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Adam Siepel

A Jamaican fruit bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

By Daniel Dunaief

Popular in late October as Halloween props and the answer to trivia questions about the only flying mammals, bats may also provide clues about something far more significant.

Despite their long lives and a lifestyle that includes living in close social groups, bats tend to be resistant to viruses and cancer, which is a disease that can and does affect other mammals with a longer life span.

Armin Scheben

In recent work published in the journal Genome Biology and Evolution, scientists including postdoctoral researcher at Cold Spring Harbor Laboratory and first author Armin Scheben, CSHL Professor and Chair of the Simons Center for Quantitative Biology Adam Siepel, and CSHL Professor W. Richard McCombie explored the genetics of the Jamaican fruit bat and the Mesoamerican mustached bat.

By comparing the complete genomes for these bats and 13 others to other mammals, including mice, dogs, horses, pigs and humans, these scientists discovered key differences in several genes.

The lower copy number of interferon alpha and higher number of interferon omega, which are inflammatory protein-coding genes, may explain a bat’s resistance to viruses. As for cancer, they discovered that bat genomes have six DNA repair and 33 tumor suppressor genes that show signs of genetic changes.

These differences offer potential future targets for research and, down the road, therapeutic work.

“In the case of bats, we were really interested in the immune system and cancer resistance traits,” said Scheben. “We lined up those genomes with other mammals that didn’t have these traits” to compare them.

Scheben described the work as a “jumping off point for experimental validation that can test whether what we think is true: that having more omega than alpha will develop a more potent anti-viral response.”

Follow up studies

This study provides valuable potential targets that could help explain a bat’s immunological superpowers that will require further studies.

“This work gives us strong hints as to which genes are involved, but fully understanding the molecular biology will require more work” explained Siepel.

In Siepel’s lab, where Scheben has been conducting his postdoctoral research since 2019, he is using human cell lines to see whether adding genetic bat elements makes them more effective in fighting off viral infections and cancer. He plans to do more of this work with mice, testing whether these bat variants help convey the same advantages in live mice.

Armin Scheben won the German Academic International Network Science Slam competition with his presentation on bat genomics.

Siepel and Scheben have discussed improving the comparative analysis by collecting information across bats and other mammals of tissue-specific gene expression and epigenetic marks which would help reveal changes not only in the content of DNA, but also in how genes are being turned on and off in different cell types and tissues. That could allow them to focus more directly on key genes to test in mice or other systems.

Scheben has been collaborating with CSHL Professor Alea Mills, whose lab has “excellent capabilities for doing genome editing in mice,” Scheben said.

Scheben’s PhD thesis advisor at the University of Western Australia, Dave Edwards described his former lab member’s work as “exciting.”

Edwards, who is Director of the UWA Centre for Applied Bioinformatics in the School of Biological Sciences, suggested that Scheben stood out for his “ability to strike up successful collaborations” as well as his willingness to mentor other trainees.

Other possible explanations

While these genetic differences could reveal a molecular biological mechanism that explains the bat’s enviable ability to stave off infections and cancer, researchers have proposed other ways the bat might have developed these virus and cancer fighting assets.

When a bat flies, it raises its body temperature. Viruses likely prefer a normal body temperature to operate optimally. 

Bats are “getting fevers without getting infections,” Scheben said.

Additionally, flight increases the creation of reactive oxygen species, which the bat needs to control on an ongoing basis.

At the same time, bats produce fewer inflammatory cytokines, which helps prevent them from having a runaway immune reaction. Some researchers have hypothesized that bats clear reactive oxygen species more effectively than humans.

A ‘eureka’ moment

The process of puzzling together all the pieces of DNA into individual chromosomes took considerable time and effort.

A Mesoamerican mustached bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

Scheben spent over 280,000 CPU hours chewing through thousands of genes in dozens of species on the CSHL supercomputer called Elzar, named for the chef from the cartoon “Futurama.” Such an effort would have taken eight years on a modern day personal computer.

During this effort, Scheben saw this “stark effect,” he said. “We had known that bats had lost some interferon alpha. What astounded me was that some bats had lost all alpha” while they had also raised interferon omega. That was the moment when he realized he found something novel and bat specific.

Scheben recognized that this finding could be one of many that lead to a better understanding of the processes that lead to cancer.

“We know that it’s unlikely that a single set of genes or a small set of genes such as we identified can fully explain the diversity of outcomes when it comes to a complex disease like cancer,” said Scheben.

A long journey

A resident of Northport, Scheben grew up in Frankfurt, Germany. He moved to London for several years, which explains his use of words like “chuffed” to describe the excitement he felt when he received a postdoctoral research offer at Cold Spring Harbor Laboratory.

When he was young, Scheben was interested in science despite the fact that classes were challenging for him.

“I was pretty poor in math and biology, but I liked doing it,” he said.

Outside of work, Scheben enjoys baking dense, whole wheat German-style bread, which he consumes with cheese or with apple, pear and nuts, and also hiking.

As for his work, which includes collaborating with CSHL Professor Rob Martienssen to study the genomes of plants like maize that make them resilient amid challenging environmental conditions, Scheben suggested it was the “best time to be alive and be a biologist” because of the combination of new data and the computational ability to study and analyze it.

Scheben recognized that graduate students in the future may scoff at this study, as they might be able to compare a wider range of mammalian genomes in a shorter amount of time.

Such a study could include mammals like naked mole rats, whales and elephants, which also have low cancer incidence and long lifespans.

Saket Navlakha

By Daniel Dunaief

Plants have to solve challenges in their environment – without a brain or the kind of mobility mammals rely on to survive – through strategies and computations that keep them alive and allow them to reproduce.

Intrigued by plants and by the neurobiology that affect decisions or behavior in a range of other organisms, Associate Professor Saket Navlakha recently joined Cold Spring Harbor Laboratory to study the processes a range of organisms use.

“Biological systems have to solve problems to survive,” said Navlakha. “The hope is that by studying these algorithms, we can inspire new methods for computer science and engineering and, at the same time, come up with new ways to predict and model behaviors of these systems.”

Navlakha, who has a doctorate in computer science from the University of Maryland College Park and conducted postdoctoral research at Carnegie Mellon University’s Machine Learning Department, focuses on the “algorithms of nature,” in which organisms evolved ways to solve problems that enhance the likelihood of their survival.

In his first three months at CSHL, Navlakha plans to do an interview tour, speaking with researchers who study cancer, molecular biology, neurology and plants.

While his primary areas of focus have been on plants and neurobiology, he appreciates that the internationally recognized research facility presents “new opportunities” for him and a lab in which he intends to hire four to six scientists over the next two years.

Adam Siepel, the chair of the Simons Center for Quantitative Biology and professor at the Watson School of Biological Sciences at Cold Spring Harbor Laboratory, led the recruitment of Navlakha.

In an email, Siepel wrote that Navlakha “immediately struck us as an ideal candidate for the center” in part because he is a “free thinker with an eye for interesting and important problems in biology.”

Navlakha believes processes and strategies that foster survival spring from a set of principles that helps them thrive and adapt. In 2018, when he was at the Salk Center for Integrative Biology, he wrote a piece for Wired magazine about species extinction. “By not preserving [species that become extinct], we are losing out on interesting ideas that evolution gave them to survive,” he said.

Even amid these losses, however, Navlakha recognizes the lessons computer scientists and engineers like him can learn. Through losses and failures, humans can understand the limitations of algorithms that only allowed a species to survive up to a point, as conditions pushed its algorithms past a tipping point.

At its core, Navlakha’s approach to these algorithms includes the idea that biological systems perform computations. He originally studied brains because they are “such an elegant computer, doing all kinds of things that modern, human-made computers can’t do,” he said.

When he was at the Salk Institute, he spoke with colleagues in plant biology who told him about research that examined how plants modify their shape amid a changing environment, which is what triggered his interest in plants.

One of the themes of his work involves understanding trade-offs. Doing well in one task typically means doing worse in another. He likened this analysis to investing in stocks. An investor can put considerable funds into one stock, like Apple, or diversify a portfolio, investing less money per stock in a variety of companies from different sectors.

“We’ve been studying how plants hedge” their bets, he said. The hedge in this description bears no relation to a collection of plants at the edge of a property.

A plant can create one huge seed that might survive a drought or other environmental threat, or it can diversify the types of seeds. “We’re really interested in understanding these trade-offs, how they hedge, and what kind of strategies” they employ, he said.

Ziv Bar-Joseph, a professor of computer science at Carnegie Mellon University who has known Navlakha for over eight years, suggested Navlakha has “deep insights.” 

In an email, Bar-Joseph described Navlakha’s biggest achievement as his work that shows how the brain uses a computational method to store and retrieve smells. 

“This work both solved an important mystery about how the brain functions and informed us on novel usages of an important computational method, thus contributing to both areas,” Bar-Joseph explained.

Navlakha doesn’t have a typical laboratory filled with beakers, pipettes or plants growing under various conditions. He relies on wet labs to provide data that he then interprets and analyzes as a part of the Simons Center for Quantitative Biology. While his training is in computer science, he has shown a talent for experimental research as well. 

Bar-Joseph recalled how Navlakha performed experiments and analysis. In a short time, Navlakha “was able to master very involved techniques and obtained very good results.” 

Navlakha explained that the work he does colors the way he sees the world. “People walk by plants without paying attention to the incredible computations that they’re doing to keep us on this planet,” he said. “Computation is the basis of life.”

A resident of Great Neck, Navlakha recently married Sejal Morjaria, an infectious disease physician at Sloan Kettering, who works with patients who have cancer. The couple met through an online dating app when he was in San Diego and she lived in New York. They chatted for a while without any expectation of seeing each other, until he traveled to Washington, D.C                                 for a conference.

Navlakha enjoys playing numerous sports, including tennis and basketball. He also played hockey. He and Morjaria participate in yoga classes together.

Navlakha, who grew up in Miami, Florida, said he had to readjust to life on Long Island after living in Southern California for several years. “San Diego makes you weak,” he joked.

In his work, Navlakha hopes to bring together two fields in a different way.

Given the importance of computations, Navlakha appreciates a corollary to the concept proposed by Rene Descartes’ “I think, therefore I am.” For Navlakha, “I compute, therefore I am” describes processes he studies among animals and plants.