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Study reveals how glial cells may play key epilepsy role

Mutation in disease model flies undermines maintenance of key ion balance.

David Orenstein | Picower Institute
May 2, 2019

A new study provides potential new targets for treating epilepsy and new fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyperactivated by stress, leading to seizures.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, the Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses, such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions — for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance — and the way it is upset by the zydeco mutation — turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton, and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton says. “So this is a really important discovery linking an observation that’s been found in glia for a long time — these calcium oscillations that no one really understood — to a real biological function in glial cells, where it’s contributing to their ability to regulate ionic balance around neurons.”

Weiss’s work lays out a detailed sequence of events, implicating several specific molecular players and processes. That richly built knowledge meant that along the way, she and the team found multiple steps in which they could intervene to prevent seizures.

She started working the problem from the calcium end. With too much calcium afoot, she asked, what genes might be in a related pathway such that, if their expression was prevented, seizures would not occur? She interfered with expression in 847 potentially related genes and found that about 50 affected seizures. Among those, one stood out both for being closely linked to calcium regulation and also for being expressed in the key cortex glia cells of interest: calcineurin. Inhibiting calcineurin activity, for instance with the immunosuppressant medications cyclosprorine A or FK506, blocked seizures in zydeco mutant flies.

Weiss then looked at the genes affected by the calcineurin pathway and found several. One day at a conference where she was presenting a poster of her work, an onlooker mentioned that glial potassium channels could be involved. Sure enough, she found a particular one called “sandman” that, when knocked down, led to seizures in the flies. Further research showed that hyperactivation of calcineurin in zydeco glia led to an increase in a cellular process called endocytosis, in which the cell was bringing too much sandman back into the cell body. Without sandman staying on the cell membrane, the glia couldn’t effectively remove potassium from the outside.

When Weiss and her co-authors interfered to suppress endocytosis in zydeco flies, they also were able to reduce seizures, because that allowed more sandman to persist where it could reduce potassium. Sandman, notably, is equivalent to a protein in mammals called TRESK.

“Pharmacologically targeting glial pathways might be a promising avenue for future drug development in the field,” the authors wrote in eLife.

In addition to that clinical lead, the study also offers some new insights for more fundamental neuroscience, Littleton and Weiss said. While zydeco flies are good models of epilepsy, Drosophila’s cortex glia do have a property not found in mammals: They contact only the cell body of neurons, not the synaptic connections on their axon and dendrite branches. That makes them an unusually useful test bed to learn how glia interact with neurons via their cell body versus their synapses. The new study, for instance, shows a key mechanism for maintaining ionic balance for the neurons.

In addition to Weiss and Littleton, the paper’s other authors are Jan Melom, who helped lead the discovery of zydeco, postdoc Kiel Ormerod, netbet online sports bettingand former postdoc Yao Zhang.

The National Institutes of Health and the JPB Foundation funded the research.

Three from MIT elected to the National Academy of Sciences for 2019

Faculty members Edward Boyden, Paula Hammond, and Aviv Regev recognized for “distinguished and continuing achievements in original research.”

Melanie Miller Kaufman | Department of Chemical Engineering
May 1, 2019

Three MIT professors — Edward Boyden, Paula Hammond, and Aviv Regev — are among the 100 new members and 25 foreign associates elected to the National Academy of Sciences on April 30. Forty percent of the newly elected members are women, the most ever elected in any one year to date.

Membership to the National Academy of Sciences is considered one of the highest honors that a scientist or engineer can receive. Current membership totals approximately 2,380 members and nearly 485 foreign associates.

Edward S. Boyden is the Y. Eva Tan Professor in Neurotechnology at MIT; leader of the Synthetic Neurobiology Group in the MIT Media Lab; associate professor of biological engineering and of brain and cognitive sciences; a McGovern Institute investigator; co-director of the MIT Center for Neurobiological Engineering; and a member of the MIT Center for Environmental Health Sciences, Computational and Systems Biology Initiative, and Koch Institute for Integrative Cancer Research at MIT.

Boyden develops new tools for probing, analyzing, and engineering brain circuits. He uses a range of approaches, including synthetic biology, nanotechnology, chemistry, electrical engineering, and optics to develop tools capable of revealing fundamental mechanisms underlying complex brain processes. He pioneered the development of optogenetics, a powerful method that enables neuronal activity to be controlled with light. He also led the team that invented expansion microscopy, in which a specimen is embedded in a gel that swells as it absorbs water, thereby expanding nanoscale features to a size where they can be seen using conventional microscopes. He is now seeking to systematically integrate these technologies to create detailed maps and models of brain circuitry.

Paula T. Hammond is the David H. Koch Chair Professor of Engineering and the head of the Department of Chemical Engineering; a founding member of the MIT Institute for Soldier Nanotechnology; and a member of the MIT Energy Initiative and Koch Institute.

Hammond’s research in nanomedicine encompasses the development of new biomaterials to enable drug delivery from surfaces with spatio-temporal control. She also investigates novel responsive polymer architectures for targeted nanoparticle drug and gene delivery, and has developed self-assembled materials systems for electrochemical energy devices. She has designed multilayered nanoparticles to deliver a synergistic combination of siRNA or inhibitors with chemotherapy drugs in a staged manner to tumors, leading to significant decreases in tumor growth and a great lowering of toxicity.

Aviv Regev is a professor of biology; a core member of the Broad Institute of Harvard and MIT; and aHoward Hughes Medical Institute investigator.

Regev studies the molecular circuitry that governs the function of mammalian cells in health and disease and has pioneered many leading experimental and computational methods for the reconstruction of circuits, including in single-cell genomics. Her work focuses on dissecting complex molecular networks to determine how they function and evolve in the face of genetic and environmental changes, as well as during differentiation, evolution and disease.

The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established in 1863 by an Act of Congress, signed by President Abraham Lincoln, the academy was charged with “providing independent, objective advice to the nation on matters related to science and technology.” Scientists are elected by their peers to membership for outstanding contributions to research. The NAS is committed to furthering science in America, and its members are active contributors to the international scientific community.

Department of Biology hosts second annual Science Slam

Eight biology contestants get one slide and three minutes to explain their research and impress their listeners.

Raleigh McElvery | Department of Biology
April 30, 2019

Trainees recently took over the Tuesday Biology Colloquium for the second annual Science Slam, hosted by MIT’s Department of Biology. Topics ranged from the science behind cancer metastasis to parasites, hangovers, and, notably, poop.

A science slam features a series of short presentations where researchers explain their work in a compelling manner, and — as the name suggests — make an impact. These presentations aren’t just talks, they’re performances geared towards a science-literate but non-specialized public audience. In this case, competitors were each given one slide and three minutes to tell their scientific tales and earn votes from audience members and judges.

The latter included Mary Carmichael, founder and CEO of the strategic communications consultancy Quark 4; John Pham, editor-in-chief of Cell; and Ari Daniel, an independent science reporter who crafts digital videos for PBS NOVA and co-produces the Boston branch of Story Collider.

Among the competitors were six graduate students and two postdocs who hailed from labs scattered throughout Building 68, the Whitehead Institute, and the Koch Institute for Integrative Cancer Research at MIT. In order of appearance:

  • Rebecca Silberman, from Angelika Amon’s lab, who spoke about how there is something special about cancer cells that allows them to thrive with the wrong number of chromosomes;
  • Tyler Smith, from Sebastian Lourido’s lab, who spoke about his organism of choice, Toxoplasma gondii, and how these parasites provide insights into fundamental biology that classic “model” organisms do not;
  • Jasmin Imran Alsous, from Adam Martin’s lab, who spoke about the coordinated cellular interactions required for fruit fly egg development;
  • Darren Parker, from Gene-Wei Li’s lab, who spoke about the ratio of ingredients needed to concoct nature’s winning recipe for the perfect cell;
  • Sophia Xu, from Jing-Ke Weng’s lab, who spoke about the molecules responsible for the kudzu flower’s capacity to alleviate hangovers;
  • Jay Thangappan, from Silvi Rouskin’s lab, who spoke about the importance of RNA structure in splicing and its consequences for many important biological processes;
  • Lindsey Backman, from Catherine Drennan’s lab, who spoke about the biochemical processes carried out by gut bacteria that make poop smell bad; and
  • Arish Shah, from Eliezer Calo’s lab, who spoke about how developing zebrafish clear maternally-contributed molecules and replace them with their own, thus becoming “independent from mom.”

The event was moderated by former Slammers, postdoc Monika Avello and graduate student Emma Kowal. The duo joined forces with the Building 68 communications team and Biology Graduate Student Council to publicize the event and host two pre-slam workshops and a practice session.

Kowal, last year’s winner, was motivated to mentor this year’s cohort because, as she puts it, most scientists either don’t recognize the importance of clear communication or don’t recognize the challenge of doing it well.

“It is rare to see graduate programs devote training time to this,” she says, “but I believe it’s worth the effort. Taking the time to distill what excites and motivates us in our research not only inspires people to netbet sports betting appvalue science and even become scientists, but also helps us connect with each other — and remember why we love doing science in the first place.”

Avello recalls signing up for last year’s slam at the last minute, and “loving the experience.”

“I wanted to facilitate the experience of thinking hard about science communication in a fun and inclusive way for other graduate students and postdocs,” she says. “I really enjoyed watching everyone wrestle with the challenge of presenting their science in such a tight, condensed format, and ultimately developing their own unique story and style.”

There were two prizes, one awarded by the three judges and another awarded by the audience. Silberman, a fifth-year graduate student whose talk was titled “Does Chromosome Imbalance Cause Cancer?,” took home the Judges’ Prize, while third-year graduate student Sophia Xu claimed the Audience Prize with her talk, “Plant Natural Products and Human Ethanol Metabolism.”

Silberman said her favorite part was watching her fellow participants’ talks develop over time during the consecutive practice sessions. “Getting the opportunity to workshop my ideas and get input from Emma, Moni, and the other participants made the final presentation much less terrifying than it would have been otherwise, and made my talk much better,” she says.

Xu saw the Slam as an opportunity to practice presenting her research in an engaging way, and take a small step toward conquering her fear of public speaking. “I was overwhelmed by the support I received, not only from the organizers, but also from the other speakers,” she says. “It felt much like what I imagine a collaborative, friendly British cooking show would be like.”

Silberman encourages Department of Biology trainees considering participating in next year’s slam to “go for it.” She adds: “As grad students, we often aren’t challenged to distill our research down to its simplest terms. It was both harder and more fun than I expected.”

Changes to the Biology major beginning Fall 2019
Raleigh McElvery
April 24, 2019

We would like to share news on changes to the Biology major that will take effect Fall of 2019. Over the past year, the department has been revising its lab curriculum in order to accommodate the increasing number of students doing interdisciplinary Biology-related majors and to respond to the large numbers of students doing UROPs. Course 7 and 7A will be consolidated into a single major. Current 7A students will graduate with a Course 7 degree.

Most of the major requirements have stayed the same. The major changes are in the lab curriculum and are described as follows:

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  •  Students who already took this course are all set.  If a student has not taken this course, there are other options to fulfill the lab requirement.
  • 7.02 will be replaced with two courses 7.002 (6 units, Fall & Spring) and 7.003 (12 units, CI-M, Fall & Spring). Both must be taken to fulfill the lab requirement and the CI-M. We hope the modularization of these courses will help students to fit them in their schedule

7.18 (30 units, CI-M) will be discontinued

  • If a student already took this course, it will count and they are all set.
  • If a student did not take it, they will need a second CI-M. 7.19 (12 units, CI-M) is a Biology CI-M that substitutes for 7.18.
  • Other CI-Ms can also be used and are listed on the degree charts.

We hope that these changes will enhance the student experience at MIT, and we are happy to hear and help you solve any concerns that you have. If you have questions, please contact the Education Office.

The fluid that feeds tumor cells

The substance that bathes tumors in the body is quite different from the medium used to grow cancer cells in the lab, biologists report.

Anne Trafton | MIT News Office
April 16, 2019

Before being tested in animals or humans, most cancer drugs are evaluated in tumor cells grown in a lab dish. However, in recent years, there has been a growing realization that the environment in which these cells are grown does not accurately mimic the natural environment of a tumor, and that this discrepancy could produce inaccurate results.

In a new study, MIT biologists analyzed the composition of the interstitial fluid that normally surrounds pancreatic tumors, and found that its nutrient composition is different from that of the culture medium normally used to grow cancer cells. It also differs from blood, which feeds the interstitial fluid and removes waste products.

The findings suggest that growing cancer cells in a culture medium more similar to this fluid could help researchers better predict how experimental drugs will affect cancer cells, says Matthew Vander Heiden, an associate professor of biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

“It’s kind of an obvious statement that the tumor environment is important, but I think in cancer research the pendulum had swung so far toward genes, people tended to forget that,” says Vander Heiden, one of the senior authors of the study.

Alex Muir, a former Koch Institute postdoc who is now an assistant professor at the University of Chicago, is also a senior author of the paper, which appears in the April 16 edition of the journal eLife. The lead author of the study is Mark Sullivan, an MIT graduate student.

Environment matters

Scientists have long known that cancer cells metabolize nutrients differently than most other cells. This alternative strategy helps them to generate the building blocks they need to continue growing and dividing, forming new cancer cells. In recent years, scientists have sought to develop drugs that interfere with these metabolic processes, and one such drug was approved to treat leukemia in 2017.

An important step in developing such drugs is to test them in cancer cells grown in a lab dish. The growth medium typically used to grow these cells includes carbon sources (such as glucose), nitrogen, and other nutrients. However, in the past few years, Vander Heiden’s lab has found that cancer cells grown in this medium respond differently to drugs than they do in mouse models of cancer.

David Sabatini, a member of the Whitehead Institute and professor of biology at MIT, has also found that drugs affect cancer cells differently if they are grown in a medium that resembles the nutrient composition of human plasma, instead of the traditional growth medium.

“That work, and similar results from a couple of other groups around the world, suggested that environment matters a lot,” Vander Heiden says. “It really was a wake up call for us that to really know how to find the dependencies of cancer, we have to get the environment right.”

To that end, the MIT team decided to investigate the composition of interstitial fluid, which bathes the tissue and carries nutrients that diffuse from blood flowing through the capillaries. Its composition is not identical to that of blood, and in tumors, it can be very different because tumors often have poor connections to the blood supply.

The researchers chose to focus on pancreatic cancer in part because it is known to be particularly nutrient-deprived. After isolating interstitial fluid from pancreatic tumors in mice, the researchers used mass spectrometry to measure the concentrations of more than 100 different nutrients, and discovered that the composition of the interstitial fluid is different from that of blood (and from that of the culture medium normally used to grow cells). Several of the nutrients that the researchers found to be depleted in netbet sports betting apptumor interstitial fluid are amino acids that are important for immune cell function, including arginine, tryptophan, and cystine.

Not all nutrients were depleted in the interstitial fluid — some were more plentiful, including the amino acids glycine and glutamate, which are known to be produced by some cancer cells.

Location, location, location

The researchers also compared tumors growing in the pancreas and the lungs and found that the composition of the interstitial fluid can vary based on tumors’ location in the body and at the site where the tumor originated. They also found slight differences between the fluid surrounding tumors that grew in the same location but had different genetic makeup; however, the genetic factors tested did not have as big an impact as the tumor location.

“That probably says that what determines what nutrients are in the environment is heavily driven by interactions between cancer cells and noncancer cells within the tumor,” Vander Heiden says.

Scientists have previously discovered that those noncancer cells, including supportive stromal cells and immune cells, can be recruited by cancer cells to help remake the environment around the tumor to promote cancer survival and spread.

Vander Heiden’s lab and other research groups are now working on developing a culture medium that would more closely mimic the composition of netbet sports betting apptumor interstitial fluid, so they can explore whether tumor cells grown in this environment could be used to generate more accurate predictions of how cancer drugs will affect cells in the body.

The research was funded by the National Institutes of Health, the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, Stand Up to Cancer, the Howard Hughes Medical Institute, and the Ludwig Center at MIT.

Back to the basics

Biology students in the MIT Biotechnology Group are applying their skills in basic science to explore careers in industry.

Raleigh McElvery
April 15, 2019

When Rachit Neupane began his PhD at MIT Biology in 2013, the prospect of a career in industry was so mystifying it seemed like a “black box.” He had only a vague idea of what it would take to stray from the well-trodden path to academia and penetrate the biotechnology sphere post-graduation — applying his knowledge of the life sciences to manufacture drugs, develop technologies, and assess business problems.

As a first-year student, Neupane joined Jacqueline Lees’s lab studying the role of epigenetic regulators in lung and colon cancer, while simultaneously enrolling in drug development classes. He hoped to learn more about taking a project all the way from the lab to the clinic, as well as how his basic biology research fit into that scheme. “I didn’t know what I didn’t know, but I wanted to find out,” he recalls.

Two years into his graduate program he received some unexpected guidance in the form of an email, inviting students to join a new group on campus, the MIT Biotechnology Group (MBG). Now nearing its five-year anniversary, MBG was founded by four graduate students from three different departments, and aims to educate MIT undergraduates, graduate students, and postdocs who, like Neupane, are curious about the biotech landscape. MBG connects these trainees with one another and with leaders in the greater Boston area.

“We started the MIT Biotech Group as a conduit through which students, postdocs, and even young professors could access the rich biotechnology community surrounding MIT,” says founding co-president James Weis SM ’17. “The breadth and scale of MBG’s influence, and especially the career decisions it has enabled, has surpassed my most optimistic projections — largely due to incredible efforts of several generations of leaders, who have grown the group into MIT’s primary point-of-contact with the biotechnology community.”

Today, MBG is still entirely student-run. Although the leadership roles are currently primarily held by students from the Departments of Biology and Biological Engineering, MBG brings together trainees from across campus, including Brain and Cognitive Sciences, Electrical Engineering and Computer Sciences, Health Sciences and Technology, Chemical Engineering, and Computational Systems Biology.

Neupane now serves as co-president alongside Catie Matthews of Chemical Engineering and the Sloan School of Management. Together, they oversee a core team of nearly 30 graduate and undergraduate students, who collaborate to host a slew of events related to life sciences entrepreneurship, industry R&D, and business.

Once Neupane graduates, second-year Biology graduate student Lena Afeyan will take his place. She has served as director of the entrepreneurship branch, and, most recently, on the executive board as the director of finance. As such, she manages the group’s budget — which covers staple events like the semester-long Industry Seminar Series and the annual Ideation pitching and networking symposium, as well as career networking nights, special lectures, and the group’s due diligence projects.

These programs complement ones hosted by individual departments. “MBG is the central place where students from all these different departments can come together to think about biotech,” Afeyan says.

She knew before she began her PhD that she wanted to go into biotech, and chose MIT Biology specifically because “it offered a rigorous program to learn basic science while being so close to a biotech hub and surrounded by engineering minds.” This basic science knowledge, she explained, would allow her to ask the right questions later in her career, in order to identify high-impact scientific advances.

According to Afeyan, her principal investigator, Richard Young, runs his lab like a mini company. Young investigates the molecular mechanisms behind gene control, and has founded four different companies in less than a decade.

“He’s built a very strong reputation in his field because he’s attacked fundamental biological questions with a lot of scientific rigor, while understanding that those same questions can have a high impact on patients with diseases like cancer,” she says.

Afeyan’s labmate, fourth-year graduate student Alicia Zamudio, joined the lab because she was interested in the research questions, irrespective of their biotech applications. Unlike Afeyan, she’d had very little exposure to industry prior to MIT, until she took a drug development class and began meeting professionals in industry. Although she found MBG less than a year ago, she’s now an officer in the branch of the group focused on industry.

“I wanted to learn more about the biotech sector and build connections with professionals in the space,” she says. As a member of MBG, she’s not just one individual reaching out to an organization; she is backed by hundreds of curious students on campus hoping to learn more.

In her role as officer, Zamudio helps MBG organize events open to the entire MIT community, including site visits to various biotech companies in the area. “Dozens of these companies are walking-distance,” she says. “No other place has the density of biotech companies that exists here in Kendall Square.”

As Zamudio prepares to graduate, she hasn’t completely discarded the possibility of pursuing an academic postdoc, but she’s leaning heavily towards a career in industry.

“Industry seems like an extremely dynamic place where you get to think about scientific problems that help people,” she says, “while making practical NetBet sportuse of a background in basic science.”

A supportive role for planarians’ multifaceted muscle
Greta Friar | Whitehead Institute
April 5, 2019

CAMBRIDGE, MA  — Planarians are flatworms best known for their incredible ability to regenerate all their body parts: chop a planarian in two and soon you will have two perfectly formed planarians. As Whitehead Institute Member Peter Reddien, also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute, has investigated planarians over the years, he has become increasingly fascinated with the functions of their muscle. Not only do planarians use muscle to move, but Reddien’s research group previously discovered they rely on muscle tissue to provide a full body map with instructions that helps guide stem cells to the right locations during both regeneration and normal turnover of cells. Muscle tissue does this by secreting positional signals that help cells identify where they are — and where they should be.

New research from Reddien and graduate student Lauren Cote shows that muscle serves yet another crucial function in planarians. In a paper published in Nature Communications on April 8, they show that muscle operates as the planarian’s connective tissue, providing basic architectural support for the body. Connective tissue functions in large part by secreting molecules that make up the extracellular matrix (ECM), a network of molecules outside of the body’s cells that provides tissues with, among other things, scaffolding, protection, separation of tissues, and a means of inter-tissue connection and communication. In vertebrates, including humans, connective tissue is a distinct tissue type containing dedicated cells such as fibroblasts that secrete most of the animal’s ECM proteins. Reddien and Cote found no such fibroblast-like cell type in planarians; instead, multipurpose muscle does it all.

The researchers began to suspect that planarian muscle might function as connective tissue when they discovered that the gene encoding a major type of ECM molecule, fibrous protein collagen, was expressed only in muscle. The researchers then catalogued the total collection of proteins found in the planarian’s ECM, called the matrisome, and tracked where the genes that code for those proteins were expressed. They identified nineteen collagen genes, and all nineteen were highly specific to muscle. The vast majority of other ECM genes followed suit.

To further test muscle’s role as connective tissue, the researchers silenced the gene hemicentin-1, which produces another ECM molecule expressed specifically in muscle. They found that when the gene was not expressed, the planarian’s inner tissues did not remain properly separated from its outer skin. In other words, a muscle-specific gene is necessary in the planarians they studied for the core connective tissue task of keeping tissues discrete.

Although it might seem unusual that planarians would use muscle tissue for both ECM secretion and body pattern maintenance, Reddien and Cote say the combination makes a certain sense.

“To establish a map of the body, muscle secretes positional signals, and in its role as connective tissue it is simultaneously creating the extracellular environment the signals travel through,” Reddien says.

Cote agrees: “Producing the body’s physical architectural support and its biochemical architectural blueprint seem to go hand in hand.”

One possibility raised by this synchronicity is that a link between connective tissue and harboring positional information exists broadly across animal species. Studies elsewhere have found some positional role or positional memory in connective tissues in several species, including axolotls, vertebrates capable of limb regeneration. Based on these observations, Reddien says, it would be interesting to consider the positional role that connective tissue cells, like fibroblasts, might play in humans and might have in instructing regeneration broadly.

 

Written by Greta Friar

 

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Peter Reddien’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. The authors also acknowledge the Eleanor Schwartz Charitable Foundation for support.

***

Full citation:

“Muscle functions as a connective tissue and source of extracellular matrix in planarians”

Nature Communications, online April 8, 2019. DOI: 10.1038/s41467-019-09539-6

Lauren E. Cote, Eric Simental, and Peter W. Reddien.

A Troubling Inheritance
Greta Friar | Whitehead Institute
April 9, 2019

CAMBRIDGE, MA — Cancers have a habit of running in the family. This is due in large part to the inheritance of versions of genes that are linked with cancer, but some researchers are investigating another heritable risk factor: epigenetic modifications. These are not changes in the DNA sequence of a gene itself but rather are processes that change a DNA sequence’s accessibility or ability to be expressed. These changes can regulate gene expression, and in certain circumstances, be passed down from parent to child alongside the genes they regulate. New research published in eLife on April 9 from the lab of Whitehead Member and Institute Director David Page, also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute investigator, and colleagues has found evidence that when atypical epigenetic modifications, or marks, caused by a gene deletion in the parent’s cells, are inherited it can lead to increased cancer incidence and shorter lifespans in mice.

Studying epigenetic inheritance in mammals can be difficult because mammalian embryos undergo strong epigenetic reprogramming, a kind of “erasing and starting over” for the next generation. Some of the parents’ epigenetic marks resist this reprogramming, but the vast majority are erased, and often what may appear to be epigenetic inheritance can be explained by other factors like environmental exposures during fetal development leading to similar epigenetic profiles.

“We had to design an experiment with a specific, well-defined initiating event, so the epigenetic patterns and health effects would be easy to track,” says first author Bluma Lesch, then a postdoctoral researcher in the Page lab at Whitehead Institute and now an assistant professor of Genetics at Yale School of Medicine and a member of the Genomics, Genetics and Epigenetics Program at Yale Cancer Center.

In order to do this, the researchers first deleted Kdm6a (also called Utx), a gene on the X chromosome that encodes a protein involved in epigenetic regulation, in the male mouse germline—the repository of cells that become sperm. Kdm6a removes epigenetic modifications from histones, the spool-like proteins that house strands of DNA. Deleting Kdm6a led to higher than usual levels of specific types of histone modifications in the genome of the mice’s sperm, which in turn prompted a secondary epigenetic shift, an increase in DNA methylation—the addition of a methyl group to DNA that can alter gene expression.

The researchers used the hypermethylated sperm to create a generation of offspring. A crucial aspect of the experiment was creating offspring that inherited the atypical epigenetic marks but not the gene deletion that netbet sports betting appcaused them in order to uncouple the effects of the two changes. Offspring were bred from a modified male germline and an unmodified female germline, so male offspring inherited a healthy X chromosome from their mothers, and an unaffected Y chromosome from their fathers. Genetically, the mice were normal, but they were formed from sperm that had been exposed to the Kdm6a deletion’s epigenetic effects.

When the researchers studied the epigenome of these offspring, they found that while many of the modifications had been erased due to reprogramming, more than 200 of the sections of DNA that had been hypermethylated in the father’s germline following Kdm6a deletion were likewise hypermethylated in the offspring. That persistence is much higher than would be expected by chance or observed in normal mice. The researchers found matching instances of hypermethylation in the offspring’s bone marrow, liver tumors, and spleen, indicating that the inherited epigenetic changes stuck with the offspring though embryonic development into adulthood. The researchers did not pinpoint the mechanism that allowed these epigenetic marks to resist reprogramming; Lesch hopes to pursue that question in the future.

Then the researchers watched the mice grow, waiting to see how the unusual DNA methylation would affect the mice’s health. For a while, the mice appeared perfectly healthy — until they hit middle age. The mice then began developing tumors, experiencing an increase in cancer incidence and a decrease in lifespan.

To get a better understanding of the effects they were seeing, Page and Lesch sought help from cancer experts Benjamin Ebert, chair of medical oncology at the Dana Farber Cancer Institute (DFCI) and member of the Broad Institute; Zuzana Tothova, DFCI investigator and associate member of the Broad Institute; and Roderick Bronson, veterinary pathologist at Harvard Medical School. The experts helped characterize the mice’s diseases. Instead of becoming more susceptible to one specific type of cancer, the mice had a diverse set of diagnoses, similar to what would be expected of normal mice at a much older age. The researchers believe this is due to hypermethylation that they observed in enhancers, regions of DNA that help increase transcription of many genes but are also commonly implicated in cancer.

Although the researchers cannot say whether the same sort of epigenetic inheritance is occurring in humans, they believe that this is a valuable question for future research. Inherited epigenetic marks would not appear in a typical genetic screen for cancer risk, and as such could be overlooked to the detriment of preventative care. Likewise, the researchers note, cancer drugs that target epigenetic mechanisms are on the rise, and there has been no research into the effects that this might have on children conceived by people taking the drugs. If human embryos are inheriting aberrant epigenetic marks in the manner observed in mice in this investigation, then people taking drugs with epigenetic targets should be warned against conceiving children until after they are clear of the effects of their medication.

“We hope that this research demonstrating the cancer risk of inherited epigenetic marks in mice adds to the burgeoning field of mammalian epigenetic inheritance research,” Page says, “and that we have drawn attention to the possible implications for human health.”

 

Written by Greta Friar

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David Page’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 the Massachusetts Institute of Technology.

***

Full citation:

“Intergenerational epigenetic inheritance of cancer susceptibility in mammals”

eLife, April 9, 2019, DOI: https://doi.org/10.7554/eLife.39380

Bluma J. Lesch, Zuzana Tothova, Elizabeth A. Morgan, Zhicong Liao, Roderick T. Bronson, Benjamin L. Ebert, and David C. Page.

The evolving definition of a gene

Professor Gerald Fink, a pioneer in the field of genetics, delivers the annual Killian Lecture.

MIT News Office
April 8, 2019

More than 50 years ago, scientists came up with a definition for the gene: a sequence of DNA that is copied into RNA, which is used as a blueprint for assembling a protein.

In recent years, however, with the discovery of ever more DNA sequences that play key roles in gene expression without being translated into proteins, this simple definition needed revision, according to Gerald Fink, the Margaret and Herman Sokol Professor in Biomedical Research and American Cancer Society Professor of Genetics in MIT’s Department of Biology.

Fink, a pioneer in the field of genetics, discussed the evolution of this definition during yesterday’s James R. Killian Jr. Faculty Achievement Award Lecture, titled, “What is a Gene?”

“In genetics, we’ve lost a simple definition of the gene — a definition that lasted over 50 years,” he said. “But loss of the definition has spawned whole new fields trying to understand the unknown information in non-protein-coding DNA.”

Established in 1971 to honor MIT’s 10th president, James Killian, the Killian Award recognizes extraordinary professional achievements by an MIT faculty member. Fink, who is also a member and former director of the Whitehead Institute, was honored for his achievements in developing brewer’s yeast as “the premier model for understanding the biology of eukaryotes” — organisms whose cells have nuclei.

“He is among the very few scientists who can be singularly credited with fundamentally changing the way we approach biological problems,” says the award citation, read by Susan Silbey, chair of the MIT faculty, who presented Fink with the award.

Genetic revolution

Growing in a “sleepy” town on Long Island, Fink had a keen interest in science, which spiked after the Soviets launched the first satellite to orbit the Earth.

“In 1957, when I went out in our backyard, I was hypnotized by the new star in the sky, as Sputnik slowly raced toward the horizon,” he said. “Overnight, science became a national priority, energized by the dread of Soviet technology and technological superiority.”

After earning his bachelor’s degree at Amherst College, Fink began studying yeast as a graduate student at Yale University, and in 1976, he developed a way to insert any DNA sequence into yeast cells.

This discovery transformed biomedical research by allowing scientists to program yeast to produce any protein they wanted, as long as they knew the DNA sequence of the gene that encoded it. It also proved industrially useful: More than half of all therapeutic insulin is now produced by yeast, along with many other drugs and vaccines, as well as biofuels such as ethanol.

At that time, scientists were operating with a straightforward definition of the gene, based on the “central dogma” of biology: DNA makes RNA, and RNA makes proteins. Therefore, a gene was defined as a sequence of DNA that could code for a protein. This was convenient because it allowed computers to be programmed to search the genome for genes by looking for specific DNA sequences bracketed by codons that indicate the starting and stopping points of a gene.

In recent decades, scientists have done just that, identifying about 20,000 protein-coding genes in the human genome. They have also discovered genetic mechanisms involved in thousands of human diseases. Using new tools such as CRISPR, which enables genome editing, cures for such diseases may soon be available, Fink believes.

“The definition of a gene as a DNA sequence that codes for a protein, coupled with the sequencing of the human genome, has NetBet sportrevolutionized molecular medicine,” he said. “Genome sequencing, along with computational power to compare and analyze genomes, has led to important insights into basic science and disease.”

However, he pointed out, protein-coding genes account for just 2 percent of the entire human genome. What about the rest of it? Scientists have traditionally referred to the remaining 98 percent as “junk DNA” that has no useful function.

In the 1980s, Fink began to suspect that this junk DNA was not as useless as had been believed. He and others discovered that in yeast, certain segments of DNA could “jump” from one location to another, and that these segments appeared to regulate the expression of whatever genes were nearby. This phenomenon was later observed in human cells as well.

“That alerted me and others to the fact that ‘junk DNA’ might be making RNA but not proteins,” Fink said.

Since then, scientists have discovered many types of non-protein-coding RNA molecules, including microRNAs, which can block the production of proteins, and long non-coding RNAs (lncRNAs), which have many roles in gene regulation.

“In the last 15 years, it has been found that these are critical for controlling the gene expression of protein-coding genes,” Fink said. “We’re only now beginning to visualize the importance of this formerly invisible part of the genome.”

Such discoveries demonstrate that the traditional definition of a gene is inadequate to encompass all of the information stored in the genome, he said.

“The existence of these diverse classes of RNA is evidence that there is no single physical and functional unit of heredity that we can call the gene,” he said. “Rather, the genome contains many different categories of informational units, each of which may be considered a gene.”

“A community of scholars”

In selecting Fink for the Killian Award, the award committed also cited his contributions to the founding of the Whitehead Institute, which opened in 1982. At the time, forming a research institute that was part of MIT yet also its own entity was considered a “radical experiment,” Fink recalled.

Though controversial at the time, with heated debate among the faculty, establishing the Whitehead Institute laid the groundwork for many other research institutes that have been established at MIT, and also helped to attract biotechnology companies to the Kendall Square area, Fink said.

“As we now know, MIT made the right decision. The Whitehead turned out to be a successful pioneer experiment that in my opinion led to the blossoming of the Kendall Square area,” he said.

Fink was hired as one of the first faculty members of the Whitehead Institute, and served as its director from 1990 to 2001, when he oversaw the Whitehead’s contributions to the Human Genome Project. He recalled that throughout his career, he has collaborated extensively not only with other biologists, but with MIT colleagues in fields such as physics, chemical engineering, and electrical engineering and computer science.

“MIT is a community of scholars, and I was welcomed into the community,” he said.