA-PK has emerged as a promising target for cancer therapy. Drugs that inhibit DNA-PK could prevent cancer cells from repairing their DNA and replicating successfully, but he warns these same remedies could also impact stem cell function. The next step is to explore DNA-PK’s other RNA binding targets and the related molecular pathways.

“We’ve demonstrated that DNA-PK has an entirely separate role that has nothing to do with DNA repair,” Calo says. “In the future, we’re excited to learn what additional RNA-related duties it may have beyond stem cell maintenance.”

Top Image: Ribosomes are assembled in the nucleoli (shown here in human cells).

Citation:
“DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis”
Nature, online February 26, 2020, DOI: 10.1038/s41586-020-2041-2
Zhengping Shao, Ryan A. Flynn, Jennifer L. Crowe, Yimeng Zhu, Jialiang Liang, Wenxia Jiang, Fardin Aryan, Patrick Aoude, Carolyn R. Bertozzi, Verna M. Estes, Brian J. Lee, Govind Bhagat, Shan Zha, and Eliezer Calo

To be long-lived or short-lived?
Nicole Davis | Whitehead
February 20, 2020

Genes are often imagined as binary actors: on or off. Yet such a simple view ignores the fact that genes’ activities, exerted by their corresponding proteins, can run the gamut from barely perceptible to off the charts. This rheostat-like range is due in part to molecular controls that determine how long the protein-making instructions for any given gene — known as messenger RNA (mRNA) — can persist before being destroyed.

Now, in a pair of papers published online in Molecular Cell, Whitehead Institute member David Bartel and his colleagues take a deep and systematic look at the dynamics of mRNA decay across thousands of genes. Their analysis — the most extensive to date — reveals surprising variability in the rate at which the ends (or “tails”) of mRNAs are shortened. In addition, the researchers uncover a link between this rate of shortening and how quickly the short-tailed mRNAs decay.

“Ultimately, these dynamics are responsible for determining how much mRNA is present for each gene, and that, of course, is really important for determining cell identity — for example, whether a cell is cancerous or a normal, healthy cell,” says Bartel, who is also a professor of biology at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. “There is a thousand-fold difference in how long mRNAs stick around. That has a very NetBet live casinoprofound effect on the amount of protein that gets made.”

TOWARDS A GLOBAL VIEW OF MRNA DEGRADATION

The anatomy of a typical mRNA consists of three key parts: a body, which contains the protein-making instructions; at one end, a string of repeating A’s known as the poly(A) tail; and at the other end, a protective biochemical cap.

Prior to the Molecular Cell studies, the future of a mRNA was known be linked to the length of its poly(A) tail — the longer the string of A’s, the longer the mRNA tends to persist. However, the speed that tails shorten as they age, and the rate at which mRNAs decay when their tails become short was known for just a handful of mRNAs.

To gain a more global picture, Bartel and his team, most recently led by graduate student Timothy Eisen, combined a set of techniques for high-throughput analyses of mRNA. These include a method for chemically modifying mRNAs as they are being made in order to distinguish newly synthesized mRNAs from those that are older, as well as sequencing-based approaches for measuring both the length of poly(A) tails and the amount of mRNA that was recently made. In addition, Eisen used computational methods to model the data they gathered and make predictions about them.

“All of the work in these papers involves time as an axis,” says Eisen. “The power of our approach is that it allowed us to plot and visualize how things change over time — and to infer for mRNAs from thousands of genes the rate at which the tail shortens and the subsequent rate at which the mRNA is destroyed.”

THE TAIL WAGS THE MRNA

By leveraging these techniques, Bartel, Eisen and their colleagues explored the mRNA dynamics for thousands of genes. One key observation is that mRNAs enter the cytoplasm with diverse poly(A) tail lengths. That variability encompasses not only the mRNAs from different genes but even those that correspond to the same gene.

“Previously, there wasn’t any reason to think there would be any differences, so people just assumed that the initial tail lengths would be the same,” says Bartel. “But it turns out there’s quite a bit of variability there.”

The Whitehead team also uncovered a striking amount of variation in the rate at which poly(A) tails are shortened. For some mRNAs, the tail shortens at a rate of about 30 nucleotides per minute. With an average tail length of around 200 nucleotides, that translates to the tail lasting just a few minutes. Other mRNAs have much more durable tails, with shortening rates of just a nucleotide or two an hour.

“That’s a thousand-fold difference,” says Eisen. Previously, researchers had shown that tail-shortening rates could vary, but they had observed only a 60-fold difference.

Bartel and his colleagues also found some striking differences among mRNAs once their poly(A) tails became short. “If we consider just those mRNA molecules that have tails of only 20 nucleotides, the ones that come from certain genes disappear much more rapidly than those coming from other genes — again spanning a thousand-fold range,” says Bartel.

That finding challenges long-held views about mRNA stability, as it had been generally assumed that short tails equaled short lives, and that all mRNAs whose tails had been shortened decay at the same rate. But it turns out that both processes are important: the rate at which mRNA tails are shortened (a process known as deadenylation), and the rate at which mRNAs decay after this shortening. Moreover, Bartel and his colleagues find that these two processes are coupled —  the more rapidly deadenylated mRNAs also degrade more rapidly once they have short tails.

“This coupling between rate of decay of short-tailed mRNAs and the rate of deadenylation is important because it prevents a large build-up of short-tailed versions of mRNAs that had undergone rapid deadenylation,” says Bartel. “Because these short-tailed versions do not build up, the thousand-fold difference that we observe in deadenylation rates can impart a thousand-fold difference in mRNA stabilities.”

SHINING A LIGHT ON MICRORNAS

MicroRNAs are small, regulatory RNA molecules that play critical roles in human biology. Their primary job is to recruit molecular machinery that shortens the poly(A) tails of mRNAs, thereby accelerating mRNA degradation, which reduces gene activity.

But strikingly, when Eisen and his colleagues harnessed their elegant system to examine microRNA activity, it appeared that these regulatory RNAs were leaving the tails of their targets completely unaltered — despite the fact that those mRNAs were being more rapidly degraded.

“That really left us scratching our heads wondering, ‘How could this be?’” adds Eisen. “It’s been known for quite some time that microRNAs operate by influencing poly(A) tail length.”

The team decided to look at the dynamics of this process, focusing on newly generated mRNAs. In this context, they observed that microRNAs accelerate both tail-shortening of target mRNAs and the subsequent decay of those mRNAs once their tails become short. “This second aspect of microRNA activity really hadn’t been appreciated before,” says Bartel. “But it’s a critical part of the story because it helps explain why we don’t see a build-up of short-tailed mRNAs.”

These findings, as well as the other results described here, significantly enhance what is known about mRNA decay and the factors that can influence it. With this expanded knowledge, Bartel and his colleagues, together with other research teams can work to uncover the molecular components and cellular contexts that cause mRNAs to have such drastically different lifetimes.

***

Written by Nicole Davis

***

Citations:

Eisen T, et al. The Dynamics of Cytoplasmic mRNA Metabolism. Molecular Cell. Published online January 2, 2020.

Eisen T, et al. MicroRNAs Cause Accelerated Decay of Short-Tailed Target mRNAs. Molecular Cell. Published online January 2, 2020.

Why C. difficile infection spreads despite increased sanitation practices

Research underscores infection is not a common hospital transmission.

Maria Iacobo | Department of Civil and Environmental Engineering
February 20, 2020

New research from MIT suggests the risk of becoming colonized by Clostridium difficile (C. difficile) increases immediately following gastrointestinal (GI) disturbances that result in diarrhea.

Once widely considered an antibiotic- and hospital-associated pathogen, recent research into C. difficile has shown the infection is more frequently acquired outside of hospitals. Now, a team of researchers has shown that GI disturbances, such as those caused by food poisoning and laxative abuse, trigger susceptibility to colonization by C. difficile, and carriers remain C. difficile-positive for a year or longer.

“Our work helps show why the hospital and antibiotic association of C. difficile infections is an oversimplification of the risks and transmission patterns, and helps reconcile a lot of the observations that have followed the more recent revelation that transmission within hospitals is uncommon,” says David VanInsberghe PhD ’19, a recent graduate of the MIT Department of Biology and lead author of the study. “Diarrheal events can trigger long-term Clostridium difficile colonization with recurrent blooms” in Nature Microbiology, published on Feb. 10.

The researchers analyzed human gut microbiome time series studies conducted on individuals who had diarrhea illnesses and were not treated with antibiotics. Observing the colonization of C. difficile soon after the illnesses were acquired, they tested this association directly by feeding mice increasing quantities of laxatives while exposing them to non-pathogenic C. difficile spores. Their results suggest that GI disturbances create a window of susceptibility to C. difficile colonization during recovery.

Further, the researchers found that carriers shed C. difficile in highly variable amounts day-to-day; the number of C. difficile cells shed in a carrier’s stool can increase by over 1,000 times in one day. These recurrent blooms likely influence the transmissibility of C. difficile outside of hospitals, and their unpredictability questions the reliability of single time-point diagnostics for detecting carriers.

“In our study, two of the people we followed with high temporal resolution became carriers outside of the hospital,” says VanInsberghe, who is now a postdoc in the Department of Pathology at Emory University. “The observations we made from their data helped us understand how people become susceptible to colonization and what the short- and long-term patterns in C. difficile abundance in carriers look like. Those patterns told us a lot about how C. difficile can spread between people outside of hospitals.”

“I believe that there is a lot of rethinking of C. diff infections at the moment and I hope our study will help contribute to ultimately better manage the risks associated with it,” says Martin Polz, senior author of the study and a visiting professor in MIT’s Parsons Laboratory for Environmental Science and Engineering within the MIT Department of Civil and Environmental Engineering.

The research team also included Joseph A. Elsherbini, a graduate student in the MIT Department of Biology; Bernard Varian, a researcher in MIT’s Division of Comparative Medicine; Theofilos Poutahidis, a professor in the Department of Pathology within the College of Veterinary Medicine at Aristotle University in Greece; and Susan Erdman, a principal research scientist in MIT’s Division of Comparative Medicine.

Pediatric Radiologist Looks to AI to Learn More from Scans
Alison F. Takemura | Slice of MIT
February 12, 2020

There’s a moment during a routine pregnancy ultrasound when everything can change. When the sonographer pauses—and frowns in concentration. Inside the fetus’s brain, did she see an abnormality? Were the cavities, called ventricles, larger than normal? In such moments, the skills of doctors like Sarah Sarvis Milla ’96 are needed. Milla is a pediatric radiologist who specializes in neuroradiology, using imaging to help diagnose and direct treatment for young patients with health problems, particularly those related to the brain and spinal cord.

Milla most often uses magnetic resonance imaging (MRI) to clarify what’s happening inside her patients, including those still in utero. She says the power of MRI can amaze even seasoned professionals. “Sometimes, consulting doctors will just walk by and say, ‘Oh my goodness, you can really see the fetus!’” she says. The scans are breathtakingly detailed; you can make out bone, tissue, brain, and eyes.

An MRI of the fetus helps not only the doctor but also the family to understand what’s happening. Families may not realize how severe an abnormality is just from the ultrasound, Milla says. “So we really try to show them the more detailed MRI images, talk to them about what they’re seeing, and answer their questions.”

These conversations are a privilege—and, sometimes, a sorrow, says Milla, who has two sons of her own, ages 9 and 11. “I have definitely cried with families when there’s been bad news.” Milla’s position has taught her gratitude for “the amazing things that happen for us to develop normally. I’ve basically seen every way that development can go wrong.”

AT MIT, Milla majored in biology, but she was also drawn to art and worked closely with two professors, Ritsuko Taho and Dennis Adams, then on the faculty of the MIT Program in Art, Culture, and Technology. Her interests in science and art fused when, as a medical student at Duke University, she was assigned to a group advised by a radiology professor. Holding up radiographs, CT scans, and MRIs of patients’ chests, he started describing what he saw and could infer about their medical conditions.

“From a contemporary artist’s standpoint, it kind of blew my mind,” says Milla. “You could put someone through a tube [for a CT scan] in one minute, take pictures, and be able to look at all their organs, and essentially be able to tell what was wrong with them—without surgery. For me, that was incredible. It was such a visual field. Radiology was like a slam dunk for me.”

Today, Milla is a clinician, teacher, and researcher at Emory University in Atlanta, Georgia. She teaches pediatric radiology and neuroradiology not just to medical students but to people anywhere along the medical career path: interns, fellows, and other physicians. “All physicians are lifelong learners,” she says.

Milla has travelled to Africa and South America to share her knowledge. In November, she visited Peru through a visiting professorship from the American Society of Neuroradiology to deliver lectures on her field—including research she and her colleagues published in 2013 on applying a new MRI protocol in children, who can have trouble staying still during a scan, that renders much clearer pictures than the conventional MRI protocol.

One of the persistent challenges of radiology, Milla explains, is that findings on imaging studies can be so subtle—a radiologist might have more of a feeling about an image than something she can pinpoint. “It’s like the game where there are two pictures, and you have to find five things different in one of the pictures,” says Milla. “We have to know what normal looks like, and then our eyes are trained to look for things out of the norm. When we find them, the brain has to use knowledge, deduction, and experience to figure out what the abnormality is.”

Now, Milla has teamed up with Matthew Gombolay SM ’13, PhD ’17, an assistant professor of interactive computing at Georgia Tech, to investigate what images are most helpful for training students—and machines—to identify these subtleties. In one project, they’re harnessing machine learning to find abnormalities responsible for epilepsy. Epilepsy is a common reason why MRIs are done in children, says Milla. About half a million children in the US have the condition. But it’s estimated that about 70 percent of those patients don’t show a discernible cause for their epilepsy on MRI scans.

“I’ve been wanting to do this project for years,” she says. Being able to spot what’s abnormal can enable surgery to cure the epilepsy or improve the patient’s condition.

Milla’s outlook on radiology’s future, bolstered by machine learning, is bright. “As a scientist, I’m always excited for new technologies that may help patients, and that is how I view the field of artificial intelligence,” she says. While she doesn’t believe algorithms will perform perfectly on their own, “AI will help doctors do their jobs more accurately and efficiently. And that’ll allow us to give results to families, in person, quicker, and with more certainty.”

Gerald Fink awarded the Genetic Society of America’s Thomas Hunt Morgan Medal

Award recognizes scientists for lifetime achievement in genetics research who has a strong history as a mentor.

Merrill Meadow | Whitehead Institute
February 10, 2020

Gerald R. Fink, Whitehead Institute founding member and former director and professor of molecular genetics in the MIT Department of Biology, has been awarded the 2020 Thomas Hunt Morgan Medal, bestowed by the Genetics Society of America (GSA). The award recognizes a distinguished scientist who has a lifetime achievement in the field of genetics and a strong history as a mentor to fellow geneticists. The GSA is an international community of more than 5,000 scientists who advance the field of genetics.

Fink, who is also the Herman and Margaret Sokol Professor at Whitehead Institute, is a former GSA president and the 1982 recipient of the GSA Medal. In honoring him with the Thomas Hunt Morgan Medal, GSA is recognizing Fink’s discovery of principles central to genome organization and regulation in eukaryotic cells.

This year, the Morgan Medal will also be awarded to David Botstein, chief scientific officer for Calico Labs and professor emeritus of molecular biology at the Lewis-Sigler Institute for Integrative Genomics at Princeton University, in recognition of his multiple contributions to genetics, including the collaborative development of methods for defining genetic pathways, mapping genomes, and analyzing gene expression.

“These awards to Gerry and David are richly deserved and I am so pleased they are being honored together,” says Whitehead Institute Director David Page. “Gerry Fink has fundamentally changed the way researchers approach biological problems, and his many discoveries have significantly shaped modern science. David Botstein has helped drive modern genetics, establishing the ground rules for human genetic mapping.” Page has worked closely with both men: beginning his research career as an investigator in Botstein’s lab, and collaborating with Fink for more than three decades at Whitehead Institute.

The medals will be formally presented to Fink and Botstein at the Allied Genetics Conference in April.

Whitehead Institute Member David Sabatini Receives the 2020 Sjöberg Prize from the Royal Swedish Academy Of Sciences
Whitehead Institute
February 4, 2020

The Royal Swedish Academy of Sciences has announced that Whitehead Institute Member David M. Sabatini is co-recipient of the 2020 Sjöberg Prize, which promotes scientific research on cancer, health, and the environment. Sabatini, who is also a professor of biology at Massachusetts Institute of Technology (MIT) and an Investigator of the Howard Hughes Medical Institute, is being recognized for discovering the mTOR protein and its role in controlling cell metabolism and growth.

Throughout his career, Sabatini has made insightful and important discoveries, beginning when, as a graduate student, he identified the mTOR protein. In mammalian cells, mTOR—which stands for “mechanistic target of Rapamycin,” an immunosuppressant drug that inhibits cell growth—is the keystone molecule in a pathway that regulates cellular metabolic processes in response to nutrients.

Sabatini’s lab has since identified most of the components of the mTOR pathway and shown how they contribute to the function of cells and organisms. In the last 10 years, his lab has deciphered the mechanisms through which the pathway senses nutrients. These discoveries have opened avenues for identifying disease vulnerabilities and treatment targets for diverse conditions—notably including key metabolic vulnerabilities in pancreatic and ovarian cancer cells and neurodevelopmental defects. He is currently working to exploit those vulnerabilities as targets for new therapies.

“Research has suggested that 60 percent of cancers have some mechanism for turning on the mTOR pathway,” Sabatini says. “I could never have imagined the implications of that first discovery. And I am grateful that, with the Sjöberg Prize, the Academy has provided us with substantial new resources for our continuing and expanding research.”

In recent weeks, Sabatini—who is also a Member of the David H. Koch Institute for Integrative Cancer Research at MIT—has been the co-recipient of the BBVA Foundation’s Frontiers of Knowledge Award in Biology and Biomedicine for discovery of the mTOR protein, and of Columbia University’s Louisa Gross Horwitz Prize for his contributions to understanding mTOR’s role in physiology and oncogenesis.

“David Sabatini’s discoveries have helped transform cellular physiology,” says Whitehead Institute director David Page, “and they have profound implications for our understanding of cancer’s development—as well as for uncovering the processes underlying neurodegenerative disease, diabetes, and aging.”

This is the fourth time the Sjöberg Prize has been awarded. One of the first winners—James P. Allison of the MD Anderson Cancer Center—was subsequently awarded the Nobel Prize in Physiology or Medicine in 2018.

The official Sjöberg Prize Lecture will be delivered by Sabatini and fellow Laureate Michael Hall at the Karolinska Institute on March 30, 2020.

Singing for joy and service

After surgery to correct childhood hearing loss, Swarna Jeewajee discovered a a desire to be a physician-scientist, and a love of a cappella music.

Shafaq Patel | MIT News correspondent
February 3, 2020

Swarna Jeewajee grew up loving music — she sings in the shower and blasts music that transports her to a happy state. But until this past year, she never felt confident singing outside her bedroom.

Now, the senior chemistry and biology major spends her Saturdays singing around the greater Boston area, at hospitals, homes for the elderly, and rehabilitation centers, with the a cappella group she co-founded, Singing For Service.

Jeewajee says she would not have been able to sing in front of people without the newfound confidence that came after she had transformative ear surgery in the spring of 2018.

Jeewajee grew up in Mauritius, a small island off the east coast of Madagascar, where she loved the water and going swimming. When she was around 8 years old, she developed chronic ear infections as a result of a cholesteatoma, which caused abnormal skin growth in her middle ear.

It took five years and three surgeries for the doctors in Mauritius to diagnose what had happened to Jeewajee’s ear. She spent some of her formative years at the hospital instead of leading a normal childhood and swimming at the beach.

By the time Jeewajee was properly diagnosed and treated, she was told her hearing could not be salvaged, and she had to wear a hearing aid.

“I sort of just accepted that this was my reality,” she says. “People used to ask me what the hearing aid was like — it was like hearing from headphones. It felt unnatural. But it wasn’t super hard to get used to it. I had to adapt to it.”

Eventually, the hearing aid became a part of Jeewajee, and she thought everything was fine. During her first year at MIT, she joined Concourse, a first-year learning community which offers smaller classes to fulfill MIT’s General Institute Requirements, but during her sophomore year, she enrolled in larger lecture classes. She found that she wasn’t able to hear as well, and it was a problem.

“When I was in high school, I didn’t look at my hearing disability as a disadvantage. But coming here and being in bigger lectures, I had to acknowledge that I was missing out on information,” Jeewajee says.

Over the winter break of her sophomore year, her mother, who had been living in the U.S. while Jeewajee was raised by her grandmother in Mauritius, convinced Jeewajee to see a specialist at Massachusetts Eye and Ear Hospital. That’s when Jeewajee encountered her role model, Felipe Santos, a surgeon who specializes in her hearing disorder.

Jeewajee had sought Santos’ help to find a higher-performing hearing aid, but instead he recommended a titanium implant to restore her hearing via a minimally invasive surgery. Now, Jeewajee does not require a hearing aid at all, and she can hear equally well from both ears.

“The surgery helped me with everything. I used to not be able to balance, and now I am better at that. I had no idea that my hearing affected that,” she says.

These changes, she says, are little things. But it’s the little things that made a large impact.

“I gained a lot more confidence after the surgery. In class, I was more comfortable raising my hand. Overall, I felt like I was living better,” she says.

This feeling is what brought Jeewajee to audition for the a cappella group. She never had any formal training in singing, but in January, during MIT’s Independent Activities Period, her friend mentioned that she wanted to start an a cappella group and convinced Jeewajee to help her launch Singing For Service.

Jeewajee describes Singing For Service as her “fun activity” at MIT, where she can just let loose. She is a soprano singer, and the group of nine to 12 students practices for about three hours a week before their weekly performances. They prepare three songs for each show; a typical lineup is a Disney melody, Josh Groban’s “You Raise Me Up,” and a mashup from the movie “The Greatest Showman.”

Her favorite part is when they take song requests from the audience. For example, Singing For Service recently went to a home for patients with multiple sclerosis, who requested songs from the Beatles and “Bohemian Rhapsody.” After the performance, the group mingles with the audience, which is one of Jeewajee’s favorite parts of the day.

She loves talking with patients and the elderly. Because Jeewajee was a patient for so many years growing up, she now wants to help people who are going through that type of experience. That is why she is going into the medical field and strives to earn an MD-PhD.

“When I was younger, I kind of always was at the doctor’s office. Doctors want to help you and give you a treatment and make you feel better. This aspect of medicine has always fascinated me, how someone is literally dedicating their time to helping you. They don’t know you, they’re not family, but they’re here for you. And I want to be there for someone as well,” she says.

Jeewajee says that because she grew up with a medical condition that was poorly understood, she wants to devote her career to search for answers to tough medical problems. Perhaps not surprisingly, she has gravitated toward cancer research.

She discovered her passion for this field after her first year at MIT, when she spent the summer conducting research in a cancer hospital in Lyon, through MISTI-France. There, she experienced an “epiphany” as she watched scientists and physicians come together to fight cancer, and was inspired to do the same.

She cites the hospital’s motto, “Chercher et soigner jusqu’à la guérison,” which means “Research and treat until the cure,” as an expression of what she will aspire to as a physician-scientist.

Last summer, while working at The Rockefeller University investigating mechanisms of resistance to cancer therapy, she developed a deeper appreciation for how individual patients can respond differently to a particular treatment, which is part of what makes cancer so hard to treat. Upon her return at MIT, she joined the Hemann lab at the Koch Institute for Integrative Cancer Research, where she conducts research on near-haploid leukemia, a subtype of blood cancer. Her ultimate goal is to find a vulnerability that may be exploited to develop new treatments for these patients.

The Koch Institute has become her second home on MIT’s campus. She enjoys the company of her labmates, who she says are good mentors and equally passionate about science. The walls of the lab are adorned with science-related memes and cartoons, and amusing photos of the team’s scientific adventures.

Jeewajee says her work at the Koch Institute has reaffirmed her motivation to pursue a career combining science and medicine.

“I want to be working on something that is challenging so that I can truly make a difference. Even if I am working with patients for whom we may or may not have the right treatment, I want to have the capacity to be there for them and help them understand and navigate the situation, like doctors did for me growing up,” Jeewajee says.

Maurice Fox, professor emeritus of biology, dies at 95

A caring mentor and staunch political activist, Fox cared deeply about his students, the department, and the scientific enterprise.

Raleigh McElvery | Department of Biology
February 1, 2020

Maurice Sanford Fox, professor emeritus of biology and former head of the Department of Biology, passed away on Jan. 26 at the age of 95.

Fox was instrumental in creating and revising several courses within the biology major, and served as department head from 1985 to 1989. His research focused on bacterial genetics, and he pioneered investigations into bacterial transformation.

“Maury was a force in the department for many years,” says current department head Alan Grossman, the Praecis Professor of Biology. “He was very involved in the graduate program, and served as a mentor and friend to many of us. He cared deeply about the department, the scientific enterprise, and bioethics.”

Fox was born in the Bronx, New York, in 1924 to a family of poor Jewish immigrants; his father had fled Russia to avoid being conscripted into the tsar’s army. Growing up, Fox had little interest in science, and considered himself small for his age and “not very noticeable.” However, one teacher took an interest in him, and encouraged him to apply to Stuyvesant High School, which specialized in math and science. It took him an hour to make the commute each day, but he relished his biology and chemistry courses, where he got to study flies and flatworms and learn how to blow glass.

Fox graduated from high school at age 16 and enrolled in Queens College with the intent of majoring in chemistry. After a year and a half, he left to enlist in the U.S. Army Air Force and attend their meteorology program, eventually becoming a full-time meteorologist and traveling all over the American South to forecast weather for the military. At the time, NetBet sporthe aspired to become a doctor, but didn’t have enough money for medical school. Instead, at age 22, he returned to Queens College to continue taking chemistry courses.

He went on to receive his PhD in chemistry from the University of Chicago, where he studied under Willard Libby and specialized in nuclear chemistry. Realizing he had no interest in nuclear weapons, Fox began scanning the bulletin boards at the University of Chicago for other opportunities post-graduation, and came across Leo Szilard’s lab. Szilard had discovered a chemical reaction, known as the “Szilard-Chalmers reaction,” which Fox had just used to complete his thesis in physical chemistry. Fox joined the lab and became fascinated with Szilard’s continuous-flow device, called a chemostat, used for growing hundreds of generations of bacteria under constant conditions. To Fox, the device was a new way to think about kinetics, which “treated living things like chemicals.”

Fox considered Szilard to be his most influential mentor, inspiring him both scientifically and personally. Szilard encouraged Fox to take biology classes, and Fox became increasingly enthralled by bacterial genetics — a subject he later taught in classes of his own.

Several years later, the two joined forces to establish the Council for a Livable World. Their plan was to create an organization that would raise money for senatorial candidates who would be “sensible” about nuclear weapons and avoid nuclear catastrophe. Fox felt this conviction to uphold the social and political responsibilities of being a researcher throughout his entire life. He fought to reduce the risks of radiation, biological warfare, and gene editing, and later went on to chair MIT’s Radiation Protection Committee and become a member of UNESCO’s International Bioethics Committee.

At the time that Fox and Szilard were building the Council for a Livable World, Fox was completing his postdoc with biochemist Rollin Hotchkiss at Rockefeller Institute for Medical Research — the country’s first biomedical institute — which later became Rockefeller University. After his postdoc, he rose through the ranks to become an associate professor before being recruited to MIT in 1962.

As a bacterial geneticist, Fox used bacterial transformation as an experimental model for genetic analysis to gain insights into mechanisms of genetic modification. He later extended his investigations to transduction and conjugation. Fox helped lay the foundation of our modern understanding of DNA mutation, recombination, and mismatch repair — efforts which directly and indirectly influenced key advancements like the search for RNA viruses and the discovery of the SOS response. He also had a keen interest in evaluating the effectiveness of medical procedures, including diagnosis and treatment of breast cancer. He was a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the National Academy of Medicine, among other prominent professional organizations.

Fox remained active in the Department of Biology for 34 years, retiring in 1996. During that time, he taught several Course 7 subjects and mentored graduate and undergraduate students, as well as postdocs.

Fox was among the founding generation of molecular biologists who migrated from the physical sciences, says David Botstein, one of Fox’s earliest trainees at MIT. He remembers Fox as both an intellectual mentor and a life coach. Fox befriended many and his house was always full of visitors, with whom he shared his love for science, culture, art, and politics. “Maury introduced me to the quantitative study of microorganisms and the importance of DNA mutation and recombination — which I had expected — but also to the rigorous and persistent skepticism that led me to constantly search for alternatives to the current thinking,” Botstein says. “In this way, Maury introduced me to an approach to science and learning that shaped my entire career.”

Michael Lichten PhD ’82 also credits Fox with teaching him how to think about science. “Maury taught as much by example as by direction, and he transmitted a deep and profound commitment to teaching that guides many of his students to this day,” he says.

“Maury was a colleague, a mentor, and, most importantly, a friend,” recalls H. Robert Horvitz, Nobel laureate and one of Fox’s former undergraduate students. “Maury truly helped shaped my life, from my undergraduate days as a student in his genetics class to many more recent days, when he always offered both warmth and wisdom.”

“This is a man who made an astonishing difference in an astonishing number of lives,” adds Evelyn Fox Keller, Fox’s sister and professor emerita of history and philosophy of science at MIT. “He made a difference to the world. His life was devoted to making the world a better place for people — and he did.”

Fox is survived by his three sons, Jonathan, Gregory, and Michael, and his sisters Evelyn and Frances, who is a professor emerita of political science at the Graduate Center, City University of New York. Fox was predeceased by his wife of more than 50 years, Sally. The Department of Biology will hold a memorial celebration of Fox’s life in the spring.