Brain cells don’t always have easily discovered roles, the way various instruments do in an orchestra.
Sometimes, different cells share a function, making it possible to perform various tasks or to process information from the environment, while other times, different cells play their own part in making it possible for an organism to optimize its circuitry to act and react on the world.
So it is for the tufted and mitral cells of land based vertebrates, which are part of the olfactory system, sending signals to the brain about the odors and triggering thoughts about moving towards a desired food or away from the scent of a predator. In many studies, the names have been used interchangeably, as scientists were not sure how to separate them.
Florin Albeanu. Photo courtesy of CSHL
Researchers have spent considerable time studying mitral cells, which project into a region of the brain called the piriform cortex. These cells are nicely organized into one layer, which makes them easy to identify and are bigger in size compared to tufted cells.
Mitral cells, which have been the celebrated stars of the olfactory system, are easier to see and sort out than their nasal cousins, the tufted cells which, by contrast, are slightly smaller.
Recently, two scientists at Cold Spring Harbor Laboratory, Florin Albeanu, an Associate Professor, and ArkarupBanerjee, an Assistant Professor, published a study that suggested there’s more than meets the eye, or, maybe, the nose, with these tufted cells.
Tufted cells, it turns out, are better at recognizing smells than mitral cells and are critical for one of two parallel neural circuit loops that help the brain process different odor features, according to a study the scientists published in the journal Neuron at the end of September.
“People had assumed mitral cells were very good at” differentiating odor, but “tufted cells are better,” Albeanu said. “How they interact with each other and what the mitral cells are computing in behaving animals remains to be seen.”
Albeanu and Arkarup, who had performed his PhD research in Albeanu’s lab before returning to CSHL in 2020, exposed mice to different odors, from fresh mint to bananas and at different concentrations. They chose these compounds because there are no known toxic effects. The scientists also screened for compounds that elicited strong responses on the dorsal surface of the olfactory bulb that they could access using optical imaging tools.
It is hard to distinguish mitral and tufted cells when doing recordings. Optical imaging, however, enabled them to see through layers and shapes, if they were recording activity in a particular type of cell.
So, Albeanu asked rhetorically, “why is this exciting?”
As it turns out, these two types of cells project to different regions of the brain. Mitral cells travel to the piriform cortex, while tufted cells travel to the anterior olfactory nucleus.
It appears at this point that tufted cells are more likely to share information with other tufted cells, while mitral cells communicate with other mitral cells, as if the olfactory system had two parallel networks. There may yet be cross interactions, Albeanu said.
Mitral cells may be part of a loop that helps enhance and predict smells that are important for an animal to learn. Tufted cells, however, appear superior to mitral cells in representing changes in odor identity and intensity. By flagging the tufted cells as sources of olfactory information, the researchers were able to suggest a different combination of cells through which animals detect smells.
“A large fraction of people in the field would expect that mitral cells and the piriform complex are representing odor identity more so than the tufted cells and the anterior olfactory nucleus, so this is the surprise,” Albeanu explained in an email. Thus far, the reaction in the research community has been positive, he added.
Throughout the review process, the researchers encountered natural skepticism.
“It remains to be determined how the findings we put forward hold when mice are engaged in odor trigger behavior” as odors are associated with particular meaning such as a reward, an lead to specific actions,” Albeanu explained. “This is what we are currently doing.”
Albeanu added that a few different streams of information may be supported by tufted and mitral cells, depending on the needs of the moment.
Arkarup Banerjee. Photo ciourtesy of CSHL
The study that led to this work started when Banerjee was a PhD student in Albeanu’s lab. Albeanu said that a postdoctoral fellow in his lab, Honggoo Chae, provided complementary work to the efforts of Banerjee in terms of data acquisition and analysis, which is why they are both co-first authors on the study.
For Banerjee, the work with these olfactory cells was an “echo from the past,” Albeanu added.
As for where the research goes from here, Albeanu said future questions and experiments could take numerous approaches.
Researchers are currently looking for markers or genes that are expressed specifically and differentially in mitral or tufted cells and they have found a few potential candidates. While some markers have been found, these do not sharply label all mitral only versus all tufted cells only.
One of the confounding elements to this search, however, is that these cells have subtypes, which means that not every mitral cell has the same genetic blueprint as other mitral cells.
Another option is to inject an agent like a virus into the piriform cortex and assess whether boosting or suppressing activity in that region in the midst of olfaction alters the behavioral response.
Additionally, researchers could use tools to alter the activity of neurons during behavior using optogenetic approaches, inducing or suppressing activity with cell type specificity and millisecond resolution.
Albeanu would like to test speculation about the roles of these cells in action, while a mice is sampling smells he presents.
By observing the reactions to these smells, he could determine an association between rewards and punishment and anything else he might want to include.
The upshot of this study, Albeanu said, is that an objective observer would have much less trouble extracting information about the identity and intensity of a smell from a tufted cell as compared with a mitral cell.
Tufted cells had been “slightly more mysterious” up until the current study.
From left, K. Barry Sharpless and John Moses. Photo from CSHL
By Daniel Dunaief
K. Barry Sharpless changed John Moses’s life. And that’s before Moses even started working as a postdoctoral researcher in Sharpless’s lab.
When Moses, who is the first chemist to work at Cold Spring Harbor Laboratory in its 132-year history, was earning his PhD in chemistry at Oxford, he read an article that Sharpless co-authored that rocked his world.
Nicknamed the “click manifesto” for introducing a new kind of chemistry, the article, which was published in Angewandte Chemie in 2001, was “one of the greatest I’ve ever read,” Moses said, and led him to alter the direction of his research.
Moses walked into the office of the late chemist Sir Jack Baldwin at Oxford, who was Moses’s PhD advisor, and announced that Sharpless, a colleague of Baldwin’s at the Massachusetts Institute of Technology, was the only chemist he wanted to work with in the next phase of his career.
Baldwin looked at Moses and said, in a “very old-fashioned gangster English, ‘That shows you’ve got some brains,’” recalled Moses.
Sharpless was important not only to Moses’s career, but also to the world.
Recently, Sharpless, who is the W.M. Kepp Professor of Chemistry at Scripps Research, became only the fifth two-time recipient of the Nobel Prize.
Sharpless will share the most recent award, which includes a $900,000 prize, with Carolyn R. Bertozzi, the Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences at Stanford University, and Morten P. Meldal, professor at the University of Copenhagen, for the invention of a type of chemistry that has implications and applications from drug discovery and delivery, to making polymers, to developing anti cancer treatments.
The way click chemistry works is that chemists bring together catalysts and reagents, often attached to sulfur or carbon, that have a high level of specific attraction for each other. The click is like the sound a seat belt makes when secured, or the click a bike helmet lock makes when the two units are connected.
Scientists have often described the click reaction as being akin to LEGO blocks coming together, with an exact and durable chemical fit.
Natural product synthesis is generally challenging and often requires complex chemistries that are not always selective. This type of chemistry can produce side reactions that create unwanted byproducts and require purification.
Click reactions, by contrast, are selective and reliable and the products are generally easy to purify. Sometimes, purification is as simple as a water wash.
“It’s a democratization of synthetic chemistry,” Moses said.
Moses said biologists have performed click reactions. Chemists have developed click tablets that can be added to a reaction to create a plug and play system.
Moses described the reactions in click chemistry as “unstoppable” and suggested that they are part of a “domino rally” in which a latent build up of reactivity can create desired products with beneficial properties.
Moses, who arrived at CSHL in 2020, has collaborated with several researchers at the famed lab. He is submitting his first collaborative paper soon with Dr. Michael Lukey, who also started in 2020 and performed his PhD at Oxford, and Dr. Scott Lyons. He is also working on a New York State Biodefense funded project to create shape shifting antibiotics that can keep up with drug resistance pathogens.
He has collaborated with Cancer Center Director David Tuveson to develop a new ligand to target a protein important in pancreatic cancer. Moses said they have a “very exciting” lead compound.
Early resistance
While the Nobel Prize committee recognized the important contribution of this approach, the concept met with some resistance when Sharpless introduced it.
“When [Sharpless] submitted this, the editor called colleagues and asked, ‘Has Barry gone crazy?’” Moses said.
Some others in the field urged the editor to publish the paper by Sharpless, who had already won a Nobel Prize for his work with chirally catalyzed oxidation reactions.
Still, despite his bona fides and a distinguished career, Sharpless encountered “significant resistance” from some researchers. “People were almost offended by it” with some calling it “old wine in new bottles,” Moses said.
In 2007, Moses attended a faculty interview at a “reasonably good” university in England,. where one of his hosts told him that click chemistry is “just bulls$#t!”
Moses recognized that he was taking a risk when he joined Sharpless’s lab. Some senior faculty advised him to continue to work with natural product synthesis.
In the ensuing years, as click chemistry produced more products, “everyone was using it and the risks diminished quickly,” Moses added.
Unique thought process
So, what is it about Sharpless that distinguishes him?
Moses said Sharpless’s wife Janet Dueser described her husband as someone who “thinks like a molecule,” Moses said.
For Moses, Sharpless developed his understanding of chemistry in a “way that I’ve never seen anyone else” do.
Moses credits Dueser, who he described as “super smart,” with coining the term “click chemistry” and suggested that their partnership has brought together his depth of knowledge with her ability to provide context.
Moses believes Sharpless “would admit that without [Dueser], his career would have been very different! In my opinion, [Dueser] contributed immeasurably to click chemistry in so many ways.”
Indeed, click chemistry won a team prize from the Royal Society of Chemistry last year in which Dueser was a co-recipient.
As for what he learned from working with a now two-time Nobel Prize winner, Moses said “relinquishing control is very powerful.”
Moses tells his research team that he will never say “no” to an innovative idea because, as with click chemistry, “you never know what’s around the corner.”
Moses said Sharpless is a fan of the book “Out of Control” by Kevin Kelly, the co-founder of Wired Magazine. The book is about the new biology of machines, social systems and the economic world. Sharpless calls Kelly “Saint Kevin.”
On a personal level, Sharpless is “humble and a nice person to talk to” and is someone he would “want to go to a pub with.”
Moses believes Sharpless isn’t done contributing to chemistry and the world and anticipates that Sharpless, who is currently 81 years old, could win another Nobel Prize in another 20 years.
An inspirational scientist, Sharpless ” is “that kind of person,” Moses said.
Peter Westcott, on right, in the lab with technicians Zakeria Aminzada, on left and Colin McLaughlin, center. Photo by Steven Lewis
By Daniel Dunaief
When Peter Westcott was growing up in Lewiston/Auburn, Maine, his father Johnathan Harris put the book “Human Genome” on his bed. That is where Westcott, who has a self-described “obsessive attention to detail,” first developed his interest in biology.
Westcott recently brought that attention to detail to Cold Spring Harbor Laboratory, where he is an assistant professor and Cancer Center member. He, his wife Kathleen Tai and their young children Myles and Raeya moved from Somerville, Massachusetts, where Westcott had been a postdoctoral fellow at the Koch Institute of Integrative Cancer Research at the Massachusetts Institute of Technology.
Westcott will take the passion and scientific hunger he developed and honed to the famed lab, where he plans to continue studies on colon cancer and the immune system.
“A lot of things attracted me to Cold Spring Harbor Laboratory,” said Westcott who had been to the lab during conferences, joining three Mechanisms and Models of Cancer meetings, and appreciated that the small size of the lab encourages collaboration and the sharing of ideas across disparate fields.
At this point, Westcott, who purchased a home in Dix Hills and started on campus on September 1st, has two technicians, Zakeria Aminzada and Colin McLaughlin working with him. He will be taking on a graduate rotation student from Stony Brook University soon and would also like to add a postdoctoral researcher within about six months. He plans to post ads for that position soon.
Research directions
Westcott said his research has two major research directions.
The first, which is more translatable, involves looking at how T cells, which he described as the “major soldiers” of the immune system, become dysfunctional in cancer. These T cells balance between attacking unwanted and unwelcome cells relentlessly, disabling and destroying them, and ignoring cells that the body considers part of its own healthy system. When the T cells are too active, people develop autoimmunity. When they aren’t active enough, people can get cancer.
“Most cancers, particularly the aggressive and metastatic ones, have disabled the immune response in one way or another, and it is our focus to understand how so we can intervene and reawaken or reinvigorate it,” he explained.
During cancer development, T cells may recognize that something on a tumor is not healthy or normal, but they sometimes don’t attack. Depending on the type of genetic program within the T cells that makes them tolerant and dysfunctional, Westcott thinks he can reverse that.
A big push in the field right now is to understand what the genetic programs are that underlie different flavors of dysfunction and what cell surface receptors researchers can use as markers to define T cells that would allow them to identify them in patients to guide treatment.
Westcott is taking approaches to ablate or remove genes called nrf4a 1, 2 and 3. He is attacking these genes individually and collectively to determine what role they play in reducing the effectiveness of the body’s immune response to cancer.
“If we knock [some of these genes] out in T cells, we get a better response and tumors grow more poorly,” he said.
Westcott is exploring whether he can remove these genes in an existing T cell response to cause a regression of tumor development. He may also couple this effort with other immunotherapies, such as vaccines and agonistic anti-CD40 antibody treatment.
As a second research direction, Westcott is also looking more broadly at how tumors evolve through critical transitions. Taking an evolutionary biology perspective, he hopes to understand how the tumors start out as more benign adenoma, then become malignant adenocarcinoma and then develop into metastatic cancer. He is focusing in particular on the patterns of mutations and potential neoantigens they give rise to across the genome, while concentrating on the immune response against these neoantigens.
Each tumor cell is competing with tumor cells with other mutations, as well as with normal cells. “When they acquire new mutations that convey a selective advantage” those cells dominate and drive the growth of a tumor that can spread to the rest of the body, Westcott said.
Using a mouse model, he can study tumors with various mutations and track their T cell response.
T cells tend to be more effective in combating tumors with a high degree of mutations. These more mutated tumors are also more responsive to immunotherapy. Westcott plans to study events that select for specific clones and that might shift the prevalence, or architecture, of a tumor.
Some of the work Westcott has done has shown that it is not enough to have numerous mutations. It is also important to know what fraction of the cancer cells contain these mutations. For neoantigens that occur in only a small fraction of the total cells in the tumor, the T cell responses aren’t as effective and checkpoint blockade therapy doesn’t work.
He wants to understand how the T cell responses against these neoantigens change when they go from being subclonal “to being present in most or all of the tumor cells,” he explained. That can occur when a single or few tumor cells acquire a selective advantage. His hypothesis is that these selective events in tumor progression is inherently immunogenic. \
By exploring the fundamental architecture of a tumor, Westcott hopes to learn the mechanisms the tumor uses to evade the immune system.
Ocean breeze
As Westcott settles in at CSHL, he is excited by the overlap between what he sees around the lab and the Maine environment in which he was raised.
“Looking out the window to the harbor feels like New England and Maine,” he said. “It’s really nostalgic for me. Being near the ocean breeze is where I feel my heart is.”
Before his father shared the “Human Genome” book with him, Westcott was interested in rocks and frogs. In high school, his AP biology teacher helped drive his interest in the subject by encouraging discussions and participation without requiring her students to repeat memorized facts. The discussions “brought to life” the subject, he said.
As for his work, Westcott chose to study colon cancer because of its prevalence in the population. He also believes colon cancer could be a model disease to study all cancers. By understanding what differentiates the 12 percent of cases that are responses to immunotherapy from the remainder that don’t respond as well to such approaches, he hopes to apply these lessons to all cancer.
Scientists drive oil accumulation in rapidly growing aquatic plants
Scientists at the U.S. Department of Energy’s Brookhaven National Laboratory and collaborators at Cold Spring Harbor Laboratory (CSHL) have engineered duckweed to produce high yields of oil. The team added genes to one of nature’s fastest growing aquatic plants to “push” the synthesis of fatty acids, “pull” those fatty acids into oils, and “protect” the oil from degradation. As the scientists explain in a paper published in Plant Biotechnology Journal, such oil-rich duckweed could be easily harvested to produce biofuels or other bioproducts.
John Shanklin. Photo from BNL
The paper describes how the scientists engineered a strain of duckweed, Lemna japonica, to accumulate oil at close to 10 percent of its dry weight biomass. That’s a dramatic, 100-fold increase over such plants growing in the wild—with yields more than seven times higher than soybeans, today’s largest source of biodiesel.
“Duckweed grows fast,” said Brookhaven Lab biochemist John Shanklin [https://www.bnl.gov/staff/shanklin], who led the team. “It has only tiny stems and roots—so most of its biomass is in leaf-like fronds that grow on the surface of ponds worldwide. Our engineering creates high oil content in all that biomass.
“Growing and harvesting this engineered duckweed in batches and extracting its oil could be an efficient pathway to renewable and sustainable oil production,” he said.
Two added benefits: As an aquatic plant, oil-producing duckweed wouldn’t compete with food crops for prime agricultural land. It can even grow on runoff from pig and poultry farms.
“That means this engineered plant could potentially clean up agricultural waste streams as it produces oil,” Shanklin said.
Leveraging two Long Island research institutions
The current project has roots in Brookhaven Lab research on duckweeds from the 1970s, led by William S. Hillman in the Biology Department. Later, other members of the Biology Department worked with the Martienssen group at Cold Spring Harbor to develop a highly efficient method for expressing genes from other species in duckweeds, along with approaches to suppress expression of duckweeds’ own genes, as desired.
As Brookhaven researchers led by Shanklin and Jorg Schwender [https://www.bnl.gov/staff/schwend] over the past two decades identified the key biochemical factors that drive oil production and accumulation in plants, one goal was to leverage that knowledge and the genetic tools to try to modify plant oil production. The latest research, reported here, tested this approach by engineering duckweed with the genes that control these oil-production factors to study their combined effects.
“The current project brings together Brookhaven Lab’s expertise in the biochemistry and regulation of plant oil biosynthesis with Cold Spring Harbor’s cutting-edge genomics and genetics capabilities,” Shanklin said.
One of the oil-production genes identified by the Brookhaven researchers pushes the production of the basic building blocks of oil, known as fatty acids. Another pulls, or assembles, those fatty acids into molecules called triacylglycerols (TAG)—combinations of three fatty acids that link up to form the hydrocarbons we call oils. The third gene produces a protein that coats oil droplets in plant tissues, protecting them from degradation.
From preliminary work, the scientists found that increased fatty acid levels triggered by the “push” gene can have detrimental effects on plant growth. To avoid those effects, Brookhaven Lab postdoctoral researcher Yuanxue Liang paired that gene with a promoter that can be turned on by the addition of a tiny amount of a specific chemical inducer.
“Adding this promoter keeps the push gene turned off until we add the inducer, which allows the plants to grow normally before we turn on fatty acid/oil production,” Shanklin said.
Liang then created a series of gene combinations to express the improved push, pull, and protect factors singly, in pairs, and all together. In the paper these are abbreviated as W, D, and O for their biochemical/genetic names, where W=push, D=pull, and O=protect.
The key findings
Overexpression of each gene modification alone did not significantly increase fatty acid levels in Lemna japonica fronds. But plants engineered with all three modifications accumulated up to 16 percent of their dry weight as fatty acids and 8.7 percent as oil when results were averaged across several different transgenic lines. The best plants accumulated up to 10 percent TAG—more than 100 times the level of oil that accumulates in unmodified wild type plants.
Some combinations of two modifications (WD and DO) increased fatty acid content and TAG accumulation dramatically relative to their individual effects. These results are called synergistic, where the combined effect of two genes increased production more than the sum of the two separate modifications.
These results were also revealed in images of lipid droplets in the plants’ fronds, produced using a confocal microscope at the Center for Functional Nanomaterials [https://www.bnl.gov/cfn/] (CFN), a DOE Office of Science user facility at Brookhaven Lab. When the duckweed fronds were stained with a chemical that binds to oil, the images showed that plants with each two-gene combination (OD, OW, WD) had enhanced accumulation of lipid droplets relative to plants where these genes were expressed singly—and also when compared to control plants with no genetic modification. Plants from the OD and OWD lines both had large oil droplets, but the OWD line had more of them, producing the strongest signals.
“Future work will focus on testing push, pull, and protect factors from a variety of different sources, optimizing the levels of expression of the three oil-inducing genes, and refining the timing of their expression,” Shanklin said. “Beyond that we are working on how to scale up production from laboratory to industrial levels.”
That scale-up work has several main thrusts: 1) designing the types of large-scale culture vessels for growing the modified plants, 2) optimizing large-scale growth conditions, and 3) developing methods to efficiently extract oil at high levels.
This work was funded by the DOE Office of Science (BER). CFN is also supported by the Office of Science (BES).
Brookhaven National Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit science.energy.gov. [https://www.energy.gov/science/]
Victoria Bautch on right with graduate student Danielle Buglak. Photo from UNC McAllister Heart Institute
By Daniel Dunaief
This is part two of a two-part series featuring Cold Spring Harbor Laboratory alums Joanna Wysocka, Robert Tjian, Victoria Bautch, Rasika Harshey and Eileen White.
Often working seven days a week as they build their careers, scientists plan, conduct and interpret experiments that don’t always work or provide clear cut results.
Driven by their passion for discovery, they tap into a reservoir of ambition and persistence, eager for that moment when they might find something no one else has discovered, adding information that may lead to a new technology, that could possibly save lives, or that leads to a basic understanding of how or why something works.
Nestled between the shoreline of an inner harbor along the Long Island Sound and deciduous trees that celebrate the passage of seasons with technicolor fall foliage, Cold Spring Harbor Laboratory has been a career-defining training ground for future award-winning scientists.
Last week two alumni of Cold Spring Harbor Laboratory, Joanna Wysocka and Robert Tjian, shared their thoughts, experiences, and reflections on the private lab that was founded in 1890. This week the article continues with reflections from alumni Rasika Harshey, Victoria Bautch and Eileen White.
Confidence builder
Lunch time presented no break from science for Rasika Harshey, and that was just as she’d hoped.
Rasika Harshey
When she was at Blackford Hall between 1979 and 1983, first as a postdoctoral researcher and then as a staff investigator in the lab of Ahmad Bukhari, Harshey said conversations frequently included discussions about research. “It was wonderful,” she said. “It was just science, 24/7.”
Bukhari was studying a virus that infects bacteria, called mu, for mutator. The viral particle genome was jumping into the host genome. “At that point, transposable elements” of DNA were “entering into our consciousness,” Harshey explained.
In her research, Harshey would induce the virus and, 30 minutes later, get 100 phage particles. Looking in the cytoplasm, however, she didn’t find any of this viral DNA until phage progeny appeared about 50 minutes later. “How is that possible?” she asked. “I wanted to solve this mystery.”
Harshey spent countless hours in the electron microscope room, isolating DNA. She knew mu was replicating, or copying itself, but she couldn’t figure out how or what it was doing. She and Bukhari proposed a model about transposable elements at a meeting called “Movable Genetic Elements” in 1979 at CSHL that generated considerable discussion.
“It was thrilling at the time for me to develop as a scientist,” Harshey said. “It seemed to me that I was saying something and people were listening. I gained a lot of confidence in myself.” The work she did turned out to be only partially correct, but it gave her the sense that she could solve problems.
With CSHL as a backdrop, Harshey enjoyed the opportunity to attend meetings and to interact with other visitors and other scientists on campus. “It was a total immersion” she said. “Summers were magical, with so many meetings one could just walk into.”
Harshey visited Barbara McClintock’s lab, which was down the hall from hers. McClintock, who won the Nobel Prize in Harshey’s final year at CSHL, showed her the maize cells.
McClintock also invited her to her cottage, where she served what Harshey recalled was a “delicious” poppyseed cake.
She described McClintock as “quiet” and a “tough cookie.”
Rasika Harshey at CSHL.Courtesy of Cold Spring Harbor Laboratory Archives, NY.
Harshey thought it was inspiring to be with McClintock, Watson and Richard Roberts, who also won a Nobel Prize. She also appreciated the opportunity to visit with Guenter Albrecht-Buehler and Joseph Sambrook. “I was in and out of Richard Roberts’s lab all the time,” she said.
For her work, Harshey needed restriction enzymes, which Phyllis Myers produced. She had to “beg” Myers for these valuable enzymes that were in short supply.
Harshey felt an urgency to commit herself to her work. When she and her husband Makkuni Jayaram were expecting a baby, she didn’t share the news until it had become obvious. She worked until the last moment before the baby was born in 1982, “but I came back,” she said.
Harshey, who also calls CSHL “home,” described it as a “place time forgot. It’s quiet and beautiful and you can do and think and talk science.” Professor in Molecular Biosciences at The University of Texas at Austin in the College of Natural Sciences, Harshey is grateful for the career and the life she’s led. “A series of accidents got me here,” she said. “I can’t believe my good fortune, that I get to do what I get to do every day.”
As a part of the history of CSHL, Harshey appreciates a culture that she has carried forward in her career. The “deep joy, commitment, excitement for biology, particularly for designing experiments, and looking at a problem from all angles” was embedded into the approach scientists took to the work they did at the lab.
She also believes the tradition at CSHL includes an “appreciation for how easy it is to get things wrong and to continually challenge your own ideas.”
Intense culture
Victoria Bautch came to Cold Spring Harbor Laboratory in the 1983 knowing that she was interested in studying aspects of developmental biology. When she saw the power of the new technology, she started working on genetically modified animals.
She was trying to figure out whether viral genes previously only linked to cancer by association could cause cancer when part of the genome was put into animals. When she inserted genes into a mouse’s DNA, some of these mice developed tumors in their blood vessels. She “didn’t know this was going to happen,” she said. “The type of tumor was a complete surprise.”
Bautch needed to know more about how blood vessels formed and functioned to understand these tumors. That’s what got her excited about studying these blood vessels. These blood vessel tumors “weren’t on my radar,” she said.
While working in the lab of Doug Hanahan, Bautch had the opportunity to interact with Judah Folkman, a Professor at Harvard University. Folkman was excited about the way these blood vessels were developing and encouraged Bautch to continue to work in this field. Folkman championed the idea that new blood vessel formation contributes to the progression of many types of tumors. He was eager to bring new people and technologies into the field.
Bautch also met mouse geneticists Nancy Jenkins and Neal Copeland who were at Jackson Labs at the time and were instrumental in her career progression. She started asking basic questions about how blood vessels forms and how they function.
Folkman was looking to “bring people into the field that had more of a basic science and molecular biology background,” Bautch said. He was hoping to add researchers who would use the new tools to understand blood vessel basics and how they are involved in tumors.
The tumor Bautch worked on was an “entree into the bigger field of blood vessels and vascular biology,” she said.
Cold Spring Harbor Laboratory provided a constructive backdrop for the work Bautch did that proved important in her career. “I was looking for an intense and very high caliber scientific environment and I feel like I found it,” she said.
Indeed, Bautch often worked seven days a week, starting at 10 or 11 in the morning and ending around 1 or 2 in the morning. During the later hours, she had an easier time accessing machines and equipment that others in the lab also needed.
Like Harshey, Bautch has her own McClintock story. “She always would say, ‘Look at your organism very carefully.’ You could learn so much from observing.”
At the time, McClintock’s advice seemed “antiquated” to Bautch, especially with researchers doing molecular biology that was more of a technological breakthrough, but now appreciates the guidance. “A really important piece of being a scientist is being observant,” sheexplained.
Bautch said other scientists were prepared to offer their responses to her work. “People were always telling you what they thought, whether you wanted it or not,” she recalled.
Now a Distinguished Professor of Biology and Co-Director of the McAlister Heart Institute at UNC Chapel Hill, Bautch recalls her time at CSHL as a combination of a “very intense life experience as well as science experience.” As for her hopes for the current crop of scientists at CSHL, Dr. Bautch hopes this generation is “more inclusive.”
An alternateexplanation of cancer
Around the same time that actress Heather Locklear was telling TV audiences about Faberge Organics Shampoo about how people can tell two friends about the shampoo who then tell two friends, researchers knew that a type of gene that promoted cancer did essentially the same thing.
Eileen White. Photo courtesy of Rutgers Cancer Institute of New Jersey
Called an oncogene, these genes caused cells to continue to divide and, as the shampoo commercial suggested “and so on and so on and so on.” Back then, scientists focused on the role oncogenes played in cell proliferation, which, with cancer, involved the runaway copying of itself.
A graduate of Smithtown High School who earned her PhD at Stony Brook University, Eileen White joined Bruce Stillman’s lab as a post doctoral fellow at Cold Spring Harbor Laboratory in 1983. After three years, White became a staff investigator, making the beginning of career-defining discoveries about the development of cancer.
“We knew that certain viruses cause cancer, and we knew that these viruses encoded oncogenes,” said Dr. White. “The whole idea was to understand how.”
Indeed, viral oncogenes, which are small and less complicated than tumor genomes, presented the opportunity to find a shortcut to understand how cancers developed in humans. Even if the human oncogene is small, the genome it sits in is huge, which is not the case of a viral oncogene that sits I a very small viral genome, she explained.
Using a DNA tumor virus that promoted cancer, White discovered that this gene prevented apoptosis, or programmed cell death. After this discovery, which she said she could “see with her own eyes” when she studied the effect of the genes on cells, she asked herself what she’d need to do to push the idea forward for this paradigm shift in thinking about cancer.
As she continued to discover more details about the viral oncogene over the years, she said other researchers discovered that the Bcl-2 human oncogene may function similarly.“I thought, ‘Well, if this is a theme that viral oncogenes and potentially cancer oncogenes are blocking apoptosis, they should be functionally interchangeable,’” White recalled, which is what she showed and published.
She substituted human Bcl2 oncogene of the viral E1B 19K oncogene and showed that they both functioned to block apoptosis interchangeably.
Courtesy of Cold Spring Harbor Laboratory Archives, NY.
These discoveries, which started at Cold Spring Harbor Laboratory, among others, helped pave the way for Dr. White’s career, where she is now professor of Molecular Biology and Biochemistry and Deputy Director at the Rutgers Cancer Institute of New Jersey. She is also Associate Director of the Ludwig Princeton Branch of the Ludwig Institute for Cancer Research at Princeton University.
The discovery also led to some anti cancer treatments. Abbott developed the first FDA approved Bcl-2 inhibitor, which others followed.
These kinds of discoveries, which lead to treatments, are why she and others “work so hard, to make a difference for patients,” she said.
Dr. White describes her time at CSHL as an “enormously enriching experience” in which she was surrounded by people who were of “exceptional scientific caliber,” including some who won the Nobel Prize while she was there.
“I had a fertile environment with people that had similar ways of thinking that was very synergistic in terms of propelling the science forward,” she said.
She appreciated the numerous meetings held at CSHL at which she felt like she could learn about anything from the depth and breadth of the material presented and discussed. During these meetings, which she still attends regularly, she has recruited post doctoral researchers to her lab whom she’s met at poster sessions.
As with other alumni of CSHL, Dr. White was particularly pleased with the robust and valuable feedback she and others received. “Critical and productive insights from the scientific community is important to the process of scientific discovery from beginning to the end,” she explained.
White suggested that the layout of the campus and the proximity of so many families created a unique and tight knit community. She recalled how the lab had Santa Claus at Christmas, hay rides to the pumpkin patch and special dinners for people who lived there.
“That very much builds camaraderie and long term friendships and long term relationships,” she said.
This is part one of a two-part series featuring Cold Spring Harbor Laboratory alums Joanna Wysocka, Robert Tjian, Victoria Bautch, Rasika Harshey and Eileen White. Part two will be in the issue of Aug. 25.
Often working seven days a week as they build their careers, scientists plan, conduct and interpret experiments that don’t always work or provide clear cut results.
Driven by their passion for discovery, they tap into a reservoir of ambition and persistence, eager for that moment when they might find something no one else has discovered, adding information that may lead to a new technology, that could possibly save lives, or that leads to a basic understanding of how or why something works.
Nestled between the shoreline of an inner harbor along the Long Island Sound and deciduous trees that celebrate the passage of seasons with technicolor fall foliage, Cold Spring Harbor Laboratory has been a career-defining training ground for future award-winning scientists.
Five alumni of Cold Spring Harbor Laboratory recently shared their thoughts, experiences, and reflections on the private lab that was founded in 1890.
While they shared their enthusiasm, positive experiences and amusing anecdotes, they are not, to borrow from scientific terminology, a statistically significant sample size. They are also a self-selecting group who responded to email requests for interviews. Still, despite their excitement about an important time in their lives and their glowing description of the opportunities they had to hone their craft, they acknowledged that this shining lab on the Sound may not be paradise for everyone.
Cold Spring Harbor Laboratory is considerably smaller than some of the research universities around the country. Additionally, scientists with a thin skin — read on for more about this — may find their peers’ readiness to offer a range of feedback challenging. Still, the lab can and has been a launching pad.
A suitcase and a dream
Joanna Wysocka’s story mirrors that of other immigrants who came to the United States from their home countries. Wysocka arrived from Poland in 1998 with one suitcase that included mementos from her family, a Polish edition of her favorite book, One Hundred Years of Solitude, and a dream of developing her scientific career.
She was also chasing something else: her boyfriend Tomek Swigut, who had come to Cold Spring Harbor Laboratory. “I was fresh off the boat without any fancy resume or anything,” Wysocka recalls. “They really took a chance on me.”
Joanna Wysocka
While she learned how to conduct scientific experiments, she also recognized early on that she was a part of something bigger than herself. Early on, she found that people didn’t hold back in their thoughts on her work. “You always got critical feedback,” she said. “People felt very comfortable picking apart each other’s data.”
The positive and negative feedback were all a part of doing the best science, she explained.
Wysocka felt the inspiration and exhilaration that comes from a novel discovery several times during her five-year PhD program.
“It’s 11 p.m. in the evening, you’re in the dark room, developing a film, you get this result and you realize you’re a person who knows a little secret that nobody else in the world knows just yet,” she recalled. “That is really wonderful.”
For special occasions, the lab celebrated such moments with margaritas. Winship Herr, her advisor, made particularly strongest ones.
In one of her biggest projects, Wysocka was working with a viral host cell factor, or HCF. This factor is critical for transcription for the Herpes simplex virus. What wasn’t clear, however, was what the factor was doing. She discovered that this factor worked with proteins including chromatin modifiers. “From this moment, it set me up for a lifetime passion of working on gene regulation and chromatin,” she said.
As for the scientific process, Wysocka said Herr offered her critical lessons about science. When she started, Herr expected two things: that she’d work hard and that she’d learn from her mistakes. During the course of her work, she also realized that any work she did that depended on the result of earlier experiments required her own validation, no matter who did the work or where it was published. “You need to repeat the results in your own hands, before you move on,” she explained.
Despite the distance from the lab to New York City and the smaller size of the lab compared with large universities, Wysocka never felt isolated. “Because of all the conferences and courses, the saying goes that ‘if you want to meet somebody in science, go to a Cold Spring Harbor bar and sit and wait.’” That, however, is not something she took literally, as she put considerable hours into her research. While she wishes she had this incredible foresight about choosing Cold Spring Harbor Laboratory, she acknowledges that she was following in Swigut’s footsteps.
The choice of CSHL worked out well for her, as her research has won numerous awards, including the Vilcek Prize for Creative Promise in Biomedical Science, which recognizes immigrant scientists who have made a contribution to U.S. society. She now works as Professor at Stanford University and is married to Swigut.
Swinging for the fences
In 1976, Robert Tjian had several choices for the next step in his developing scientific career after he completed his PhD at Harvard University. James Watson, who had shared the Nobel Prize in 1962 for the double helix molecular structure of DNA with Francis Crick and Maurice Wilkins and was director at Cold Spring Harbor Laboratory, convinced him to conduct his postdoctoral research at CSHL.
Robert Tjian
The contact with Watson didn’t end with his recruitment. Tjian, who most people know as “Tij,” talked about science on almost a daily basis with Watson, which he considered an ‘incredible privilege.”
Although he only worked at CSHL for two years, Tjian suggested the experience had a profound impact on a career that has spanned six decades.
Learning about gene discovery was the main driver of his time at CSHL. An important discovery during his work at CSHL was to “purify a protein that binds to the origin of replication of a tumor virus, which was what [Watson] wanted me to do when he recruited me,” he said. That launched his career in a “positive way.”
Tjian feels fortunate that things worked out and suggested that it’s rare for postdoctoral students to achieve a transformative career experiment in such a short period of time either back then or now. He attributes that to a combination of “being in the right place at the right time,” luck and hard work.
At Berkeley, where he is Professor of Biochemistry, Biophysics and Structural Biology and has been running a lab since 1979, he has observed that the most successful researchers are the ones who are “swinging for the fences. If you don’t swing for the fences and get lucky, you sure as hell aren’t going to hit a home run.”
Tjian learned how to run a lab from his experience at CSHL. He selects for risk takers who are independent and feels the only way to motivate people is to ensure that the work they are pursuing involves questions they want to solve.
One of the most important and hardest lessons he learned during his research career was to “fail quickly and move on.” He tells his student that about 85 percent of their experiments are going to fail, so “get used to it and learn from it.”
Despite his short and effective stay at CSHL, Tjian suggested he made “more than his fair share” of mistakes. Terri Grodzicker, who is currently Dean of Academic Affairs at CSHL, taught Tjian to do cell culture, which he had never done before. He contaminated nearly all the cultures for about a month.
While Tjian described the lab as a “competitive place,” he felt like his colleagues “helped each other.”
When he wasn’t conducting his experiments or contaminating cultures, he spent time on the tennis court, playing regularly with Watson. Watson wasn’t “exactly the most coordinated athlete in the world,” although Tjian respected his “remarkably good, natural forehand.” He was also one of the few people who was able to use the lab boat, which he used to fish for striped bass and bluefish early in the morning. “I would try to drag all kinds of people out there,” he said.
While his CSHL experience was “the best thing” for him, Tjian explained that the lab might not be the ideal fit for everyone, in part because it’s considerably smaller than larger universities. At Berkeley, he has 40 to 55 PhD students in molecular biology and he can interact with 40,000 undergraduates, which is a “very different scale.”
Tjian has returned many times to CSHL and is planning to visit the lab at the end of August for a meeting he’s organizing on single molecule microscopy.
Each time he comes back, he “always felt like I was coming home,” he said.
What if scientists could train the immune system to recognize something specific on the outside of unwanted cells?
That’s what new Cold Spring Harbor Laboratory fellow Corina Amor is doing, as she found an antigen on the surface of senescent cells. She hopes to train a patient’s T-cells to search for these cells, much like providing a police dog with the scent of a missing person or escaped convict.
Amor, who joined Cold Spring Harbor Laboratory in January after earning her medical degree inat Universidad Complutense de Madrid in Spain and her PhD in the lab of CSHL Adjunct Professor Scott Lowe, recently found a surface molecule called uPAR that is upregulated on senescent, or aging, cells.
If senescent cells excessively accumulate, it can lead to tissue decline and disease like lung and liver fibrosis, Lowe, who is the Cancer Biology Chair at Memorial Sloan Kettering Cancer Center, explained in an email. Senescent cells also contribute to tissue decline as people age.
Studies suggest eliminating these senescent cells could provide therapeutic benefit, she added.
Using artificial T-cells, called CAR-T, for Chimeric Antigen Receptor, Amor looks to use specific antigens to find these senescent cells and eliminate them.
“It was sort of a crazy idea, but it worked and, while much more preclinical and clinical work needs to be done, the concept could lead to better treatments for lung and liver fibrosis, and other diseases that increase as we age,” Lowe wrote.
The combination of an inflamed environment and an ineffective immune system can create conditions that favor the growth and development of cancer.
Amor, who currently has one technician and is planning to add a graduate student this summer at her lab at CSHL, is building on her PhD research.
“My doctoral work was the development of the first CAR-T cells that are able to target senescent cells,” she said. “We were the first in the world to do this.”
Amor, who was recently named to the 2022 Forbes 30 under 30 Europe list, describes this approach as a new frontier for treating senescent cells and one in which researchers would need to clear numerous hurdles before developing clinical therapies.
She is searching for other antigens on the surface of cancerous and fibrous cells that would increase the specificity of these synthetic immune cells.
Combining antigens could be the key to avoiding off target effects that might cause the immune system to attack healthy cells.
Amor plans to tap into CSHL’s affiliation with Northwell Health to analyze clinical samples that might provide a better understanding of various potential markers.
Fellowship route
Cold Spring Harbor Laboratory is one of several programs in the country that provides talented researchers with the opportunity to go directly from finishing their PhD to leading their own lab.
Amor is following in the footsteps of her MSKCC mentor Lowe, who also had been an independent fellow at CSHL.
Lowe saw some similarities in their career paths, as they both made “unexpected discoveries during our Ph.D. research that were not only important, but clearly set a path for future research,” he explained in an email.
Lowe describes Amor as an “intense and driven scientist” who has an “extraordinary bandwidth to get things done, and a mental organization that allows her to execute science efficiently.” He believes her work is game changing at many levels and opens up numerous new directions for scientific study.
Lowe is “extraordinarily proud of [Amor] for becoming a CSHL fellow – and I hope she both contributes and benefits from the lab as I did,” he wrote in an email.
Amor said CSHL provided an ideal balance between finding collaborators who worked in similar areas, without competing for the same resources and conducting similar research.
“The last thing you want is to go somewhere and be completely isolated,” she said. “You also don’t want to be at a place where there’s three other people doing the same thing and you’re not adding anything.”
She feels like she had a “nice synergy” with CSHL, which is trying to expand its immunology research.
As the first person to bring cellular therapy to CSHL, she has already started collaborating with several groups.
Amor recognizes the challenges ahead in training scientists who often have their own ideas about the questions they’d like to ask.
“The science is the easy part” and it comes naturally, but there is a “learning curve in how to manage people,” she said.
She appreciates the opportunity to talk with senior researchers at Cold Spring Harbor Laboratory and plans to attend courses and seminars for principal investigators who are starting out.
When she was in graduate school, Amor said she rotated through different labs. When everything didn’t work as she might have hoped during those rotations, she said she had the opportunity to learn from those experiences.
“When training people in the lab, I try to be really specific about what I want to do” while also ensuring that the researchers understand and appreciate the bigger picture and context for individual experiments, she said.
Originally from Madrid, Amor felt comfortable during her five years in Manhattan and is enjoying the open space and fresh air of Long Island in her role at CSHL. She also appreciates the chance to kayak in the waters around Long Island.
When she was around seven years old, Amor said her mother Esperanza Vegas was diagnosed with breast cancer. By participating in a clinical trial for a new drug, her mother fought off the disease.
“That made me realize how important science and research is,” Amor said.
During her educational training, Amor went directly from high school into a six-year program in which she earned a bachelor’s degree and a medical degree.
By the time she finished her PhD, she was hooked on research.
She appreciates the advice she received from Lowe, who encouraged her to conduct experiments despite the risks.
“Don’t get paralyzed at the beginning by fear,” she said. “Do the experiment and see what happens.”
Estrogen plays an important role in the developing mouse brain. By facilitating connections to other brain regions, estrogen turns on genes that affect how the brain of male and female rodents develops and, down the road, how mice behave.
Cold Spring Harbor Laboratory Associate Professor Jessica Tollkuhn this week, along withgraduate student Bruno Gegenhuber who recently earned his PhD, published research in the journal Nature that demonstrates how a specific region of the brain, called the bed nucleus of the stria terminalis, or BNST, responds to estrogen when the hormone receptor binds to DNA.
Male rodents convert a surge in testosterone into estrogen, which then triggers the development of more cells in the BNST than in female rodents. Later on in life, this can affect mating, parenting and aggression.
At this point, there is no data on how the BNST is masculinized in humans, although it is bigger in adult men than in women. Scientists also don’t know what the BNST does in humans. The BNST in humans is not much bigger than it is in mice.
On a broader scale, by understanding how estrogen shapes the developing brain differently in males and females, Tollkuhn hopes to discover the progression of behavioral disorders that are often more prevalent in one gender than the other. Boys have more neurodevelopmental disorders than girls, such as autism, language delays, dyslexia and attention deficit hyperactivity disorder, or ADHD. Girls, on the other hand, particularly after puberty, have twice the incidence of major depression compared to their contemporary male counterparts, Tollkuhn said.
Tollkuhn is part of a collaboration, funded by the Simons Foundation, to study autism. The CSHL researcher doesn’t believe autism originates in any particular brain region, describing it as a complex disorder with many causes.
“I do think that sex differences in brain regions such as the BNST can intersect with other genetic and environmental factors to increase vulnerability to developing certain symptoms in boys,” she explained.
In rodents, estrogen protects against programmed cell death. In the BNST and a few other brain regions, there are sex differences in cell death that are dependent on hormone exposure. A male mouse without exposure to estrogen would not have a larger BNST.
History of her research
Tollkuhn has been looking for estrogen receptor alpha in the brain since she started her post doctoral research at UCSF in 2007. The genome-wide targets of this receptor in breast cancer cells were first described in 2006.
Back then, the technology wasn’t good enough to capture estrogen receptor alpha binding in the small, sparse population of cells. These receptors, after all, aren’t in most brain cells.
The receptors for a hormone that plays such an important developmental role sit in the same place in males and females.
Tollkuhn’s assumption going into this study was that estrogen receptor alpha would have access to different genes in adult males and females, based on the different life histories of when the two sexes had prior estrogen exposure, which was transient in the developing male brain and fluctuated in females after puberty.
That, however, was not the case. Giving females and males the same hormones caused the genome to respond the same way.
“It’s really the differences of which hormones are present in the circulation that determines what genes are active,” she explained in an email.
Future studies
Tollkuhn is interested in the variation of hormones, receptors and gene responses between individuals within a single species and among various species.
She suggested that a spectrum of variability in sexual differentiation likely exists within and across species. The differences in the way these hormones and receptors shape individual development “is advantageous” because the plasticity in behaviors makes a species more resilient to subtle or dramatic changes in the environment, enabling an organism to alter its behaviors depending on internal states such as hunger, time of year, or place in a social hierarchy.
Tollkuhn would also like to know the genomic targets of androgen receptor, within the BNST and elsewhere. She would like to look at where estrogen receptors and androgen receptor are expressed in the developing human brain. She also plans to study estrogen receptor beta, which is “poorly understood even outside the brain.”
Studying these receptors and the genes they alter could enhance an understanding of cognition and mood, as well as measures of stress and anxiety.
Women with estrogen receptor positive breast cancer sometimes take a medication that blocks estrogen in the breast and in the brain. A side effect of this medicine, however, is that it causes women to have menopausal-type symptoms, such as disrupted sleep, thermoregulatory issues like “hot flashes,” and mood disorders.
Tollkuhn and Cassandra Greco, a graduate student at Stony Brook University, will investigate how different breast caner medications that target estrogen receptor alpha differentially affect its recruitment to the genome.
Tollkuhn plans to test the three most commonly prescribed treatments to see how they are affecting the brain and what they are doing to the estrogen receptor regulated genes in the brain.
She hopes one day to help develop a therapy with more specific targets that doesn’t have the same side effects.
Science origin story
When she was young, Tollkuhn liked reading books about biology, but didn’t discover her interest in research until she attended Mills College in Oakland, CA.
She got her first research experience working at biotech companies during her undergraduate studies. At that point, she learned that she was capable of doing challenging experiments.
In addition to continuing to read about a range of other research experiments, Tollkuhn enjoys the challenge of research.
“The joy of this job is that I get paid to ask questions that are interesting,” she said.
Above, from left, CSHL Associate Professor Steven Shea, Yunyao Xie, a former postdoctoral researcher in Shea’s lab, and Roman Dvorkin at work. Photo from CSHL
By Daniel Dunaief
The black box has a blue spot.
Often considered so mysterious that it has been called “the black box,” the brain has a small cluster of cells called the locus coeruleus (LC), or blue spot because it appears blue.
The LC is the predominant source of the neurotransmitter noradrenaline, which plays numerous roles, including triggering the “fight or flight” response, sleep/wake regulation and memory.
Recently, Cold Spring Harbor Laboratory Associate Professor Stephen Shea and his post doctoral researcher Roman Dvorkin demonstrated that the LC was involved in normal maternal social behavior. In the publication Journal of Neuroscience, they demonstrated that surrogate mothers had a spike in this neurotransmitter just at the time when they retrieved young pups that had rolled out of the nest.
“Most of the research on noradrenaline and the LC has been involved in non-social behavior,” said Shea. Researchers have recorded it extensively during “cognitive tasks and memory formation.”
The evidence for its involvement in social behaviors has been more indirect. With the exception of a study 35 years ago that made a few recordings in cats, the current research is the “first time anyone has recorded” the LC during a more normal social behavior, Shea said.
Research on this blue spot could prove valuable in connection with understanding and treating a wide range of diseases and disorders. Noradrenaline (NA) is “one of the systems that is disturbed in anxiety and depression,” Dvorkin said. It also may be involved in other diseases, like autism. Scientists have conducted research on the LC and ADHD, Parkinson’s disease and Alzheimer’s disease, Dvorkin explained.
Some studies have also linked Rett syndrome, for example, which is a rare inherited genetic disorder that affects mostly girls and can alter the ability to speak, walk and eat, to lower levels of noradrenaline.
“There’s evidence that the LC has pathology in Mecp2 mice,” said Shea, referring to a gene traced to Rett. “We are working on that directly.”
Researchers believe studying the structure of the LC could lead to diagnostics and therapeutics for some of these diseases. Dvorkin suggested that this kind of research is “important to see how it works under normal, awake conditions.”
Monitoring the release of this neurotransmitter during a typical social behavior among female mice provides a context-connected understanding of its potential role.
“When people are studying this, they often use investigator-contrived tasks,” Shea said. “This is the system that preexisted for mice to use for other purposes.”
Shea has done earlier work with the LC, particularly as the sense of smell is so prominent in social interactions for mice. He demonstrated that anesthetized mice exposed to the scent of an unfamiliar mouse react as if they have a familiarity with the mouse.
She believes the LC initiates sensory plasticity or sensory learning. NA can affect the sensory responses in parts of the brain that carry information, creating a stored memory. While his extensive work offers some clues about the role of the LC in mice, all vertebrates have the LC in their brain stems, including humans.
Shea said other research has demonstrated the involvement of the LC in cognitive tasks and memory formation, including during periods of sleep and wakefulness.
Blocking the release of noradrenaline is challenging in part because it is compact and the cells in the brain interact with so many of their neighbors, which makes turning on or off a specific signal from one region especially challenging.
At the University of Washington, Richard D. Palmiter and S.A. Thomas published a visible and definitive paper in 1997 in the journal Cell that brought the LC to other researcher’s attention.
These researchers created complete knockout mice, where they found that rodents lacking noradrenaline were “really bad mothers,” according to Shea.
In their research, Dvorkin and Shea used optogenetics and chemogenetics to inactivate the LC and the release of noradrenaline.
Future experiments
Below, a mouse retrieving a pup that has rolled out of its nest. Photo by Roman Dvorkin
The next step in this research could involve understanding the relative importance of the signal from the LC and noradrenaline.
In typical life settings, mice and other vertebrates confront competing signals, in which a pup rolls out of the nest at the same time that one of their many predators, like a hawk or other bird is circling overhead.
“That could be a next step” in this research, said Dvorkin.
Dvorkin believes it is possible to increase or decrease the threat level for mice gradually, in part because mice learn quickly when the threat is not real or what to avoid if the threat is too risky.
Shea is also looking more closely at courtship behavior.
The LC could be involved in sexual selection and in dominance hierarchies, enhancing the aggressive behavior of alpha males towards less dominant males.
“We see big signals associated with events in courtship, including when the female and male begin to mate,” said Shea.
A resident of East Northport, Dvorkin lives with his wife Paolina and their nine year-old son Adam, who is in third grade at Pulaski Road School.
Originally from Afula in northern Israel, Dvorkin has been working in Shea’s lab for over five years. Outside the lab, he enjoys spending time with his family, taking pictures, and swimming at the JCC.
Dvorkin has enjoyed his work at CSHL, which he described as a “great experience in a beautiful place,” where he can appreciate the quiet and where he has received considerable support.
In the future, he’d like to apply his expertise in working on neuronal cell cultures and behaving animals to address translative questions, such as neurodegeneration.
This LINCATS map shows the hospitals, incubators and collaborative institutions that will be involved in the regional initiative to translate biomedical discoveries into clinical applications to improve health outcomes, address health disparities across communities, and educate the workforce.
The initiative, secured by Senator Schumer, will receive $10 million in federal funds
Stony Brook University will lead a new, innovative network of regional biomedical research institutions to accelerate translational research that will impact and advance clinical care for many physical and mental health conditions. Called the Long Island Network for Clinical and Translational Science (LINCATS), it will be headquartered at Stony Brook University. The initiative will be in collaboration with Brookhaven National Lab (BNL), Cold Spring Harbor Laboratory, and the Northport VA Medical Center. Central to LINCATS establishment is $10 million in federal funding secured by Senator Chuck Schumer and supported by Senator Gillibrand, part of Congress’ omnibus funding bill of which Long Island will receive some $50 million.
The overall mission of LINCATS is to accelerate the public health impact of research, especially for underserved communities across Long Island, by offering access to innovative and transformative research programs and educational services. To improve the health of Long Island’s three million-plus population, the bioscience collaborative will engage in work ranging from basic research and clinical trials, to addressing vulnerable populations and disparities, and incorporating innovative research and practices such as the use of bioinformatics, artificial intelligence, telehealth, genotyping, proteomics, and engineering-driven medicine.
“I am incredibly grateful to Senator Schumer for securing such crucial funding for the establishment of the Long Island Network for Clinical and Translational Science (LINCATS) at Stony Brook University,” said Stony Brook University President Maurie McInnis. “Through LINCATS, the entire Long Island community and the greater New York region will have access to a comprehensive health research network that is capable of a rapid response to emergent healthcare risks, including a future global pandemic. New York and the nation are fortunate to have such a visionary leader as Senator Schumer, who champions the cutting-edge science research and health innovation that will provide important and much-needed economic boosts to development on Long Island.”
The initial funding will help to scale-up operations of this research and healthcare service network, creating an ecosystem that will fast-track the application of new scientific discoveries in clinical medical care, helping to provide new treatments to more patients throughout Long Island.
“With renowned institutions like BNL, Cold Spring Harbor Lab, and Stony Brook University, Long Island is a hub for world-class scientific research and groundbreaking discoveries,” said Senator Chuck Schumer. “To bolster continued success and innovation, I worked to ensure that, as part of Congress’s historic bipartisan budget agreement, $10 Million will head to Stony Brook to help create the Long Island Network for Clinical and Translation Science. This federal funding will help scale-up operations of this research and healthcare service network, creating an ecosystem that will fast-track the application of new scientific discoveries in clinical medical care. Not only will LINCATS put Long Island on the map as a center of clinical healthcare research, it will help provide innovative new treatments to benefit more patients throughout the region.“
One specific aspect of the collaborative work will be researching and addressing diseases and environmental factors that are prevalent on Long Island, such as Lyme disease, emerging pathogens and environmental risks due to the impact of climate change on coastal resiliency, as well as the unique challenges related to opiate addiction.
“LINCATS is Stony Brook’s response to the National Institutes of Health’s call to action to create research hubs designed to expand and elevate the bench-to-bedside ecosystem within communities nationwide,” said Richard J. Reeder, PhD, Vice President for Research at Stony Brook University. “We are fully committed to supporting this prominent team of biomedical researchers and practitioners who are set to lead and deliver groundbreaking discoveries.”
LINCATS will also serve as a catalyst to create hundreds of new jobs in the bioscience sector, and potentially thousands of jobs when the infrastructure is fully operational. The network will provide a workforce of both scientists and clinicians from multiple institutions working in partnership with all communities across Long Island to address all health care challenges.
Anissa Abi-Dargham, MD, SUNY Distinguished Professor, Vice Chair for Research and the Lourie Endowed Chair in Psychiatry, will serve as the Principal Investigator and Director of LINCATS. The LINCATS leadership team at Stony Brook includes 17 members, virtually all of whom are prominent faculty scientists and medical scientists in multiple fields at the University, such as Pharmacological Sciences, Infectious Diseases, Biotechnology, and Public Health.
“I am extremely thankful for Senator Schumer’s support of LINCATS. The funds will allow us to deepen our investments in the infrastructure, training, and community engagement pillars necessary to fulfill the mission of LINCATS,” says Dr. Abi-Dargham. “I am also grateful for the team of scientists, educators and community members who worked with me to develop the large collaborative project, and for the assistance of the Office of Proposal Development under the direction of Nina Maung.”
When the program is officially in place, funds will also be used for core personnel, supplies and equipment, support for multidisciplinary research, and the construction of an inpatient research unit at Stony Brook Hospital for the purpose of translational and clinical biomedical research.
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