Thursday, March 14th, 2019

Time	Event
11:00a	A new approach to drugging a difficult cancer target One of the most common cancer-promoting genes, known as Myc, is also one of the most difficult to target with drugs. Scientists have long tried to develop drugs that block the Myc protein, but so far their efforts have not been successful. Now, using an alternative strategy, MIT researchers have discovered a compound that can reduce Myc activity by tying up the protein that is Myc’s usual binding partner, leaving Myc partnerless and unable to perform its usual functions. The research team, led by Angela Koehler, an assistant professor of biological engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, found that the compound they developed could suppress tumor growth in mice with certain types of cancer. The compound has been licensed by an MIT spinout that is now seeking to develop more powerful versions that could potentially be tested in human patients. Koehler is the senior author of the study, which appears online in the journal Cell Chemical Biology on March 14. MIT postdoc Nicholas Struntz and graduate student Andrew Chen are the lead authors of the study, and the research team also includes authors from the Broad Institute of MIT and Harvard, Stanford University, Baylor College of Medicine, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute. A new approach For decades, cancer researchers have been trying to find ways to shut off Myc, which is a transcription factor — a protein that controls the expression of other genes. Known as a “master regulator,” Myc controls many genes involved in basic cellular functions such as growth and metabolism. When it becomes overexpressed, as it does in about 70 percent of cancers, it drives uncontrolled cell growth and proliferation. Myc usually forms a structure known as a heterodimer with the Max protein, and these proteins together bind to DNA to turn on gene transcription. Drug development efforts have traditionally focused on disrupting the interaction of Myc and Max, which has proven difficult. Most of the compounds that researchers have tested have proven too weak, or not specific enough to the Myc-Max interaction. Koehler encountered similar difficulties, but several years ago, she decided to pursue a different strategy, based on the Max protein. The idea was to try to find compounds that would interact with Max, and then see if they had any effect on Myc’s ability to drive cell growth. Using a technology developed by Koehler known as a microarray binding assay, the researchers screened a library of about 20,000 compounds, including both natural products and a collection of compounds synthesized by the Broad Institute, as possible drug candidates. The top six hits, in terms of ability to bind to Max and inhibit Myc transcriptional activity in another assay, all came from the Broad Institute collection. The researchers tested the compounds in several different cancer cell lines and identified one that appeared to be most effective at halting cell growth. At first, the researchers were unsure how this compound was blocking Myc activity, but experiments revealed that it was stabilizing a structure in which two molecules of Max bind together, forming a structure called a homodimer. This reduces the formation of the Myc-Max heterodimer and leads to a decrease in Myc levels, which the researchers believe may be the result of the unpartnered protein being broken down within cells. Shrinking tumors The researchers found that the compound slowed cell growth in a variety of Myc-dependent human cancer cells, including models for hepatocellular carcinoma, T-cell acute lymphoblastic leukemia, and Burkitt’s lymphoma. They also tested the compound in mice, and found that even though the compound they originally identified was not optimized for maximum potency, it could slow tumor progression in mouse models of hepatocellular carcinoma and T-cell acute lymphoblastic leukemia. “The discovery and detailed validation of a small molecule targeting Max homodimers represents a significant advance over previous attempts to directly inhibit either Myc itself or Myc-Max dimerization,” says Robert Eisenman, a principal investigator at the Fred Hutchinson Cancer Research Center, who was not involved in the study. “It not only provides new insight into how Myc functions but reveals what is likely to be an important exploitable vulnerability in Myc-driven cancers.” Kronos Bio, the company that has licensed the rights to the compound described in this paper, is now working to optimize it to be more potent and more efficient. Koehler’s lab is also working on learning more about how this compound works, as well as determining the structure of the complex that it forms with the Max homodimer, in hopes of potentially developing better versions. “This particular compound isn’t going to be a drug — it’s really just a tool to clarify the relevance of stabilizing Max homodimers as a strategy to perturb Myc function,” Koehler says. “That can guide people in the pharmaceutical industry who are thinking about trying to drug Myc, to maybe think about other ways to find Max homodimer stabilizers.” Her lab is also pursuing other ways to target Myc, such as finding ways to stabilize a homodimer of two Myc molecules, which would likely end up being degraded within the cell. “There may be different ways to stabilize biomolecular interactions within the Myc-Max network that could lead to different ways of perturbing Myc function,” she says. The research was funded, in part, by the National Cancer Institute, including the Koch Institute Support (core) Grant, the National Institutes of Health, the Leukemia and Lymphoma Society, the Ono Pharma Foundation, the MIT Deshpande Center for Technological Innovation, the MIT Center for Precision Cancer Medicine, the AACR-Bayer Innovation and Discovery Grant, and the Merkin Institute Fellows Program at the Broad Institute. (Comment on this)
11:00a	Brain wave stimulation may improve Alzheimer’s symptoms By exposing mice to a unique combination of light and sound, MIT neuroscientists have shown that they can improve cognitive and memory impairments similar to those seen in Alzheimer’s patients. This noninvasive treatment, which works by inducing brain waves known as gamma oscillations, also greatly reduced the number of amyloid plaques found in the brains of these mice. Plaques were cleared in large swaths of the brain, including areas critical for cognitive functions such as learning and memory. “When we combine visual and auditory stimulation for a week, we see the engagement of the prefrontal cortex and a very dramatic reduction of amyloid,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study. Further study will be needed, she says, to determine if this type of treatment will work in human patients. The researchers have already performed some preliminary safety tests of this type of stimulation in healthy human subjects. MIT graduate student Anthony Martorell and Georgia Tech graduate student Abigail Paulson are the lead authors of the study, which appears in the March 14 issue of Cell. Memory improvement The brain’s neurons generate electrical signals that synchronize to form brain waves in several different frequency ranges. Previous studies have suggested that Alzheimer’s patients have impairments of their gamma-frequency oscillations, which range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory. In 2016, Tsai and her colleagues first reported the beneficial effects of restoring gamma oscillations in the brains of mice that are genetically predisposed to develop Alzheimer’s symptoms. In that study, the researchers used light flickering at 40 hertz, delivered for one hour a day. They found that this treatment reduced levels of beta amyloid plaques and another Alzheimer’s-related pathogenic marker, phosphorylated tau protein. The treatment also stimulated the activity of debris-clearing immune cells known as microglia. In that study, the improvements generated by flickering light were limited to the visual cortex. In their new study, the researchers set out to explore whether they could reach other brain regions, such as those needed for learning and memory, using sound stimuli. They found that exposure to one hour of 40-hertz tones per day, for seven days, dramatically reduced the amount of beta amyloid in the auditory cortex (which processes sound) as well as the hippocampus, a key memory site that is located near the auditory cortex. “What we have demonstrated here is that we can use a totally different sensory modality to induce gamma oscillations in the brain. And secondly, this auditory-stimulation-induced gamma can reduce amyloid and Tau pathology in not just the sensory cortex but also in the hippocampus,” says Tsai, who is a founding member of MIT’s Aging Brain Initiative. The researchers also tested the effect of auditory stimulation on the mice’s cognitive abilities. They found that after one week of treatment, the mice performed much better when navigating a maze requiring them to remember key landmarks. They were also better able to recognize objects they had previously encountered. They also found that auditory treatment induced changes in not only microglia, but also the blood vessels, possibly facilitating the clearance of amyloid. Dramatic effect The researchers then decided to try combining the visual and auditory stimulation, and to their surprise, they found that this dual treatment had an even greater effect than either one alone. Amyloid plaques were reduced throughout a much greater portion of the brain, including the prefrontal cortex, where higher cognitive functions take place. The microglia response was also much stronger. “These microglia just pile on top of one another around the plaques,” Tsai says. “It’s very dramatic.” The researchers found that if they treated the mice for one week, then waited another week to perform the tests, many of the positive effects had faded, suggesting that the treatment would need to be given continually to maintain the benefits. In an ongoing study, the researchers are now analyzing how gamma oscillations affect specific brain cell types, in hopes of discovering the molecular mechanisms behind the phenomena they have observed. Tsai says she also hopes to explore why the specific frequency they use, 40 hertz, has such a profound impact. The combined visual and auditory treatment has already been tested in healthy volunteers, to assess its safety, and the researchers are now beginning to enroll patients with early-stage Alzheimer’s to study its possible effects on the disease. “Though there are important differences among species, there is reason to be optimistic that these methods can provide useful interventions for humans,” says Nancy Kopell, a professor of mathematics and statistics at Boston University, who was not involved in the research. “This paper and related studies have the potential for huge clinical impact in Alzheimer’s disease and others involving brain inflammation.” The research was funded, in part, by the Robert and Renee Belfer Family Foundation, the Halis Family Foundation, the JPB Foundation, the National Institutes of Health, and the MIT Aging Brain Initiative. (Comment on this)
2:00p	Exotic “second sound” phenomenon observed in pencil lead The next time you set a kettle to boil, consider this scenario: After turning the burner off, instead of staying hot and slowly warming the surrounding kitchen and stove, the kettle quickly cools to room temperature and its heat hurtles away in the form of a boiling-hot wave. We know heat doesn’t behave this way in our day-to-day surroundings. But now MIT researchers have observed this seemingly implausible mode of heat transport, known as “second sound,” in a rather commonplace material: graphite — the stuff of pencil lead. At temperatures of 120 kelvin, or -240 degrees Fahrenheit, they saw clear signs that heat can travel through graphite in a wavelike motion. Points that were originally warm are left instantly cold, as the heat moves across the material at close to the speed of sound. The behavior resembles the wavelike way in which sound travels through air, so scientists have dubbed this exotic mode of heat transport “second sound.”   The new results represent the highest temperature at which scientists have observed second sound. What’s more, graphite is a commercially available material, in contrast to more pure, hard-to-control materials that have exhibited second sound at 20 K, (-420 F) — temperatures that would be far too cold to run any practical applications. The discovery, published today in Science, suggests that graphite, and perhaps its high-performance relative, graphene, may efficiently remove heat in microelectronic devices in a way that was previously unrecognized. “There’s a huge push to make things smaller and denser for devices like our computers and electronics, and thermal management becomes more difficult at these scales,” says Keith Nelson, the Haslam and Dewey Professor of Chemistry at MIT. “There’s good reason to believe that second sound might be more pronounced in graphene, even at room temperature. If it turns out graphene can efficiently remove heat as waves, that would certainly be wonderful.” The result came out of a long-running interdisciplinary collaboration between Nelson’s research group and that of Gang Chen, the Carl Richard Soderberg Professor of Mechanical Engineering and Power Engineering. MIT co-authors on the paper are lead authors Sam Huberman and Ryan Duncan, Ke Chen, Bai Song, Vazrik Chiloyan, Zhiwei Ding, and Alexei Maznev. “In the express lane” Normally, heat travels through crystals in a diffusive manner, carried by “phonons,” or packets of acoustic vibrational energy. The microscopic structure of any crystalline solid is a lattice of atoms that vibrate as heat moves through the material. These lattice vibrations, the phonons, ultimately carry heat away, diffusing it from its source, though that source remains the warmest region, much like a kettle gradually cooling on a stove. The kettle remains the warmest spot because as heat is carried away by molecules in the air, these molecules are constantly scattered in every direction, including back toward the kettle. This “back-scattering” occurs for phonons as well, keeping the original heated region of a solid the warmest spot even as heat diffuses away. However, in materials that exhibit second sound, this back-scattering is heavily suppressed. Phonons instead conserve momentum and hurtle away en masse, and the heat stored in the phonons is carried as a wave. Thus, the point that was originally heated is almost instantly cooled, at close to the speed of sound. Previous theoretical work in Chen’s group had suggested that, within a range of temperatures, phonons in graphene may interact predominately in a momentum-conserving fashion, indicating that graphene may exhibit second sound. Last year, Huberman, a member of Chen’s lab, was curious whether this might be true for more commonplace materials like graphite. Building upon tools previously developed in Chen’s group for graphene, he developed an intricate model to numerically simulate the transport of phonons in a sample of graphite. For each phonon, he kept track of every possible scattering event that could take place with every other phonon, based upon their direction and energy. He ran the simulations over a range of temperatures, from 50 K to room temperature, and found that heat might flow in a manner similar to second sound at temperatures between 80 and 120 K. Huberman had been collaborating with Duncan, in Nelson’s group, on another project. When he shared his predictions with Duncan, the experimentalist decided to put Huberman’s calculations to the test. “This was an amazing collaboration,” Chen says. “Ryan basically dropped everything to do this experiment, in a very short time.” “We were really in the express lane with this,” Duncan adds. Upending the norm Duncan’s experiment centered around a small, 10-square-millimeter sample of commercially available graphite. Using a technique called transient thermal grating, he crossed two laser beams so that the interference of their light generated a “ripple” pattern on the surface of a small sample of graphite. The regions of the sample underlying the ripple’s crests were heated, while those that corresponded to the ripple’s troughs remained unheated. The distance between crests was about 10 microns. Duncan then shone onto the sample a third laser beam, whose light was diffracted by the ripple, and its signal was measured by a photodetector. This signal was proportional to the height of the ripple pattern, which depended on how much hotter the crests were than the troughs. In this way, Duncan could track how heat flowed across the sample over time. If heat were to flow normally in the sample, Duncan would have seen the surface ripples slowly diminish as heat moved from crests to troughs, washing the ripple pattern away. Instead, he observed “a totally different behavior” at 120 K. Rather than seeing the crests gradually decay to the same level as the troughs as they cooled, the crests actually became cooler than the troughs, so that the ripple pattern was inverted — meaning that for some of the time, heat actually flowed from cooler regions into warmer regions. “That’s completely contrary to our everyday experience, and to thermal transport in almost every material at any temperature,” Duncan says. “This really looked like second sound. When I saw this I had to sit down for five minutes, and I said to myself, ‘This cannot be real.’ But I ran the experiment overnight to see if it happened again, and it proved to be very reproducible.” According to Huberman’s predictions, graphite’s two-dimensional relative, graphene, may also exhibit properties of second sound at even higher temperatures approaching or exceeding room temperature. If this is the case, which they plan to test, then graphene may be a practical option for cooling ever-denser microelectronic devices. “This is one of a small number of career highlights that I would look to, where results really upend the way you normally think about something,” Nelson says. “It’s made more exciting by the fact that, depending on where it goes from here, there could be interesting applications in the future. There’s no question from a fundamental point of view, it’s really unusual and exciting.” This research was funded in part by the Office of Naval Research, the Department of Energy, and the National Science Foundation. (Comment on this)
2:00p	Tectonics in the tropics trigger Earth’s ice ages, study finds Over the last 540 million years, the Earth has weathered three major ice ages — periods during which global temperatures plummeted, producing extensive ice sheets and glaciers that have stretched beyond the polar caps. Now scientists at MIT, the University of California at Santa Barbara, and the University of California at Berkeley have identified the likely trigger for these ice ages. In a study published today in Science, the team reports that each of the last three major ice ages were preceded by tropical “arc-continent collisions” — tectonic pileups that occurred near the Earth’s equator, in which oceanic plates rode up over continental plates, exposing tens of thousands of kilometers of oceanic rock to a tropical environment. The scientists say that the heat and humidity of the tropics likely triggered a chemical reaction between the rocks and the atmosphere. Specifically, the rocks’ calcium and magnesium reacted with atmospheric carbon dioxide, pulling the gas out of the atmosphere and permanently sequestering it in the form of carbonates such as limestone. Over time, the researchers say, this weathering process, occurring over millions of square kilometers, could pull enough carbon dioxide out of the atmosphere to cool temperatures globally and ultimately set off an ice age. “We think that arc-continent collisions at low latitudes are the trigger for global cooling,” says Oliver Jagoutz, an associate professor in MIT’s Department of Earth, Atmospheric, and Planetary Sciences. “This could occur over 1-5 million square kilometers, which sounds like a lot. But in reality, it’s a very thin strip of Earth, sitting in the right location, that can change the global climate.” Jagoutz’ co-authors are Francis Macdonald and Lorraine Lisiecki of UC Santa Barbara, and Nicholas Swanson-Hysell and Yuem Park of UC Berkeley. A tropical trigger When an oceanic plate pushes up against a continental plate, the collision typically creates a mountain range of newly exposed rock. The fault zone along which the oceanic and continental plates collide is called a “suture.” Today, certain mountain ranges such as the Himalayas contain sutures that have migrated from their original collision points, as continents have shifted over millenia. In 2016, Jagoutz and his colleagues retraced the movements of two sutures that today make up the Himalayas. They found that both sutures stemmed from the same tectonic migration. Eighty million years ago, as the supercontinent known as Gondwana moved north, part of the landmass was crushed against Eurasia, exposing a long line of oceanic rock and creating the first suture; 50 million years ago, another collision between the supercontinents created a second suture. The team found that both collisions occurred in tropical zones near the equator, and both preceded global atmospheric cooling events by several million years — which is nearly instantaneous on a geologic timescale. After looking into the rates at which exposed oceanic rock, also known as ophiolites, could react with carbon dioxide in the tropics, the researchers concluded that, given their location and magnitude, both sutures could have indeed sequestered enough carbon dioxide to cool the atmosphere and trigger both ice ages. Animation showing suture zones developing as tectonic plates evolved over the last 540 million years. MIT researchers found sutures in the tropical rain belt, shown in green, were associated with Earth's major ice ages. Credit: Swanson-Hysell research group  Interestingly, they found that this process was likely responsible for ending both ice ages as well. Over millions of years, the oceanic rock that was available to react with the atmosphere eventually eroded away, replaced with new rock that took up far less carbon dioxide. “We showed that this process can start and end glaciation,” Jagoutz says. “Then we wondered, how often does that work? If our hypothesis is correct, we should find that for every time there’s a cooling event, there are a lot of sutures in the tropics.” Exposing Earth’s sutures The researchers looked to see whether ice ages even further back in Earth’s history were associated with similar arc-continent collisions in the tropics. They performed an extensive literature search to compile the locations of all the major suture zones on Earth today, and then used a computer simulation of plate tectonics to reconstruct the movement of these suture zones, and the Earth’s continental and oceanic plates, back through time. In this way, they were able to pinpoint approximately where and when each suture originally formed, and how long each suture stretched. They identified three periods over the last 540 million years in which major sutures, of about 10,000 kilometers in length, were formed in the tropics. Each of these periods coincided with each of three major, well-known ice ages, in the Late Ordovician (455 to 440 million years ago), the Permo-Carboniferous (335 to 280 million years ago), and the Cenozoic (35 million years ago to present day). Importantly, they found there were no ice ages or glaciation events during periods when major suture zones formed outside of the tropics. “We found that every time there was a peak in the suture zone in the tropics, there was a glaciation event,” Jagoutz says. “So every time you get, say, 10,000 kilometers of sutures in the tropics, you get an ice age.” He notes that a major suture zone, spanning about 10,000 kilometers, is still active today in Indonesia, and is possibly responsible for the Earth’s current glacial period and the appearance of extensive ice sheets at the poles. This tropical zone includes some of the largest ophiolite bodies in the world and is currently one of the most efficient regions on Earth for absorbing and sequestering carbon dioxide. As global temperatures are climbing as a result of human-derived carbon dioxide, some scientists have proposed grinding up vast quantities of ophiolites and spreading the minerals throughout the equatorial belt, in an effort to speed up this natural cooling process. But Jagoutz says the act of grinding up and transporting these materials could produce additional, unintended carbon emissions. And it’s unclear whether such measures could make any significant impact within our lifetimes. “It’s a challenge to make this process work on human timescales,” Jagoutz says. “The Earth does this in a slow, geological process that has nothing to do with what we do to the Earth today. And it will neither harm us, nor save us.” However, Lee Kump, dean of the College of Earth and Mineral Sciences at Penn State University, sees at least one silver lining for this slow, natural sequestration process in the Earth’s future. “Emissions of carbon dioxide from human activity today rival the most massive volcanic episodes in Earth history, far exceeding the capacity of rock weathering feedbacks to counter the buildup,” says Kump, who was not involved in the research. “However, as anthropogenic carbon emissions wane, natural restoration processes like these will begin the multimillennial repair job of restoring atmospheric carbon dioxide to pre-Anthropocene levels.” (Comment on this)

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