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      Deep-learning technique predicts clinical treatment outcomes

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      When it comes to treatment strategies for critically ill patients, clinicians want to be able to consider all their options and timing of administration, and make the optimal decision for their patients. While clinician experience and study has helped them to be successful in this effort, not all patients are the same, and treatment decisions at this crucial time could mean the difference between patient improvement and quick deterioration. Therefore, it would be helpful for doctors to be able to take a patient’s previous known health status and received treatments and use that to predict that patient’s health outcome under different treatment scenarios, in order to pick the best path.

      Now, a deep-learning technique, called G-Net, from researchers at MIT and IBM provides a window into causal counterfactual prediction, affording physicians the opportunity to explore how a patient might fare under different treatment plans. The foundation of G-Net is the g-computation algorithm, a causal inference method that estimates the effect of dynamic exposures in the presence of measured confounding variables — ones that may influence both treatments and outcomes. Unlike previous implementations of the g-computation framework, which have used linear modeling approaches, G-Net uses recurrent neural networks (RNN), which have node connections that allow them to better model temporal sequences with complex and nonlinear dynamics, like those found in the physiological and clinical time series data. In this way, physicians can develop alternative plans based on patient history and test them before making a decision.

      “Our ultimate goal is to develop a machine learning technique that would allow doctors to explore various ‘What if’ scenarios and treatment options,” says Li-wei Lehman, MIT research scientist in the MIT Institute for Medical Engineering and Science and an MIT-IBM Watson AI Lab project lead. “A lot of work has been done in terms of deep learning for counterfactual prediction but [it’s] been focusing on a point exposure setting,” or a static, time-varying treatment strategy, which doesn’t allow for adjustment of treatments as patient history changes. However, her team’s new prediction approach provides for treatment plan flexibility and chances for treatment alteration over time as patient covariate history and past treatments change. “G-Net is the first deep-learning approach based on g-computation that can predict both the population-level and individual-level treatment effects under dynamic and time varying treatment strategies.”

      The research, which was recently published in the Proceedings of Machine Learning Research, was co-authored by Rui Li MEng ’20, Stephanie Hu MEng ’21, former MIT postdoc Mingyu Lu MD, graduate student Yuria Utsumi, IBM research staff member Prithwish Chakraborty, IBM Research director of Hybrid Cloud Services Daby Sow, IBM data scientist Piyush Madan, IBM research scientist Mohamed Ghalwash, and IBM research scientist Zach Shahn.

      Tracking disease progression

      To build, validate, and test G-Net’s predictive abilities, the researchers considered the circulatory system in septic patients in the ICU. During critical care, doctors need to make trade-offs and judgement calls, such as ensuring the organs are receiving adequate blood supply without overworking the heart. For this, they could give intravenous fluids to patients to increase blood pressure; however, too much can cause edema. Alternatively, physicians can administer vasopressors, which act to contract blood vessels and raise blood pressure.

      In order to mimic this and demonstrate G-Net’s proof-of-concept, the team used CVSim, a mechanistic model of a human cardiovascular system that’s governed by 28 input variables characterizing the system’s current state, such as arterial pressure, central venous pressure, total blood volume, and total peripheral resistance, and modified it to simulate various disease processes (e.g., sepsis or blood loss) and effects of interventions (e.g., fluids and vasopressors). The researchers used CVSim to generate observational patient data for training and for “ground truth” comparison against counterfactual prediction. In their G-Net architecture, the researchers ran two RNNs to handle and predict variables that are continuous, meaning they can take on a range of values, like blood pressure, and categorical variables, which have discrete values, like the presence or absence of pulmonary edema. The researchers simulated the health trajectories of thousands of “patients” exhibiting symptoms under one treatment regime, let’s say A, for 66 timesteps, and used them to train and validate their model.

      Testing G-Net’s prediction capability, the team generated two counterfactual datasets. Each contained roughly 1,000 known patient health trajectories, which were created from CVSim using the same “patient” condition as the starting point under treatment A. Then at timestep 33, treatment changed to plan B or C, depending on the dataset. The team then performed 100 prediction trajectories for each of these 1,000 patients, whose treatment and medical history was known up until timestep 33 when a new treatment was administered. In these cases, the prediction agreed well with the “ground-truth” observations for individual patients and averaged population-level trajectories.

      A cut above the rest

      Since the g-computation framework is flexible, the researchers wanted to examine G-Net’s prediction using different nonlinear models — in this case, long short-term memory (LSTM) models, which are a type of RNN that can learn from previous data patterns or sequences — against the more classical linear models and a multilayer perception model (MLP), a type of neural network that can make predictions using a nonlinear approach. Following a similar setup as before, the team found that the error between the known and predicted cases was smallest in the LSTM models compared to the others. Since G-Net is able to model the temporal patterns of the patient’s ICU history and past treatment, whereas a linear model and MLP cannot, it was better able to predict the patient’s outcome.

      The team also compared G-Net’s prediction in a static, time-varying treatment setting against two state-of-the-art deep-learning based counterfactual prediction approaches, a recurrent marginal structural network (rMSN) and a counterfactual recurrent neural network (CRN), as well as a linear model and an MLP. For this, they investigated a model for tumor growth under no treatment, radiation, chemotherapy, and both radiation and chemotherapy scenarios. “Imagine a scenario where there’s a patient with cancer, and an example of a static regime would be if you only give a fixed dosage of chemotherapy, radiation, or any kind of drug, and wait until the end of your trajectory,” comments Lu. For these investigations, the researchers generated simulated observational data using tumor volume as the primary influence dictating treatment plans and demonstrated that G-Net outperformed the other models. One potential reason could be because g-computation is known to be more statistically efficient than rMSN and CRN, when models are correctly specified.

      While G-Net has done well with simulated data, more needs to be done before it can be applied to real patients. Since neural networks can be thought of as “black boxes” for prediction results, the researchers are beginning to investigate the uncertainty in the model to help ensure safety. In contrast to these approaches that recommend an “optimal” treatment plan without any clinician involvement, “as a decision support tool, I believe that G-Net would be more interpretable, since the clinicians would input treatment strategies themselves,” says Lehman, and “G-Net will allow them to be able to explore different hypotheses.” Further, the team has moved on to using real data from ICU patients with sepsis, bringing it one step closer to implementation in hospitals.

      “I think it is pretty important and exciting for real-world applications,” says Hu. “It’d be helpful to have some way to predict whether or not a treatment might work or what the effects might be — a quicker iteration process for developing these hypotheses for what to try, before actually trying to implement them in in a years-long, potentially very involved and very invasive type of clinical trial.”

      This research was funded by the MIT-IBM Watson AI Lab. More

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      Professor Emery Brown has big plans for anesthesiology

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      Emery N. Brown — the Edward Hood Taplin Professor of Medical Engineering and of Computational Neuroscience at MIT, an MIT professor of health sciences and technology, an investigator with The Picower Institute for Learning and Memory at MIT, and the Warren M. Zapol Professor of Anaesthesia at Harvard Medical School and Massachusetts General Hospital (MGH) — clearly excels at many roles. Renowned internationally for his anesthesia and neuroscience research, he embodies a unique blend of anesthesiologist, statistician, neuroscientist, educator, and mentor to both students and colleagues. Notably, Brown is one of the most decorated clinician-scientists in the country; he is one of only 25 people — and the first African-American, statistician, and anesthesiologist — to be elected to all three National Academies (Science, Engineering, and Medicine).

      Now, he is handing off one of his many key roles and responsibilities. After almost 10 years, Brown is stepping down as co-director of the Harvard-MIT Program in Health Sciences and Technology (HST). He will turn his energies toward working to develop a new joint center between MIT and MGH that uses the study of anesthesia to design novel approaches to controlling brain states. While a goal of the new center will be to improve anesthesia and intensive care unit management, according to Brown, it will also study related problems such as treating depression, insomnia, and epilepsy, as well as enhancing coma recovery.

      Founded in 1970, HST is one of the oldest interdisciplinary educational programs focused on training the next generation of clinician-scientists and engineers, who learn to translate science, engineering, and medical research into clinical practice, with the aim of improving human health. The MIT Institute for Medical Engineering and Science (IMES), where Brown is associate director, is HST’s home at MIT. Brown was the first HST co-director after the establishment of IMES in 2012; Wolfram Goessling is the Harvard University co-director of HST.

      “Emery has been an exemplary leader for HST during his tenure, and has helped it become a hub for the training of world-class scientists, engineers, and clinicians,” says Anantha Chandrakasan, dean of the MIT School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. “I am deeply grateful for his many years of service and wish him well as he moves on to new endeavors.”

      Elazer R. Edelman, director of IMES, calls Brown “a phenom who has been dedicated to our programs for years.”

      “With his thoughtful leadership and understated style, Emery made many contributions to the HST community,” Edelman continues. “On a personal note, this is bittersweet for me, as Emery has been a partner and mentor in my role as IMES director. And while I know that he will always be there for me, as he has been for all of us at IMES and HST, I will miss our late-night calls and midday conferences on matters of import for MIT, IMES, and HST.”

      Brown says “it was an honor and a privilege to co-direct HST with Wolfram.”

      “The students, staff, and faculty are simply amazing,” Brown continues. “Although, now more than 50 years old, HST remains at the vanguard for training PhD and MD students to work at the intersection between engineering, science, and medicine.”

      Goessling also thanks Brown for his leadership: “I truly valued Emery’s partnership and friendship, working together to deepen ties between the MIT and Harvard sides of HST. I am particularly grateful for working with Emery on our combined diversity efforts, leading to the HST Diversity Ambassadors initiative that made HST a better and stronger program.”

      According to Edelman, Brown was instrumental in the transition to new paradigms and relationships with HMS in the context of IMES. In 2014, he led the establishment of clear criteria for HST faculty membership, thereby strengthening the community of faculty experts who train students and provide research opportunities. More recently, he provided guidance through the turmoil of the ongoing Covid-19 pandemic, including the transition to online instruction and the return to the classroom. And Brown has always been a strong supporter of student diversity efforts, serving as an advocate and advisor to HST students.

      Brown holds BA, MA, and PhD degrees from Harvard University, and an MD from Harvard Medical School. He has been recognized with many awards, including the 2020 Swartz Prize in Theoretical and Computational Neuroscience, the 2018 Dickson Prize in Science, and an NIH Director’s Pioneer Award. Brown also served on President Barack Obama’s BRAIN Initiative Working Group. Among his many accomplishments, he has been cited for developing neural signal processing algorithms to characterize how neural systems represent and transmit information, and for unlocking the neurophysiology of how anesthetics produce the states of general anesthesia.

      Edelman says the process is underway to name a successor to Brown as co-director of HST at MIT. More

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      The downside of machine learning in health care

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      While working toward her dissertation in computer science at MIT, Marzyeh Ghassemi wrote several papers on how machine-learning techniques from artificial intelligence could be applied to clinical data in order to predict patient outcomes. “It wasn’t until the end of my PhD work that one of my committee members asked: ‘Did you ever check to see how well your model worked across different groups of people?’”

      That question was eye-opening for Ghassemi, who had previously assessed the performance of models in aggregate, across all patients. Upon a closer look, she saw that models often worked differently — specifically worse — for populations including Black women, a revelation that took her by surprise. “I hadn’t made the connection beforehand that health disparities would translate directly to model disparities,” she says. “And given that I am a visible minority woman-identifying computer scientist at MIT, I am reasonably certain that many others weren’t aware of this either.”

      In a paper published Jan. 14 in the journal Patterns, Ghassemi — who earned her doctorate in 2017 and is now an assistant professor in the Department of Electrical Engineering and Computer Science and the MIT Institute for Medical Engineering and Science (IMES) — and her coauthor, Elaine Okanyene Nsoesie of Boston University, offer a cautionary note about the prospects for AI in medicine. “If used carefully, this technology could improve performance in health care and potentially reduce inequities,” Ghassemi says. “But if we’re not actually careful, technology could worsen care.”

      It all comes down to data, given that the AI tools in question train themselves by processing and analyzing vast quantities of data. But the data they are given are produced by humans, who are fallible and whose judgments may be clouded by the fact that they interact differently with patients depending on their age, gender, and race, without even knowing it.

      Furthermore, there is still great uncertainty about medical conditions themselves. “Doctors trained at the same medical school for 10 years can, and often do, disagree about a patient’s diagnosis,” Ghassemi says. That’s different from the applications where existing machine-learning algorithms excel — like object-recognition tasks — because practically everyone in the world will agree that a dog is, in fact, a dog.

      Machine-learning algorithms have also fared well in mastering games like chess and Go, where both the rules and the “win conditions” are clearly defined. Physicians, however, don’t always concur on the rules for treating patients, and even the win condition of being “healthy” is not widely agreed upon. “Doctors know what it means to be sick,” Ghassemi explains, “and we have the most data for people when they are sickest. But we don’t get much data from people when they are healthy because they’re less likely to see doctors then.”

      Even mechanical devices can contribute to flawed data and disparities in treatment. Pulse oximeters, for example, which have been calibrated predominately on light-skinned individuals, do not accurately measure blood oxygen levels for people with darker skin. And these deficiencies are most acute when oxygen levels are low — precisely when accurate readings are most urgent. Similarly, women face increased risks during “metal-on-metal” hip replacements, Ghassemi and Nsoesie write, “due in part to anatomic differences that aren’t taken into account in implant design.” Facts like these could be buried within the data fed to computer models whose output will be undermined as a result.

      Coming from computers, the product of machine-learning algorithms offers “the sheen of objectivity,” according to Ghassemi. But that can be deceptive and dangerous, because it’s harder to ferret out the faulty data supplied en masse to a computer than it is to discount the recommendations of a single possibly inept (and maybe even racist) doctor. “The problem is not machine learning itself,” she insists. “It’s people. Human caregivers generate bad data sometimes because they are not perfect.”

      Nevertheless, she still believes that machine learning can offer benefits in health care in terms of more efficient and fairer recommendations and practices. One key to realizing the promise of machine learning in health care is to improve the quality of data, which is no easy task. “Imagine if we could take data from doctors that have the best performance and share that with other doctors that have less training and experience,” Ghassemi says. “We really need to collect this data and audit it.”

      The challenge here is that the collection of data is not incentivized or rewarded, she notes. “It’s not easy to get a grant for that, or ask students to spend time on it. And data providers might say, ‘Why should I give my data out for free when I can sell it to a company for millions?’ But researchers should be able to access data without having to deal with questions like: ‘What paper will I get my name on in exchange for giving you access to data that sits at my institution?’

      “The only way to get better health care is to get better data,” Ghassemi says, “and the only way to get better data is to incentivize its release.”

      It’s not only a question of collecting data. There’s also the matter of who will collect it and vet it. Ghassemi recommends assembling diverse groups of researchers — clinicians, statisticians, medical ethicists, and computer scientists — to first gather diverse patient data and then “focus on developing fair and equitable improvements in health care that can be deployed in not just one advanced medical setting, but in a wide range of medical settings.”

      The objective of the Patterns paper is not to discourage technologists from bringing their expertise in machine learning to the medical world, she says. “They just need to be cognizant of the gaps that appear in treatment and other complexities that ought to be considered before giving their stamp of approval to a particular computer model.” More

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      The promise and pitfalls of artificial intelligence explored at TEDxMIT event

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      Scientists, students, and community members came together last month to discuss the promise and pitfalls of artificial intelligence at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) for the fourth TEDxMIT event held at MIT. 

      Attendees were entertained and challenged as they explored “the good and bad of computing,” explained CSAIL Director Professor Daniela Rus, who organized the event with John Werner, an MIT fellow and managing director of Link Ventures; MIT sophomore Lucy Zhao; and grad student Jessica Karaguesian. “As you listen to the talks today,” Rus told the audience, “consider how our world is made better by AI, and also our intrinsic responsibilities for ensuring that the technology is deployed for the greater good.”

      Rus mentioned some new capabilities that could be enabled by AI: an automated personal assistant that could monitor your sleep phases and wake you at the optimal time, as well as on-body sensors that monitor everything from your posture to your digestive system. “Intelligent assistance can help empower and augment our lives. But these intriguing possibilities should only be pursued if we can simultaneously resolve the challenges that these technologies bring,” said Rus. 

      The next speaker, CSAIL principal investigator and professor of electrical engineering and computer science Manolis Kellis, started off by suggesting what sounded like an unattainable goal — using AI to “put an end to evolution as we know it.” Looking at it from a computer science perspective, he said, what we call evolution is basically a brute force search. “You’re just exploring all of the search space, creating billions of copies of every one of your programs, and just letting them fight against each other. This is just brutal. And it’s also completely slow. It took us billions of years to get here.” Might it be possible, he asked, to speed up evolution and make it less messy?

      The answer, Kellis said, is that we can do better, and that we’re already doing better: “We’re not killing people like Sparta used to, throwing the weaklings off the mountain. We are truly saving diversity.”

      Knowledge, moreover, is now being widely shared, passed on “horizontally” through accessible information sources, he noted, rather than “vertically,” from parent to offspring. “I would like to argue that competition in the human species has been replaced by collaboration. Despite having a fixed cognitive hardware, we have software upgrades that are enabled by culture, by the 20 years that our children spend in school to fill their brains with everything that humanity has learned, regardless of which family came up with it. This is the secret of our great acceleration” — the fact that human advancement in recent centuries has vastly out-clipped evolution’s sluggish pace.

      The next step, Kellis said, is to harness insights about evolution in order to combat an individual’s genetic susceptibility to disease. “Our current approach is simply insufficient,” he added. “We’re treating manifestations of disease, not the causes of disease.” A key element in his lab’s ambitious strategy to transform medicine is to identify “the causal pathways through which genetic predisposition manifests. It’s only by understanding these pathways that we can truly manipulate disease causation and reverse the disease circuitry.” 

      Kellis was followed by Aleksander Madry, MIT professor of electrical engineering and computer science and CSAIL principal investigator, who told the crowd, “progress in AI is happening, and it’s happening fast.” Computer programs can routinely beat humans in games like chess, poker, and Go. So should we be worried about AI surpassing humans? 

      Madry, for one, is not afraid — or at least not yet. And some of that reassurance stems from research that has led him to the following conclusion: Despite its considerable success, AI, especially in the form of machine learning, is lazy. “Think about being lazy as this kind of smart student who doesn’t really want to study for an exam. Instead, what he does is just study all the past years’ exams and just look for patterns. Instead of trying to actually learn, he just tries to pass the test. And this is exactly the same way in which current AI is lazy.”

      A machine-learning model might recognize grazing sheep, for instance, simply by picking out pictures that have green grass in them. If a model is trained to identify fish from photos of anglers proudly displaying their catches, Madry explained, “the model figures out that if there’s a human holding something in the picture, I will just classify it as a fish.” The consequences can be more serious for an AI model intended to pick out malignant tumors. If the model is trained on images containing rulers that indicate the size of tumors, the model may end up selecting only those photos that have rulers in them.

      This leads to Madry’s biggest concerns about AI in its present form. “AI is beating us now,” he noted. “But the way it does it [involves] a little bit of cheating.” He fears that we will apply AI “in some way in which this mismatch between what the model actually does versus what we think it does will have some catastrophic consequences.” People relying on AI, especially in potentially life-or-death situations, need to be much more mindful of its current limitations, Madry cautioned.

      There were 10 speakers altogether, and the last to take the stage was MIT associate professor of electrical engineering and computer science and CSAIL principal investigator Marzyeh Ghassemi, who laid out her vision for how AI could best contribute to general health and well-being. But in order for that to happen, its models must be trained on accurate, diverse, and unbiased medical data.

      It’s important to focus on the data, Ghassemi stressed, because these models are learning from us. “Since our data is human-generated … a neural network is learning how to practice from a doctor. But doctors are human, and humans make mistakes. And if a human makes a mistake, and we train an AI from that, the AI will, too. Garbage in, garbage out. But it’s not like the garbage is distributed equally.”

      She pointed out that many subgroups receive worse care from medical practitioners, and members of these subgroups die from certain conditions at disproportionately high rates. This is an area, Ghassemi said, “where AI can actually help. This is something we can fix.” Her group is developing machine-learning models that are robust, private, and fair. What’s holding them back is neither algorithms nor GPUs. It’s data. Once we collect reliable data from diverse sources, Ghassemi added, we might start reaping the benefits that AI can bring to the realm of health care.

      In addition to CSAIL speakers, there were talks from members across MIT’s Institute for Data, Systems, and Society; the MIT Mobility Initiative; the MIT Media Lab; and the SENSEable City Lab.

      The proceedings concluded on that hopeful note. Rus and Werner then thanked everyone for coming. “Please continue to reflect about the good and bad of computing,” Rus urged. “And we look forward to seeing you back here in May for the next TEDxMIT event.”

      The exact theme of the spring 2022 gathering will have something to do with “superpowers.” But — if December’s mind-bending presentations were any indication — the May offering is almost certain to give its attendees plenty to think about. And maybe provide the inspiration for a startup or two. More

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      Nonsense can make sense to machine-learning models

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      For all that neural networks can accomplish, we still don’t really understand how they operate. Sure, we can program them to learn, but making sense of a machine’s decision-making process remains much like a fancy puzzle with a dizzying, complex pattern where plenty of integral pieces have yet to be fitted. 

      If a model was trying to classify an image of said puzzle, for example, it could encounter well-known, but annoying adversarial attacks, or even more run-of-the-mill data or processing issues. But a new, more subtle type of failure recently identified by MIT scientists is another cause for concern: “overinterpretation,” where algorithms make confident predictions based on details that don’t make sense to humans, like random patterns or image borders. 

      This could be particularly worrisome for high-stakes environments, like split-second decisions for self-driving cars, and medical diagnostics for diseases that need more immediate attention. Autonomous vehicles in particular rely heavily on systems that can accurately understand surroundings and then make quick, safe decisions. The network used specific backgrounds, edges, or particular patterns of the sky to classify traffic lights and street signs — irrespective of what else was in the image. 

      The team found that neural networks trained on popular datasets like CIFAR-10 and ImageNet suffered from overinterpretation. Models trained on CIFAR-10, for example, made confident predictions even when 95 percent of input images were missing, and the remainder is senseless to humans. 

      “Overinterpretation is a dataset problem that’s caused by these nonsensical signals in datasets. Not only are these high-confidence images unrecognizable, but they contain less than 10 percent of the original image in unimportant areas, such as borders. We found that these images were meaningless to humans, yet models can still classify them with high confidence,” says Brandon Carter, MIT Computer Science and Artificial Intelligence Laboratory PhD student and lead author on a paper about the research. 

      Deep-image classifiers are widely used. In addition to medical diagnosis and boosting autonomous vehicle technology, there are use cases in security, gaming, and even an app that tells you if something is or isn’t a hot dog, because sometimes we need reassurance. The tech in discussion works by processing individual pixels from tons of pre-labeled images for the network to “learn.” 

      Image classification is hard, because machine-learning models have the ability to latch onto these nonsensical subtle signals. Then, when image classifiers are trained on datasets such as ImageNet, they can make seemingly reliable predictions based on those signals. 

      Although these nonsensical signals can lead to model fragility in the real world, the signals are actually valid in the datasets, meaning overinterpretation can’t be diagnosed using typical evaluation methods based on that accuracy. 

      To find the rationale for the model’s prediction on a particular input, the methods in the present study start with the full image and repeatedly ask, what can I remove from this image? Essentially, it keeps covering up the image, until you’re left with the smallest piece that still makes a confident decision. 

      To that end, it could also be possible to use these methods as a type of validation criteria. For example, if you have an autonomously driving car that uses a trained machine-learning method for recognizing stop signs, you could test that method by identifying the smallest input subset that constitutes a stop sign. If that consists of a tree branch, a particular time of day, or something that’s not a stop sign, you could be concerned that the car might come to a stop at a place it’s not supposed to.

      While it may seem that the model is the likely culprit here, the datasets are more likely to blame. “There’s the question of how we can modify the datasets in a way that would enable models to be trained to more closely mimic how a human would think about classifying images and therefore, hopefully, generalize better in these real-world scenarios, like autonomous driving and medical diagnosis, so that the models don’t have this nonsensical behavior,” says Carter. 

      This may mean creating datasets in more controlled environments. Currently, it’s just pictures that are extracted from public domains that are then classified. But if you want to do object identification, for example, it might be necessary to train models with objects with an uninformative background. 

      This work was supported by Schmidt Futures and the National Institutes of Health. Carter wrote the paper alongside Siddhartha Jain and Jonas Mueller, scientists at Amazon, and MIT Professor David Gifford. They are presenting the work at the 2021 Conference on Neural Information Processing Systems. More

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      Differences in T cells’ functional states determine resistance to cancer therapy

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      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in humans. Some patients with NSCLC receive a therapy called immune checkpoint blockade (ICB) that helps kill cancer cells by reinvigorating a subset of immune cells called T cells, which are “exhausted” and have stopped working. However, only about 35 percent of NSCLC patients respond to ICB therapy. Stefani Spranger’s lab at the MIT Department of Biology explores the mechanisms behind this resistance, with the goal of inspiring new therapies to better treat NSCLC patients. In a new study published on Oct. 29 in Science Immunology, a team led by Spranger lab postdoc Brendan Horton revealed what causes T cells to be non-responsive to ICB — and suggests a possible solution.

      Scientists have long thought that the conditions within a tumor were responsible for determining when T cells stop working and become exhausted after being overstimulated or working for too long to fight a tumor. That’s why physicians prescribe ICB to treat cancer — ICB can invigorate the exhausted T cells within a tumor. However, Horton’s new experiments show that some ICB-resistant T cells stop working before they even enter the tumor. These T cells are not actually exhausted, but rather they become dysfunctional due to changes in gene expression that arise early during the activation of a T cell, which occurs in lymph nodes. Once activated, T cells differentiate into certain functional states, which are distinguishable by their unique gene expression patterns.

      The notion that the dysfunctional state that leads to ICB resistance arises before T cells enter the tumor is quite novel, says Spranger, the Howard S. and Linda B. Stern Career Development Professor, a member of the Koch Institute for Integrative Cancer Research, and the study’s senior author.

      “We show that this state is actually a preset condition, and that the T cells are already non-responsive to therapy before they enter the tumor,” she says. As a result, she explains, ICB therapies that work by reinvigorating exhausted T cells within the tumor are less likely to be effective. This suggests that combining ICB with other forms of immunotherapy that target T cells differently might be a more effective approach to help the immune system combat this subset of lung cancer.

      In order to determine why some tumors are resistant to ICB, Horton and the research team studied T cells in murine models of NSCLC. The researchers sequenced messenger RNA from the responsive and non-responsive T cells in order to identify any differences between the T cells. Supported in part by the Koch Institute Frontier Research Program, they used a technique called Seq-Well, developed in the lab of fellow Koch Institute member J. Christopher Love, the Raymond A. (1921) and Helen E. St. Laurent Professor of Chemical Engineering and a co-author of the study. The technique allows for the rapid gene expression profiling of single cells, which permitted Spranger and Horton to get a very granular look at the gene expression patterns of the T cells they were studying.

      Seq-Well revealed distinct patterns of gene expression between the responsive and non-responsive T cells. These differences, which are determined when the T cells assume their specialized functional states, may be the underlying cause of ICB resistance.

      Now that Horton and his colleagues had a possible explanation for why some T cells did not respond to ICB, they decided to see if they could help the ICB-resistant T cells kill the tumor cells. When analyzing the gene expression patterns of the non-responsive T cells, the researchers had noticed that these T cells had a lower expression of receptors for certain cytokines, small proteins that control immune system activity. To counteract this, the researchers treated lung tumors in murine models with extra cytokines. As a result, the previously non-responsive T cells were then able to fight the tumors — meaning that the cytokine therapy prevented, and potentially even reversed, the dysfunctionality.

      Administering cytokine therapy to human patients is not currently safe, because cytokines can cause serious side effects as well as a reaction called a “cytokine storm,” which can produce severe fevers, inflammation, fatigue, and nausea. However, there are ongoing efforts to figure out how to safely administer cytokines to specific tumors. In the future, Spranger and Horton suspect that cytokine therapy could be used in combination with ICB.

      “This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer,” Horton says.

      Spranger agrees that this work will help researchers develop more innovative cancer therapies, especially because researchers have historically focused on T cell exhaustion rather than the earlier role that T cell functional states might play in cancer.

      “If T cells are rendered dysfunctional early on, ICB is not going to be effective, and we need to think outside the box,” she says. “There’s more evidence, and other labs are now showing this as well, that the functional state of the T cell actually matters quite substantially in cancer therapies.” To Spranger, this means that cytokine therapy “might be a therapeutic avenue” for NSCLC patients beyond ICB.

      Jeffrey Bluestone, the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the University of California-San Francisco, who was not involved with the paper, agrees. “The study provides a potential opportunity to ‘rescue’ immunity in the NSCLC non-responder patients with appropriate combination therapies,” he says.

      This research was funded by the Pew-Stewart Scholars for Cancer Research, the Ludwig Center for Molecular Oncology, the Koch Institute Frontier Research Program through the Kathy and Curt Mable Cancer Research Fund, and the National Cancer Institute. More

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      Exploring the human stories behind the data

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      Shaking in the back of a police cruiser, handcuffs digging into his wrists, Brian Williams was overwhelmed with fear. He had been pulled over, but before he was asked for his name, license, or registration, a police officer ordered him out of his car and into back of the police cruiser, saying into his radio, “Black male detained.” The officer’s explanation for these actions was: “for your safety and mine.”

      Williams walked away from the experience with two tickets, a pair of bruised wrists, and a desire to do everything in his power to prevent others from experiencing the utter powerlessness he had felt.

      Now an MIT senior majoring in biological engineering and minoring in Black studies, Williams has continued working to empower his community. Through experiences in and out of the classroom, he has leveraged his background in bioengineering to explore interests in public health and social justice, specifically looking at how the medical sector can uplift and support communities of color.

      Williams grew up in a close-knit family and community in Broward County, Florida, where he found comfort in the routine of Sunday church services, playing outside with friends, and cookouts on the weekends. Broward County was home to him — a home he felt deeply invested in and indebted to.

      “It takes a village. The Black community has invested a lot in me, and I have a lot to invest back in it,” he says.

      Williams initially focused on STEM subjects at MIT, but in his sophomore year, his interests in exploring data science and humanities research led him to an Undergraduate Research Opportunities Program (UROP) project in the Department of Political Science. Working with Professor Ariel White, he analyzed information on incarceration and voting rights, studied the behavior patterns of police officers, and screened 911 calls to identify correlations between how people described events to how the police responded to them.

      In the summer before his junior year, Williams also joined MIT’s Civic Data Design Lab, where he worked as a researcher for the Missing Data Project, which uses both journalism and data science to visualize statistics and humanize the people behind the numbers. As the project’s name suggests, there is often much to be learned from seeking out data that aren’t easily available. Using datasets and interviews describing how the pandemic affected Black communities, Williams and a team of researchers created a series called the Color of Covid, which told the stories behind the grim statistics on race and the pandemic.

      The following year, Williams undertook a research-and-development internship with the biopharmaceutical company Amgen in San Francisco, working on protein engineering to combat autoimmune diseases. Because this work was primarily in the lab, focusing on science-based applications, he saw it as an opportunity to ask himself: “Do I want to dedicate my life to this area of bioengineering?” He found the issue of social justice to be more compelling.

      At the same time, Williams was drawn toward tackling problems the local Black community was experiencing related to the pandemic. He found himself thinking deeply about how to educate the public, address disparities in case rates, and, above all, help people.

      Working through Amgen’s Black Employee Resource Group and its Diversity, Inclusion, and Belonging Team, Williams crafted a proposal, which the company adopted, for addressing Covid-19 vaccination misinformation in Black and Brown communities in San Mateo and San Francisco County. He paid special attention to how to frame vaccine hesitancy among members of these communities, understanding that a longstanding history of racism in scientific discovery and medicine led many Black and Brown people to distrust the entire medical industry.

      “Trying to meet people where they are is important,” Williams says.

      This experience reinforced the idea for Williams that he wanted to do everything in his power to uplift the Black community.

      “I think it’s only right that I go out and I shine bright because it’s not easy being Black. You know, you have to work twice as hard to get half as much,” he says.

      As the current political action co-chair of the MIT Black Students’ Union (BSU), Williams also works to inspire change on campus, promoting and participating in events that uplift the BSU. During his Amgen internship, he also organized the MIT Black History Month Takeover Series, which involved organizing eight events from February through the beginning of spring semester. These included promotions through social media and virtual meetings for students and faculty. For his leadership, he received the “We Are Family” award from the BSU executive board.

      Williams prioritizes community in everything he does, whether in the classroom, at a campus event, or spending time outside in local communities of color around Boston.

      “The things that really keep me going are the stories of other people,” says Williams, who is currently applying to a variety of postgraduate programs. After receiving MIT endorsement, he applied to the Rhodes and Marshall Fellowships; he also plans to apply to law school with a joint master’s degree in public health and policy.

      Ultimately, Williams hopes to bring his fight for racial justice to the policy level, looking at how a long, ongoing history of medical racism has led marginalized communities to mistrust current scientific endeavors. He wants to help bring about new legislation to fix old systems which disproportionately harm communities of color. He says he aims to be “an engineer of social solutions, one who reaches deep into their toolbox of social justice, pulling the levers of activism, advocacy, democracy, and legislation to radically change our world — to improve our social institutions at the root and liberate our communities.” While he understands this is a big feat, he sees his ambition as an asset.

      “I’m just another person with huge aspirations, and an understanding that you have to go get it if you want it,” he says. “You feel me? At the end of the day, this is just the beginning of my story. And I’m grateful to everyone in my life that’s helping me write it. Tap in.” More

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      in Data Management & Statistics

      Enabling AI-driven health advances without sacrificing patient privacy

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      There’s a lot of excitement at the intersection of artificial intelligence and health care. AI has already been used to improve disease treatment and detection, discover promising new drugs, identify links between genes and diseases, and more.

      By analyzing large datasets and finding patterns, virtually any new algorithm has the potential to help patients — AI researchers just need access to the right data to train and test those algorithms. Hospitals, understandably, are hesitant to share sensitive patient information with research teams. When they do share data, it’s difficult to verify that researchers are only using the data they need and deleting it after they’re done.

      Secure AI Labs (SAIL) is addressing those problems with a technology that lets AI algorithms run on encrypted datasets that never leave the data owner’s system. Health care organizations can control how their datasets are used, while researchers can protect the confidentiality of their models and search queries. Neither party needs to see the data or the model to collaborate.

      SAIL’s platform can also combine data from multiple sources, creating rich insights that fuel more effective algorithms.

      “You shouldn’t have to schmooze with hospital executives for five years before you can run your machine learning algorithm,” says SAIL co-founder and MIT Professor Manolis Kellis, who co-founded the company with CEO Anne Kim ’16, SM ’17. “Our goal is to help patients, to help machine learning scientists, and to create new therapeutics. We want new algorithms — the best algorithms — to be applied to the biggest possible data set.”

      SAIL has already partnered with hospitals and life science companies to unlock anonymized data for researchers. In the next year, the company hopes to be working with about half of the top 50 academic medical centers in the country.

      Unleashing AI’s full potential

      As an undergraduate at MIT studying computer science and molecular biology, Kim worked with researchers in the Computer Science and Artificial Intelligence Laboratory (CSAIL) to analyze data from clinical trials, gene association studies, hospital intensive care units, and more.

      “I realized there is something severely broken in data sharing, whether it was hospitals using hard drives, ancient file transfer protocol, or even sending stuff in the mail,” Kim says. “It was all just not well-tracked.”

      Kellis, who is also a member of the Broad Institute of MIT and Harvard, has spent years establishing partnerships with hospitals and consortia across a range of diseases including cancers, heart disease, schizophrenia, and obesity. He knew that smaller research teams would struggle to get access to the same data his lab was working with.

      In 2017, Kellis and Kim decided to commercialize technology they were developing to allow AI algorithms to run on encrypted data.

      In the summer of 2018, Kim participated in the delta v startup accelerator run by the Martin Trust Center for MIT Entrepreneurship. The founders also received support from the Sandbox Innovation Fund and the Venture Mentoring Service, and made various early connections through their MIT network.

      To participate in SAIL’s program, hospitals and other health care organizations make parts of their data available to researchers by setting up a node behind their firewall. SAIL then sends encrypted algorithms to the servers where the datasets reside in a process called federated learning. The algorithms crunch the data locally in each server and transmit the results back to a central model, which updates itself. No one — not the researchers, the data owners, or even SAIL —has access to the models or the datasets.

      The approach allows a much broader set of researchers to apply their models to large datasets. To further engage the research community, Kellis’ lab at MIT has begun holding competitions in which it gives access to datasets in areas like protein function and gene expression, and challenges researchers to predict results.

      “We invite machine learning researchers to come and train on last year’s data and predict this year’s data,” says Kellis. “If we see there’s a new type of algorithm that is performing best in these community-level assessments, people can adopt it locally at many different institutions and level the playing field. So, the only thing that matters is the quality of your algorithm rather than the power of your connections.”

      By enabling a large number of datasets to be anonymized into aggregate insights, SAIL’s technology also allows researchers to study rare diseases, in which small pools of relevant patient data are often spread out among many institutions. That has historically made the data difficult to apply AI models to.

      “We’re hoping that all of these datasets will eventually be open,” Kellis says. “We can cut across all the silos and enable a new era where every patient with every rare disorder across the entire world can come together in a single keystroke to analyze data.”

      Enabling the medicine of the future

      To work with large amounts of data around specific diseases, SAIL has increasingly sought to partner with patient associations and consortia of health care groups, including an international health care consulting company and the Kidney Cancer Association. The partnerships also align SAIL with patients, the group they’re most trying to help.

      Overall, the founders are happy to see SAIL solving problems they faced in their labs for researchers around the world.

      “The right place to solve this is not an academic project. The right place to solve this is in industry, where we can provide a platform not just for my lab but for any researcher,” Kellis says. “It’s about creating an ecosystem of academia, researchers, pharma, biotech, and hospital partners. I think it’s the blending all of these different areas that will make that vision of medicine of the future become a reality.” More