Author: mantulin

Tissue chip headed to International Space Station for osteoarthritis study

Successfully launched project aims to understand why some injuries result in develop post-traumatic osteoarthritis while others heal and recover.

Daniel J. Darling | Department of Biological Engineering
May 7, 2019

On May 4, a National Center for Advancing Translational Sciences (NCATS)-supported tissue-chip system with direct clinical applications to health conditions here on Earth was launched on the SpaceX CRS 17/Falcon 9 rocket.

Hundreds of millions of people worldwide suffer from osteoarthritis (OA), and there are currently no disease-modifying drugs that can halt or reverse the progression of OA — only painkillers for short-term symptomatic relief. Millions of healthy young to middle-aged individuals develop post-traumatic osteoarthritis (PTOA) as a result of a traumatic joint injury, like a tear of the anterior cruciate ligament or meniscus, especially in young women playing sports. Exercise-related injuries are also said to be frequent sources of joint injury for crew members living aboard the International Space Station (ISS), and pre-existing joint injuries may also affect astronaut performance in space. These conditions are compounded and worsened by exposure of crew members to weightlessness and radiation on the ISS.

After a traumatic joint injury, there is an immediate upregulation of inflammatory proteins called cytokines in the joint synovial fluid, proteins which are secreted mainly by cells in the joint’s synovial lining. When mechanical trauma to cartilage caused by the initial injury is accompanied by cytokine penetration into cartilage, degradation of cartilage and subchondral bone over weeks and months often progresses to full-blown, painful PTOA in 10-15 years.

To study PTOA on Earth and in space, investigators at MIT have developed a cartilage-bone-synovium micro-physiological system in which primary human cartilage, bone, and synovium tissues (obtained from donor banks) are co-cultured for several weeks. During culture, investigators can monitor intracellular and extracellular biomarkers of disease using quantitative experimental and computational metabolomics and proteomics analyses, along with detection of disease-specific fragments of tissue matrix molecules. In addition, this co-culture system allows investigators to test the effects of potential disease-modifying drugs to prevent cartilage and bone loss on Earth and in space.

Experiments aboard the ISS utilize a Multi-purpose Variable-G Platform, made by Techshot Inc., to study the effects of microgravity and ionizing radiations on a knee tissue chip prepared using cartilage-bone-synovium tissues secured on a biocompatible material. The platform enables automated nutrient media transfer and collection for test conditions with and without disease-modifying drugs, including tests using a one-gravity control system.

These investigations on Earth and in the ISS have the potential to lead to the discovery of treatments and treatment regimens that, if administered immediately after a joint injury, could halt the progression of OA disease before it becomes irreversible. The goal is to treat the root cause of PTOA and prevent permanent joint damage, rather than mask the symptoms with painkillers later in life, as is currently done. These studies are funded by the NIH National Center for Advancing Translational Sciences and the ISS-National Lab.

A new approach to targeting tumors and tracking their spread

Researchers develop nanosized antibodies that home in on the meshwork of proteins surrounding cancer cells.

Helen Knight | MIT News correspondent
May 6, 2019

The spread of malignant cells from an original tumor to other parts of the body, known as metastasis, is the main cause of cancer deaths worldwide.

Early detection of tumors and metastases could significantly improve cancer survival rates. However, predicting exactly when cancer cells will break away from the original tumor, and where in the body they will form new lesions, is extremely challenging.

There is therefore an urgent need to develop new methods to image, diagnose, and treat tumors, particularly early lesions and metastases.

In a paper published today in the Proceedings of the National Academy of Sciences, researchers at the Koch Institute for Integrative Cancer Research at MIT describe a new approach to targeting tumors and metastases.

Previous attempts to focus on the tumor cells themselves have typically proven unsuccessful, as the tendency of cancerous cells to mutate makes them unreliable targets.

Instead, the researchers decided to target structures surrounding the cells known as the extracellular matrix (ECM), according to Richard Hynes, the Daniel K. Ludwig Professor for Cancer Research at MIT. The research team also included lead author Noor Jailkhani, a postdoc in the Hynes Lab at the Koch Institute for Integrative Cancer Research.

The extracellular matrix, a meshwork of proteins surrounding both normal and cancer cells, is an important part of the microenvironment of tumor cells. By providing signals for their growth and survival, the matrix plays a significant role in tumor growth and progression.

When the researchers studied this microenvironment, they found certain proteins that are abundant in regions surrounding tumors and other disease sites, but absent from healthy tissues.

What’s more, unlike the tumor cells themselves, these ECM proteins do not mutate as the cancer progresses, Hynes says. “Targeting the ECM offers a better way to attack metastases than trying to prevent the tumor cells themselves from spreading in the first place, because they have usually already done that by the time the patient comes into the clinic,” Hynes says.

The researchers began developing a library of immune reagents designed to specifically target these ECM proteins, based on relatively tiny antibodies, or “nanobodies,” derived from alpacas. The idea was that if these nanobodies could be deployed in a cancer patient, they could potentially be imaged to reveal tumor cells’ locations, or even deliver payloads of drugs.

The researchers used nanobodies from alpacas because they are smaller than conventional antibodies. Specifically, unlike the antibodies produced by the immune systems of humans and other animals, which consist of two “heavy protein chains” and two “light chains,” antibodies from camelids such as alpacas contain just two copies of a single heavy chain.

Nanobodies derived from these heavy-chain-only antibodies comprise a single binding domain much smaller than conventional antibodies, Hynes says.

In this way nanobodies are able to penetrate more deeply into human tissue than conventional antibodies, and can be much more quickly cleared from the circulation following treatment.

To develop the nanobodies, the team first immunized alpacas with either a cocktail of ECM proteins, or ECM-enriched preparations from human patient samples of colorectal or breast cancer metastases.

They then extracted RNA from the alpacas’ blood cells, amplified the coding sequences of the nanobodies, and generated libraries from which they isolated specific anti-ECM nanobodies.

They demonstrated the effectiveness of the technique using a nanobody that targets a protein fragment called EIIIB, which is prevalent in many tumor ECMs.

When they injected nanobodies attached to radioisotopes into mice with cancer, and scanned the mice using noninvasive PET/CT imaging, a standard technique used clinically, they found that the tumors and metastases were clearly visible. In this way the nanobodies could be used to help image both tumors and metastases.

But the same technique could also be used to deliver therapeutic treatments to the tumor or metastasis, Hynes says. “We can couple almost anything we want to the nanobodies, including drugs, toxins or higher energy isotopes,” he says. “So, imaging is a proof of concept, and it is very useful, but more important is what it leads to, which is the ability to target tumors with therapeutics.”

The ECM also undergoes similar protein changes as a result of other diseases, including cardiovascular, inflammatory, and fibrotic disorders. As a result, the same technique could also be used to treat people with these diseases.

In a recent collaborative paper, also published in Proceedings of the National Academy of Sciences, the researchers demonstrated the effectiveness of the technique by using it to develop nanobody-based chimeric antigen receptor (CAR) T cells, designed to target solid tumors.

CAR T cell therapy has already proven successful in treating cancers of the blood, but it has been less effective in treating solid tumors.

By targeting the ECM of tumor cells, nanobody-based CAR T cells became concentrated in the microenvironment of tumors and successfully reduced their growth.

The ECM has been recognized to play crucial roles in cancer progression, but few diagnostic or therapeutic methods have been developed based on the special characteristics of cancer ECM, says Yibin Kang, a professor of molecular biology at Princeton University, who was not involved in the research.

“The work by Hynes and colleagues has broken new ground in this area and elegantly demonstrates the high sensitivity and specificity of a nanobody targeting a particular isoform of an ECM protein in cancer,” Kang says. “This discovery opens up the possibility for early detection of cancer and metastasis, sensitive monitoring of therapeutic response, and specific delivery of anticancer drugs to tumors.”

This work was supported by a Mazumdar-Shaw International Oncology Fellowship, fellowships for the Ludwig Center for Molecular Oncology Research at MIT, the Howard Hughes Medical Institute and a grant from the Department of Defence Breast Cancer Research Program, and imaged on instrumentation purchased with a gift from John S. ’61 and Cindy Reed.

The researchers are now planning to carry out further work to develop the nanobody technique for treating tumors and metastases.

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, and 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 value 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.”

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 tumor 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 tumor 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.

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 revolutionized 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.

School of Science announces 2019 Infinite Mile Awards

Ten staff members in the School of Science are recognized for going above and beyond their job descriptions to support a better Institute.

School of Science
April 2, 2019

The MIT School of Science has announced the winners of the 2019 Infinite Mile Award, which is presented annually to staff members within the school who demonstrate exemplary dedication to making MIT a better place.

Nominated by their colleagues, these winners are notable for their unrelenting and extraordinary hard work in their positions, which can include mentoring fellow community members, innovating new solutions to problems big and small, building their communities, or going far above and beyond their job descriptions to support the goals of their home departments, labs, and research centers.

The 2019 Infinite Mile Award winners are:

Christine Brooks, an administrative assistant in the Department of Chemistry, nominated by Mircea Dincă and several members of the Dincă, Schrock, and Cummins groups;

Annie Cardinaux, a research specialist in the Department of Brain and Cognitive Sciences, nominated by Pawan Sinha;

Kimberli DeMayo, a human resources consultant in the Department of Mathematics, nominated by Nan Lin, Dennis Porche, and Paul Seidel, with support from several other faculty members;

Arek Hamalian, a technical associate at the Picower Institute for Learning and Memory, nominated by Susumu Tonegawa;

Jonathan Harmon, an administrative assistant in the Department of Mathematics, nominated by Pavel Etingof and Kimberli DeMayo, with support from several other faculty members;

Tanya Khovanova, a lecturer in the Department of Mathematics, nominated by Pavel Etingof, David Jerison, and Slava Gerovitch;

Kelley Mahoney, an SRS financial staff member in the Kavli Institute for Astrophysics and Space Research, nominated by Sarah Brady, Michael McDonald, Anna Frebel, Jacqueline Hewitt, Jack Defandorf, and Stacey Sullaway;

Walter Massefski, the director of instrumentation facility in the Department of Chemistry, nominated by Timothy Jamison and Richard Wilk;

Raleigh McElvery, a communications coordinator in the Department of Biology, nominated by Vivian Siegel with support from Amy Keating, Julia Keller, and Erika Reinfeld; and

Kate White, an administrative officer in the Department of Brain and Cognitive Sciences, nominated by Jim DiCarlo, Michale Fee, Sara Cody-Larnard, Rachel Donahue, Federico Chiavazza, Matthew Regan, Gayle Lutchen, and William Lawson.

The recipients will receive a monetary award in addition to being honored at a celebratory reception, along with their peers, family and friends, and the recipients of the 2019 Infinite Kilometer Award this month.

Biologists find a way to boost intestinal stem cell populations

Study suggests that stimulating stem cells may protect the gastrointestinal tract from age-related disease.

Anne Trafton | MIT News Office
March 28, 2019

Cells that line the intestinal tract are replaced every few days, a high rate of turnover that relies on a healthy population of intestinal stem cells. MIT and University of Tokyo biologists have now found that aging takes a toll on intestinal stem cells and may contribute to increased susceptibility to disorders of the gastrointestinal tract.

The researchers also showed that they could reverse this effect in aged mice by treating them with a compound that helps boost the population of intestinal stem cells. The findings suggest that this compound, which appears to stimulate a pathway that involves longevity-linked proteins known as sirtuins, could help protect the gut from age-related damage, the researchers say.

“One of the issues with aging is organ dysfunction, accompanied by a decline in the activity of the stem cells that nurture and replenish that organ, so this is a potentially very useful intervention point to either slow or reverse aging,” says Leonard Guarente, the Novartis Professor of Biology at MIT.

Guarente and Toshimasa Yamauchi, a professor at the University of Tokyo, are the senior authors of the study, which appears online in the journal Aging Cell on March 28. The lead author of the paper is Masaki Igarashi, a former MIT postdoc who is now at the University of Tokyo.

Population growth

Guarente’s lab has long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction.

In a paper published in 2016, Guarente and Igarashi found that in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In their new study, they set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals.

“That has real implications for health because just having more stem cells is all well and good, but it might not equate to anything in the real world,” Guarente says. “Knowing that the guts are actually more stress-resistant if they’re NR- supplemented is pretty interesting.”

Protective effects

Guarente says he believes that NR is likely acting through a pathway that his lab previously identified, in which boosting NAD turns on not only SIRT1 but another gene called mTORC1, which stimulates protein synthesis in cells and helps them to proliferate.

“What we would hypothesize is that the NAD replenishment in old mice is driving this pathway of growth that’s working through SIRT1 and TOR to reverse the decline that has occurred with aging,” he says.

The findings suggest that NAD might have a protective effect against diseases of the gut, such as colitis, in older people, he says. Guarente and his colleagues have previously found that NAD precursors can also stimulate the growth of blood vessels and muscles and boost endurance in aged mice, and a 2016 study from researchers in Switzerland found that boosting NAD can help replenish muscle stem cell populations in aged mice.

In 2014, Guarente started a company called Elysium Health, which sells a dietary supplement containing NR combined with another natural compound called pterostilbene, which is an activator of SIRT1.

The research was funded, in part, by the National Institutes of Health and the Glenn Foundation for Medical Research.

Whitehead Institute’s David Page to conclude term as director

Search committee chaired by MIT President Emerita Susan Hockfield will identify new director for eminent biomedical institute.

Lisa Girard | Whitehead Institute
March 27, 2019

Whitehead Institute, the world-renowned nonprofit research institution dedicated to improving human health through basic biomedical research, has announced that Institute Director David C. Page — a Whitehead Institute member since 1988 and director since 2004 — will complete his current term as director and president in summer 2020. An international search has been launched for Page’s successor.

“David’s tenure as director has been a period of incredible richness for Whitehead Institute,” says Charles D. Ellis, chair of the Whitehead Institute Board of Directors. “It has been rich in the path-breaking science that our researchers have done; in the intellectual ferment and creative environment that Whitehead members have fostered; and in the sense of community and common purpose that David has nurtured. He has led us with great skill and vision through a dynamic period of growth and continuous exploration, and he will pass to his successor an organization primed to tackle the challenges offered by a swiftly evolving bioscience landscape.”

Since its founding in 1982, Whitehead Institute has been one of the world’s most influential biomedical research centers — producing a continual stream of significant discoveries and new research tools and approaches. Whitehead Institute is a legally and financially independent organization closely affiliated with MIT, and Whitehead Institute members hold MIT faculty appointments. The 17 Whitehead Institute members include two National Medal of Science winners, nine National Academy of Sciences members, four National Academy of Medicine members, and four Investigators of the Howard Hughes Medical Institute. In addition, the institute’s prestigious Whitehead Fellows Program has fostered generations of biomedical science leaders — including Harvard Medical School Dean George Daley, celebrated MIT cancer researcher and professor of biology Angelika Amon, Broad Institute President and Founding Director Eric Lander, and NASA astronaut and space biologist Kate Rubins.

Whitehead Institute and MIT have been Page’s professional home since he earned an MD from Harvard Medical School and the Harvard-MIT Health Sciences and Technology Program and completed research in David Botstein’s lab at MIT in 1984. After serving as the institute’s first Whitehead Fellow, he became a Whitehead member and MIT faculty member in 1988. Page was appointed associate director of the institute in 2002, interim director in 2004, and director in 2005.

Throughout his 35 years at Whitehead Institute, Page has run a thriving and productive research lab. His groundbreaking studies on the Y chromosome changed the way biomedical science views the function of sex chromosomes. That work earned him wide recognition, including a Macarthur Foundation Fellowship and a Searle Scholar Award; and he has been an Investigator of the Howard Hughes Medical Institute since 1990. His research twice earned inclusion in Science magazine’s “Top 10 Breakthroughs of the Year,” first for mapping a human chromosome and then for sequencing the human Y chromosome. Today, his lab is pursuing a deep understanding of the role of sex chromosomes in health and disease — work with the potential to fundamentally change the practice of medicine and improve the quality of care for women and men alike.

As director, Page has made a mark on all facets of the Whitehead Institute organization. During his tenure, he oversaw the creation of the Institute’s Intellectual Property Office; strengthened its core facilities; and established new platforms, such as the Metabolomics Center. He also enhanced the leadership structure by appointing three associate directors; and he supported the creation of the child care center. Perhaps most important for the long run, Page has guided a robust renewal of faculty and has helped to prepare the organization for the eventual retirement of the Institute’s founding generation of members.

The search for Page’s successor will be guided by a committee of noted leaders in education, biomedical research, and nonprofit organizations, including Susan Hockfield (chair), MIT professor of neuroscience and president emerita; Laurie H. Glimcher, president and CEO of the Dana-Farber Cancer Institute and former dean of Weill Cornell Medical College; Alan Grossman, the Praecis Professor of Biology and head of the MIT Department of Biology; Paul L. Joskow, former president and CEO of Alfred P. Sloan Foundation and the Elizabeth and James Killian Professor of Economics Emeritus at MIT; Amy E. Keating, professor in the departments of Biology and Biological Engineering at MIT; David Sabatini, Whitehead Institute member and associate director, and professor of biology at MIT; Phillip A. Sharp, Nobel laureate and MIT Institute professor and professor of biology; and Sarah Williamson, CEO of FCLT Global and former partner at Wellington Management Company (Joskow, Sharp, and Williamson are also members of the Whitehead Institute Board of Directors.)

The committee will be assisted by global executive search firm Russell Reynolds Associates.

“Whitehead Institute is one of the world’s premier research institutions,” says Hockfield. “It possesses an innovative and collaborative culture; rich talent and intellectual capital; a robust relationship with MIT; and a place at the heart of the Kendall Square innovation community. These factors make it an ideal opportunity for a director with vision, scientific courage, and a passion to address basic biomedical science’s most significant challenges.”

“The scientists of Whitehead Institute have helped to drive biomedical research forward and onto exciting new paths,” says Page. “In coming years, the Institute itself will experience a generational evolution, and my successor will help define the organization’s future — and by extension, help shape the direction of biomedical research for decades to come.”

The new director will have an impressive line of predecessors: Whitehead Institute’s founding director was Nobel laureate and former Caltech president David Baltimore; he was succeeded by globally respected researcher and science enterprise leader Gerald Fink, and then by National Medal of Science recipient Susan Lindquist — Page’s immediate predecessor.