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Aviv Regev to join Genentech in August
Broad Institute
May 11, 2020

After 14 years at the Broad Institute, Aviv Regev will be taking up an extraordinary opportunity to influence biomedicine in August 2020. She has accepted the position of Executive Vice President of Genentech Research and Early Development, one of the most influential roles in the pharmaceutical industry, with the opportunity to make transformative change in therapeutic development. Below, find a note to the Broad community from Eric.

ERIC LANDER’S NOTE:

I’m writing today to share the bittersweet news that, after 14 years at the Broad Institute, Aviv Regev will be taking up an extraordinary opportunity to influence biomedicine. She has accepted the position of Executive Vice President of Genentech Research and Early Development, and a member of the Roche Extended Corporate Executive Committee reporting to the CEO of Roche.

This is one of the most influential roles in the pharmaceutical industry, with the opportunity to make transformative change in therapeutic development.

Aviv will continue at the Broad until August 1, when she will officially assume the role at Genentech. She will continue to travel back and forth to maintain her lab activities at the Broad for another year, until summer 2021. She also plans to have a lab at Genentech.

Aviv was not looking for a new position. She had been clear that there was simply no place in academic science that she would want to be other than the Broad Institute.

The offer to be one of the senior leaders of Roche and Genentech came as a surprise, but it offered the opportunity to do something extraordinary — shape the entire therapeutic portfolio of one of the world’s best biopharma firms.

Aviv’s departure is a great loss for the Broad community, but I am thrilled for her to have this amazing opportunity.

Aviv is a force of nature.

She was the first faculty member recruited after the formation of the Broad Institute, which she joined in 2006 after running a computational biology lab as Fellow at the Bauer Center at Harvard.

Over the next fourteen years, Aviv has had an extraordinary impact on the science in the Broad community — propelling advances in both experimental and computational biology:

  • She pioneered the creation of methods for single-cell biology, making it possible to read out and interpret gene expression in individual cells.
  • Starting with an initial paper reporting single-cell RNA sequencing of 18 cells, she has led a revolution that has touched every area of biology at Broad and around the world.
  • At the Broad, she founded the Klarman Cell Observatory, which has become the leading nexus for creativity advances in the methodology and application of cell circuits, single-cell biology, and tissue biology.
  • In parallel, she has taken on the analytical challenge of extracting deep biological insights from the massive amounts of data generated by single-cell biology — drawing on the frontiers of data science and machine learning.
  • She amplified the impact through her work to form the Human Cell Atlas, an international collaboration to understand all cell types in the human body that now involves more than 1,100 institutions in 71 countries.
  • She has also built strong ties between Broad and Israel, including with the Broad-ISF Partnership.

Aviv has also played a central role in the Broad’s culture of mentorship. She has led a thriving lab, training dozens of postdocs and graduate students who now pursue independent academic careers as leaders in their own areas. As Chair of the Faculty, Aviv has helped to support the extended Broad faculty. In less formal but numerous ways, she has served as a mentor and sounding board for so many people at all levels.

She has also been a member of the Executive Leadership Team, guiding our most important institutional decisions.

Finally, she has been such a tremendous friend and colleague to me.

As hard as it is to contemplate the Broad without her, both Aviv and I know that the Broad community will use the transition as an opportunity to further strengthen our community — with Broadies stepping up to contribute scientific vision and institutional leadership.

Aviv and I are committed to ensuring the long-term success of the activities she has led. In particular, the Klarman Cell Observatory and its remarkable capabilities and community around single-cell and tissue biology will continue as an essential part of the Broad, led by deeply engaged champions. With their leadership, KCO will remain a vibrant and thriving community for many years to come. Aviv will also continue to co-chair the Human Cell Atlas Initiative, and Broad will remain as dedicated as ever to the ambitious international effort.

I am grateful to Aviv for her commitment to ensuring that the Broad only grows stronger and for her eagerness to remain engaged with the Broad community in the months and years ahead.

It’s hard to convey news about transitions in the midst of the pandemic, with many Broadies working round the clock on the scientific response and without the ability to get together.

We will, however, have a chance to celebrate Aviv — either in person or virtually — before August.

For now, I hope you will join me in congratulating Aviv on this new challenge and in thanking her for all that she has done.

Pollen research inspires art
May 10, 2020
Fu-shuang Li, a research scientist in Whitehead Institute Member Jing-Ke Weng’s lab, has collected flowers or ferns from over 160 different species as part of his research into the chemistry of a super-tough molecule in pollen and plant spores that gives them their tough outer shells and helped plants survive their original migration to land. Collecting the flowers often requires careful timing. Many plants bloom for a brief window, and that window is the only time they produce the pollen that Li needs for his research. There’s no way to know exactly when each plant will bloom, other than to observe them, and if Li misses this window for any of the species, he has to wait a whole year for another chance to collect the pollen he needs. Because of this, Li has spent many hours walking the sprawling grounds of the Arnold Arboretum in the Jamaica Plain neighborhood of Boston, one of his main collection sites, to check in on the plants he needs and see if they are ready for collection.

At the Arnold Arboretum. Photo: Fu-shuang Li/ Whitehead Institute

During his regular visits to observe the plants, Li became taken with the beauty of the flowers and ferns he was collecting, inspiring him to turn some of his research samples into art. In doing so, Li is contributing to a rich tradition of combining science and art—from historical scientific sketches to artistic modern microscopy—and following in the footsteps of other Whitehead scientists. On each collection trip, Li first takes the samples he needs for his research and then, with permission from the managers of the sites, he takes a few extra. He presses these extra flowers and ferns to preserve them. Not all 160 species lend themselves to pressing—some are too bulky, or fade and crumble instead of drying nicely. Li has turned the ones that did press well into small laminated cards.

“My favorites are the ferns,” Li says, looking through the collection of cards. “I think they are very beautiful.”

Several other members of Weng’s lab have aided Li in gathering the large number of specimens required for his research. In order to procure samples from all of the species that he needs, the group has collected not only from the Arnold Arboretum of Harvard University, but also from the Botanic Garden of Smith College and the University of Connecticut’s Ecology and Evolutionary Biology Greenhouse. Last year, Li designed baseball caps bearing images of pollen under an electron microscope. He gave one of these hats to Andrew Mitchell, the Weng Lab member who collected the most specimens, second to Li, last spring. This year, he plans to gift some of the flower-art cards to the people who assist him.

Photo: Conor Gearin/ Whitehead Institute

A tough subject

Li is using the many samples that he and his lab have collected to investigate sporopollenin, an impressively tough molecule that is found in both pollen and spores—small reproductive cells that ferns and other non-pollen bearing plants use to procreate.

“Among organic things, sporopollenin is one of the strongest you can find in nature,” Li says.

Photo: “Three Species Pollen Grains” by Asja Radja is licensed under CC-BY-4.0

The molecule’s toughness played a key role in plants’ evolutionary history. Plant life began in the ocean, and in order to make the jump to land, plants and their reproductive cells needed to be able to handle the terrestrial world’s harsh conditions, such as exposure to the sun’s UV radiation and drought. Sporopollenin’s chemical structure makes it incredibly durable, unreactive to its environment, and protective against UV; this gave spores, and later pollen, the protection they needed to survive on land. Besides its significance in the origins of terrestrial ecosystems, sporopollenin is an exciting blueprint for nature-inspired design. Li, Weng, and collaborators cracked the chemical structure of sporopollenin a few years ago. Using this information, researchers may be able to create products that mimic sporopollenin’s durability and inertness, for example in medical implants that need to stay intact and unreactive in patients’ bodies.

Pitch pine. Photo: “Pinus rigida cone Poland” by Crusier is licensed under CC BY 3.0

The researchers first identified the structure of sporopollenin in pitch pine. Now Li is investigating differences in the molecule across plant species, tracing the molecule’s evolution along with that of the plant kingdom—hence the need for his extensive collection trips. Weng and Li are especially interested in finding out how sporopollenin changed with the evolution of flowering plants in order to better understand the differences in pollen characteristics that arose alongside changes in plant structure and modes of pollination.

Pollen endures in nature, and now art

Sporopollenin’s hardiness, and the longevity it gives to pollen and spores, inspired Li’s next art project: pollen rings. Rings symbolize endurance, Li says—their perfect circles can represent eternity, or a life-long commitment to another person. Pollen grains, meanwhile, can stay intact for thousands or even millions of years. Pollen is abundant in fossil records and one of the first pollen rings that Li made contains fossil pollen from the Cretaceous Period, the age of dinosaurs.

“Pollen is special. The morphology survives for millions of years,” Li says. “So I always thought about the meaning of putting it in a ring.”

Photo: Conor Gearin/ Whitehead Institute

Li has also made rings using pine and lily pollen. Each type of pollen has its own color. The rings made of pine pollen are bright yellow, while the ones made with lily have a slightly purplish hue. Li creates the rings by mixing the pollen with resin and shaping the mixture in a mold. The rings are then hardened under UV light. Li observed a fun display of sporopollenin’s protective qualities during this process. The more pollen he mixed into a ring, the longer that ring would take to harden—he suspects because the sporopollenin absorbs UV. After the rings are hardened, Li sands and polishes them. He is saving the most carefully polished ring as a present for his wife.

Seeking further inspiration

Inspecting flowers at the Arnold Arboretum. Photo: Fu-shuang Li/ Whitehead Institute

As Li plans for his next round of collection trips this spring, he is also looking for his next art project. Unfortunately, due to the coronavirus pandemic, some of Li’s upcoming collection trips have been cancelled, meaning that he may miss his window to catch a few of the plants he needs in bloom. However, the Arnold Arboretum is still accessible, so sometime soon Li will tread the familiar, winding paths through the trees there, checking to see if the few remaining plants he needs for his research have bloomed and waiting for his next spark of inspiration to ignite, starting him on a new artistic endeavor.

Written by Greta Friar

Kerry Emanuel, David Sabatini, and Peter Shor receive BBVA Frontiers of Knowledge awards

Laureates recognized for contributions to climate change, biomedicine, and quantum cryptography.

Sandi Miller | Department of Mathematics
May 8, 2020

The BBVA Foundation awarded three MIT professors Frontiers of Knowledge Awards for their work in climate change, biology and biomedicine, and quantum computation. Department of Earth, Atmospheric, and Planetary Sciences Professor Kerry A. Emanuel, Department of Biology Professor David Sabatini, and Department of Mathematics Professor Peter Shor were recognized in the 12th edition of this annual award.

Kerry Emanuel

Emanuel, the Cecil and Ida Green Professor of Atmospheric Science, earned the BBVA’s Climate Change award “for his fundamental contributions to the understanding of tropical cyclones and how they are affected by climate change,” according to the committee’s citation. “By understanding the essential physics of atmospheric convection … he has unraveled the behavior of tropical cyclones — hurricanes and typhoons — as our climate changes.” He was also lauded for “extraordinary effectiveness in communicating the science of climate change to the public and policymakers.”

Emanuel is the co-founder (with Daniel H. Rothman) and co-director of the MIT Lorenz Center, a climate think tank that fosters creative approaches to learning how climate works. He was the first to link greater hurricane intensity to climate change-induced warming of sea surface waters.

“It is hard to imagine an area of climate science where one person’s leadership is so incontestable,” says Bjorn Stevens, BBVA Foundation committee chairman and director of the Max Planck Institute for Meteorology.

Hurricanes have long been known as destructive natural events, but the underlying physics of them was still largely unknown. Throughout the 1980s and 1990s, after completing degrees at MIT and later joining the EAPS faculty, Emanuel pinned down the mechanisms behind hurricanes. In his research detailing how warming surface oceans fuel storms and increase the intensity, he called them “massive, natural machines that convert the heat they extract from the ocean into wind energy.”

A changing climate will see more powerful hurricanes. Emanuel warns that this will complicate the already-tough task of making accurate forecasts, and predicts that hurricanes will spread into more regions of the planet.

His models currently predict a 5 percent increase in hurricane intensity (i.e., wind speed) for each 1-degree rise in ocean temperatures. “Three degrees of warming would make hurricanes 15 percent more intense, but their destructive potential would actually triple; in other words, with this 15 percent increase in wind speed, the damage would increase by around 45 percent,” says Emanuel, the author of “Divine Wind: The History and Science of Hurricanes” (Oxford Unviersity Press, 2005) and “What We Know about Climate Change” (MIT Press, 2018).

“Today’s most intense hurricanes may have a wind speed at the surface of 85 meters per second, but by the end of this century, unless we curb greenhouse gas emissions, we could start to see speeds of up to 90-92 meters per second. A hurricane’s destructive potential is determined by its wind speed, so in fact, the destructiveness of these storms for human populations would be considerably greater.”

Emanuel says that the international community “is not doing nearly enough” to combat climate change. “We need to stop listening to the voices of denial, and instead listen to our own children, who are crying out for us to act.”

David Sabatini

Sabatini, an MIT professor of biology and member of the Whitehead Institute for Biomedical Research and the Koch Institute for Integrative Cancer Research, shares his Frontiers of Knowledge Award in Biology and Biomedicine with Michael Hall of the University of Basel, for the discovery of a protein kinase that regulates cellular metabolism and growth.

Their discovery of mTOR is used in the study of a wide array of health conditions, including obesity, aging, cancer, diabetes, epilepsy, Alzheimer’s, and Parkinson’s. “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.”

Sabatini began his PhD thesis on understanding the mechanism of action of rapamycin, a natural anti-fungal agent proved to have immunosuppressive and anti-cancer properties. It is used to prevent organ rejection in transplant patients.

The two scientists arrived at their findings independently. Hall discovered the target of rapamycin (TOR) protein in yeast cells in 1993 during his time as a senior investigator; Sabatini isolated it in mammals while still a doctoral student, in 1994, and gave it the name mTOR.

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 explains that “mTOR is a switch that turns on in the presence of nutrients, so the body can build material, and when there are no nutrients available it breaks the material down.” The on/off switch of the mTOR switch controls a cascade of hundreds of molecular signals, many of which are still unknown to science.

“The molecular mechanisms that regulate the growth of organisms and coordinate it with the availability of nutrients were unknown until two decades ago,” said the committee.

After the molecule was isolated in yeast and mammals, both researchers began the task of unraveling its multiple organismal functions. 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. His 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.

Rapamycin is used as an immunosuppressant to prevent rejection of transplanted organs and as an anti-cancer agent. In the treatment of cardiovascular diseases, it is used as a coating for coronary stents to stop new blockages forming in the bloodstream.

Because mTOR is a nutrient sensor, additional research points to caloric restriction for increasing longevity. TOR was the first known protein that influences longevity in all of the four species that scientists commonly use to study aging: yeast, worms, flies, and mice. “We are just scratching the surface” of possible mTOR applications, he says.  “I don’t know if it will help us live to be 120, but I think it will have beneficial effects on different physiological systems, and I am practically sure that it will ameliorate aspects of aging-related diseases.”

Peter Shor

Shor, the Morss Professor of Applied Mathematics, was recognized in the Basic Sciences category for his role in the development of quantum computation and cryptology. He shares this award with IBM Research’s chemical physicist Charles H. Bennett and University of Montreal computer scientist Gilles Brassard.

The award committee remarked on the leap forward in quantum technologies, an advance that draws heavily on the new laureates’ pioneering contributions. The committee stated that their work “spans multiple disciplines and brings together concepts from mathematics, physics, and computer science. Their ideas are playing a key role in the development of quantum technologies for communication and computation.”

Bennett and Brassard invented quantum cryptography in the 1980s to ensure the physical inviolability of data communications. The importance of this work became apparent 10 years later when Shor discovered that a hypothetical quantum computer would render effectively useless the conventional cryptography systems underpinning the privacy and security of today’s internet communications.

Bennett and Brassard’s BB84 protocol — generally acknowledged as the first practical application of the science of quantum information — underpins the security of all our internet communications and transactions, and is based on the existence of mathematical problems that computers cannot solve. Until, as the citation states, “Shor discovered that quantum computers could factorize integers much faster than any supercomputer, therefore compromising the security of conventional cryptographic schemes.”

Says Brassard, “The importance of our work became much more evident after Shor destroyed everything else.” Shor’s Algorithm is now one of the quantum algorithms that comprise the fast-developing language to be spoken by tomorrow’s quantum computers.

Another of Shor’s contributions is an algorithm used to correct quantum computer errors, “an essential requirement for enabling and scaling quantum computations,” the committee wrote.

Quantum computers are exposed to a large volume of noise, causing numerous errors. “Everyone thought that you couldn’t correct errors on quantum computers,” recalls Shor, “because as soon as you try to measure a quantum system you disturb it. In other words, if you try to measure the error so as to correct it, you disturb it and computation is interrupted. My algorithm showed that you can isolate and fix the error and still preserve the computation.”

Quantum cryptography is one of the most advanced branches of quantum technology, which the laureates view as a long-term prospect. “It will be five or 10 years before a quantum computer can do anything approaching useful,” says Shor. With time, however, he is convinced that these machines will deliver revolutionary applications. For example, in biomedicine, “it takes enormous amounts of computer time to simulate the behavior of molecules,” he says. “But quantum computers could achieve that, and help design new drugs.”

The BBVA Foundation promotes knowledge based on research and artistic and cultural creation, and supports activity on the analysis of emerging issues in five strategic areas: environment, biomedicine and health, economy and society, basic sciences and technology, and culture. The Frontiers of Knowledge Awards, spanning eight prize categories, recognize research and creative work of excellence as embedded in theoretical advances, technological developments, or innovative artistic works and styles, as well as fundamental contributions in addressing key challenges of the 21st century.

Since its launch in 2009, the BBVA also has given awards to MIT’s Susan Solomon for climate change; Marvin Minsky, Adi Shamir, Silvio Micali, Shafi Goldwasser, and Ronald Rivest for information and computer technologies; Stephen Buchwald for basic sciences; Edward Boyden for biology and biomedicine; and Daron Acemoglu for economics.

Study finds ‘volume dial’ for turning neural communication up or down
Picower Institute
May 6, 2020

Neuroscientists at MIT’s Picower Institute for Learning and Memory have found that a protein acts like a volume dial for the release of neurotransmitters, the chemicals that neurons release across connections called synapses to stimulate muscles or communicate with other neurons in brain circuits. The findings help explain how synapses work and could better inform understanding of some neurological disorders.

Working in the model of fruit flies, the team determined that the protein Synaptotagmin 7 (SYT7), which is also found in humans and other mammals, constrains the number and availability of neurotransmitter-containing blobs, called vesicles, for release at the synapse. Neurons deploy vesicles to sites called “active zones” to release them across synapses, a process called “vesicle fusion.”  When the scientists reduced SYT7, they saw much more neurotransmitter release at synapses. When they increased the protein, neurotransmitter release dropped significantly.

“You can think of this as almost like a radio’s volume dial,” said senior author Troy Littleton, Menicon Professor of Neuroscience in MIT’s Departments of Biology and Brain and Cognitive Sciences. “If a neuron wants to send more signal out all it has to do is basically reduce the levels of SYT7 protein that it is making. It’s a very elegant way for neurons to turn up or down the amount of output that they are giving.”

The study’s co-lead authors are Zhuo Guan, a research scientist, and Mónica C. Quiñones-Frías, who successfully defended her doctoral thesis on the work May 4. She noted that by acting as that volume dial, the protein could change the nature of a synapse’s activity in a circuit, a property called “synaptic plasticity.”

“Syt7 regulates neurotransmission in a dose-dependent manner and can act as a switch for short term synaptic plasticity,” Quiñones-Frías said.

Research scientist Yulia Akbergenova is also a co-author of the study published in eLife.

Synaptic surprise

Important as they are, the study’s findings are not ones the team was originally looking for.

For decades, neuroscientists have known that the synaptotagmin protein family plays key roles in synaptic function. In fact, Littleton’s 1993 doctoral dissertation showed that SYT1 promoted a quick release of neurotransmitters when triggered by an influx of calcium ions. But even with SYT1 disabled, synapses could still release neurotransmitters on a slower timeframe. No one has found what promotes that subsequent slower release, but many scientists had pinned their hopes on it being SYT7.

“That’s been something that the whole field, including my lab, has really been searching for,” Littleton said. “So it was a real surprise when we knocked it out and saw just the opposite of what we expected.”

Mutants and microscopes

To study SYT7 the team focused its experiments on synapses in a well characterized locale: the junction between a fly neuron and muscle. The team not only wanted to see what differences changing the protein’s levels would make in synaptic activity there, but also track how it made those differences.

They changed the amount of SYT7 the neuron could produce by mutating and breeding flies in which the gene was completely eliminated, only one copy could be expressed, or in which the gene was overexpressed, producing more SYT7 than normal. For each of these fly lines they measured the surprising inverse relationship between SYT7 and synaptic transmission.

Also, using a technique the lab invented to visually flag neurotransmitter release every time it happens, they mapped how active individual synapses at the neuron-muscle junction were over time. In flies engineered to produce less SYT7 they saw many more synapses with a high propensity for release than they did in normal flies.

Once they confirmed SYT7’s restrictive role, the natural question was how does SYT7 constrain neurotransmitter release. Synapses are very complex, after all, and crucial aspects of SYT7’s role within that machinery had yet to be characterized.

When they compared synapses in normal flies and those missing SYT7 they didn’t see major differences in anatomy or calcium influx that could explain how SYT7 works to limit release.

They then turned their attention to the cycle in which vesicles release their neurotransmitter cargo and are then sent back into the cell to refill with neurotransmitter before rejoining a pool of vesicles ready for redeployment. Their experiments showed that neurons lacking SYT7 didn’t recycle the vesicles differently but they nevertheless had more vesicles in the readily releasable pool (RRP). Moreover, mutants in which SYT7 was overexpressed substantially limited the vesicles in that pool.

“SYT7 limits release in a dosage-sensitive manner by negatively regulating the number of synaptic vesicles available for fusion and slowing recovery of the RRP following stimulation,” they determined.

The final step was to track down where SYT7 resides in the synaptic machinery. Under the microscope they were able to pin it down in a network of tubes surrounding, but not within the active zones. The vantage point is right where other proteins regulating vesicle trafficking also reside, giving SYT7 a clear opportunity to interact with those proteins to regulate the return of vesicles to the active zones.

Implications for disease and plasticity

Understanding more about SYT7’s role at the synapse in mammals could matter in several ways, Littleton said. Two years ago, researchers showed that the protein is reduced in mice harboring a genetic cause of Alzheimer’s disease. And in February another paper showed that patients with bipolar disorder exhibited lower levels of the protein than people who do not have the disorder. Mice with SYT7 knocked out showed some manic and depressive behaviors.

More fundamentally, Littleton and Quiñones-Frías said, is the flexibility or plasticity it can afford. Because SYT7 regulates neurotransmitter release by slowing down the resupply of releasable vesicles, an increase in its levels can transform a synapse from being the kind that sends out large bursts of signal (and therefore transmits more information) early on and then peters out into one that builds up its signal over time. Such distinctions in release timeframe can make important differences in circuit information processing in the brain.

Although the team was able to identify SYT7’s effect at synapses and show key aspects of how it functions, they still hope to determine the exact mechanism that allows the protein to gate vesicle fusion. That work is ongoing.

The National Institutes of Health and the JPB Foundation provided support for the research.

A tale of biologists, some dice, and keeping each other sane
Tyler S. | MIT Graduate Admissions
May 6, 2020

Every other Sunday, six biologists gather around my apartment’s dining table. The meeting starts out normally enough, each of us giving one science and one non-science update about our lives since we last met. We recap our previous meeting. What happens next is less normal. I begin narrating:

“The barroom is dimly lit, and rain patters against the windows. A slightly out-of-tune ballad floats from the lone musician in the corner. The three gentlemen across the table from you stare intensely.”

My voice slips into a poorly done southern drawl.

“‘So, do we have a deal?’ You notice a fourth individual leaning against the exit watching you, hand on the hilt of a dagger. In fact, everyone in this bar is watching you. This was not the plan. What do you do?”

Three years ago, we sat around the table in the first-year lounge with a few sheets of paper and a handful of dice. I was introducing the majority of the group to their first experience with the infamous tabletop roleplaying game Dungeons & Dragons. I, the Dungeon Master, would give them a world filled with characters, cities, beasts, and adventures galore. Each of the players would take the persona of an individual in this world and react to the scenarios and conflicts that I throw at them. The rolling of dice determines whether a character’s proposed action succeeds or fails. Their adventures have ranged from sneaking (unsuccessfully) into an upper-class gala to saving the city of Kye’s Peak from a demon army. At its core, Dungeons & Dragons is a collaborative storytelling endeavor. It is a choose-your-own-adventure book with an infinite number of choices and an equally infinite number of outcomes.


A map of the fictitious world Estrael, created and drawn by Tyler in 2014

In the three years since our group started, a lot has changed. It is no secret that graduate school can be stressful and isolating. We’ve split up into five different labs. Most of our waking hours are spent either working on or thinking about our projects. It can be hard to fully unplug from our work. When we’re not at the lab bench, there’s always that data analysis hanging over our head that we should be doing instead of reading leisurely. Aside from the occasional “hi” at the monthly coffee or cookie hour, finding time to just hang out is difficult and can seem near impossible. We are no longer the inseparable first year cohort playing daily games of darts or pool.

But we have told stories. Cas the Ninth, Cleaver of Men, defeated her rival Ravnok to become “Champion of the Pit.” Aro reunited with his star-crossed lover. Chancce enrolled in the prestigious Naturium to learn control over his unpredictable arcane powers. The team executed an elaborate heist to steal an airship, escaping by the skin of their teeth. For every tense moment of derring-do, there has been an equal moment of crying from laughter as they spend 60 minutes haggling over the price of a ring.


Patience, the tiefling bard played and drawn by Emma

Despite three years of change, twice a month we still come together around a table. We give our life updates. We slip into our character voices. We leave the world of failed experiments and unexplainable biology behind, and immerse ourselves in another, more fantastical, world. I don’t know what they’ll do next. Maybe they’ll go on vacation to the beaches of the Sunlight Isles or try to solve the mysteries of the Baerwood. Perhaps Captain Brookshield will find them and exact her revenge.

These moments are rare instances where the world drops away and we’re just some friends hanging out, with nothing but the fate of a small rural village to think about. We’ve all mutually agreed to make time for these meetings; not because of the importance of Dungeons & Dragons itself, but because of the importance of partaking in a form of fellowship with one another. I encourage you to find some form of “scheduled fun.” It doesn’t have to be Dungeons & Dragons, but commit to getting away from graduate school for an afternoon and simply enjoy each other’s presence. While the game is what first brought us to the table, it is the people playing it that have kept us returning.


“The Snake Slayers”

Making medicine runs in the family
Greta Friar | Whitehead Institute
May 5, 2020

What do the painkillers morphine and codeine, the cancer chemotherapy drug vinblastine, the popular brain health supplement salidroside, and a plethora of other important medicines have in common? They are all produced in plants through processes that rely on the same family of enzymes, the aromatic amino acid decarboxylases (AAADs). Plants, which have limited ability to physically react to their environments, have instead evolved to produce a stunning array of chemicals that allow them to do things like deter pests, attract pollinators, and adapt to changing environmental conditions. A lot of these molecules have also turned out to be useful in medicine—but it’s unusual for one family of enzymes to be responsible for so many different molecules of importance to both plants and humans. New research from Whitehead Institute Member Jing-Ke Weng, who is also an associate professor of biology at the Massachusetts Institute of Technology, and postdoctoral researcher Michael Torrens-Spence delves into the science behind the AAADs’ unusual generative capacity.

Plants create their useful molecules through biochemical pathways made up of chains of enzymes. Each enzyme acts as an assembly worker, taking in a molecule—starting with a basic building block like an amino acid—and performing biochemical modifications in sequence. The altered molecules get passed down the line until the last enzyme creates the final natural product. Once the pathway enzymes for a molecule of interest have been identified, researchers can copy their corresponding genes into organisms like yeast and bacteria that are capable of producing the molecules at scale more easily than the original plants. The AAAD family of enzymes function as gatekeepers to plants’ specialized molecule production because they operate at the beginning of many of the enzyme assembly lines; they take various amino acids, molecules that are widely available in nature, and direct them into different enzymatic pathways that produce unique molecules that only exist in plants. When an AAAD evolves to perform a new function, as has occurred frequently in their evolutionary history, this change high up in the assembly lines can cascade into the development of new biochemical pathways that create new natural products—leading to the diversity of medicines that stem from AAAD-gated pathways.

Due to the AAADs’ prominent role in the production of medically important molecules, Weng and Torrens-Spence decided to investigate how the AAADs came to be so prolific. In research published in the journal PNAS on May 5, the researchers illuminate the structural and functional underpinnings of the AAADs’ diversity. They also demonstrate how their detailed knowledge of the enzymes can be used to engineer novel enzymatic pathways to produce important molecules of interest from plants.

“We characterized these enzymes very thoroughly, which is a great starting place for manipulating the system and engineering it to do something new. That’s particularly exciting when you’re dealing with enzymes at the interface between primary and specialized plant metabolism; it can apply to a lot of downstream drugs,” Torrens-Spence says.

The AAAD family evolved from one ancestral enzyme into a diverse set of related enzymes over a relatively short period of time. This sort of diversification occurs when an enzyme gets accidentally duplicated, after which one copy has evolutionary pressure on it to maintain the same function, but the other copy suddenly has free range to evolve. If the superfluous enzyme mutates to do something new that is useful to the organism, from then on both enzymes, with their distinct roles, are likely to be maintained. In the case of the AAADs, this process occurred many times, leading to a large number of enzymes that appear almost exactly alike, yet can do very different things.

In order to explain the AAADs’ successful rate of diversification, the researchers took a close look at four enzymes in the AAAD family with different roles, and discovered the composition and three-dimensional shape—the crystal structure—of each. The crystal structure allowed the researchers to see how these molecular machines hold and modify specific molecules; this meant that they could understand why some AAADs initiate certain specialized-molecule production lines while other AAADs initiate alternative production lines. The researchers next used genetics and biochemistry to pinpoint the differences between the enzymes and how small genetic variations enact very major changes to the enzyme’s underlying machinery. This detailed analysis explained, among others things, how a subset of enzymes that evolved out of the AAADs, the aromatic acetaldehyde synthases (AASs), came to perform a completely different action on molecules while still being so similar to true AAADs that the two types of enzymes are often mistaken for each other.

After the researchers developed this thorough understanding of the AAAD family of enzymes, as well as knowledge of the AAAD-containing pathways that create useful medicinal molecules, they applied this knowledge by engineering an entirely new pathway to create a molecule of interest, (S)-norcoclaurine, a precursor molecule for morphine and other poppy-based painkillers. Torrens-Spence combined enzymes from pathways in different species to invent a novel chain of enzyme reactions that can produce (S)-norcoclaurine in fewer steps than is seen in nature. This experiment was a proof of concept that Torrens-Spence says shows the potential for such biosynthetic engineering, for example as a method to produce plant-based drugs more easily.

“Often with these molecules of interest, you figure out the pathway in plants and copy-paste it into a more scalable system, like yeast, that will produce larger quantities of the molecule,” Torrens-Spence says. “Here we’re applying engineering principles to biology, so that we can innovate and build something new.”

Written by Greta Friar

***

Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an associate professor of biology at Massachusetts Institute of Technology.

***

Citation:

“Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins”

PNAS, May 5, 2020

DOI: https://doi.org/10.1073/pnas.1920097117

Michael P. Torrens-Spence (1), Ying-Chih Chiang (2†), Tyler Smith (1,3), Maria A. Vicent (1,4), Yi Wang (2), and Jing-Ke Weng (1,3)

1 Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

2 Department of Physics, the Chinese University of Hong Kong, Shatin, N.T., Hong Kong.

3 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

4 Department of Biology, Williams College, Williamstown, Massachusetts 01267, USA.

† Present address: School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.

Myth-busting on YouTube

Postdoc Izabella Pena uses social media to combat the infodemic about the Covid-19 pandemic.

Fernanda Ferreira | School of Science
May 4, 2020

In mid-March, Izabella Pena received a WhatsApp text from a friend in Indianapolis, Indiana. “He said, ‘Oh, I got your audio message from a priest in rural São Paulo,’” remembers Pena, a postdoc in Department of Biology Professor David Sabatini’s lab at the Whitehead Institute for Biomedical Research.

Pena had recorded the five-minute audio message about risk groups and the novel coronavirus SARS-CoV-2 for her family’s text thread after she heard one-too-many comments about how only the elderly caught the more severe forms of Covid-19. She never imagined it would spread like wildfire. “I realized the power of these tools,” says Pena of WhatsApp. “You can really reach people and share your information.”

While Pena’s message was fact-checked and scientifically correct, a lot of the information being shared on these platforms isn’t. In Pena’s native Brazil, the messaging platform WhatsApp has played an outsized role in the spread of fake news concerning SARS-CoV-2. Seeing the onslaught of misinformation, Pena first panicked. Then she fought back, choosing to use the vehicles of fake news to spread facts. “We scientists need to learn how to use WhatsApp, YouTube, and Twitter to communicate,” says Pena. “Because that’s how people are getting their information.”

At first, Pena’s misinformation-busting efforts were focused on friends and family. She recorded short audio messages in Portuguese to answer their questions and try to convince them that Covid-19 isn’t just another cold. The rapid spread of her audio messages, which alerted listeners about the importance of physical isolation and risk groups, sparked an idea: to take her science communication efforts from WhatsApp to YouTube, where she could reach a larger audience. Video also has the benefit of being a visual medium, where there’s a face attached to the information being shared. “I think that if people see you, there’s more reliability,” says Pena.

Pena uploaded her first video in late March, answering questions she had received via WhatsApp about Covid-19. Since then, she’s uploaded another five videos and is aiming to release one a week while the pandemic lasts. Many of these videos are in direct response to the messages she gets from viewers. “For example, everybody is asking when is life going to go back to normal, and I think life is only going to go back to ‘normal’ when there’s a vaccine,” says Pena. On April 10, she uploaded a video focused on vaccines, explaining what exactly a vaccine is and how they are made.

On camera, Pena is warm and inviting, delivering updated information about the coronavirus’s biology and epidemiology without clunky jargon and with an abundance of analogies. In a recent video that delved into the biology of SARS-CoV-2 and the different treatments being explored for the virus, she compared the human protein TMPRSS2, which primes the virus’ spike protein to enable the fusion of the virion to a cell’s membrane, to the scissors you use to open a tough plastic snack bag.

In using analogies, Pena is following the advice of Paulo Freire, a famed Brazilian educator and one of her personal idols. “Freire says that the best way to teach something very complicated to someone is to try to bring that concept close to their lives,” says Pena.

Trying to make complex and novel science digestible requires time. According to Pena, just writing the script and developing the analogies takes a couple of hours. “I collect all the information I need before I write the script,” says Pena, whose videos include a long list of references in the description, an unexpected sight on YouTube. “Then I film and edit the video. It all takes a few hours.”

Pena’s videos are filmed late at night because she continues to perform research during the pandemic, mostly virtually. But, she explains, “I’m part of the essential personnel in my lab.” Pena’s work in the Sabatini Lab focuses on the lysosome, the garbage disposal unit of cells that breaks down old cell parts and waste to recycle nutrients. It’s the perfect organelle for someone who has always enjoyed cell metabolism.

“I’ve always liked how chemicals in the cells are made and broken down,” says Pena. Her PhD research at the University of Campinas in Brazil investigated how metabolic problems in the brain could cause epilepsy. Since joining the Sabatini lab in 2018, Pena studies neurodegenerative disorders, like Parkinson’s and Huntington’s, and what role the lysosome plays in them. “For neurodegenerative diseases, there’s a lot of evidence that there’s lysosome influence,” she says. “There are many lysosome gene mutations associated to these disorders, so it’s a nice target to look at.”

Mostly working from home in Cambridge, Massachusetts, Pena is analyzing data and writing grants and papers, balancing her research with her “after-hours job” as a science communicator. “It’s a lot of commitment and dedication, but I believe this is very important, so I’ll keep doing it,” she says. “We are living a hard time, where science and education are constantly under attack. As scientists, we need to help inform people with accurate and life-saving information”.

Recently, Pena added another job title to her resumé: vice-president of ContraCovid, an initiative to make coronavirus information accessible to Latino and immigrant individuals. “We are sharing information in four languages: English, Portuguese, Spanish, and Haitian Creole, to benefit the community here in the U.S. and abroad,” says Pena. But ContraCovid wants to do more, including creating videos like Pena’s in other languages and recruiting more scientists, so that their materials can reach more and more people.

Accessibility of information is at the front of Pena’s mind when she sits down to make a new video. “If you look at how scientists communicate with each other, it’s a bit intimidating,” says Pena. The jargon and the excess of data make it hard for the general public to locate the main takeaways. Pena focuses on stripping away the excess and delivering the message, such as the importance of flattening the curve, in an easily digestible manner.

When imagining her viewers, Pena thinks of her mother. “My mom is not a scientist, but she’s super into technology like YouTube and WhatsApp,” says Pena, who usually sends her audio clips and videos to her mom first, only uploading them once her mom gives the go-ahead. “My mom helps a lot with sharing the videos because she has lots of followers,” Pena laughs. That’s actually how her involvement in Covid-19 outreach started: with her mom wildly sharing Pena’s audio message about risk groups with her numerous followers.

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.