Now, a paradigm-shifting study led by researchers at the Icahn School of Medicine at Mount Sinai in New York in collaboration with the University of Helsinki and Massachusetts General Hospital sheds light on how variations in immune genetics influence lung cancer risk, potentially paving the way for enhanced prevention strategies and screening.

The findings were described in the February 22 online issue of Science.

The investigators utilized genetic epidemiology and multimodal genomic analyses of data from the UK Biobank, validating it in FinnGen. Their study focused on human leukocyte antigen (HLA) molecules — the most diverse genes in the human genome and at the core of immune recognition. These genes contain instructions to make proteins, which play a crucial role in presenting foreign antigens on cell surfaces. This process aids the immune system in identifying and eliminating threats such as cancer cells.

Surprisingly, the study found that individuals with heterozygosity (having different versions of a gene) at HLA-II, rather than HLA-I, experienced a decreased risk of lung cancer. This effect was particularly pronounced among smokers, a population already at higher risk for lung cancer due to exposure to carcinogens.

“Our findings challenge conventional thinking by demonstrating that immune genetics, specifically HLA-II heterozygosity, plays a significant role in lung cancer risk, especially among smokers,” says co-senior author Diego Chowell, PhD, Assistant Professor of Oncological Sciences, and Immunology and Immunotherapy at Icahn Mount Sinai. “Further, when we added polygenic risk scores — which is a measure of genetic predisposition based on multiple genes — to the analysis, it increased the lifetime risk of lung cancer, specifically in smokers who have identical versions of the HLA-II genes.

The implications of this research extend beyond lung cancer, offering a new perspective on cancer risk assessment, the researchers say. The conventional thinking on the causes of cancer is that the disease is caused by random mutations arising during DNA replication, inherited mutations, and environmental factors. The research showed that the immune system is also part of the etiology of cancer, Dr. Chowell says. By considering immune genetics alongside hereditary and environmental factors, the investigators’ aim to develop more effective prevention strategies, potentially harnessing the immune system to combat cancer.

“These results highlight a previously overlooked aspect of cancer risk assessment,” says co-senior author Robert Samstein, MD, PhD, Assistant Professor of Radiation Oncology, and Immunology and Immunotherapy at Icahn Mount Sinai. “Our study marks a big step toward understanding the intricate interplay between the immune system and cancer risk. We hope that by identifying individuals with increased susceptibility based on their immune genetics, we can implement more targeted screening, prevention, and treatment strategies.”

Next, the research team plans to delve deeper into the mechanisms underlying HLA heterozygosity’s protective effects, with a focus on preclinical models of disease. Additionally, they aim to explore the role of non-classical CD4 T cells and HLA class II in cancer biology, opening the door for potential progress in the mitigation and treatment of cancer.

The paper is titled “An immunogenetic basis for lung cancer risk.”

The remaining authors of the paper, all with Icahn Mount Sinai except where indicated, are: Chirag Krishna, PhD (Pfizer); Anniina Tervi, PhD (University of Helsinki); Miriam Saffern (PhD candidate); Eric A. Wilson, PhD; Seong-Keun Yoo, PhD; Nina Mars, MD, PhD (University of Helsinki and The Broad Institute of Harvard and MIT); Vladimir Roudko, PhD; Byuri Angela Cho, PhD; Samuel Edward Jones, PhD (University of Helsinki); Natalie Vaninov (PhD candidate); Myvizhi Esai Selvan, PhD; Zeynep H Gu?mu?s, PhD; FinnGen Consortium; Tobias L. Lenz, PhD (University of Hamburg); Miriam Merad, MD, PhD; Paolo Boffetta, MD (Stony Brook University in New York and University of Bologna); Francisco Marti?nez-Jime?nez, PhD (Stony Brook University in New York and Vall d’Hebron Institute of Oncology, Barcelona); and Hanna M. Ollila, PhD (Massachusetts General Hospital, Harvard Medical School, The Broad Institute, and University of Helsinki).

Then, in a burst of innovation in form and function, the ancestors of snakes evolved legless bodies that could slither across the ground, highly sophisticated chemical detection systems to find and track prey, and flexible skulls that enabled them to swallow large animals.

Those changes set the stage for the spectacular diversification of snakes over the past 66 million years, allowing them to quickly exploit new opportunities that emerged after an asteroid impact wiped out roughly three-quarters of the planet’s plant and animal species.

But what triggered the evolutionary explosion of snake diversity — a phenomenon known as adaptive radiation — that led to nearly 4,000 living species and made snakes one of evolution’s biggest success stories?

A large new genetic and dietary study of snakes, from an international team led by University of Michigan biologists, suggests that speed is the answer. Snakes evolved up to three times faster than lizards, with massive shifts in traits associated with feeding, locomotion and sensory processing, according to the study scheduled for online publication Feb. 22 in the journal Science.

“Fundamentally, this study is about what makes an evolutionary winner. We found that snakes have been evolving faster than lizards in some important ways, and this speed of evolution has let them take advantage of new opportunities that other lizards could not,” said University of Michigan evolutionary biologist Daniel Rabosky, senior author of the upcoming Science paper.

“Snakes evolved faster and — dare we say it — better than some other groups. They are versatile and flexible and able to specialize on prey that other groups cannot use,” said Rabosky, a curator at the U-M Museum of Zoology and a professor in the Department of Ecology and Evolutionary Biology.

For the study, researchers generated the largest, most comprehensive evolutionary tree of snakes and lizards by sequencing partial genomes for nearly 1,000 species. In addition, they compiled a huge dataset on lizard and snake diets, examining records of stomach contents from tens of thousands of preserved museum specimens.

They fed this mountain of data into sophisticated mathematical and statistical models, backed by massive amounts of computer power, to analyze the history of snake and lizard evolution through geological time and to study how various traits, such as limblessness, evolved.

This multipronged approach revealed that while other reptiles have evolved many snakelike traits — 25 different groups of lizards also lost their limbs, for instance — only snakes experienced this level of explosive diversification.

Take Australia’s legless gecko, for example.

Like snakes, this lizard lost its legs and evolved a flexible skull. Yet the creature has barely diversified over millions of years. No evolutionary explosion — just a couple of species scraping out a living in the Australian outback.

So, it seems there is something special about snakes that enabled them to hit the evolutionary jackpot. Maybe something in their genes that allowed them to be evolutionarily flexible while other groups of organisms are much more constrained.

“A standout aspect of snakes is how ecologically diverse they are: burrowing underground, living in freshwater, the ocean and almost every conceivable habitat on land,” said Alexander Pyron, study co-author and an associate professor of biology at George Washington University. “While some lizards do some of these things — and there are many more lizards than snakes — there are many more snakes in most of these habitats in most places.”

The ultimate causes, or triggers, of adaptive radiations is one of the big mysteries in biology. In the case of snakes, it’s likely there were multiple contributing factors, and it may never be possible to tease them apart.

The authors of the upcoming Science study refer to this once-in-evolutionary-history event as a macroevolutionary singularity with “unknown and perhaps unknowable” causes.

A macroevolutionary singularity can be viewed as a sudden shift into a higher evolutionary gear, and biologists suspect these outbursts have happened repeatedly throughout the history of life on Earth. The sudden emergence and subsequent dominance of flowering plants is another example.

In the case of snakes, the singularity started with the nearly simultaneous (from an evolutionary perspective) acquisition of elongated legless bodies, advanced chemical detection systems and flexible skulls.

Those crucial changes allowed snakes, as a group, to pursue a much broader array of prey types, while simultaneously enabling individual species to evolve extreme dietary specialization.

Today, there are cobras that strike with lethal venom, giant pythons that constrict their prey, shovel-snouted burrowers that hunt desert scorpions, slender tree snakes called “goo-eaters” that prey on snails and frog eggs high above the ground, paddle-tailed sea snakes that probe reef crevices for fish eggs and eels, and many more.

“One of our key results is that snakes underwent a profound shift in feeding ecology that completely separates them from other reptiles,” Rabosky said. “If there is an animal that can be eaten, it’s likely that some snake, somewhere, has evolved the ability to eat it.”

For the study, the researchers got an inside look at snake dietary preferences by reviewing field observations and stomach-content records for more than 60,000 snake and lizard specimens, mostly from natural history museums. The contributing museums included the University of Michigan Museum of Zoology, home to the world’s largest research collection of snake specimens.

“Museum specimens give us this incredible window into how organisms make a living in nature. For secretive animals like snakes, it’s almost impossible to get this kind of data any other way because it’s hard to observe a lot of their behavior directly,” said study co-lead author Pascal Title of Stony Brook University, who completed his doctorate at U-M in 2018.

The study’s 20 authors are from universities and museums in the United States, the United Kingdom, Australia, Brazil and Finland.

“What I love about this study is how it integrates hard-earned field and museum data with new genomic and analytical methods to show a basic biological truth: Snakes are exceptional and frankly quite cool,” said co-lead author Sonal Singhal of California State University, Dominguez Hills, who started work on the project as a U-M postdoctoral scholar.

The chemical structures of these molecules, which consist of a dense, highly complex knot of oxidized rings and nitrogen atoms, has attracted the interest of organic chemists worldwide, who aimed to recreate these structures from scratch in the laboratory. However, despite considerable effort, it has remained an elusive task. Until now, that is.

A team of Yale chemists, writing in the journal Science, has succeeded in synthesizing eight of the compounds for the first time using an approach that combines inventive chemical strategy with the latest technology in small molecule structure determination.

“These molecules have been an outstanding challenge in the field of synthetic chemistry,” said Seth Herzon, the Milton Harris ’29 Ph.D. Professor of Chemistry in Yale’s Faculty of Arts and Sciences and corresponding author of the new study. “A number of research groups have tried to recreate these molecules in the lab, but their structures are so dense, so intricately connected, that it hasn’t been possible. I’ve been reading about efforts to synthesize these compounds since I was a graduate student in the early 2000s.”

In nature, the molecules are found in some species of bryozoa — small, aquatic animals that feed by filtering prey from the water via tiny tentacles. Researchers worldwide consider bryozoans to be a potentially valuable source of new medications, and many molecules isolated from bryozoans have been studied as novel anticancer agents. However, the complexity of the molecules often limits their further development.

Herzon’s team looked at a particular species of bryozoa called Securiflustra securifrons.

“We worked on these molecules about a decade ago, and though we were not successful in recreating them at that time, we gleaned insight into their structure and chemical reactivity, which informed our thinking,” Herzon said.

The new approach involved three key strategic elements. First, Herzon and his team avoided constructing a reactive heterocyclic ring, known as an indole, until the end of the process. A heterocyclic ring contains two or more elements — and this specific ring is known to be reactive and create problems, Herzon said.

Second, the researchers used methods known as oxidative photocyclizations to construct some of the key bonds in the molecules. One of these photocyclizations involved the reaction of a heterocycle with molecular oxygen, which was first studied by Yale’s Harry Wasserman in the 1960s.

Lastly, Herzon and his team employed microcrystal electron diffraction (MicroED) analysis to help visualize the structure of the molecules. Herzon said conventional methods for structure determination were inadequate in this context.

The result of the new approach is eight new synthetic molecules with therapeutic potential — and the promise of more new chemistry to come.

“These molecules hit right at my love of complex synthetic challenges,” said Herzon, who is also a member of the Yale Cancer Center and holds joint appointments in pharmacology and therapeutic radiology at Yale School of Medicine. “On a molecular weight basis, they are modest relative to other molecules we’ve studied in my lab. But from the vantage point of chemical reactivity, they present some of the greatest challenges we’ve ever taken on.”

Co-first authors of the new study are Yale chemistry graduate students Brandon Alexander and Noah Bartfield. Co-authors are Vaani Gupta, a Yale chemistry graduate student; Brandon Mercado, a Yale X-ray crystallographer and lecturer in the Department of Chemistry; and Mark Del Campo of Rigaku Americas Corporation.

The National Science Foundation helped fund the research.

Hung-Wei Tseng, a UC Riverside associate professor of electrical and computer engineering, has laid out a paradigm shift in computer architecture to do just that in a recent paper titled, “Simultaneous and Heterogeneous Multithreading.”

Tseng explained that today’s computer devices increasingly have graphics processing units (GPUs), hardware accelerators for artificial intelligence (AI) and machine learning (ML), or digital signal processing units as essential components. These components process information separately, moving information from one processing unit to the next, which in effect creates a bottleneck.

In their paper, Tseng and UCR computer science graduate student Kuan-Chieh Hsu introduce what they call “simultaneous and heterogeneous multithreading” or SHMT. They describe their development of a proposed SHMT framework on an embedded system platform that simultaneously uses a multi-core ARM processor, an NVIDIA GPU, and a Tensor Processing Unit hardware accelerator.

The system achieved a 1.96 times speedup and a 51% reduction in energy consumption.

“You don’t have to add new processors because you already have them,” Tseng said.

The implications are huge.

Simultaneous use of existing processing components could reduce computer hardware costs while also reducing carbon emissions from the energy produced to keep servers running in warehouse-size data processing centers. It also could reduce the need for scarce freshwater used to keep servers cool.

Tseng’s paper, however, cautions that further investigation is needed to answer several questions about system implementation, hardware support, code optimization, and what kind of applications stand to benefit the most, among other issues.

The paper was presented at the 56th Annual IEEE/ACM International Symposium on Microarchitecture held in October in Toronto, Canada. The paper garnered recognition from Tseng’s professional peers in the Institute of Electrical and Electronics Engineers, or IEEE, who selected it as one of 12 papers included in the group’s “Top Picks from the Computer Architecture Conferences” issue to be published this coming summer.

Gabor Csathy, professor and head of the Department of Physics and Astronomy at the Purdue University College of Science, along with PhD students Haoyun Huang, Waseem Hussain, and recent PhD graduate Sean Myers, led this discovery from the West Lafayette campus of Purdue. Csathy credits lead author Huang as having conceived, led the measurements and writing a large part of the manuscript. All the ultra-low-temperature measurements were completed in Csathy’s Physics Building lab. In his lab they conduct research on strongly correlated electron physics, sometimes referred to as topological electron physics.

Weak interactions of electrons are well established, and the behavior is quite predictable. When electrons interact weakly, the electron is commonly considered the natural building block of the entire system. But when the electrons interact strongly, interpreting the systemic behavior by thinking of individual electrons becomes nearly impossible.

“This occurs in very few instances, like in the fractional quantum Hall regime which we study, for example,” says Csathy. “To explain fractional quantum Hall states, the composite fermion, a very intuitive fundamental building block, comes in different flavors. They can account for a whole subset of the fractional quantum Hall states. But all the fully developed, (i.e topologically protected), fractional quantum Hall states could be accounted for by only two types of composite fermions: the two-flux and four-flux composite fermions. Here we reported a new fractional quantum Hall state that cannot be explained by any of these previous ideas! Instead, we need to invoke the existence of a new type of emergent particle, the so-called six-flux composite fermions. The discovery of new fractional quantum Hall states is scarce enough. However, the discovery of a new emergent particle in condensed matter physics is truly rare and amazing.”

For now, these ideas will be used to expand our understanding of the ordering of the known fractional quantum Hall states into a “periodic table.” It is especially notable to this process that the emergent composite fermion particle is unique in that the electron captures six quantized magnetic flux quanta, forming the most intricate composite fermion known to date.

“The numerology of this complicated physics puzzle requires quite some patience,” says Haoyun Huang, Csathy’s PhD student. “Take the nu=2/3 fractional state as an example. Since 2/3=2/(2*2-1), the nu=2/3 state belongs to the two-flux family. Similarly, for the nu=2/7 fractional state, 2/7=2/(2*4-1), so this state belongs to the four-flux family. In contrast, the fractional states we discovered closely relate to 2/11=2/(2*6-1). Before our work, no fully quantized fractional quantum Hall state was seen that could be associated with six-flux composite fermions. The situation was completely different on the theory front: The existence of these kinds of composite fermions was predicted by Jainendra Jain in his highly influential theory of composite fermions published in 1989. The associated quantization was not observed during these 34 years.”

The material used in this study was grown by a Princeton University team led by Loren Pfeiffer. The GaAs semiconductor electrical quality played a huge role in the success of this research. According to Csathy, this Princeton group is leading the world in growing the highest quality GaAs-based materials.

“The GaAs they grow is very special, as the number of imperfections is astonishingly low,” he says. “The combination of low disorder and the ultra-low-temperature measurement expertise in the Csathy lab made this project possible. One reason we were measuring these samples is that very recently the Princeton group has significantly improved the quality of the GaAs semiconductor, as measured by the tiny amounts of defects present. These improved samples will, for sure, continue to constitute a playground for new physics.”

This exciting discovery is part of ongoing research by Csathy’s team. The team continues to push the limits of discovery in their persistent pursuit of topological electron physics.

Low-temperature measurements in Csathy’s lab were supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences program, under Award No. DE-SC0006671. Sample growth efforts of the Princeton team were supported by the Gordon and Betty Moore Foundation Grant No. GBMF 4420 and the National Science Foundation MRSEC Grant No. DMR-1420541.

Researchers used more than a decade of acoustic data to monitor bowhead whales’ movements between their usual overwintering grounds in the Bering Sea and summer feeding grounds in the Chukchi and Beaufort Seas. The whales departed the summer feeding grounds about six weeks later in 2022 than in 2008, based on the acoustic data.

Some are also spending winter farther north in the Chukchi Sea, where commercial traffic in particular has been increasing. That means they could be lingering longer in shipping lanes, which grow busier as sea ice shrinks.

“A shift like this may not necessarily be a bad thing for the whales, but any time we see more overlap with whales and shipping traffic, we should be concerned,” said Angela Szesciorka, a marine scientist at Oregon State University’s Marine Mammal Institute who led the study. “There will be winners and losers, but only time will tell.”

The study was published in Geophysical Research Letters, which publishes high-impact, short-format reports with immediate implications spanning all Earth and space sciences.

Whales on the move

Historically, the population of bowhead whales that Szesciorka studies has spent their winters in the Bering Sea. In April, they’d head north through the Chukchi Sea and into the Beaufort Sea off the Canadian and Alaska coasts, head west to the Russian Chukotka Peninsula, and finally go back south around mid-November. During the 2008-2009 International Polar Year, researchers put an underwater microphone called a hydrophone at the Chukchi Plateau for the first time and were surprised to hear bowhead whales in late spring and summer, much farther north than their previously understood migratory paths.

Traditional knowledge held in Indigenous Arctic communities has suggested the whales’ migration patterns are changing in recent years, and data from a handful of satellite-tagged whales has reflected that. As temperatures warm the waters and sea-ice extent drops, the whole Arctic ecological web is forced to change, from tiny plankton and krill up to whales. Scientists wondered if climate change was behind the shift in bowhead whale migration patterns, but they needed more information on the whales’ migration patterns over time to figure it out.

Szesciorka and her coauthors had previously monitored bowhead whale movements through the Bering Strait using data from hydrophones. They used hydrophones to monitor bowhead whales in the western Beaufort Sea and Chukchi Plateau from 2008 to 2022.

“Bowhead whales are highly vocal,” Szesciorka said. “Males sing pretty much twenty-four-seven from fall through spring, so you know when they’re there.”

The recordings revealed that the whales shifted their winter departure time from the western Beaufort Sea 45 days later in 2022 than they had in 2008. They also spent more time in the summer in the Chukchi Sea, and some appeared to entirely forgo migrating back to the Bering Sea as they normally would.

Some of these changes are most likely due to increased food availability in the Chukchi Sea as a result of warmer waters and declining sea ice, the study suggests. But scientists will need to do more research to know for sure.

“The changes we are seeing in migration patterns lead to many questions,” Szesciorka said. “How many whales are going to the Chukchi Sea in the summer? What are they feeding on? Do the same individuals return each year? We’re essentially learning on the fly how whales are responding to changing climate.”

There’s also concern that Indigenous harvests of bowhead whale could be impacted. Bowhead whales could end up abandoning parts of their historic ranges, leaving some tribes with no access to this traditional food and cultural resource. Having tribal involvement in whale management is critical, Szesciorka said.

Seasonal shifts and ship strikes

Spending more time farther north, where commercial shipping traffic is increasing as sea-ice extent drops, could put the whales at increased risk of hazardous encounters with vessels.

“With this general northward shift paired with an increase in vessels and shipping, the threat of ship strikes will probably increase,” Szesciorka said. Shipping in the western Chukchi Sea has increased about 13% since 2009; however, there hasn’t yet been an increase in bowhead ship-strikes “that we know of,” she emphasized. Ship strikes can only be confirmed during harvests; other whales may die and wash ashore undetected.

But Szesciorka sees opportunity.

“Right now, the Arctic is kind of the wild west,” she said. “As sea ice continues to decline, shipping, especially large commercial vessels that go much faster than smaller fishing boats, is only going to increase. It’s better to start thinking about this sooner rather than later so we can prevent problems rather than try to respond to them.” One solution would be to establish speed limits in bowhead whale seasonal habitat, reducing the risk of ship strikes and noise pollution, she said.

The shift in bowhead whales’ seasonal movements is happening quickly, apace with the other rapid changes in the Arctic. But that’s not necessarily a bad thing. The whales might be nimble enough to keep up with the changes, Szesciorka said.

“We saw these changes in migration patterns in just nine years,” she said. “For a species that can live to 200, that’s pretty stark. That shows they can adapt to their changing environments for now. But will there be a point where they can’t adapt anymore? We have to wait and see.”