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Cold Spring Harbor Laboratory

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Sam Kleeman. Photo by Caryn Koza/CSHL
From left, Sam Kleeman, Assistant Professor Tobias Janowitz, Miriam Ferrer Gonzalez and Emma Davidson. Photo by Caryn Koza/CSHL
Sam Kleeman at Lake Tahoe
Sam Kleeman in front of a sequoia grove at Yosemite.

By Daniel Dunaief

This is part 2 of a two-part series.

Cancers not only compromise human health, but they can also suppress the body’s immune response. A little studied small protein called cystatin C, which is secreted by numerous cells, may render the immune system less effective in its response to tumors.

Sam Kleeman, a PhD student in Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz’s lab, recently published results in the journal Cell Genomics that demonstrate a link between elevated levels of this protease inhibitor, the suppression of the immune system, and the development of cancer.

Kleeman was able to demonstrate a potential role “Cystatin C might play in damping down the immune response to tumors,” he said.

Cystatin C is a known cysteine protease inhibitor, but the biological and organ-level relevance of this has not been characterized in detail. This protein could be one of many mechanisms by which glucocorticoids can reduce the effectiveness of the immune system.

Cystatin C could drive the progression of the disease, which could explain why Kleeman has found evidence that higher levels coordinate with worse outcomes.

Starting with the data

Pursuing an interest in data- driven research, Kleeman, who has a Bachelor of Medicine and Surgery from New College at the University of Oxford, searched the UK Biobank, which provides health data for numerous people in the United Kingdom. 

In this Biobank, Kleeman, who joined Cold Spring Harbor Laboratory in August of 2020, found that cystatin C was the best prognostic indicator of cancer deaths.

“I was a little surprised by this,” Kleeman said as he had heard of cystatin C as a marker of kidney function, but was not aware of any association with cancer mortality. Some studies had found evidence for this previously, but those were in small cohorts and were poorly understood, he explained.

A healthy kidney clears most proteins quickly, pumping it out into urine. A kidney that’s not functioning optimally, however, allows it to accumulate.

In his research, Kleeman removed cystatin C selectively in cancer cells, causing the tumors to grow more slowly. The main changes in the architecture of the tumor was that it reduced the frequency of macrophages with expression of a protein called Trem2. While the exact mechanism is not known, it’s likely that immune control of the tumor increases without cystatin C.

Kleeman also demonstrated a similar effect on the connection between levels of Covid-19 and mortality in a paper published in iScience.

The biological mechanism explaining the correlation is nuanced. Patients with higher levels of glucocorticoids can be associated with poor outcomes. It is not a simple relationship, he said, which makes causality difficult to assess.

Kleeman believes cystatin C secretion in response to glucocorticoids has context dependency. Not all cells posses inducible cystatin C secretion.

The research primarily found that only macrophages and cancer cells can secrete cystatin C in response to glucocorticoids.

He describes a “two hit” model, by which glucocorticoids plus an inflammatory stimulus recruit macrophages. The model applies to all inflammatory stores, but is co-opted in the case of cancer.

At this point, drugs aren’t available to inhibit or reduce cystatin C. Instead, Kleeman suggested that a viable research target route might involve creating a specific antibody.

Some researchers have created so-called knockout mice, which don’t have this protein. These mice can survive without it, although eliminating all cystatin C creates other problems.

Kleeman speculated that the protein could play a role in preventing significant immune reaction against sperm.

Indeed, this protein is secreted at high levels in the testes. Males without it have lower sperm function and production.

Kleeman hopes this work acts as a starting point to understand the mechanism better by which glucocorticoids modify immune response to cancer, and to investigate cystatin C as a possible therapeutic target.

Long standing partnership

As an undergraduate, Kleeman took a class with Janowitz, which kicked off a mentorship that now spans two continents.

Kleeman appreciates the comfort level Janowitz has in working on higher-risk, higher-reward topics or on ideas that haven’t already attracted considerable attention from other scientists.

“There’s a tendency in science towards group think,” Kleeman said. In the history of medicine and science, many widely accepted theories turn out to be wrong. “Patients undoubtedly benefit from a diversity of thought in science and medicine,” he explained.

When he completes his PhD, Kleeman said it would be a “dream to have a dual appointment” in which he could conduct research and work in the clinic with patients. To get there, he knows he needs to establish his research profile that includes a genuine track record of achievement while demonstrating that he can function as a reliable and effective clinician.

Kleeman’s thesis research lies outside the field of cystatin C, which started out as a curiosity and developed into the recent publication. He wanted to “understand what UK Biobank could teach us about cancer patients.” With Janowitz and Cold Spring Harbor Laboratory Professor Hiro Furukawa, Kleeman is working to understand how a specific type of cancer could cause an auto-immune disease.

A resident of Forest Hills, Kleeman lives about 45 minutes from the lab. Outside of work, he enjoys visiting national parks. He has visited 10 so far, including Yosemite National Park, Zion and Rocky Mountain National Park. 

Professionally, Kleeman feels it is a privilege to be a PhD student. He appreciates that he can explore his interests without too many restrictions and is eager to make the most of the opportunity.

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From left, Sam Kleeman, Assistant Professor Tobias Janowitz, Miriam Ferrer Gonzalez and Emma Davidson. Photo by Caryn Koza/CSHL

By Daniel Dunaief

This part one of a two part series.

It’s a bit like shaking corn kernels over an open flame. At first, the kernels rustle around in the bag, making noise as they heat up, preparing for the metamorphosis.

That’s what can happen in any of the many laboratories scattered throughout Long Island, as researchers pursue their projects with support, funding and guidance from lab leaders or, in the science vernacular, principal investigators.

Sometimes, as happened recently at the benches of Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz, several projects can pop at around the same time, producing compelling results, helping advance the careers of developing scientists and leading to published papers.

PhD graduate Miriam Ferrer Gonzalez and MD/ PhD student Sam Kleeman recently published separate studies.

In an email, Janowitz suggested the work for these papers is “time consuming and requires a lot of energy.” He called the acceptance of the papers “rewarding.” 

In a two-part series, Times Beacon Record News Media will describe the research from each student. This week, the focus is on Ferrer Gonzalez. Check back next week for a profile of the work of Kleeman.

Miriam Ferrer Gonzalez

Miriam Ferrer Gonzalez. Photo by Caryn Koza/CSHL

Miriam Ferrer Gonzalez was stuck. She had two results, but couldn’t seem to figure out how to connect them. First, in a mouse model of the ketogenic diet — heavy on fats, without including carbohydrates —cancer tumors shrunk. That was the good news.

The bad news, which was even more pronounced than the good, was that this diet was not only starving the tumors, but was triggering an earlier onset of cachexia, in which bodies weaken and waste away. The cachexia overpowered the mice, causing them to die sooner than if they had a normal diet.

Ferrer, a student in residence from Spain who was conducting her research at Cold Spring Harbor Laboratory while earning her PhD at the University of Cambridge in the UK, thought the two discoveries were paradoxically uncoupled. A lower tumor burden, she reasoned, should have been beneficial.

In presenting and discussing her findings internally to the lab group, Ferrer received the kind of feedback that helped her hone in on the potential explanation.

“Finding out the mechanism by which a ketogenic diet was detrimental for both the body and the cancer was the key to explaining this uncoupling,” Ferrer explained.

The adrenal glands of mice fed a ketogenic diet were not producing the necessary amount of the hormone corticosterone to sustain survival. She validated this broken pathway when she discovered higher levels of corticosterone precursors that didn’t become functional hormones.

To test this hypothesis, she gave mice dexamethasone, which boosted their corticosterone levels. These mice had slower growing tumors and longer lives.

Ferrer recently published her paper in the journal Cell Metabolism.

To date, the literature on the ketogenic diet and cancer has been “confusing,” she said, with studies that show positive and negative effects.

“In our study, we go deeper to explain the mechanism rather than only talking about glucose-dependency of cancer cells and the use of nutritional interventions that deprive the tumor of glucose,” said Ferrer. She believed those factors are contributing to slower tumor growth, but are not solely responsible.

Thus far, there have been case studies with the ketogenic diet shrinking tumors in patients with cancer and, in particular, with glioblastoma, but no one has conducted a conclusive clinical trial on the ketogenic diet.

Researchers have reported on the beneficial effects of this diet on epilepsy and other neurological diseases, but cancer results have been inconclusive.  For the experiments in Janowitz’s lab, Ferrer and technician Emma Davidson conducted research on mouse models.

Ferrer, who is the first author on the paper, has been working with this system for about four years. Davidson, who graduated from the College of Wooster in Ohio last year and is applying to MD and MD/PhD programs, contributed to this effort for about a year.

Next steps

From left, Emma Davidson, Assistant Professor Tobias Janowitz, Sam Kleeman and Miriam Ferrer Gonzalez. Photo by Caryn Koza/CSHL

Now that she earned her PhD, Ferrer is thinking about the next steps in her career and is considering different institutions across the country. Specifically, she’s interested in eating behavior, energy homeostasis, food intake and other metabolic parameters in conditions of stress. She would also like to focus on how hormonal cycles in women affect their eating behavior.

Originally from a small city in Spain called Lleida, which is in the western part of Catalonia, Ferrer appreciated the opportunity to learn through courses and conferences at Cold Spring Harbor Laboratory.

Until she leaves the lab in the next few months, Ferrer plans to work with Davidson to prepare her to take over the project for the next year.

The follow up experiments will include pharmacologically inducing ferroptosis of cancer cells in mice fed a ketogenic diet. They hope to demonstrate that early induction of ferroptosis, or a type of programmed cell death, prevents tumor growth and prevents the tumor-induced reprogramming of the rest of the body that causes cachexia.

These experiments will involve working with mice that have smaller and earlier tumors than the ones in the published paper. In addition, they will combine a ketogenic diet, dexamethasone and a ferroptosis inducing drug, which they didn’t use in the earlier experiments.

Janowitz has partnered with Ferrer since 2018, when she conducted her master’s research at the University of Cambridge. As the most senior person in Janowitz’s lab, Ferrer has helped train many of the people who have worked in his lab. She has found mentoring rewarding and appreciates the opportunity to invest in people like Davidson.

Ferrer, who is planning a wedding in Spain in September, is a fitness and wellness fan and has taken nutrition courses. She does weight lifting and running.

Ferrer’s parents don’t have advanced educational degrees and they supported their three children in their efforts to earn their degrees.

“I wanted to be the best student for my parents,” said Ferrer, who is the middle child. She “wanted to make my parents proud.

The hand off

Emma Davidson and Miriam Gonzalez Ferrer examine an adrenal gland sample section from a cachectic mouse. Photo by Caryn Koza/CSHL

For her part, Davidson is looking forward to addressing ways to implement further treatment methods with a ketogenic diet and supplemental glucocorticoids to shrink tumors and prevent cachexia. 

Davidson appreciated how dependable Ferrer was during her time in the lab. Just as importantly, she admired how Ferrer provided a “safe area to fail.”

At one point, Davidson had taken all the cells she was planning to use to inject in mice. Ferrer reminded her to keep some in stock.

“Open lines of communication have been very beneficial to avoid more consequential failures,” Davidson said, ”as this mistake would have been.”

Davidson developed an interest in science when she took a high school class called Principles in Biological Science and Human Body Systems. When she was learning about the cardiovascular system, her grandfather had a heart attack. In speaking with doctors, Davidson acted as a family translator, using the language she had studied to understand what doctors were describing.

Like Ferrer, Davidson lives an active life. Davidson is preparing for the Jones Beach Ironman Triathlon in September, in which she’ll swim 1.2 miles, bike 56 miles and run a half marathon. She plans to train a few hours during weekdays and even more on weekends for a competition she expects could take about six hours to complete.

Davidson started training for these events with her father Mark, an independent technology and operations consultant and owner of Exoro Consulting Group.

Longer term, Davidson is interested in medicine and research. After she completes her education, she will try to balance between research and clinical work.

 

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John Moses. Photo courtesy of CSHL

By Daniel Dunaief

It sounds like something straight out of a superhero origin story.

With resistance to widely used drugs becoming increasingly prevalent among bacteria, researchers and doctors are searching for alternatives to stem the tide.

That’s where shape shifting molecules may help. Cold Spring Harbor Laboratory Professor of Organic and Click Chemistry John Moses and his team have attached the drug vancomycin to a molecule called bullvalene, whose atoms readily change position and configuration through a process called a thermal sigmatropic rearrangement as atoms of carbon break and reform with other carbon atoms.

The combination of the bullvalene and vancomycin proved more effective than vancomycin alone in wax moth larva infected with vancomycin resistant Enteroccoccus bacteria.

“Can I make a molecule that changes shape and will it affect bacteria? That was the question,” Moses said. The promising early answer was, yes!

Moses believes that when the bullvalene core is connected to other groups like vancomycin, the relative positions of the drug units change, which likely change properties related to binding.

The urgency for novel approaches such as this is high, as drug resistant bacteria and fungi infect about 2.8 million people in the United States per year, killing about 35,000 of them. 

In his own life, Moses said his father almost died from a bacterial infection five years ago. Vancomycin saved his father’s life, although the infection became resistant to the treatment. Other drugs, however, conquered the resistant strain.

“We need to work hard and develop new antibiotics, because, without them, there will be a lot more misery and suffering,” Moses explained.

To be sure, an approach like this that shows promise at this early stage with an insect may not make the long journey from a great idea to a new treatment, as problems such as dosage, off target effects, toxicity, and numerous other challenges might prevent such a treatment from becoming an effective remedy.

Still, Moses believes this approach, which involves the use of click chemistry to build molecules the way a child puts together LEGO blocks, can offer promising alternatives that researchers can develop and test out on a short time scale.

“We shouldn’t be restricted with one set of ideas,” Moses said. “We should keep testing hypotheses, whether they are crazy or whatever. We’ve got to find alternative pathways. We’re complementary” to the standard approach pharmaceutical companies and researchers take in drug discovery.

Looking to history, Moses explained that the founders of the Royal Society in 1660 followed the motto “nullius in verba,” or take nobody’s word for it. He believes that’s still good advice in the 21st century.

The shape shifting star

Moses has described this bullvalene as a Rubik’s Cube, with the parts moving around and confounding the bacteria and making the drug more effective.

The CSHL scientist and his team don’t know exactly why shape shifting makes the drug work in this moth model.

He speculated that the combination of two vancomycin units on either side of a bullvalene center is punching holes in the cell wall of the bacteria.

Moses is eager to try to build on these encouraging early developments. “If you can make it, then you can test it,” he said. “The sooner the better, in my opinion.”

Moses acknowledged that researchers down the road could evaluate how toxic this treatment might be for humans. It didn’t appear toxic for the wax moth larvae.

Welcoming back a familiar face

Adam Moorhouse
Photo by Rebecca Koelln

In other developments in his lab, Moses recently welcomed Adam Moorhouse back to his team. Moorhouse, who serves as Chemistry Data Analyst, conducted his PhD research in Moses’s lab at the University of Oxford.

Moorhouse graduated in 2008 and went on to work in numerous fields, including as an editor for the pharmaceuticals business and for his own sales consultancy. In 2020, he had a motorcycle accident (which he said was his fault) in which he broke 16 bones and was hospitalized for a while. During his recovery, he couldn’t walk.

At the time, he was working in the intense world of sales. After the accident, Moorhouse decided to build off his volunteer work with disabled children and become a high school teacher. After about 18 months of teaching, Moorhouse reconnected with Moses.

“It’s nice getting here and thinking about chemistry and thinking about ideas and communicating those ideas,” Moorhouse said.

He has hit the ground running, contributing to grants and helping to translate intellectual property into commercial ventures.

The chance to work on projects that get molecules into humans in the clinic was “really exciting,” Moorhouse said. “I’m back to try and support that.”

Moorhouse will be working to procure funding and to build out the business side of Moses’s research efforts.

“Where I’d like to lend a hand is in driving ongoing business discussions,” Moorhouse said. He wants to “get these small molecules into the clinic so we can see if they can actually treat disease in humans.” The vehicle for that effort eventually could involve creating a commercial enterprise.

Like Moses, Moorhouse is inspired and encouraged by the opportunity for small operations like the lab to complement big pharmaceutical companies in the search for treatments.

Moses believes the work his lab has conducted has reached the stage where it’s fundable. “We’ve done something that says, ‘we checked the box,’” he said. “Let’s find out more.”

Currently living on campus at CSHL, Moorhouse appreciates the opportunity to do some bird watching on Long Island, where some of his favorites include woodpeckers, herons, egrets, robins and mockingbirds.

He is tempted to get back on a motorcycle and to return to mountain biking.

As for his work, Moorhouse is excited to be a part of Moses’s lab.

“Back in my PhD days, [Moses] was always an idea machine,” Moorhouse said. “The aim is to move ideas to the clinic.”

 

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A statue of Charles Darwin (and finch) created by sculptor Pablo Eduardo overlooks the harbor on the campus of Cold Spring Harbor Laboratory. Photo courtesy of CSHL

By Tara Mae

Scientific study is a perpetual testimony to the feats and foibles of human nature, intricately intertwined in ways that continue to be excavated by inquiring minds bold enough to imagine. 

Cold Spring Harbor Laboratory (CSHL), which has largely been a titan in such innovative investigations, will offer a series of walking tours on select weekends from Saturday, May 20, through Sunday, August 27, starting at 10 a.m. The hour and a half long tours will traverse the past, present, and future of the complex and its work therein. 

“We are most excited to get people to the Laboratory who have always wondered what goes on here. So many have heard about us, driven by us, read about us, but they have never dug deeper. This walking tour is the chance to learn who we are,” said Caroline Cosgrove, CSHL’s Community Engagement Manager.

Conducted by trained tour guides, including Cold Spring Harbor Laboratory graduate students and postdoctoral fellows, the walks strive to bridge the gap between the physical realm and scientific theory. 

“These tours encompass the stunning grounds, the Lab’s history, and our current facilities and work. Community members, whether they have a background and interest in science, can come and learn from current graduate students about the world-renowned work going on in their very backyard,” explained Cosgrove. 

Probing CSHL’s ongoing research and program development for plant and quantitative biology, cancer, and neuroscience, the tours will encompass details about its historic and modern architecture, Nobel legacy, and identity evolution. Additionally, these scenic, scholarly strolls explore the practices and procedures of CSHL, with behind-the-scenes sneak peaks into the inner workings of scientific investigation. 

“As long as the tour guide’s laboratory is open and available, folks get a walk through and see the student’s own lab station,” Cosgrove said. “Whether it’s a cancer research lab, a neuroscience lab, a plant research lab, you get to see where all the magic happens.” 

Established in 1890, CSHL’s North Shore campus is a beacon of biology education, with 52 laboratories and more than 1100 staff from more than 60 countries. Eight scientists associated with CSHL have earned a Nobel Prize in physiology or medicine. This internationally recognized center of scientific research is also a local history and education site, where students of all ages and backgrounds come to study. 

“History has been, and will continue to be, made here. Please come get to know us,” said Cosgrove. 

Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor offers walking tours on May 20 and 21, June 24 and 25, July 29 and 30 and Aug. 26 and 27 at 10 a.m. Tours begin in the lobby of the Grace Auditorium. Tickets are $5 per person. To order, visit www.cshl.edu/public-events/tour-cshl/. For more information, call 516-367-8800.

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Lucas Cheadle with two pieces of artwork in his office, from left by Porferio Tirador 'Gopher' Armstrong, a Cheyenne-Caddo native from Oklahoma and Oklahoma Kiowa artist Robert Redbird. Photo by Austin Ferro

By Daniel Dunaief

Cold Spring Harbor Laboratory Assistant Professor Lucas Cheadle knows a thing or two about under represented groups in the field of Science, Technology, Engineering and Mathematics.

Of Chickasaw, Choctaw and Cherokee lineage, Cheadle, who was born in Ada, Oklahoma, was recently named one of 31 inaugural Howard Hughes Medical Institute’s (HHMI) Freeman Hrabowski scholars.

Lucas Cheadle. Photo by Steve Ryan/ AP Images for HHMI

The first scholars in this highly competitive and unique program, which drew 1,036 applicants, will receive funding that will last at least five years and could get as much as $8.6 million each for their promising early research and for supporting diversity, equity and inclusion in their labs.

“This is the first time a program of this type and magnitude has been attempted,” said HHMI Vice President and Chief Scientific Officer Leslie Vosshall. The scholars are “doing things that set them in the top one percent in creativity and boldness and we are certain we are going to have really healthy, inclusive, diverse labs.”

Vosshall said the scholars, which include scientists from 22 institutions, including Columbia, Harvard, Duke, Cornell, Princeton, the University of Pennsylvania, and Massachusetts Institute of Technology, hit it “out of the park” in their science and diversity efforts.

HHMI, which has committed $1.5 billion for Freeman Hrabowski Scholars, will award about 30 of these select scholarships every other year for the next 10 years, supporting promising scientists who can serve as mentors for under represented groups while also creating a network of researchers who can provide advice and collaborations.

The first group of scientists to receive this support is “diverse in such a way that it reflects the U.S. population,” Vosshall said.

The program is named after Freeman Hrabowski, who was born in Birmingham, Alabama and was president of the University of Maryland, Baltimore County, from 1992 to 2022. Hrabowski, who was arrested during the civil rights movement, created a tutoring center in math and science for African Americans in high school and college and helped create the Meyerhoff Scholars Program.

Cheadle was celebrating the December holidays in Oklahoma when he learned he was a semifinalist, which was “really surprising and exciting,” he recalled. Becoming an HHMI scholar is “amazing” and “very validating,” he said.

Bruce Stillman, President and CEO of CSHL, suggested that HHMI recognition is “a prestigious achievement” and, in a email, wrote that he was “pleased that [Cheadle] was included in the list of remarkable scientists.”

Stillman predicted that Cheadle’s passion about increasing diversity in science would have a “major influence” on CSHL.”

Scientific questions

Cheadle appreciates how HHMI funds the scientist, not individual projects. With this unrestricted funding, which includes full salary and benefits and a research budget of about $2 million over the first five years and eligibility to participate in HHMI capital equipment purchasing programs, Cheadle and other scholars can pursue higher-risk, higher-reward projects.

“If I have a crazy idea tomorrow, I can do that with this with funding,” Cheadle explained.

Cheadle, who joined CSHL in August of 2020, studies the way the immune system shapes brain development, plasticity and function. He also seeks to understand how inflammatory signals that disrupt neural circuit maturation affect various disorders, such as autism.

Last September, Cheadle and his lab, which currently includes six postdoctoral researchers, two PhD students, one master’s student, a lab manager and two technicians, published a paper in Nature Neuroscience that showed how oligodendrocyte precursor cells, or OPCs, help shape the brain during early development.

Previously, scientists believed OPCs produced cells that surrounded and supported neurons. Cheadle’s recent work shows that they can play other roles in the brain as well, which are also likely instrumental in neural circuit construction and function.

When young mice raised in the dark received their first exposure to light, these OPCs engulfed visual processing circuits in the brain, which suggested that they helped regulated connections associated with experience.

With this new position and funding, Cheadle also plans to explore the interaction between the development of nerves in the periphery of the brain and different organs in the body, as well as how immune cells sculpt nerve connectivity.

He is not only studying this development for normal, healthy mice, but is also exploring how these interactions could explain why inflammation has arisen as such an important player in neurodevelopmental dysfunction.

Stillman explained that Cheadle’s work will “have broad implications.”

A talented, balanced team

Cheadle is committed to creating a balanced team of researchers from a variety of backgrounds.

“As principal investigators,” Cheadle said, “we have to actively work to have a diverse lab.”

He has posted advertisements on women’s college forums to garner more applications from women and under represented groups. He has also adopted a mentorship philosophy that focuses on inclusivity. 

Cheadle explained that he hopes to be adaptable to the way other people work. Through weekly lab meetings, mentorship arrangements and reciprocal interactions, he hopes to provide common ground for each aspiring scientist.

He recognizes that such goals take extra effort, but he feels the benefits outweigh the costs.

During annual events, Cheadle also leans in to the cultural diversity and differences of his staff. He hosts a pre-Thanksgiving pot luck dinner, where everybody brings a food item that’s important and close to them. 

Last year, he made pashofa out of cracked corn that his stepmom sent him from the Chickasaw Nation in Oklahoma. Pashofa is a traditional meat and corn Chickasaw dish. Other lab members brought tropical beverages common in Brazil.

In terms of diversity in science, Cheadle believes such efforts take years to establish. Through an approach that encourages people from different backgrounds to succeed in his lab, Cheadle hopes to share his thoughts and experiences with other researchers.

Cheadle last summer hosted a Chickasaw student on campus to do research. He is working with the Chickasaw Nation to expand that relationship.

As for the Freeman Hrabowski scholars, Vosshall said all HHMI wants to do is “allow everybody to do science.-

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HHMI Chief Scientific Officer Vosshall celebrates benefits of diversity in science

By Daniel Dunaief

It’s not one or the other. She believes in both at the same time. For Leslie Vosshall, Vice President and Chief Scientific Officer at Howard Hughes Medical Institute, science and diversity are stronger when research goals and equity work together.

Leslie Vosshall. Photo by Frank Veronsky

That’s the mission of the new and unique HHMI Freeman Hrabowski Scholars program. HHMI this week named 31 inaugural scholars as a part of an effort designed to support promising scientists who provide opportunities to mentor historically under represented groups in research.

Cold Spring Harbor Laboratory Assistant Professor Lucas Cheadle was among the 31 scientists who became HHMI scholars (see related story above), enabling him to receive financial support for the next five years and up to $8.6 million for the next decade.

In an interview, Vosshall said the “special sauce of this group” of scientists who distinguished themselves from among the 1,036 who applied was that they excel as researchers and as supporters of diversity. Bringing in people who may not have had opportunities as scientific researchers not only helps their careers but also enables researchers to take creative approaches to research questions.

“When you bring in people from the ‘out group’ who have been historically excluded, they have an energy of getting into the playing field,” she said. That innovation can translate into successful risk taking.

As an example, Vosshall cited Carolyn Bertozzi, a chemist at Stanford University who shared the 2022 Nobel Prize in Chemistry for helping to develop the field of bioorthogonal chemistry, which involves a set of reactions in which scientists study molecules and their interactions in living things without interfering with natural processes.

Her lab developed the methods in the late 1990’s to answer questions about the role of sugars in biology, to solve practical problems and to develop better tests for infectious diseases. “This scrappy band of women chemists tried this crazy stuff” which provided “massive innovations in chemical biology,” Vosshall said. Mainstream science often solidifies into a groove in which the same thing happens repeatedly. “Innovation comes from the edges,” she added.

In her own to hire staff in her lab, Vosshall has taken an active approach to find candidates from under served communities. “People who have pulled themselves up have worked so hard to get to where they are,” she said. “It’s important to dig deeper to find talent everywhere.”

Keeping away from the off-ramp

The number of under represented groups in science has improved over the last few decades. Indeed, when Vosshall joined Rockefeller University, where she is the Robin Chemers Neustein Professor, she couldn’t count 10 women faculty. Now, 23 years later, that number has doubled.

The number of people in under represented groups in graduate programs has increased. The problem, Vosshall said, is that they “take the off-ramp” from academic science” because they don’t always feel “welcome in the labs.” Supporting diversity will keep people in academic science, who can and will make important discoveries in basic and translational science.

As a part of the Freeman Hrabowski program, HHMI plans to survey people who were trainees in these labs to ask about their mentoring experience. By tracking how developing scientists are doing, HHMI hopes to create a blueprint for building diversity.

HHMI has hired a consultant who will analyze the data, comparing the results for the results and career trajectories. The research institute will publish a paper on the outcome of the first cohort. Researchers in this first group will not only receive money, but will also have an opportunity to interact with each other to share ideas.

New approach

When Vosshall earned her PhD, she considered an alternative career. She bought a training book for the Legal Scholastic Aptitude Test and considered applying to law school, as she was “fed up with how I was treated and fed up with science”

Nonetheless, Vosshall, who built a successful scientific career in which she conducts research into olfactory cues disease-bearing insects like mosquitoes seek when searching for humans, remained in the field.

To be sure, Vosshall and HHMI aren’t advocating for principal investigators to hire only people from under represented groups. The promising part of this scholarship is that HHMI found it difficult to get the final number down to 31, which “makes me optimistic that the [scientific and mentorship] talent is out there,” she said. Over the next decade, HHMI plans to name about 30 Freeman Hrabowski scholars every other year. If each lab provides research opportunities across different levels, this will help create a more diverse workforce in science, which, she said, benefits both prospective researchers and science.

 

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Kyle Swentowsky in front of the maize fields at CSHL’s Upland Farm preserve. Photo courtesy of CSHL

By Daniel Dunaief

Farmers typically plant the sweet corn that fills Long Islander’s table some time between late April and June, with flavorful yellow kernels ready to eat about eight weeks later.

But what if corn, which is planted and harvested on a typical annual crop schedule, were perennial? What if farmers could plant a type of corn that might have deeper roots, would become dormant in the winter and then grew back the next year?

Kyle Swentowsky, holding corn on the north fork of Long Island.

Cold Spring Harbor Laboratory postdoctoral researcher Kyle Swentowsky, working in the lab of  Professor Dave Jackson, is interested in the genetics of perennial grasses, which includes maize, wheat, rice, barley, sorghum and others. He uses maize as a model.

Extending the work he did as part of his PhD research at the University of Georgia, Swentowsky, who arrived at CSHL in July of 2021, is searching for the genes that cause the major differences between annual and perennial grasses.

Kelly Dawe, who was Swentowsky’s PhD advisor, described him as “passionate” “diligent” and “thoughtful.” Dawe explained that perennials have been beneficial in the farming of other crops. Perennial rice has enabled farmers to save 58.1 percent on labor costs and 49.2 percent on input costs with each regrowth cycle, Dawe explained, adding, “The rice work is much farther along, but could have a similar impact on corn.”

Aside from producing crops over several years without requiring replanting, perennial corn also has several other advantages. Perennials, which have deeper roots, can grow in soil conditions that might not be favorable for annual crops, which can help stabilize the soil and expand the range of farmable land.

Recently, people have also considered how scientists or farmers might take some of the sub-properties of perennials and apply them to annual crops without converting them to perennials. Some annuals with perennial traits might stay green for longer, which means they could continue the process of photosynthesis well after annuals typically stop.

A complex challenge

Scientists have been trying to make perennial corn for about 50 years. The perennial process is not as simple as other plant traits.

“We don’t understand all the underlying sub properties of being perennial,” Swentowsky said. “It’s very complicated and involves a lot of regions in the genome. My work aims to get at some of these sub traits and genomic loci that are involved in this process.”

In his work, Swentowsky is interested in the sub traits that the major genes control. He expects that a reliable perennial corn wouldn’t make the annual variety obsolete. Even after researchers develop an effective perennial corn, farmers may still cultivate it as an annual in some environments.

In the bigger picture, Swentowsky, like other plant researchers at CSHL and elsewhere around the world, recognizes the challenge of feeding a population that will continue to increase while climate change threatens the amount of arable land.

Plant breeders need to continue to come up with ways to increase crop yield to boost food production, he suggested. While some people have considered dedicating resources to back up plans like astro-botany — or growing crops in space — Swentowsky suggested this was challenging and urged ongoing efforts to produce more food on Earth.

Impressed with the way Matt Damon’s character in the movie The Martian farms potatoes on the Red Planet, Swentowsky suggested that such an agricultural effort would be challenging on a large scale in part because of the extreme temperature variations.

As for work on Earth, perennial corn may also remove more carbon dioxide from the air, reducing the presence of greenhouse gases such as carbon dioxide.

Swentowsky cautioned that the idea of carbon farming is still relatively new and researchers don’t know what would make a good carbon farming plant yet. At this point, his work has involved breeding and back crossing corn plants. Once he develops a better idea of what genes are involved in the perennial life cycle, he will consider taking a trans-genetic approach or use the gene editing tool Crispr to test the effects of the involved genes.

Swentowsky expects that several genetic changes may be necessary to develop a perennial plant. He and others have mapped the master regulators of perenniality to three major genes. He believes it’s likely that dozens or even hundreds of other genes scattered throughout the genome play a small role influencing perennial sub-traits.

California roots

A current resident of Long Beach, Swentowsky grew up in Sacramento, California. He earned his undergraduate and master’s degrees at the University of California at Santa Barbara. After six years, he was “tired of perfect weather,” he laughed. He would sweat through football games in January, when it was 80 degrees amid a cloudless sky.

As an undergraduate, he took a plant development course and appreciated the elegant way scientists tested plants. His two favorite scientists are Gregor Mendel, whose pioneering pea work led to the field of modern genetics, and Barbara McClintock, a former CSHL scientist whose Nobel Prize winning research on corn led to an understanding of transposable elements, or jumping genes in which genes change position on a chromosome. 

Outside of the lab, Swentowsky enjoys traveling, including camping and backpacking, spending time on the beach, attending reggae, alternative, classic rock, hip hop and electric concerts and going to breweries. During the winter, his favorite beers are stout and porter. In warmer weather, he imbibes sour IPA.

Swentowsky doesn’t just study corn: he also enjoys eating it. One of his favorites is elote, or Mexican street corn. He grills the corn on a barbecue, covers it with mayonnaise and cotija cheese and sprinkles lyme or chili powder on it.

Swentowsky, who is funded through the summer of 2025 at CSHL, appreciates the opportunity to contribute to work that could support future farming efforts. He hopes that studying perenniality in corn could have future applications.

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CSHL Associate Professor Stephen Shea and Postdoc Yunyao Xie in Shea’s lab. Photo from CSHL/2020

By Daniel Dunaief

Good parenting, at least in mice, is its own reward.

No, mice don’t send their offspring to charter schools, drive them to endless soccer and band practices or provide encouragement during periods of extreme self doubt.

What these rodents do, however, protects their young from danger.

When a young mouse wanders, rolls or strays from the nest, it becomes distressed, calling out mostly to its mother, who is the more effective parent, to bring it back to safety.

Responding to these calls, the mother mouse carries the young back to the safety of the nest.

This behavior involves a reward system in a region of the mouse brain called the ventral tegmental area, or VTA. When the mouse effectively retrieves its young, the VTA releases the neurotransmitter dopamine, which is the brain’s way of saying “well done!”

In a paper published in December in the journal Neuron, Cold Spring Harbor Laboratory Associate Professor Stephen Shea and his postdoctoral researcher Yunyao Xie, who worked in the lab from 2019 to 2021, likened the release of dopamine in this area to a neurological reward for engaging in the kind of behavior that protects their young.

The research “proposes a mechanism that shapes behavior in accordance with that reward,” Shea said. The connection between dopamine in a reward system is an established paradigm.

“There was plenty of smoke there,” he said. “We didn’t pull this out of thin air.”

Indeed, in humans, mothers with postpartum depression have disrupted maternal mood, motivation and caregiving. PPD is linked to dysfunction of the mesolimbic dopamine system, which is a neural circuit that involves the VTA, Xie explained.

“Studies using functional magnetic resonance imaging (fMRI) revealed that the reward brain areas including VTA in healthy mothers have higher response to their own babies’ smiling faces than those in mothers with PPD,” Xie added.

What’s new in this research, however, is that it is “a study of how these signals use mechanisms to shape behavior and social interaction,” Shea said.

How the process works

The feedback loop between dopamine in the VTA and behavior involves a cumulative combination of dopamine interactions.

Dopamine is not at its highest level when the mouse mom is engaging in effective pup retrieval.

“Dopamine is shaping future, not current behavior,” Shea said. “If dopamine was driving the mouse on a current trial, a high dopamine level would be associated with high performance. The trial found the opposite: a low dopamine level was associated with high performance in a given trial, and vice versa.”

Like a skater laying her blades down effortlessly and gracefully across the ice after spending hours exerting energy practicing, the mother mouse engaged in the kind of reinforcement learning that required less dopamine to lead to effective pup saving behavior.

As the performance increases, dopamine diminishes over time, as the reward is “more expected,” reflecting a nuanced dynamic, Shea said.

To test the correlation between dopamine levels in the VTA and behavior, Shea and Xie created an enclosure with two chambers. They put a naive virgin female mouse, which they called surrogates, on one side and played specific sounds behind a door on each side of the chamber. The test mice initially had “no experience in maternal behaviors,” Xie explained.

As these surrogates became more experienced by either observing mothers or practicing on their own, the amplitude of the VTA dopamine signals got smaller.

To provide a control for this experiment, Xie monitored a group of naive virgin female mice who spent less time with pups and had to figure out how to retrieve them on their own under similar neurological monitoring conditions. The dopamine signals in this group stayed elevated over days and their performance in maternal behaviors remained poor.

Through these experiments, Xie and Shea concluded that “there is a negative correlation between the dopamine signals in the VTA and their performance in maternal behaviors,” explained Xie.

‘Mind blowing’ moment

In her experiments, Xie used optogenetic tools that allowed her to inhibit the activity of dopaminergic neurons in the VTA with high temporal precision.

Shea appreciated Xie’s hard work and dedication and suggested the discoveries represent a “lot of her creativity and innovation,” he said.

A native of China, Xie said her grandparents used to have a garden in which they taught her the names and morphologies of different plants during her childhood. She enjoyed drawing these plants.

In graduate school, she became more interested in neuroscience. She recalls how “mind-blowing” it was when she learned about the work by 1963 Nobel laureates Alan Hodgkin, Sir Andrew Fielding Huxley and John Eccles, who established a mathematical model to describe how action potentials in neurons are initiated and propagated.

In the study Xie did with Shea, she found that the dopamine signals in the VTA encoded reward prediction errors in maternal behaviors that was consistent with the mathematical model.

In the bigger picture, Xie is interested in how neural circuits shape behaviors. The neural circuits of most natural behaviors, such as defensive behaviors and maternal behaviors are hard-wired, she added.

Mice can also acquire those behaviors through learning. She is interested in how pup cues are perceived as rewards and subsequently facilitate learning maternal behavior. She found a great fit with Shea’s lab, which focuses on the neural mechanism of maternal behavior.

Xie enjoyed her time at Cold Spring Harbor Laboratory, where she could discuss science with colleagues by the bench, at the dining room or at one of the many on site seminars. She also appreciated the opportunity to attend neuroscience seminars with speakers from other schools, which helped expand her horizons and inspire ideas for research.

Next steps

As for the next steps, Shea said he believes there is considerable additional follow up research that could build on these findings. He would like to apply methods that measure the activity in individual neurons. Additionally, with a number of targets for dopamine, he wants to figure out what areas the neurotransmitter reaches and how the signals are used when they get there. More broadly, he suggested that the implications for this research extend to human diseases. 

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From left, Alea Mills and Xueqin Sun Photo from CSHL

By Daniel Dunaief

People have natural defenses against cancer. Proteins like P53 search for unwelcome and unhealthy developments. 

Sometimes, mutations in P53, which is known as the “guardian of the genome,” rob the protein of its tumor fighting ability. In more than seven out of ten cases, the brain tumor glioblastoma, which has a grim prognosis for people who develop it, has an intact P53 protein.

So what happened to P53 and why isn’t it performing its task?

That’s what Cold Spring Harbor Laboratory Professor and Cancer Center member Alea Mills and postdoctoral researcher Xueqin “Sherine” Sun wanted to know.

Starting with the idea that something epigenetic was somehow blocking P53, Sun conducted numerous detailed experiments with the gene editing tool CRISPR-Cas9.

She knocked out parts of the chromatin regulating machinery, which determines whether factors for DNA replication, gene expression, and the repair of DNA damage can access genes and perform their tasks.

The researchers wanted to find “something specific to glioblastoma,” Mills said in an interview. Working with a team of researchers in Mills’s lab, Sun focused on the protein BRD8.

In experiments with mice, Sun and her colleague inhibited this specific protein by destroying the gene that encodes it. That step was enough to stop the tumor from growing and allowed the mouse to live longer.

Mills and Sun published their work in the prestigious journal Nature just before the holidays.

The article generated considerable buzz in the scientific community, where it was in the 99th percentile among those published at the same time in attracting attention and downloads. It also attracted attention on social media platforms like Twitter and LinkedIn.

“We see this as a major discovery, and are not surprised that many others think that the impact is extraordinary,” Mills said. The paper “has the potential of having a significant impact in the future. The work is completely novel.”

While finding a connection between BRD8 and glioblastoma suggests a target for researchers to consider in their search for new glioblastoma treatments, a potential new approach for patients could be a long way off.

“We cannot predict how long it will take to be able to help patients” who have glioblastoma, Mills said.

A promising step

From left, Alea Mills and Xueqin Sun Photo from CSHL

Still, this finding provides a promising step by showing how knocking out the BRD8 protein can enable P53 to gain access to a life threatening tumor.

Sun and Mills said BRD8 and its partners lock down genes that are normally turned on by P53.

“What you inherit from mom and dad is one thing,” said Mills. “How it’s packaged, the epigenetic mechanism that keeps it wrapped up or open, is key in how it’s all carried out within your body.”

By targeting BRD8, Mills and her team opened the chromatin, so P53 could bind and turn on other cancer fighting genes.

After receiving patient samples from Northwell Health, Stanford and the Mayo Clinic, the team studied tissue samples from patients battling glioblastoma. Those patients, they found, had higher concentrations of BRD8 than people without brain cancer.

Researchers and, down the road, pharmaceutical companies and doctors, are careful to make sure removing or reducing the concentration of any protein doesn’t have so-called “off target effects,” which would interfere with normal, healthy processes in cells.

Mills said they tested such actions in the context of neural stem cells in the brain. At this point, removing BRD8 didn’t have any “deleterious consequence,” she said. 

Her lab is working to see the effect of reducing or removing the mouse version, also called Brd8, during development by engineering mice that lack this protein.

Future research

An important next step in this research involves searching for and developing viable inhibitors of the BRD8 protein.

For histone readers like BRD8, researchers look for an active domain within the protein. The goal is to interrupt the interface in their interactions with histones.

In creating molecules that can block the action of a protein, researchers often start with the structure of the protein or, more specifically, the active site.

Sun, who is currently applying for jobs to run her own lab after working at Cold Spring Harbor Laboratory for over eight years, is hoping to purify enough of the protein and determine its structure.

Sun is working on x-ray crystallography, in which she purifies the protein, crystallizes it and then uses x-rays to determine the atomic structure.

Sun described the search for the structure of the protein as an “important direction” in the research. “Once we solve the structure” researchers can focus on drug design, testing and other experiments.

She suggested that the search for a small molecule or compound that might prove effective in inhibiting BRD8 would involve optimizing efficiency and activity.

There is a “long way to go” in that search, Sun added.

She is working to generate a chemical compound in collaboration with other groups.

A long, productive journey

Born and raised in China, Sun has been an active and important contributor to Mills’s lab.

“I’ll miss [Sun] personally as well as in the lab,” Mills said. “She’s been a really good role model and teacher across the Cold Spring Harbor campus and in my lab.”

Mills is “really excited about [Sun’s] future,” she said. “She’ll be really great” at running her own lab.”

For her part, Sun enjoyed her time on Long Island, where she appreciated the natural environment and the supportive culture at Cold Spring Harbor Laboratory.

Sun described her time on Long Island as a “very exciting and satisfying journey.” 

She is determined to study and understand cancer for a number of reasons.

“I know people who died of cancer,” she said. “It’s a terrible disease and it’s urgent to find more efficient therapeutic strategies to stop cancers and improve human heath.”

Sun is also eager to embrace the opportunity to mentor and inspire other students of science.

“Teaching is very important,” she said. She looks forward to helping students grow as professionals to create the “next generation of scientists.”

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CSHL’s David Spector (center) and postdoctoral fellows Rasmani Hazra on left and Gayan Balasooriya on right. Photo courtesy of CSHL

By Daniel Dunaief

One came from India, the other from Sri Lanka. After they each earned their PhD’s, they arrived on Long Island within seven months of each other about seven years ago, joining a lab dedicated to studying and understanding cancer. Each of them, working on separate projects, made discoveries that may aid in the battle against heart disease.

Working for principal investigator David Spector at Cold Spring Harbor Laboratory, postdoctoral fellow Rasmani Hazra, who grew up in Burdwan, India, found a link between a gene that affects cancer in mice that also can lead to a problem with the development of heart valves.

Hazra worked with two long noncoding RNAs that are highly expressed in mouse embryonic stem cells, which have the ability to differentiate into many different types of cells.

Specifically, she found that mice that didn’t have Platr4 developed heart-related problems, particularly with their valves.

At the same time, postdoctoral fellow Gayan Balasooriya, who was born and raised in Sri Lanka, discovered that a single, non-sex gene is governed by different epigenetic mechanisms based on whether the gene is inherited from the mom or the dad.

While it was known that males are more susceptible to heart disease than females, researchers did not know which copy of the gene related to those diseases are expressed. This discovery could help in understanding the development of heart defects.

“Although we ended up at heart development” in both of these published studies, “we didn’t initiate” looking for heart-related information, said Spector. “The science led us there.

Spector, however, expects that the lessons learned about differentiation in the context of the developing heart can also “impact out knowledge about tumors” which he hopes will eventually lead to advances in how to treat them.

He added that any clinical benefit from this work would take additional research and time.

An on and off switch

In Hazra’s study, which was published in the journal Developmental Cell, she worked with Platr4 because humans have several possible orthologous genes. 

When Platr4 expression, which shuts down after birth, is deleted from cells or embryos, the mice died from heart valve problems.

The human equivalent of Platr4 is located on chromosome 4. At this point, clinical case studies have connected the deletion of this chromosome to cardiac defects in humans.

Hazra said her project initially examined the function of these long non-coding sections of RNA. She was exploring how they affected differentiation. She found this link through in vitro studies and then confirmed the connection in live mice.

Spector explained that this work involved extensive collaborations with other researchers at Cold Spring Harbor Laboratory, including teaming up with researchers who can do electrocardiograms on mice and who can assess blood flow.

A shared mouse imaging resource also helped advance this research.

“One of the advantages of Cold Spring Harbor Laboratory is that we have over 10 shared resources, each of which specializes in sophisticated technologies that scientists can use on their own projects,” he said. Each lab doesn’t have to learn and develop its own version of these skills.

Hazra plans to continue to study other long noncoding RNA. She is also working on glioblastoma, which is a form of brain cancer.

Hazra plans to start her own lab next fall, when she completes her postdoctoral research.

Inactive gene

Balasooriya, meanwhile, published his research in the journal Nature Communications.

He used RNA sequencing to identify numerous genes. He also looked at whether the RNAs originated from the mom or dad’s genes in individual cells.

Also planning to start his own lab next fall, Balasooriya found changes that alter gene expression between the alleles from the mother and the father experimentally and through data mining approaches.

“What was most surprising in my studies is that [he identified] the gene from the father’s side and the mother’s side are regulated in a different manner,” Balasooriya said. “I’m interested in following up on that finding.”

The next step for him is to look not only at the heart, but, more broadly, at how monoallelic gene expression changes the way regulators affect development and disease.

“I want to do a deep dive to find out the mechanisms” involved in this expression of a single copy of the gene, Balasooriya said, which could provide ways to understand how to control the process.

In the long run, this kind of research could provide insights into ways to treat heart disease as well as other diseases like cancer and immune diseases.

Growing up in the North Western Province in Sri Lanka, Balasooriya was interested in math and science. After he finished his bachelor’s degree in biology in Sri Lanka, he earned a master’s in molecular biology at the University of Hertfordshire in England. He “got so excited about biology and exploring new fields” that he decided to pursue his PhD at the University of Cambridge, England.

After college, he worked in computer science for a while and realized he was not passionate about it, which encouraged him to do his master’s. The experience in computer science helped him with bioinformatics.

As for Spector, he is pleased with the work of both of his postdoctoral researchers. “This is what being a principal investigator is all about, having young people join your lab, sitting down with them, discussing a potential project, not really knowing where it’s going to go,” he said.

He described both members of his team as “extremely successful” who were able to make discoveries that they shared in prestigious journals. Balasooriya and Hazra both laid the groundwork to go and start their own careers. 

“Seeing the fruits of their work is the most rewarding experience” as the leader of a lab, Spector said.

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Isabella Rossellini ‘s new one woman show Darwin’s Smile reconciles two worlds that are often at the opposite ends: art and science. Photo by © André Rau/CSHL

By Daniel Dunaief

A model and actress, Isabella Rossellini has spent her life as a part of numerous stories. Nowadays, the 70-year old Rossellini, who has a home in Bellport, is eager to share the next chapter in her story-telling.

This time, Rossellini will bring her one-woman show “Darwin’s Smile,” which she originally wrote in French but will perform in English, to Cold Spring Harbor Laboratory’s Grace Auditorium for a two-day run on Saturday and Sunday, March 4 and 5, 2023.

Tapping into her love for animals, Rossellini plans to share her observations and insights about the nexus between her art as an actress and the science she studied and observed when she earned her Master’s Degree from Hunter College in animal behavior and conservation.

“What I would like to do is share my wonderment and stupor about information I learned” about animals, Rossellini said in a recent interview with Times Beacon Record News Media. “Science is notoriously difficult. The language is very enigmatic. Even to read Darwin is complicated. Once you get it, it’s really incredible.”

Indeed, Rossellini wrote the show as an extension of  the 1872 book by Charles Darwin titled Expression of the Emotions in Man and Animals, which was published 13 years after his famous On the Origin of Species.

Darwin studied a range of expressions from people all over the world and discovered that some of those expressions, such as smiling, responding to fear, or being disgusted, are the same regardless of the cultural background.

Darwin, Rossellini said, believed that evolution through natural selection shaped these expressions of emotion, the same way natural selection might affect a bone, the horns on a buck or the shape of a bird’s beak. The core of emotion across species appeals to her as an actress and as someone who appreciates and admires animals.

“Modeling is all about expression,” said Rossellini, who was the world’s highest paid model in 1982. “Yes, you have to be beautiful, and all this. What makes a good model is not so much beauty. People respond to emotion, rather than a beautiful nose or a beautiful mouth.”

As she did with her series of shorts called “Green Porno,” in which Rossellini dressed as creatures such as a praying mantis, shrimp, snails, spiders, and whales, among others, and described their mating, Rossellini uses humor to entertain and educate in “Darwin’s Smile.”

At one point, she dresses as a peacock with an attractive tail. Darwin, Rossellini said, found the brilliant colors of those feathers overwhelming, which gave him a headache.

Rossellini emerges from her peacock costume in another costume and sings a song, slowly, in French.

In her show, Rossellini uses her acting skills to convey emotions that use the same words. Repeating “I love you and I want to be with you all my life,” she shares that thought with rage, love and sadness, making it clear through her acting that humans derive meaning from a range of cues.

On a scientific level, Rossellini would like to challenge the idea that research into animals can’t include a recognition of their emotions. The science of behaviorism suggested that researchers shouldn’t “project any emotion into animals,” she said. Many scientists look, instead, directly at the behavior of animals.

“Darwin did not have that problem,” she said. He recognized that his dog was happy to see him and that a cat was angry.

As for the emotions she feels when she views her own acting performances, Rossellini suggested her experience mirrors that of many other actors and actresses. “It’s difficult to see oneself on screen in front of everybody,” she said. The mental image she has of herself sometimes conflicts with what she sees on screen.

“It’s very disturbing,” she said. “I don’t really like to watch my past work.”

The movies also create some melancholy for her, as they can evoke memories of her experiences during filming. She said the film “Blue Velvet” conjures thoughts of the time she and the cast, with whom she shared close friendships, worked together in Wilmington, North Carolina.

Sometimes she watches her movies twice. The first time, she adjusts to herself on screen. The second time, she follows the storyline and plot.

In terms of movies that came out this year, Rossellini said the film EO, which is about the life of a donkey who performs in a circus and then moves from one challenging circumstance to another, “makes you feel for the farm animal.” She described the film, which was made in Poland by director Jerzy Skolimowski, as “kind of beautiful.”

As for her life, Rossellini, who is the daughter of famed director Roberto Rossellini and actress Ingrid Bergman, said her interest in animals started when she was around 14 and her father gave her the book King Solomon’s Ring by Konrad Lorenz.  

When she read the book, she thought “this is what I want to be,” Rossellini said. Only later, after modeling and acting, both of which she continues to do, did she add ethology to the mix. 

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Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor will host a special performance of “Darwin’s Smile” at Grace Auditorium on March 4, with doors opening at 5 p.m. The show starts at 6 p.m., followed by a reception and Q&A with Rossellini led by Helen Hou, an assistant professor and neuroscientist at CSHL. 

An encore performance (sans Q&A and reception) will be held March 5, with doors opening at 3 p.m. and showtime at 4 p.m. For tickets, visit www.cshl.edu. For further information, call 516-367-8800.

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