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Ila Fiete studies how the brain performs complex computations




While doing a postdoc about 15 years ago, Ila Fiete began searching for faculty jobs in computational neuroscience — a field that uses mathematical tools to investigate brain function. However, there were no advertised positions in theoretical or computational neuroscience at that time in the United States.

“It wasn’t really a field,” she recalls. “That has changed completely, and [now] there are 15 to 20 openings advertised per year.” She ended up finding a position in the Center for Learning and Memory at the University of Texas at Austin, which along with a small handful of universities including MIT, was open to neurobiologists with a computational background.

Computation is the cornerstone of Fiete’s research at MIT’s McGovern Institute for Brain Research, where she has been a faculty member since 2018. Using computational and mathematical techniques, she studies how the brain encodes information in ways that enable cognitive tasks such as learning, memory, and reasoning about our surroundings.

One major research area in Fiete’s lab is how the brain is able to continuously compute the body’s position in space and make constant adjustments to that estimate as we move about. 

“When we walk through the world, we can close our eyes and still have a pretty good estimate of where we are,” she says. “This involves being able to update our estimate based on our sense of self-motion. There are also many computations in the brain that involve moving through abstract or mental rather than physical space, and integrating velocity signals of some variety or another. Some of the same ideas and even circuits for spatial navigation might be involved in navigating through these mental spaces.”

No better fit

Fiete spent her childhood between Mumbai, India, and the United States, where her mathematician father held a series of visiting or permanent appointments at the Institute for Advanced Study in Princeton, NJ, the University of California at Berkeley, and the University of Michigan at Ann Arbor.

In India, Fiete’s father did research at the Tata Institute of Fundamental Research, and she grew up spending time with many other children of academics. She was always interested in biology, but also enjoyed math, following in her father’s footsteps.

“My father was not a hands-on parent, wanting to teach me a lot of mathematics, or even asking me about how my math schoolwork was going, but the influence was definitely there. There’s a certain aesthetic to thinking mathematically, which I absorbed very indirectly,” she says. “My parents did not push me into academics, but I couldn’t help but be influenced by the environment.”

She spent her last two years of high school in Ann Arbor and then went to the University of Michigan, where she majored in math and physics. While there, she worked on undergraduate research projects, including two summer stints at Indiana University and the University of Virginia, which gave her firsthand experience in physics research. Those projects covered a range of topics, including proton radiation therapy, the magnetic properties of single crystal materials, and low-temperature physics.

“Those three experiences are what really made me sure that I wanted to go into academics,” Fiete says. “It definitely seemed like the path that I knew the best, and I think it also best suited my temperament. Even now, with more exposure to other fields, I cannot think of a better fit.”

Although she was still interested in biology, she took only one course in the subject in college, holding back because she did not know how to marry quantitative approaches with biological sciences. She began her graduate studies at Harvard University planning to study low-temperature physics, but while there, she decided to start explore quantitative classes in biology. One of those was a systems biology course taught by then-MIT professor Sebastian Seung, which transformed her career trajectory.

“It was truly inspiring,” she recalls. “Thinking mathematically about interacting systems in biology was really exciting. It was really my first introduction to systems biology, and it had me hooked immediately.”

She ended up doing most of her PhD research in Seung’s lab at MIT, where she studied how the brain uses incoming signals of the velocity of head movement to control eye position. For example, if we want to keep our gaze fixed on a particular location while our head is moving, the brain must continuously calculate and adjust the amount of tension needed in the muscles surrounding the eyes, to compensate for the movement of the head.

“Bizarre” cells

After earning her PhD, Fiete and her husband, a theoretical physicist, went to the Kavli Institute for Theoretical Physics at the University of California at Santa Barbara, where they each held fellowships for independent research. While there, Fiete began working on a research topic that she still studies today — grid cells. These cells, located in the entorhinal cortex of the brain, enable us to navigate our surroundings by helping the brain to create a neural representation of space.

Midway through her position there, she learned of a new discovery, that when a rat moves across an open room, a grid cell in its brain fires at many different locations arranged geometrically in a regular pattern of repeating triangles. Together, a population of grid cells forms a lattice of triangles representing the entire room. These cells have also been found in the brains of various other mammals, including humans.

“It’s amazing. It’s this very crystalline response,” Fiete says. “When I read about that, I fell out of my chair. At that point I knew this was something bizarre that would generate so many questions about development, function, and brain circuitry that could be studied computationally.”

One question Fiete and others have investigated is why the brain needs grid cells at all, since it also has so-called place cells that each fire in one specific location in the environment. A possible explanation that Fiete has explored is that grid cells of different scales, working together, can represent a vast number of possible positions in space and also multiple dimensions of space.

“If you have a few cells that can parsimoniously generate a very large coding space, then you can afford to not use most of that coding space,” she says. “You can afford to waste most of it, which means you can separate things out very well, in which case it becomes not so susceptible to noise.”

Since returning to MIT, she has also pursued a research theme related to what she explored in her PhD thesis — how the brain maintains neural representations of where the head is located in space. In a paper published last year, she uncovered that the brain generates a one-dimensional ring of neural activity that acts as a compass, allowing the brain to calculate the current direction of the head relative to the external world.

Her lab also studies cognitive flexibility — the brain’s ability to perform so many different types of cognitive tasks.

“How it is that we can repurpose the same circuits and flexibly use them to solve many different problems, and what are the neural codes that are amenable to that kind of reuse?” she says. “We’re also investigating the principles that allow the brain to hook multiple circuits together to solve new problems without a lot of reconfiguration.”



WCLC: Xcovery’s Xalkori challenger shines in phase 3 lung cancer showdown




Xcovery pitted its ALK inhibitor against Pfizer’s Xalkori—the first-ever FDA-approved drug in its class—and came out on top. The drug, ensartinib, shrank tumors in three-quarters of previously untreated lung cancer patients, compared to Xalkori’s 67%, and staved off cancer for two years, more than double the time Xalkori logged.

The phase 3 study tested ensartinib as a firstline treatment against Xalkori (crizotinib) in 290 patients with ALK-positive non-small cell lung cancer. As of July 1, ensartinib had shrunk the tumors of 75% of patients, topping Xalkori’s 67% mark. And even though Xalkori did unusually well in the study, keeping cancer at bay for a median of 12.7 months, Xcovery’s drug trounced it with median progression-free survival of 25.8 months. The median overall survival—how long the drug extended patients’ lives—had not been reached.

“Interestingly, crizotinib overperformed in the study; the duration of response for patients on crizotinib was 27.3 months, which is much higher than what we’ve seen in other studies for patients on crizotinib,” said Leora Horn, M.D., director of the Thoracic Oncology Program and a professor at the Vanderbilt-Ingram Cancer Center, who presented the study.

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“It was the best performance ever done by crizotinib in any randomized study” in previously untreated patients, said Xcovery Chief Medical Officer Giovanni Selvaggi, a thoracic oncologist by training who previously worked on Novartis’ ALK inhibitor Zykadia. 

RELATED: Xcovery hires CEO, CMO to lead assault on ALK NSCLC market

Ensartinib also did better than Xalkori in a small group of patients whose disease had spread to the brain. All 11 patients whose brain tumors were large and defined enough to be seen on a scan saw their tumors shrink, Selvaggi said. Seven of the 11 patients (64%) had enough shrinkage to be considered responders, compared to just one-fifth of the 19 patients on Xalkori.

The most common side effect was a sunburn-like rash, “a new toxicity” for ALK inhibitors, Horn said.

“It’s a very benign rash that can be compared to a sunburn and it normally goes away with continued treatment and topical therapies,” Selvaggi said. Unlike the rash that comes with meds that target EGFR, which often gets worse the longer patients take the drug, patients taking ensartinib do not need to stop treatment to get rid of the rash, he added.

The study started enrolling patients who were tested for the ALK mutation in local laboratories but about 40 patients in, it switched over to recruiting those who were centrally tested at larger labs, Horn said. It did this to cut down on false positive results from local testing. Of the 43 patients who were locally tested, 11 were thought to be ALK-positive before central testing showed they were actually negative; seven received ensartinib and two got Xalkori, Horn said.

“Since we only target the ALK protein with this drug, if patients are ALK-negative, it would not be expected to slow tumor growth,” Selvaggi said.

Understandably, the false positive patients would skew the data, so the investigators also reported results for what they called a modified intent-to-treat population of only centrally tested patients. The progression-free survival for this group had not been reached by the data cutoff, meaning more than half of the patients did not see their cancer worsen by then. This figure stayed at 12.7 months for patients on crizotinib.

RELATED: Pfizer’s Lorbrena makes play for earlier lung cancer use with Xalkori-topping data

Up next? Discussing the data with regulators and eventually, a filing: “We are excited to bring an effective and safe new option to patients and their physicians and therefore we are planning to share the data with regulatory agencies as our next step,” Selvaggi said. It’s been a long time coming for the Scripps Florida spinout that made the Fierce 15 class of 2007.

The thing is, if ensartinib can ultimately win approval, it’ll have more drugs to battle than just Xalkori. Roche’s Alecensa, the class’ current sales leader, and Zykadia both topped Xalkori on their way to earning first-line approvals in 2017, and Pfizer’s Lorbrena—Xalkori’s follow-up med—earlier this week posted top-line results showing it could beat out its predecessor, too.


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NIH to fund new diagnostic tests for the emerging, severe childhood illness linked to COVID-19




While most children exposed to the novel coronavirus suffer only a mild infection, others may develop a rare but severe reaction that attacks several organs at once, requiring intensive rescue care.

To better diagnose this complication of COVID-19—known as Multisystem Inflammatory Syndrome in Children, or MIS-C—the National Institutes of Health launched a research funding program that will offer up to $20 million in grants over the next four years.

MIS-C can be fatal, and has been shown to affect the heart, lungs, kidneys, brain, skin and eyes. A study by the Centers for Disease Control and Prevention tracking a group of MIS-C patients—at a median age of eight years old—showed 80% required intensive care, with many receiving ventilator support and treatments for circulatory shock.

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Most had tested positive for COVID-19 by either molecular or antibody tests, but early signs and symptoms can range from almost none at all to those seen and unseen—such as fever and cough, or abdominal pain and diarrhea, as well as hidden inflammation of the heart’s coronary arteries. 

The NIH’s new effort aims to incorporate new diagnostics for the different genetic, immune, viral and environmental factors that may help predict a child’s chances of progressing to MIS-C.

“We urgently need methods to distinguish children at high risk for MIS-C from those unlikely to experience major ill effects from the virus, so that we can develop early interventions to improve their outcomes, ” said Diana Bianchi, director of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

RELATED: NIH picks seven COVID-19 diagnostic tests in ‘Shark Tank’ competition, unlocking $248.7M in scale-up funding

The institute’s project—dubbed PreVAIL kIds, for Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence—dovetails with the NIH’s “Shark Tank-like” Rapid Acceleration of Diagnostics initiative, which recently advanced seven projects to its final phases.

PreVAIL kIds will support studies to evaluate genes and other pediatric biomarkers, and projects using machine learning techniques to help develop new tests, by gathering funds from multiple NIH institutes and centers focused on related organs, diseases and determinants of health.


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Biogen nabs speedy FDA review for controversial Alzheimer’s drug




Biogen’s aducanumab is inching closer to an FDA decision. The Big Biotech, along with partner Eisai, announced on Friday that the FDA accepted its regulatory submission for aducanumab, its once-failed Alzheimer’s drug—with priority review to boot.

The agency expects to decide the fate of the treatment by March 7, 2021. Along the way, it will hold an advisory committee meeting. It has not set a date for the meeting, but Jefferies analyst Michael Yee expects it sometime in the first quarter of 2021.

How the FDA rules on aducanumab will show how far the FDA and its commissioner, Stephen Hahn, M.D., are willing to diverge from its established approval standards. Under U.S. law, companies need to show “substantial” evidence of effectiveness to win approval.

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Aducanumab has had a bumpy ride, failing a futility analysis in March 2019, which led Biogen to axe its phase 3 program. Eight months later, the company resurrected the drug saying the analysis was “incorrect,” arguing that it was based on a smaller dataset that featured fewer patients who received high-dose aducanumab. Adding in the additional data showed aducanumab reduced clinical decline, the company said.

Biogen believes that, if approved, aducanumab would become the first treatment to slow decline in people with Alzheimer’s disease, a neurodegenerative disorder whose treatments focus on controlling symptoms. The data, however, are not so clear. In Yee’s words, “the phase 3 data was largely mixed and still inconclusive.”

RELATED: In a test for Hahn’s FDA, Biogen submits controversial Alzheimer’s drug aducanumab

The data underpinning the filing come from a phase 1b study, as well as a pair of phase 3 studies that tested aducanumab in patients with early-stage and mild Alzheimer’s. The phase 3 results were mixed, with one study suggesting that aducanumab is no better than placebo, while the other linked the drug to improved scores on a dementia scale.

Patients who received the highest dose of aducanumab in a phase 3 trial dubbed EMERGE showed statistically significant improvement on a clinical dementia scale. But the same patient group in the ENGAGE phase 3 study did worse than patients taking placebo on that same measure, as well as on a test of cognitive function.

RELATED: 2019’s top 15 clinical trial flops (and a flip-flop) | Flip-flop: Aducanumab

Biogen did not use a priority review voucher to snag a speedy review, “suggesting FDA sees this as an unmet need and willing to review this under an accelerated window,” Yee wrote in an investor note.

Optimists argue that the speedy review suggests the agency is “comfortable with the totality of the data, recognizes high unmet need, and really wants to get an Alzheimer’s drug approved,” Yee wrote. Others might read less into the priority review, as the FDA could still ask Biogen for more data or extend their review period.

Some analysts have been cautiously optimistic. Cantor Fitzgerald’s Alethia Young wrote earlier this year that she was “reasonably confident” the FDA would accept aducanumab’s application, adding the caveat that she and her colleagues “don’t view this approval as certain,” given “the complicated issues around the statistical analysis and the inconsistent outcomes from both pivotal trials.” Brian Abrahams of RBC Capital Markets estimated a 30% chance the FDA would approve the drug “despite the mixed ph.III data.”

But Baird analyst Brian Skorney has dismissed aducanumab’s chances, saying the bulk of the data shows aducanumab doesn’t provide a clinical benefit.

“If Biogen said based on this data it was running another study, the stock would be down because the data doesn’t justify investing in another study. The regulatory threshold is higher than that,” Skorney wrote in December. “The bottom line is, the FDA standard of approval is substantial evidence of efficacy and the cumulative data for aducanumab falls really far of this standard.”


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