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Muscle plays surprising role in tissue regeneration

Posted: 22 Nov 2017 10:00 AM PST

Researchers at the Whitehead Institute have illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration.

In a paper appearing online today in Nature, they reveal that a subtype of muscle fibers in flatworms is required for triggering the activity of genes that initiate the regeneration program. Notably, in the absence of these muscles, regeneration fails to proceed. Another type of muscle, they report, is required for giving regenerated tissue the proper pattern — for example, forming one head instead of two.

"One of the central mysteries in organ and tissue regeneration is: How do animals initiate all of the cellular and molecular steps that lead to regeneration?" says senior author Peter Reddien, a member of Whitehead Institute, professor of biology at MIT, and investigator with the Howard Hughes Medical Institute. "We've helped answer this question by revealing a surprising molecular program that operates within a subgroup of muscle cells that helps establish the molecular information required for proper tissue regeneration after injury."

For more than a decade, Reddien and the researchers in his laboratory have studied the biological mechanisms that underlie regeneration in a tiny flatworm called planarians. These worms possess some impressive regenerative capabilities: When sliced in two, each piece of the worm can regrow the body parts needed to form two complete organisms. In previous studies, Reddien's team identified a set of always-on genes, known as position control genes (PCGs), that provide cells with region-specific instructions, like a set of GPS coordinates, that tell cells where they are in the body, and thus what body part to regenerate. Interestingly, PGCs are active in planarian muscle cells, suggesting muscle may play a major role in the regeneration process.

"This discovery raised a lot of questions about how muscle participates in this process," Reddien says.

In planarians, there are a handful of muscle cell types. For example, if you imagine the worms as simple cylindrical tubes, there are longitudinal muscle fibers, which run head-to-tail along the tubes' long axis. There are also circular fibers, which are perpendicular to the longitudinal fibers and hug the tubes' outer circumference.

To assess the roles of these different muscle cell types in regeneration, first author Lucila Scimone and her colleagues needed a method to selectively remove them. When myoD, a gene found specifically in the longitudinal fibers, is inhibited, those fibers fail to form. Similarly, the nkx1-1 gene marks the circular fibers, and when its function is reduced, they do not develop. Using these genes as molecular scalpels, Scimone and her co-authors could test the effects of ablating these distinct muscle groups on regeneration.

Surprisingly, when the longitudinal fibers were removed, the results were dramatic. The worms live quite normally, but when they are injured (the head removed, for example) they cannot regenerate the missing parts.

"This is an amazing result; it tells us that these longitudinal fibers are essential for orchestrating the regeneration program from the very beginning," says Scimone, a scientist in Reddien's lab.

As the researchers dug deeper into the finding, they learned that the functions of two critical genes are disrupted when longitudinal fibers are missing. These genes, called notum and follistatin, are known for their fundamental roles in regeneration, controlling head-versus-tail decisions and sustained cell proliferation, respectively, following tissue injury.

In addition to this essential role for longitudinal fibers, the research team also uncovered a key role for circular fibers. When these muscles are missing, planarians are able to regenerate missing body parts, but what regrows is abnormally patterned. For example, two heads may be regenerated within a single outgrowth, instead of one.

These results underscore an important and previously unappreciated role for muscle, widely known for its contractile properties, in instructing the tissue regeneration program. The Whitehead researchers will continue to probe the role of different muscle cell types in planarian regeneration and also explore whether other animals with regenerative capabilities possess a similar muscle-localized program for conferring positional information.

"It's hard to understand what limits humans' abilities to regenerate and repair wounds without first knowing what mechanisms are enabling some animals, like planarians, to do it so amazingly well," Reddien says.

This work was supported by the National Institutes of Health, Howard Hughes Medical Institute, and the Eleanor Schwartz Charitable Foundation.

Gearing up for the internet of things

Posted: 22 Nov 2017 09:55 AM PST

Telecommunications is gearing up for explosive growth of the internet of things (IoT), the massive collection of devices — smart watches, smart thermostats, traffic and energy monitors, etc. — that will be given network connectivity so that they can communicate and exchange data.

The big question raised by the IoT is capacity: How can a telecommunications network with limited spectrum serve thousands or millions of devices at once? Existing networks cannot support the addition of exponentially more devices, nor the near-instantaneous connection speed necessary for machine-to-machine communication. The next-generation network, 5G, must be designed to meet these requirements.

How to prepare global wireless networks for the IoT was the topic of discussion at the National Science Foundation Workshop on Low-Latency Wireless Random-Access, hosted by MIT's Laboratory for Information and Decision Systems (LIDS) and sponsored by the National Science Foundation (NSF) and the Center for the Science of Information (CSoI). The two-day event took place on the MIT campus in early November, and more than 20 speakers from MIT, other universities, and companies including Qualcomm, SigFox, and Huawei presented their work on how to solve the network challenges created by the IoT.

"Developing solutions for massive multi-access wireless communications is a fascinating, domain-spanning challenge for researchers with considerable practical applications," said MIT associate professor and LIDS faculty member Yury Polyanskiy, who organized the workshop.

The IoT will transform industries such as agriculture, transportation, utilities, athletics, and more by introducing smart devices and many networked monitors. The monitors will provide live environmental feedback, which the devices can use to optimize their functions. Determining 5G standards and protocols that will allow these transformative technological developments is a complex undertaking.

There are numerous hurdles to redesigning wireless infrastructure for the IoT. First, current networks are optimized for a relatively small set of users, mostly human, sending large amounts of data — a phone call, a video — in a continuous stream, with different connections centrally organized. To accommodate the IoT, networks will have to manage decentralized, intermittent transmission of many small data packets from many, many more users, mostly machines.

This vast increase in machines on the network will lead to more interference, which causes latency or loss of connectivity. Just like people have trouble getting a call through at a large event where there are too many other people on their phones, machines will have trouble sending their data if the network gets overloaded with devices needing connectivity. Devices that spend too much time searching for a working connection will also wear out their batteries, an issue for IoT monitors that are meant to be very low energy and low cost.

Another big challenge for the IoT is that it requires extremely low latency, or lag. As anyone who has used the internet knows, data don't always transmit at the speed you want them to. And although a half-loaded video or delayed text may be a pain for humans, for machines even a few milliseconds of lag can have serious consequences. A smart car interpreting traffic data, for instance, cannot afford any lag. This is why the goal for 5G is an ambitious one millisecond latency between devices.

These issues were discussed at length during the workshop. Two sessions were dedicated to information theory, with academic speakers sharing their models for better massive machine-type communications. Sessions also covered topics including reliability and security.

"We don't have one thing to solve, we have many things to solve," said the first speaker of the event, Christophe Fourtet, co-founder and chief science officer of telecommunications company SigFox.

The workshop provided a somewhat rare opportunity for academia and industry to exchange ideas, as these communities are often siloed from each other.

"Academics played a major role in establishing early telecommunication standards, but this has become more rare recently. With 5G calling for radically new simple network-access methods, though, it's a great opportunity for academics to play a big role again," said Polyanskiy.

Presenter Swarun Kumar, assistant professor at Carnegie Mellon University and an MIT alumnus, echoed Polyanskiy's sentiments. "The time from academic research to industry in this field is too slow," Kumar said. He made an appeal to the members of industry present at the workshop to reach out to him and other academics, noting that they could solve problems more efficiently together. Kumar presented a local network that he and colleagues at Carnegie Mellon had implemented around the campus as a proof-of-concept for their innovations to network infrastructure.

After each set of presentations, speakers returned to the front of the room for a panel Q&A, and in between sessions, speakers and attendees had a chance to mingle and talk over refreshments. The event organizers affirmed that these moments were some of the most valuable of the workshop: a chance for everyone present to open up dialogue and, perhaps, plant the seeds of collaborations that will build a better network.

Over the river and do some good

Posted: 22 Nov 2017 09:10 AM PST

Boston is home to two National Cancer Institute-designated cancer centers: MIT's Koch Institute for Integrative Cancer Research and the Dana-Farber/Harvard Cancer Center (DF/HCC). Each works to advance the fight against cancer in its own unique way.

The latter draws on the collective resources of Dana-Farber Cancer Institute (DFCI), Beth Israel Deaconess Medical Center, Boston Children's Hospital, Brigham and Women's Hospital, Massachusetts General Hospital (MGH), Harvard Medical School (HMS), and Harvard T.H Chan School of Public Health. The Koch Institute (KI) integrates life sciences researchers with cancer-oriented engineers to develop new insights, tools, and technologies to detect, monitor, and treat the disease.

The work of the KI builds on that of its predecessor, the MIT Center for Cancer Research, which made seminal contributions to the understanding of cancer biology in its three-plus decades as MIT's hub of cancer research. Clinical collaborations have been an important component of this enterprise for years — but never on the scale of the Bridge Project.  

The Bridge Project was launched in 2012 to provide seed funding for collaborative research teams comprised of investigators from both MIT and Harvard University. Its goal is to foster interdisciplinary studies that combine innovative tools and methods with the translational expertise of clinical oncologists to solve today's most challenging problems in cancer research and care. It is a simple idea, uniquely suited to this community.

"In Boston, we are blessed with differently focused, world-class cancer researchers on both sides of the Charles River," says founding donor Arthur Gelb ScD '61, who is an emeritus trustee of DFCI and an emeritus MIT Corporation member. "The Bridge Project's operating presumption is that spanning the gap between them — to enable truly joint research at the intersection of their disciplines — is destined to produce new, highly original, and powerful approaches to defeating cancer. The early history of the Bridge Project suggests that is exactly the case."

MIT President Emerita Susan Hockfield says Gelb "had advocated collaboration between MIT and DF/HCC for a long time."

"He presented the idea to me in one of our very first conversations, shortly after I became president," Hockfield explains. "But we didn't have a vehicle to make it happen until the KI."

When the Koch Institute opened its interdisciplinary doors in 2011, the Bridge Project was one of the first initiatives to walk through them.

Fast-moving research

The first funding cycle was modest, yet aspirational. Four grants were awarded to target two of the most deadly, hard-to-treat cancer types — brain and pancreatic. In subsequent cycles, the Bridge Project expanded to include several additional high-need disease areas, including advanced breast cancer, aggressive lung cancer, and notoriously hard-to-detect ovarian cancer, and brought the total number of projects funded to 15 within the first four years of the program.

Among these efforts was a project by KI member Angela Belcher, the James Mason Crafts Professor and professor of biological engineering and materials science and engineering at MIT, who teamed up with oncologists Michael Birrer, then the director of medical gynecologic oncology at MGH, and professor of medicine at HMS, and Marcela del Carmen, an associate professor of gynecologic oncology at MGH and professor of obstetrics, gynecology, and reproductive biology at HMS, to adapt and refine the Belcher laboratory's highly sensitive optical imaging system harnessing genetically-engineered, nanoscale fluorescent probes for early detection, real-time imaging, and monitoring of ovarian cancers. The team initially piloted the technology as a tool for image-guided surgery, and is now using it in advanced pre-clinical investigations for diagnostics and therapy of early-stage tumors.

Another early-funded project, led by MIT associate professor of bology and KI member Matthew Vander Heiden and fellow physician-scientists William Kaelin Jr., a professor of medicine at DFCI and HMS, and Daniel Cahill, an assistant professor of neurosurgery at HMS and MGH, was focused on the development of a new imaging modality for tumors known as IDH-mutant gliomas. Their approach is being tested as a way to monitor drug response in patients with these tumors. The project also supported the discovery of novel approaches to target these cancers.

Projects like these were just the beginning, says Tyler Jacks, director of the Koch Institute and co-leader of the Bridge Project. "As the Bridge Project gained momentum, so did the possibilities. The standards are very high — we are looking for true collaborations, rooted in real clinical need and fueled by truly innovative approaches. In exchange, we are able to catalyze progress and bring real advances to patients, very quickly."

What is it about these projects that makes them so promising? "There's a continuum of discovery," explains Jacks' co-leader David Livingston, deputy director of DF/HCC, in an interview with Bloomberg Radio. "[It] begins in basic research laboratories, goes to patients in clinics and hospitals, and then comes back, and turns into new therapeutics or new diagnostics or a new ability to figure out how [a] tumor is going to behave."

This quick-paced cycle of discovery and innovation, coupled with clinical application, is why investors and others find the Bridge Project so appealing.

In 2015, the Bridge Project received a $20 million challenge grant from the Commonwealth Foundation for Cancer Research to further expand the program; this doubled the number of projects to be funded and introduced new Footbridge grants, for proof-of-concept studies, and Expansion Bridge grants to rapidly launch clinical trials. One of the first expansion projects is moving a new MIT-developed vaccine technology into clinical trials for lung cancer at DFCI. A second, a collaboration between KI member Michael Hemann, an associate professor of Biology at MIT; David Weinstock, an associate professor of medicine at DFCI and HMS; and Ann LaCasce, an assistant professor in medicine at HMS and instructor in medical oncology at DFCI, is already seeing promising results in active Phase 1 trials for lymphoma-targeting combination therapy. Other projects, new and continuing, will spring into action as additional funds are raised toward this challenge.

An additional research focus on pediatric brain cancer, initiated in 2016, spawned three new off-cycle projects, including the first-ever Bridge Project super-team, consisting of eight laboratories across Harvard and MIT, combining expertise in genomics, cell signaling, immunology, microfluidics, and nanotechnology, to develop non-invasive diagnostics and combination therapeutics to target aggressive gliomas in young patients.

Thanks to continuing support from philanthropic donors, and the tireless work of researchers, administrators, and reviewers, the Bridge Project has processed 160 applications and funded 37 projects led by researchers from 78 laboratories at MIT and DF/HCC. Each project includes researchers from both sides of the Charles River: 92 percent of past Bridge Project teams have joint publications, and 11 invention disclosures have been filed. The program, which is entirely supported by philanthropy, has raised more than $30 million, but there is more work to be done, especially in regard to the challenge grant.

Investing in success

Bridge Project research is poised to directly improve patient outcomes. A collaboration between Weinstock and KI member Scott Manalis, the Andrew and Erna Viterbi Professor and professor of biological and mechanical engineering, has seen startling success.

Their initial proposal to use a novel microfluidic device to measure the drug sensitivity of tumor cells has proven successful across a variety of cancer types. With published results in studying both acute lymphoblastic leukemia and glioblastoma multiforme, the MIT team's cell-weighing technology is now being evaluated in a clinical laboratory at DFCI in which live cells from an individual patient can be exposed to different drugs to measure sensitivity, with the ultimate goal of determining if the technology can identify the best course of treatment for that patient. Their approach has seen particular success in mirroring how patients with multiple myeloma respond to different therapies.

The KI/DFCI collaboration also earned a prestigious U54 grant from the National Cancer Institute, amplifying the effect of the Bridge Project work through federal funding and multi-institutional support. The technology is being further developed by Travera, the team's newly-launched startup.

Indeed, entrepreneurship offers yet another path to clinical translation. MIT spinoff PanTher Therapeutics, focused on improving therapeutic solutions to inoperable solid tumors, grew directly out of a Bridge Project grant.

"The Bridge Project gave us the money to do the science," says CEO Laura Indolfi, a former postdoc in the laboratory of KI member Elazer Edelman, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology. "Once we saw the results — a 12 times improvement in response rate for pancreatic cancer — we were able to take that proof-of-concept to business validation as a finalist in the MIT $100K Entrepreneurship Competition, and incubate it."

With support from MIT's Deshpande Center for Technological Innovation, Indolfi and her team were able to de-risk the project and scale it up, launching PanTher in 2015. The team then won a "golden ticket" to LabCentral from Bristol-Myers Squibb in 2016, providing the company with lab space to further develop their technology. They are currently transitioning from seed funding to Series A and hope to begin clinical trials in 2019; conversations with the U.S. Food and Drug Administration (FDA) are already underway.

Such clinical impact is usually a long way off for university researchers. The typical "bench to bedside" trajectory is on the order of a decade or more; to have so many projects in pre-clinical studies, pursuing FDA approval for clinical trials in such a short period of time is a testament to the Bridge Project's goal of meeting the most urgent, unmet needs of cancer care.

Beyond the bridge

The Bridge Project has yielded unexpected benefits for researchers. Following the review of their collaborative Bridge Project application, KI member Darrell Irvine, a professor of biological engineering and materials science and engineering at MIT, and two DFCI immunologists, Michael Goldberg, an assistant professor of cancer immunology and virology at DFCI and assistant professor of microbiology and immunobiology at HMS, and Kai Wucherpfennig, director of DFCI's Center for Cancer Immunotherapy Research and a professor of microbiology and immunobiology at HMS, decided to apply together for outside funding to support their proposed work. In 2014, they received a prominent Team Science Award from the Melanoma Research Association to improve the use of immunotherapy in cancer treatment through targeted nanoparticle delivery of small molecule drugs.

There are also instances of Bridge Project research changing the course of investigators' career paths. Indolfi, for example, took on the drug delivery work of her advisor's Bridge Project award as a side project, never imagining that it would be spun out and lead her into entrepreneurship.

Former MIT Department of Biology graduate student Mark Stevens, on the other hand, was positive that he was industry-bound when he joined the Manalis Lab. However, as he was starting to wrap up his initial thesis work using the lab's microfluidic device to measure the masses of cells to learn about their metabolic properties, he became attracted to his advisor's nascent collaboration with DFCI, which was just taking off. He was drawn to the project's potential for patient-centric development, and using cell lines, mouse models, and patient samples from the collaborating labs at DFCI, ultimately added a component focused on testing for tumor drug susceptibility to his thesis. 

Two years past his PhD thesis defense, Stevens now holds a joint appointment between MIT and DFCI, driven by the Bridge Project's support, where aforementioned clinical studies with the cell-weighing technology are ongoing. He describes this new position as an opportunity to provide much-needed translation, in every sense of the word, between academic and clinical settings.

"There is a lot of lip service paid to interdisciplinary research, which can have less familiar, or well-defined metrics for success," Stevens says. "This uncertainty leads to an environment where what is actually supported is relatively subject-specific, niche expertise. Programs like the Bridge Project provide a context where interdisciplinary boundaries can really be pushed."

As a result, Stevens finds himself in what he calls a "nexus" position: working to make connections between fundamental biology research and clinical need, and pushing research forward on a much faster timescale than he had originally anticipated.

Such accelerated trajectories were exactly what Gelb had in mind when he first approached the institutional leaders about the potential partnership. The collaborative nature of the work, Gelb says, provides "viewpoints, tools, and methods that would not necessarily occur to researchers focused only on the underlying biology, important as that may be." This multidisciplinary perspective is, with every new project, reshaping the way cancer researchers talk to and learn from each other.

Of course, one can argue that many of these conversations would or could have happened without an official agreement, but like so many scientific endeavors, making connections is key — among researchers and investors alike.

"The Bridge Project got off the ground through philanthropic funding," says Hockfield. "It would have been impossible for us to make those clinically relevant projects work if we had had to wait for the standard grant mechanisms."

These initial investments in the Bridge Project are paying off, in the clinic, in the marketplace, and in an increasingly resource-challenged research environment. In September, the Bridge Project was honored by Boston's life sciences and biotech community, having been chosen by a panel of judges as the winning "Big Idea" at the Xconomy inaugural awards ceremony. Additionally, the collaboration has been credited by some for contributing to the high scores that both partnering institutions received on their respective Cancer Center Support Grant reviews by the National Cancer Institute in 2014.

Still, the research will not rest on these laurels, nor will the people behind it. The Bridge Project is, at its heart, about people — patients, researchers, physicians, and all those who keep its momentum moving forward. The Bridge Project is about rapid acceleration of progress. The ideas and technologies being developed in research laboratories have the potential to affect the cancer patients of today and tomorrow, but it is the investigators themselves, together with their philanthropic partners, who are, at an unprecedented rate, bridging the gaps between bench and bedside.

Addressing America’s climate future

Posted: 22 Nov 2017 08:40 AM PST

United States Senator Sheldon Whitehouse (D-RI) spoke at MIT on Nov. 20 about efforts to deny the legitimacy of climate science and how such misinformation can be combated.

"In this, the era of climate change, we need more than ever the guidance and innovation of science to make the right decisions," Whitehouse said. "[But] the enterprise of science now has … an industrial-strength rival ... that apes science's form but has the perverted purpose to defeat the influence of science on public policy."

Whitehouse's remarks were delivered in the second talk of the MIT Environmental Solutions Initiative's 2017-18 People and the Planet lecture series.

Whitehouse discussed the 100 organizations, trade associations, think tanks, foundations, and public relations firms that he says were created as front groups for the fossil fuel industry.

"[Their purpose] is to create faux science that looks enough like real science to create the illusion of controversy to deprecate real science thus to delay or defeat regulation," he said.

Whitehouse works actively to identify political activities funded with contributions from fossil fuel companies. Climate politics, in his view, were significantly affected by Citizens United v. Federal Election Commission, the U.S. Supreme Court decision that led to the practice of industries pouring money into political funding groups. In many cases, these groups do not have to reveal their donors.

"Citizens United opened up enormous amounts of unlimited money into politics, and it did not take the political influencers very long to figure out how to hide their identity to make that money dark money," Whitehouse said. He added that this decision has allowed those with a business interest in denying climate change to muddy the waters with misinformation and bully Republican candidates who may otherwise be amenable to discussing climate change policy. He said that bringing transparency to various funding sources will give voters more clarity during election cycles.

Whitehouse encouraged people to step up in support of the understanding and acceptance of climate change. He called on various institutions, including universities, to create mechanisms and entities to help scientists defend their research and refute climate denial.

"If a science building caught fire, you wouldn't leave it to the scientists to fight the fire. You'd call the fire department because the fire department has the equipment and skills to fight the fire," he said. "In the same way, the science enterprise needs a group that has the equipment and skills to defend the enterprise of science … science generally and universities specifically will need a common strategy to resist this potent and approaching adversary."

He suggested individuals could also make a difference by demanding that powerful corporations make climate change policy a priority, in particular with their elected representatives in Washington.

"If corporate America stood up in Congress on this issue they could blow out the fossil fuel industry folks," he said. "Sure they look terrifying … because nobody else is on the field. But if anybody else would show up on the field with any kind of clout … off we go!"

Whitehouse was elected in 2006 and has made climate change and other environmental challenges among his central legislative priorities. Since April 2012, he has spoken about the social and environmental effects of climate change each week the Senate is in session in a series of speeches titled "Time to Wake Up." He has also been publicly critical of the Trump administration's nominees to environmental posts — most recently Kathleen Hartnett White, who has been tapped to lead the Council on Environmental Quality.

In July 2017, Whitehouse introduced legislation, the American Opportunity Carbon Fee Act, with fellow Senator Brian Schatz (D-HI) and Congressmen Earl Blumenauer (D-OR) and David Cicilline (D-RI). This bill would institute a fee on all major generators of carbon pollution. Starting in 2018, these industries would be required to pay $49 per metric ton of carbon pollution, with the potential for adjustments depending on methane and other greenhouse gas emissions. The fee would then increase by 2 percent per year.  

In an effort to attract bipartisan support for their bill, Whitehouse and his co-sponsors wrote the legislation so that revenue created by the carbon fee would be used to lower corporate income tax rates. Senator Lindsey Graham (R-SC) became the first Senate Republican to voice support for a carbon tax, though he has not yet cosponsored the Whitehouse bill.

Rhode Island is nicknamed the Ocean State, and Senator Whitehouse has long recognized the critical role that ocean ecosystems play in protecting the environment both locally and globally. He organized the bi-partisan Senate Oceans Caucus with Senator Lisa Murkowski (R-AK) in 2011 to address illegal fishing, ocean debris, and improved monitoring of ocean systems. The group now boasts more than 30 members.

John E. Fernández, director of MIT's Environmental Solutions Initiative, said he was pleased that the senator brought his unique perspective and long-standing commitment for an improved environment to the MIT community. "In our extraordinarily contentious times we are due for some more cool and sedate reflection. We are also due for action and solutions," said Fernández. "In hosting the senator this evening we intend to take one more step in advancing MIT's unique role in providing the conditions for reason and action on climate change and the environment."

David Goldston, the director of the MIT Washington Office, appreciated the steps suggested by Whitehouse for becoming involved in the environment. "The really important takeaway for MIT, especially for students, is that if you care about this issue this is the time to be active, not alienated," he said.

Whitehouse ended the evening on a positive note. "Hope kind of springs eternal," he said. "You wait … and you work … and you lean in … and things come and things go and you sustain your disappointments and then someday the door opens. … There are plenty of things that can be surprisingly good that can happen if we are ready, if we can move, and if we can lean in when those moments come."