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Advancing knowledge in medical and genetic sciences

Three MIT faculty members selected for funding from the G. Harold and Leila Y. Mathers Foundation.

Danielle Randall | Department of Chemistry
June 27, 2018

Research proposals from Laurie Boyer, associate professor of biology; Matt Shoulders, the Whitehead Career Development Associate Professor of Chemistry; and Feng Zhang, associate professor in the departments of Brain and Cognitive Sciences and Biological Engineering, Patricia and James Poitras ’63 Professor in Neuroscience, investigator at the McGovern Institute for Brain Research, and core member of the Broad Institute, have recently been selected for funding by the G. Harold and Leila Y. Mathers Foundation. These three grants from the Mathers Foundation will enable, over the next three years, key projects in the researchers’ respective labs.

Regenerative medicine holds great promise for treating heart failure, but that promise is unrealized, in part, due to a lack of sufficient understanding of heart development at the mechanistic level. Boyer’s research aims to achieve a deep, mechanistic understanding of the gene control switches that coordinate normal heart development. She then aims to leverage this knowledge and design effective strategies for rewiring faulty circuits in aging and disease.

“We are very grateful to receive support and recognition of our work from the Mathers Foundation,” said Boyer. “This award will allow us to build upon our prior work and to embark upon high risk projects that could ultimately change how we think about treating diseases resulting from faulty wiring of gene expression programs.”

Shoulders’ goal, with this support from the Mathers Foundation, is to elucidate underlying causes of osteoarthritis. There is currently no cure for osteoarthritis, which is perhaps the most common aging-related disease and is characterized by a progressive deterioration of joint cartilage culminating in inflammation, debilitating pain, and joint dysfunction. The Shoulders Group aims to test a new model for osteoarthritis — specifically, the concept that a collapse of proteostasis in aging cartilage cells creates an unrecoverable cartilage repair defect, thus initiating a self-amplifying, destructive feedback loop leading to pathology. Proteostasis collapse in aging cells is a well-known, disease-causing phenomenon that has previously been considered primarily in the context of neurodegenerative disorders. If correct, the proteostasis collapse model for osteoarthritis could one day lead to a novel class of therapeutic options for the disease.

“We are delighted to receive this generous support from the Mathers Foundation, which makes it possible for us to pursue an outside-the-box, high-risk/high-impact idea regarding the origins of osteoarthritis,” said Shoulders. “The research we are now able to pursue will not only provide fundamental, molecular-level insights into joint function, but also could change how we think about this widespread disease.”

Many genetic diseases are caused by the change of just a single base of DNA. Zhang is a leader in the field of genome editing, and he and his team have developed an array of tools based on the microbial immune CRISPR-Cas systems that can manipulate DNA and RNA in human cells. Together, these tools are changing the way molecular biology research is conducted, and they hold immense potential as therapeutic agents to correct thousands of genetic diseases. Now, with the support of the Mathers Foundation, Zhang is working to realize this potential by developing a CRISPR-based therapeutic that works at the level of RNA and offers a safe, effective route to treating a range of diseases, including diseases of the brain and central nervous system, which are difficult to treat with existing gene therapies.

“The generous support from the Mathers Foundation allows us the freedom to explore this exciting new direction for CRISPR-based technologies,” Zhang stated.

Known for their generosity and philanthropy, G. Harold and Leila Y. Mathers created their foundation with the goal of distributing their wealth among sustainable, charitable causes, with a particular interest in basic scientific research. The Mathers Foundation, whose ongoing mission is to advance knowledge in the life sciences by sponsoring scientific research and applying learnings and discoveries to benefit mankind, has issued grants since 1982.

3Q: Nancy Hopkins on the impact and potential of cancer prevention

Mechanism-based cancer prevention is poised to further decrease the numbers of U.S. cancer deaths, says MIT professor emerita.

Anne Trafton | MIT News Office
June 25, 2018

Great progress has already been made in reducing the cancer death toll through prevention, according to a new article in the June 25 issue of Genes and Development by MIT Professor Emerita Nancy Hopkins and colleagues from the Broad Institute, Fox Chase Cancer Center, University of Texas M.D. Anderson Cancer Center, and Oxford University. The potential for further reduction is great for two reasons, these researchers say: If these approaches can be more widely applied, in principle about half of current U.S. cancer deaths could be prevented over the next two to three decades; and new discoveries about how cancer develops could help scientists develop even better prevention and screening methods. MIT News spoke with Hopkins, the Amgen Inc. Professor of Biology Emerita, about why this is an exciting time for cancer research.   

netbet sports bettingWhat does your new article reveal about the impact of cancer prevention and early detection?

A: We’ve described how researchers are integrating the dramatic advances in understanding the molecular biology of cancer to explain long-known facts about how lifestyle choices and factors in the environment affect how cancers arise, and how they progress to become detectable tumors.

Prevention and early detection have already had a tremendous impact on reducing U.S. cancer death rates. In the cancer prevention community, netbet sports bettingit is well-known that about half of current U.S. cancer deaths could, in theory, be prevented over the next two to three decades simply by the full uptake of proven methods of cancer prevention. This important fact is not as well appreciated by the larger cancer research community. This is not a fault of the cancer researchers; it simply reflects the reality that after years of investment and growth, the field of cancer is very broad, with most people working in areas of specialty.

Given the difficulties in treating established cancers, preventing many cancers entirely would obviously produce a quantal leap in reducing U.S. cancer death rates. But in addition, we believe that recent progress in understanding the molecular mechanisms that underlie cancer, and new technologies associated with these advances, could also lead to novel approaches to preventing cancer, detecting it at earlier stages when treatment is often far more successful, or even intercepting the progression of incipient cancers before they develop into tumors.

Q: What interventions have had success preventing cancer, and what promising new approaches are on the horizon?

A: Spectacular examples of preventing cancers from arising in the first place (formally called “primary cancer prevention”) include (1) successful efforts that reduced smoking rates in the United States (from over 40 percent in the 1960s to about 15 percent today) and that have led to a decline in the incidence of lung cancer and a dozen or more other types of cancer caused by smoking; (2) vaccines for cancer-causing viruses, including hepatitis B virus (a cause of liver cancer) and papilloma viruses (the cause of cervical, head and neck, and several other cancers); (3) clean air and water acts and safer workplace laws in the United States that have prevented workers as well as the general population from exposure to high concentrations of certain industrial chemicals known to cause cancer; (4) the development of drugs to cure hepatitis C infection, which are expected to prevent the development of liver cancer in the future; (5) campaigns such as the one in Australia to prevent skin cancers (particularly melanoma) by behavioral changes related to sun exposure.

As for promising new approaches to primary cancer prevention, the fuller uptake of proven methods of prevention is obviously one way to ensure a dramatic decrease in U.S. cancer death rates in the next two to three decades. This would require a greater investment in public health measures. As our article outlines, we are only now coming to understand the mechanisms by which factors such as obesity, inflammation, and some lifestyle choices synergize with long-appreciated risk factors to promote cancer. Based on this improved understanding, prevention could also be aided by research into new drugs, for example to prevent nicotine addiction or to intercept cancer progression by targeting inflammation. Exciting, too, is the possibility that DNA sequencing of cancer genomes may help to identify additional external causes of cancers based on the “mutational signatures” they leave in our DNA after exposures. If so, these agents may prove to be removable or avoidable in future.

We also discuss a second type of intervention to prevent cancer. This is screening, sometimes referred to as “secondary cancer prevention,” which can detect precancers and cancers at an early enough stage to remove them completely or treat them much more successfully. Spectacular successes to date include the Pap test that has greatly reduced deaths from cervical cancer in the United States and elsewhere; newer molecular tests focused on HPV-virus detection have proven similarly effective and are now replacing traditional Pap tests which require expert pathologic interpretations, making screening more widely available. A second success is colonoscopy, which has been enormously successful at detecting precancerous polyps and early-stage colon cancers that can be removed through the endoscope, or detected earlier when they’re more likely to be responsive to treatment. Additionally, other less-invasive methods of colon cancer screening are readily available and highly effective. Also successful has been mammography in combination with follow-up treatment. Along with greatly improved treatment, it is credited with contributing to the declining death rate from breast cancer.

Q: What types of new screening methods do you believe could help to further improve early detection of cancer?

A: Many of the most successful screening methods are for cancers that develop on body surfaces and hence can be detected by visual inspection. Imaging can be hugely successful for cancers that lie deeper in the body — breast for example — but imaging that becomes more and more sensitive can identify many abnormalities that may not be cancer at all. This can lead to costly and invasive testing of what are sometimes referred to as “incidentalomas.” Much needed are novel methods of screening that may combine imagining with other markers to make it possible to distinguish true cancers from noncancerous aberrations occurring in internal organs.

The holy grail of cancer screening would be blood tests to detect early-stage cancers, and many efforts are now directed to this goal. This is an extremely exciting time for the emergence of powerful molecular diagnostics that can help pinpoint very early-stage tumors. Some of these rely on relatively noninvasive methods, such as measurement of DNA signatures found in the blood. Widespread availability and demonstrated effectiveness of such methods would greatly enhance the field of secondary prevention, but there remain substantial challenges and it is not yet known if this approach will succeed. Also very exciting are methods being developed by bioengineers here at MIT and in other places to try to amplify other signals arising from tumors that may be difficult to detect otherwise and include, for example, completely noninvasive urine-based tests.

After decades of effort, cancer is gradually coming under control thanks to prevention and early detection, improvements in “conventional” cancer treatment (imaging, surgery, radiation, chemotherapy, and some adjuvant therapies), and novel approaches to treatment based on immunotherapy and more personalized drugs. But it is likely that for now, the full implementation of proven methods of prevention offers the most reliable approach to large-scale reduction of U.S. cancer deaths. Meanwhile, research into novel mechanism-based approaches to preventing the initiation and progression of cancer may one day prevent the majority of cancers from occurring in the first place.

Fighting implicit bias in STEM with increased cognitive control

In a visit with the Department of Biology, Lydia Villa-Komaroff PhD '75 explains how “thinking fast makes changing slow.”

Raleigh McElvery | Department of Biology
June 26, 2018

The brain carries out many processes automatically and without our conscious recognition. This means that when we encounter certain information — like the name on a resume suggesting a specific gender or race — we make an immediate and unintentional judgement. At the Building 68 Department of Biology retreat on June 14, keynote speaker Lydia Villa-Komaroff PhD ’75 explained the physiological roots of this implicit bias and offered potential solutions.

Villa-Komaroff is a biologist and business woman advocating for diversity in STEM. When she received her PhD from the Department of Biology in 1975, she was one of the first Mexican American women to receive a doctorate in the sciences. She served as the chief operating officer and vice president of research for MIT’s Whitehead Institute for Biomedical Research for two years, and later founded her own one-woman consulting firm, Intersections, SBD. She is a board member, former CEO, and former chief science officer of the biotech company Cytonome/ST, LLC, and a member of the Biology netbet online sports bettingDepartment Visiting Committee. She is also a co-founding member of the Society for the Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS).

According to Villa-Komaroff, it’s not that STEM fields are completely without diversity. Rather, there are fewer members of underrepresented groups in positions of academic power relative to their peer populations. Women and underrepresented minorities tend to hold instructor roles or assistant professorships, and are less likely to become full professors, deans, and presidents.

“There has been some progress,” she said, “since the proportion of women and underrepresented groups has climbed. Women have climbed at a faster rate than have individuals from underrepresented ethnic groups, but the rate of increase in both of those groups is still slow relative to the changing population. Clearly something is going on in our society, and it has been going on for a very long time, longer than any of us have been around. So what might that be?”

Data are amassing, and not only from sociologists and psychologists, but from neuroscientists as well, Villa-Komaroff pointed out. Research has shown that humans are wired to make quick decisions that serve us well must of the time, but these inclinations can also cause us to misjudge the abilities of the person before us.

Since the brain is constantly confronted with a deluge of information, over the course of time it developed two systems to sift through all the input. System 1 is automatic: It’s running all the time, requires very little energy, and is crucial to our survival — permitting us to recognize danger and possible threats in a split second. It also allows us to complete habitual tasks, like playing the violin or holding a pipette, with very little conscious effort.

System 2 begets what we generally consider to be “thinking.” It is deliberate and requires a lot of energy to run. Often without our conscious awareness, System 1 overtakes System 2 and our decisions are driven by our instincts. Villa-Komaroff said we need to fight this tendency to “trust our instincts” when it comes time to select colleagues or students. It’s not simply about activating your thinking, it’s about challenging it.

“I’m sorry to say that we — that is those of us in the hard sciences — have been the most resistant to thinking that this might be in the case,” she said. “I can’t tell you how many times my colleagues have said to me, ‘This is not a problem for us because we care only about merit, and that is what we are basing our decisions upon.’ It’s true we care about merit, but that is not the factor on which we often base our first initial decisions.”

In fact, it has been shown that science faculty presented with two applications for a lab manager position, identical except for the names “Jennifer” and “John,” will evaluate John as more competent, give him more money, and offer him more career mentorship. The kicker is that these implicit biases aren’t just limited to a particular segment of the population. Women often have biases against other women, and the same is true for members of underrepresented groups.

But hope is not lost, Villa-Komaroff said. We can do something to counter this tendency if we just teach ourselves to recognize our own biases and deliberately work to override them.

In one study, researchers noticed that the panels at the American Society for Microbiology General Meeting consisted primarily of males. The panel committees that selected them also happened to be predominantly all-male. The researchers presented these data to the selection committees, and gave them an explicit call to action: Do something about it. The next year, the number of female speakers increased, and the number of all-male session planning committees decreased.

In another study, researchers took 92 medicine, science, and engineering departments from the University of Wisconsin at Madison and divided them into a matching control and test group, where the test group was invited to enroll in a short, two-and-a-half hour workshop on implicit bias. Despite the fact that, on average, just 25 percent of the faculty from the test group departments attended the session, afterwards they reported more self-initiated efforts to promote gender equity and better conflict resolution. Most notably, over the next several years the percentage of hires from underrepresented groups rose from 8 percent to 11 percent, while the controls saw a decrease from 10 percent to 5 percent. 

As part of the Strategies and Tactics to Increase Diversity and Excellence (STRIDE) program at the University of Michigan, full professors must now attend workshops on implicit bias in the fall during peak faculty recruitment season. Between 2001 and 2007, the percentage of faculty searches resulting in a female hire rose from 15 percent to 32  in STEM disciplines. If nothing else, these kinds of interventions may kick in the second, deliberate decision-making system, and allow us to see past the name on the resume.

Stem cell-derived zika model suggests mechanisms underlying microcephaly
Nicole Giese Rura | Whitehead Institute
June 21, 2018

Cambridge, MA  – Scientists turn to model organisms, like mice and yeast, to investigate the biology underlying emerging diseases. But for the Zika virus, the lack of a good model hampered this type of research. Now, a team of researchers in the laboratory of Whitehead Institute Founding Member Rudolf Jaenisch has devised a way to model Zika and other neural diseases in a dish. Their work is described this week in the journal PNAS.

The Zika virus was identified in 1947 in Uganda, but a 2013 epidemic in French Guinea first brought it to the public’s attention. As the disease spread throughout the Americas and the Caribbean in 2014, abnormalities, such as microcephaly in newborns, were increasingly reported when mothers were infected during their first trimester. Scientists’ efforts to better understand the virus and its mechanisms quickly hit a snag: mice, which are often used to model disease pathology, are not vulnerable to the Zika virus unless their innate immune defenses are knocked out. Additionally, neural diseases, such as those that cause microcephaly, affect cells that reside deep in the brain, and they cannot be easily accessed for observation and manipulation.

In order to circumvent these challenges and to model Zika in the lab, the researchers turned to induced pluripotent stem cells (iPSCs)–adult cells that have been pushed back to a embryonic stem cell-like state. iPSCs can in turn be nudged to mature into almost any cell type in the body. In previous work, Julien Muffat and Yun Li, former postdoctoral researchers in the Jaenisch lab, were the first to use iPSCs to create microglia, the specialized immune cells that maintain the brain and spinal cord and care for them after injury.

In the current work, Muffat and Li teamed up with Attya Omer, also a graduate student in the Jaenisch lab, and Lee Gehrke’s lab at MIT to study the effect of the Zika virus on iPSC-derived versions of three neural cell types critical during human fetal brain development: microglia, neural progenitors, and astrocytes. Whether the Zika virus can infect these cells and how well the cells can clear the virus could provide insight into why the virus can cause birth defects like microcephaly. Using their model, the team determined that after being infected with a strain derived from the initial Ugandan Zika virus, microglia can survive and can continue to harbor the virus. This is important because in a developing embryo, microglia move from the yolk sac to the developing brain very early in gestation. The study shows that, like their in vivo counterparts, iPSC-derived microglia could invade the immature neural tissue of a brain organoid, and pre-infected microglia could transfer the virus to the organoids. According to Muffat, NetBet sportthis suggests that if microglial precursors are infected before their journey, they could shuttle the Zika virus to the developing brain and infect the neural progenitors residing there.

Neural progenitor cells, which during gestation produce the neurons and glia that constitute the majority of the human brain, are particularly vulnerable to the Zika virus and die when infected. To better understand why these cells are so susceptible, the team compared how the Zika virus and the closely related dengue virus affect the neural progenitor cells. Dengue, which does not cause birth defects like microcephaly, triggers a strong cellular immune response, called interferon, in the neural progenitors, which enables the progenitor cells to efficiently fight and clear the dengue virus. In sharp contrast, when exposed to the Zika virus, neural progenitors mount little if any interferon immune defense. Pretreating the neural progenitor cells with interferon before exposure to the Zika virus impedes the virus’s progression and proliferation, and reduces cell death. These results suggest that therapeutically altering interferon levels could prevent some of the more dire effects of Zika infection on the neural progenitor cells.

According to the team, using iPSC-derived cells has great potential for modeling Zika virus as well as many other diseases that affect the central nervous system.

This work was supported by the European Leukodystrophy Association, the Brain & Behavior Research Foundation, the Simons Foundation (SFARI 204106), the International Rett Syndrome Foundation, Howard Hughes Medical Institute, the National Institutes of Health (NIH grants HD 045022, R37-CA084198, AI100190), the ELA Foundation, the Emerald Foundation, and Biogen. Jaenisch is a cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics.

Written by Nicole Giese Rura
***
Rudolf Jaenisch’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 professor of biology at Massachusetts Institute of Technology.
 ***
Full citation:
“Human Induced Pluripotent Stem Cell-derived Glial Cells and Neural Progenitors Display Divergent Responses to Zika and Dengue Infections”
PNAS, online June 18, 2018.
Julien Muffat (1,8), Yun Li (1,8), Attya Omer (1,8), Ann Durbin (3,4,5), Irene Bosch (3,4,5), Grisilda Bakiasi (6), Edward Richards (7), Aaron Meyer (7), Lee Gehrke (3,4,5), Rudolf Jaenisch (1,2).
1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA
3. IMES, Massachusetts Institute of Technology, Cambridge MA 02139, USA
4. Department of Microbiology and Immunobiology, Harvard Medical School, Boston 02115, USA
5. Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA
6. Bryn Mawr College, Bryn Mawr, PA
7. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA
8. These authors contributed equally
Biologists discover how pancreatic tumors lead to weight loss

Shortfall of digestive enzymes can lead to tissue breakdown in early stages of pancreatic cancer.

Anne Trafton | MIT News Office
June 20, 2018

Patients with pancreatic cancer usually experience significant weight loss, which can begin very early in the disease. A new study from MIT and Dana-Farber Cancer Institute offers insight into how this happens, and suggests that the weight loss may not necessarily affect patients’ survival.

In a study of mice, the researchers found that weight loss occurs due to a reduction in key pancreatic enzymes that normally help digest food. When the researchers treated these mice with replacement enzymes, they were surprised to find that while the mice did regain weight, they did not survive any longer than untreated mice.

Pancreatic cancer patients are sometimes given replacement enzymes to help them gain weight, but the new findings suggest that more study is needed to determine whether that actually benefits patients, says Matt Vander Heiden, an associate professor of biology at MIT and a member of the Koch Institute for Integrative Cancer Research.

“We have to be very careful not to draw medical advice from a mouse study and apply it to humans,” Vander Heiden says. “The study does raise the question of whether enzyme replacement is good or bad for patients, which needs to be studied in a clinical trial.”

Vander Heiden and Brian Wolpin, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, are the senior authors of the study, which appears in the June 20 issue of Nature. The paper’s lead authors are Laura Danai, a former MIT postdoc, and Ana Babic, an instructor in medicine at Dana-Farber.

Starvation mode

In a 2014 study, Vander Heiden and his colleagues found that muscle starts breaking down very early in pancreatic cancer patients, usually long before any other signs of the disease appear.

Still unknown was how this tissue wasting process occurs. One hypothesis was that pancreatic tumors overproduce some kind of signaling factor, such as a hormone, that circulates in the bloodstream and promotes breakdown of muscle and fat.

However, in their new study, the MIT and Dana-Farber researchers found that this was not the case. Instead, they discovered that even very tiny, early-stage pancreatic tumors can impair the production of key digestive enzymes. Mice with these early-stage tumors lost weight even though they ate the same amount of food as normal mice. These mice were unable to digest all of their food, so they went into a starvation mode where the body begins to break down other tissues, especially fat.

The researchers found that when they implanted pancreatic tumor cells elsewhere in the body, this weight loss did not occur. That suggests the tumor cells are not secreting a weight-loss factor that circulates in the bloodstream; instead, they only stimulate tissue wasting when they are in the pancreas.

The researchers then explored whether reversing this weight loss would improve survival. Treating the mice with pancreatic enzymes did reverse the weight loss. However, these mice actually survived for a shorter period of time than mice that had pancreatic tumors but did not receive the enzymes. That finding, while surprising, is consistent with studies in mice that have shown that calorie restriction can have a protective effect against cancer and other diseases.

“It turns out that this mechanism of tissue wasting is actually protective, at least for the mice, in the same way that limiting calories can be protective for mice,” Vander Heiden says.

Human connection

The intriguing findings from the mouse study prompted the research team to see if they could find any connection between weight loss and survival in human patients. In an analysis of medical records and blood samples from 782 patients, they found no link between degree of tissue wasting at the time of diagnosis and length of survival. That finding is important because it could reassure patients that weight loss does not necessarily mean that the patient will do worse, Vander Heiden says.

“Sometimes you can’t do anything about this weight loss, and this finding may mean that just because the patient is eating less and is losing weight, that doesn’t necessarily mean that they’re shortening their life,” he says.

The researchers say that more study is needed to determine if the same mechanism they discovered in mice is also occurring in human cancer patients. Because the mechanism they found is very specific to pancreatic tumors, it may differ from the underlying causes behind tissue wasting seen in other types of cancer and diseases such as HIV.

“From a mechanistic standpoint, this study reveals a very different way to think about what could be causing at least some weight loss in pancreatic cancer, suggesting that not all weight loss is the same across different cancers,” Vander Heiden says. “And it raises questions that we really need to study more, because some mechanisms may be protective and some mechanisms may be bad for you.”

Clary Clish, director netbet sports betting appof the Metabolomics Platform at the Broad Institute, and members of his research group also contributed to this work. The research was funded, in part, by the Lustgarten Foundation, a National Institutes of Health Ruth Kirschstein Fellowship, Stand Up 2 Cancer, the Ludwig Center for Molecular Oncology at MIT, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the MIT Center for Precision Cancer Medicine, and the National Institutes of Health.

Updates to biology laboratory requirements

The Department of Biology will be modifying its laboratory classes to increase flexibility in the curriculum.

Raleigh McElvery
June 13, 2018

As part of an initiative to increase flexibility in the curriculum, the Department of Biology will be modifying its laboratory requirements over the next two years. These changes will make it easier for students to become acquainted with lab techniques during their first year at MIT, permitting them to join faculty-run labs as part of the Undergraduate Research Opportunities Program (UROP) soon after they arrive.

Effective fall of 2019, the 18-unit 7.02 (Introduction to Experimental Biology and Communication) will be replaced by two new classes: the six-unit 7.002 (Fundamentals of Experimental Molecular Biology) and the 12-unit 7.003 (not yet named).  7.02 will continue to be offered in the fall of 2018 and spring of 2019 while 7.002 is introduced concurrently.

“This modification to our curriculum should enable students to gain experience in laboratory techniques and approaches as early as their first year,” says Department Head Alan Grossman. “It will prepare them to join research labs as UROP students and to work with graduate students, postdocs, and faculty members in a collaborative research setting.”

7.02 has traditionally served as an introduction to experimental concepts and methods in molecular biology, biochemistry, and genetics. However, it requires the time commitment of roughly one-and-a-half full classes, making it difficult for first-year students to fit it into their schedule while still completing their General Institute Requirements. Students taking 7.02  also bring a wide range of lab experiences; some have completed related internships during high school, while others have little or no research experience.

“7.02 prepares students to pursue UROPs in the biological sciences,” says Dennis Kim, undergraduate officer and Ivan R. Cottrell Professor of Immunology. “However, the 18 units of 7.02 make the course difficult to take before sophomore year. 7.002 can be taken at an earlier time, even in the first year. This will give students an experimental laboratory experience at an earlier stage of their education, facilitating the pursuit of UROPs.”

7.002 will be fewer units, not have any pre-requisites, and allow first-year students to get acquainted with basic methods of molecular biology. 7.003, by contrast, will serve as a second subject in experimental biology, and likely require co-requisites like 7.03 (Genetics) and 7.05 (General Biochemistry).

7.002 will be offered for the first time during the fall of 2018, although students will still have the option to enroll in 7.02 at this time. Beginning in the fall of 2019, 7.003 will be offered as a follow-up to 7.002, and 7.02 will no longer be offered. 7.002 will fulfill six units towards completion of the Institute Lab Requirement.

“These revisions to our lab curriculum stem from our larger effort to give students more flexibility in selecting their classes,” Grossman says. “The structure of 7.002 should also make it easier for students to receive additional information and guidance from department faculty members about opportunities in curiosity-driven life science research.”

The development and launch of 7.002 is supported by the d’Arbeloff Fund.

Ankur Jain joins Whitehead Institute and the Department of Biology

Biophysicist will investigate the biology of RNA aggregation.

Merrill Meadow | Whitehead Institute
June 11, 2018

Biophysicist Ankur Jain will join the Whitehead Institute as its newest member this coming September. Jain will also be appointed an assistant professor in the MIT Department of Biology. In his research, he will use a combination of innovative approaches to investigate the biology of RNA aggregation.

While it is understood that protein aggregation is a key factor in certain neurological diseases, relatively little is known about RNA aggregation, its underlying biology, and the role it plays in disease. A class of neurological disorders called repeat expansion diseases, which includes amyotrophic lateral sclerosis (ALS) and fragile X syndrome, are marked by stretches of DNA nucleotide repeats in their cognate disease gene. The presence of repeats is associated with clumps of RNA aggregates and RNA binding proteins that undergo phase transition to form an “RNA gel” in the nucleus. At the Whitehead Institute, Jain will continue his investigation into the properties of these RNA aggregates in order to learn how they form, what properties they possess, and how they could be disrupted to restore normal cellular processes. Jain will use nuclear speckles — areas in the nucleus associated with pre-mRNA splicing — as a model for physiological RNA-protein granules.

His lab will also investigate the role of RNA-DNA interactions in chromatin organization — the complex, dynamic structure of DNA and proteins in the nucleus. There are instances of nucleotide repeats in our genome that occur even in the absence of repeat expansion disease genes. Repetitive DNA sequences at the end of our chromosomes interact with proteins to form our telomeres, structures critical for chromosome maintenance. Jain will study the RNA transcribed from the telomeric sequences in order to understand their structure and if they undergo phase separation similar to the one seen in repeat expansion diseases. In addition, Jain will build on his specialized expertise in quantitative light microscopy to drive development of new imaging-based technologies.

“Ankur brings an approach grounded in a combination of soft-matter physics and cell biology to help pioneer an important — potentially ground-breaking — way of investigating and understanding RNA aggregation and RNA-DNA interaction,” says David C. Page, Whitehead Institute director and member. “His insights are exciting, and the intellectual and scientific creativity he brings to his research is energizing.”

Jain is currently completing a postdoc with Ronald Vale at University of California at San Francisco. He earned a PhD in biophysics and computational biology from the University of Illinois at Urbana-Champaign in 2013, and a bachelor’s degree (with honors) in biotechnology and biochemical engineering from Indian Institute of Technology Kharagpur in 2007. He holds a National Institutes of Health Pathway to Independence Award (also known as a K99 Award), and has been a lead author on peer-reviewed studies in the journals Nature and Proceedings of the National Academy of Sciences.

“Understanding the biology of RNA aggregation and phase separation has the potential to crack open long-time mysteries in cell biology,” Jain explains. “I am grateful for the chance to pursue my investigations in the intellectually rich and scientifically fruitful environment that Whitehead Institute and MIT have to offer.”

Decoding RNA-protein interactions

Scientists leverage one step, unbiased method to characterize the binding preferences of more than 70 human RNA-binding proteins.

Raleigh McElvery
June 7, 2018

Thanks to continued advances in genetic sequencing, scientists have identified virtually every A, T, C, and G nucleotide in our genetic code. But to fully understand how the human genome encodes us, we need to go one step further, mapping the function of each base. That is the goal of the Encyclopedia of DNA Elements (ENCODE) project, funded by the National Human Genome Research Institute and launched on the heels of the Human Genome Project in 2003. Although much has already been accomplished — mapping protein-DNA interactions and the inheritance of different epigenetic NetBet live casinostates — understanding the function of a DNA sequence also requires deciphering the purpose of the RNAs encoded by it, as well as which proteins bind to those RNAs.

Such RNA-binding proteins (RBPs) regulate gene expression by controlling various post-transcriptional processes — directing where the RNAs go in the cell, how stable they are, and which proteins will be synthesized. Yet these vital RNA-protein relationships remain difficult to catalog, since most of the necessary experiments are arduous to complete and difficult to interpret accurately.

In a new study, a team of MIT biologists and their collaborators describes the binding specificity of 78 human RBPs, using a one-step, unbiased method that efficiently and precisely determines the spectrum of RNA sequences and structures these proteins prefer. Their findings suggest that RBPs don’t just recognize specific RNA segments, but are often influenced by contextual features as well — like the folded structures of the RNA in question, or the nucleotides flanking the RNA-binding sequence.

“RNA is never naked in the cell because there are always proteins binding, guiding, and modifying it,” says Christopher Burge, director of the Computational and Systems Biology PhD Program, professor of biology and biological engineering, extramural member of the Koch Institute for Integrative Cancer Research, associate member of the Broad Institute of MIT and Harvard, and senior author of the study. “If you really want to understand post-transcriptional gene regulation, then you need to characterize those interactions. Here, we take advantage of deep sequencing to give a more nuanced picture of exactly what RNAs the proteins bind and where.”

MIT postdoc Daniel Dominguez, former graduate student Peter Freese, and current graduate student Maria Alexis are the lead authors of the study, which is part of the ENCODE project and appears in Molecular Cell on June 7.

A method for the madness

From the moment an RNA is born, it is coated by RBPs that control nearly every aspect of its lifecycle. RBPs generally contain a binding domain, a three-dimensional folded structure that can attach to a specific nucleotide sequence on the RNA called a motif. Because there are over 1,500 different RBPs found in the human genome, the biologists needed a way to systematically determine which of those proteins bound to which RNA motifs.

After considering a number of different approaches to analyze RNA-protein interactions both directly in the cell (in vivo) and isolated in a test tube (in vitro), the biologists settled on an in vitro method known as RNA Bind-n-Seq (RBNS), developed four years ago by former Burge lab postdoc and co-author Nicole Lambert.

Although Lambert had previously tested only a small subset of proteins, RBNS surpassed other approaches because it was a quantitative method that revealed both low and high affinity RNA-protein interactions, required only a single procedural step, and screened nearly every possible RNA motif. This new study improved the assay’s throughput, systematically exploring the binding specificities of more than 70 human RBPs at a high resolution.

“Even with that initial small sample, it was clear RBNS was the way to go, and over the last three-and-a-half years we’ve been gradually building on this approach,” Dominguez says. “Since a single RBP can select from billions of unique RNA molecules, our approach gives you a lot more power to detect the all those possible targets, taking into account RNA secondary structure and contextual features. It’s an extremely deep and detailed assay.”

First, the researchers purified the human RBPs, mixing them with randomly-generated synthetic RNAs roughly 20 nucleotides long, which represented virtually all the RNAs an RBP could bind to. Next, they extracted the RBPs along with their bound RNAs and sequenced them. With the help of their collaborators from the University of California at San Diego and University of Connecticut Health, the team conducted additional assays to glean what these RNA-protein interactions might look like in an actual cell, and infer the cellular function of the RBPs.

The researchers expected most RBPs to bind to a unique RNA motif, but to their surprise they found the opposite: Many of the proteins, regardless of structural class, seemed to prefer similar short, unfolded nucleotide sequence motifs.

“Human cells express hundreds of thousands of distinct transcripts, so you might think that each RBP would bind a slightly different RNA sequence in order to distinguish between targets,” Alexis says. “In fact, one might assume that having distinct RBP motifs would ensure maximum flexibility. But, as it turns out, nature has built in substantial redundancy; multiple proteins seem to bind the same short, linear sequences.”

Redundant motifs with distinct targets and functions

This overlap in RBP binding preference suggested to the scientists that there must be some other indicator besides the sequence of the motif that signaled RBPs which RNA to target. Those signals, it turned out, stemmed from the spacing of the motifs as well as which nucleotide bases flank its binding sites. For the less common RBPs that targeted non-linear RNA sequences, the precise way the RNA folded also seemed to influence binding specificity.

The obvious question, then, is: Why might RBPs have evolved to rely on contextual features instead of just giving them distinct motifs?

Accessibility seems like one of the more plausible arguments. The researchers reasoned that linear RNA segments are physically easier to reach because they are not obstructed by other RNA strands, and they found that more accessible motifs are more likely to be bound. Another possibility is that having many proteins target the same motif creates some inter-protein competition. If one protein increases RNA stability and another decreases it, whichever binds the strongest will prevent the other from binding at all, enabling more pronounced changes in gene activity between cells or cell states. In other scenarios, proteins with similar functions that target the same motif could provide redundancy to ensure that regulation occurs in the cell.

“It’s definitely a difficult question, and one that we may never truly be able to answer,” Dominguez says. “As RBPs duplicated over evolutionary time, perhaps altering recognition of the contextual features around the RNA motif was easier than changing the entire RNA motif. And that would give new opportunities for RBPs to select different cellular targets.”

This study marks one of the first in vitro contributions to the ENCODE Project. While in vivo assays reveal information specific to the particular cell line or tissue in which they were conducted, RBNS will help define the basic rules of RNA-protein interactions — so fundamental they are likely to apply across many cell types and tissues.

The research was funded by the National Institutes of Health ENCODE Project, an NIH/NIGMS grant, the National Defense Science and Engineering Graduate Fellowship, Kirschstein National Research Service Award, Burroughs Wellcome Postdoctoral Fund, and an NIH Individual Postdoctoral Fellowship.

Network of diverse noncoding RNAs acts in the brain

Scientists identify the first known network consisting of three types of regulatory RNAs.

Nicole Giese Rura | Whitehead Institute
June 7, 2018

Scientists at MIT’s Whitehead Institute have identified a highly conserved network of noncoding RNAs acting in the mammalian brain. While gene regulatory networks are well described, this is the first documented regulatory network comprised of three types of noncoding RNA: microRNA, long noncoding RNA, and circular RNA. The finding, which is described online this week in the journal Cell, expands our understanding of how several noncoding RNAs can interact to regulate each other.

This sophisticated network, which is conserved in placental mammals, intrigued Whitehead Member David Bartel, whose lab identified it.

“It has been quite an adventure to unravel the different elements of netbet sports bettingthis network,” says Bartel, who is also a professor of biology at MIT and investigator with the Howard Hughes Medical Institute. “When we removed the long noncoding RNA, we saw huge increases in the microRNA, which, with the help of a second microRNA turned out to reduce the levels of the circular RNA.”

RNA may be best known for acting as a template during protein production, but most RNA molecules in the cell do not actually code for proteins. Many play fundamental roles in the splicing and translation of protein-coding RNAs, whereas others play regulatory roles. MicroRNAs, as the name would suggest, are small, about 22 nucleotides (nucleotides are the building blocks of RNA); long noncoding RNAs (lncRNAs) are longer than 200 nucleotides; and circular RNAs (circRNAs) are looped RNAs formed by atypical splicing of either lncRNAs or protein-coding RNAs. These three types of noncoding RNAs have been shown previously to be vital for controlling protein-coding gene expression, and in some instances their dysregulation is linked to cancer or other diseases.

Previous work by Bartel and Whitehead member and MIT Professor Hazel Sive identified hundreds of lncRNAs conserved in vertebrate animals, including Cyrano, which contains an unusual binding site for the microRNA miR-7.

In the current research, Ben Kleaveland, a postdoc in Bartel’s lab and first author of the Cell paper, delves into Cyrano’s function in mice. His results are surprising: a regulatory network centered on four noncoding RNAs — a lncRNA, a circRNA, and two microRNAs — acting in mammalian neurons. The network employs multiple interactions between these noncoding RNAs to ultimately ensure that the levels of one microRNA, miR-7, are kept extremely low and the levels of one circRNA, Cdr1as, are kept high.

Several aspects of this highly tuned network are unique. The lncRNA Cyrano targets miR-7 for degradation. Cyrano is exceptionally efficient, and in some cells, reduces miR-7 by an astounding 98 percent — a stronger effect than scientists have ever documented for this phenomenon, called target RNA-directed microRNA degradation. In the described network, unchecked miR-7 indirectly leads to degradation of the circRNA Cdr1as. CircRNAs such as this one are usually highly stable because the RNA degradation machinery needs to latch onto the end of an RNA molecule before the machinery can operate. In the case of Cdr1as, the circRNA contains a prodigious number of sites that can interact with miR-7: 130 in mice and 73 in humans. As these sites are bound by miR-7, another microRNA, miR-671, springs into action and directs slicing of the Cdr1as. This renders Cdr1as vulnerable to degradation.

The network’s precise function still eludes researchers, but evidence suggests that it may be important in brain function. All four components of the network are enriched in the brain, particularly in neurons, and recently, Cdr1as has been reported to influence neuronal activity in mice.

“We’re in the early stages of understanding this network, and there’s so much left to discover,” Kleaveland says. “Our current hypothesis is that Cdr1as is not only regulated by miR-7 but also facilitates miR-7 function by delivering this microRNA to neuronal synapses.”

This work was supported by the National Institutes of Health and the Howard Hughes Medical Institute.