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Power of 3

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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.

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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.”

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Ellen Pikitch, left, with Christine Sanora, taken in 2015 while the two scientists were researching Shinnecock Bay. Photo by Peter Thompson

By Daniel Dunaief

It’s one thing to make a commitment to a good idea; it’s another to follow through. Ellen Pikitch, endowed professor of ocean conservation science in the School of Marine and Atmospheric Sciences at Stony Brook University, is making sure countries around the world know where and how they can honor their commitment to protect the ocean.

In 2015, the United Nations had agreed to designate at least 10 percent of the oceans as Marine Protected Areas, which would restrict fishing and foster conservation. The goal of the proposal is to reach that figure by next year. 

Three years ago, with the support of the Italian Ministry of Environment and private donations, Pikitch started the labor-intensive process of finding ocean regions that countries could protect. 

Ellen Pikitch, right, with Natasha Gownaris at the United Nations Ocean Conference in June of 2017. Photo Courtesy of IOCS

She published the results of her analysis in the journal Frontiers in Marine Science. Her research could help countries move from the current 7.8 percent of oceans protected to the 10 percent target, and beyond that figure in the ensuing years.

The United States has met its target, although most of its marine protected ares are far from human population centers, so the coverage is uneven, Pikitch explained. The rest of the world has some gaps in high priority areas.

“I’m hoping that the study will light a fire under the policymakers so that they do meet their commitment,” said Pikitch. “It’s quite feasible for them to meet the goal. We’ve given [policymakers] advice in this paper about how exactly it could be done.”

The maps in the paper show areas that are within the current jurisdiction that are priority areas and are unprotected.

“There is quite a bit of area that meets this description — more than 9 percent — so there is flexibility in how countries can use the results and reach or exceed” the 10 percent target by next year, Pikitch explained in an email.

To determine where nations can enhance their ocean protection, Pikitch, Assistant Professor Christina Santora at the Institute for Ocean Conservation Science at Stony Brook University and Stony Brook graduate Natasha Gownaris, who is now an assistant professor in environmental studies at Gettysburg College, pulled together information from 10 internationally recognized maps indicating the location of global marine priority areas.

“We are standing on the shoulders of giants, capitalizing or leveraging all the hard work that has gone into other maps,” said Gownaris. 

One of the most unexpected findings from the study for Pikitch is that 14 percent of the ocean was considered important by two to seven maps, but over 90 percent of those areas remained unprotected. A relatively small part of this area is on the high seas, while most is within exclusive economic zones, which nations can control.

To preserve this resource that continues to remove carbon dioxide from the atmosphere while serving a critical role in the world’s food chain, conservationists have focused on marine protected areas because they provide the “one thing we felt was going to be the most effective single step,” said Mark Newhouse, the executive vice president for newspapers at Advance Publications and president of the Ocean Sanctuary Alliance. “It could happen overnight. A country could say, ‘This area is off limits to fishing,’ and it is.”

Countries can protect areas within their exclusive economic zones “more quickly than figuring out a way to solve global warming,” Newhouse added.

Santora explained the urgency to take action. “The situation in the ocean is worsening and we can’t wait to have perfect information to act,” Santora wrote in an email. “What we can do is put strong, effectively managed MPAs in the right places, with a high level of protection, that are well managed and enforced.”

Members of the Ocean Sanctuary Alliance, which counts Pikitch as its scientific officer, recognize that the 7.8 percent figure includes areas where countries have announced their intention to protect a region, but that doesn’t necessarily include any enforcement or protection.

“Intentions don’t protect the environment,” Newhouse said.

Ambassadors from several nations have reached out to OSA to discuss the findings. 

These diplomats are “exactly the people we want paying attention” to the research Pikitch and her team put together, Newhouse said.

Pikitch also plans to reach out proactively.

According to Pikitch’s recent analysis, the largest gaps in policy coverage occurred in the Caribbean Sea, Madagascar and the southern tip of Africa, the Mediterranean Sea and the Coral Triangle area, although they found additional widespread opportunities as well.

Pikitch calculated that an additional 9.34 percent of areas within exclusive economic zones would join the global marine protected area network if all the unprotected area identified as important by two or more initiatives joined the MPA network. 

“When effectively managed, when strong protections are put in place, they work,” Pikitch said.

Indeed, one such example is in Cabo Pulmo, Mexico, where establishing a marine protected area resulted in an 11-fold increase in the biomass of top predators within a decade. Many MPAs become sites for ecotourism, which can bring in hefty sums as people are eager to see the endemic beauty in their travels.

Pikitch hopes this kind of study spreads the word about the benefit of protecting the ocean and that policymakers and private citizens recognize that protecting sensitive regions also benefits fisheries, refuting the notion that environmentally driven policy conflicts with the goal of economic growth.

The groups involved in this study are already discussing the new goal for the ocean. Several diplomats and scientists would like to see the bar raised to 30 percent by 2030, although the United Nations hasn’t committed to this new target yet.

“Studies show that 10 percent is insufficient — it is a starting point,” Santora wrote. “I do think that targets beyond 2020 will increase.”

Pikitch said the ocean has always been one of her passions. Her goal is to “leave the world in better shape than I found it” for her children and six grandchildren.

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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.”

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Ken Dill. Photo from SBU

By Daniel Dunaief

Over the course of decades, aging skin tends to wrinkle, revealing laugh or frown lines built up through a lifetime of laughter, tears and everything in between. Similarly, when people age, the proteins in their bodies don’t fold up as neatly. Free radicals cause these misfolded proteins, which are then susceptible to further damage.

The cumulative effect of these misfolded proteins, which is a part of natural cell aging, can contribute to cell death and, ultimately, the death of an individual.

Researchers have typically focused on the way one or two proteins unfold as damage increases from oxygen that has an uneven number of electrons.

Ken Dill. Photo from SBU

Ken Dill, a distinguished professor and director of the Laufer Center for Physical and Quantitative Biology at Stony Brook University, and colleagues including Adam de Graff, a former postdoctoral researcher in Dill’s lab who is currently a senior scientist at Methuselah Health based in Cambridge, England, and Mantu Santra, a postdoctoral researcher in Dill’s lab, recently published research that explored the global effects of unfolding on the proteome. Their model represents average proteins, not individual proteins, detail by detail.

Researchers use the roundworm as a model of human aging because of the similarity of the main processes. The worm model presents opportunities to explore the cumulative effect on proteins because of its shorter life span. Worms in normal conditions typically live about 20 days. Worms, however, that are subjected to higher temperatures or that live in the presence of free radicals can survive for only a few hours.

The shorter life span correlates with the imbalance between the rate at which cells create new proteins and the collapse of misfolded proteins damaged by free radicals, the scientists explained in a paper published online recently in the journal Proceedings of the National Academy of Sciences.

While numerous processes occur during aging, including changes in DNA, lipids and energy processes, Dill explained that organisms, from worms, to flies, to mice to humans experience increasing oxidative damage over the course of their lives.

“The evidence made us think about proteome collapse as a dominant process,” Dill said.

De Graff explained that the paper uses the premise that “certain conformations of a protein are much more susceptible to oxidative damage than others. If you’re folded, you’re pretty safe.”

In the past, researchers have considered linking the way protein misfolding leads to cell death to a potential approach to cancer. If, for example, scientists could subject specific cancer cells to oxidative damage and to develop an accumulation of misfolded proteins, they could selectively kill those cells.

A few years ago, researchers explored the possibility of developing a therapeutic strategy that tapped into the mechanism of cell death. To survive with an accumulation of mutated proteins, cancer cells have increased the levels of chaperone concentrations because they need to handle numerous mutated, incorrectly folded proteins. 

A drug called 17-AAG aimed to reduce the chaperones. It worked for some cancers but not others and had side effects. New efforts are continuing in this area, Dill said.

Other researchers, including De Graff, are looking at ways to improve protein folding and, potentially, provide therapeutic benefits for people as they age.

At Methuselah Health De Graff and his colleagues are leveraging the fact that certain conformations are more susceptible to damage and thus the creation of altered “proteoforms.” Identifying these proteoforms could be key to the early detection of disease and the development of preventative treatments, De Graff explained.

Methuselah Health is not interested in treating the downstream symptoms of disease but, rather, its upstream causes.

Going forward, Dill hopes other experimental scientists continue to generate data that enables a closer look at the link between oxidative damage, protein misfolding and cell death.

Some people in the aging field look at individual proteins, he explained. In neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, which are associated and correlated with protein misfolding, scientists are taking numerous approaches. So far, however, researchers haven’t found a successful approach to tackle aging or diseases by altering misfolded proteins.

Dill hopes people will come to appreciate a role for modeling in understanding such varied cellwide processes such as aging. “How do we convey to people who are used to thinking about detailed biochemistry why modeling matters at all?” he asked. “We have our work cut out for us to communicate what we think matters and a way forward in terms of drug discovery.”

Theoretically, some proteins that are at a high enough concentration might be more important in the aging and cell death process than others, Dill said. “If you could reduce their concentration, you might pull the cell back from the tipping point for other proteins,” he said, but researchers know too little about if or how they should do this. He credits De Graff and Santra with doing considerable work to bring this study together.

A resident of Port Jefferson with his wife, Jolanda Schreurs, Dill is pleased that their house has solar panels. 

The couple’s son Tyler is married and has purchased a house in San Diego. Despite professing a lack of interest in biology at an early age, Tyler is working as a staff development engineer for Illumina, a company that makes DNA sequencing machines.

The couple’s younger son Ryan is earning his doctorate as a physical chemist at the University of Colorado in Boulder. He works with lasers, solar energy and quantum entanglements.

As for the most recent research, Dill suggested that it is “premised on the importance of oxidative damage, including by free radicals, which is now well established,” he explained in an email. “It then seeks to explain their effects on how proteins fold and misfold.”

De Graff added that the model in the PNAS paper attempts to “understand the consequences of slowed protein synthesis and turnover” that occurs during aging.

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William Farr. Photo by Anja von der Linden

By Daniel Dunaief

It’s not exactly a symphony, with varying sounds, tones, cadences and resonances all working together to take the listener on an auditory journey through colors, moods and meaning. In fact, the total length of the distortion is so short — about 0.1 seconds — that it’s a true scratch-your-ear-and-you’ll-miss-it moment.

And yet, astrophysicists like William Farr, an associate professor in the Department of Physics and Astronomy at Stony Brook University and a group leader in gravitational wave astronomy with the Simons Foundation Flatiron Institute, are thrilled that they have been able to measure distortions in space and time that occur at audio frequencies that they can convert into sounds. These distortions were made millions or even billions of years ago from merging black holes.

Farr, in collaboration with a team of scientists from various institutions, recently published a paper in Physical Review Letters on the topic. 

While the ability to detect sounds sent hurtling through space billions of years before Tyrannosaurus Rex stalked its prey on Earth with its mammoth jaw and short forelimbs offers some excitement in and of itself, Farr and other scientists are intrigued by the implications for basic physical principles.

General relativity, a theory proposed by Albert Einstein over 100 years ago, offers specific predictions about gravitational waves traveling through space.“The big excitement is that we checked those predictions and they matched what we saw. It’s a very direct test of general relativity and its predictions about a super extreme environment near a black hole,” said Farr. There are other tests of general relativity, but none that directly test its predictions so close to the event horizon of a black hole, he explained.

General relativity predicts a spectrum of tones from a black hole, much like quantum mechanics predicts a spectrum line from a hydrogen atom, Farr explained.

The result of this analysis “provides another striking confirmation of the theory of general relativity and also demonstrates that there are even more exciting things that can be done with gravitational wave astrophysics,” Marilena Loverde, an assistant professor of physics at the C. N. Yang Institute for Theoretical Physics at Stony Brook University, explained in an email. Loverde suggested that Farr is “particularly well-known for bringing powerful new statistical techniques to extract science from vast astrophysical data sets.”

Farr and his colleagues discovered two distortions that they converted into tones from one merger event. By measuring the frequency of the first one, they could predict the frequency for all the other tones generated in the event. They detected one more event, whose frequency and decay rate were consistent with general relativity given the accuracy of the measurement.

So, what does the merger of two black holes sound like, from billions of light years away? Farr suggested it was like a “thunk” sent over that tremendous distance. The pitch of that sound varies depending on the masses of the black holes. The difference in sound is akin to the noise a bear makes compared with a chipmunk: A larger black hole, or animal, in this comparison, makes a noise with a deeper pitch.

He used data from the Laser Interferometer Gravitational-Wave Observatory, or LIGO, which is a twin system located in Livingston, Louisiana, and Hanford, Washington. LIGO had collected data from black hole merger events over a noncontinuous six-month period from 2015 to 2017.

Farr chose the loudest one, which came from 1.5 billion years ago. Farr was using data from the instrument, which collects gravitational waves as they reach the two different locations, when it was less sensitive. Given the original data, he might not have discovered anything. He was, however, delighted to discover the first tone.

If something that far away emitted a gravitational wave sound that lasts such a short period of time, how, then, could the LIGO team and Farr’s analysis be sure the sound originated with the cosmic collision?

“We make ‘extreme’ efforts to be sure about this,” Farr explained in an email. “It is one reason we built two instruments (so that something weird happening in one does not fool us).” He said he makes sure the signal is consistently recorded in both concurrently. To rule out distortions that might come from other events, like comets slamming into exoplanets, he can measure the frequency of the event and its amplitude.

Black holes form when stars collapse. After the star that, in this case, was likely around 25 times the mass of the sun, exploded, what was left behind had an enormous mass. When another, nearby star becomes a black hole, the two black holes develop an orbit like their progenitor stars. When these stars become black holes, they will emit enough gravitational waves to shrink the orbit, leading to a merger over a few billion years. That’s what he “heard” from the last second or fraction of a second.

Farr expects to have the chance to analyze considerably more data over the next few months. First, he is working to analyze data that has already been released and then he will explore data from this year’s observations, which includes about 25 more mergers.

“The detectors are getting more sensitive,” he said. This year, scientists can see about 30 percent further than they could in the first and second observing runs, which translates into seeing over twice the total volume.

Farr has been at Stony Brook for almost a year. Prior to his arrival, he had lived in England for five years. He and his wife, Rachel, who have a 3½-year-old daughter, Katherine, live in Stony Brook.

As for his work, Farr is thrilled that he will have a chance to study more of these black hole merger sounds that, while not exactly Mozart, are, nonetheless, music to his ears. “Each different event tells us different things about how stars form and evolve,” he said.

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Jessica Schleider. Photo from SBU

By Daniel Dunaief

Many teenagers who are struggling with depression need help. According to several estimates, less than half of teens with depression receive treatment that would help them manage through everything from negative feelings toward themselves and their lives to a lack of control over events during the day.

Jessica Schleider, an assistant professor of clinical psychology in the College of Arts and Sciences at Stony Brook University, wants to offer teenagers battling depression a new kind of assistance.

Jessica Schleider on a hike with her dog Penny. Photo by David Payne

Schleider is seeking participants for a new study, called Project Track to Treat, that offers teenagers from 11 to 16 years old symptom-tailored treatment. After participating teens respond to surveys she sends them on smartphones, she will provide single-session, computer-based interventions that address symptoms such as hopelessness or withdrawal from daily activities.

Schleider recently received a five-year, $2 million Early Independence Award from the National Institutes of Health to test the benefits of these half-hour computer sessions.

The funds will go toward study staff, the cost of recruiting youths and families for the study, equipment, statistical packages for the analyses she plans to run and compensation for the families who take part.

“A vast majority of teenagers who experience depression never access treatment,” Schleider said, potentially because teens are not typically in a position where they can seek out treatment on their own. “Between the lack of access to services and the limited potency of services, there needs to be a broader array of options and layers we can provide.”

In the world of clinical psychology, three to four months is generally considered brief treatment. A single computer-based session that a teenager can access at any time offers support during a much shorter time frame.

The idea behind the briefer, more targeted intervention is that it could offer help. The goal of the session is to create positive momentum, to teach teens useful skills for coping with depression-related difficulties, and to offer it in a setting where modern teenagers spend much of their time, online, Schleider suggested.

Jessica Shleider with husband David Payne and their dog Penny.
Photo from Jessica Schleider

“For young people who would never go to a therapist, the question may be whether there is something else that could help, and [Schleider’s] work may offer one such ‘something else,’” John Weisz, a professor in the Department of Psychology at Harvard University, wrote in an email. It’s also possible, explained Weisz, who has known Schleider since 2013 when she worked in his lab, that a single session might encourage teenagers to believe that other types of therapy can also help if they try.

Part of the motivation for this study is to determine if the nature of the symptoms — which she will explore through survey questions — can inform how teenagers will respond to a single, therapeutic session.

Schleider created these programs from available research in psychology and education. She adapted some of those programs to these specific circumstances and she taught herself rudimentary coding with html. She currently has three programs available on her website, which interested parents and teenagers can explore at www.schleiderlab.org/participate.

The teenagers participating in the study will receive questions a few times a day for three weeks about how they are feeling, checking to see any signs of depression. From those interactions, Schleider will be able to determine which symptom is the most central and which might lead to other symptoms over time. She hopes to take parameters from that to see if those symptoms predict how much a participant will respond to a session.

Schleider will also measure how teenagers respond to training through the study. If their emotional state deteriorates, the researchers can intervene and can monitor the level of risk and refer any cases appropriately. “Our top priority as researchers is to make sure the kids are taken care of,” she said.

She was skeptical before she started working on brief sessions. “I was on the side of, of course you can’t do anything in one session,” Schleider said. “I thought you need several sessions to make a sustained change.”

In looking at the available research, however, she discovered that through 50 randomized control trials in 2017, the magnitude of the effect of the trials was between small to medium range, which matched the effect of sessions ranging from an hour to 16 sessions for other teenagers. After her study, she realized that “there is something to this. We need to do more work to find out what to do and how to harness it for our youth.”

Through monitoring over two years, Schleider hopes to gain a better awareness of who will benefit from this session and under what time frame they might see an improvement.

She hopes teenagers can share their thoughts and ideas for how to improve these programs. She also offers some of these teenagers to help reconstruct the content and language and references.

Teenagers who don’t participate in the Track to Treat study can participate in an anonymous Project Yes effort, which is a program evaluation initiative. These participants can offer feedback on these sessions.

For a subset of teenagers, one session likely won’t be sufficient. 

Weisz suggested that Schleider, who joined Stony Brook last year, is a “terrific addition” to the university and the community. “I believe her work will reflect very well on both.” Weisz added that Schleider’s colleagues in the Department of Psychology at Stony Brook “are among the finest psychological scientists in the nation,” where Schleider can “take her work to a very high level.”

Schleider, who joined Stony Brook last year, lives in Coram with her husband, David Payne, who is a medical resident in radiology at Stony Brook Hospital. 

As for her work, Schleider said she recognizes that there is no panacea, but that this approach is “something when the alternative is nothing.”

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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.”

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From left, Luisa Escobar-Hoyos, Lucia Roa and Ken Shroyer Photo by Cindy Leiton

By Daniel Dunaief

The prognosis and treatment for cancer varies, depending on the severity, stage and type of disease. With pancreatic ductal adenocarcinoma, the treatment options are often limited and the prognosis for most patients by the time doctors make a diagnosis is often bleak.

Researchers at the Renaissance School of Medicine’s Pathology Department at Stony Brook University have been testing for the presence of a protein called keratin 17, or K17, by staining tissue specimens or needle aspiration biopsy specimens. This measures the proportion of tumor cells that have high levels of expression.

This protein is typically active during embryological development or in stem cells, which are a type of cell that can differentiate into a wide range of other cells. It is also active in pancreatic cancer.

Ken Shroyer, department chairman; Luisa Escobar-Hoyos, assistant professor of pathology; and Lucia Roa, assistant professor of pathology recently published a paper in the journal Scientific Reports in which they documented how the level of this protein can indicate the prognosis for patients. K17 above a certain level typically suggests a worse prognosis.

The Stony Brook scientists want to understand why some pancreatic cancers are more aggressive than others, with the hope that they might be able to develop more effective ways to treat the most aggressive form of the disease.

In the recent research, the level of K17 not only indicated the prognosis for the most aggressive form of the disease, but it is also considered a “cause of making the tumors more aggressive,” Escobar-Hoyos added, which confirmed their previously published research and which unpublished data also supports.

Shroyer suggested that this research paper has been a validation of their plan to pursue the development of K17 as a way to differentiate one form of this insidious cancer from another.

While other cancers, such as cervical cancer, have proven quicker and easier to use K17 for its predictive power, the current work reflects the lab’s focus on pancreatic cancer. As such the research is a “great step forward to generate our first pancreatic cancer paper,” Shroyer said. His lab had previously published papers on other biomarkers in pancreatic cancer.

Escobar-Hoyos indicated that she and Shroyer anticipate that K17, which is one of a family of 54 different types of keratins in the human body, likely plays numerous roles in promoting cancer.

Indeed, K17 may promote the invasiveness of these cells, allowing them to spread from the original organ, in this case the pancreas, to other parts of the body. They are testing that concept through ongoing work in their lab.

The researchers believe that K17 may accelerate metastasis, but that line of thinking is “still at a relatively early stage,” Escobar-Hoyos said.

This protein may also change the metabolism of the cell. They believe K17 blocks the uptake of certain drugs by enhancing specific metabolic pathways. 

Additionally, K17 causes the degradation of p27, which is a tumor suppressor that controls cell division.

The researchers used two different ways to monitor the levels of protein, through mRNA analysis and through immunohistochemical localization. In the latter case, that involved staining the cells to look for the presence of the protein.

Roa, who is the first author on the paper, stained the slides and worked with Shroyer to score them.

The assistant professor, who came to Long Island with her daughter Laura who earned her bachelor’s degree and master’s in public policy at SBU, had been a pathologist and medical doctor when she lived in Colombia. She learned the IHC staining technique at Yale University just after she graduated from medical school and worked for six years as a postdoctoral fellow on several projects using IHC.

Roa is thrilled that she’s a part of a supportive team that could help develop techniques to improve patient diagnosis and care.

“We care deeply about developing a tool that will help us to treat patients and we value working together to accomplish this,” Roa explained in an email.

At this point, Shroyer and his team have identified key factors that cause K17 to be overexpressed. They are pursuing this line of research in the lab.

“We think K17 expression is dictated by something different than genetic status,” said Escobar-Hoyos. “This is speculation, but we think it might be triggered based on a patient’s immunity.”

After this study, the pathology team is looking to validate their results through different cohorts of patients. They are working with the Pancreatic Cancer Action Network and their scientific collaborators at Perthera Inc. to process tissue sections from these cases for K17 staining in their lab.

They are also at the early stages in the development of a collaboration with investigators at MD Anderson Cancer Center.

“If we can validate that K17 IHC testing is able to predict a response to the standard of care, then we’ll have permission to start a prospective analysis linked to a clinical trial,” Shroyer said.

Shroyer’s team is trying to understand how K17 becomes activated, what happens when they block that activation, and how it impacts the survival and tumor growth in animal models of pancreatic cancer.

In collaborations with other researchers, they are exploring how K17 impacts the therapeutic vulnerability of pancreatic cancer to over 2,000 FDA-approved compounds.

“There are a discrete list of compounds that are able to kill K17 positive cells,” Shroyer said. He is aiming to start phase 0 trials to validate the molecular model. If the data is sufficiently convincing, they can apply to the FDA to begin phase 1 trials.

He hopes this study is the first of many steps the lab will take in providing clues about how to diagnose and treat pancreatic cancer, which has been an intractable disease for researchers and doctors.

“This paper helps establish and confirm that K17 is an important and promising prognostic biomarker in pancreatic cancer,” Shroyer said. “For us, this is foundational for all the subsequent mechanistic studies that are in progress to understand how K17 drives cancer aggression.”

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Dr. Minsig Choi and Paul Bingham. Photo from Stony Brook Medicine

By Daniel Dunaief

The Stony Brook Cancer Center is seeking patients with pancreatic cancer for a phase 3 drug trial of a treatment developed by a husband and wife team at SBU.

Dr. Minsig Choi. Photo from Stony Brook Medicine

Led by Minsig Choi, the principal investigator of the clinical trial and a medical oncologist at Stony Brook Cancer Center’s gastroenterology team, the study is part of a multicenter effort to test whether a drug known as CPI-613, or devimistat, can extend the lives of people battling against a form of cancer that often has a survival rate of around 8 percent five years after its discovery.

Paul Bingham. Photo from Stony Brook Medicine

Patients at Stony Brook will either receive the conventional treatment of FOLFIRINOX, or a combination of a FOLFIRINOX and CPI-613. An earlier study demonstrated a median survival of 20 months with the combination of the two drugs, compared with 11 months with just the standard chemotherapy.

“Pancreatic cancer is such a bad disease,” Choi said. “The overall survival is usually less than a year and life expectancy is very limited.”

Choi said the company that is developing the treatment, Rafael Pharmaceuticals, wanted Stony Brook to be a part of the larger phase 3 study because the drug was developed at the university. Indeed, Stony Brook is the only site on Long Island that is offering this treatment to patients who meet the requirements for the study.

People who have received treatment either from Stony Brook or at other facilities are ineligible to be a part of the current trial, Choi said. Additionally, patients with other conditions, such as cardiac or lung issues, would be excluded.

Additionally, the current study is only for “advanced patients with metastatic” pancreatic cancer, he said. People who have earlier forms of this cancer usually receive surgery or other therapies.

“When you’re testing new drugs, you want to start in a more advanced” clinical condition, he added.

Choi said patients who weren’t a part of the study, however, would still have other medical options.

Zuzana Zachar. Photo from Stony Brook Medicine

“The clinical trial is not the only way to treat” pancreatic cancer, he said. These other treatments would include chemotherapy options, palliative care, radiation therapy and other supportive services through social workers.

Choi anticipates that the current study, which his mentor Philip A. Philip, a professor in the Department of Oncology at the Barbara Ann Karmanos Cancer Institute in Detroit is leading, would likely provide preliminary results in the next 18 to 24 months.

If the early results prove especially effective, the drug may receive a fast-track designation at the Food and Drug Administration. That, however, depends on the response rate and the way patients tolerate the treatment.

At this point, Choi anticipates that most of the side effects will be related to the use of chemotherapy, which causes fatigue and weakness. The CPI-613, at least in preliminary studies, has been “pretty well tolerated,” although it, like other drug regimes, can cause upset stomachs, diarrhea and nausea, he said.

Doctors and researchers cautioned that cancer remains a problematic disease and that other drugs to treat forms of cancer have failed when they reach this final stage before FDA approval, in part because cancer can and often does develop ways to work around efforts to eradicate it.

Still, the FDA wouldn’t have approved the use of this drug in this trial unless the earlier studies had shown positive results. Prior to this broader clinical effort, patients who used CPI-613 in combination with FOLFIRINOX had a tumor response rate of 61 percent, compared with about half that rate without the additional treatment.

Paul Bingham, an associate professor in the Department of Biochemistry and Cell Biology at Stony Brook University, and his wife Zuzana Zachar, a research assistant professor and director of Master in Teaching Biology Program at the Institute for STEM Education at Stony Brook, originally invented and discovered the family of drugs that includes CPI-613.

Bingham and Zachar, who are consultants to Rafael Pharmaceuticals, “provide basic scientific support” in connection with this phase 3 trial. “When the FDA asks questions, sometimes it requires us to do basic science” to offer replies, he said.

Zachar and Bingham developed this drug because they anticipated that attacking cancer cell’s metabolism could lead to an effective treatment. Cancer requires considerable energy to continue on its deadly course. This drug, which is a lipoate analog and is an enzyme cofactor in several central processes in metabolism, tricks the disease into believing that it has sufficient energy. Interrupting this energy feedback mechanism causes the cancer cell to starve to death. 

While other cells use some of the same energy feedback pathways, they don’t have the same energy demands and the introduction of the drug, which has tumor-specific effects, is rarely fatal for those cells.

The lipoate analog is a “stable version of the normally transient intermediary that lies to the regulatory systems, which causes them to shut down the metabolism of cancer cells,” Bingham said. These cells “run out of energy.”

Zachar said the process of understanding how CPI-613 could become an effective treatment occurred over the course of years and developed through an “accretion of data that starts to fill in a picture and eventually you get enough information to say that it could be” a candidate to help patients. The process is more “incremental than instantaneous.”

Bingham and Zachar are working on a series of additional research papers that reflect the way different tumors and tumor types have different sensitivities to CPI-613. They expect to publish at least one new paper this year and several more next year.

The researchers who developed this drug have had some contact with patients through the process. While they are not doctors, they are grateful that the work they’ve done has “extended and improved people’s lives,” Bingham said, and they are “grateful for that opportunity.”

Zachar added that she is “thrilled that we’ve been able to help.” She appreciates the contribution the patients make to this research because they “stepped to the line and took the risk to try this drug.”

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