In a study published on Tuesday, Oct. 31, that funded by the Tobacco Center for Regulatory Science through grants from the National Institutes of Health and the U.S. Food and Drug Administration, researchers from Yale, the University of Missouri and Georgetown University analyzed retail sales from 2018 to 2023 and found that restricting flavored e-cigarettes increased conventional cigarette sales. As research has shown that traditional cigarettes are more dangerous than electronic cigarettes, current regulations against flavored electronic cigarettes may pose a public health threat, according to the new study. The research also notes that traditional cigarette sales have increased disproportionately for brands most often used by underage youth. 

“As smoking’s health harms increase with the intensity of use, evidence that e-cigarette flavor restrictions yield an additional 15 cigarettes purchased for every 1 less 0.7mL e-cigarette pod sold suggests that these policies’ public health costs may outweigh their benefits,” Abigail Friedman, an assistant professor at the Yale School of Public Health, wrote to the News.

Both e-cigarettes and traditional cigarettes contain nicotine, which is an addictive substance, according to the NIH National Institute on Drug Abuse. But only traditional cigarettes have tar, which contains particles that can cause cancer and reduce the lung’s ability to absorb oxygen. 

Tar also damages the small hairs, or cilia, that help protect people’s lungs from dirt and infection, according to Alex C. Liber, an assistant professor at Georgetown University’s School of Medicine. He said that the saying “people smoke for the nicotine and die from the tar” is famous in the field. 

“The cigarette is the most dangerous consumer product ever created by man,” Liber told the News. “E-cigarettes are not as dangerous, at least based on the evidence we have.”

Liber also expressed concerns about the Food and Drug Administration establishing policies that indirectly encourage smokers to use traditional cigarettes instead of e-cigarettes. 

The Hill reported last week that the Biden Administration is looking to propose a ban on menthol and flavored cigarettes, saying that the FDA sent the rule to the White House for review in mid-October. 

The FDA has implemented a Premarket Tobacco Approval Process, requiring all tobacco products to be approved by the FDA before they are marketed. 

“I personally think e-cigarettes are over-regulated to the point that it is detrimental to public health,” Michael Pesko, professor of economics at the University of Missouri, told the News. “It’s odd that a lot of places don’t allow menthol e-cigarettes but they do allow menthol cigarettes to be sold. It’s unusual that we would regulate the less harmful product more.”

Friedman, Liber and Pesko said they hope that the FDA will take this new study into consideration when designing future regulation for electronic cigarette products. 

James McKinney, an FDA spokesman, told the News “the FDA does not comment on specific studies.” 

According to their website, The Tobacco Center Regulatory Science program “helps inform and assess FDA’s ongoing and potential regulatory activities.”

“This is high quality evidence that e-cigarettes as commercial products with flavors have the positive effect of reducing combustible use that would otherwise be occurring,” Pesko told the News. “[The FDA] hasn’t approved any flavored e-cigarettes yet. That might be a little short sighted.”

In 2022, 173.5 billion cigarettes were sold to retailers in the United States. 

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The genome editing platform, which uses CRISPR-Cas9 technology, was developed in a collaboration between neurosurgery professor Jiangbing Zhou and genetics professor Yong-Hui Jiang. It is designed to deliver cures for two rare genetic brain diseases: Angelman syndrome and HIST1H1E syndrome.

The grant to develop the platform has two phases. The first, worth $26.5 million, will fund the technology for testing in non-human primates, during which the team will apply for approval from the Food and Drug Administration for the gene therapy delivery platform. In the second phase, which is worth $13.4 million, both the Foundation for Angelman Syndrome Therapeutics and Rush University Medical Center — which specialize in bringing technologies from the lab to patients — will begin clinical trials.

“This grant supports the translation of promising technologies from the laboratory into the clinic, where it can directly benefit patients — known as ‘bench to bedside’ — which is the hallmark of FAST’s unique patient advocacy strategy,” Alana Newhouse, president of FAST, wrote to the News. “The group, the largest funder of Angelman syndrome research in the world, is dedicated to bringing effective treatment into current medical practice.” 

According to the NIH, Angelman syndrome affects the nervous system, causing delayed development and seizures. HIST1H1E syndrome, which is more rare than Angleman syndrome, can cause intellectual disability and heart anomalies. Both diseases are diagnosed in children.

The grant will fund a new gene therapy technology called stimuli-responsive traceless engineering platform, which supports the delivery of molecules called ribonucleoproteins throughout the brain. This platform, according to experts the News interviewed, could cure diseases in the brain through a one-time treatment. 

Zhoe developed the technology, and Jiang tested it in mouse models. Their labs will continue to work together on the grant. 

“This is really a fruitful collaboration between myself, a biomedical engineer, and Yong-Hui, a physician scientist who has a lot of knowledge in disease modeling and clinical translation and first line experience dealing with patients with neurogenetic diseases,” Zhou wrote to the News. 

In the past, researchers have attempted to deliver gene therapy to the brain using two methods: viral vectors and nanoparticles. 

However, viral vectors remain in cells long after reaching them. Viral vectors can continue to cut and unintentionally edit the genome, making them a dangerous cancer risk, according to Zhou and Jiang. 

Nanoparticles are less dangerous, but they are too large to reach the brain. At 100 to 200 nanometers across, they can not pass the blood-brain barrier and reach the brain cells, Jiang said. 

In contrast, the STEP delivery platform uses molecules that are only 12 to 14 nanometers in diameter, allowing them to disperse through the brain with ease. 

Zhou told the News that the platform for drug delivery he designed is versatile and can be applied to over three thousand different neurogenetic diseases.

“We hope to characterize the delivery system as a platform and if successful we can apply the same or similar systems for other neurogenetic diseases,” Zhou wrote to the News. “We are actually developing similar therapies for a few other diseases, including Alzheimer’s disease, at this moment.”

Jiang, who designed the mouse model for Angelman syndrome that is now widley used in research in his lab 20 years ago, also spoke about the potential impact of the gene delivery technology. 

There are some diseases, he said, that can be treated with the insertion or deletion of genetic information in a single location. Through a combination of the new delivery platform and existing CRISPR-Cas-9 gene editing technology, those diseases could be cured.

After the platform is FDA approved, only the targeting molecules that CRISPR uses to find specific genes would need to be switched out to cure a new disease, Zhou said. 

“There are at least a few hundred diseases for sure which may be cured,” Jiang told the News.

He said he hopes this will make treatments for neurogenetic diseases more accessible for patients. 

Zhou described the possibility of getting approval for the swapping mechanism as being similar to the COVID-19 vaccine approval process. While the first vaccine was difficult to get approved, the boosters were not, since they use the same underlying technology. 

For the researchers involved, treating these genetic diseases can be personal. Jiang, in addition to working in the lab, is a doctor who helps treat patients with Angelman and HIST1H1E syndromes. He spoke to the News after a full day at work. 

“I am a physician, and I see all these patients in my clinic,” Jiang said. “I really connect to these families.”

Clinical psychologist James McPartland, the director of the Yale Developmental Disabilities Clinic, will be working on the grant in its second phase once the gene editing platform is being tested in humans.

According to McPartland, the research the NIH grant funds could play a major role to help those affected by the genetic diseases.

“I got an email from a mom of a child with Angelman syndrome this morning, and it said ‘let’s cure Angelmans’, and I think that’s the goal of this kind of work,” he said.  “For a clinical psychologist doing research on the outside of human skulls using EEG, this is science fiction — it’s very exciting to be even a small part of it.”

Angelman syndrome affects 500,000 individuals worldwide. 

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Following the film’s screening, Edwards joined Ted Wittenstein ’04 LAW ’12, lecturer in Global Affairs and the executive director of the Jackson School’s International Security Studies research hub, for a discussion about the movie. The event was hosted in partnership with the Schmidt Program on Artificial Intelligence and Emerging Technologies and the Yale Film Society.

The film, which was released in theaters Friday, envisions a future war between humans and advanced artificial intelligence robots. 

“It was noteworthy that [Edwards] was eager to visit Yale and engage with our students on the eve of a major studio release, ” Wittenstein wrote to the News. “I was impressed with Gareth Edwards’ creative vision, and his desire to make a film that not only was commercially successful but also thought-provoking on questions of AI ethics, machine intelligence, and human consciousness.”

While the topic of artificial intelligence feels significant in today’s national conversation, Edwards told the News, he envisions the film as an allegorical tool to address tribalism in human society. 

Edwards said that the film is about having empathy for people that are different.

“It’s not really about technology,” he said. “It is really about humans.” 

Edwards described being influenced by the popular science documentary series, Q.E.D., which he watched as a child. In one episode, he recalled, children were arbitrarily given armbands colored red and blue without being told why. On the first day, the playground was evenly colored with red and blue bands. 

By the third day, all the children with red armbands were on one side of the playground, and all children with blue armbands were on the other. 

“We have this thing inside us to connect most to people that are most similar to us and ban together against the people that are most different.” Edwards told the News. “It probably helped us survive for millions of years, but now it’s a problem. We are smart enough that we should be able to see past it, but we keep doing it.”

Prior to the screening, Nydia del Carmen ’26, president of the Yale Film Society and also a YTV editor for the News, moderated a conversation with Edwards at a Pierson College Tea. 

At the tea, Edwards spoke about his journey in the film industry.  

“Interviewing Gareth was a dream come true,” del Carmen said. “Gareth emphasized the failures he had to endure to get to where he was. I think that really resonated with a lot of young filmmakers within the event. At least for my part it was very inspiring to hear.”

Edwards described his career trajectory, including his background as an independent film enthusiast in central England, his days as a special effects artist working for the BBC and his work on his first major blockbuster, “Godzilla” in 2014.

Edwards spoke to film majors hoping to break into the industry at the tea. According to the director, who graduated from the Surrey Institute of Art & Design, film school is not a prerequisite to making movies — students can rent a camera and start shooting at any time, he said.

“It’s like there’s nothing stopping anyone now.” Edwards said. “I think [film is] really democratized.”

For Edwards, the freedom of directing lower-budget films is what drew him to “The Creator,” After directing the Star Wars film “Rogue One,” Edwards said he wanted to write and direct his own project, without the constraints of a franchise. 

Compared to the hundreds of millions of dollars he had to work with during “Rogue One,” he said, the “The Creator” operated with a relatively small $18 million.

“He was a terrific verbal storyteller,” Matthew Siff  ’25, who attended both the Pierson College Tea and the pre-screening, told the News.

When Edwards wrote the script for “The Creator,” he said he initially thought that the concept of sentient artificial intelligence was “a distant dream.” 

Audiences will watch the film in a world familiar with language models like ChatGPT and rapid advances in artificial technology. For Wittenstein, “The Creator” may indicate a rising social anxiety around AI technology and U.S. geopolitical competition with China. 

“[The film] underscores the importance of developing AI systems that are reliable, safe, and aligned with human values,” Wittenstein said. “Film as a medium – especially science fiction, for which Gareth Edwards has gained world renown — can serve as an important vehicle for reflection on the trends in technology that are shaping our world.”

Edwards, however, said he is unsure of what the consequences of evolving artificial intelligence may be. Edwards said he is fascinated by the concept of creating artificial intelligence that could think like a human. 

He said he believes that the next phase of machine learning will involve the creation of more sophisticated algorithms inspired by human brain chemistry — ones that could resemble human consciousness.

“I think [consciousness is] replicable,” Edwards said. “It might be a hundred years or a thousand years or next year and there will be a consciousness we will be able to interact with that’s not biological.”

Edwards said that even now he feels it can be difficult to draw a line between real human consciousness and software. 

He said that this is particularly true with AI chatbots. 

“I play with ChatGPT and I get convinced there is someone there,” Edwards said. “It makes you question, maybe that’s all we are. Just a load of neuron networks. And I think that’s why people find it so concerning: it’s sort of holding a mirror up to ourselves, and showing that maybe we are not special.”

“The Creator” was filmed in eight countries including Nepal, Cambodia and Thailand.

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The watch on your wrist ticks steadily throughout the day, collecting and transmitting information about your heart rate, oxygen saturation and the levels of sugar in your blood. Sensors scan your face and body, making inferences about your state of health.

By the time you see a doctor, algorithms have already synthesized this data and organized it in ways that fit a diagnosis, detecting health problems before symptoms arise. 

We aren’t there yet, but, according to Harlan Krumholz, a professor of medicine at the School of Medicine, this could be the future of healthcare powered by artificial intelligence.

“This is an entirely historic juncture in the history of medicine,” Krumholz said. “What we’re going to be able to do in the next decades, compared to what we have been able to do, is going to be fundamentally different and much better.” 

Over the past months, Yale researchers have published a variety of papers on machine learning in medicine, from wearable devices that can detect heart defects to algorithms that can triage COVID-19 patients. Though much of this technology is still in development, the rapid surge of AI innovation has prompted experts to consider how it will impact healthcare in the near future. 

Questions remain about the reliability of AI conclusions, the ethics of using AI to treat patients and how this technology might transform the healthcare landscape. 

Synergy: human and artificial intelligence at Yale

Two recent Yale studies highlight what the future of AI-assisted health care could look like. 

In August, researchers at the School of Medicine developed an algorithm to diagnose aortic stenosis, a narrowing of a valve in the body’s largest blood vessel. Currently, diagnosis usually entails a preliminary screening by the patient’s primary care provider and then a visit to the radiologist, where the patient must undergo a diagnostic doppler exam.

The new Yale algorithm, however, can diagnose a patient from just an echocardiogram performed by a primary care doctor.

“We are at the cusp of doing transformative work in diagnosing a lot of conditions that otherwise we were missing in our clinical care,” said Dr. Rohan Khera, senior author of the study and clinical director of the Yale Center for Outcomes Research & Evaluation, CORE. “All this work is powered by patients and their data, and how we intend to use it is to give back to the most underserved communities. That’s our big focus area.”

The algorithm was also designed to be compatible with cheap and accessible handheld ultrasound machines, said lead author Evangelos Oikonomou, a clinical fellow at the School of Medicine. This would bring first-stage aortic stenosis testing to the community, instead of being limited to those that are referred to a skilled and potentially expensive radiologist. It could also allow the disease to be diagnosed before symptoms arise. 

In a second study, researchers used AI to support physicians in hospitals by predicting COVID-19 outcomes for emergency room patients — all within 12 hours. 

According to first author Georgia Charkoftaki, an associate research scientist at the Yale School of Public Health, hospitals often run out of beds during COVID-19 outbreaks. AI-powered predictions could help determine which patients need inpatient care and which patients can safely recover at home.

The algorithm is also designed to be adaptable to other diseases. 

“When [Respiratory Syncytial Virus] babies come to the ICU, they are given the standard of care, but not all of them respond,” Charkoftaki said. “Some are intubated, others are out in a week. The symptoms [of RSV] are similar to COVID and so we are working on a study for clinical metabolomics there as well.”

However, AI isn’t always accurate, Charkoftaki admitted.

As such, Charkoftaki said that medical professionals need to use AI “in a smart way.” 

“Don’t take it blindly, but use it to benefit patients and the discovery of new drugs,” Charkoftaki told the News. “You always need a brain behind it.” 

Machines in medicine

Though the concept of artificial intelligence has existed since mathematician Alan Turing’s work in the 1950s, the release of ChatGPT in November 2022 brought AI into public conversation. The chatbot garnered widespread attention, reaching over 100 million users in two months.

According to Lawrence Staib ENG ’90, a professor of radiology and biomedical engineering, AI-powered healthcare does not yet consist of asking a sentient chatbot medical questions. Staib, who regularly uses machine learning models in his research with medical imaging, says AI interfaces are more similar to a calculator: users input data, an algorithm runs and it generates an output, like a number, image, or cancer stage. The use of these algorithms is still relatively uncommon in most medical fields.

While the recent public conversation on AI has centered around large language models — programs like ChatGPT which are trained to understand text in context rather than as isolated words — these algorithms are not the focus of most AI innovation in healthcare, Staib said. 

Instead, researchers are using machine learning in healthcare to recognize patterns humans would not detect. When trained on large databases, machine learning models often identify “hidden signals,” said David van Dijk, an assistant professor of medicine and computer science. In his research, van Dijk works to develop novel algorithms for discovering these hidden signals, which include biomarkers and disease mechanisms, to diagnose patients and determine prognosis. 

“You’re looking for something that’s hidden in the data,” van Dijk said. “You’re looking for signatures that may be important for studying that disease.” 

Staib added that these hidden signals are also found in medical imaging. 

In a computerized tomography — or CT — scan, for example, a machine learning algorithm can identify subtle elements of the image that even a trained radiologist might miss. 

While these pattern recognition algorithms could be helpful in analyzing patient data, it is sometimes unclear how they arrive at conclusions and how reliable those conclusions are. 

“It may be picking up something, and it may be pretty accurate, but it may not be clear what it’s actually detecting,” Staib cautions.

One famous example of that ambiguity occurred at the University of Washington, where researchers designed a machine learning model to distinguish between wolves and huskies. Since all the images of wolves were taken in snowy forests and all the images of huskies were taken in Arizona, the model learned to identify the species based on their environment. When the algorithm was given an image of a husky in the snow, it was always classified as a wolf. 

To address this issue, researchers are working on explainable artificial intelligence: the kind of program, Staib said, that “not only makes a judgment, but also tells you how it made that judgment or how confident it is in that judgment.”

Experts say that the goal of a partnership between human experts and AI is to reduce human error and clarify AI’s judgment process. 

“In medicine, well-intended practitioners still sometimes miss key pieces of information,” Krumholtz said.

Algorithms, Krumholtz said, can make sure that nothing “falls through the cracks.” 

But he added the need for human oversight will not go away. 

“Ultimately, medicine still requires intense human judgements,” he said. 

Big data and its pitfalls

The key to training a successful machine-learning model is data — and lots of it. But where this data comes from and how it is used can raise ethical questions, said Bonnie Kaplan, a professor of biostatistics and faculty affiliate at the Solomon Center for Health Law and Policy at Yale Law School.

The Health Insurance Portability and Accountability Act, or HIPPA, regulates patient data collected in healthcare institutions, such as hospitals, clinics, nursing homes and dentists offices, Kaplan said. If this data is scrubbed of identifying details, though, health institutions can sell it without patient consent. 

This kind of scrubbed patient information constitutes much of the data with which health-related machine learning models are trained. 

Still, health data is collected in places beyond healthcare institutions, like on period tracking apps, genetics websites and social media. Depending on the agreements that users sign — knowingly or not — to access these services, related health data can be sold with identifying information and without consent, experts say. And if scrubbed patient data is combined with this unregulated health data, it becomes relatively easy to identify people, which in turn poses a serious privacy risk.

“Healthcare data can be stigmatizing,” Kaplan told the News. “It can be used to deny insurance or credit or employment.”

For researchers, AI in healthcare raises other questions as well: who is responsible for regulating it, what privacy protections should be in place and who is liable if something goes wrong.

Kaplan said that while there’s a “general sense” of what constitutes ethical AI usage, “how to achieve [it], or even define the words, is not clear.”

While some, like Krumholz, are optimistic about the future of AI in healthcare, others like Kaplan point out that much of the current discourse remains speculative. 

“We’ve got all these promises that AI is going to revolutionize healthcare,” Kaplan said. “I think that’s overblown, but still very motivating. We don’t get those utopian dreams, but we do get a lot of great stuff.”

Sixty million people use ChatGPT every day.

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AAAS is the world’s largest multidisciplinary scientific society, with individual members from over 91 countries. The institution is also a leading publisher of cutting-edge research through its Science journal family. In a tradition dating back to 1874, the AAAS council annually recognizes remarkable scientists, innovators and engineers from a variety of disciplines to be fellows. 

The new fellows from Yale are Liza Comita, Enrique De La Cruz, Erika Edwards, Vanessa Ezenwa, Eduardo Fernandez-Duque, David Lewkowicz and Priyamvada Natarajan. 

“To me, recognition from AAAS means that my fellow scientists think the work we are doing in my laboratory is advancing knowledge in my field,” wrote Vanessa Ezenwa, Yale Professor of Ecology and Evolutionary Biology, in an email to the News. “This is what I strive to do every day as a scientist, so it’s an honor to be recognized for it.”

Ezenwa studies how parasites interact with their hosts in their natural environment, providing insight into how infectious diseases work. Since most novel human diseases originate in animals, studying infectious diseases in the wild is critical to determining how new human diseases are likely to emerge.

In addition to Ezenwa, one other of Yale’s seven newly recognized AAAS fellows is also a member of  the ecology and evolutionary biology department.

Erika Edwards, professor of ecology and evolutionary biology and curator of botany at the Peabody Museum of Natural History, is currently in Argentina collecting plant samples. She studies the evolution of photosynthetic metabolism, or how so many plant lineages independently adapted to transform light, water and carbon dioxide into sugar.

“I especially love that we have such a great cohort of new fellows at Yale this year — and I’m proud of my dept (EEB) for having two new fellows at once!” Edwards wrote in an email to the News.

Among the additional Yale fellows include two departmental chairs.

Priyamvada Natarajan, the chair of the department of astronomy, studies the formation and function of supermassive black holes and the mapping of dark matter in galaxies.

Enrique De La Cruz, chair of the department of molecular biophysics and biochemistry and head of Branford College, researches actin cytoskeleton, molecular motor proteins and nucleotide signaling enzymes.

Another leader in her field, professor of tropical forest ecology Liza Comita is the co-director of the Yale Center for Natural Carbon Capture. She studies the ecological patterns that drive biodiversity in pristine and human-altered tropical forests, combining field studies and statistical techniques.

The final two newly recognized AAAS fellows research social interactions. 

David Lewkowicz, adjunct professor in the Yale Child Study Center, researches how basic perceptual and attention skills contribute to the development of speech and language, providing a basis for new therapeutic interventions for autism. 

Eduardo Fernandez-Duque, professor of anthropology, studies the pair-bonding, sexual monogamy and biparental care behavior of owl-monkeys. Through observing live-primates he hopes to understand the evolution of human behavior.

“This is recognition not of me, but of everything we have done,” Fernandez-Duque said. “This is an acknowledgement to how this is a project that has established itself, that has an international recognition, that is contributing to science and all that makes it more likely that my younger colleagues will continue this work.”

The new AAAS fellows will receive a certificate and pin to commemorate their election in Washington, D.C. later this year.

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Until now, it was an open question of how these concentrations were achieved, but Yale scientists have quantitatively modeled the journey of elemental isotopes from the Earth’s core, up to its mantle and finally to its crust, accurately predicting the geochemistry of the islands. On Jan. 17, the Yale team of Jun Korenaga, professor of earth and planetary sciences, and doctoral student Amy Ferrick published a paper in The Proceedings of the National Academy of Sciences, which is the first paper to quantitatively illustrate how both tungsten and helium isotopes can travel from the core to the crust of the earth via diffusion, forming oceanic island basalt.

“We showed that the core-mantle diffusion quantitatively transports tungsten and helium isotopes to almost exactly match the geochemistry of the hotspot islands,” Korenaga told the News.

In rocks, some elemental isotopes, including helium-3 and tungsten-184 are archaic signatures, only formed through stars and fission. Their counterparts, helium-4 and tungsten-182, are instead formed through radioactive decay and are found in much greater quantities on the planet’s surface. Oceanic island basalt, found in Hawaii and Iceland, has significantly more primordial isotopes in its crust than in other parts of the surface. 

It was previously theorized that the tungsten and helium isotope signatures were achieved by slow convection within the mantle, allowing for helium-3 and tungsten-184 to congregate near the bottom and emerge from the depths via large magma plumes. However, according to Korenaga this does not accurately represent the convection of the mantle, and requires numerous factors to be aligned in order to achieve the proper ratio of isotopes. 

The research findings outline a diffusion process from the core to the mantle that occurs at the necessary rate for the concentration of archaic signatures observed in oceanic islands to be achieved. Furthermore, this is the only theory that provides a single solution to how high levels of both primordial tungsten and primordial helium are found.

“I modeled the diffusion process at the core-mantle boundary, tracking the isotopic ratios of tungsten and helium over Earth’s entire history of 4 billion years,” Ferrick said in describing her research process 

Through her computer model, she determined the isotopic composition of the deep-mantle reservoir from Earth’s formation to the present day. 

Then, Ferrick modeled a magma plume, which is when a hot spot rises through the entirety of the mantle to the crust above. The plume, formed of background mantle, pulls along magma from the deep-reservoir. This results in the plume having a much greater concentration of primordial isotopes than the average magma of the mantle.

The composition of rocks on Hawaii and Iceland matched her model’s predictions for the isotopic ratios of both helium and tungsten in the magma plume.

Ferrick began the model for a class project, but after discovering the remarkable result — that all ocean island primordial isotope signatures could be explained through diffusion — she continued her research with Korenga. 

“It’s particularly exciting that this publication developed from a project that Amy carried out early in her Ph.D. program,” wrote Maureen Long, chair of earth and planetary sciences, in an email to the News. “We encourage our graduate students to dive into cutting-edge research from Day 1 in our program — one of the thrilling things about doing a Ph.D. is the creation of new knowledge, and our students do that right off the bat. I love seeing the amazing science that our grad students produce here in EPS.”

Amy Ferrick presented her research at the 2022 American Geophysical Union conference.

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Transfer RNAs, or tRNAs, are part of the system that brings genetic information from its storage location in the DNA to its construction site in the ribosomes where proteins are synthesized. 

While humans typically use 20 amino acids in our proteins, the Dieter Söll Lab has optimized the use of a 21st amino acid: selenocysteine. 

By genetically engineering tRNA, researchers — including Yale’s Natalie Krahn and Oscar Vargas-Rodriquez — are able to manipulate the properties of the protein that the ribosomes produce. 

“The overarching goal of the lab is to create tools to change the meaning of the genetic code,” Vargas-Rodriquez told the News. “We can introduce new chemistry to the code and create proteins that are not naturally available.” 

The team’s work was published in Nucleic Acids Research on July 27th.

The ribosome can be thought of as a machine for reading genetic code from tRNAs, according to Joseph Puglisi, a professor of structural biology at Stanford. Transfer RNA molecules are shaped like an L, and must fit into specific crevices in the ribosome. 

If the L-shapes are distorted, the tRNAs get stuck, and the ribosome must reshape itself to continue protein synthesis. It is as if the cogs in a machine do not quite fit. 

Krahn was able to do a single point mutation in the tRNA to remove this roadblock, transforming a cysteine amino acid into an adenine amino acid. This provided for seamless protein synthesis and a new method for creating selenocysteine-containing proteins.

The Puglisi lab at Stanford was able to facilitate this genetic engineering by visualizing where the L-shaped tRNAs got stuck in the ribosome machinery. 

“Our small contribution was to solve the three-dimensional structures of the tRNAs when they were bound for the ribosome, and what we saw is that they fold up into the right structure despite their novel features, but there is a bit of a clash between parts of the tRNA and parts of the ribosome,” Puglisi said.

This engineering process of a single nucleotide mutation is simple to perform in the lab. It can be applied to insert selenocysteine into a wide variety of proteins where it may not be, altering chemical properties and function. 

“Applications are very broad; you can make synthetic proteins, “ Krahn said. “For example, we have made hydrogenase. These are hypothesized to be used in biological energy production, but there are issues with it: they can be oxygen sensitive and they are not very good at producing hydrogen. What we found is we can actually make hydrogenase that is very oxygen-tolerant, and is capable of doing its job in an aerobic environment, which is not normally the case.” 

Selenoproteins also occur naturally. Humans have 25 selenoproteins, many of which are necessary for the body to function, according to Krahn. If these proteins have mutations or one has a low selenium diet, it can reduce selenoprotein levels, causing many diseases. Low selenoprotein levels have been associated with COVID, cancer and neurological diseases, Krahn said. However, it is unknown whether the low selenoprotein levels are causing the diseases, or if they are only a symptom. 

The tRNA technology allows researchers to create selenoproteins in the lab, a task previously infeasible. This allows scientists to further study human systems that involve selenoproteins, and determine the root cause of their association with complex diseases.

According to Puglisi, developing the selenocysteine translation system was truly a team effort.

“It was a fun project because it allowed us to contribute our structural and mechanistic insights into really what was Dieter and Natalie’s beautiful work in discovering and characterizing these tRNAs,” Puglisi said.

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Arnar Geirsson, surgeon-in-chief of cardiac surgery at the Yale New Haven Health system, performed the hospital’s first robotic mitral valve replacement surgery in 2018. YNHH is the only hospital that performs robotic-assisted mitral valve surgeries in New England and has become one of the leading university-affiliated hospitals for robotic-assisted cardiac surgery in the United States. Geirsson’s team published a study on 200 consecutively successful robotic-assisted mitral valve procedures for degenerative mitral regurgitation in the Annals of Cardiothoracic Surgery. It was accepted for publication on Aug. 2. 

“Robotic cardiac surgery is an emerging field of practice that is significantly safer and less invasive than traditional heart surgery,” Geirsson wrote to the News. “Tiny robotic instruments are inserted and controlled through very small cuts in the patient’s chest, thereby eliminating the need to cut the breastbone and open the chest widely to reach the heart. While traditional heart surgery may leave a ten-inch scar, robotic cardiac surgery leaves just a few one-inch scars under the armpit or below the breast.”

In a patient with mitral valve regurgitation, the valve between the left heart chambers does not close completely. This allows blood to leak backwards across the valve instead of circulating the body, resulting in symptoms of tiredness or shortness of breath. Severe mitral valve regurgitation can cause heart rhythm problems or heart failure and often requires surgery to correct.

The less invasive nature of robotic-assisted mitral valve repairs leads to a quicker recovery period. Patients can be up and walking hours after surgery, with many able to go home soon after. In a few weeks, patients are able to resume their full spectrum of daily activities. 

Traditional operating methods require breaking the sternum — a bone that requires two months to heal — in order to access the heart. In contrast, robotic-assisted mitral valve repair patients may begin driving cars two weeks post-surgery.

The robotic-assisted mitral valve repair, which requires a much smaller incision than the traditional approach, is less painful for the patient. While patients require opioids to manage pain after open mitral valve repairs, patients with a robotic-assisted repair only need over-the-counter medications. In 2019, an estimated 9.7 million people misused prescription pain medications according to the U.S. department for health and human services. As such, reducing opioid prescriptions has the potential to save lives.

Repairing mitral valves with robots also changes the experience of the surgeon in the operating room, as the procedure requires different tools and techniques.

“The surgeon uses tiny robotic instruments that are remotely-controlled.” said Andrea Amabile, first author on the paper. “The surgeon sits at a console which is separated from the operating table. [Surgeons] sit there, involved in a 3D representation of what [they] see inside the chest of the patient.”

The robot provides a surgeon with superior visualization, according to Michael LaLonde, coordinator for the Robotic Mitral Valve Program at the hospital. He said that the robot arms each have an endowrist that provides 360 degrees of freedom, enabling the surgeons to manipulate their instruments in a minimally invasive way that is not supported by an open procedure. 

Amabile explained that two robots are in the operating room at YNHH and serve as huge systems that immerse the surgeon inside of the heart. The lead surgeon uses one machine, the assistant uses the other and a video stream of the surgery is projected onto a tv screen. This method facilitates collaboration as it ensures that the entire team has a clear view of the operation.

However, LaLonde cautions that it may take some time for robotic-assisted mitral valve repair to become the standard of care. The procedure is tricky and often becomes the specialty of surgeons. Smaller hospitals with lower volumes of patients may not have the chance to perform the surgery enough times necessary for adapting to a new robotic-assisted approach.

“In developing the program, it took us over a year and over 50 training sessions to become proficient enough to feel comfortable working on a valve in a human being,” LaLonde said. “Nationally, about 15 percent of mitral values are now repaired using the robotic technique.”

At the hospital, however, the residents are learning. Since the entire surgery is visualized by the robotic arms within the patient, residents have a unique opportunity to rewatch the procedure with the same level of resolution that the lead surgeon had during the operation. 

These recordings have proven to be a very effective educational and training modality, according to LaLonde. 

“During my rotation on cardiac surgery, I was able to see both types of procedures,” said Alyssa Morrison MED ’24, a data collector for the paper. “From my experience on the wards and from the research papers we were able to publish, [we observed that] patients had a shorter length of stay with the robotic procedure, which is incredible.” 

The first robotic-assisted mitral repair surgery was performed in 1998.

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Fleming, a faculty member and research scientist in the Yale physics department, has been appointed deputy director and chief research officer of the U.S. Department of Energy’s Fermi National Accelerator Laboratory, located outside of Chicago, Illinois. 

She will hold a joint appointment as a professor of physics at the University of Chicago, where she will continue her Liquid Argon Time Projection Chamber research. Fleming has been involved with Fermilab experiments since 1997, but is now transitioning from a research-focused role to a leadership-centric one within the organization.

“I will still be involved in neutrinos, but playing a different role,” Fleming told the News.

The new position involves administering research in the accelerator complex, scientific computing, working on particle physics at the Large Hadron Collider and advancing newer quantum science efforts at Fermilab.

Fleming’s research career has been defined by studying neutrinos, which are small fundamental particles with a near-zero mass and zero electrical charge.  Now she is expanding her role from being a collaborator on neutrino-focused projects to leading the lab’s entire investigation in the domain of particle physics. 

One of the challenges she faces in this new role is executing the DUNE project, the largest U.S. based particle physics project ever. DUNE will extend from Fermilab, based in Illinois, to South Dakota in order to detect minute differences in neutrino and antineutrino oscillation, with the hopes of determining how matter was produced in the early universe. DUNE is slated to finish construction by 2029. 

Fleming’s involvement with neutrino research, and her collaboration with Fermilab through the DUNE and MicroBooNE projects, shaped her time at Yale.

“Dr. Fleming has had a broad impact on the department,” Karsten Heeger, Chair of the Yale physics department, wrote to the News. “On the research side she led the development of liquid argon neutrino detectors at Yale and R&D on these detectors at the new Wright Lab. In the department she recently served as Director of Graduate Studies and helped lead the program through the pandemic.”

Eighteen years ago, when Fleming first came to Yale, she founded Girls’ Science Investigations, a program designed to motivate middle school-age girls to pursue scientific careers. The program will continue at Yale under the leadership of Rona Ramos, a lecturer in the physics department.  

Fleming hopes to continue promoting girls’ science education through programs at Fermilab and potentially also at the University of Chicago. In fact, Fleming’s involvement with Girls’ Scientific Salon as a Fermilab Lederman Fellow was what sparked Girls’ Science Investigations.

At Yale, Fleming has conducted research in neutrino detection mechanisms. Liquid Argon Time Projection Chambers, initially prototyped in Europe, were brought to the U.S. for the first time in 2007 by Fleming’s lab. 

The devices have since been incorporated into both the MicroBooNE and DUNE experiments due to their incredible precision in detecting neutrino oscillations. Fleming will continue her neutrino research at the University of Chicago as a professor in the physics department.

Chair of the Department of Physics at the University of Chicago Peter Littlewood is looking forward to welcoming Fleming to the university’s physics community. 

“The fact that Liquid Argon detectors are the detectors of choice is very much being propelled by Fleming and all of her research,” Littlewood said. “Having that program here is tremendous for us. Accelerator-based neutrino physics is the premier thing being pushed by the U.S. high energy community. Having that work here puts our department at the center of what is going to be a very exciting few decades of research in this area.”

The particle physics community is currently in the midst of a planning process that occurs every decade with the critical P5 process subpanel, a conference meant to advise U.S. investments in particle physics. 

Scientists are gathering to question the future of U.S.-based and international particle physics, and the subpanel will soon embark on multiple months of meetings. With Fermilab involved in these talks, Fleming will be at the forefront of new projects that emerge from the discussion.

Fleming described her role as a “real eye opener in terms of the breath of science that encompasses the lab’s mission.”

Fleming began her role as Fermilab’s chief research officer and deputy director on Sept. 6, 2022.

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“Jumping genes,” or DNA sequences that move from one location on the genome to another, comprise almost half of human genetic information. Originally believed to be junk DNA, jumping genes are now known to perform critical regulatory functions, but are regularly silenced, meaning they stop moving. This results in a stabilized cell. Yale researchers in the Iwasaki Lab have directly connected one type of jumping gene, LINE-1, to neurodegenerative diseases through the development of a novel mouse model. Their work was published in the scientific journal Neuron earlier this month.

“This is the first time it was demonstrated that Long Interspersed Nuclear Elements, or LINE-1, can lead directly to neurodegenerative disease,” Sterling Professor of immunobiology Akiko Iwasaki said. “We created a new mouse model where we can turn on these genes artificially and ask: ‘What is the consequence?’”

Previous studies have linked LINE-1 expression to ataxia telangiectasia (AT), a severe neurodegenerative disorder, but this is the first time the relationship was shown directly by altering the expression of the gene within a mouse model. This experimental setup shows LINE-1 overactivation is sufficient for AT development, bridging the gap from correlation to causation, according to Iwasaki. 

CRISPR-Cas9 was used to directly control the expression level of LINE-1 in a novel mouse model, which was developed by the paper’s first author, Takehiro Takahashi, a researcher in the Iwasaki Lab. This is the first time the expression of a transposable retroelement has been controlled in this manner.

“Takehiro put in this huge effort, developing a system where he can modulate LINE-1 expression in a mouse, and by doing that, brought the field forward, showing direct evidence that a retroelement can cause disease,” said Eric Song, former researcher in Iwasaki’s lab and current medical resident at Yale New Haven Hospital. “Retroelements have been implicated in many other diseases, ranging from other autoimmune disorders to cancer, but people haven’t been able to show an effect because of an inability to modulate expression. Instead of having correlative studies, Takehiro’s tool is going to support acquiring direct evidence.”

Precise control of LINE-1 activation is especially valuable in this study because in the healthy brain, some LINE-1 activation is expected. The jumping genes give rise to heterogeneity and plasticity in the brain, adding to the complexity of the circuit. This supports complicated tasks, such as learning. 

However, overactivation can be dangerous. The paper shows that a small increase in LINE-1 activity is sufficient to cause DNA damage and ER stress, leading to toxicity within the cells, and eventually death of the neurons.

Takahashi compared jumping gene activity in the brain to a double-edged sword: “Neurons are taking advantage of jumping properties to generate plasticity, while they are more vulnerable because they are utilizing these activities,” he said.

LINE-1 is a retroelement, meaning that in order to jump to a new location, it must be transcribed into RNA and then reverse-transcribed into DNA. This reverse-transcription enzyme is also critical to the HIV life cycle, since as a retrovirus, it also performs RNA to DNA transformation. 

The Iwasaki lab has given mice with neurodegenerative disorders HIV medications and found that the progression of neuron degradation stopped. 

“We used HIV inhibitors to block the retrotransposition activity of LINE-1 and in those animals we were able to prevent the onset of neurodegeneration as well as ataxia,” said Iwasaki. “This means that existing FDA-approved drugs may be useful in treating certain types of cerebellar ataxia.”

While human clinical trials are necessary to determine whether HIV medications are a viable option for AT patients, this study provides a source of hope for those with the currently incurable disease.
AT is estimated to impact 1 in every 40,000 people in the US.

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