Power of 3

Dave Jackson. Photo from CSHL

By Daniel Dunaief

Just as humans have competing impulses — should we eat or exercise, should we wait outside in the rain to meet a potential date or seek shelter, should we invest in a Spanish tutor or a lacrosse coach — so, too, do plants, albeit not through the same deliberate abstract process.

Working with corn, Dave Jackson, a professor at Cold Spring Harbor Laboratory, has discovered that the gene Gß, (pronounced Gee-Beta,) balances between the competing need to grow and to defend itself against myriad potential threats.

By looking at variations in the gene, Jackson and his postdoctoral fellows, including Qingyu Wu and Fang Xu, have found that some changes in Gß can lead to corn ears with more kernels. The results of this work, which were published in the Proceedings of the National Academy of Sciences last month, suggest that altering this gene may eventually increase the productivity of agricultural crops.

Indeed, the study of this gene included an analysis of why some mutations are lethal. An overactive Gß gene turns the corn brown and kills it. This occurs because the gene cranks up the immune system, causing the plant to attack itself.

Other scientists have found mutations in this gene in plants including arabodopsis and rice.

“We are the first to figure out why the mutations are lethal in corn,” Jackson said. “That’s also true in rice. Rice mutations were made over a decade ago and they also caused the plants to die. Nobody knew why. The main puzzle was solved.”

Dialing back this immune response, however, can encourage the plant to dedicate more resources to growth, although Jackson cautions that the research hasn’t reached the point where scientists or farmers could fine tune the balance between growth and defense.

“We are not there yet,” he said. “That’s what would be possible, based on this knowledge.”

Even in the safer environment of an agricultural field, however, plants can’t abandon all efforts at defense.

“Plants need some defense, but probably much less than if they were growing in the wild,” he said.

By altering the balance toward growth, Jackson is looking at mutations that make more stem cells, which can produce flowers and, eventually kernels. The next steps in this research will not likely include scientists in Jackson’s lab. Qingyu Wu plans to move on to a research position in China. 

Penelope Lindsay. Photo by Patricia Waldron

A prolific plant scientist and mentor, Jackson has seen several of his lab members leave CSHL to pursue other opportunities. Recently, he has added three new postdoctoral researchers to his team: Thu Tran, Jae Hyung Lee and Penelope Lindsay.

Jackson plans to use single-cell sequencing in his future research. Using this technique, scientists can find regulatory relationships between genes and monitor cell lineages in development. Jackson described this approach as an “amazing new technology” that’s only been around for a few years. He hopes to use this technique to find new leads into genes that control growth.

Lindsay, who is joining the lab this month, would like to build on her experience as a plant biologist by adding computational expertise. A graduate of the Boyce Thompson Institute in upstate Ithaca, where she was working on the symbiotic relationship between some plants and a specific type of fungi in the soil, Lindsay would also like to work on single-cell sequencing. She plans to continue to study “how specific genotypes produce a phenotype” or how its genes affect what it becomes.

Jackson’s lab’s focus on the undifferentiated cells of the meristem appealed to Lindsay.

Lindsay first met Jackson a few years ago, when he was giving a talk at Cornell University. It was there, fittingly enough, that she had learned about the work that led to the current paper in the Proceedings of the National Academy of Sciences about growth versus defense.

“I was really impressed with the techniques and with the connection to basic research,” Lindsay said. She was excited to learn how Jackson and his students took biochemical approaches to understand how this signaling pathway affected development.

Cold Spring Harbor Laboratory also intrigued Lindsay, who was interested to join a facility that encouraged collaborations among labs.

Born in New York City, Lindsay spent some of her time in upstate New York before moving to Florida, where she also attended college.

Surrounded by family members who have found outlets for their creativity through art — her mother, Michelle Cartaya, is an artist who takes nature photos and her father, Ned Lindsay, remodels homes — she initially attended New College of Florida in Sarasota expecting to pursue a degree in English. Once in college, however, she found excellent scientific mentors, who encouraged her to pursue research.

As a graduate student, Lindsay was greatly intrigued by the signaling pathway between plants and the symbiotic relationship with arbuscular mycorrhizal fungi. During her graduate work, she studied a mutated version of a plant that lacked a signaling protein that encourages this collaboration. When she added considerable amount of the protein to the plant, she expected to restore the symbiosis, but she found the exact opposite.

“The amount of the protein is critical,” she said. “If you have too much, that’s a bad thing. If you don’t have enough, it’s also bad. It’s like Goldilocks.”

A new resident of Huntington, Lindsay, who was a disc jockey for a community radio station in Ithaca and makes electronic music using synthesizers and computers, is looking forward to starting her work at Cold Spring Harbor Laboratory and to living near New York City.

Lindsay continues to find plants fascinating because they “get everything they need” while living in one place their entire lives. “They have so many sophisticated biochemical pathways to protect themselves,” she said.

Saket Navlakha

By Daniel Dunaief

Plants have to solve challenges in their environment – without a brain or the kind of mobility mammals rely on to survive – through strategies and computations that keep them alive and allow them to reproduce.

Intrigued by plants and by the neurobiology that affect decisions or behavior in a range of other organisms, Associate Professor Saket Navlakha recently joined Cold Spring Harbor Laboratory to study the processes a range of organisms use.

“Biological systems have to solve problems to survive,” said Navlakha. “The hope is that by studying these algorithms, we can inspire new methods for computer science and engineering and, at the same time, come up with new ways to predict and model behaviors of these systems.”

Navlakha, who has a doctorate in computer science from the University of Maryland College Park and conducted postdoctoral research at Carnegie Mellon University’s Machine Learning Department, focuses on the “algorithms of nature,” in which organisms evolved ways to solve problems that enhance the likelihood of their survival.

In his first three months at CSHL, Navlakha plans to do an interview tour, speaking with researchers who study cancer, molecular biology, neurology and plants.

While his primary areas of focus have been on plants and neurobiology, he appreciates that the internationally recognized research facility presents “new opportunities” for him and a lab in which he intends to hire four to six scientists over the next two years.

Adam Siepel, the chair of the Simons Center for Quantitative Biology and professor at the Watson School of Biological Sciences at Cold Spring Harbor Laboratory, led the recruitment of Navlakha.

In an email, Siepel wrote that Navlakha “immediately struck us as an ideal candidate for the center” in part because he is a “free thinker with an eye for interesting and important problems in biology.”

Navlakha believes processes and strategies that foster survival spring from a set of principles that helps them thrive and adapt. In 2018, when he was at the Salk Center for Integrative Biology, he wrote a piece for Wired magazine about species extinction. “By not preserving [species that become extinct], we are losing out on interesting ideas that evolution gave them to survive,” he said.

Even amid these losses, however, Navlakha recognizes the lessons computer scientists and engineers like him can learn. Through losses and failures, humans can understand the limitations of algorithms that only allowed a species to survive up to a point, as conditions pushed its algorithms past a tipping point.

At its core, Navlakha’s approach to these algorithms includes the idea that biological systems perform computations. He originally studied brains because they are “such an elegant computer, doing all kinds of things that modern, human-made computers can’t do,” he said.

When he was at the Salk Institute, he spoke with colleagues in plant biology who told him about research that examined how plants modify their shape amid a changing environment, which is what triggered his interest in plants.

One of the themes of his work involves understanding trade-offs. Doing well in one task typically means doing worse in another. He likened this analysis to investing in stocks. An investor can put considerable funds into one stock, like Apple, or diversify a portfolio, investing less money per stock in a variety of companies from different sectors.

“We’ve been studying how plants hedge” their bets, he said. The hedge in this description bears no relation to a collection of plants at the edge of a property.

A plant can create one huge seed that might survive a drought or other environmental threat, or it can diversify the types of seeds. “We’re really interested in understanding these trade-offs, how they hedge, and what kind of strategies” they employ, he said.

Ziv Bar-Joseph, a professor of computer science at Carnegie Mellon University who has known Navlakha for over eight years, suggested Navlakha has “deep insights.” 

In an email, Bar-Joseph described Navlakha’s biggest achievement as his work that shows how the brain uses a computational method to store and retrieve smells. 

“This work both solved an important mystery about how the brain functions and informed us on novel usages of an important computational method, thus contributing to both areas,” Bar-Joseph explained.

Navlakha doesn’t have a typical laboratory filled with beakers, pipettes or plants growing under various conditions. He relies on wet labs to provide data that he then interprets and analyzes as a part of the Simons Center for Quantitative Biology. While his training is in computer science, he has shown a talent for experimental research as well. 

Bar-Joseph recalled how Navlakha performed experiments and analysis. In a short time, Navlakha “was able to master very involved techniques and obtained very good results.” 

Navlakha explained that the work he does colors the way he sees the world. “People walk by plants without paying attention to the incredible computations that they’re doing to keep us on this planet,” he said. “Computation is the basis of life.”

A resident of Great Neck, Navlakha recently married Sejal Morjaria, an infectious disease physician at Sloan Kettering, who works with patients who have cancer. The couple met through an online dating app when he was in San Diego and she lived in New York. They chatted for a while without any expectation of seeing each other, until he traveled to Washington, D.C                                 for a conference.

Navlakha enjoys playing numerous sports, including tennis and basketball. He also played hockey. He and Morjaria participate in yoga classes together.

Navlakha, who grew up in Miami, Florida, said he had to readjust to life on Long Island after living in Southern California for several years. “San Diego makes you weak,” he joked.

In his work, Navlakha hopes to bring together two fields in a different way.

Given the importance of computations, Navlakha appreciates a corollary to the concept proposed by Rene Descartes’ “I think, therefore I am.” For Navlakha, “I compute, therefore I am” describes processes he studies among animals and plants.

Donghui Zhu

By Daniel Dunaief

About 5 percent of people who suffer from Alzheimer’s disease have a genetic mutation that likely contributed to a condition that causes cognitive declines.

That means the vast majority of people with Alzheimer’s have other risk factors.

Donghui Zhu, an associate professor of biomedical engineering in the Institute for Engineering-Driven Medicine who joined Stony Brook University this summer, believes that age-related decline in the presence of the element magnesium in the brain may exacerbate or contribute to Alzheimer’s.

Donghui Zhu

The National Institutes of Health believes the former associate professor at the University of North Texas may be on the right track, awarding Zhu $3.5 million in funding. Zhu believes magnesium helps prevent the loss of neurons, in part because of the connection between this element, inflammation and the development of Alzheimer’s.

Numerous other factors may also contribute to the development of Alzheimer’s. Diabetes, lifestyle, a specific sleep cycle and low exercise levels may all play a role in leading to cognitive declines associated with Alzheimer’s, Zhu said.

According to some prior research, people with Alzheimer’s have a lower level of free magnesium in their body and in their serum levels than people who don’t suffer from this disease, he added.

In the short term, he aspires to try to link the magnesium deficiency to neuronal inflammation and Alzheimer’s disease.

Zhu plans to use some of the funds from the grant, which will run for the next five years, on animal models of Alzheimer’s. If his study shows that a lower level of magnesium contributes to inflammation and the condition, he would like to add magnesium back to their systems. Magnesium acts as an antioxidant and an anti-inflammatory agent.

“If we supply a sufficient amount of magnesium, can we slow down or reverse the process of this disease?” Zhu asked. “We hope it would.”

Any potential cognitive improvement in animal models might offer a promising alternative to current treatments, which often only have limited to moderate effects on patient symptoms.

In the longer term, Zhu would like to contribute to an understanding of why Alzheimer’s disease develops in the first place. Knowing that would lead to other alternative treatments as well.

“I don’t think my group or we alone can solve this puzzle,” he said. “We are all trying to chip in so the scientific community can have an answer or solution for the public.”

Like people with many other diseases or disorders, any two people with an Alzheimer’s diagnosis don’t necessarily have the same causes or type of the progressive disorder.

Women represent two-thirds of the Alzheimer’s population. Zhu said this isn’t linked to the longer life span for women, but may be more of a by-product of the change in female hormones over time.

In his research, he plans to study female and male animal models separately, as he looks to understand how the causes and progression of the disease may differ by gender.

In the human population, scientists have linked drug addiction or alcoholism with a higher risk of developing Alzheimer’s. He plans to perform additional studies of this connection as well.

“It’s the consensus in the community that alcohol addiction will increase the risk of developing Alzheimer’s disease,” Zhu said. People who consume considerable alcohol have reduced blood flow to the brain that can endanger or threaten the survival of blood vessels.

“This is another topic of interest to us,” he added.

Zhu is collaborating with other experts in drug addiction studies to explore the link with Alzheimer’s. 

In his research, he hopes to link his background in biology and engineering to tackle a range of translational problems. 

Stefan Judex, a professor and interim chair in the Department of Biomedical Engineering at Stony Brook, is excited about the potential for Zhu’s work.

Zhu is “a fast rising star in the field of biomaterials and fills a gap in our department and the university,” Judex explained in an email. “He is well-equipped to apply his unique research skills to a number of diseases, ultimately aiding in preventing and treating those conditions.”

In addition to his work on Alzheimer’s, Zhu also pursues studies in several other areas, including nano-biomaterials, biodegradable or bio-resorbable materials, regenerative medicine for cardiovascular and orthopedic applications, and drug delivery device and platforms

During his doctoral studies and training at the University of Missouri in Columbia, he focused on dementia and neuron science, while his postdoctoral research at the University of Rochester involved engineering, where he did considerable work on tissue engineering and biomaterials.

Zhu decided he had the right training and experience to do both, which is how he picked up on tissue engineering, regenerative medicine and neuroscience.

“They are not totally exclusive to each other,” he said. “There are many common theories or technologies, methods and models we can share.”

Adults don’t generate or create new neurons. He hopes in the future that an engineering approach may help to reconnect neurons that may have lost their interaction with their neighbors, in part through small magnesium wires that can “help guide their reconnection,” which is, he said, a typical example of how to use biomaterials to promote neuro-regeneration.

In his lab, he works on the intersection between engineering and medicine. The interdisciplinary and translational nature of the research attracted him to the new Institute for Engineering-Driven Medicine at Stony Brook.

He described Stony Brook as the “total package for me” because it has a medical school and hospital, as well as an engineering department and entrepreneurial support.

He has already filed numerous patents and would like to form start-up companies to apply his research.

Judex wrote that he is “incredibly pleased and proud that Dr. Zhu joined” Stony Brook and that it is “incredible that he received this large grant within the first few months since his start.”

In his career, Zhu would like to contribute to new treatments.

“Some day,” he said, he hopes to “put a real product on the market.”

 

Nicholas Gladman with a harvest of sorghum at Cornell University’s Long Island Horticultural Research Lab in Riverhead. Photo by Sendi Mejia

By Daniel Dunaief

When people buy a bag of potato chips, they often find that half of the bag is filled with air. The same is true of a sorghum plant, which produces livestock feed and is converted into ethanol, part of many gases that power cars.

Nicholas Gladman

In a typical sorghum plant, half of the flowers become grain, while the other half remain infertile. As the world grapples with food shortages and scientists seek ways to increase the yield of a wide array of plants, researchers at Cold Spring Harbor Laboratory wondered whether they could increase that yield.

Building on previous work done in the lab of Doreen Ware, an adjunct professor at CSHL, postdoctoral fellow Nicholas Gladman characterized a mutation for a single gene that lowered the level of a hormone. The effect of the lower hormone, or jasmonic acid, at a specific time and place within plant development doubled the fertility of the sorghum plant.

“When we don’t have a functional version of this enzyme, it releases this form of development that wouldn’t normally occur,” Gladman said. “You get increased fertility in flowers.”

The gene they studied is called MSD2. The researchers published their work in International Journal of Molecular Sciences. Another gene, MSD1, which Ware’s lab characterized in 2018, is a likely regulator for MSD2. Other genes may also serve as regulators of MSD2, Gladman said. Disruptions in either gene leads to altered flower development and seed production.

Gladman’s postdoctoral research adviser Zhanguo Xin collaborated on the work. Xin, who is a research molecular biologist at the United States Department of Agriculture’s Agricultural Research Service, explained that Gladman characterized the mutants, identified the interaction between MSD1 and MSD2 and identified the regulatory sequences of MSD1.

This research could extend to other cereal crops, which have the same conserved sets of genes that affect their growth and fertility.

A concern in altering any gene resides in the overall effect on the health of the plant. Creating a super plant that falls over and dies in a slight wind, can’t fend off common infections, or requires a perfect blend of soil would likely offset the benefit of the increased fertility. Plant geneticists would like to ensure any mutation doesn’t make the plant less viable in the long run.

“Sometimes there can be a trade off between an agriculturally beneficial genetic change by introducing other detrimental effects,” Gladman explained in an email. “Optimally, plant geneticists will try to ensure the side effects of any mutation are insignificant to farmers; sometimes, this is more difficult and the downsides may not always present themselves at the early stages of lab investigation.”

This particular gene is narrowly and spatially expressed within the plant, Gladman said, and the researchers haven’t been able to identify or quantify the effect of this gene on anything else other than flowers and floral architecture.

The gene and the hormone would be a concern if it were expressed more broadly and at high levels throughout other plant tissues, but that doesn’t seem to be the case, he said.

The researchers have looked at other tissues, such as the leaf and stem, and have found that MSD2 is expressed in low levels in these other areas. Plants that have the MSD2 mutation do not demonstrate any noticeable differences in growth compared to nonmutants in the field or in greenhouse conditions. If this mutated gene had an agricultural benefit, farmers would likely crossbreed a plant that had this gene with an elite sorghum hybrid line

Ideally, the benefits of the increased fertility would combine with benefits of all the genetic components of the hybrid lines as well. The way the researchers involved in this study produced this more fertile version of sorghum is an “acceptable type of breeding for organic or conventional farming,” Gladman said.

While the plant increases the grain number per seed head, it doesn’t necessarily produce greater overall yield in part because the seeds are smaller. Researchers haven’t been able to confirm that yet in a field condition, although they hope that’s the case.

Gladman was grateful for the opportunity to work in Ware’s lab and to collaborate with Xin. The effects of disrupting similar genes in maize and Arabidopsis, which is a plant in the mustard family that scientists often use in genetic studies, influences flower fertility.

He said researchers in Ware’s lab can perform additional developmental analysis. The researchers in Ware’s lab may seek additional collaborators for other analyses down the road as well.

“How this particular pathway is triggered and cross-communicates with other developmental pathways is very complex, but influences so much about traits that control grain production and yield that it is essential for further investigations,” he explained.

Gladman arrived at Cold Spring Harbor Laboratory in 2017. Prior to conducting research on Long Island, he finished his doctorate at the University of Wisconsin at Madison, where he worked on Arabidopsis. He decided he wanted to get more involved with crop species and explored research opportunities at United States Department of Agriculture labs. He was working with Xin in Lubbock, Texas, before transitioning to Cold Spring Harbor Laboratory.

Gladman has been delighted by the “wonderful place to learn,” where he is surrounded by “people who are always willing to talk and engage and collaborate.”

A resident of Greenlawn, Gladman enjoys hiking along the Hudson and in the Adirondacks. He credits a high school biology class he took in Grandview Heights High School in Columbus, Ohio, with instilling in him and his three brothers an appreciation and love of science. He particularly enjoyed a unit on the “genetics of disease” that inspired him to pursue a career in the sciences.

As for his work, Gladman is excited to be a part of research that may, one day, increase the productivity of crop species. He said thoughts about food shortages are “a constant concern and driver of our research.”

 

Interns Nylette Lopez (rear) and Stephanie Taboada characterize catalysts as they attempt to convert carbon dioxide and methane into synthesis gas this past summer at Brookhaven National Laboratory. Photo from BNL.

By Daniel Dunaief

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

Local medical and research institutions are aware of the challenges women face in science and are taking steps to ensure that women receive equal opportunities for success in science, technology, engineering and mathematics (or STEM). Times Beacon Record News Media reached out to members of each institution and received an overview of some initiatives.

Brookhaven National Laboratory 

The Department of Energy-funded research facility has created a number of opportunities for women, including Brookhaven Women in Science. This effort has been active for over four decades and its mission, according to Peter Genzer, a BNL spokesman, is to support the development of models, policies and practices that enhance the quality of life for BNL employees and emphasize the recruitment, hiring, promotion and retention of women.

BWIS offers annual awards, outreach events and various networking opportunities in the lab and community, while the lab’s Talent Management Group partners with BWIS to bring classes and speakers to discuss issues specific to women.

In October, the group hosted Kimberly Jackson, a vice chair and associate professor of chemistry and biochemistry at Spelman College, who gave a talk titled “Realigning the Crooked Room in STEM.”

The Leona Woods Distinguished Postdoctoral Lectureship Award at BNL, meanwhile, celebrates the scientific accomplishments of female physicists, physicists from under-represented minority groups and LGBTQ physicists and to promote diversity and inclusion. BNL awarded the lectureship this year to Kirsty Duffy, a fellow at Fermi National Accelerator Laboratory.

For the past five years, BNL has also partnered with a local chapter of Girls Inc., which helps to “encourage young women towards careers” in STEM, Genzer explained in an email.

BNL has also collaborated with the Girl Scouts of Suffolk County to organize a new patch program that encourages Girl Scouts to work in scientific fields. As of September, county Girl Scouts can earn three new Brookhaven Lab patches, and the lab hopes to extend the program nationwide across the Department of Energy complex.

BNL also provides six weeks of paid time off at 100 percent of base pay for a primary caregiver after birth or adoption and one week of full pay for a secondary caregiver. BNL is exploring plans to enhance support for primary and secondary caregivers, Genzer said.

Cold Spring Harbor Laboratory

Cold Spring Harbor Laboratory has taken several recent steps as part of an ongoing effort to encourage gender diversity.

In October, a group of four CSHL administrators traveled to the University of Wisconsin in Madison to discuss mentoring. The goal was to train them on how to design and deliver mentoring training regularly to the faculty, postdocs and graduate students on campus, said Charla Lambert, the diversity, equity and inclusion officer for research at CSHL. The first version of the training will occur next spring. The ultimate goal is to ensure the research environment at CSHL emphasizes good mentoring practices and is more inclusive for all mentees.

CSHL has also hosted a three-day workshop in leadership practices for postdoctoral researchers and junior faculty since 2011. The workshop, which is run through the Meetings & Courses Program, trains about 25 postdoctoral researchers and junior faculty each year and has about one per year from CSHL, addresses how to hire and motivate people, while providing constructive feedback.

Lambert said family-friendly policies were already a part of CSHL policies, which include a child care facility. Members of the faculty receive extra funding when they travel to conferences to provide additional child care.

Lambert, who is a program manager for extramural Meetings & Courses overseeing diversity initiatives, has worked to get the demographic data for participants centralized, analyzed and used in developing policies. She believes this kind of data centralization is an area for potential improvement in the research division, where she is working to ensure an equitable distribution of resources among CSHL scientists.

Throughout her nine-year career at CSHL, Lambert said she has worked with the meetings and courses division to make sure the 9,000 scientists who visit the facility each year include women as invited speakers. She also works to reach course applicants from a wide range of institutions, including outside of prestigious research schools.

Ultimately, Lambert is hoping to help change the culture of science among the researchers with whom she interacts from a wide range of institutions. She feels that those people who leave the STEM fields because something about the culture of science didn’t work for them represent a “huge loss” to the field and creates a “survivorship bias.”

Stony Brook University 

For Stony Brook, gender diversity is “very important,” said Latha Chandran, the vice dean for Academic and Faculty Affairs at the Stony Brook University Renaissance School of Medicine. 

Chandran said more men entered the field of medicine 14 years ago. That has completely changed, as women have outnumbered their male counterparts in medicine for the last three or four years.

Chandran cited a number of statistics to indicate changes at the medical school. For starters, women faculty constituted 38 percent of the total in 2011. This April, that number climbed to 48.1 percent. That puts Stony Brook in the top 79th percentile of medical schools in terms of female representation.

While the overall numbers are higher, women are still underrepresented in the top tiers of the medical school, as 18 percent of the department chairs are women. She hopes more women can lead departments and that they can serve as role models that others can aspire to follow.

As for harassment, Chandran said Stony Brook was above the national mean in 2011. For almost all categories, Stony Brook is now below the national mean.

In 2011, Stony Brook created We Smile, which stands for We can Eradicate Student Mistreatment in the Learning Environment. The goal of this program is to educate people about harassment and to ensure that any mistreatment is reported. Through this effort, Stony Brook medical students are aware of the policies and procedures surrounding reporting.

Stony Brook is also addressing any bias in admission procedures by prospective applicants, who receive a standardized scenario to address with an admissions officer. In 2025, admissions officers will not have any information about the qualifications of the individual and will evaluate his or her response during interviews only based on response to scenarios.

Stony Brook University has almost finalized its search for a chief diversity candidate. Chandran expects that the medical school will “continue to make progress.”

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.

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.

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.”

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.

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.