Author: Raleigh McElvery

Tyler Jacks wins 2020 AACR Princess Takamatsu Memorial Lectureship
American Association for Cancer Research
May 28, 2020

PHILADELPHIA – The American Association for Cancer Research (AACR) is recognizing Tyler Jacks, PhD, Fellow of the AACR Academy, with the 2020 AACR Princess Takamatsu Memorial Lectureship.

Jacks is director of the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), co-director of the Ludwig Center at MIT, and a Howard Hughes Medical Institute Investigator. He is being recognized for transforming cancer research and the development of therapeutic treatments through his remarkable advancement of genetically engineered mouse models and for his seminal discoveries related to oncogenes, tumor suppressor genes, cell death, and immune system regulation of tumor progression.

“Dr. Jacks is a highly esteemed cancer scientist, and we are delighted to recognize his exceptional body of innovative work,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “His groundbreaking research has provided deep insights into cancer initiation and progression and has led to the identification of promising new treatments for cancer patients worldwide. He is revered for his tremendous research achievements as well as for his commitment to collaborative research across the world.  He is richly deserving of this prestigious accolade, which honors the life and work of Princess Takamatsu.”

The AACR Princess Takamatsu Memorial Lectureship is awarded to a scientist whose novel and significant fundamental scientific work has had or may have a far-reaching impact on the detection, diagnosis, treatment, or prevention of cancer, and who embodies the dedication of the Princess to outstanding cancer research and advances that emanate from multinational collaborations. Her Imperial Highness Princess Kikuko Takamatsu was personally instrumental in promoting progress against cancer.  She became a champion of these causes following her mother’s death from bowel cancer in 1933 at the young age of 43.

Jacks is a world-renowned researcher whose career has focused on understanding the genetic events that drive the development of cancer by applying the most advanced techniques of genetic engineering to develop mouse models of disease. He and researchers in his laboratory have engineered mice to carry mutations in many genes known to be involved in human cancer, including tumor suppressor genes such as Rb; oncogenes such as K-Ras; and genes involved in oxidative stress, DNA damage and repair, and epigenetic control of gene expression. These preclinical models have since enabled researchers to further investigate the fundamental initiation and progression mechanisms of colon, lung, pancreatic, and ovarian cancers as well as astrocytomas, peripheral nervous system tumors, retinoblastoma, and soft tissue sarcomas. Furthermore, these mice have been used as essential tools for the testing of novel approaches to cancer prevention, early detection, interception, and treatment. Recently, Jacks has used new genetic engineering techniques to study additional cancer processes, including metastasis and tumor-immune cell interactions.

An active AACR member since 1994, Jacks was elected to the inaugural class of Fellows of the AACR Academy in 2013, served as AACR President from 2009 to 2010, served as a member of the AACR Board of Directors from 2001 to 2004, and is a Trustee Emeritus of the AACR Foundation. Jacks has further served the AACR as chair of the AACR Membership Development Task Force and a member of the AACR Academy Steering Committee; Science Policy and Government Affairs Committee; Cancer Prevention, Early Detection, and Interception Committee; the AACR Team Science Award Committee; and the AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research Committee. Jacks was honored with the AACR Award for Outstanding Achievement in Cancer Research in 1997.

Jacks’ scientific accomplishments have been recognized with numerous honors throughout his career, including the MIT James R. Killian Jr. Faculty Achievement Award (2015), Sergio Lombroso Award in Cancer Research (2015), the Simon M. Shubitz Award (2005), the Paul Marks Prize for Cancer Research (2005), the Chestnut Hill Award for Excellence in Cancer Research (2002), and the Amgen Award (1998). In addition, Jacks is an elected Fellow of the American Academy of Arts and Sciences, member of the National Academy of Sciences, and member of the National Academy of Medicine.

Jacks received his undergraduate degree in Biology from Harvard University and completed his doctorate in Biochemistry under the tutelage of Nobel Laureate Harold Varmus at the University of California, San Francisco.

Cellular players get their moment in the limelight
Greta Friar | Whitehead Institute
May 27, 2020

In order to understand our biology, researchers need to investigate not only what cells are doing, but also more specifically what is happening inside of cells at the level of organelles, the specialized structures that perform unique tasks to keep the cell functioning. However, most methods for analysis take place at the level of the whole cell. Because a specific organelle might make up only a fraction of an already microscopic cell’s contents, “background noise” from other cellular components can drown out useful information about the organelle being studied, such as changes in the organelle’s protein or metabolite levels in response to different conditions.

Whitehead Institute Member David Sabatini and Walter Chen, a former graduate student in Sabatini’s lab and now a pediatrics resident at Boston Children’s Hospital and Boston Medical Center and a postdoctoral researcher at Harvard Medical School, developed in recent years a method for isolating organelles for analysis that outstrips previous methods in its ability to purify organelles both rapidly and specifically. They first applied the method to mitochondria, the energy-generating organelles known as the “powerhouses of the cell,” and published their study in Cell in 2016. Subsequently, former Sabatini lab postdoctoral researcher Monther Abu-Remaileh and graduate student Gregory Wyant applied the method to lysosomes, the recycling plants of cells that break down cell parts for reuse, as described in the journal Science in 2017. In collaboration with former Sabatini lab postdoctoral researcher Kivanc Birsoy, Sabatini and Chen next developed a way to use the mitochondrial method in mice, as described in PNAS in 2019. Now, in a paper published in iScience on May 22, Sabatini, Chen, and graduate student Jordan Ray have extended the method for use on peroxisomes, organelles that play essential roles in human physiology.

“It’s gratifying to see this toolkit expand so we can use it to gain insight into the nuances of these organelles’ biology,” Sabatini says.

Using their organellar immunoprecipitation techniques, the researchers have uncovered previously unknown aspects of mitochondrial biology, including changes in metabolites during diverse states of mitochondrial function. They also uncovered new aspects of lysosomal biology, including how nutrient starvation affects the exchange of amino acids between the organelle and the rest of the cell. Their methods could help researchers gain new insights into diseases in which mitochondria or lysosomes are affected, such as mitochondrial respiratory chain disorders, lysosomal storage diseases, and Parkinson’s Disease. Now that Sabatini, Chen, and Ray have extended the method to peroxisomes, it could also be used to learn more about peroxisome-linked disorders.

DEVELOPING A POTENT METHOD

The researchers’ method is based on “organellar immunoprecipitation,” which utilizes antibodies, immune system proteins that recognize specific perceived threats that they are supposed to bind to and help remove from the body. The researchers create a custom tag for each type of organelle by taking an epitope, the section of a typical perceived threat that antibodies recognize and bind to, and fusing it to a protein that is known to localize to the membrane of the organelle of interest, so the tag will attach to the organelle. The cells containing these tagged organelles are first broken up to release all of the cell’s contents, and then put in solution with tiny magnetic beads covered in the aforementioned antibodies. The antibodies on the beads latch onto the tagged organelles. A magnet is then used to collect all of the beads and separate the bound organelles from the rest of the cellular material, while contaminants are washed away. The resulting isolated organelles can subsequently be analyzed using a variety of methods that look at the organelles’ metabolites, lipids, and proteins.

With their method, Chen and Sabatini have developed an organellar isolation technique that is both rapid and specific, qualities that prior methods have typically lacked. The workflow that Chen and Sabatini developed is fast—this new iteration for peroxisomes takes only 10 minutes to isolate the tagged organelles once they have been released from cells. Speed is important because the natural profile of the organelles’ metabolites and proteins begins to change once they are released from the cell, and the longer the process takes, the less the results will reflect the organelle’s native state.

“We’re interested in studying the metabolic contents of organelles, which can be labile over the course of an isolation,” Chen says. “Because of their speed and specificity, these methods allow us to not only better assess the original metabolic profile of a specific organelle but also study proteins that may have more transient interactions with the organelle, which is very exciting.”

PEROXISOMES TAKE THE LIMELIGHT

Peroxisomes are organelles that are important for multiple metabolic processes and contribute to a number of essential biological functions, such as producing the insulating myelin sheaths for neurons. Defects in peroxisomal function are found in various genetic disorders in children and have been implicated in neurodegenerative diseases as well. However, compared to other organelles such as mitochondria, peroxisomes are relatively understudied. Being able to get a close-up look at the contents of peroxisomes may provide insights into important and previously unappreciated biology. Importantly, in contrast to traditional ways of isolating peroxisomes, the new method that Sabatini, Chen, and Ray have developed is not only fast and specific, but also reproducible and easy to use.

“Peroxisomal biology is quite fascinating, and there are a lot of outstanding questions about how they are formed, how they mature, and what their role is in disease that hopefully this tool can help elucidate,” Ray says.

An exciting next step may be to adapt the peroxisome isolation method so it can be used in a mammaliam model organism, such as mice, something the researchers have already done with the mitochondrial version.

“Using this method in animals could be especially helpful for studying peroxisomes because peroxisomes participate in a variety of functions that are essential on an organismal rather than cellular level,” Chen says. Going forward, Chen is interested in using the method to profile the contents of peroxisomes in specific cell types across a panel of different mammalian organs.

While Chen sets out to discover what unknown biology the peroxisome isolation method can reveal, researchers in Sabatini’s lab are busy working on another project: extending the method to even more organelles.

Written by Greta Friar

***

David Sabatini’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

***

Citations:

G. Jordan Ray, Elizabeth A. Boydston, Emily Shortt, Gregory A. Wyant, Sebastian Lourido, Walter W. Chen, David M. Sabatini,  “A PEROXO-Tag Enables Rapid Isolation of Peroxisomes from Human Cells,” iScience, May 22, 2020.

Bayraktar et al., “MITO-Tag Mice enable rapid isolation and multimodal profiling of mitochondria from specific cell types in vivo,” PNAS, Jan 2, 2019.

Abu-Remaileh et al., “Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes,” Science, Nov 10, 2017.

Chen et al., “Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism,” Cell, August 25, 2016.

Decoding development

Despite being 2,000 miles apart, two researchers are devising deep learning algorithms to predict embryonic tissue folding.

Raleigh McElvery
May 18, 2020

Since March when MIT’s new COVID-19 policies took effect, the research labs on campus have been vacant, save a skeleton crew of essential workers. Despite being separated from their benches, microscopes, and pipets, biologists have devised creative solutions to continue working remotely. In one lab, a postdoc and an undergraduate are using their time at home to develop a deep learning algorithm to spot hidden clues about embryonic development.

Professor Adam Martin’s lab studies the fruit fly embryo, which consists of a single layer of cells encircling a yolk core about three hours after fertilization. Within the next few minutes, a band of cells on the surface furrows inward, forming a critical fold that helps determine where the cells will go and what roles they will eventually play.

Postdoc Hannah Yevick has spent most of her time in the Martin lab focusing on the protein myosin, which forms a network of connections that links cells together and helps generate the force needed to fold the embryo. With her eye to the microscope, she’s been investigating how this ball of cells compensates for damage and continues to fold correctly despite occasional disruptions to the myosin network. But it remains unclear how cells coordinate to overcome such impediments, and what factors besides myosin aid the process. Yevick began to wonder if there was a way to extract hidden clues from her microscope pictures that would predict which embryos would develop properly and which would not.

Deep learning, a type of machine learning, has become a popular tool to detect and classify visual data. Just like the brain, deep learning algorithms run on sets of interconnecting nodes that can be trained to distinguish features and predict outcomes. (For example, differentiating a cat from a dog, or recognizing a friend in a Facebook picture.) Before an algorithm can complete these tasks on its own, however, researchers must train it using a set of practice images. Some scientists are training algorithms intended for use in clinical settings, from AI-based chatbots to diagnostic assistance that helps predict whether a patient has cancer.

Man in shirt and tie
Prateek Kalakuntla, a third-year Course 20 major and Course 6 minor.

“Deep learning shows great promise in clinical settings,” Yevick says, “and that got me thinking about ways to bring it back into the lab, and dig deeper into fundamental questions about development.”

Although she conducts computational analyses to decipher her microscopy images of fly embryos, Yevick hadn’t considered leveraging deep learning algorithms to predict developmental outcomes until a few months ago. In fact, she’d never tried any machine learning techniques at all. Sitting at home sans microscope during a pandemic seemed like the perfect time to start.

Right before the Martin lab dispersed per MIT’s COVID-19 policies, Yevick gained a collaborator: undergraduate researcher Prateek Kalakuntla, a third-year Course 20 (Biological Engineering) major with a minor in Course 6 (Electrical Engineering and Computer Science). He returned to his home in Dallas, Texas while Yevick remained in Cambridge.

“I was looking for a new project, and this seemed like the perfect one to start from home,” Kalakuntla says. “Our experience of practical machine learning is limited, so we assign ourselves research to do individually, and then check in with each other regularly.”

Despite nearly 2,000 miles separating them, the duo meets via Zoom once or twice a week to discuss their progress. They have been taking online tutorials in deep learning, provided by MIT OpenCourseWare, and gleaning information from scientific papers and colleagues.

“When you’re learning new things, it’s fun to have someone else to bounce ideas off,” Yevick says. “We’re exploring machine learning and gaining basic skills that will help us shape and address important questions moving forward.”

Two people at computer
Adam Martin and Hannah Yevick examine a video of a folding embryo.

At the moment, they’re practicing by constructing codes pulled from online exercises. Eventually, they aim to create and train their own algorithm and feed it images of embryos, taken just a few minutes into the stage of development where the layer of cells begins to furrow inward. The algorithm will then predict whether or not the embryo will develop correctly over the course of the 15-minute folding process.

Yevick and Kalakuntla intend to collect images from the entire lab, gathering as much data as possible to teach the algorithm to discern successful folds from failed ones. But they hope the algorithm will eventually teach them a thing or two as well — namely, where and when critical proteins are working to influence development.

“We’re feeding the algorithm entire images, but it’s pulling out what it deems to be the most interesting parts,” Kalakuntla says. “These could be specific regions of tissue or time periods that provide hints about the necessary proteins and cell shapes, which we can then analyze further.”

Although they’ll train their algorithm on images of fruit fly embryos, Kalakuntla hopes their model could eventually be applied to other organisms like mice or frogs — and even predict outcomes for data sets lacking images of later developmental stages.

“Machine learning can give us a birds-eye view of how cells coordinate collective movements, and show us ‘signatures’ that we might not have otherwise considered,” Yevick says. “Working remotely is certainly not ideal, but it’s given us the chance to gain new skills like this.”

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

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.

Life and learning find a way

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

Raleigh McElvery
April 24, 2020

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

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

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

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

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

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

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

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

An experimental overview from 7.003.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Top image: A screenshot of a video by Vanessa Cheung explaining a cDNA synthesis procedure.
Posted: 4.24.20