RNA editing study finds many ways for neurons to diversify

All starting from the same DNA, neurons ultimately take on individual characteristics in the brain and body. Differences in which genes they transcribe into RNA help determine which type of neuron they become, and from there, a new MIT study shows, individual cells edit a selection of sites in those RNA transcripts, each at their own widely varying rates.

The new study surveyed the whole landscape of RNA editing in more than 200 individual cells commonly used as models of fundamental neural biology: tonic and phasic motor neurons of the fruit fly. One of the main findings is that most sites were edited at rates between the “all-or-nothing” extremes many scientists have assumed based on more limited studies in mammals, says senior author Troy Littleton, the Menicon Professor in the MIT departments of Biology and Brain and Cognitive Sciences. The resulting dataset and open-access analyses, recently published in eLife, set the table for discoveries about how RNA editing affects neural function and what enzymes implement those edits.

“We have this ‘alphabet’ now for RNA editing in these neurons,” Littleton says. “We know which genes are edited in these neurons, so we can go in and begin to ask questions as to what is that editing doing to the neuron at the most interesting targets.”

Andres Crane PhD ’24, who earned his doctorate in Littleton’s lab based on this work, is the study’s lead author.

From a genome of about 15,000 genes, Littleton and Crane’s team found, the neurons made hundreds of edits in transcripts from hundreds of genes. For example, the team documented “canonical” edits of 316 sites in 210 genes. Canonical means that the edits were made by the well-studied enzyme ADAR, which is also found in mammals, including humans. Of the 316 edits, 175 occurred in regions that encode the contents of proteins. Analysis indeed suggested 60 are likely to significantly alter amino acids. But they also found 141 more editing sites in areas that don’t code for proteins but instead affect their production, which means they could affect protein levels, rather than their contents.

The team also found many “non-canonical” edits that ADAR didn’t make. That’s important, Littleton says, because that information could aid in discovering more enzymes involved in RNA editing, potentially across species. That, in turn, could expand the possibilities for future genetic therapies.

“In the future, if we can begin to understand in flies what the enzymes are that make these other non-canonical edits, it would give us broader coverage for thinking about doing things like repairing human genomes where a mutation has broken a protein of interest,” Littleton says.

Moreover, by looking specifically at fly larvae, the team found many edits that were specific to juveniles, versus adults, suggesting potential significance during development. And because they looked at full gene transcripts of individual neurons, the team was also able to find editing targets that had not been cataloged before.

Widely varying rates

Some of the most heavily edited RNAs were from genes that make critical contributions to neural circuit communication such as neurotransmitter release, and the channels that cells form to regulate the flow of chemical ions that vary their electrical properties. The study identified 27 sites in 18 genes that were edited more than 90 percent of the time.

Yet neurons sometimes varied quite widely in whether they would edit a site, which suggests that even neurons of the same type can still take on significant degrees of individuality.

“Some neurons displayed ~100 percent editing at certain sites, while others displayed no editing for the same target,” the team wrote in eLife. “Such dramatic differences in editing rate at specific target sites is likely to contribute to the heterogeneous features observed within the same neuronal population.”

On average, any given site was edited about two-thirds of the time, and most sites were edited within a range well between all-or-nothing extremes.

“The vast majority of editing events we found were somewhere between 20 percent and 70 percent,” Littleton says. “We were seeing mixed ratios of edited and unedited transcripts within a single cell.”

Also, the more a gene was expressed, the less editing it experienced, suggesting that ADAR could only keep up so much with its editing opportunities.

Potential impacts on function

One of the key questions the data enables scientists to ask is what impact RNA edits have on the function of the cells. In a 2023 study, Littleton’s lab began to tackle this question by looking at just two edits they found in the most heavily edited gene: complexin. Complexin’s protein product restrains release of the neurotransmitter glutamate, making it a key regulator of neural circuit communication. They found that by mixing and matching edits, neurons produced up to eight different versions of the protein with significant effects on their glutamate release and synaptic electrical current. But in the new study, the team reports 13 more edits in complexin that are yet to be studied.

Littleton says he’s intrigued by another key protein, called Arc1, that the study shows experienced a non-canonical edit. Arc is a vitally important gene in “synaptic plasticity,” which is the property neurons have of adjusting the strength or presence of their “synapse” circuit connections in response to nervous system activity. Such neural nimbleness is hypothesized to be the basis of how the brain can responsively encode new information in learning and memory. Notably, Arc1 editing fails to occur in fruit flies that model Alzheimer’s disease.

Littleton says the lab is now working hard to understand how the RNA edits they’ve documented affect function in the fly motor neurons.

In addition to Crane and Littleton, the study’s other authors are Michiko Inouye and Suresh Jetti.

The National Institutes of Health, The Freedom Together Foundation, and The Picower Institute for Learning and Memory provided support for the study.

de MIT News https://ift.tt/g8tpx5j

What makes a good proton conductor?

A number of advanced energy technologies — including fuel cells, electrolyzers, and an emerging class of low-power electronics — use protons as the key charge carrier. Whether or not these devices will be widely adopted hinges, in part, on how efficiently they can move protons.

One class of materials known as metal oxides has shown promise in conducting protons at temperatures above 400 degrees Celsius. But researchers have struggled to find the best materials to increase the proton conductivity at lower temperatures and improve efficiency.

Now, MIT researchers have developed a physical model to predict proton mobility across a wide range of metal oxides. In a new paper, the researchers ranked the most important features of metal oxides for facilitating proton conduction, and demonstrated for the first time how much the flexibility of the materials’ oxide ions improves their ability to transfer protons.

The researchers believe their findings can guide scientists and engineers as they develop materials for more efficient energy technologies enabled by protons, which are lighter, smaller, and more abundant than more common charge carriers like lithium ions.

“If you understand the mechanism of a process and what material traits govern that mechanism, then you can tune those traits to improve the speed of that process — in this case, proton conduction,” says Bilge Yildiz, the Breen M. Kerr Professor in the departments of Nuclear Science and Engineering (NSE) and Materials Science and Engineering (DMSE) at MIT and the senior author of a paper describing the work. “For this application, we need to understand these quantitative relations between the proton transfer and the material’s structural, chemical, electronic, and dynamic traits. Establishing these relations can help us screen material databases to find compounds that satisfy those material traits, or even go beyond screening. There could be ways to use generative AI tools to create compounds that optimize for those traits.”

The paper appears in the journal Matter. Joining Yildiz are Heejung W. Chung, the paper’s first author and an MIT PhD student in DMSE; Pjotrs Žguns, a former postdoc in DMSE; and Ju Li, the Carl Richard Soderberg Professor of Power Engineering in NSE and DMSE.

Making protons hop

Protons are already used at scale in electrolyzers for hydrogen production and in fuel cells. They are also expected to be used in promising energy-storage technologies such as proton batteries, which could be water-based and rely on cheaper materials than lithium-ion batteries. A more recent and exciting application is low-energy, brain-inspired computing to emulate synaptic functions in devices for artificial intelligence.

“Proton conductors are important materials in different energy conversion technologies for clean electricity, clean fuels, and clean industrial chemical synthesis,” explains Yildiz. “Inorganic, scalable proton conductors that work at room temperature are also needed for energy-efficient brain-inspired computing.”

Protons, which are the positively charged state of hydrogen, are different from lithium or sodium ions because they don’t have their own electrons — protons consist of just the bare nucleus. Therefore, protons prefer to embed into the electron clouds of nearby ions, hopping from one to the next. In metal oxides, protons embed into oxygen ions, forming a covalent bond, and hop to a nearby oxygen ion through a hydrogen bond. After every hop, the covalent H-O bond rotates to prevent the proton from shuttling back and forth.

All that hopping and rotating got MIT’s researchers thinking that the flexibility of those oxide ion sublattices must be important for conducting protons. Indeed, their previous studies in another class of proton conductors had shown how lattice flexibility impacts proton transport.

For their study, the researchers created a metric to quantify lattice flexibility across materials that they call “O…O fluctuation,” which measures the change in spacing between oxygen ions contributed by phonons at finite temperature. They also created a dataset of other material features that influence proton mobility and set out to quantify how important each one is for facilitating proton conduction.

“We were trying to better understand how protons move through these inorganic materials so that we can optimize them and improve the efficiency of downstream energy and computing applications,” Chung explains.

The researchers ranked the importance of all seven features they studied, which also included structural and chemical traits of materials, and trained a model on the findings to predict how well materials would conduct protons. The model found that the two most important features in predicting proton transfer barriers are the hydrogen bond length and the oxygen sublattice flexibility characterized by the O…O fluctuation metric. The shorter the hydrogen bond length, the better the material was at transporting protons, which aligned with previous studies of metal oxides. The researchers’ O…O fluctuation metric was the new and the second most important feature they studied. The more flexible the oxygen ion chains, the better the proton conduction.

Better proton conductors

The researchers believe their model could be used to estimate proton conduction across a broader range of materials.

“We always have to be cautious about generalizing findings, but the local chemistries and structures we studied have a wide enough spectrum that we think this finding is broadly applicable to a range of inorganic proton conductors,” Yildiz says.

Beyond being used to screen for promising materials, the researchers say their findings could also be used to train generative AI models to create materials optimized for proton transfer. As our understanding of materials improves, that could enable a new class of hyper-efficient clean energy technologies.

“There are very large materials databases generated recently in the field, for example those by Google and Microsoft, that could be screened for these relations we’ve found,” Yildiz says. “If the material compound that satisfies these parameters does not exist, we could also use these parameters to generate new compounds. That would enable increases in the energy efficiency and viability of clean energy conversion and low-power computing devices. For that, we need to figure out how to get more flexible oxide ion sublattices that are percolated. What are the composition and structure metrics that I can use to design the material to have that flexibility? Those are the next steps.”

The research was supported by the U.S. Department of Energy’s Energy Frontier Center – Hydrogen in Energy and Information Sciences – and the National Science Foundation’s Graduate Research Fellowship Program.

de MIT News https://ift.tt/RVTcO3l

Deep-learning model predicts how fruit flies form, cell by cell

During early development, tissues and organs begin to bloom through the shifting, splitting, and growing of many thousands of cells.

A team of MIT engineers has now developed a way to predict, minute by minute, how individual cells will fold, divide, and rearrange during a fruit fly’s earliest stage of growth. The new method may one day be applied to predict the development of more complex tissues, organs, and organisms. It could also help scientists identify cell patterns that correspond to early-onset diseases, such as asthma and cancer.

In a study appearing today in the journal Nature Methods, the team presents a new deep-learning model that learns, then predicts, how certain geometric properties of individual cells will change as a fruit fly develops. The model records and tracks properties such as a cell’s position, and whether it is touching a neighboring cell at a given moment.

The team applied the model to videos of developing fruit fly embryos, each of which starts as a cluster of about 5,000 cells. They found the model could predict, with 90 percent accuracy, how each of the 5,000 cells would fold, shift, and rearrange, minute by minute, during the first hour of development, as the embryo morphs from a smooth, uniform shape into more defined structures and features.

“This very initial phase is known as gastrulation, which takes place over roughly one hour, when individual cells are rearranging on a time scale of minutes,” says study author Ming Guo, associate professor of mechanical engineering at MIT. “By accurately modeling this early period, we can start to uncover how local cell interactions give rise to global tissues and organisms.”

The researchers hope to apply the model to predict the cell-by-cell development in other species, such zebrafish and mice. Then, they can begin to identify patterns that are common across species. The team also envisions that the method could be used to discern early patterns of disease, such as in asthma. Lung tissue in people with asthma looks markedly different from healthy lung tissue. How asthma-prone tissue initially develops is an unknown process that the team’s new method could potentially reveal.

“Asthmatic tissues show different cell dynamics when imaged live,” says co-author and MIT graduate student Haiqian Yang. “We envision that our model could capture these subtle dynamical differences and provide a more comprehensive representation of tissue behavior, potentially improving diagnostics or drug-screening assays.”

The study’s co-authors are Markus Buehler, the McAfee Professor of Engineering in MIT’s Department of Civil and Environmental Engineering; George Roy and Tomer Stern of the University of Michigan; and Anh Nguyen and Dapeng Bi of Northeastern University.

Points and foams

Scientists typically model how an embryo develops in one of two ways: as a point cloud, where each point represents an individual cell as point that moves over time; or as a “foam,” which represents individual cells as bubbles that shift and slide against each other, similar to the bubbles in shaving foam.

Rather than choose between the two approaches, Guo and Yang embraced both.

“There’s a debate about whether to model as a point cloud or a foam,” Yang says. “But both of them are essentially different ways of modeling the same underlying graph, which is an elegant way to represent living tissues. By combining these as one graph, we can highlight more structural information, like how cells are connected to each other as they rearrange over time.”

At the heart of the new model is a “dual-graph” structure that represents a developing embryo as both moving points and bubbles. Through this dual representation, the researchers hoped to capture more detailed geometric properties of individual cells, such as the location of a cell’s nucleus, whether a cell is touching a neighboring cell, and whether it is folding or dividing at a given moment in time.

As a proof of principle, the team trained the new model to “learn” how individual cells change over time during fruit fly gastrulation.

“The overall shape of the fruit fly at this stage is roughly an ellipsoid, but there are gigantic dynamics going on at the surface during gastrulation,” Guo says. “It goes from entirely smooth to forming a number of folds at different angles. And we want to predict all of those dynamics, moment to moment, and cell by cell.”

Where and when

For their new study, the researchers applied the new model to high-quality videos of fruit fly gastrulation taken by their collaborators at the University of Michigan. The videos are one-hour recordings of developing fruit flies, taken at single-cell resolution. What’s more, the videos contain labels of individual cells’ edges and nuclei — data that are incredibly detailed and difficult to come by.

“These videos are of extremely high quality,” Yang says. “This data is very rare, where you get submicron resolution of the whole 3D volume at a pretty fast frame rate.”

The team trained the new model with data from three of four fruit fly embryo videos, such that the model might “learn” how individual cells interact and change as an embryo develops. They then tested the model on an entirely new fruit fly video, and found that it was able to predict with high accuracy how most of the embryo’s 5,000 cells changed from minute to minute.

Specifically, the model could predict properties of individual cells, such as whether they will fold, divide, or continue sharing an edge with a neighboring cell, with about 90 percent accuracy.

“We end up predicting not only whether these things will happen, but also when,” Guo says. “For instance, will this cell detach from this cell seven minutes from now, or eight? We can tell when that will happen.”

The team believes that, in principle, the new model, and the dual-graph approach, should be able to predict the cell-by-cell development of other multiceullar systems, such as more complex species, and even some human tissues and organs. The limiting factor is the availability of high-quality video data.

“From the model perspective, I think it’s ready,” Guo says. “The real bottleneck is the data. If we have good quality data of specific tissues, the model could be directly applied to predict the development of many more structures.”

This work is supported, in part, by the U.S. National Institutes of Health.

de MIT News https://ift.tt/qJ4Xt2Z

A better DNA material for genetic medicine

To our immune system, a potentially lifesaving gene therapy can look a lot like a dangerous infection. That’s because most genetic medicine uses viruses or double-stranded DNA to deliver genetic information to target cells. DNA in its traditional double helix form can lead to toxic immune stimulation and be difficult to package into cellular delivery vehicles. As a result, the reach of genetic medicine is limited today.

Kano Therapeutics is taking a different approach to genetic therapies. The company is developing gene-editing technologies using circular single-stranded DNA (cssDNA), a biomolecule that is less toxic than double stranded DNA and more stable than RNA, and could be delivered more efficiently to many parts of the body to treat genetic diseases, cancers, and more.

The company, which was founded by former MIT postdoc Floris Engelhardt, professor of biological engineering Mark Bathe, and John Vroom MBA ’22, is developing a platform for manufacturing cssDNA of customized lengths and sequences, which could deliver genetic material to fix or replace faulty genes.

“We can work with CRISPR and other gene-editing technologies,” Engelhardt says. “CRISPR finds a location in a genome, binds to it, and cuts at that location. That allows you to edit a gene or stop a gene from functioning. But what if you have a loss-of-function disease where you need to insert a new piece of genetic code? Our approach allows you to replace whole genes or add genetic information.”

Making DNA flexible

Around 2019, Bathe’s lab published research describing ways to engineer the sequence and length of cssDNA molecules, which have been used in labs for decades but have increasingly drawn interest for improving gene therapies. Several pharmaceutical companies immediately reached out.

“Single-stranded DNA is a little like messenger RNA, which can code for any protein in any cell, tumor, or organ,” Bathe says. “It fundamentally encodes for a protein, so it can be used across diseases, including rare diseases that may only affect a few people in the country.”

Engelhardt had also worked on cssDNA as a PhD student in Munich. She met Bathe at a conference.

“We were considering collaborating on research,” Engelhardt recalls. “Then Mark heard I was finishing my PhD and said, ‘Wait a minute. Instead of collaborating, I should hire you.’”

Within 48 hours of submitting her PhD thesis, Engelhardt received an email asking her to apply to Bathe’s lab as a postdoc. She was drawn to the position because she would be focusing on research that had the potential to help patients.

“MIT is very good at creating industry-focused postdocs,” Engelhardt says. “I was inspired by the idea of doing postdoc work with the goal of spinning out a company, as opposed to doing solely academic-focused research.”

Bathe and Engelhardt learned from members of the pharmaceutical industry how single-stranded DNA could help overcome limitations in gene and cell therapies. Although CRISPR-based treatments have recently been approved for a few genetic diseases, CRISPR’s effectiveness has been limited by its potential toxicity and inefficient delivery to specific sites in the body. Also, those treatments can only be administered once because CRISPR often gets labeled as foreign by our immune systems and rejected from the body.

Engelhardt began exploring MIT’s resources to help commercialize her research. She met Vroom through an online “founder speed dating” event at MIT. She also received support from the Venture Mentoring Service, took classes at MIT’s Sloan School of Management, and worked with MIT’s Industrial Liaison Program. Early on, Bathe suggested Engelhardt work with MIT’s Technology License Office, something she says she tells every founder to do the moment they start thinking about commercializing their research.

In 2021, Kano won the $20,000 first place prize at the MIT Sloan Healthcare Innovation Prize (SHIP) to commercialize a new way to design and manufacture single-stranded DNA. Kano uses fermentation to produce its cssDNA less expensively than approaches based on chemical DNA synthesis.

“No one had the ability to access this type of genetic material, and so a lot of our work was around creating the highest-quality, economically scalable process to allow circular single-stranded DNA to be commercially viable,” Engelhardt says.

Engelhardt and Vroom began meeting with investors as soon as Engelhardt finished her postdoc work in 2021. The founders worked to raise money over the next year while Vroom finished his MBA.

Today, Kano’s circular ssDNA can be used to insert entire genes, up to 10,000 nucleotides long, into the body. Kano is planning to partner with pharmaceutical companies to make their gene therapies more targeted and potent. For instance, pharmaceutical partners could use Kano’s platform to join the CD19 and CD20 genes, which are expressed in certain tumor cells, and stipulate that only if both genes bind to a cell receptor do they enter that cell’s genome and make edits.

Overall, Engelhardt says working with circular single-stranded DNA makes Kano’s approach more flexible than platforms like CRISPR.

“We realized working with pharmaceutical companies early on in my postdoc there was a lack of design understanding because of the lack of access to these molecules,” Engelhardt says. “When it comes to gene or cell therapies, people just think of the gene itself, not the flanking sequences or anything else that goes around the gene. Now that the DNA isn’t stuck in a double helix all the time, I can create small, three-dimensional structures — think loops or hairpins — that work, for example, as a binding protein that pulls it into the nucleus. That unlocks a completely new path for DNA because it makes it engineerable — not only on a structural level but also a sequence level.”

Partnering for impact

To facilitate more partnerships, Kano is signing agreements with partners that give it a smaller percentage of eventual drug royalties but allow it to work with many companies at the same time. In a recent collaboration with Merck KGaA, Kano combined its circular cssDNA platform with the company’s lipid nanoparticles solutions for delivering gene therapies. Kano is also in discussions with other large pharmaceutical companies to jointly bring cancer drugs into the clinic over the next two years.

“That’s exciting because we’ll be implementing our DNA into partners’ drug system, so when they file their new drug and dose their first patients, our DNA is going to be the therapeutic information carrier for efficacy,” Engelhardt says. “As a first-time founder, this is where you want to go. We talk about patient impact all the time, and this is how we’re going to get it.”

Kano is also developing the first databank mapping cssDNA designs to activity, to speed up the development of new treatments.

“Right now, there is no understanding of how to design DNA for these therapies,” Engelhardt says. “Everyone who wants to differentiate needs to come up with a new editing tool, a new delivery tool, and there’s no connecting company that can enable those areas of expertise. When partners come to us, we can say, ‘The gene sequence is all yours.’ But often it’s not just about the sequence. It’s also about the promoter or flanking sequence that allows you to insert your DNA into the genome, or that makes DNA package well into your delivery nanoparticle. At Kano, we’re building the best knowledgebase to use DNA material to treat diseases.”

de MIT News https://ift.tt/e7bDxnu

Making clean energy investments more successful

Governments and companies constantly face decisions about how to allocate finite amounts of money to clean energy technologies that can make a difference to the world’s climate, its economies, and to society as a whole. The process is inherently uncertain, but research has been shown to help predict which technologies will be most successful. Using data-driven bases for such decisions can have a significant impact on allowing more informed decisions that produce the desired results.

The role of these predictive tools, and the areas where further research is needed, are addressed in a perspective article published Nov. 24 in Nature Energy, by professor Jessika Trancik of MIT’s Sociotechnical Systems Research Center and Institute of Data, Systems, and Society and 13 co-authors from institutions around the world.

She and her co-authors span engineering and social science and share “a common interest in understanding how to best use data and models to inform decisions that influence how technology evolves,” Trancik says. They are interested in “analyzing many evolving technologies — rather than focusing on developing only one particular technology — to understand which ones can deliver.” Their paper is aimed at companies and governments, as well as researchers. “Increasingly, companies have as much agency as governments over these technology portfolio decisions,” she says, “although government policy can still do a lot because it can provide a sort of signal across the market.”

The study looked at three stages of the process, starting with forecasting the actual technological changes that are likely to play important roles in coming years, then looking at how those changes could affect economic, social, and environmental conditions, and finally, how to apply these insights into the actual decision-making processes as they occur.

Forecasting usually falls into two categories, either data-driven or expert-driven, or a combination of those. That provides an estimate of how technologies may be improving, as well as an estimate of the uncertainties in those predictions. Then in the next step, a variety of models are applied that are “very wide ranging,” Trancik says, “different models that cover energy systems, transportation systems, electricity, and also integrated assessment models that look at the impact of technology on the environment and on the economy.”

And then, the third step is “finding structured ways to use the information from predictive models to interact with people that may be using that information to inform their decision-making process,” she says. “In all three of these steps, how you need to recognize the vast uncertainty and tease out the predictive aspects. How you deal with uncertainty is really important.”

In the implementation of these decisions, “people may have different objectives, or they may have the same objective but different beliefs about how to get there. And so, part of the research is bringing in this quantitative analysis, these research results, into that process,” Trancik says. And a very important aspect of that third step, she adds, is “recognizing that it’s not just about presenting the model results and saying, ‘here you go, this is the right answer.’ Rather, you have to bring people into the process of designing the studies and interacting with the modeling results.”

She adds that “the role of research is to provide information to, in this case, the decision-making processes. It’s not the role of the researchers to push for one outcome or another, in terms of balancing the trade-offs,” such as between economic, environmental, and social equity concerns. It’s about providing information, not just for the decision-makers themselves, but also for the public who may influence those decisions. “I do think it’s relevant for the public to think about this, and to think about the agency that actually they could have over how technology is evolving.”

In the study, the team highlighted priorities for further research that needs to be done. Those priorities, Trancik says, include “streamlining and validating models, and also streamlining data collection,” because these days “we often have more data than we need, just tons of data,” and yet “there’s often a scarcity of data in certain key areas like technology performance and evolution. How technologies evolve is just so important in influencing our daily lives, yet it’s hard sometimes to access good representative data on what’s actually happening with this technology.” But she sees opportunities for concerted efforts to assemble large, comprehensive data on technology from publicly available sources.

Trancik points out that many models are developed to represent some real-world process, and “it’s very important to test how well that model does against reality,” for example by using the model to “predict” some event whose outcome is already known and then “seeing how far off you are.” That’s easier to do with a more streamlined model, she says.

“It’s tempting to develop a model that includes many, many parameters and lots of different detail. But often what you need to do is only include detail that’s relevant for the particular question you’re asking, and that allows you to make your model simpler.” Sometimes that means you can simplify the decision down to just solving an equation, and other times, “you need to simulate things, but you can still validate the model against real-world data that you have.”

“The scale of energy and climate problems mean there is much more to do,” says Gregory Nemet, faculty chair in business and regulation at the University of Wisconsin at Madison, who was a co-author of the paper. He adds, “while we can’t accurately forecast individual technologies on their own, a variety of methods have been developed that in conjunction can enable decision-makers to make public dollars go much further, and enhance the likelihood that future investments create strong public benefits.”

This work is perhaps particularly relevant now, Trancik says, in helping to address global challenges including climate change and meeting energy demand, which were in focus at the global climate conference COP 30 that just took place in Brazil. “I think with big societal challenges like climate change, always a key question is, ‘how do you make progress with limited time and limited financial resources?’” This research, she stresses, “is all about that. It’s about using data, using knowledge that’s out there, expertise that’s out there, drawing out the relevant parts of all of that, to allow people and society to be more deliberate and successful about how they’re making decisions about investing in technology.”

As with other areas such as epidemiology, where the power of analytical forecasting may be more widely appreciated, she says, “in other areas of technology as well, there’s a lot we can do to anticipate where things are going, how technology is evolving at the global or at the national scale … There are these macro-level trends that you can steer in certain directions, that we actually have more agency over as a society than we might recognize.”

The study included researchers in Massachusetts, Wisconsin, Colorado, Maryland, Maine, California, Austria, Norway, Mexico, Finland, Italy, the U.K., and the Netherlands. 

de MIT News https://ift.tt/wh3Jscm

President Tharman Shanmugaratnam of Singapore visits MIT

President Tharman Shanmugaratnam of the Republic of Singapore visited MIT on Tuesday, meeting campus leaders while receiving the Miriam Pozen Prize and delivering a lecture on fiscal policy at the MIT Sloan School of Management.

“We really have to re-orient fiscal policy and develop new fiscal compacts,” said Tharman in his remarks, referring to the budget policy challenges countries face at a time of expanding government debt.

His talk, “The Compacts We Need: Fiscal Choices and Risk-sharing for Sustained Prosperity,” was delivered before a capacity audience of students, faculty, administrators, and staff at MIT’s Samberg Center.

Tharman is a trained economist who for many years ran Singapore’s central bank and has become a notable presence in global policymaking circles. Presenting a crisp summary of global trends, he observed that debt levels in major economies are at or beyond levels once regarded as unsustainable.

“There is no realistic solution to putting government debts back on a sustainable path other than having to make major adjustments to taxes and spending,” he said. However, he emphasized that his remarks were distinctly not “a call for austerity.” Instead, as he outlined, well-considered public investment can reduce the need for additional spending and thus be fiscally sound over time.

For instance, he noted, sound policy approaches can reduce individuals’ health care needs by better providing the conditions in which people stay healthy. Lowering some of these individual burdens and investing in community-building policies can help society both fiscally and by enhancing social solidarity.

“The challenge is to make these adjustments while re-fashioning fiscal policy so that people can see the adjustments — they can see the value in government spending that their taxes are contributing to — and to make adjustments in a way that doesn’t reduce growth,” Tharman said. “You do need growth for solidarity.”

In this sense, he proposed, “We need new fiscal compacts, new retirement compacts, and new global compacts to address the risks that are posed in the minds of individuals, as well as the largest risks” in society. Countries are vulnerable to a variety of shocks, he noted, calling climate change the “defining challenge of our time.” And yet, he added, for all of this, sensible policymaking can encourage people, creating more support for public-minded governance.

“It is that sharing of hopes and aspirations that is at the heart of true solidarity, not the sharing of fears,” Tharman concluded.

Before the lecture, Tharman was greeted by MIT Provost Anantha Chandrakasan, who presented him with a small gift from the MIT Glass Lab, and MIT Sloan Dean Richard Locke. Locke then made welcoming remarks at the event, praising Tharman’s “remarkable leadership in international financial policy, among other things.” After the lecture, Tharman also met with a group of MIT students from Singapore.

The Miriam Pozen Prize is awarded every two years by the MIT Golub Center for Finance and Policy, part of MIT Sloan. The prize, which recognizes extraordinary contributions to financial policy, was created to draw attention to the important research on financial policy conducted at the Golub Center, whose mission is to support research and educational initiatives related to governments’ roles as financial institutions and as regulators of the global financial system. It is named for the mother of MIT Sloan Senior Lecturer Robert C. Pozen, who is also the former executive chairman of MFS Investment Management, and a former vice chairman of Fidelity Investments and president of Fidelity Management and Research Company.

In introductory remarks. Robert Pozen said he was “deeply honored” to present the prize, adding, “It’s very unusual to have someone who is both a brilliant economist and an effective political leader, and that combination is exactly what we’re trying to honor and recognize.”

The previous recipients of the award are Mario Draghi PhD ’77, the former prime minister of Italy and president of the European Central Bank; and the late Stanley Fischer PhD ’69, an influential MIT economist who later became governor of the Bank of Israel, and then vice-chairman of the U.S. Federal Reserve. Draghi received the honor in 2023, and Fischer in 2021.

Tharman was first elected to his current office in 2023. In Singapore, he previously served as, among other roles, deputy prime minister, minister for finance, minister for education, and chairman of the Monetary Authority of Singapore.

Tharman holds a BA in economics from the London School of Economics, an MA in economics from the University of Cambridge, and an MPA from the Harvard Kennedy School at Harvard University.

MIT and Singapore have developed a sustained and productive relationship in research and education over the last quarter-century. The Singapore-MIT Alliance for Research and Technology (SMART), formally launched in 2007, is MIT’s first research center located outside of the United States, featuring work in several interdisciplinary areas of innovation.

The MIT-Singapore program also provides MIT students with research, work, and educational opportunities in Singapore. Additionally, MIT Institute Professor Emeritus Thomas Magnanti, who was present at Tuesday’s event, was the founding president of the Singapore University of Technology and Design, in 2009.

Tuesday’s event also had introductory remarks from Deborah J. Lucas, Sloan Distinguished Professor of Finance at MIT Sloan and director of the MIT Golub Center for Finance and Policy; Peter Fischer, Golub Distinguished Senior Fellow at MIT Sloan and a former under secretary in the U.S. Treasury Department; and Robert C. Merton, School of Managament Distinguished Professor of Finance at MIT Sloan.

In her comments, Lucas said that Tharman “personifies the qualities the award was created to honor,” while Fischer cited his emphasis on “the betterment of humankind.”

Merton praised Tharman’s “deep commitment for advancing financial policy in a way that serves both national and global arenas.” He added: “You have always believed that policy is not just about numbers, but about people. And that sound financial [policies] serve the many, not just the few.”

de MIT News https://ift.tt/Rlztacn

New method improves the reliability of statistical estimations

Let’s say an environmental scientist is studying whether exposure to air pollution is associated with lower birth weights in a particular county.

They might train a machine-learning model to estimate the magnitude of this association, since machine-learning methods are especially good at learning complex relationships.

Standard machine-learning methods excel at making predictions and sometimes provide uncertainties, like confidence intervals, for these predictions. However, they generally don’t provide estimates or confidence intervals when determining whether two variables are related. Other methods have been developed specifically to address this association problem and provide confidence intervals. But, in spatial settings, MIT researchers found these confidence intervals can be completely off the mark.

When variables like air pollution levels or precipitation change across different locations, common methods for generating confidence intervals may claim a high level of confidence when, in fact, the estimation completely failed to capture the actual value. These faulty confidence intervals can mislead the user into trusting a model that failed.

After identifying this shortfall, the researchers developed a new method designed to generate valid confidence intervals for problems involving data that vary across space. In simulations and experiments with real data, their method was the only technique that consistently generated accurate confidence intervals.

This work could help researchers in fields like environmental science, economics, and epidemiology better understand when to trust the results of certain experiments.

“There are so many problems where people are interested in understanding phenomena over space, like weather or forest management. We’ve shown that, for this broad class of problems, there are more appropriate methods that can get us better performance, a better understanding of what is going on, and results that are more trustworthy,” says Tamara Broderick, an associate professor in MIT’s Department of Electrical Engineering and Computer Science (EECS), a member of the Laboratory for Information and Decision Systems (LIDS) and the Institute for Data, Systems, and Society, an affiliate of the Computer Science and Artificial Intelligence Laboratory (CSAIL), and senior author of this study.

Broderick is joined on the paper by co-lead authors David R. Burt, a postdoc, and Renato Berlinghieri, an EECS graduate student; and Stephen Bates an assistant professor in EECS and member of LIDS. The research was recently presented at the Conference on Neural Information Processing Systems.

Invalid assumptions

Spatial association involves studying how a variable and a certain outcome are related over a geographic area. For instance, one might want to study how tree cover in the United States relates to elevation.

To solve this type of problem, a scientist could gather observational data from many locations and use it to estimate the association at a different location where they do not have data.

The MIT researchers realized that, in this case, existing methods often generate confidence intervals that are completely wrong. A model might say it is 95 percent confident its estimation captures the true relationship between tree cover and elevation, when it didn’t capture that relationship at all.

After exploring this problem, the researchers determined that the assumptions these confidence interval methods rely on don’t hold up when data vary spatially.

Assumptions are like rules that must be followed to ensure results of a statistical analysis are valid. Common methods for generating confidence intervals operate under various assumptions.

First, they assume that the source data, which is the observational data one gathered to train the model, is independent and identically distributed. This assumption implies that the chance of including one location in the data has no bearing on whether another is included. But, for example, U.S. Environmental Protection Agency (EPA) air sensors are placed with other air sensor locations in mind.

Second, existing methods often assume that the model is perfectly correct, but this assumption is never true in practice. Finally, they assume the source data are similar to the target data where one wants to estimate.

But in spatial settings, the source data can be fundamentally different from the target data because the target data are in a different location than where the source data were gathered.

For instance, a scientist might use data from EPA pollution monitors to train a machine-learning model that can predict health outcomes in a rural area where there are no monitors. But the EPA pollution monitors are likely placed in urban areas, where there is more traffic and heavy industry, so the air quality data will be much different than the air quality data in the rural area.

In this case, estimates of association using the urban data suffer from bias because the target data are systematically different from the source data.

A smooth solution

The new method for generating confidence intervals explicitly accounts for this potential bias.

Instead of assuming the source and target data are similar, the researchers assume the data vary smoothly over space.

For instance, with fine particulate air pollution, one wouldn’t expect the pollution level on one city block to be starkly different than the pollution level on the next city block. Instead, pollution levels would smoothly taper off as one moves away from a pollution source.

“For these types of problems, this spatial smoothness assumption is more appropriate. It is a better match for what is actually going on in the data,” Broderick says.

When they compared their method to other common techniques, they found it was the only one that could consistently produce reliable confidence intervals for spatial analyses. In addition, their method remains reliable even when the observational data are distorted by random errors.

In the future, the researchers want to apply this analysis to different types of variables and explore other applications where it could provide more reliable results.

This research was funded, in part, by an MIT Social and Ethical Responsibilities of Computing (SERC) seed grant, the Office of Naval Research, Generali, Microsoft, and the National Science Foundation (NSF).

de MIT News https://ift.tt/zRNg38A