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Power of 3

Yali Xu and Christopher Vakoc at the 2013 Don Monti Memorial Research Foundation’s Anniversary Ball. Photo from Yali Xu

By Daniel Dunaief

It’s like a top scorer for another team that the greatest minds can’t seem to stop. Whatever they throw at it, it seems to slip by, collecting the kinds of points that can eventually lead to a life-threatening loss. The scorer is a transcription factor called MYB, and the points it collects can, and often do, lead to breast and colon cancer and leukemia.

Researchers have known for over 30 years that stopping MYB could help with cancer treatment. Unlike other possible targets, however, MYB didn’t seem to have the kind of structural weakness that pharmaceutical companies seek, where developing a small molecule could prevent the cancer signals MYB delivered. Some researchers have decided that drugs won’t stop this high-profile cancer target.

Cold Spring Harbor Laboratory Associate Professor Christopher Vakoc and his graduate research assistant Yali Xu, however, have figured out a way around this seemingly intractable problem. The CSHL scientists recently published their results in the journal Cancer Cell.

MYB binds at a small nub to a large and important coactivation protein called TFIID (which is pronounced TF-two-D). This protein is involved in numerous life functions and, without it, organisms couldn’t survive. Vakoc and Xu found that they could use a small peptide decoy to trick MYB into believing it had attached to this protein when, it reality, it hit the equivalent of a molecular dead end.

In a mouse model of acute myeloid leukemia, this peptide caused leukemias to shrink in size by about 80 percent. “What we’ve discovered is head and shoulders above anything we’ve come across before,” Vakoc said.

As with many scientific discoveries, researchers have to clear numerous hurdles between this conceptual discovery and any potential new cancer therapy. “This is not a medicine a person can take,” Vakoc said.

Indeed, scientists and pharmaceutical companies would need to study what leukemia cells escaped this type of treatment to understand how a cancer might rebound or become resistant after an initial treatment. “Our goal is to develop something with longer lasting effects” that doesn’t become ineffective after three to six months, Vakov said. He described understanding the way a disease reacts to a treatment as an “arms race.” Nature inevitably “finds a way to outsmart our decoy. We’d like to know how [it] does it. We’re always trying to study both sides and trying to anticipate” the next steps.

Down the road, Vakoc could foresee researchers and, ultimately, physicians using this kind of approach in combination with other drugs or therapies, the way doctors now provide patients who have the HIV infection with a cocktail of drugs. Conceptually, however, Vakoc is thrilled that this work “highlights what’s possible.”

One of the most encouraging elements of this approach, Vakoc said, is that it combats MYB without harming organ systems. When the researchers gave the treatment to rodents, the mice were “running around, eating and gaining weight.” Their body tissues appeared normal, and they didn’t demonstrate the same sensitivity that is a common byproduct of chemotherapy treatment, such as losing any hair or having problems in their gut.

An important step in this study, Vakoc said, was to understand the basics of how MYB and TFIID found each other. That, Xu said, was one of the first steps in her graduate work, which took about five years to complete.

In Vakoc’s lab, which includes 13 other researchers, he described how scientists make thousands of perturbations to cancer and normal cells, while they are hunting for cancer-specific targets. By using this screening technique, Vakoc and his team can stress test how cancer cells and normal cells react when they are deprived of certain proteins or genes.

“This began as a screen,” he said. “We took leukemia and normal blood cells and did a precise comparison of the perturbation.” They searched for what had the most specific toxicity and, to their surprise, found that interfering with the binding between MYB and TFIID had the strongest effect. “Once we understood what this nub was doing, we applied all kinds of biochemical assay experiments,” Vakov added.

Ultimately, the peptide they found was a fragment of a larger protein that’s active in the cell. Vakoc credits Xu for her consistent and hard work. “When we started on this hunt, we had no idea where this was headed,” he said. Xu was “relentless” in trying to find the answers. “She pieced it all together. It took a great amount of imagination and intellect to solve this puzzle.”

Vakoc suggested that Xu, who plans to defend her thesis this spring and graduate this summer, has set a great example for the other members of his lab. “I now have 13 other people inspired to outdo her work,” he said. “We know we have a new standard.”

Xu is grateful for the support she has received from Vakoc and appreciates the journey from her arrival as a graduate student from China to the verge of her graduation. “It’s very satisfying when you look back and think how things evolved from the beginning to the end” of her graduate work, said Xu, who lives near Huntington Village and enjoys the chance to visit local restaurants and sample coffee and ice cream when she isn’t conducting research toward her doctorate.

The scientific effort, which was published recently, has attracted the attention of others, particularly those who are studying MYB. Vakoc recently received an email from members of a foundation that is funding research on a solid tumor in which scientists believe MYB plays a role. He is writing grants to get more financial support to pursue this concept. Vakoc is encouraged by the opportunity to make progress with a protein that has been “staring [scientists] in the face for three decades.”

Alexander Krasnitz. Photo by Gina Motis?CSHL

By Daniel Dunaief

Seeing into the future is one of the most challenging, and potentially rewarding, elements of studying cancer. How, scientists and doctors want to know, can they take what evidence they have —through a collection of physical signs and molecular signatures — and determine what will be?

Researchers working on a range of cancers have come up with markers to divide specific types of cancers to suggest the likely course of a disease.

With prostate cancer, the medical community uses a combination of the prostate-specific antigen (PSA), magnetic resonance imagining (MRI) and biopsy results, which are summarized as the Gleason score, to diagnose the likely outcome of the disease. This analysis offers probable courses for developing symptoms.

Cold Spring Harbor Laboratory Professor Michael Wigler and Associate Professor Alexander Krasnitz recently published an article in the journal Cancer Research of a promising study of eight patients that suggests a way of using molecular signatures to determine whether a prostate is likely to contain cells that will threaten a patient’s health or whether the cells are in a quieter phase.

The third most common cancer among Americans, prostate cancer kills an average of 21,000 men each year. Doctors and their patients face difficult decisions after a prostate cancer diagnosis.

“A major challenge is to determine which prostate cancers have aggressive potential and therefore merit treatment,” Herbert Lepor, a professor and Maritin Spatz Chair of Urology at the NYU Langone Medical Center School of Medicine, explained in an email. A collaborator on the study, Lepor provided a clinical perspective and shared patient samples.

A conversation with a doctor after such a diagnosis may include a discussion about how the cancer is not likely to pose an immediate risk to a patient’s life, Krasnitz explained. In that case, doctors do not recommend surgery, which might cause other problems, such as incontinence.

Doctors typically recommend active surveillance to monitor the disease for signs of progression. Some patients, however, make their own decisions, electing to have surgery. The Gleason score, which is typically 3, 4 or 5, can’t provide “meaningful information regarding aggressiveness of the disease,” Lepor explained. “The unique genetic profile of a cancer cell should have infinite more prognostic capability.”

Wigler and Krasnitz, who have been collaborating since Krasnitz arrived at CSHL in 2005, use several hundred single cells from biopsy cores. The research group, which Krasnitz described as a large team including research investigator Joan Alexander and computational science manager Jude Kendall, look for cells with a profile that contains the same irregularities.

“If you take two cells and their irregularities are highly coincident, then perhaps these two cells are sisters or cousins,” Krasnitz explained in an email. “If they are less coincident, then the two cells are more like very distant relatives. We looked for, and sometimes found, multiple cells with many coincident irregularities. This was our evidence for a clonal population.”

By looking at how many biopsy cores contain clonal cells, and then determining how far these clonal cells have spread out through the prostate, the researchers gave these patient samples a score. In this group, these scores, determined before any intervention, closely tracked a detailed analysis after surgery.

“We get a high correlation” between their new score and a more definitive diagnosis that comes after surgery, Krasnitz said. “Our molecular score follows the final verdict from the pathology more closely than the pathological score at diagnosis from the biopsy.”

Wigler, Krasnitz, Lepor and other researchers plan to continue to expand their work at Langone to explore the connection between their score and the course of the disease. Lepor explained that he has been collaborating with Wigler and Krasnitz for five years and suggested this is “an exceptional opportunity since it bridges one of the strongest clinical programs with a strong interest in science (NYU Urology) and a world-class research program interested in clinical care (CSHL).

The research team has submitted a grant to the National Institutes of Health and hopes to expand their studies and provide “compelling evidence” that single-cell genomic mapping “will provide an unmet need defining aggressiveness of prostate cancers,” Lepor said.

While Krasnitz is encouraged by the results so far, he said the team has work ahead of them to turn this kind of analysis into a diagnostic tool physicians can use with their patients.

Realistically, it could take another five years before this score contributes to clinical decision-making, Krasnitz predicted. “You can’t do it overnight,” he cautioned. When this test offers specific signals about the likely outcome for a patient, a researcher would likely need to wait several years as the patient goes on active surveillance to see whether the score has predictive value for the disease in a larger population.

Krasnitz has a sense of urgency to produce such a test because there is “no point in delaying something that potentially looks promising and that one day might well be a part of a clinical practice.”

The work that led to their article took three or four years to complete. The study required technical improvements in the way the researchers processed DNA from single cells. They also had to develop algorithmic improvements that allowed them to use copy number variation to determine clonal structure. The scientists tapped into a wealth of information they gained by taking cells from several locations within the prostate.

Krasnitz was born in Kiev, now part of the Ukraine, and grew up in the former Soviet Union. A resident of Huntington, he lives with his wife Lea, who produces documentaries, including “Maria — The Russian Empress” on Dagmar of Denmark, who was also known as Maria, mother of Nicholas II, the last Romanov czar who was overthrown in 1917. As for his work with Wigler, Krasnitz is excited about the possibilities. “It’s very encouraging,” he said. “We look forward to a continuation of this.”

Above, Scott Kelly, right, with his twin brother Mark. Photo by Robert Markowitz

By Daniel Dunaief

Dear readers,

Each week, in the Power of Three, Times Beacon Record News Media highlights the efforts of dedicated scientists at Stony Brook University, Cold Spring Harbor Lab and Brookhaven National Lab. This week, we will feature astronaut Scott Kelly, who set an American record for consecutive days in space.

Kelly not only conducted research on flowers and performed space walks while orbiting the Earth, he also became his own living laboratory, taking blood samples to compare to his twin brother Mark. Some day, the pioneering studies from the twins may turn the dream of a trip to Mars and beyond into a reality.

He had a spectacular view for close to a year, watching 16 sunrises and sunsets each day aboard the International Space Station. He even pretended to catch a pass thrown by television host Stephen Colbert from over 249 miles away.

A view of Earth aboard the ISS. Photo by Scott Kelly

Astronaut Scott Kelly set an American record for consecutive days in space, floating from one part of the multinational station to another for 340 days. During that journey, in which Kelly traveled over 143 million miles with cosmonaut Mikhail Kornienko, the New Jersey native conducted numerous experiments, including on himself. NASA plans to use the information gained from Kelly’s mission to design future extended trips into space, including any future journey to Mars.

Kelly, who returned to Earth in March of 2016, recently published a book titled “Endurance: A Year in Space, a Lifetime of Discovery” (Knopf), in which he shared a long journey from underachieving high school student to celebrated astronaut.

“There are things about the experience that are absolutely amazing,” he said, “but, then, at the same time, the things that make everything amazing also make other things more difficult.” For starters, moving from a Soyuz rocket to the space station isn’t as simple as stepping out of a car and opening another door. When the rocket attaches to the station, it can take hours to equalize the pressure. In a film or documentary of life in space, “You can’t show 11 hours of docking or six hours of preparation to go out on a space walk,” Kelly said.

Once aboard, the astronaut, who had lived on the space station on an earlier six-month mission, said he had to adapt to the logistics of meals in space. Gravity doesn’t hold the astronauts on a chair or their food on a plate. For close to a year, he couldn’t relax his body while eating, which meant that he felt like he was standing and balancing during meals.

Scott Kelly and Mark Kelly in 1967. Photo from Scott Kelly

Kelly said the transition from life on Earth to the station, and then back again, requires adjustments. One of the most significant scientific efforts he was a part of originated from a conversation Kelly had with a NASA scientist, asking him what he should say if a reporter asked if NASA was comparing the changes in his body to those of his identical twin brother Mark. The NASA scientist then asked if he and his brother, who is a retired astronaut, would consider participating in such an effort. Thus, the NASA Twins Study was born.

Before his mission, Kelly got several small tattoos on his body, to make sure he was drawing blood from the same place each time. Scientists have spent over a year examining changes in his genes. While more results will be published next year, the work so far shows an uptick in the methylation of Scott’s DNA. That means he potentially had more signals that can turn on or off genes.

Additionally, Scott’s telomeres, which protect the ends of DNA strands, were longer during the same period than those of his Earth-bound twin. Also, Scott returned from space closer to two inches taller than his brother because the discs in Scott’s spinal column weren’t compressed by gravity. That difference didn’t last long, however, as his spine returned to normal after he came back to Earth.

While life aboard the space station included movies like “50 Shades of Grey” in Russian and books like “The Right Stuff” by Thomas Wolfe, which Kelly said inspired him to become an astronaut, it also involved unusual environmental challenges.

Scott Kelly. Photo from NASA

As part of his training, Kelly needed to recognize any of the symptoms of carbon dioxide buildup in his system. His girlfriend Amiko Kauderer provided some necessary observations during one particular conversation. Within seconds of speaking with him, Kauderer told him to stop talking to her and check the carbon dioxide levels. She quickly had diagnosed that the carbon dioxide levels, while not dangerously high, were above Kelly’s comfort level.

Kelly explained that the routine in space doesn’t leave much time for relaxation or down time. “You have one day on the weekend when you’re off,” he said. “You can arrange your workweek such that you’re taking advantage of that. You still have stuff like cleaning the space station and you still have to exercise and organize the living environment.”

Indeed, astronauts need to exercise aboard the station or risk losing bone mass and encountering muscular atrophy during their missions. In addition to stretching his body, Kelly expanded the typical limits of his responsibility for some scientific experiments.

As he chronicled in his book, he was following a protocol for growing zinnias. When the flowers weren’t flourishing, Kelly asked NASA if he could take over the decision-making process, which NASA approved. “The satisfaction came more from the idea that it was an experiment that we were making the decisions on and controlling,” he said.

Typically, he reported what he saw to NASA, and scientists back on Earth came up with a plan that they sent to Kelly. While they required considerable effort, the astronaut also took satisfaction in the three space walks he conducted during his journey. As with the movie “Gravity,” Kelly recognized the danger that orbiting space debris, even small pieces, could pose for the space station and him. “You could get hit with something that would not only put a hole in your visor, but would put a hole in your head,” he said.

Kelly didn’t bother watching out for such objects when he’s outside the station because he’d “never see it coming at you at 17,000 miles an hour.” As for what he could see from space, Kelly watched wildfires in California and Hurricane Patricia, which was a storm off the coast of Oman. In addition to information NASA might take from his mission that could inform decisions about future missions, Kelly hopes people view his experience, and his success, as a model for them.

“There’s a lot of opportunities for redemption in the United States,” Kelly said. “It’s not the preferred or easy path, but it is a path, especially in this country.”

Minghua Zhang

By Daniel Dunaief

Minghua Zhang spent a sabbatical year in China trying to improve climate models, which included analyzing errors of current models.

A professor at the School of Marine and Atmospheric Sciences at Stony Brook University, Zhang focused on the Southern Great Plains of the United States. He explored how the current models did not accurately simulate convection, which created a warm and dry bias.

In convection, heat and moisture get carried upward. The models account for summer rainfall but do not calculate the organizational structure of the convective systems, which led them to simulate insufficient precipitation.

By adding in the new information, Zhang predicts in recent research published in the scientific journal, Nature Communications, that the projected warming in the region would be 20 percent less than previously thought. Precipitation, meanwhile, would be about the same as it is today, instead of the drying that was previously anticipated.

“The resolution of the models is not high enough to predict the change of the convection with a high degree of precision,” Zhang explained in an email.

He suggested that using 10 times the specificity of model calculations, he expects a clearer picture of the likely climate by the end of the 21st century. This is like looking through binoculars at a nondescript moving shape in the distance. By adding focal power to the lens, the image can become sharper and clearer.

The climate is a big picture view of trends over the course of many years. That is distinct from weather, which involves day-to-day variations and which meteorologists describe each morning and evening with colorful images of cold and warm fronts on local maps.

“You have many things you can’t see and now you have better binoculars,” he suggested. “This tiny thing in the binoculars can make a bigger impact. What we see is that these [variables] actually matter.”

Zhang suggested that a climate model that better accounts for summer rainfall still includes higher temperatures in this sensitive region. “The warming is going to be there and will be significant,” he said. If carbon dioxide emissions continue at their current rate, the warming will still be about five degrees by the end of the century, he suggested. That, he predicted, will still have a significant impact on agriculture.

Edmund Chang, a professor at the School of Marine and Atmospheric Sciences at Stony Brook who was not involved in this study, said this research addresses “a specific bias of the model that needs to be taken care of.” He added that researchers know that the “models are not perfect” and suggested that the “scientific and climate modeling community is trying to refine and improve” these tools.

Chang agreed that the refinement “doesn’t change the fact that we still project a large increase in the temperatures over the central United States.”

The Southern Great Plains region has some unique elements that make climate predictions challenging. It has considerable organized convection, which increases the occurrence of tornadoes. There’s also a large coupling between the soil moisture and the clouds, which means that whatever happens on the land has feedback for the atmosphere.

Zhang said his research focus is on climate simulation modeling. He knew the models had problems simulating convective events, which is why he started exploring this specific region. “The way the models are constructed, the granules are not small enough,” he said.

Chang expected that this work would “spur more research on trying to understand this mechanism. Model developers will need to try to find out how to improve the physical model.”

Zhang has been working for the last two years with scientists from Tsinghua University in China, which included his time on sabbatical. “When you are on sabbatical, you have more time to really think about problems,” he said.

Chang added that sabbaticals can provide some time to focus on specific scientific questions. During a typical semester that includes administrative responsibilities and teaching, professors “are very busy,” He said. “We really don’t have an extended period of time to focus on one project. The sabbatical gives us a chance to focus.”

Zhang hopes this study “motivates people to think about how to improve their models in describing” other climate systems.

One of the many challenges scientists like Zhang face in developing these climate models is that their computers are still not powerful enough to resolve elements like clouds, which not only dot the landscape and provide shade during the summer but also send the sun’s energy back into space.

The system he’s studying is “chaotic by nature,” which makes accounting for elements that change regularly challenging. He suggested that these studies were akin to the butterfly effect. Scientists have suggested that someone who went back in time and committed a seemingly trivial act, like killing a single butterfly, might return to his familiar time and surroundings to discover profound changes.

While that’s an exaggeration, that’s still the kind of system he said researchers are confronting as they try to account for, and weigh, climate defining factors. That’s why he’s looking for statistical, or probabilistic, predictions that are averaged over time periods.

The United States, China and the European Union are all pursuing more powerful computers for these kinds of applications, Zhang said.

Zhang, who is the editor-in-chief of the Journal of Geophysical Research: Atmospheres, has been involved in an advisory capacity with the United States Department of Energy in developing these models. A

s for this specific effort, Zhang said he was pleased that the paper pointed out a research direction to refine models for climate in this area. “What we see is that these things [including convection] actually matter,” he said. “That’s the main contribution of this paper.”

The greater bamboo lemur will struggle to survive amid a shorter rainy season. Photo by Jukka Jernvall

By Daniel Dunaief

An elusive primate is living on a shrinking island within an island. The greater bamboo lemur, which is one of the world’s most endangered primates, now inhabits a small section of Madagascar, where it can find the type of food it needs to survive.

The greater bamboo lemur, which was one of numerous lemurs featured in the 2014 iMax movie, “Island of Lemurs: Madagascar,” is finding that the time when it can eat the most nutritious types of bamboo is narrowing each year amid a longer dry season.

Patricia Wright has dedicated her life to helping lemurs in Madagascar. File photo from SBU

In a publication last week in the journal Current Biology, Patricia Wright, the founder of Centro ValBio research campus, driving force behind the creation of Ranofamana National Park and a distinguished professor of anthropology at Stony Brook University, along with several other researchers, including Jukka Jernvall from the University of Helsinki and Alistair Evans from Monash University, showed that the population of lemurs is threatened by a changing climate. The bamboo that sustains the greater bamboo lemurs depends on water to produce shoots that are higher in nutrition.

Indeed, when the rains come, the new bamboo shoots are “filled with protein,” said Wright. Jernvall, however, predicted that the driest season will get longer by a day each year. By 2070, rains necessary for bamboo growth and greater bamboo lemur survival will be delayed by as much as two months.

This is problematic not only for the current generation of greater bamboo lemurs but also for the more vulnerable younger generations, who need their lactating mothers to eat more nutritious bamboo to help them grow. Bamboo shoots typically come up from the ground about two weeks after the rains begin, in the middle of November. Bamboo lemurs, whose annual clocks are set to the rhythm of an island off the southeast coast of Africa that is the size of California, are born around the time of these bamboo-shoot-producing rains.

“Any village elder will tell you that the rains used to come at about Nov. 15 and continue until March 15,” Wright said. “That’s the way the world was, even in the 1980s and 1990s and probably many years before that. Suddenly, we started to get some evidence of climate changes and periods of a longer dry season.”

Above, a mother greater bamboo lemur holds her infant, which weighs about half a pound at birth. Photo by Jukka Jernvall

Wright is currently in Madagascar, where she says there is a drought right now. “No water for our research station means no electricity since we are near a hydroelectric power plant,” she explained by email. In fact, in some years, the rains start as late as January, which reduces the food offerings for the mother lemur, who weighs about 6.5 pounds, and her offspring, who need considerable nutrition to grow from birth weights Wright estimates are less than half a pound. The lemur mother “has to have nutritious shoots to feed her baby milk,” Wright said. “She can survive on leaves and trashy stuff in the culm, but she can’t raise her babies” on it.

Wright and Jernvall worked together in 2005 on a study of climate and another type of lemur called sifakas, whose name comes from the alarm sound it makes. In their earlier work, Wright and Jernvall found that aging sifakas with worn teeth could still produce offspring, but that their infants typically died if the weather was dry during the lactation season, Jernvall explained in an email.

“This alerted us about the potential impact of climate change,” he continued. “The bamboo lemur were an obvious concern because they are critically endangered and because they eat the very tough bamboo.”

Jernvall said the work on bamboo lemurs combines Wright’s efforts in Madagascar with climate modeling he performed with Jussi Eronen at the University of Helsinki and an analysis of dental features conducted by Evans and Sarah Zohdy, who is currently at Auburn University. Stacey Tecot, who is on sabbatical from the University of Arizona, also contributed to the research.

Wright believes some efforts can help bring these bamboo lemurs, who survive despite consuming large amounts of cyanide in their bamboo diet, back from the brink. Creating a bamboo corridor might improve the outlook.

Growing bamboo would not only benefit the lemurs, who depend on it for their survival, but would also provide raw materials for the Malagasy people, who use it to construct their homes, to build fences and to cover their waterways.

Bamboo corridors could be a “win-win situation,” where scientists and local communities grew and then harvested these hearty grasses, Wright continued. She has started a bamboo pilot study near one of the small populations of lemurs and hopes the lemurs can expand their range.

The greater bamboo lemur will struggle to survive amid a shorter rainy season. Photo by Jukka Jernvall

Like other animals with unusual lifestyles, the greater bamboo lemurs offer a potential window into an unusual adaptation. Through their typical diet, lemurs consume a high concentration of cyanide, which is stored in the bamboo. Understanding the bamboo lemur could provide evidence of how one species manages to remain unaffected by a toxin often associated with spies and murder mysteries.

As a part of her efforts to improve the chances of survival for this lemur, Wright is considering moving some lemurs to a protected area. She needs permission from Madagascar officials before taking any such actions and recently met with Madagascar National Park official to discuss such remediation efforts.

In Madagascar, Wright said observing the bamboo lemur is challenging because it is such a “cryptic animal.” She has sat beneath a tree where a lemur is hiding for seven hours waiting for it to emerge, watching as a lemur brought in its legs and curled up its body to hide from the scientist’s inquisitive eyes. “I’d get really hungry, so they would win and I would leave,” Wright recalled.

She suggests that the data in the Current Biology article demonstrates the urgency to take action to protect these primates. “We are trying our best to help the bamboo lemur not go extinct,” she said. “Bamboo corridors should help, but we may have to irrigate the bamboo during November to January.”

Pavel Osten. Photo by Joelle Wiggins

By Daniel Dunaief

Male mice, as it turns out, might also be from Mars, while female mice might be from Venus. Looking at specific cells in the brain of rodents, Cold Spring Harbor Laboratory Associate Professor Pavel Osten has found some noteworthy differences in their brain cells.

In the scientific journal Cell, Osten presented data that showed that in 10 out of 11 subcortical regions of the mouse brain, female mice showed greater flexibility and even more cells. These regions of the brain are responsible for reproduction, and social and parenting behaviors. “There were more cells [in these regions] in the female brain, even though the brains tended to be bigger in the males,” Osten said.

These results are part of a multiyear collaboration called the National Institutes of Health’s Brain Initiative Cell Census Network.

In the recent Cell article, Osten indicated that his analysis offered a surprising result in the number of cells of specific types in various regions of the cortex. “Those areas that have higher cognitive functions have different compositions,” he said. The ratios of cell types “vary according to the level of cognitive function.” In retrospect, Osten indicated that he saw the logic in such a cellular organization. “It makes sense that different cortical areas would have different cell type composition tuned to the specific cortical functions,” he explained.

In an email, Hongkui Zeng, the executive director of structured science at the Allen Institute for Brain Science, in Seattle, Washington, suggested that “people never looked at this issue carefully before. She added that the “sexual dimorphism was somewhat expected, but it is still interesting to see the real data.”

Pavel Osten sailing in St. Barts and St. Martin last summer. Photo from Pavel Osten

Osten used a system called qBrain to see and count inhibitory neurons in the mouse brain. Over the next five years, he and his collaborators will build an online resource database for other researchers that will have distribution maps for numerous cell types throughout the mouse brain.

Osten estimates that there could be hundreds or even a thousand cell types within the brain that are largely uncharacterized in their specialized functions. A cell type is defined by its function in terms of its morphology, including dendritic and axonal branches. These cells are also defined by their physiology, which includes spiking properties, and connectivity, which indicates which cell is talking to other cells.

The anatomy and physiology of the cells will validate these transcriptome single-cell RNAseq studies, which probe for the variability between cells based on their gene expression, which includes differences due to day-to-day variability and differences from distinct cell types.

By analyzing the location and modulatory functions of these cell types, Osten would like to determine ways human brains differ from other animal brains. “In the human, we can mainly analyze the location and distribution which includes the ratios of specific cell types and our hypothesis is that fine-tuning the ratios of neuronal cell types may be a powerful evolutionary mechanism for building more efficient circuits and possibly even for distinguishing between human and other animals,” Osten explained in an email.

Humans, he continued, don’t have the largest brains or the most neurons. At one point, spindle neurons were considered unique to humans, but other researchers have shown that great apes, elephants and cetaceans, which is a group that includes whales and dolphins, also have them.

Osten’s hypothesis is that one of the differences is that the ratios of cells of different types built a computational circuit that’s more powerful than the ones in other species.

When he studies mouse brains, Osten collects information across the entire brain. With humans, he explores one cubic centimeter. The human work is just starting in his lab and represents a collaboration with Zsófia Maglóczky from the Hungarian Academy of Sciences at the Institute of Experimental Medicine in Budapest.

Each mouse brain dataset is between 200 gigabytes and 10 terabytes, depending on the resolution Osten uses to image the brain. He can process 10 terabytes of data in about a week.

Osten uses machine learning algorithms that develop with guidance from human experts. This comes from a long-standing collaboration with Sebastian Seung, a professor of computer science at Princeton University.

He suggested that the research has a translational element as well, offering a way to study cellular and wiring elements characteristic of diseases. “We are looking at several of the models that are well established for autism.” He is also planning to write grants to find funds that supports the analysis of brains from people with schizophrenia and Alzheimer’s disease.

The analysis is a promising avenue of research, other scientists said. “It will be extremely interesting to compare the ratio of different cell types in various diseased brains with normal healthy brains, to see if the diseases may preferentially affect certain cell types and why and how,” Zeng explained in an email. “This could be very helpful for us to devise therapeutic means” to treat diseases.

Zeng has known Osten for about seven years. Last year, she began a collaboration using qBrain to quantify cell types.

A current resident of Williamsburg, where his reverse commute is now about 40 minutes, Osten works with a company he and Seung started called Certerra, which provides a rapid analysis of brain activity at different times. The company, located in Farmingdale, has a growing customer base and has a staff of about five people.

As for the recent work, researchers suggested it would help continue to unlock mysteries of the brain. This research is “a basic but important step toward understanding how the brain works,” Zeng added. “This paper provides a new and efficient approach that will be powerful when combined with genetic tools that can label different cell types.”

Heather Lynch at Spigot Peak in the Antarctic. Photo by Catherine Foley

By Daniel Dunaief

Counting penguins is like riding the highs and lows of Yankees rookie Aaron Judge’s home run streaks, followed by his series of strike outs. He’s not as bad as his strike outs suggest, although he’s also not a sure thing at the plate either.

Similarly, in local populations, the Adélie penguin, which waddles to and fro squawking on land and gliding gracefully through the water, isn’t as clear a barometer of changes in the environment. Also, like Judge, when populations rise and fall, people are eager to offer their explanations for exactly what’s happening, even if the sensational explanations — he’s not that good, no, wait, he’s the greatest ever — may overstate the reality.

Heather Lynch visits Cape Lookout in Antarctica during recent trip that included an NBC TV crew that produced a feature for ‘Sunday Night with Megan Kelly.’ Photo by Jeff Topham

“We have to be careful not to be overreactive,” said Heather Lynch, an associate professor of ecology and evolution at Stony Brook University. “The concern is that, when we see increases or decreases, the implication is that there’s a miraculous recovery or a catastrophic crash.”

That, however, is inconsistent with Lynch’s recent results, which were published in the journal Nature Communications. Examining penguin data from 1982 to 2015, Lynch, Christian Che-Castaldo, who is a postdoctoral researcher in Lynch’s lab, and nine other researchers looked to see if there’s a way to connect the size of the population to changes in the environment. The study involved two teams of researchers, one supported by NASA and the other backed by the National Science Foundation.

“It’s a noisy system,” Lynch concluded. Managers of the populations of krill, small crustaceans that are the mainstay of the Adélie diet, try to use time series of key indicator species to understand what’s going on in the marine realm. In this article, Lynch said, local Adélie penguin populations may not be a clear signal of the health of the krill stocks because penguin abundance fluctuates for reasons she and her team couldn’t pinpoint.

These penguins, which Lynch has counted during her field work in the Antarctic, exhibit changes in population that can run contrary to the health, or stressed condition, of the environment.

“You can’t have your finger on the pulse” with the available data, Lynch said. “Part of our inability to model year-to-year changes is because we can’t measure the right things in the environment.”

The drivers of abundance fluctuations likely involve other animals or aspects of the krill fisheries they couldn’t model, she suggested.

“There’s a lot we don’t know about what penguins do under water, where they spend a large portion of their time and where they feed,” Grant Humphries, who was in Lynch’s lab for a year and now runs his own data science company in Scotland called Black Bawks Data Science Ltd, explained in an email. “The signals that drive year to year changes might actually lie there.”

Tom Hart, a researcher of the Department of Zoology at the University of Oxford who was not involved in this study, explores local scale variation in penguin populations. Locally, Hart said in an interview by Skype, “Things are incredibly noisy. When you aggregate, you get good signals, but with some error.” He suggested that this research drives him on further, showing that “local influences are important” because there’s so much variance left to explain. Lynch’s research is “a really good study and shows very well what’s happening on the regional scale, but leaves open what happens below that,” he said.

Indeed, Lynch suggested that by putting sites together, researchers can look at larger areas, which provide a clearer picture on shorter time scales.

Michael Polito, an assistant professor in the Department of Oceanography and Coastal Sciences at Louisiana State University who was not involved in the study, suggests that this extensive analysis indicates that “you can still look at the relationship between the abundance of penguins and the environment in a robust way. Even though any individual time series may not be the best way to understand these relationships, in the aggregate you can use them.”

Managers who set fishery policies in Antarctic waterways are often concerned about harvesting too much krill, leaving the penguins without enough food to survive and feed their chicks.

The challenge with this result, Lynch acknowledges, is that it makes setting krill boundaries more difficult.

A strategy that involves resetting conservation targets based on annual monitoring appears unrealistic given these results, Lynch said. “From a practical standpoint, we threw in everything we could and could explain only a tiny fraction of the variation,” she said.

Hart added that this is “not an argument to fish away,” he said. “We need to understand what’s going on at a local scale and we’re not there yet.”

To get people involved, Lynch and her team created a science competition, called Random Walk of the Penguins, to see who could predict the overall penguin populations for Adélie, gentoo and chinstrap penguins from the 2014 to 2017 seasons.

The competition, which was a collaborative effort with Oceanites, Black Bawks Data Science and Driven Data included $16,000 in prize money, which was donated by NASA. Entrants could use data from the 1982 through the 2013 seasons. The contest drew competitors from six continents. Of the five winners, all were from different countries.

Humphries, who was the lead on the data science computation, said the results were “somewhat humbling” because competitors were able to make “decent predictions” using only the time series. “With long-term predictions and for determining the tipping points, there is still a lot of work to be done.”

Lynch is relieved that her co-authors supported the direction the article took. “I’m a skeptic by nature and more than happy to throw orthodoxy (or even my own previous work) under the bus,” she wrote in an email. “I do hope that others will use our model as a starting point and we’ll never go back to the old days where everyone looked only at ‘their sites.’”

Adam Gonzalez. Photo from SBU

By Daniel Dunaief

More than four days after lift off, pioneering astronauts Neil Armstrong and Buzz Aldrin had landed in the Sea of Tranquility on the surface of the moon. The NASA schedule, which included preparing the vehicle for an emergency abort of the mission in the event of a problem, called for a nap of four hours. Once they were there, however, Armstrong and Aldrin couldn’t imagine taking a four-hour respite.

“Both Armstrong and Aldrin were, understandably, excited about where they were and decided to forgo the sleeping and changed history,” Thomas Williams, element scientist in Human Factors and Behavioral Performance at NASA, described in an email.

A future trip to Mars, however, would involve considerably longer delayed gratification, with the round trip estimated to take over 400 days. The stresses and strains, the anxiety about an uncertain future and the increasing distance from family and friends, not to mention the smell of cut grass and the appearance of holiday decorations, could weigh on even the most eager of astronauts.

Determined to prepare for contingencies, NASA is funding research to understand ways to combat the mental health strains that might affect future astronauts who dare to go further than anyone has ever gone.

‘Being in long-duration space missions with other people, we expect the mental health risk will be much more elevated’. — Adam Gonzalez

Gonzalez, an assistant professor of psychiatry at Stony Brook University, received over $1 million in funding from NASA to explore ways to help these future astronauts who might be anxious or depressed when they’re on the way to the red planet.

In a highly competitive process, Gonzalez received the financial support to provide guidance on what NASA considers a low-probability, high-consequence mental health event, according to Williams.

Gonzalez “was funded because of the soundness of his research proposal and the clinical and technological expertise of the research team he assembled to help NASA address this research gap,” Williams explained.

Gonzalez started providing three different types of psychological assistance to 135 people in the middle of September. He is testing ways to provide mental health assistance with a delay that could require over 40 minutes to travel back and forth.

One group of test subjects will use a system called myCompass, which is a mental health self-help program. Another group will use myCompass coupled with a delayed text messaging response from a therapist, and a third will have a myCompass system along with delayed video messaging from a therapist.

“Being in long-duration space missions with other people — in this case, months and potentially years — stuck in extremely close quarters with others, we expect the mental health risk will be much more elevated relative to what they are going to have on the International Space Station,” Gonzalez said.

Williams said astronauts to date have not had any diagnosable disorders, but NASA has seen fluctuations in their mood, which appears linked to workload demands and the phase of the mission, Williams said. For astronauts, NASA does not want a continuing negative trend that, over a longer term, could turn into a problem.

“Part of what we hope to achieve with [Gonzalez’s] research is a validated approach to address any of these concerns,” Williams said, adding that astronauts typically understand that their contributions involve work in “high-demand, extreme environments,” Williams said.

Still, like explorers in earlier centuries, astronauts on a trip to Mars will journey farther and for a longer period of time than anyone up to that point. MyCompass is a “good, efficacious program” that takes a “trans-diagnostic cognitive behavioral therapy approach,” Gonzalez said. He suggested that the program is broad enough to help individuals manage their emotions more generally, as opposed to targeting specific types of health disorders.

Gonzalez emphasized that the choice of using myCompass as a part of this experiment was his and might not be NASA’s. The purpose of this study is to investigate different methods for communicating for mental health purposes when real-time communication isn’t possible.

William suggested that Gonzalez’s work, among others, could lead to individualized procedures for each astronaut. In addition to his work with NASA, Gonzalez also assists people at the front lines after man-made or natural disasters. He has worked with Benjamin Luft, the director of Stony Brook University’s WTC Wellness Program, on a program that offers assistance to first responders after the 9/11 attacks.

Gonzalez’s father, Peter, was a police officer who worked on the World Trade Center cleanup and recovery efforts. The elder Gonzalez has since had 9/11-related health conditions.

Gonzalez and associate professor Anka Vujanovic, the co-director of the Trauma and Anxiety Clinic at the University of Houston, are putting together a research project for the Houston area. Vujanovic did a mental health survey on Houston area firefighters earlier this year. They are inviting these firefighters to complete an online survey and telephone assessment to determine their mental health after Hurricane Harvey.

They are also conducting a three- to four-hour resilience training workshop for Houston area firefighters engaged in Harvey disaster relief efforts. “This resilience program, developed by [Gonzalez] and his colleagues, has shown promising results in reducing various mental health symptoms when tested among first responders in the aftermath of Hurricane Sandy,” Vujanovic explained in an email.

Vujanovic has known Gonzalez for over 10 years and suggested his questions were focused on “how can we better serve others, how can we improve existing interventions and how can we develop culturally sensitive approaches for vulnerable, understudied populations.” Gonzalez, who grew up in Bensonhurst, Brooklyn, and came to Stony Brook in 2012, said he was always interested in helping others.

Williams suggested that this kind of research can help people outside the space program. “We openly share and encourage the sharing of any of our relevant research findings to help address societal needs,” he added. Gonzalez’s research is “a great example of how a NASA focus on delivering personalized interventions in support of long-duration spaceflight could potentially be generalized to more rural settings where mental health providers may be scarce.”

From left, Zachary Lippman and Dave Jackson, professors at CSHL who are working on ways to alter promoter regions of genes to control traits in tomato and corn. Photo by Ullas Pedmale

By Daniel Dunaief

He works with tomatoes, but what he’s discovered could have applications to food and fuel crops, including corn, rice and wheat.

Using the latest gene editing technique called CRISPR, Zachary Lippman, a professor at Cold Spring Harbor Laboratory, developed ways to fine-tune traits for fruit size, branching architecture and plant shape. Called quantitative variation, these genetic changes act as a dimmer switch, potentially increasing or decreasing specific traits. This could help meet specific agricultural needs. Looking at the so-called promoter region of genes, Lippman was able to “use those genes as proof of principal” for a technique that may enable the fine-tuning of several traits.

For decades, plant breeders have been looking for naturally occurring mutations that allow them to breed those desirable traits, such as a larger fruit on a tomato or more branches on a plant. In some cases, genetic mutations have occurred naturally, altering the cell’s directions. At other times, breeders have sought ways to encourage mutations by treating their seeds with a specific mutagenic agent, like a chemical.

In an article in the journal Cell, Lippman said the results reflect a road map that other researchers or agricultural companies can use to create desirable traits. This article provides a way to “create a new, raw material for breeders to have access to tools they never had before,” he said. Lippman has taken a chunk of the DNA in the promoter region, typically on the order of 2,000 to 4,000 base pairs, and let the CRISPR scissors alter this part of the genetic code. Then, he and his scientific team chose which cuts from the scissors and subsequent repairs by the cell’s machinery gave the desired modifications to the traits they were studying.

Invented only five years ago, CRISPR is a genetic editing technique that uses tools bacteria have developed to fight off viral infections. Once a bacteria is attacked by a virus, it inserts a small piece of the viral gene into its own sequence. If a similar virus attacks again, the bacteria immediately recognizes the invader and cuts the sequence away.

Scientists sometimes use these molecular scissors to trim specific gene sequences in a process called a deletion. They are also working toward ways to take another genetic code and insert a replacement. “Replacement technology is only now starting to become efficient,” Lippman said. Clinical researchers are especially excited about the potential for this technique in treating genetic conditions, potentially removing and replacing an ineffective sequence.

In Lippman’s case, he used the scissors to cut in several places in the promoter regions of the tomato plant. Rather than targeting specific genes, he directed those scissors to change the genome at several places. When he planted the new seeds, he explored their phenotype, or the physical manifestation of their genetic instructions. These phenotypes varied along a continuum, depending on the changes in their genes.

By going backward and then comparing the genes of the altered plants to the original, he could then hone in on the precise changes in the genetic code that enabled that variation. This technique allows for a finer manipulation than turning on or off specific genes in which an organism, in this case a plant, would either follow specific instructions or would go on a transcriptional break, halting production until it was turned on again.

At this point, Lippman has worked with each trait individually but hasn’t done quantitative variation for more than one at a time. “The next question,” he said, “is to do this multitargeting.” He will also use the tool to study how genes are instructed to turn on and off during growth, including exploring the levels and location of expression.

Lippman is talking with agricultural and scientific collaborators and hopes to go beyond the tomato to exploring the application of this approach to other crops. He is working with Dave Jackson, who is also a professor at Cold Spring Harbor Laboratory, on applying this model to corn.

The scientific duo has known each other for 20 years. Jackson taught his collaborator when Lippman was a graduate student at Cold Spring Harbor Laboratory and Jackson was chair of his thesis committee.

They have worked together on and off since Lippman became a faculty member about nine years ago. Last year, the two received a National Science Foundation genome grant to work on using CRISPR to study the effect of changes in promoter regions in their respective plant specialties.

“Unfortunately for us, tomato has a faster life cycle than corn, but we hope to have some results in corn this fall,” Jackson explained in an email. Lippman hopes to continue on the path toward understanding how regulatory DNA is controlling complex traits. “We can use this tool to dissect critical regulatory regions,” he said. “When we create this variation, we can look at how that translates to a phenotypic variation.”

Lippman said he is especially excited about the fundamental biological questions related to plant growth and development. When other scientists or agricultural companies attempt to use this approach, they may run into some challenges, he said. Some plants are “not transformable [genetically] easily.” These plants can be recalcitrant to plant transformation, a step sometimes needed for CRISPR gene editing. Still, it is “likely that CRISPR will work in all organisms,” he said.

Lippman hopes others discuss this technique and see the potential for a system that could help to customize plants. “My hope and my anticipation is that people all over the world will look at this paper and say, ‘Let’s start to try this out in our own systems.’ Hopefully, there will be a grass roots effort to import this tool.”

Anne Churchland. Photo from CSHL

By Daniel Dunaief

Someone is hungry and is walking through a familiar town. She smells pizza coming from the hot brick oven on her left, she watches someone leaving her favorite Chinese restaurant with the familiar takeout boxes, and she thinks about the fish restaurant with special catches of the day that she usually enjoys around this time of year. How does she make her decision?

While this scenario is a simplified one, it’s a window into the decision-making process people go through when their neurons work together. A team of 21 neuroscientists in Europe and the United States recently created a new collaboration called the International Brain Laboratory to explore how networks of brain cells support learning and decision-making.

“We understand the simple motor reflex,” such as when a doctor taps a knee and a foot kicks out, said Anne Churchland, an associate professor at Cold Spring Harbor Laboratory and the American spokesperson for this new effort. Scientists, however, have only a limited understanding of the cognitive processes that weigh sensory details and a recollection of the outcomes from various courses of action that lead to decision-making, Churchland said.

Scientists likened the structure of the new multilaboratory effort to the circuitry involved in the brain itself. The brain is “massively parallel,” said Alexandre Pouget, a professor at the University of Geneva and the spokesperson for the IBL. “We know it’s working on consensus building across areas so, in that respect, the IBL is similar.”

A greater awareness of the decision-making process could provide a step into understanding the brain network problems involved in mental health disorders.

Churchland’s lab is one of three facilities that will house a new behavioral apparatus to study decision-making in mice. The other sites will be in the United Kingdom and in Portugal. Eventually, other labs will use this same technique and house the same apparatus.

An ongoing challenge in this field of research, Churchland said, is that scientists sometimes create their own models to test the neurological basis of behavior. While these approaches may work in their own labs, they have created a reproducibility problem, making it difficult for others who don’t have expertise in their methods to duplicate the results.

Creating this behavioral apparatus will help ensure that the collaborators are approaching the research with a reliable model that they can repeat, with similar results, in other facilities.

While the scientists will all be exploring the brain, they will each be responsible for studying the activity of circuits in different parts. The researchers will collect a wealth of information and will share it through a developing computer system that allows them to maneuver through the mountains of data.

To address this challenge, the IBL is creating a data architecture working group. Kenneth Harris, a professor of quantitative neuroscience at the University College London, is the chair of the effort. He is currently looking to hire additional outside staff to help develop this process.

Harris suggested that the process of sharing data in neurophysiology has been challenging because of the complex and diverse data these scientists share. “In neuroscience, we have lots of different types of measurements, made simultaneously with lots of different experimental methods, that all have to be integrated together,” he explained in an email.

The IBL collaboration will make his job slightly easier than the generic problem of neurophysiology data sharing because “all the labs will be studying how the brain solves the same decision-making task,” he continued.

Harris is looking to hire a data coordinator, a senior scientific programmer and a scientific MATLAB programmer. He has a data management system already running with his lab that he plans to extend to the IBL.

Pouget said there are two milestones built into the funding from the Wellcome Trust and the Simons Foundation for this new collaboration. After two years, the researchers have to have a data sharing platform in place, which will allow them to share data live as they collect it.

Second, they plan to develop standardized behaviors in all 11 of the experimental labs, where the behavior has to be as indistinguishable from one lab to another as possible.

In addition to the experimentalists involved in this initiative, several theoretical neurobiologists will also contribute and will be critical to unraveling the enormous amounts of data, Pouget suggested. “If you’re going to tackle really hard computational problems, you better have people trained in that area,” he said, adding that he estimates that only about 5 percent of neuroscientists are involved in the theoretical side, which is considerably lower than the percent in an area like physics.

Researchers involved in this project will have the opportunity to move from one lab to another, conducting experiments and gaining expertise and insights. The principal investigators are also in the process of hiring 21 postdoctoral students.

Churchland said each scientist will continue to conduct his or her own research while also contributing to this effort. The IBL is consuming between a quarter and a third of her time.

Pouget suggested that Churchland was “instrumental in representing the International Brain Laboratory to the Simons Foundation,” where she is the principal investigator on that grant. “Her role has been critical to the organization,” he said.

Churchland said the effort is progressing rapidly. “It’s moving way faster” than expected. “This is the right moment, with an incredible team of people, to be working together. Everyone is dedicated to the science.”

Harris indicated that he believes this effort could be transformative for the field. “Neuroscience has lagged behind many other scientific domains” in creating large-scale collaborations, he explained. “If we can show it works, we will change the entire field for good.”