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Cold Spring Harbor Laboratory

Photo by ©Constance Brukin, 2018/ CSHL

By Daniel Dunaief

This article is part one in a two-part series.

Women have made great strides in science, but they haven’t yet found equal opportunity or a harassment-free work environment.

After the National Academy of Sciences published a study in 2018 that highlighted sexual harassment and unconscious bias, a team of scientists came together at Cold Spring Harbor Laboratory last December to discuss ways to improve the work environment.

Led by Carol Greider, an alumni of CSHL and the director of molecular biology and genetics at Johns Hopkins and a Nobel Laureate, and Jason Sheltzer, a fellow at CSHL, the group recently released its recommendations in the journal Science.

While the atmosphere and opportunities have changed, “It’s not a clear-cut enlightenment and everybody is on board,” said Leemor Joshua-Tor, a professor at CSHL and a member of the group that discussed the challenges women face in science at the Banbury Center last year.

The Science article highlights earlier work that estimates that 58 percent of women experienced unwanted sexual attention or advances at some point in their careers. The authors write that this harassment is often ignored or excused, which can cause talented and capable women to leave the field of scientific research.

A member of the group that came together to discuss how to continue to build on the progress women have made in the STEM fields, Nancy Hopkins, an Amgen Inc. professor of biology emerita at the Massachusetts Institute of Technology, helped bring attention to the disparity between opportunities for men and women in science in the 1990s.

“My generation pushed [opportunities for women] forward and got through the door,” Hopkins said. “We found out that when you get through the door, the playing field wasn’t level.”

Hopkins said the progress is “still not enough” and that leaders like Greider and Sheltzer, whom she praised for tackling this nettlesome issue, “are now identifying problems that we accepted.”

For starters, the group agrees with the National Academy of Sciences, Engineering and Medicine, which believes treating sexual harassment in the same way as scientific misconduct would help. 

The scientists, which include CSHL’s CEO Bruce Stillman, recommend creating institutional and government offices to address substantiated claims of sexual misconduct and to educate institutions on harassment policy, using the same structures for research misconduct as models. 

An office that verified these claims could offer reporting chains, consistent standards of evidence and defined protocols.

Additionally, the scientists believe researchers should have to answer questions from funding agencies about whether they have been found responsible for gender-based harassment at any point in the prior 10 years, as well as whether they have been a part of a settlement regarding a claim of professional misconduct, research misconduct or gender-based harassment in the same time period. 

This policy, they urge, could prevent institutions from tolerating serial offenders who have generated a high level of research funding over the years.

“People that go through a complete investigation and have been found to have committed egregious harassment [can] get a job somewhere else, where nobody knows and everything happens again,” Joshua-Tor said. This policy of needing to answer questions about harassment in the previous decade would prevent that scenario.

The dependence scientists have on lab leaders creates professional risk for students who report harassment. The fortunes of the trainees are “very much dependent on the principal investigator in an extreme way,” explained Joshua-Tor. Senior faculty members affect the future of their staff through letters of recommendation.

“There’s a lot at stake,” said Joshua-Tor, especially if these lab leaders lose their jobs. Indeed, their students may suffer from a loss of funding. The authors recommend finding another researcher with a proven track record of mentorship to manage the lab.

Even though many senior scientists have considerable responsibilities, Joshua-Tor said principal investigators have assumed mentorship duties for others in unusual circumstances. 

“There were cases where people died,” so other scientists in neighboring labs took over their staff, she explained.

If, however, the institution can’t find another researcher who is available to take on these additional responsibilities, the authors recommend that the funding agency make bridge funding available to these researchers.

In addition to claims of harassment, the scientists discussed the difficulty women face from conscious and unconscious bias.

Joshua-Tor recalls an experience in a physics lab when she was an undergraduate. She was a lab partner with a man who was a “fantastic theoretician,” but couldn’t put together an experiment, so she connected the circuits. “The professor would come and talk” to her lab partner about the experimental set up while ignoring her and treating her as if she were “air.”

The scientists cited how male postdoctoral researchers tend to receive higher salaries than their female counterparts, while male faculty also receive larger salaries and start-up offers. Men may also get a larger share of internal funding, as was alleged with a $42 million donation to the Salk Institute.

To provide fair salaries, institutions could create anonymized salary data to an internal committee or to an external advisory committee for regular review, the scientists suggested.

Additionally, the researchers urged work-life balance through family-friendly policies, which include encouraging funding agencies to consider classifying child care as an acceptable expense on federal grants. Conferences, they suggest, could also attempt to provide on-site childcare and spaces for lactation.

While these extra efforts would likely cost more money, some groups have already addressed these needs.

“The American Society for Cell Biology has a fantastic child care program, where, if you are traveling, they have funds to alleviate extra child care services at home,” Joshua-Tor said. “If this is something we need and it’s in everybody’s psyche that it has to be taken care of for a meeting, it will be commonplace.”

Finally, the group addressed the challenge of advancing the careers of women in science. Female authors are often underrepresented in high-impact journals. Women also tend to dedicate more time to teaching and mentorship. The group encouraged holistic evaluations, which focus on an analysis of a candidate’s scientific and institutional impact.

Hopkins suggested that the solutions to these challenges at different institutions will vary. “You have to pick solutions that work in your culture” and that involve the administration. Ultimately, leveling the playing field doesn’t happen just once. “You’ve got to solve it and stay on it,” she urged.

Next week’s article explores some of the efforts of Stony Brook University, Brookhaven National Lab and Cold Spring Harbor Laboratory to provide an inclusive environment that ensures women have an equal opportunity to succeed in the STEM fields.

Mirna Kheir Gouda

By Daniel Dunaief

Mirna Kheir Gouda arrived in Commack from Cairo, Egypt, in 2012, when she was entering her junior year of high school. She dealt with many of the challenges of her junior year, including taking the Scholastic Aptitude Test, preparing for college and adjusting to life in the United States.

Her high school counselor at Commack High School, Christine Natali, suggested she apply to Stony Brook University. Once she gained admission, she commuted by train to classes, where she planned to major in biology on the road to becoming a doctor.

She did not know much about research and wanted to be involved in it to learn, especially because Stony Brook is so active in many fields.

“After some time conducting research, I came to be passionate about it and it was no longer just another piece of my resume, but rather, part of my career,” she explained in an email.

She reached out to Gábor Balázsi, a relatively new faculty member at the time, who suggested she consider joining a lab.

Balázsi uses synthetic gene circuits to develop a quantitative knowledge of biological processes such as cellular decision making and the survival and evolution of cell populations.

Balázsi knew Kheir Gouda from the 2015 international Genetically Engineered Machine team, which consisted of 14 members selected from 55 undergraduate students.

“Having this iGEM experience,” which included deciding on a project, raising funds, carrying out the project and preparing a report in nine months, was a “very promising indication” that Kheir Gouda would be an “excellent student,” Balázsi explained in an email.

Kheir Gouda chose Balázsi’s laboratory, where she worked with him and his former postdoctoral fellow Harold Bien, who offered her guidance, direction and encouragement.

As a part of the honors program, Kheir Gouda had to conduct an independent research project.

She wanted to “work on a project that involved adaptations and I always thought, ‘What happens when the environment changes? How do cells adapt?’”

She started her project by working with a mutant gene circuit that was not functioning at various levels, depending on the mutation. She wanted to know how cells adapt after beneficial but costly function loss.

An extension of this research, as she and Balázsi discussed, could involve a better understanding of the way bacterial infections become resistant to drugs, which threaten their survival.

“The idea for the research was hers,” Balázsi explained in an email. Under Bien’s mentorship skills, Kheir Gouda’s knowledge “developed quickly,” Balázsi said.

Balázsi said he and Kheir Gouda jointly designed every detail of this project.

Kheir Gouda set up experiments to test whether a yeast cell could overcome various mutations to an inducer, which regains the function of the genetic gene circuit.

Seven different mutations caused some type of loss of function of the inducible promoter of the gene circuit function. Some caused severe but not complete function loss, while others led to total function loss. Some were more able to “reactivate the circuit” rescuing its function, while others used an alternative pathway to acquire a resistance.

The presence of the resistance gene was necessary for cell survival, while the circuit induction was not necessary. At the end of the experiment, cells were resistant to the drug even in the absence of an inducer.

“This synthetic gene circuit in yeast cells can provide a model for the role of positive feedback regulation in drug resistance in yeast and other cell types,” Balázsi explained.

Kheir Gouda said she and Balázsi worked on the mathematical modeling toward the end of her research.

“What our work suggests is that slow growth can turn on quiescent genes if they are under positive feedback regulation within a gene network,” Balázsi wrote.

This mathematical model of limited cellular energy could also apply to cancer, which might slow its own growth to gain access to a mechanism that would aid its survival, Balázsi suggested. 

Recently, Kheir Gouda, who graduated from Stony Brook in 2018, published a paper about her findings in the journal Proceedings of the National Academy of Sciences, which is a prestigious and high-profile journal for any scientist.

“Because PNAS has a lot of interdisciplinary research, we thought it would be a good fit,” Kheir Gouda said. The work she did combines evolutionary biology with applied math and synthetic biology.

The next steps in this research could be verifying how evolution restores the function of other synthetic gene circuits or the function of natural network modules in various cell types, Balázsi suggested.

Kheir Gouda’s experience proved positive for her and for Balázsi, who now has eight undergraduates working in his lab. “The experience of mentoring a successful undergraduate might help make me a better mentor for other undergraduates and for other graduate students or postdoctoral researchers, because it helps set goals based on a prior example,” Balázsi said.

He praised Kheir Gouda’s work, appreciating how she learned new techniques and methods while also collaborating with a postdoctoral fellow in Switzerland, Michael Mahart, who is an author on the paper.

“It is unusual for an undergraduate to see a research project all the way through to completion, including a publication in PNAS,” marveled Balázsi in an email. He said he was excited to have mentored a student of Kheir Gouda’s character.

Kheir Gouda has continued on a research path. After she graduated from Stony Brook, she worked for a year on cancer research in David Tuveson’s lab at Cold Spring Harbor Laboratory. She then transitioned to working at the Massachusetts Institute of Technology for Assistant Professor of Chemical Engineering Kate Galloway. Kheir Gouda, who started working at MIT in October, plans to continue contributing to Galloway’s effort until she starts a doctoral program next fall.

Kheir Gouda said her parents have been supportive throughout her education.

“I want to take this opportunity to thank them for all the sacrifices they made for me,” Kheir Gouda said.

She is also grateful for Balázsi’s help.

He has “always been a very supportive mentor,” she explained. She would like to build on a career in which she “hopes to answer basic biology questions but also build on research and clinical tools.”

By Daniel Dunaief

It’s a big leap from an encouraging start to a human, especially when it comes to deadly diseases like amyotrophic lateral sclerosis, or Lou Gehrig’s disease. Cold Spring Harbor Laboratory Associate Professor Molly Hammell knows that all too well.

Hammell has been studying a linkage between a mutated form of a protein called TDP-43 and ALS for eight years. About a year and a half ago, she worked with 178 human samples from the New York Genome Center’s ALS Consortium and found a connection between a subset of people with the disease and the presence of abnormal aggregate forms of the protein.

“It’s really rewarding to see evidence in clinical samples from the processes that we predicted from cell culture and animal models,” she explained in an email.

Molly Hammell. Photo from CSHL

About 30 percent of the people with ALS Hammell examined had pathology of this protein in the upper motor neurons of the upper cortex. In this area, the mutated form of TDP allowed more so-called jumping genes to transcribe themselves. A normal TDP protein silences these jumping genes, keeping order amid potential gene chaos. The change in the protein, however, can reduce the ability of the protein to serve this important molecular biology maintenance function.

By using complementary studies of cell culture, the associate professor tried to determine whether knocking out or reducing the concentration of normal TDP caused an increase in these retrotransposons.

When she knocked out the TDP, she found a de-silencing of these jumping genes “was rapid,” she said. “We could see that in the samples we collected.”

Before she got the larger sample, Hammell worked with a smaller pilot data set of 20 patients. She found that three of the patients had this abnormal protein and an active set of these jumping genes.

“It’s hard to make an argument for something you’d only seen in three patients,” she said. “Getting that second, independent much larger cohort convinced us this is real and it’s repeatable, no matter whose patient cohort we’re looking at.”

Several diseases show similar TDP pathology, including Alzheimer’s and fronto-temporal dementia. She started with ALS because she believed “if we’re ever going to see” the link between the mutated protein and a disorder, she would “see it here” because a larger fraction of patients with ALS have TDP-43 pathology than any other disease.

The findings with ALS are a compelling start and offer a potential explanation for the role of the defective protein in these other conditions.

“We think it’s possible in a subset of patients with other neurodegenerative diseases that there might be overlapping” causes, Hammell said “We’re trying to get more data to branch out and better understand overlapping alterations.”

With these other diseases, she and her colleagues would like to explore whether TDP pathology is a necessary precondition in conjunction with some other molecular biological problems or whether these conditions can proceed without the disrupted protein.

The reaction among researchers working on ALS to Hammell’s finding has been encouraging.

Hemali Phatnani, the director of the Center for Genomics of Neurodegenerative Disease at the New York Genome Center, suggested Hammell’s work “opens up really interesting lines of investigation” into a potential disease mechanism for ALS. The research suggests a “testable hypothesis.”

Phatnani, who has been in her role for about five years, said she and Hammell speak frequently and that they serve as sounding boards for each other, adding that Hammell is “definitely a well-regarded member of the community.” 

Hammell has also been working through the Neurodegeneration Challenge Network in the Chan Zuckerberg Initiative, or CZI. This work brings together scientists who study Alzheimer’s, Parkinson’s, ALS and Huntington’s diseases. The group works to develop new approaches to the treatment and prevention of these diseases. These scientists, which includes researchers from Harvard University, Stanford University, Vanderbilt and Mount Sinai, among others, have webinars once a month and attend a conference each year.

Hammell was one of 17 researchers awarded the Ben Barres Early Career Acceleration Award from the CZI in 2018, which helped fund the research. She thinks the scientists from the CZI are excited about the general possibility that there’s overlapping disease mechanisms, which her work or research from other scientists in the effort might reveal. The CZI is “trying to get researchers working on different diseases to share their results to see if that’s the case,” she explained in an email.

She recognizes that numerous molecular and cellular changes also occur during the course of a disease.“There are always skeptics,” Hammell concedes. In her experiments, she sees what has happened in patient samples, but not what caused it to happen. She also has evidence that the retrotransposon silencing happens because of TDP-43 pathology.

“What we still need to confirm is whether or not the retrotransposons are themsleves contributing to killing the neurons,” she said.

If Hammell confirms a mechanistic link, other studies may lead to a treatment akin to the approach researchers have taken with viruses that alter the genetic code.

Future therapies for a subset of patients could include antiviral treatments that select specific genes.

Over time, she said her lab has cautiously added more resources to this work. As she has gotten increasingly encouraging results, she has hired more scientists who dedicate their work to this effort, which now includes two postdoctoral fellows, two graduate students and three staff scientists.

Some scientists in her lab still explore technology development and are devoted to fixing the experimental methods and data analysis strategies she uses to look for transposon activity.

Hammell is inspired by the recent results and recalled how she found what she expected in human samples about 18 months ago. She said she was “giddy” and she ran into someone else’s lab to “make sure I hadn’t done it incorrectly. It’s really exciting to see that your research might have an impact.”

Researchers regularly gather at the Banbury Center at Cold Spring Harbor to share ideas about to counteract Lyme Disease.

Lyme disease, the increasingly common tick-borne disease, may soon be preventable. 

Experts from academia, government and industry have been discussing at Cold Spring Harbor Laboratory’s Banbury Center the benefits and scientific feasibility of developing a vaccine that would essentially stop the infection in humans. 

The highlights of those discussions are summarized in a new study published Oct. 17 in Clinical Infectious Disease. Its conclusion: 

“We are now positioned at a crossroad where advanced technologies allow for application of new genetic strategies for immunizations, possible identification of new immunogens, and repurpose of proven vaccine candidates not only for humans but also for domestic animals and environmental reservoirs.” 

In laymen’s terms: New techniques are there, it’s creating a lot of excitement and there’s hope. 

The study is the culmination of more than 3 years of meetings held at the lab, where the most promising strategies for counteracting the infection were discussed. 

Lyme disease is caused by a bacterium transmitted through the bite of an infected tick. Traditionally, vaccines have been used to treat infectious diseases and rely on human antibodies to attack the germ. One of the new vaccines, which might be used in combination with traditional techniques, actually impacts the tick.

“What was discovered several years ago, to everyone’s surprise, a Lyme vaccine worked inside the tick itself and inactivated the Lyme bacteria. Newer vaccines are being designed to disrupt the mechanism for transmission of the Lyme bacteria from tick to human,” said Dr. Steven Schutzer, one of the study’s lead authors. 

Researchers cannot speculate when the vaccines will become publicly available, but they said they feel encouraged that they are in the pipeline with some trials underway.

Lyme disease can be treated with antibiotics, such as doxycycline, and is most successfully eradicated with early diagnosis. The only preventative measure to date, the researchers note, is to simply avoid tick bites. That strategy, though, has been ineffective at stopping the disease’s prevalence. Each year, more than 300,000 people are diagnosed with the disease. In Suffolk County, 600 people are diagnosed with Lyme disease, the highest rate in New York State. 

Lyme disease symptoms include fever, fatigue and headache, symptoms that often mimic other illnesses. It is often diagnosed by its characteristic bullseye skin rash, but not all cases present with a rash. Left untreated, the disease can infect the joints, heart and nervous system. Some people suffer from a post-treatment Lyme disease syndrome and have trouble thinking six months after they finish treatment, according to the Centers for Disease Control and Prevention. 

Former Suffolk County Legislator Vivian Viloria-Fisher was recently diagnosed with meningitis, induced she said, by a severe case of Lyme disease. After hearing other people’s stories about how Lyme disease can cause major illnesses, even a heart attack, she said a vaccine would be welcomed. 

During the Cold Spring Harbor meetings, a recognition emerged among participants that an effective vaccine was an important public health tool and the best path to follow to counteract the disease. 

Schutzer emphasized, though, that getting vaccinated for Lyme disease, a noncontagious disease, would be a personal choice, rather than a public health mandate. 

“When the pathogen is highly contagious, vaccines are most effective when a large population is vaccinated, creating herd immunity, and leading to the protection of the individual and of the community,” the researchers state in the study. “A vaccine directed against the causative agent B. burgdorferi, or against the tick vector that transmits this bacterium, will only protect the vaccinated person; thus, in this case, herd immunity does not apply toward protection of the community.” 

Stony Brook University researcher Jorge Benach participated in the meetings and noted Lyme vaccines are currently available for dogs but not appropriate for humans. 

“There’s clearly a need,” he said. “A lot of things need to be considered before an approval of a vaccine.”

One of those factors: 25 percent of ticks carrying the Lyme bacterium also carry other infectious organisms. 

Both researchers said they valued the rare opportunity to commingle, discuss and share expertise about a certain aspect of science under one roof during the Banbury Center’s meetings on Lyme disease.  

Dr. Rebecca Leshan, executive director of the Banbury Center at Cold Spring Harbor Lab, is proud that the meetings can impact the wider community. 

“I can’t overemphasize the importance of the small meetings convened at the Banbury Center of Cold Spring Harbor Laboratory,” she said. “They provide a truly unique opportunity for experts to engage with counterparts they may never otherwise meet and stimulate new ideas and strategies. And the beautiful Lloyd Harbor setting may provide a bit of extra inspiration for all those who participate.”

The first meetings of the group resulted in improved diagnostics that has already had major effects, with FDA approval of a number of tests. Outcomes from the most recent meetings, she said, continue to set the right course of action. 

Photo by © Kevin P. Coughlin/Office of Governor Andrew M. Cuomo

After two years of extensive renovation and with generous support from New York State, Cold Spring Harbor Laboratory’s historic Demerec Laboratory was reborn as a state-of-the-art research facility. Governor Andrew Cuomo cut the ribbon for the building’s reopening on Oct. 30, celebrating how the state will benefit from this new chapter in CSHL research.

“It’s good for Long Island, it’s good for the economy, but also it is doing work that I believe will improve the quality of life for thousands and thousands of people. I believe this work will actually save lives and there is nothing more important than that,” Governor Cuomo said during his visit. “That is the work that the people in this facility are dedicated to and God bless them for that. The state is honored to be playing a small role today.”

The Demerec Laboratory, home to four Nobel laureates, has been both a bastion and compass point for genetics research in New York and the world. Its new research will focus on taking a more holistic approach to treating cancer and the disease’s impact on the entire body.

According to the CSHL’s website, the new center “will enable newly developed compounds to be refined by world-leading chemists to develop next-generation therapies. This research will form a basis for collaboration with private foundations and pharmaceutical companies, while advancing the development of new drugs. 

In addition, the center will support ongoing research activities aimed to develop therapeutics for breast cancer, leukemia, autism, obesity, diabetes and lung cancer. The primary goal of such research activities will include the development of advanced drug compounds targeting underlying biological pathways.” 

To prepare the Demerec building for 21st-century science, it had to be gutted, with extensive renovations of the basement and interior, while leaving the historic 1950s brutalist exterior largely unchanged.

“We really challenged ourselves to preserve the history of the building as much as possible,” said Centerbrook design firm architect Todd E. Andrews, who planned the renovation.

The result is a modern facility uniquely designed for a scientific approach that considers disease not as a stand-alone subject of study but as a complex system that focuses on the patient.

“Too often [scientists] are not looking at the patient and the system of the patient … even though there are obvious signs that we should be looking,” said Dr. Tobias Janowitz, one of the next generation of Demerec Lab scientists and research-clinicians dedicated to rethinking cancer medicine.

Other Demerec researchers will include Nicholas Tonks, who investigates relationships between diabetes, obesity and cancer, and Linda Van Aelst, a neuroscientist who is interested in how sleep and signals from the brain may be impacted by cancer. Semir Beyaz, who studies how a patient’s nutrition can affect cancer treatment, will also join the team.

While the Demerec Laboratory’s faculty hasn’t been finalized, the researchers will be working alongside the rest of the CSHL community — including 600 scientists, students and technicians — to create a distinctly collaborative and cross-disciplinary culture.

Governor Cuomo called the Demerec building and the larger CSHL campus “hallowed ground for scientific research,” after dedicating $25 million in 2017 toward the $75 million renovation and said he is confident the space and its scientists will deliver a new wave of scientific progress.

“We invested over $620 million statewide in life sciences with $250 million in Long Island alone in biotech. Why? Because we believe that is an economic cluster that is going to grow and that is going to create jobs and it already is,” the governor said. “I believe Long Island is going to be the next Research Triangle.“

Renovating a single research facility may seem like a small step toward the state’s goal, but this particular building has made Long Island a scientific hot spot once again.

“While the Demerec building is comparatively smaller than larger projects that the governor has initiated … it is arguably one of the most productive buildings in all of science,” said CSHL President and CEO Bruce Stillman. “This renovation allows us to really think about where the Lab will take things next. It will have, I hope, a global impact on the research community, especially in the biomedical sciences.

Pictured from left: Laurel Hollow Mayor Daniel DeVita, President of Long Island Association Kevin Law, Northwell Health CEO Michael Dowling, President of Empire State Development Eric Gertler, Commissioner of Health for NYS Dr. Howard Zucker, CSHL President and CEO Bruce Stillman, Governor Andrew M. Cuomo, CSHL Honorary Trustee Jim Simons, CSHL Chair of the Board of Trustees Marilyn Simons, Nassau County Supervisor Laura Curran, NYS State Assemblyman Chuck Lavine, NYS Assemblyman Steve Stern, NYS Senator Jim Gaughran and CSHL COO John Tuke.   Photo by © Kevin P. Coughlin/Office of Governor Andrew M. Cuomo

 

Peter Koo. Photo by ©Gina Motisi, 2019/ CSHL

By Daniel Dunaief

We built a process that works, but we don’t know why. That’s what one of the newest additions to Cold Spring Harbor Laboratory hopes to find out.

Researchers have applied artificial intelligence in many areas in biology and health care. These systems are making useful predictions for the tasks they are trained to perform. Artificial intelligence, however, is mostly a hands-off process. After these systems receive training for a particular task, they learn patterns on their own that help them make predictions.

How these machines learn, however, has become as much of a black box as the human brains that created these learning programs in the first place. Deep learning is a way to build hierarchical representations of data, explained Peter Koo, an assistant professor at the Simons Center for Quantitative Biology at CSHL, who studies the way each layer transforms data and the next layer builds upon this in a hierarchical manner.

Koo, who earned his doctorate at Yale University and performed his postdoctoral research at Harvard University, would like to understand exactly what the machines we created are learning and how they are coming up with their conclusions.

“We don’t understand why [these artificial intelligence programs] are making their predictions,” Koo said. “My postdoctoral research and future research will continue this line of work.”

Koo is not only interested in applying deep learning to biological problems to do better, but he’s also hoping to extract out what knowledge these machines learn from the data sets to understand why they are performing better than some of the traditional methods.

“How do we guide black box models to learn biologically meaningful” information? he asked. “If you have a data set and you have a predictive model that predicts the data well, you assume it must have learned something biologically meaningful,” he suggested. “It turns out, that’s not always the case.”

Deep learning can pick up other trends or links in the data that might not be biologically meaningful. In a simplistic example, an artificial intelligence weather system that tracked rain patterns during the spring might conclude, after seven rainy Tuesdays, that it rains on Tuesdays, even if the day of the week and the rain don’t have a causative link.

“If the model is trained with limited data that is not representative, it can easily learn patterns that are correlative in the training data,” Koo said. He tries to combat this in practice by holding out some data, which is called validating data. Scientists use it to evaluate how well the model generalizes to new data.

Koo plans to collaborate with numerous biologists at Cold Spring Harbor Laboratory, as well as other quantitative biologists, like assistant professors Justin Kenney and David McCandlish.

In an email, Kenney explained that the Simons Center is “very interested in moving into this area, which is starting to have a major impact on biology just as it has in the technology industry.”

The quantitative team is interested in high-throughput data sets that link sequence to function, which includes assays for protein binding, gene expression, protein function and a host of others. Koo plans to take a “top down” approach to interpret what the models have learned. The benefit of this perspective is that it doesn’t set any biases in the models.

Deep learning, Koo suggested, is a rebranding of artificial neural networks. Researchers create a network of simple computational units and collectively they become a powerful tool to approximate functions.

A physicist by training, Koo taught himself his expertise in deep learning, Kenney wrote in an email. “He thinks far more deeply about problems than I suspect most researchers in this area do,” he  wrote. Kenney is moving in this area himself as well, because he sees a close connection between the problem of how artificial intelligence algorithms learn to do things and how biological systems mechanistically work.

While plenty of researchers are engaged in the field of artificial intelligence, interpretable deep learning, which is where Koo has decided to make his mark, is a considerably smaller field.

“People don’t trust it yet,” Koo said. “They are black box models and people don’t understand the inner workings of them.” These systems learn some way to relate input function to output predictions, but scientists don’t know what function they have learned.

Koo chose to come to Cold Spring Harbor Laboratory in part because he was impressed with the questions and discussions during the interview process.

Koo, daughter Evie (left) and daughter Yeonu (right) during Halloween last year. Photo by Soohyun Cho

He started his research career in experimental physics. As an undergraduate, he worked in a condensed matter lab of John Clarke at the University of California at Berkeley. He transitioned to genomics, in part because he saw a huge revolution in next-generation sequencing. He hopes to leverage what he has learned to make an impact toward precision medicine. 

Biological researchers were sequencing all kinds of cancers and were trying to make an impact toward precision medicine. “To me, that’s a big draw,” Koo said, “to make contributions here.”

A resident of Jericho, Koo lives with his wife, Soohyun Cho, and their 6-year-old daughter Evie and their 4-year old-daughter Yeonu.

Born and raised in the Los Angeles area, he joined the Army Reserves after high school, attended community college and then transferred to UC Berkeley to get his bachelor’s degree in physics.

As for his decision to join Cold Spring Harbor Laboratory, Koo said he is excited with the opportunity to combine his approach to his work with the depth of research in other areas. 

“Cold Spring Harbor Laboratory is one of those amazing places for biological research,” Koo said. “What brought me here is the quantitative biology program. It’s a pretty new program” that has “incredibly deep thinkers.”

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

By Daniel Dunaief

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

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

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

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

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

Margaret Churchland with the lab group at CSHL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ela Elyada. Photo by Giulia Biffi

By Daniel Dunaief

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Bruce Stillman. Photo courtesy of CSHL

By Daniel Dunaief

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

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

How does it feel winning the Gairdner Award?

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

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

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

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

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

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

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

What are some of the other major initiatives at CSHL?

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

Any other technological advances?

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

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

What are some of the newer efforts at the lab?

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

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

What will CSHL researchers study related to obesity?

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

What worries you about society?

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

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

How is the lab contributing to education?

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

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

By Daniel Dunaief

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

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

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

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

Megan Crow. Photo by Constance Brukin

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

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

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

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

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

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

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

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

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

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

Megan Crow. Photo by Daniel Katt

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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