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Cold Spring Harbor Laboratory

Anne Churchland with former postdoctoral fellow Matt Kaufman at Cold Spring Harbor Laboratory. The microscope is a 2-photon microscope and is one of three techniques used to measure neural activity in the mouse brain. Photo from Margot Bennett

By Daniel Dunaief

Fidgeting, rocking and other movements may have some benefit for thinking. Yes, all those people who shouted to “sit still” may have been preventing some people from learning in their own way.

In a new experiment conducted on mice published in the journal Nature Neuroscience this week, Anne Churchland, an associate professor at Cold Spring Harbor Laboratory, linked idiosyncratic mouse movements to performance in a set of tasks that required making decisions with rewards.

“Moving when deep in thought is a natural thing to do,” Churchland said. “It deeply engages the brain in ways that were surprising to us.”

She suggested that many people believe thinking deeply requires stillness, like the statue of The Thinker created by Auguste Rodin. “Sometimes it does, but maybe not for all individuals,” adding that these movements, which don’t seem connected to the task at hand, likely provide some benefit for cognition.

“We don’t know yet for sure what purpose these movements are serving,” she said.

Margaret Churchland with the lab group at CSHL

Mammals tend to exhibit a process called “optimal motor control.” If a person is reaching out to grab a cup, she tends to move her arm in a way that is energy conserving. Indeed, extending this to her rodent study, Churchland suggests that somehow these ticks, leg kicks or other movements provide assistance to the brain.

In theory, she suggested that these movements may be a way for the brain to recruit movement-sensitive cells to participate in the process. These brain cells that react to movement may then participate in other thought processes that are unrelated or disconnected from the actions themselves.

Churchland offers an analogy to understanding the potential benefit of these extra movements in the sports world. Baseball players have a wide range of stereotyped movements when they step up to the plate to hit. They will touch their shirt, tug on their sleeves, readjust their batting gloves, lift up their helmet or any of a range of assorted physical activities that may have no specific connection to the task of hitting a baseball.

These actions likely have “nothing to do” with the objective of a baseball hitter, but they are a “fundamental part of what it means to go up to bat,” she said.

In her research, Churchland started with adult mice who were novices at the kinds of tasks she and her colleagues Simon Musall and Matt Kaufman, who are the lead authors on the paper, trained them to do. Over a period of months, the mice went from not understanding the objective of the experiment to becoming experts. The animals learned to grab a handle to start a trial or to make licking movements.

These CSHL researchers tracked the behavior and neural activity of the mice every day.

Churchland said a few other groups have measured neural activity during learning, but that none has studied the kind of learning her lab did, which is how animals learn the structure of an environment.

The extra movements that didn’t appear to have any connection to the learned behaviors transitioned from a disorganized set of motions to an organized pattern that “probably reflected, in the animal’s mind, a fundamental part of what it means to make a decision.”

Churchland suggested that some of these conclusions may have a link to human behavior. Each animal, however, has different behaviors, so “we always need to confirm that what we learn in one species is true for another,” she wrote in an email.

Parents, teachers, coaches and guest lecturers often look at the faces of young students who are shaking their legs, rocking in their chair, twiddling their thumbs or spinning their pens between their fingers. While these actions may be distracting to others, they may also play a role in learning and cognition.

The study “suggests that allowing certain kinds of movements during learning is probably very important,” Churchland said. “When we want people to learn something, we shouldn’t force them to sit still. We should allow them to make movements they need to make which will likely help” in the learning process.

Churchland believes teachers already know that some students need to move. These educators also likely realize the tension between allowing individual students to be physically active without creating a chaotic classroom. “Most teachers are working hard to find the right balance,” she explained in an email.

She also suggested that different students may need their own level of movement to stimulate their thinking.

Some adults may have already developed ways to enhance their own thinking about decisions or problems. Indeed, people often take walks that may “finally allow those circuits you need for a decision to kick in.”

Down the road, she hopes to collaborate with other scientists who are working with nonhuman primates, such as marmosets, which are new world monkeys that live in trees and have quick, jerky movements, and macaques, which are old world monkeys and may be familiar from their island perch in an exhibit in the Central Park Zoo.

Churchland said extensions of this research could also go in numerous directions and address other questions. She is hoping to learn more about attention deficit hyperactivity disorder and the brain.

“We don’t know when that strategy [of using movement to trigger or enhance thinking] interferes with the goal,” she said. “Maybe the movements are a symptom of the learner trying to engage, but not being able to do so.”

Ultimately, Churchland expects that different pathways may support different aspects of decision making, some of which can and likely are connected to movement.

Ela Elyada. Photo by Giulia Biffi

By Daniel Dunaief

They have the ability to call the body’s armed forces. They may interact with the immunological foot soldiers and, then, somehow, inactivate them, allowing the destructive cancer they may aid and abet to continue causing havoc.

This is one hypothesis about how a newly discovered class of fibroblasts may play a role in the progression of pancreatic cancer.

Ela Elyada, a postdoctoral fellow in David Tuveson’s lab at Cold Spring Harbor Lab, partnered up with Associate Professor Paul Robson at the Jackson Laboratory in Farmington, Connecticut, to find a new class of fibroblast in pancreatic cancer.

This cell, which they called antigen-presenting cancer-associated fibroblasts (or apCAFs) had the same kind of genes that are usually found in immune cells. Cells with these genes have signals on their surface that present antigens, or foreign parts of viruses and bacteria to helper T-cells. Elyada and Robson showed that the apCAFs can use their immune cell genes to present peptides to helper T-cells.

With the apCAFs, the researchers hypothesize that something about the immunological process goes awry, as the T-cells show up but don’t engage.

Elyada and Robson suspect that the activation process may be incomplete, which prevents the body’s own defense system from recognizing and attacking the unwelcome cancer cells.

While she was excited about the potential of finding a different type of cell, Elyada needed to convince herself, and the rest of the scientific community, that what she’d found was truly original, as opposed to a scientific mirage.

“We spent hours and hours trying to understand what is different in this type of cell,” Elyada said. “Like everything new you find, as a scientist, you really question yourself, ‘Is it real? Is it an artifact of the single cell?’ It was really important for me to do everything I could from every angle to make sure they were not macrophages that looked like fibroblasts or cancer cells that looked like fibroblasts.”

After considerable effort, Elyada was sure without a doubt that the group had found fibroblasts and that these specific cells, which typically are involved in connective tissue but which pancreatic cancer uses to form a shell around it, contained these immunological genes.

She sees these cells in different experiments from other people inside and outside the lab, which further supports her work and found the apCAFs in mice and human pancreatic ductal adenocarcinoma, which is the fourth leading cause of cancer-related deaths in the world.

The fibroblasts, which are not cancerous, play an unclear role in pancreatic cancer. 

Elyada explained that single-cell sequencing enables scientists to look at individual cells, instead of at a whole population of cells. Scientists “have started to utilize this method to look at differences between cells we thought were the same,” she said. “It’s useful for looking at the fibroblast population. Scientists have appreciated that there’s probably a lot of heterogeneity,” but they hadn’t been able to describe or define it as well without this technique.

The results of this research, which was a collaboration between Elyada, Robson and others, were recently published in the journal Cancer Discovery. Robson said it was a “great example of how [single-cell RNA sequencing] can be very useful in revealing new biology, in this case, a new subtype of cancer-associated fibroblast.”

Earlier work in the labs of Robson and Tuveson, among others, have shown heterogeneity within cancer-associated fibroblast populations. These often carry a worse prognosis.

“We are very interested in continuing to explore this heterogeneity across tumor types and expect we will continue to find new subtypes and, although we have yet to confirm, would expect to see other solid tumor types to contain apCAFs,” Robson said.

“We still need to work hard to reveal their function in the full animal, but if they turn out to be tricking the immune cells, they could be a target for different immune-related inhibition methods,” explained Elyada.

The newly described fibroblast cells may be sending a signal to the T-cells and then either trapping or deactivating them. Elyada and Robson both said these results, which they developed after working together since 2016, have led to numerous other questions. They want to know how they work, what the mechanisms are that allow their formation, what signals they trigger in T-cells and many other questions.

Elyada is working with Pasquale Laise in Andrea Califano’s lab at Columbia University to gather additional information that uses this single-cell sequencing data.

Laise has “a unique way of analyzing [the information] to look at how the sequencing can predict if proteins are active or not active in a cell,” she said. Laise is able to predict the activity of transcription factors according to the expression level of their known target.

Elyada may be able to use this information to understand the source cell from which the fibroblasts are coming.

Originally from Israel, Elyada has been working as a postdoctoral researcher in Tuveson’s lab for about six years. She lives in Huntington Village with her husband Gal Nechooshtan, a postdoctoral researcher at Cold Spring Harbor Laboratory’s Woodbury complex. The couple has two daughters, Maayan, who is 10, and Yael, who is 8.

Elyada hopes to return to Israel next year, where she’d like to secure a job as a professor and build on the work she’s done at CSHL.“I definitely want to keep working on this. This would hopefully be a successful project in my future lab.”

Bruce Stillman. Photo courtesy of CSHL

By Daniel Dunaief

Bruce Stillman, the president and CEO of Cold Spring Harbor Laboratory, was recently awarded the prestigious Canada Gairdner International Award for his contributions to research about the way DNA copies itself. The 60-year-old prize, which Stillman will receive in a ceremony in October and that he shares with his former postdoctoral fellow John Diffley, includes a financial award of $100,000 Canadian dollars that he can spend however he’d like.

A native Australian, Stillman, who has been at Cold Spring Harbor Laboratory since 1979, recently shared his thoughts about the award, research at the lab and his concerns about science in society with Times Beacon Record News Media. 

How does it feel winning the Gairdner Award?

It’s one of the most prestigious awards in the life sciences in the world and it’s certainly a great honor to win it and to join the list of spectacular scientists in the history of the award. There are some really fantastic scientists who I very much admire who have received this award.

How does it relate to the research you’ve conducted?

The field of DNA replication and chromosome inheritance was recognized. It is something I’ve devoted my entire career to. There are a lot of people that have made important contributions to this field. I’m pleased to be recognized with [Diffley] who was my former postdoc. [It’s validating] that the field was recognized.

Has CSH Laboratory been at the cutting edge of discoveries using the gene-editing tool CRISPR?

Cold Spring Harbor didn’t discover CRISPR. Like many institutions, we’ve been at the forefront of applying CRISPR and gene editing. The most spectacular application of that has been in the plant field. Zachary Lippman, Dave Jackson and Rob Martienssen are using genetic engineering to understand plant morphogenesis and development, thereby increasing the yield of fruit. Hopefully, this will be expanded into grains and have another green revolution.

CSHL has also been making strides in cancer research, particularly in Dave Tuveson’s lab, with organoids.

Organoids came out of people studying development. Hans Clevers [developed organoids] in the Netherlands … Tuveson is at the forefront of that. The full promise hasn’t been realized yet. From what I’ve seen, we are quite excited about the possibility of using organoids as a tool to get real feedback to patients. It is rapidly moving forward with the Lustgarten Foundation and with Northwell Health.

What are some of the other major initiatives at CSHL?

The laboratory’s investment about 10 or 15 years ago in understanding cognition in the brain has paid off enormously. Neuroscientists here are at the forefront of understanding cognition and how the brain does computation in complicated decisions. [Scientists are also] mapping circuits in the brain. It took a lot of investment and kind of the belief that studying rodent cognition could have an impact on human cognition, which was controversial when we started it here, but has paid out quite well. At the same time, we are studying cognitive dysfunction particularly in autism. 

Any other technological advances?

There’s been a real revolution in the field of structural biology… [Researchers] have the ability to look at single biological molecules in the electron microscope. It shoots electrons through a grid that has individual biological molecules. The revolution, which was done elsewhere by many people actually, led to the ability to get atomic resolution structures of macro molecular complexes. 

Cold Spring Harbor invested a lot of money, well over $10 million to build a facility and staff a facility to operate this new technology. I’ve been working on this area for about 12, 13 years now … Our structural biologists here in neuroscience, including neuroscientists Hiro Furukawa and Leemor Joshua-Tor have really helped introduce a lot of new biology into CSHL.

What are some of the newer efforts at the lab?

One of the big new initiatives we started is in the field of cancer. As you know by looking around, there’s an obesity epidemic in the Western world. We started a fairly large initiative, understanding the relationship between obesity and cancer and nutrition, and we’re not unique in this. We’re going to have some significant contributions in this area. 

Cancer cells and the tumor affect the whole body physiology. The most severe [consequence] is that advanced cancer patients lose weight through a process called cachexia. We hired [new staff] in this new initiative, renovated a historic building, the Demerec building at a fairly substantial expense, which was supported by New York State. 

What will CSHL researchers study related to obesity?

We’re absolutely going to be focusing on understanding mostly how obesity impacts cancer and the immune system, then how cancer impacts the whole body physiology. Hopefully, once we start to understand the circuits, [we] will be able to intervene. If we can control obesity, we will by logic reduce cancer impact.

What worries you about society?

What worries me is that there is a tendency in this country to ignore science in policy decisions … The number of people not getting vaccinated for measles is ridiculous. There is this kind of pervasive anti-science, anti-technology view that a lot of Americans have. They want the benefits of science and everything that can profit for them. 

There are certain groups of people who misuse data, deliberately abuse misinformation on science to promote agendas that are completely irrational. One of the worst is anti-vaccination. … We should as a society have severe penalties for those who choose to go that route. They shouldn’t send their children to schools, participate in public areas where they could spread a disease that effectively was controlled. Imagine if polio or tuberculosis came back?

How is the lab contributing to education?

People need to act like scientists. It’s one of the reasons we have the DNA Learning Center, to teach people to think like scientists. If 99.99 percent of the evidence suggests [something specific] and 0.01 percent suggest something [else], you have to wonder whether those very small and vocal minority are correct.

From left, Megan Crow, Associate Professor Jesse Gillis and postdoctoral researcher Sara Ballouz Photo by Gina Motisi/CSHL

By Daniel Dunaief

Diversity has become a buzz word in the workplace, as companies look to bring different perspectives that might represent customers, constituents or business partners. The same holds true for the human brain, which contains a wide assortment of interneurons that have numerous shapes and functions.

Interneurons act like a negative signal or a brake, slowing or stopping the transmission. Like a negative sign in math, though, some interneurons put the brakes on other neurons, performing a double negative role of disinhibiting. These cells of the nervous system, which are in places including the brain, spinal chord and retina, allow for the orderly and coordinated flow of signals.

One of the challenges in the study of these important cells is that scientists can’t agree on the number of types of interneurons.

“In classifying interneurons, everyone argues about them,” said Megan Crow, a postdoctoral researcher in Jesse Gillis’ lab at Cold Spring Harbor Laboratory. “People come to this question with many different techniques, whether they are looking at the shape or the connectivity or the electrophysiological properties.”

Megan Crow. Photo by Constance Brukin

Crow recently received a two-year grant from the National Institutes of Health to try to measure and explain the diversity of interneurons that, down the road, could have implications for neurological diseases or disorders in which an excitatory stimulus lasts too long.

“Understanding interneuron diversity is one of the holy grails of neuroscience,” explained Gillis in an email. “It is central to the broader mission of understanding the neural circuits which underlie all behavior.”

Crow plans to use molecular classifications to understand these subtypes of neurons. Her “specific vision” involves exploiting “expected relationships between genes and across data modalities in a biologically thoughtful way,” said Gillis.

Crow’s earlier research suggests there are 11 subtypes in the mouse brain, but the exact number is a “work in progress,” she said.

Her work studying the interneurons of the neocortex has been “some of the most influential work in our field in the last two to three years,” said Shreejoy Tripathy, an assistant professor in the Department of Psychiatry at the University of Toronto. Tripathy hasn’t collaborated with Crow but has been aware of her work for several years.

The interactivity of a neuron is akin to personalities people demonstrate when they are in a social setting. The goal of a neuronal circuit is to take an input and turn it into an output. Interneurons are at the center of this circuit, and their “personalities” affect the way they influence information flow, Crow suggested.

“If you think of a neuron as a person, there are main personality characteristics,” she explained. Some neurons are the equivalent of extraverted, which suggests that they have a lot of adhesion proteins that will make connections with other cells.

“The way neurons speak to one another is important in determining” their classes or types, she said.

A major advance that enabled this analysis springs from new technology, including single-cell RNA sequencing, which allows scientists to make thousands of measurements from thousands of cells, all at the same time.

“What I specialize in and what gives us a big leg up is that we can compare all of the outputs from all of the labs,” Crow said. She is no longer conducting her own research to produce data and, instead, is putting together the enormous volume of information that comes out of labs around the world.

Megan Crow. Photo by Daniel Katt

Using data from other scientists does introduce an element of variability, but Crow believes she is more of a “lumper than a splitter,” although she would like to try to understand variation where it is statistically possible.

She believes in using data for which she has rigorous quality control, adding, “If we know some research has been validated externally more rigorously than others, we might tend to trust those classifications with more confidence.”

Additionally she plans to collaborate with Josh Huang, the Charles Robertson professor of neuroscience at Cold Spring Harbor Laboratory, who she described as an interneuron expert and suggested she would use his expertise as a “sniff test” on certain experiments.

At this point, Crow is in the process of collecting baseline data. Eventually, she recognizes that some interneurons might change in their role from one group to another, depending on the stimuli.,

Crow hasn’t always pursued a computational approach to research. 

In her graduate work at King’s College London, she produced data and analyzed her own experiments, studying the sensory experience of pain.

One of the challenges scientists are addressing is how pain becomes chronic, like an injury that never heals. The opioid crisis is a problem for numerous reasons, including that people are in chronic pain. Crow was interested in understanding the neurons involved in pain, and to figure out a way to treat it. “The sensory neurons in pain sparked my general interest in how neurons work and what makes them into what they are,” she said.

Crow indicated that two things brought her to the pain field. For starters, she had a fantastic undergraduate mentor at McGill University, Professor of Psychology Jeff Mogil, who “brought the field to life for me by explaining its socio-economic importance, its evolutionary ancient origins, and showed me how mouse behavioral genetic approaches could make inroads into a largely intractable problem.”

Crow also said she had a feeling that there might be room to make an impact on the field by focusing on molecular genetic techniques rather than the more traditional electrophysiological and pharmacological approaches.

As for computational biology, she said she focuses on interpreting data, rather than in other areas of the field, which include building models and simulations or developing algorithms and software.

In the bigger picture, Crow said she’s still very interested in disease and would like to understand the role that interneurons and other cells play. “If we can get the tools to be able to target” some of the cells involved in diseases, “we might find away to treat those conditions.”

The kind of research she is conducting could start to provide an understanding of how cells interact and what can go wrong in their neurodevelopment.

Gillis praises his postdoctoral researcher for the impact of her research.

“Just about any time [Crow] has presented her work — and she has done it a lot — she has ended up convincing members of the audience so strongly that they either want to collaborate, adapt her ideas, or recruit her,” Gillis wrote in an email. 

Crow grew up in Toronto, Canada. She said she loved school, including science and math, but she also enjoyed reading and performing in school plays. She directed a play and was in “The Merchant of Venice.” In high school, she also used to teach skiing.

A resident of Park Slope in Brooklyn, Crow commutes about an hour each way on the train, during which she can do some work and catch up on her reading.

She appreciates the opportunity to work with other researchers at Cold Spring Harbor, which has been “an incredible learning experience.”

Tobias Janowitz with research technician Ya Gao at Cold Spring Harbor Lab Photo by ©Gina Motisi, 2019/CSHL

By Daniel Dunaief

It’s a low-tech setting with high stakes. Scientists present their findings, often without slides and pictures, to future colleagues and collaborators in a chalk talk, hoping faculty at other institutions see the potential benefit of offering them an employment opportunity.

For Tobias Janowitz, this discussion convinced him that Cold Spring Harbor Laboratory was worth uprooting his wife and three young children from across the Atlantic Ocean to join.

Chalk talks in most places encourage people to “defend their thinking. Here, it was completely different. They moved on from my chalk talk quickly,” said Janowitz in a recent interview.

Research technician Ya Gao and Tobias Janowitz at Cold Spring Harbor Lab. Photo by ©Gina Motisi, 2019/CSHL

Janowitz recalled how CSHL CEO Bruce Stillman asked him “what else will you do that’s important and high risk. He moved me on from that discussion within five minutes and essentially skipped a step I’d usually spend at another institution. It’s a very special place.”

Janowitz, who earned a medical degree and a doctorate from the University of Cambridge, came to the lab to work in a field where he’s distinguished himself with cancer research that points to the role of a glycoprotein called interleukin 6, or IL-6, in a specific step in the progression of the disease, and as a medical oncologist. He will work as a clinician scientist, dedicated to research and discovery and advancing clinical care, rather than delivering standard care.

As CSHL continues to develop its ongoing relationship with Northwell Health, Janowitz said he expects to be “one of the intellectual bridges between the two institutions.”

In his research, the scientist specializes in understanding the reciprocal interaction between a tumor and the body. Rather than focusing on one type of cancer, he explores the insidious steps that affect an organ or system and then wants to understand the progression of signals and interactions that lead to conditions like cachexia, in which a person with cancer loses weight and his or her appetite declines, depriving the body of necessary nutrition.

CSHL Cancer Center Director David Tuveson appreciates Janowitz’s approach to cancer.

“Few scientists are ready to embrace the macro scale of cancer, the multiple organ systems and body functions which are impaired,” Tuveson said. Janowitz is “trying to understand the essential details [of cachexia and other cancer conditions] so he can interrupt parts of it and give patients a better chance to go on clinical trials that would fight their cancer cells.”

A successful and driven scientist and medical doctor, Janowitz “is very talented and could be anywhere,” Tuveson said, and was pleased his new colleague decided to join CSHL.

Janowitz suggested that the combination of weight loss and loss of appetite in advancing cancer is “paradoxical. Why would you not be ravenously hungry if you’re losing weight? What is going on that drives this biologically seemingly paradoxical phenomenon? Is it reversible or modifiable?”

At this point, his research has shown that tumors can reprogram the host metabolism in a way that it “profoundly affects immunity and can affect therapy.” Reversing cachexia may require an anti-IL-6 treatment, with nutritional support.

As he looks for clinical cases that could reveal the role of this protein in cachexia, Janowitz has seen that patients with IL-6-producing tumors may have a worse outcome, a finding he is now seeking to validate.

At this point, treatment for other conditions with anti-IL-6 drugs has produced few side effects, although patients with advanced cancer haven’t received such treatment. Researchers know how to dose antibodies to IL-6 in the human body and treatment intervals would last for a few weeks.

Scientists have long thought of cancer as being like a wound that doesn’t heal. IL-6 is important in infections and inflammation.

Ultimately, Janowitz hopes to extend his research findings to other diseases and conditions. To do that, he would need to take small steps with one disease before expanding an effective approach to other conditions. “Are disease processes enacting parts of the biological response that are interchangeable?” he asked. “I think that’s the case.”

Eventually, Janowitz hopes to engage in patient care, but he first needs to obtain a license to practice medicine in the United States. He hopes to take the steps to achieve certification in the next year.

He plans to gather samples from patients on Long Island to study cancer and its metabolic consequences, including cachexia.

Several years down the road, the scientist hopes the collaborations he has with neuroscientists can reveal basic properties of cancer.

Tuveson believes Janowitz has “the potential of having a big impact individually as well as on everyone around him,” at Cold Spring Harbor Laboratory. “We are lucky to recruit him and want him to succeed and solve vexing problems so patients get better.”

Janowitz lives in Cold Spring Harbor Laboratory housing with his wife Clary and their three children, Viola, 6, Arthur, 4, and Albert, 2.

Clary is a radiation oncologist who hopes to start working soon at Northwell Health.

The Janowitz family has found Long Island “very welcoming” and appreciates the area’s “openness and willingness to support people who have come here,” he said. The family enjoys exploring nature.

The couple met at a production of “A Midsummer Night’s Dream,” which was performed by a traveling cast of the Globe in Emmanuel College Gardens in Cambridge, England.

As with many others, Janowitz has had family members who are living with cancer, including both of his parents. His mother has had cancer for more than a decade and struggles with loss of appetite and weight. He has met many patients and their relatives over the years who struggle with these phenomena, which is part of the motivation for his dedication to this work.

Most cancer patients, Janowitz said, are “remarkable individuals. They adjust the way that they interact with the world and themselves when they get life changing diagnoses.” Patients have a “very reflected and engaged attitude” with the disease, which makes looking after them “incredibly rewarding.”

From left, Anne Churchland and Tatiana Engel. Photo from CSHL

By Daniel Dunaief

Movies have often used an image of a devil on one shoulder, offering advice, and an angel on another, suggesting a completely different course of action. People, however, weigh numerous factors when making even the simplest of decisions.

The process the brain uses to make decisions involves excitatory and inhibitory neurons, which are spread throughout the brain. Technology has made it possible to study thousands of these important cells on an active mouse, showing areas that are active at the same time.

Anne Churchland, an associate professor at Cold Spring Harbor Laboratory, and Tatiana Engel, an assistant professor at the same facility, are collaborating on a three-year grant from the National Institutes of Health that will study the way neurons interact to understand the patterns that lead to decisions. 

Engel said she, Churchland and another collaborator on the project, Stanford University Professor Krishna Shenoy, applied for the funding in response to a call from the NIH to develop computational methods and models for analyzing large-scale neural activity recordings from the brain.

Churchland and Shenoy will provide experimental data for the computational models Engel’s lab will develop. The data is “huge and complex,” Engel said, and researchers need new methods to understand it. “The simple techniques don’t translate to large-scale recordings,” Engel said.

Churchland and Engel jointly hired James Roach, a postdoctoral researcher who recently earned his doctorate from the University of Michigan and works in both of their labs. 

Churchland’s lab will provide data from the mouse model, while Engel’s lab brings computational expertise.

“Little is known about how these neurons are connected to behavior,” Engel said. Their research will hope to explain the role of inhibitory cells, which may have a more finely tuned function beyond keeping cells from remaining in an excited state.

The prevailing view in the field is that inhibitory neurons provide a balancing input to the network to prevent it from generating too much excitation or creating a seizure. Inhibitors are like the regulators that tap the brakes on a network that’s becoming too active.

Excitatory neurons, by contrast, are the ones that have an important job, representing the decisions individuals make.

Churchland is going to measure neural activity using a 2-photon microscope that allows her to measure the activity of about 600 neurons simultaneously. 

“This provides an incredible opportunity to analyze the data, using tools borrowed from machine learning and dynamical systems,” she explained in an email.

What Churchland’s data has helped show, however, is that the inhibitory neurons are doing more than providing a global braking signal. “They have some dedicated role in the circuit and we don’t know what that role is yet,” Engel said.

The team will build neural circuit models to help understand how the system is wired and what role each type of cell plays in various behaviors.

“We are developing computational frameworks where we can go and analyze activities of large groups of cells and, from the data, determine how individual cells contribute to the activity of the population,” Engel said.

Brains have considerable plasticity, which means that when one area of the brain isn’t functioning for whatever reason — through an injury or a temporary blockage ‒ other areas can compensate. “The whole problem is immensely complicated to figure out what a brain area is doing normally,” she explained. The picture can “completely change when there’s brain damage.”

Research is moving in the direction of understanding and manipulating large neural circuits at once, rather than a single area at a time. 

“Models can extract general principles, which still hold true even in more complex” systems Engel said. The principles include understanding how excitatory and inhibitory cells are balanced. “Models can help you figure out what works and doesn’t work.”

Roach, the current postdoctoral researcher working with Engel and Churchland, will start with modeling and then will develop experiments to test the role of inhibitory cells. He has already worked on computer programs that interpret neurological circuits and laboratory results. He is also receiving laboratory training.

At this point, Engel and Churchland are working on basic science. Engel explained that this type of research is the foundation for translation work that will lead to an improved diagnosis and treatment of neurological disorders. Basic science can, and often does, provide insights and information that help those working to understand or treat disease, she suggested.

Churchland was pleased with her collaboration with Engel.

Engel is “best known for modeling work she did studying neural mechanisms of attention,” Churchland explained in an email. “She is a great addition to Cold Spring Harbor! We work together in the same building and are trying to unravel the mysteries of how large groups of neurons in the brain work together to make decisions.”

A resident of the facilities at Cold Spring Harbor Laboratory, Engel grew up in Vologda, which is over 300 miles north of Moscow. Starting in seventh grade, she attended physics and math schools, first in her home town and then at a boarding school at the Moscow State University.

She learned to appreciate the value of science from the journals her parents subscribed to, including one for children called Kvant magazine. She solved physics problems in that magazine. “I enjoyed the articles and problems in Kvant,” she explained in an email.

As for her work, Engel suggested that there were many discoveries ahead. “It is an exciting and transformative time in neuroscience,” she said.

Jason Sheltzer. Photo by ©Gina Motisi, 2018/CSHL

By Daniel Dunaief

A diagnosis of cancer brings uncertainty and anxiety, as a patient and his or her family confront a new reality. But not all cancers are the same and not all patients are the same, making it difficult to know the severity of the disease.

As doctors increasingly focus on individual patient care, researchers are looking to use a wealth of information available through new technology to assist with everything from determining cancer risks, to making early diagnoses, to providing treatment and aftercare.

Jason Sheltzer, a fellow at Cold Spring Harbor Laboratory, and his partner Joan Smith, a senior software engineer at Google, have sought to use the genetic fingerprints of cancer to determine the likely course of the disease.

By looking at genes from 20,000 cancer patients, Sheltzer and Smith found that a phenomenon called copy number variation, in which genes add copies of specific long or short sequences, is often a good indicator of the aggressiveness of the cancer. Those cancers that have higher copy number variation are also likely to be the most aggressive. They recently published their research in the journal eLife.

While the investigation, which involved work over the course of four years, is in a preliminary stage, this kind of prognostic biomarker could offer doctors and patients more information from which to make decisions about treatment. It could also provide a better understanding of the course of a disease, as copy number variation changes as cancer progresses.

“The main finding is simply that copy number variation is a much more potent prognostic biomarker than people had realized,” Sheltzer said. “It appears to be more informative than mutations in most single genes.”

Additionally, despite having data from those thousands of patients, Sheltzer and Smith don’t yet know if there’s a tipping point, beyond which a cancer reaches a critical threshold.

Some copy number changes also were more problematic than others. “Our analysis suggested that copy number alterations affecting a few key oncogenes and tumor suppressors seemed to be particularly bad news for patient prognosis,” Sheltzer said, adding that they weren’t able to do a clinical follow-up to determine how genes changed as the cancer progressed. 

“Hopefully, we can follow up this study, where we can do a longitudinal analysis,” he said.

Joan Smith. Photo by Seo-young Silvia Kim

Smith, who has written computer code for Twitter, Oracle and now Google, wrote code that’s specific to this project. “The analysis we’ve done here is new and is on a much more significant scale than the analysis we did in the past,” she said.

Within the paper, Smith was able to reuse parts of code that were necessary for different related experiments. Some of the reusable code cleaned up the data and provided a useful format, while some of the code searched for genetic patterns.

“There is considerable refinement that went into writing this code, and into writing code in general,” she explained in an email.

Smith has a full-time job at Google, where she has to clear any work she does with Sheltzer with the search engine. Before publication, she sent the paper to Google for approval. She works with Sheltzer “on her personal time,” and her efforts have “nothing to do with Google or Google Tools.”

The search engine company “tends to be supportive of employees doing interesting and valuable external work, as long as it doesn’t make use of any Google confidential information or Google owned resources,” including equipment supplies or facilities, she explained in an email.

The phenomenon of copy number variation occurs frequently in people in somatic cells, including those who aren’t battling a deadly disease Sheltzer said. “People in general harbor a lot of normal copy number variation,” he added.

Indeed, other types of repetitive changes in the genome have played a role in various conditions.

Some copy number variations, coupled with deletions, can be especially problematic. A tumor suppressor gene called P53, which is widely studied in research labs around the world, can accumulate copy number variations.

“Patients who have deletions in P53 tend to accumulate more copy number alterations than patients who don’t,” Sheltzer said. “A surprising result from our paper is that copy number variation goes above and beyond P53 mutations. You can control for P53 status and still find copy number variations that act as significant prognostic biomarkers.”

The copy number variations Sheltzer and Smith were examining were affecting whole genes, of about 10,000 bases or longer.

“We think that is because cancers are Darwinian,” explained Sheltzer. “The cells are competing against one another to grow the fastest and be the most aggressive. If a cancer amplifies one potent oncogene, it’s good for the cancer. If the cancer amplifies 200 others, it conveys a fitness penalty in the context of cancer.”

Smith is incredibly pleased to have the opportunity to contribute her informatics expertise to Sheltzer’s research, bringing together skill sets that are becoming increasingly important to link as technology makes it possible to accumulate a wealth of data in a much shorter term and at considerably lower expense.

Smith has a physics degree from MIT and has been in the technology world ever since.

“It’s been super wonderful and inspiring to get to do both” technology work and cancer research, she said.

The dynamic scientific duo live in Mineola. They chose the location because it’s equidistant between their two commutes, which are about 35 minutes. When they are not working, the couple, who have been together for eight years and have been collaborating in their research for almost all of them, enjoy biking, usually between 30 to 60 miles at a time.

Sheltzer greatly appreciates Smith’s expertise in using computer programs to mine through enormous amounts of data.

They are working on the next steps in exploring patient data.

Tim Sommerville. Photo by Brian Stallard, 2018/ CSHL

By Daniel Dunaief

Many research efforts search for clues about the signals or processes that turn healthy cells into something far worse. Scientists look at everything from different genes that are active to signs of inflammation to the presence of proteins that aren’t typically found in a system or organ.

Tim Somerville, a postdoctoral researcher in Chris Vakoc’s laboratory at Cold Spring Harbor Laboratory, recently took a close look at a specific protein whose presence in a high concentration in pancreatic cancer typically worsens the expectations for a disease with an already grim prognosis.

This protein, called P63, has a normal, healthy function in skin cells for embryos and in maintaining normal skin for adults, but it doesn’t perform any important tasks in the pancreas.

Tim Somerville at Cold Spring Harbor Laboratory. Photo by Brian Stallard, 2018/ CSHL

Somerville wanted to know whether the protein appeared as a side effect of the developing cancer, like the appearance of skinny jeans someone wears after a diet starts working, or whether it might be a contributing cause of the cancer’s growth and development.

“What was unclear was whether [the higher amount of P63] was a correlation, which emerges as the disease progresses, or something more causal,” he said, adding that he wanted to find out whether “P63 was driving the more aggressive features” of pancreatic cancer.

Somerville increased and decreased the concentration of P63 in tissue cells and organoids, which are copies of human tumors, hoping to see whether the change had any effect on the cancer cells.

The postdoctoral researcher knocked out the amount of P63 through the use of CRISPR, a gene-editing technique. He also overexpressed P63, which is also a transcription factor.

“From those complementary experiments, we were able to show that P63 is driving a lot of the aggressive features of cancer cells,” Somerville concluded. “Rather than being a correlation that’s observed, it is functionally driving the cancer itself.”

Somerville recently published his research in the journal Cell Reports.

As a transcription factor, P63 recognizes specific DNA sequences and binds to them. With P63, Somerville observed that it can bind to DNA and switch on many genes that are active in the worse form of pancreatic cancer. He and his collaborators describe P63 as a master regulator of the gene program.

Pancreatic cancer is often discovered after the irreversible conversion of normal, functional cells into a cancerous tumor that can spread to other organs. It also resists chemotherapy. Research teams in the labs of Vakoc and Dave Tuveson, the director of the Cancer Center at CSHL, and other principal investigators at CSHL and elsewhere are seeking to understand it better so they can develop more effective treatments.

Tim Somerville. Photo by Yali Xu

Vakoc was impressed with the work his postdoctoral researcher performed in his lab. Somerville is “one of the most scholarly young scientists I have ever met,” Vakoc explained in an email. “He is simply brilliant and thinks deeply about his project and is also driven to find cures for this deadly disease.”

At this point, Somerville is pursuing why P63 is activated in the pancreas. If he can figure out what triggers it in the first place, he might be able to interfere with that process in a targeted way. He also might be able to think about ways to slow it down or stop the disease.

The form of P63 that is active in the pancreas is not a mutated version of the protein that functions in the skin. If scientists tried to reduce P63, they would need to develop ways to suppress the cancer promoting functions of P63 without suppressing its normal function in the skin.

Many of the genes and proteins P63 activates are secreted factors and some of them contribute to inflammation. Indeed, researchers are exploring numerous ways inflammation might be exacerbating the progression of cancer.

P63 is also active in other types of cancer, including lung, head and neck cancers. Frequently, elevated levels of P63 in these other forms of cancer also lead to a worse prognosis.

Somerville explained that the changes P63 makes in a pancreatic cancer cell may expose new weaknesses. By studying cells in which he has overexpressed the protein, he hopes to see what other addictions the cells may have, which could include a reliance on other proteins that he could make compounds to target.

A resident of Huntington, Somerville has worked in Vakoc’s lab for three years. While he has spent considerable time studying P63, he is also looking at other transcription factors that are involved in pancreatic cancer.

Somerville wants to contribute to the discovery of why one form of pancreatic cancer is so much worse than the other. “If we can understand it, we can find new ways to stop it,” he said.

Originally from Manchester, England, Somerville is working in the United States on a five-year visa and plans to continue contributing to Vakoc’s lab for the next couple of years. At that point, he will consider his options, including a potential return to the United Kingdom.

Tim Somerville. Photo by Gina Motisi, 2018/CSHL

Somerville appreciates the opportunity to work on pancreatic cancer with Vakoc and with Tuveson, whose lab is next door. The researcher is enjoying his time on Long Island, where he takes walks, enjoys local restaurants and, until recently, had been playing on a Long Island soccer team, which played its matches in Glen Cove.

For Somerville, Cold Spring Harbor Laboratory has exceeded his high expectations. “The research that goes on here and the interactions you can have at meetings” have all contributed to a “great experience,” he said.

Somerville is excited to be a part of the pancreatic cancer team.

“With the work from [Tuveson’s] lab and ours, we’re finding new things we didn’t know,” he said. “It’s only when you understand those different things and the complexity that you can start thinking about how to tackle this in a more successful way. If the research carries on, we’ll make improvements in this disease.”

Photo by Ela Elyada

By Daniel Dunaief

What if, instead of defeating or removing enemy soldiers from the battlefield, a leader could convince them to join the fight, sending them back out to defeat the side they previously supported? That’s the question Giulia Biffi, a postdoctoral researcher at Cold Spring Harbor Laboratory, is asking about a particular type of cells, called fibroblasts, that are involved in pancreatic cancer.

Fibroblasts activated by cancer cells secrete a matrix that surrounds cancer cells and makes up about 90 percent of pancreatic tumors.

Giulia Biffi. Photo by ©Gina Motisi, 2018/CSHL

Responding to a molecule called IL-1, an inflammatory potential tumor-promoting fibroblast may enhance the opportunity for cancer to grow and spread. Another type of fibroblast responds to TGF-beta, which potentially enables them to restrain tumors.

Researchers had suggested that the inflammatory fibroblasts are tumor promoting, while the myofibroblasts are tumor defeating, although at this point, that still hasn’t been confirmed experimentally.

Researchers knew TGF-beta was important in biology, but they didn’t know that it was involved in preventing the activation of an inflammatory tumor-promoting version.

Biffi, however, recently found that IL-1 promotes the formation of inflammatory fibroblasts. She believes these fibroblast promote tumor growth and create an immunosuppressive environment.

In an article published in the journal Cancer Discovery, Biffi showed that it’s “not only possible to delete the population, but it’s also possible to convert [the fibroblasts] into the other type, which could be more beneficial than just getting rid of the tumor-promoting cells,” she said.

Biffi works in Director Dave Tuveson’s CSHL Cancer Center laboratory, which is approaching pancreatic cancer from numerous perspectives.

Her doctoral adviser, Sir Shankar Balasubramanian, the Herchel Smith Professor of Medicinal Chemistry at the University of Cambridge, suggested that the work she did in Tuveson’s lab is an extension of her successful research in England.

“It is evident that [Biffi] is continuing to make penetrating and important advances with a deep and sophisticated approach to research,” Balasubramanian explained in an email. “She is without a doubt a scientist to watch out for in the future.”

To be sure, at this stage, Biffi has performed her studies on a mouse model of the disease and she and others studying fibroblasts and the tumor microenvironment that dictates specific molecular pathways have considerable work to do to extend this research to human treatment.

She doesn’t have similar information from human patients, but the mouse models show that targeting some subsets of fibroblasts impairs cancer growth.

“One of the goals we have is trying to be able to better classify the stroma from pancreatic cancer in humans,” Biffi said. The stroma is mixed in with the cancer cells, all around and in between clusters of cells.

The results with mice, however, suggest that approaching cancer by understanding the molecular signals from fibroblasts could offer a promising additional resource to a future treatment. In a 10-day study of mice using a specific inhibitor involved in the pathway of inflammatory fibroblasts, Biffi saw a reduction in tumor growth.

If Biffi can figure out a way to affect the signals produced by fibroblasts, she might be able to make the stroma and the cancer cells more accessible to drugs. One potential reason other drugs failed in mouse models is that there’s increased collagen, which is a barrier to drug delivery. Drugs that might have failed in earlier clinical efforts could be reevaluated in combination with other treatments, Biffi suggested, adding if scientists can manage to target the inflammatory path, they might mitigate some of this effect.

A native of Bergamo, Italy, which is near Milan, Biffi earned her doctorate at the Cancer Research UK Cambridge Institute. Biffi lives on a Cold Spring Harbor property which is five minutes from the lab.

When she was young, Biffi wanted to be a vet. In high school, she was fascinated by the study of animal behavior and considered Dian Fossey from “Gorillas in the Mist” an inspiration. When she’s not working in the lab, she enjoys the opportunity to see Broadway shows and to hike around a trail on the Cold Spring Harbor campus.

Biffi started working on fibroblasts three years ago in Tuveson’s lab. “I really wanted to understand how fibroblasts become one population or the other when they were starting from the same cell type,” she said. “If they have different functions, I wanted to target them selectively to understand their role in pancreatic cancer to see if one might have a tumor restraining role.”

A postdoctoral researcher for over four years, Biffi is starting to look for the next step in her career and hopes to have her own lab by the end of 2019 or the beginning of 2020.

When she was transitioning from her doctoral to a postdoctoral job, she was looking for someone who shared her idealistic view about curing cancer. Several other researchers in Cambridge suggested that she’d find a welcome research setting in Tuveson’s lab. Tuveson was “popular” among principal investigators in her institute, Biffi said. “I wanted to work on a hard cancer to treat and I wanted to work with [Tuveson].”

Biffi hopes that targeting the inflammatory pro-tumorigenic fibroblasts and reprogramming them to the potentially tumor-restraining population may become a part of a pancreatic cancer treatment.

She remains optimistic that she and others will make a difference. “This can be a frustrating job,” she said. “If you didn’t have hope you can change things, you wouldn’t do it. “I’m optimistic.”

Biffi points to the hard work that led to treatments for the flu and for AIDS. “Years back, both diseases were lethal and now therapeutic advances made them manageable,” she explained in an email. “That is where I want to go with pancreatic cancer.”

Adrian Krainer in his lab. Photo by ©Kathy Kmonicek, 2016/CSHL

By Daniel Dunaief

This Sunday, Adrian Krainer is traveling to California to visit with Emma Larson, a Middle Island girl whose life he helped save, and to see an actor who played the fictional super spy James Bond.

A professor at Cold Spring Harbor Laboratory, Krainer is the recipient of the Breakthrough Prize in Life Sciences, which noted Silicon Valley benefactors including Facebook’s Mark Zuckerberg and Google’s Sergey Brin financed seven years ago. Pierce Brosnan will host the event, which National Geographic will broadcast live starting at 10 p.m. Eastern time.

Dr. Adrian Krainer and Emma Larson. Photo from Diane Larson

Krainer will split the $3 million prize money with Frank Bennett, a senior vice president of research and a founding member of Ionis Pharmaceuticals. The duo helped develop the first treatment for spinal muscular atrophy, the leading genetic cause of death among infants, which affects 1 in 10,000 births.

Prior to the Food and Drug Administration’s approval of Ionis and Biogen’s treatment, which is called Spinraza, people with the most severe cases of this disease lost the ability to use their muscles and even to breathe or swallow. Many children born with the most severe symptoms died before they were 2 years old.

“No one deserves it more,” said Dianne Larson, whose 5-year-old daughter Emma has been in a trial for the drug Krainer helped develop since 2015. When Emma started the trial as a 2-year-old, she couldn’t crawl anymore. Now, she’s able to push herself in a wheelchair, stand and take steps while holding onto something. Emma refers to Krainer as the person who helped make “my magic medicine.”

People with medical needs “kind of take for granted that there’s a medicine out there,” Larson said. “You don’t think about the years of dedication and research and hours and hours and money it costs to do this.”

Bruce Stillman, president and chief executive officer at Cold Spring Harbor Laboratory, said that this award was well deserved and was rooted in basic science. Krainer’s “insights were substantial and he realized that he could apply this unique knowledge to tackle SMA,” Stillman wrote in an email. “He did this with spectacular results.”

Dr. Adrian Krainer with the Larson family, Matthew, Diane and Emma. Photo from Diane Larson

Children with the most severe case of this disease had faced a grim diagnosis. “Now those children have a treatment that will keep them alive and greatly improve the prospects for a normal life,” Stillman added.

New York recently added SMA to its newborn screening test.

Krainer, who specialized in a process called RNA splicing during his research training, began searching for ways to help people with spinal muscular atrophy in 2000.

SMA mostly originates when the gene SMN1 has a defect that prevents it from producing the SMN protein,  called survival of motor neuron. This protein is important for the motor neurons, the nerve cells that control voluntary muscles.

As it turns out, people have a backup gene, called SMN2, which produces that important protein. The problem with this backup gene, however, is that it produces the protein in lower amounts. Additionally, RNA gene splicing leaves out a segment that’s important for the stability of the protein.

Looking at the backup gene, Krainer began his SMA work by seeking to understand what caused this splicing inefficiency, hoping to find a way to fix the process so that more function protein could be made from the SMN2 gene.

Collaborating with Bennett since 2004, Krainer developed and tested an antisense olignucleotide, or ASO. This molecule effectively blocked the binding of a repressor protein to the SMN2 transcript. By blocking this repressor’s action, the ASO enabled the correct splicing of the survival of motor neuron protein.

Emma Larson standing during her Mandarin lesson at Middle Country Public Library. Photo from Diane Larson

At first, Krainer tested the cells in a test tube and then in culture cells. When that worked, he went on to try this molecule in an SMA mouse model. He then worked with Ionis Pharmaceuticals and Biogen to perform the tests with patients. These tests went through hundreds of patients in numerous countries, as diseases like SMA aren’t limited by geographic boundaries.

“Everything worked” in the drug process, which is why it took a “relatively short time” to bring the treatment to market, Krainer said.

People who have worked with Krainer for years admire his character and commitment to his work.

Joe and Martha Slay, who founded the nonprofit group FightSMA, helped recruit Krainer to join the search for a treatment.

Joe Slay recalls how Krainer made an effort to meet with children with SMA. He recalls seeing Krainer during a pickup football game, running alongside children in wheelchairs, handing them the ball and tossing it with them.

Krainer brought his family, including his three children, to meet with the SMA community. The trip had a positive effect on his daughter Emily, who said it “subliminally had an impact on wanting to work in this field.” 

Currently a third-year resident in a combined pediatric neurology residency and fellowship program, his daughter is “very excited for him and proud.” She recalls spending Christmas holidays and New Years celebrations at the lab, where she met with his friends and co-workers.

Emily Krainer said a few people in her residency know about the role her father played in developing a treatment the hospital is employing.

The treatment is the “talk of child neurology right now,” she said.

Researchers hope the recognition for the value of basic research that comes with the breakthrough prize will have an inspirational effect on the next generation.

“The idea of prizes like this is to highlight to the public that scientists spend many years working without public recognition but make really important contributions to society,” Stillman suggested.

For Larson, the research Krainer did was key to a life change.

“To me, science is hope,” Larson said. “If we didn’t have this science, we wouldn’t have any hope,” adding that she would like her daughter to become a scientist someday.