Babak Andi holds a 3-D model of the coronavirus responsible for the COVID-19 pandemic. Photo courtesy of BNL
By Daniel Dunaief
For close to two and a half years, the world has had a microbial enemy. The SARS-CoV2 virus, which causes Covid-19, has resulted in close to 6.5 million deaths, caused lockdowns, restricted travel, closed businesses, and sickened millions. The key to fighting such a dangerous enemy lies in learning more about it and defeating its battle plan.
Working with principal investigator Daniel Keedy, Assistant Professor at the City University of New York and Diamond Light Source in the United Kingdom, Babak Andi, who is a beamline scientist from the structural biology group at Brookhaven National Laboratory, spent over two years studying a key viral enzyme.
Recently, the researchers revealed the structure at five temperatures of an enzyme called Mpro, for main protease. This enzyme, which separates proteins the virus makes, is critical for the maturation of the SARS-CoV-2 virus particles. They published their work in the Journal of the International Union of Crystallography (IUCrJ).
Using the Frontier Macromolecular Crystallography (FMX) beamline at the National Synchrotron Light Source II at BNL, Andi collected data on the structure of the enzyme at temperatures ranging from 100 degrees Kelvin, which is about negative 280 degrees Fahrenheit, all the way up to 310 degrees Kelvin, which is normal body temperature. “Nobody had done that, specifically for this protein,” said Andi.
Keedy, who guided the data collection, processed the information and wrote most of the paper, described the effort as a “great collaboration.” The gradual change in the conformation of the enzyme helped the scientists learn how it may move or shape-shift in general, he explained.
Keedy had worked with BNL in the past and pursued research at the FMX beamline because the scientists at BNL had “been working with Mpro on site, and were very approachable and open to the idea.”
Finding the specific structure of important proteins like Mpro can help researchers, pharmaceutical companies and doctors search for inhibitors or small molecules that could be specific to these proteins and that might interfere with their function.
Andi and other scientists at this beamline worked through the pandemic shutdown because of the potential practical application of what they were doing.
“We almost had all the infrastructures in place to allow other scientists to connect and operate the beamlines remotely, enabling them to collect data on Covid-19 virus proteins,” said Andi. “In my opinion, being able to support all the academic and industrial scientists to collect data for Covid-19 research was our greatest achievement during the worst period of the pandemic.”
While coming into the lab in those early months raised concerns about their own health, Andi and his colleagues, who developed safety protocols, felt an urgency to conduct this research.
“When Covid hit, we had a sense that this is our duty, this is our job to contribute to this field, to make sure that every scientist who works on Covid-19 had easy access to our beamlines, facilities and all the tools [necessary] to make new drugs,” said Andi.
How they solved the structure
The technology for the beamline enables Andi and other scientists to collect data quickly and even remotely. Speed helps because the longer x-rays hit a protein, the more likely they are to cause the kind of damage that makes determining the structure difficult, particularly at higher temperatures.
The first step in this research was in producing this protein, which Andi’s collaborators at BNL in the biology department provided. The biology department also helped with crystallization.
Andi prepared the beamline and aligned the x-ray beam, which are necessary to collect data.
The scientists rotated and moved the crystal through the x-ray, distributing the beam over the length of the crystal to minimize radiation damage.
The small size of the x-ray beam made it possible to keep the beam focused on the smallest dimension of the structure. The researchers studied the crystal at five different temperatures, starting at cryogenic all the way up to physiological.
Of the 195,000 structures listed in the Protein Data Bank, or PDB, only five had been determined at body temperature. That includes two from the group of collaborators who participated in this study.
Andi collected three or four data sets at each temperature.
“The different conformations we saw may inspire a new twist on antiviral drug development that targets a different place in the protein, but with a similar or better effect,” Keedy explained.
The researchers did not include other factors that might affect the conformation of the protein, such as pH, pressure, the number of ions or salts in the environment, among others. For the Mpro protease to work, it has to bond to another similar protein, forming a dimer.
Andi said the Pfizer treatment Paxlovid binds to the active site of this enzyme, inactivating it.
The drugs he is looking for are similar, although he is also searching for other places on the enzyme besides its active site.
Keedy hopes to try to make a monomeric form of the enzyme through a mutation. He could then find drug-like small molecules that target the exposed interface between the two copies.
BNL origins
After he completed his PhD and post doctoral work at the University of Oklahoma, Andi started his career at BNL 11 years ago as a post doctoral researcher.
During his childhood, Andi was initially interested in astronomy. When he enrolled at a university outside the United States, he took an entrance exam.
“Based on your score, it tells you which discipline of science you can go into,” he said. His score directed him to the field of cell and molecular biology.
“I’m happy this happened,” he said. “I find that I’m actually more interested in molecular biology than in astronomy.”
Outside of work, Andi enjoys do-it-yourself projects. Astronomy also continues to appeal to him, as he is fascinated with astrophotography and reads astronomy articles.
As for the work with a Covid enzyme, Andi hopes he has other opportunities to contribute.
“I am interested [in continuing] the research in this field,” he explained. “That depends on time, resources and current or future priorities.”
Aleida Perez during BNL's virtual teaching sessions this summer
By Daniel Dunaief
For well over two years, herd immunity, vaccination status, social distancing, masking and airborne particles became regular topics of conversation.
People have a range of understanding of these terms and how to apply them to understanding the fluid conditions that are an evolving part of the pandemic.
Aleida Perez
This summer, with funding from the National Science Foundation, a group of scientists and doctors from Brookhaven National Laboratory, Stony Brook University, New York University and MoMath, the National Museum of Mathematics, worked together with middle school and high school teachers around Long Island to prepare lesson plans on how to use and understand the application of statistics to the pandemic.
“It was a wildly successful summer,” said Dr. Sharon Nachman, Chief of the Division of Pediatric Infectious Diseases at Stony Brook Children’s Hospital. “We spent hours and hours of time” working with teachers who developed lessons that addressed a host of issues related to COVID-19.
It was “an amazing experience” and the teachers “were the best part,” said Dr. Nachman.
Allen Mincer, Professor of Physics at New York University, has been working on and off with BNL for over two decades on various educational programs. He has been more actively engaged in the last four years.
As he and his collaborators were discussing possible educational outreach topics, they focused on the disruptive disease that changed the world over the last few years.
“This year, we were talking about it and, instead of doing random applications of statistics, we figured, why not do something that’s very practical in everyone’s mind,” Mincer said.
The projects and discussions, which were all conducted virtually, centered on numerous misconceptions people have about the pandemic. Teachers focused on questions including: what is the “efficiency” of a vaccine and how is it determined, what does a positive virus test result mean, if I am vaccinated, why do I care if others are, why take a vaccine when there are side effects, and I have to go to school and mix with people, so why shouldn’t I also let down my guard in other ways, among others.
“The challenges that this virus brings concerning topics like herd immunity was very interesting,” said Scott Bronson, manager of outreach to K-12 teachers and student for BNL’s Office of Educational Programs.
Scott Bronson during the BNL virtual teaching sessions this summer.
For teachers and their students, the realities of the pandemic were the backdrop against which these teachers were seeking to provide guidance. “It was happening live,” said Bronson. “What is herd immunity? That’s where the work of [Dr. Nachman and Mincer] came together beautifully.”
Bronson added that students will have a chance to explore the kinds of questions pharmaceutical companies are addressing, such as “What would you want the next vaccine to do” and “What would you do to make the vaccine better at preventing infection.”
The organizers put together teams of three to four high school and middle school teachers who created statistics lessons plans for the group.
“The way we worked it out, we put teachers in groups,” said Aleida Perez, supervisor of student research and citizen science programs for Brookhaven National Laboratory’s Office of Educational Programs. “We wanted to have different teachers with different courses and different perspectives on how to do things.”
One of the overarching goals was to help students understand such lessons as what it means to have a negative result on a virus test or what it meant when scientists and pharmaceutical companies described a vaccine’s efficacy.
The teachers explored the probability of side effects like myocarditis and whether the “benefit outweighs the risk of taking the vaccine,” Perez said.
For many of the teachers, the discussion expanded beyond COVID to an analysis of any infectious agent. Indeed, one of the groups of teachers described a zombie apocalypse.
The teachers provided a “nice overview to look at the education of public students,” said Perez.
The group hopes to make these lessons available for other teachers, although they haven’t determined where or how to post them.
The scientific team also hasn’t determined yet how to measure the long term impact or effectiveness of these lessons.
ATLAS project
As a part of the team involved in the ATLAS physics program at the Large Hadron Collider in Geneva, Switzerland, Mincer uses statistics to design, test and implement the tools to pick and choose from numerous reactions and then to study the data collected.
“We actually keep about a billion events out of the 100 trillion or so interactions the LHC produces in a year,” Mincer explained.
In previous years, Mincer has taught about statistics in general and its use in ATLAS. This year, he focused on statistics and its application to pandemic questions.
Several years ago, Mincer taught a freshman seminar called “Great science, fabulous science and voodoo science,” in which he described what students could learn from statistics, how the media covers science, science and government policy and how lawyers use science in the courtroom.
“After explaining statistics [and sharing] why we can only say we have evidence down to this level, I had a student tell me he’s dropping out of science as a major because he wanted certainty and I disillusioned him,” Mincer said.
As for the work with the high school teachers, Mincer said it was “great what they have been able to do” in preparing lessons for their students and sharing information about statistics.
Mincer has received some additional funds from the NSF to support two more such educational outreach programs, one of which will tentatively cover climate change.
“Statistics can be used to quantify the likelihood of events in the absence of climate change,” he explained.
Statistics provide a tool to document subtle but potentially significant changes in climate.
While Bronson wouldn’t commit to a discussion of climate change for the next group of teachers, he said he “wouldn’t be surprised if we look at climate change” and that “there’s a lot of interesting areas to explore in this field.”
Arjun Venkatesan is testing an enhanced coagulation approach to treat contaminated water.
Photo by John Griffin/Stony Brook University
By Daniel Dunaief
One person’s toilet flush is another’s pool of information.
Arjun Venkatesan, Associate Director for the New York State Center for Clean Water Technology at Stony Brook University, has gathered information from wastewater plants to search for traces of opioids and other chemicals.
Such monitoring is a “great tool” and relies on the sensitivity of the method, Venkatesan said.
Indeed, other scientists, including Professor Christopher Gobler, Endowed Chair of Coastal Ecology and Conservation at the School of Marine and Atmospheric Sciences at Stony Brook, have used wastewater monitoring to collect information about the prevalence of Covid-19 in a community.
Gobler explained that such monitoring has proven to be an “ideal way to track community infections. Through early to mid 2022, positive test rates and wastewater virus levels tracked perfectly. Since then, people began home testing and now, wastewater epidemiology is probably our best sign of community infection rates.”
In a joint effort through the Center for Cleanwater Technology, Venkatesan’s team monitors for chemicals, including opioids and other drugs. Such tracking, which college campuses and local governments have done, does not involve gathering information from any specific home. Instead, the scientists take anonymous samples from a larger dorm or a neighborhood, hoping to track changes in the presence of chemicals or a virus to enable health care mitigation efforts.
Venkatesan has been looking at common over-the-counter drugs and anti-viral treatments that residents used to treat Covid-19 infection, particularly before the development and distribution of several vaccines. He noticed an increase in over the counter use that matched the increase of Covid cases, which suggested that the infected people took these pain medicines for their symptoms first.
Venkatesan’s group monitored the use of these drugs over the last two years to confirm the trends. This baseline allowed him to “see increasing trends” in usage, he said. The increase “clearly indicates something more than what the drugs are regularly used for.”
Opioids
Venkatesan’s group has been working with the Department of Health to develop standard protocols to measure drugs at these sewage treatment plants. The testing needs to be updated to account for changes in consumption of new drugs that are being synthesized.
Each sample Venkatesan and his colleagues collect typically has hundreds of thousands of people in it, because the treatment plants process sewage for a large collection of communities. “This keeps anonymity,” he said. “We don’t want to dig up [information] from a single family home.”
The method is also cost effective when a single sample represents a larger population. This kind of information, however, could help public health professionals monitor the presence of drugs broadly in a community, providing them with a way to track the prevalence of addictive and potentially harmful drugs.
Venkatesan is developing methods to track fentanyl, a highly addictive drug linked to numerous deaths throughout the country and the world. Studies in other regions have demonstrated elevated levels of this drug.
Venkatesan said New York State responded to the pandemic by developing surveillance over the last few years. The approach was not well known and was limited mostly to illicit drugs. The pandemic made a significant impact, which helped officials appreciate the value of such a tool.
The state could also theoretically monitor for any chemicals that are stable enough in sewage.
While Venkatesan hasn’t measured traces of alcohol at sewage treatment plants, researchers and public health officials could create a screen to measure it. He was involved in a study that monitored for alcohol and nicotine consumption in many cities. “We could get interesting trends and understand community and population health in a better way,” he said. The pandemic has “helped establish the importance of this network.”
Surveys in which people call and ask about the consumption of drugs or alcohol can contain self-reporting error, as respondents may not know exactly how much they drink or may be reluctant to share those details.
Wastewater monitoring could capture trends, including whether communities have a spike in the use of drugs or alcohol on Friday nights or on weekends.
The Centers for Disease Control and Prevention created standardized methods for monitoring Covid-19 in the wastewater of cities and states.
Wastewater monitoring techniques are different for detecting viruses compared to chemicals. Venkatesan’s group is developing different method to screen for opioids. “We are excited about it,” he said. “Hopefully, next year, we should be able to monitor communities.”
As long as the sampling doesn’t cross any predetermined ethical line, monitoring could provide an effective way of looking at the trends and data, he said.
With so much water flowing through pipes and treatment plants, one of the biggest challenges in these efforts is to understand variables that affect what the scientists are monitoring.
The time between when a toilet is flushed in an apartment to the time when it reaches a plant can vary, depending on numerous variables, which creates uncertainty in the data.
To reduce this variability, scientists could do some sampling in manholes, between treatment plants.
Scientific roots
Venkatesan took an elective at the end of college in environmental science when he attended Anna University in Chennai, India. It was the first time he observed a wastewater treatment plant.
Fascinated by the process, he earned a Master’s in Environmental Engineering at the University of Nevada, Las Vegas and then went on to get a PhD at Arizona State. He also did his post doctoral research in Arizona.
Stony Brook was looking for a scientist to screen for contaminants in drinking water, including PFAS chemicals, which is a group of chemicals that are stable, hard to break down and are linked to thyroid cancer, among others.
PFAS chemicals are used in cleaners, textiles, fire-fighting foam and other applications.
Venkatesan leads drinking water efforts, while waste water epidemiology remains an ongoing project of interest.
Gobler hired Venkatesan five years ago to help run and then to exclusively run the drinking water initiative at Stony Brook.
Through the process, Venkatesan has “brought new insights and research programs related to wastewater epidemiology, bisolids and many other topics,” Gobler explained. Venkatesan has “exceeded expectations,” as he transitioned from a postdoctoral researcher to become Associate Director for Drinking Water Initiatives.”
Gobler called his colleague a “complete professional” who is “very positive and a good person to work with.”
In his research, Venkatesan develops technologies to remove these PFAS chemicals, while monitoring is also a part of that effort. Activated carbon filters can remove these chemicals from groundwater. These filters, however, require frequent replacement. Venkatesan is exploring ways to improve the life of the carbon filter.
PFAS chemicals make rain water unsafe to drink. Removing PFAS chemicals is an “important research topic locally and globally.”
Victoria Bautch on right with graduate student Danielle Buglak. Photo from UNC McAllister Heart Institute
By Daniel Dunaief
This is part two of a two-part series featuring Cold Spring Harbor Laboratory alums Joanna Wysocka, Robert Tjian, Victoria Bautch, Rasika Harshey and Eileen White.
Often working seven days a week as they build their careers, scientists plan, conduct and interpret experiments that don’t always work or provide clear cut results.
Driven by their passion for discovery, they tap into a reservoir of ambition and persistence, eager for that moment when they might find something no one else has discovered, adding information that may lead to a new technology, that could possibly save lives, or that leads to a basic understanding of how or why something works.
Nestled between the shoreline of an inner harbor along the Long Island Sound and deciduous trees that celebrate the passage of seasons with technicolor fall foliage, Cold Spring Harbor Laboratory has been a career-defining training ground for future award-winning scientists.
Last week two alumni of Cold Spring Harbor Laboratory, Joanna Wysocka and Robert Tjian, shared their thoughts, experiences, and reflections on the private lab that was founded in 1890. This week the article continues with reflections from alumni Rasika Harshey, Victoria Bautch and Eileen White.
Confidence builder
Lunch time presented no break from science for Rasika Harshey, and that was just as she’d hoped.
Rasika Harshey
When she was at Blackford Hall between 1979 and 1983, first as a postdoctoral researcher and then as a staff investigator in the lab of Ahmad Bukhari, Harshey said conversations frequently included discussions about research. “It was wonderful,” she said. “It was just science, 24/7.”
Bukhari was studying a virus that infects bacteria, called mu, for mutator. The viral particle genome was jumping into the host genome. “At that point, transposable elements” of DNA were “entering into our consciousness,” Harshey explained.
In her research, Harshey would induce the virus and, 30 minutes later, get 100 phage particles. Looking in the cytoplasm, however, she didn’t find any of this viral DNA until phage progeny appeared about 50 minutes later. “How is that possible?” she asked. “I wanted to solve this mystery.”
Harshey spent countless hours in the electron microscope room, isolating DNA. She knew mu was replicating, or copying itself, but she couldn’t figure out how or what it was doing. She and Bukhari proposed a model about transposable elements at a meeting called “Movable Genetic Elements” in 1979 at CSHL that generated considerable discussion.
“It was thrilling at the time for me to develop as a scientist,” Harshey said. “It seemed to me that I was saying something and people were listening. I gained a lot of confidence in myself.” The work she did turned out to be only partially correct, but it gave her the sense that she could solve problems.
With CSHL as a backdrop, Harshey enjoyed the opportunity to attend meetings and to interact with other visitors and other scientists on campus. “It was a total immersion” she said. “Summers were magical, with so many meetings one could just walk into.”
Harshey visited Barbara McClintock’s lab, which was down the hall from hers. McClintock, who won the Nobel Prize in Harshey’s final year at CSHL, showed her the maize cells.
McClintock also invited her to her cottage, where she served what Harshey recalled was a “delicious” poppyseed cake.
She described McClintock as “quiet” and a “tough cookie.”
Rasika Harshey at CSHL.Courtesy of Cold Spring Harbor Laboratory Archives, NY.
Harshey thought it was inspiring to be with McClintock, Watson and Richard Roberts, who also won a Nobel Prize. She also appreciated the opportunity to visit with Guenter Albrecht-Buehler and Joseph Sambrook. “I was in and out of Richard Roberts’s lab all the time,” she said.
For her work, Harshey needed restriction enzymes, which Phyllis Myers produced. She had to “beg” Myers for these valuable enzymes that were in short supply.
Harshey felt an urgency to commit herself to her work. When she and her husband Makkuni Jayaram were expecting a baby, she didn’t share the news until it had become obvious. She worked until the last moment before the baby was born in 1982, “but I came back,” she said.
Harshey, who also calls CSHL “home,” described it as a “place time forgot. It’s quiet and beautiful and you can do and think and talk science.” Professor in Molecular Biosciences at The University of Texas at Austin in the College of Natural Sciences, Harshey is grateful for the career and the life she’s led. “A series of accidents got me here,” she said. “I can’t believe my good fortune, that I get to do what I get to do every day.”
As a part of the history of CSHL, Harshey appreciates a culture that she has carried forward in her career. The “deep joy, commitment, excitement for biology, particularly for designing experiments, and looking at a problem from all angles” was embedded into the approach scientists took to the work they did at the lab.
She also believes the tradition at CSHL includes an “appreciation for how easy it is to get things wrong and to continually challenge your own ideas.”
Intense culture
Victoria Bautch came to Cold Spring Harbor Laboratory in the 1983 knowing that she was interested in studying aspects of developmental biology. When she saw the power of the new technology, she started working on genetically modified animals.
She was trying to figure out whether viral genes previously only linked to cancer by association could cause cancer when part of the genome was put into animals. When she inserted genes into a mouse’s DNA, some of these mice developed tumors in their blood vessels. She “didn’t know this was going to happen,” she said. “The type of tumor was a complete surprise.”
Bautch needed to know more about how blood vessels formed and functioned to understand these tumors. That’s what got her excited about studying these blood vessels. These blood vessel tumors “weren’t on my radar,” she said.
While working in the lab of Doug Hanahan, Bautch had the opportunity to interact with Judah Folkman, a Professor at Harvard University. Folkman was excited about the way these blood vessels were developing and encouraged Bautch to continue to work in this field. Folkman championed the idea that new blood vessel formation contributes to the progression of many types of tumors. He was eager to bring new people and technologies into the field.
Bautch also met mouse geneticists Nancy Jenkins and Neal Copeland who were at Jackson Labs at the time and were instrumental in her career progression. She started asking basic questions about how blood vessels forms and how they function.
Folkman was looking to “bring people into the field that had more of a basic science and molecular biology background,” Bautch said. He was hoping to add researchers who would use the new tools to understand blood vessel basics and how they are involved in tumors.
The tumor Bautch worked on was an “entree into the bigger field of blood vessels and vascular biology,” she said.
Cold Spring Harbor Laboratory provided a constructive backdrop for the work Bautch did that proved important in her career. “I was looking for an intense and very high caliber scientific environment and I feel like I found it,” she said.
Indeed, Bautch often worked seven days a week, starting at 10 or 11 in the morning and ending around 1 or 2 in the morning. During the later hours, she had an easier time accessing machines and equipment that others in the lab also needed.
Like Harshey, Bautch has her own McClintock story. “She always would say, ‘Look at your organism very carefully.’ You could learn so much from observing.”
At the time, McClintock’s advice seemed “antiquated” to Bautch, especially with researchers doing molecular biology that was more of a technological breakthrough, but now appreciates the guidance. “A really important piece of being a scientist is being observant,” sheexplained.
Bautch said other scientists were prepared to offer their responses to her work. “People were always telling you what they thought, whether you wanted it or not,” she recalled.
Now a Distinguished Professor of Biology and Co-Director of the McAlister Heart Institute at UNC Chapel Hill, Bautch recalls her time at CSHL as a combination of a “very intense life experience as well as science experience.” As for her hopes for the current crop of scientists at CSHL, Dr. Bautch hopes this generation is “more inclusive.”
An alternateexplanation of cancer
Around the same time that actress Heather Locklear was telling TV audiences about Faberge Organics Shampoo about how people can tell two friends about the shampoo who then tell two friends, researchers knew that a type of gene that promoted cancer did essentially the same thing.
Eileen White. Photo courtesy of Rutgers Cancer Institute of New Jersey
Called an oncogene, these genes caused cells to continue to divide and, as the shampoo commercial suggested “and so on and so on and so on.” Back then, scientists focused on the role oncogenes played in cell proliferation, which, with cancer, involved the runaway copying of itself.
A graduate of Smithtown High School who earned her PhD at Stony Brook University, Eileen White joined Bruce Stillman’s lab as a post doctoral fellow at Cold Spring Harbor Laboratory in 1983. After three years, White became a staff investigator, making the beginning of career-defining discoveries about the development of cancer.
“We knew that certain viruses cause cancer, and we knew that these viruses encoded oncogenes,” said Dr. White. “The whole idea was to understand how.”
Indeed, viral oncogenes, which are small and less complicated than tumor genomes, presented the opportunity to find a shortcut to understand how cancers developed in humans. Even if the human oncogene is small, the genome it sits in is huge, which is not the case of a viral oncogene that sits I a very small viral genome, she explained.
Using a DNA tumor virus that promoted cancer, White discovered that this gene prevented apoptosis, or programmed cell death. After this discovery, which she said she could “see with her own eyes” when she studied the effect of the genes on cells, she asked herself what she’d need to do to push the idea forward for this paradigm shift in thinking about cancer.
As she continued to discover more details about the viral oncogene over the years, she said other researchers discovered that the Bcl-2 human oncogene may function similarly.“I thought, ‘Well, if this is a theme that viral oncogenes and potentially cancer oncogenes are blocking apoptosis, they should be functionally interchangeable,’” White recalled, which is what she showed and published.
She substituted human Bcl2 oncogene of the viral E1B 19K oncogene and showed that they both functioned to block apoptosis interchangeably.
Courtesy of Cold Spring Harbor Laboratory Archives, NY.
These discoveries, which started at Cold Spring Harbor Laboratory, among others, helped pave the way for Dr. White’s career, where she is now professor of Molecular Biology and Biochemistry and Deputy Director at the Rutgers Cancer Institute of New Jersey. She is also Associate Director of the Ludwig Princeton Branch of the Ludwig Institute for Cancer Research at Princeton University.
The discovery also led to some anti cancer treatments. Abbott developed the first FDA approved Bcl-2 inhibitor, which others followed.
These kinds of discoveries, which lead to treatments, are why she and others “work so hard, to make a difference for patients,” she said.
Dr. White describes her time at CSHL as an “enormously enriching experience” in which she was surrounded by people who were of “exceptional scientific caliber,” including some who won the Nobel Prize while she was there.
“I had a fertile environment with people that had similar ways of thinking that was very synergistic in terms of propelling the science forward,” she said.
She appreciated the numerous meetings held at CSHL at which she felt like she could learn about anything from the depth and breadth of the material presented and discussed. During these meetings, which she still attends regularly, she has recruited post doctoral researchers to her lab whom she’s met at poster sessions.
As with other alumni of CSHL, Dr. White was particularly pleased with the robust and valuable feedback she and others received. “Critical and productive insights from the scientific community is important to the process of scientific discovery from beginning to the end,” she explained.
White suggested that the layout of the campus and the proximity of so many families created a unique and tight knit community. She recalled how the lab had Santa Claus at Christmas, hay rides to the pumpkin patch and special dinners for people who lived there.
“That very much builds camaraderie and long term friendships and long term relationships,” she said.
This is part one of a two-part series featuring Cold Spring Harbor Laboratory alums Joanna Wysocka, Robert Tjian, Victoria Bautch, Rasika Harshey and Eileen White. Part two will be in the issue of Aug. 25.
Often working seven days a week as they build their careers, scientists plan, conduct and interpret experiments that don’t always work or provide clear cut results.
Driven by their passion for discovery, they tap into a reservoir of ambition and persistence, eager for that moment when they might find something no one else has discovered, adding information that may lead to a new technology, that could possibly save lives, or that leads to a basic understanding of how or why something works.
Nestled between the shoreline of an inner harbor along the Long Island Sound and deciduous trees that celebrate the passage of seasons with technicolor fall foliage, Cold Spring Harbor Laboratory has been a career-defining training ground for future award-winning scientists.
Five alumni of Cold Spring Harbor Laboratory recently shared their thoughts, experiences, and reflections on the private lab that was founded in 1890.
While they shared their enthusiasm, positive experiences and amusing anecdotes, they are not, to borrow from scientific terminology, a statistically significant sample size. They are also a self-selecting group who responded to email requests for interviews. Still, despite their excitement about an important time in their lives and their glowing description of the opportunities they had to hone their craft, they acknowledged that this shining lab on the Sound may not be paradise for everyone.
Cold Spring Harbor Laboratory is considerably smaller than some of the research universities around the country. Additionally, scientists with a thin skin — read on for more about this — may find their peers’ readiness to offer a range of feedback challenging. Still, the lab can and has been a launching pad.
A suitcase and a dream
Joanna Wysocka’s story mirrors that of other immigrants who came to the United States from their home countries. Wysocka arrived from Poland in 1998 with one suitcase that included mementos from her family, a Polish edition of her favorite book, One Hundred Years of Solitude, and a dream of developing her scientific career.
She was also chasing something else: her boyfriend Tomek Swigut, who had come to Cold Spring Harbor Laboratory. “I was fresh off the boat without any fancy resume or anything,” Wysocka recalls. “They really took a chance on me.”
Joanna Wysocka
While she learned how to conduct scientific experiments, she also recognized early on that she was a part of something bigger than herself. Early on, she found that people didn’t hold back in their thoughts on her work. “You always got critical feedback,” she said. “People felt very comfortable picking apart each other’s data.”
The positive and negative feedback were all a part of doing the best science, she explained.
Wysocka felt the inspiration and exhilaration that comes from a novel discovery several times during her five-year PhD program.
“It’s 11 p.m. in the evening, you’re in the dark room, developing a film, you get this result and you realize you’re a person who knows a little secret that nobody else in the world knows just yet,” she recalled. “That is really wonderful.”
For special occasions, the lab celebrated such moments with margaritas. Winship Herr, her advisor, made particularly strongest ones.
In one of her biggest projects, Wysocka was working with a viral host cell factor, or HCF. This factor is critical for transcription for the Herpes simplex virus. What wasn’t clear, however, was what the factor was doing. She discovered that this factor worked with proteins including chromatin modifiers. “From this moment, it set me up for a lifetime passion of working on gene regulation and chromatin,” she said.
As for the scientific process, Wysocka said Herr offered her critical lessons about science. When she started, Herr expected two things: that she’d work hard and that she’d learn from her mistakes. During the course of her work, she also realized that any work she did that depended on the result of earlier experiments required her own validation, no matter who did the work or where it was published. “You need to repeat the results in your own hands, before you move on,” she explained.
Despite the distance from the lab to New York City and the smaller size of the lab compared with large universities, Wysocka never felt isolated. “Because of all the conferences and courses, the saying goes that ‘if you want to meet somebody in science, go to a Cold Spring Harbor bar and sit and wait.’” That, however, is not something she took literally, as she put considerable hours into her research. While she wishes she had this incredible foresight about choosing Cold Spring Harbor Laboratory, she acknowledges that she was following in Swigut’s footsteps.
The choice of CSHL worked out well for her, as her research has won numerous awards, including the Vilcek Prize for Creative Promise in Biomedical Science, which recognizes immigrant scientists who have made a contribution to U.S. society. She now works as Professor at Stanford University and is married to Swigut.
Swinging for the fences
In 1976, Robert Tjian had several choices for the next step in his developing scientific career after he completed his PhD at Harvard University. James Watson, who had shared the Nobel Prize in 1962 for the double helix molecular structure of DNA with Francis Crick and Maurice Wilkins and was director at Cold Spring Harbor Laboratory, convinced him to conduct his postdoctoral research at CSHL.
Robert Tjian
The contact with Watson didn’t end with his recruitment. Tjian, who most people know as “Tij,” talked about science on almost a daily basis with Watson, which he considered an ‘incredible privilege.”
Although he only worked at CSHL for two years, Tjian suggested the experience had a profound impact on a career that has spanned six decades.
Learning about gene discovery was the main driver of his time at CSHL. An important discovery during his work at CSHL was to “purify a protein that binds to the origin of replication of a tumor virus, which was what [Watson] wanted me to do when he recruited me,” he said. That launched his career in a “positive way.”
Tjian feels fortunate that things worked out and suggested that it’s rare for postdoctoral students to achieve a transformative career experiment in such a short period of time either back then or now. He attributes that to a combination of “being in the right place at the right time,” luck and hard work.
At Berkeley, where he is Professor of Biochemistry, Biophysics and Structural Biology and has been running a lab since 1979, he has observed that the most successful researchers are the ones who are “swinging for the fences. If you don’t swing for the fences and get lucky, you sure as hell aren’t going to hit a home run.”
Tjian learned how to run a lab from his experience at CSHL. He selects for risk takers who are independent and feels the only way to motivate people is to ensure that the work they are pursuing involves questions they want to solve.
One of the most important and hardest lessons he learned during his research career was to “fail quickly and move on.” He tells his student that about 85 percent of their experiments are going to fail, so “get used to it and learn from it.”
Despite his short and effective stay at CSHL, Tjian suggested he made “more than his fair share” of mistakes. Terri Grodzicker, who is currently Dean of Academic Affairs at CSHL, taught Tjian to do cell culture, which he had never done before. He contaminated nearly all the cultures for about a month.
While Tjian described the lab as a “competitive place,” he felt like his colleagues “helped each other.”
When he wasn’t conducting his experiments or contaminating cultures, he spent time on the tennis court, playing regularly with Watson. Watson wasn’t “exactly the most coordinated athlete in the world,” although Tjian respected his “remarkably good, natural forehand.” He was also one of the few people who was able to use the lab boat, which he used to fish for striped bass and bluefish early in the morning. “I would try to drag all kinds of people out there,” he said.
While his CSHL experience was “the best thing” for him, Tjian explained that the lab might not be the ideal fit for everyone, in part because it’s considerably smaller than larger universities. At Berkeley, he has 40 to 55 PhD students in molecular biology and he can interact with 40,000 undergraduates, which is a “very different scale.”
Tjian has returned many times to CSHL and is planning to visit the lab at the end of August for a meeting he’s organizing on single molecule microscopy.
Each time he comes back, he “always felt like I was coming home,” he said.
When Jacqueline Olsen learned the day before her birthday last November that she needed surgery for lung cancer, she felt anxious about a procedure she knew could be painful and could involve a lengthy recovery.
“It’s not only my birthday, it’s Thanksgiving,” said Olsen, who is a resident of St. James and is an agent for personal insurance such as home, auto and umbrella insurance. “Everybody was real tense. It was not a pleasant holiday.”
Olsen’s father, William Leonard, and father-in-law, James Olsen, had died of lung cancer after having open chest surgeries. The pain of what her father went through 48 years ago and father-in-law over 20 years ago was fresh in her mind as she readied herself for her own procedure.
Dr. Ankit Dhamija
Speaking with doctors at Stony Brook University Hospital, Olsen heard about newer, better options.
Dr. Ankit Dhamija, Cardiothoracic Surgeon and Director of Thoracic Robotic Surgery at Stony Brook Medicine, suggested to Olsen that she was a candidate for a robot-assist surgery called the da Vinci Surgical System.
Olsen and her family gathered considerable information about the procedure.
“I did some research on it and it said it would be a faster recovery and I would be up and back to my normal self pretty soon afterward,” said Olsen. “It seemed like a less invasive surgery.”
The robotic surgery does not involve turning over the procedure to a machine, Dr. Dhamija explained.
Instead, the process involves making considerably smaller incisions and guiding the robot through the body to remove the cancerous tissue.
“The robot is a machine that is an extension of our hands,” said Dr. Dhamija, who has performed about 500 such procedures with the help of a robot, including around 70 since he arrived at Stony Brook.
The robotic system allows surgeons like Dr. Dhamija and Dr. Henry Tannous, Cardiothoracic Surgeon and Chief of the Cardiothoracic Surgery Division at Stony Brook Medicine, among others, to sit in the operating room with the patient while the robot enters through an incision. The robot provides a three dimensional view of the inside of the body, magnifying cells by ten times.
The robot assist can also improve the ability of surgeons to perform fine operations.
The system “does have a machine algorithm associated with it that actually is known to reduce tremors in surgeons that have tremors,” said Dr. Dhamija. “Someone that may not be able to do a certain portion of the operation due to their technical limitations can subsequently do it with the robot.”
Dr. Henry Tannous
In the procedure, the surgeon can see and maneuver through the body effectively, searching for the specific cells to remove.
An interventional radiologist can inject a dye which under CT guidance allows the surgeon to “see where the lesion is and to verify that you have adequate margins” or the border between cancerous and non-cancerous cells, Dr. Dhamija said. “Having the dye in there to identify [the cancer] is helpful,” he added.
By using the robot instead of creating a large incision, doctors can reduce the time patients spend in a hospital down to as little as one to three days from the four to eight days after an open chest lobectomy.
“There’s so much to be said about someone [recovering] in their own home,” said Dr. Dhamija. They “get to sleep properly, their bowel habits are more normal, and they get to reengage in their daily life functions sooner. I’m a big proponent of a patient taking charge of their own postoperative care.”
Indeed, Stony Brook doctors have become so confident and comfortable with the robot assist that it has become the main platform for thoracic oncology patients at Stony Brook Medicine, explained Dr. Tannous. Tannous estimates that 90 percent of the lobectomies will be performed robotically in 2022, up from 10 to 20 percent in 2021.
In an email, Dr. Tannous wrote that other specialties that have adopted the robotic platform include gynecology, urology, colorectal, bariatrics, and general surgery.
Stony Brook is also expanding robotic surgery to include cardiac procedures in 2023.
Dr. Tannous said robotic procedures that cut down on recovery time means less risk of hospital-acquired infections, lower extremities blood clots, and numerous other benefits.
Some day, theoretically, the robot may enable remote procedures, with surgeons operating the robot with the help of an on-site local medical team. That could be helpful for astronauts who develop a medical problem far from home where they need emergency surgery.
An important caveat with that, Dr. Dhamija said, is that the staff on site would need to be able to complete a procedure if an open chest surgery became necessary.
Olsen, who was out of the hospital less than 24 hours after she had surgery in late May, has become a fan of the technology and of the team at Stony Brook.
Olsen, who has three scars on her back and two on her side, felt pain for about a week. As she recovered, she never felt the need to fill a prescription for a stronger painkiller, choosing to treat the pain with Motrin. She plans to continue to take blood tests every three months and to get CAT scans every six months.
Olsen was thrilled with the quality of care she received and is pleased she can look forward to sharing quality summer time during the family’s annual beach trip. “It’s heaven to me,” she said, where she can “spoil my grandchildren.
As for a perspective on her surgery, she said the difference between 20 years ago and now is “unbelievable. It was such an awful experience” for her father and father in law. “This was a million times better.”
The temperatures at the poles are heating up more rapidly than those at the equator. Pixabay photo
By Daniel Dunaief
On any given day, heat waves can bring record-breaking temperatures, while winter storms can include below average cold temperatures or snow.
Edmund Chang. Photo from SBU
Weather and climate experts don’t generally make too much of a single day or even a few days amid an otherwise normal trend. But, then, enough of these exceptional days over the course of years can skew models of the climate, which refers to average temperature and atmospheric conditions for a region.
If the climate is steady, “we should see approximately the same number of hot and cold records being broken,” said Edmund Chang, Professor at the School of Marine and Atmospheric Sciences at Stony Brook University. “Over the past few decades, we have seen many more hot records being broken than cold records, indicating the climate is getting hotter.”
Recent heat
Indeed, just last week, before a heatwave hit the northeastern United States, the United Kingdom reported the hottest day on record, with the temperature at Heathrow Airport reaching above 104 degrees.
Erinna Bowman, who grew up in Stony Brook and has lived in London since 2009, said the temperature felt “like a desert,” with hot, dry heat radiating up in the urban setting. Most homes in London don’t have air conditioning, although public spaces like supermarkets and retail stores do.
“I’m accustomed to the summer getting quite hot, so I was able to cope,” said Bowman. Indeed, London is usually considerably cooler during the summer, with average temperatures around 73 degrees.
Michael Jensen. Photo from BNL
News coverage of the two extraordinarily hot days in London “was very much framed in the context of a changing climate,” Bowman said. The discussion of a hotter temperature doesn’t typically use the words “climate change,” but, instead, describes the phenomenon as “global heating.”
For climate researchers in the area, the weather this summer has also presented unusual challenges.
Brookhaven National Laboratory meteorologist Michael Jensen spent four years planning for an extensive study of convective clouds in Houston, in a study called Tracking Aerosol Convection Interactions, or Tracer.
“Our expectation is that we would be overwhelmed” with data from storms produced in the city, he said. “That’s not what we’re experiencing.”
The weather, which has been “extremely hot and extremely dry,” has been more typical of late August or early September. “This makes us wonder what August is going to look like,” he said.
Jensen, however, is optimistic that his extensive preparation and numerous pieces of equipment to gather meteorological data will enable him to collect considerable information.
Warming at the poles
Broadly speaking, heat waves have extended for longer periods of time in part because the temperatures at the poles are heating up more rapidly than those at the equator. The temperature difference between the tropics and the poles causes a background flow from west to east that pushes storms along, Chang explained.
The North Pole, however, has been warming faster than the tropics. A paper by his research group showed that the lower temperature gradient led to a weakening of the storm track.
When summer Atlantic storms pass by, they provide relief from the heat and can induce more clouds that can lead to cooler temperatures. Weakening these storms can lead to fewer clouds and less cooler air to relieve the heat, Chang added.
Rising sea levels
Malcolm Bowman. Photo from SBU
Malcolm Bowman, who is Erinna Bowman’s father and is Distinguished Service Professor at the School of Marine and Atmospheric Sciences at Stony Brook University, believes the recent ice melting in Greenland, which has been about 10 degrees above normal, could lead to a rise in sea levels of about one inch this summer. “It will slowly return to near normal as the fresh water melt spreads slowly over all the world’s oceans,” he added.
Bowman, who has studied sea level rises and is working on mitigation plans for the New York area in the event of a future major storm, is concerned about the rest of the hurricane season after the level of warming in the oceans this summer.
“Those hurricanes which follow a path over the ocean, especially following the Gulf Stream, will remain strong and may gather additional strength from the heat of the underlying water,” he explained in an email.
Bowman is the principal investigator on a project titled “Long Island South Shore Sea Gates Study.”
He is studying the potential benefit of six possible sea gates that would be located across inlets along Nassau and Suffolk County. He also suggests that south shore sand dunes would need to be built up to a height of 14 feet above normal high tide.
Meanwhile, the Army Corps of Engineers has come up with a tentatively selected plan for New York Harbor that it will release some time in the fall. Bowman anticipates the study will be controversial as the struggle between green and grey infrastructure — using natural processes to manage the water as opposed to sending it somewhere else — heats up.
As for the current heat waves, Bowman believes they are a consistent and validating extension of climate change.
Model simulations
In his lab, Chang has been looking at model simulations and is trying to understand what physical processes are involved. He is comparing these simulations with observations to determine the effectiveness of these projections.
To be sure, one of the many challenges of understanding the weather and climate is that numerous factors can influence specific conditions.
“Chaos in the atmosphere could give rise to large variations in weather” and to occasional extremes, Chang said.
Before coming to any conclusions about longer term patterns or changes in climate, Chang said he and other climate modelers examine collections of models of the atmosphere to assess how likely specific conditions may occur due to chaos even without climate change.
“We have to rule out” climate variability to understand and appreciate the mechanisms involved in any short term changes in the weather, he added.
Still, Chang said he and other researchers are certain that high levels of summer heat will be a part of future climate patterns.
“We are confident that the increase in temperature will result in more episodes of heat waves,” he said.
Stony Brook Breast Cancer Screening mobile truck. (8/24/18)
By Daniel Dunaief
Some groups of people on Long Island have a much higher incidence of a particular type of cancer than others.
On an age adjusted rate, African American men, for example, were almost twice as likely to develop prostate cancer from 2014 to 2018 as Caucasians. Out of 100,000 African American men, 216.6 had prostate cancer compared with 123.9 out of 100,000 white men, according to data from the National Cancer Institute.
Dr. Linda Mermelstein. Photo from Stony Brook Medicine
Dr. Linda Mermelstein, Associate Director of Stony Brook Cancer Center’s Office for Community Outreach and Engagement, is working with her team to address those stark differences and to empower members of the community to protect their health and make informed decisions.
“A lot of our focus is on addressing disparities” in cancer care in various communities throughout Long Island, Dr. Mermelstein said.
The Cancer Center Outreach and Engagement office has taken numerous steps to inform the public about research and care. The center has a Mobile Mammography Unit, which travels into communities to provide access to screening for breast cancer.
On June 5, at the Latina Sisters Support Inc. Spanish Fair in Brentwood, the Cancer Center’s Community Outreach and Engagement staff provided mobile mammography screening and cancer prevention and screening education.
At that event, the Suffolk County Department of Health Services provided human papillomavirus and Covid-19 vaccines and Stony Brook School of Health Professionals offered blood pressure screening.
An information chasm
Dr. Jedan Phillips. Photo from Stony Brook Medicine
Dr. Jedan Phillips, Medical Director for Stony Brook Health Outreach and Medical Education and Associate Professor of Family, Population and Preventive Medicine at the Renaissance School of Medicine, explained that Covid-19 exposed the “chasm” between what the health care profession believed and the reality of what works and what doesn’t.
During the pandemic, Stony Brook University brought a vaccination pod to Uniondale in Nassau County, which is a predominantly African American community. “Because we had no relationship there, we might have wasted over 200 doses of the vaccine” as residents were reluctant to get vaccinated, he said. “Even though [Stony Brook] offered something that would help, people chose against it. It’s not about the vaccine. It’s something deeper.”
Dr. Phillips said East Elmhurst, Queens, where he grew up, was “ravaged by Covid. I know at least 10 people in my community who were regular figures in my life that died. I saw how vulnerable of a position we were in as a group and I felt I needed to get involved.”
Dr. Phillips, who has a family medical practice in East Patchogue, together with Dr. Yuri Jadotte, Assistant Professor and Associate Program Director for the Preventive Medicine Residency in the Department of Family, Population and Preventive Medicine at Stony Brook, created three focus groups to survey the views and understanding of African American men on prostate cancer.
Many African American men don’t get screened for prostate cancer, even though such screenings could lead to earlier treatment and better outcomes.
By listening to what inspires African American men throughout Long Island to take action, Dr. Phillips hopes to tailor information to that type of delivery.
“It’s important to listen and understand,” Dr. Phillips said. Understanding what motivates people and seeking to provide the formats in which they prefer to access information can help establish a community connection and demonstrate cultural compassion.
Part of Dr. Phillips’s focus on preventive medicine comes from his experience with his father, who died from complications related to diabetes. His father, who was an inspiration for him, “didn’t live life in a preventive way,” which made managing his health more difficult, Dr. Phillips said.
With the numerous programs offered by the Office for Community Outreach and Engagement, Dr. Mermelstein said the group has four primary goals.
Dr. Jedan Phillips provides medical care.
“We want to monitor and understand what is the cancer burden in our catchment area” which includes Nassau and Suffolk County, she said. “Much of our activities are identifying the issues in terms of cancer” and understanding any barriers towards cancer care, like education, screening, diagnosis and treatment.
Secondly, she wants to provide cancer prevention services, screening, education and community navigation. Third, the group has a bi-directional engagement, with researchers getting to know the community and community advocates and the community learning about the research process.
Finally, the group seeks to catalyze the research by focusing on disparities, providing research services to the entire community based on specific needs.
One of Dr. Mermelstein’s first actions after heading up this team in 2019 was to create a community advisory council for the Stony Brook Cancer Center.
Janine Logan, Vice President of Communications and Population Health with the Long Island Health Collaborative, serves on that advisory council.“What I’m most excited about is that the committee understands the importance of knowing what your community thinks and needs,” Logan said.
Logan is pleased with the work the Stony Brook Cancer Center has done to educate residents about the lifestyle behaviors that can contribute to cancer, such as smoking, inactivity, and nutrition.
“They’ve done a lot of work in reaching out and educating communities to help them understand that these simple, modifiable behaviors can reduce their risk” of developing cancer, Logan said.
The effort at the Cancer Center to educate the public about the danger’s of the sun dovetails with some of the work she has done at the Long Island Health Collaborative.
Indeed, the Cancer Center Community Outreach and Engagement hosted a “Block the sun, not the fun” gathering on May 7 at the Smith Haven Mall in Lake Grove.
The Stony Brook Cancer Center is also working with the Suffolk County Department of Health Services Cancer Prevention and Health Promotion Coalition to provide information about sunscreen safety.
In addition to the disparity among African American men who develop prostate cancer, the outreach effort also addressed the difference among hispanic women who have a higher incidence of cervical cancer than the non-hispanic Caucasian population.
In Suffolk County, about 10.2 Hispanic and Latino women out of 100,000 Hispanic and Latino women develop cervical cancer, which is higher than the 5.9 per 100,000 for white, non-Hispanic women, according to the National Cancer Institute.
Human papillomarvirus is estimated to cause about 36,500 cases of cancer in men and women every year in the United States. The HPV vaccination, which works best before exposure to the virus, can prevent 33,700 of those cancers. Because the vaccine doesn’t prevent all cancers, women still need screening to protect themselves.
Previously employed for 22 years with the Suffolk County Department of Health Services, Dr. Mermelstein, who has a medical degree and a master’s in public health, briefly retired, before taking this job at Stony Brook.
“I wanted to do something to help address cancer after I retired, and so I contacted Stony Brook Cancer Center and began in this position about four months after I retired,” she explained.
Those interested in reaching out to the Office for Community Outreach and Engagement can call 631-444-4263 or email [email protected].
Paolo Boffetta. Photo by Jeanne Neville/Stony Brook Medicine
By Daniel Dunaief
Screening for cancer can help people take steps to head off the development of a disease that could threaten the quantity and quality of their lives.
During the start of the pandemic, people around the world stopped screening for cervical, breast and colorectal cancer, according to a recent study led by Paolo Boffetta, Associate Director for Population Sciences at Stony Brook University’sCancer Center.
The results of the study were recently published in the journal JAMA Oncology.
Compared to 2019, screenings for breast cancer dropped in the first few months after the start of the pandemic by 35.6 percent for breast cancer, 41.8 percent for colorectal cancer, and 54.1 percent for cervical cancer compared to the same period in 2019.
Paolo Boffetta. Photo by Jeanne Neville/Stony Brook Medicine
Boffetta chose these three cancers because they are the ones public health authorities recommend for the population at large. Screenings can improve patient outcomes.
“For some/ most cancer, the earlier the better for detection,” explained Stony Brook Cancer Center Director Yusuf Hannun.
Boffetta, who is also Adjunct Professor at the Icahn School of Medicine at Mount Sinai in New York City, suggested that the longer-term impact of a reduction in screenings in the early part of the pandemic won’t be clear to doctors or patients in the short term.
“It will take a little bit of time to have a full understanding of this,” said Boffetta. Depending on the specific type, cancers “that are detected by screenings would not otherwise appear for a few years.”
Boffetta suggested that the pandemic, apart from the illnesses and symptoms that threatened the health of people who were battling the virus itself, affected public health services. He believes several factors likely contributed to the decrease in screenings. Patients around the world were reluctant or restricted in their ability to leave their homes amid lockdowns.
Additionally, some cancer centers likely reduce the number of people they monitored to cut back on the density of patients in health care facilities, although Boffetta did not gather any data on the reduction in the number of screenings at health care centers.
The positive news amid this study, which surveyed cancer screening data in PubMed and other medical journals from 19 countries from January 2020 through December 2021, was that the number of patients screened returned to a more normal level within several months of the start of the pandemic.
“An important finding is that by the summer of 2020, the decrease in screenings for breast cancer and cervical cancer seem to have disappeared,” Boffetta said by phone from Italy, where he is a part-time professor at the University of Bologna. “For colorectal cancer [the decrease in screenings] lasted longer,” through the end of 2020.
Boffetta described the reduction in screenings and then a return to normal as a U-shaped curve, with an initial decline followed by a recovery. Doctors typically screen for colorectal cancers by using a colonoscopy. This technique requires several hours in the hospital. Patients may have been “more reluctant to go back to such a complex procedure, compared to the mammography or pap smear” which screen for breast and cervical cancers, respectively.
Boffetta is conducting a broad study of the cancer literature from early findings to clinical diagnosis to treatment. At this point, he has finished a paper on the frequency and types of clinical diagnoses amid the pandemic. He is collecting data for another study that will examine cancer treatment.
“We are interested in how the pandemic affected each of these stages,” he said.
Hannun suggested that Boffetta’s work expertise help address important health care questions related to the pandemic and other threats to public health, adding, “Epidemiology is essential for understanding the pandemic and many chronic diseases, especially cancer with exposure issues.
A lab update
Boffetta joined Stony Brook University in April of 2020, soon after the start of the pandemic.
Also a Professor in the Department of Family, Population and Preventive medicine at the Renaissance School of Medicine at Stony Brook University, Boffetta will return to the United States in a few weeks from Italy.
Boffetta has added Research Coordinator Germana Giupponi and postdoctoral fellow Malak Khalifeh to his research efforts at Stony Brook.
Germana Giupponi
A native of Italy, Giupponi, who started working with Boffetta in July of 2020 and provides administrative support and coordination with Boffetta’s collaborators, earned her master’s degree from the University of Milan.
Khalifeh joined Boffetta’s lab in March, is originally from Lebanon and conducted her PhD research in France at the University of Bordeaux. She is studying the link between the exposure people have to various chemicals in drinking water and bladder cancer. The bladder is especially susceptible to toxins from the environment.
Boffetta, meanwhile, has started teaching some graduate level classes at Stony Brook on cancer epidemiology for master’s and PhD students. He will teach one class this fall.
He is also continuing his studies with survivors of the World Trade Center attacks.
He has been comparing the survival of these first responders to the overall population in New York, comparing how the risk of cancer changed over the course of the 21 years since the attacks.
Boffetta has been working with Ben Luft, Director of the Stony Brook WTC Wellness Program at the Renaissance School of Medicine. Luft has provided clinical and research support for WTC responders.
Boffetta continues to have academic affiliations with other academic institutions, including Harvard University and Vanderbilt University.
Boffetta and his wife Antonella Greco, who have been living in New York City, plan to move to the Stony Brook area. Their three daughters live in Brooklyn, Italy and Argentina. Now that pandemic restrictions have lifted, Boffetta has been able to return to the opera and museums and has done some skiing and hiking.
As for this study, Boffetta suggested that the findings about screenings were consistent with what he might have expected during the beginning of the pandemic.Delaying screenings could mean that some people discover cancers at a more advanced state by the time they diagnose them, he said.
Markus Seeliger, third from left, with members of his lab, from left, Terrence Jiang. Aziz Rangwala, Ian Outhwaite, Victoria Mingione,YiTing Paung, and Hannah Philipose. Photo from Markus Seeliger
By Daniel Dunaief
When a dart hits the center of a target, the contestant often gets excited and adds points to a score. But what if that well-placed dart slipped off the board before someone could count the points, rendering such an accurate throw ineffective?
With some cases of cancer treatments, that’s what may be happening, particularly when a disease develops a mutation that causes a relapse. Indeed, people who have chronic myeloid leukemia typically receive a treatment called Imatinib, or Gleevac.
The drug works, hitting a target called a kinase, which this white blood cell cancer needs to cause its cells to continue to divide uncontrollably. Patients, however, develop a mutation called N368S, which reduces the effectiveness of the drug.
While mutations typically make it more difficult for a drug to bind to its target, that’s not what’s happening with this specific mutation. Like the dart hitting the center of a board, the drug continues to reach its target.
Instead, in a model of drug resistance several scientists have developed, the mutation causes the drug to decouple.
Pratyush Tiwary with this year’s US top 20 students who are going to the international chemistry olympiad. Photo from Toward
A team of experimental and computational researchers including Markus Seeliger, Associate Professor of Pharmacological Sciences at Stony Brook University, and Pratyush Tiwary, Associate Professor in the Department of Chemistry & Biochemistry at the University of Maryland, published two research papers explaining a process that may also affect the way mutations enable resistance to other drugs.
Seeliger described how different disease-associated mutations bind to Gleevac in a paper published in the Proceedings of the National Academy of Sciences.
Working with scientists at Memorial Sloan Kettering Cancer Center and Goethe University in Frankfurt, Germany, Seeliger used nuclear magnetic resonance spectroscopy, or NMR. The researchers showed how the drug bound to its target and then released.
Understanding the way diseases like cancer develop such resistance could affect drug discovery, giving pharmaceutical companies another way to prepare for changes diseases make that reduce the effectiveness of treatments.
A ‘hot paper’
Tiwary published research in which Seeliger was a coauthor in late April in the journal Angewandte Chemie that the publication labeled a “hot paper” for its implications in the field. Tiwary developed a way to simulate the kinetic processes that enable the mutated kinases to release the drug.
Tiwary created an artificial intelligence model that extended the time he analyzed the drug-protein interaction from milliseconds all the way out to thousands of seconds.
“Even within the simulation world, if you can quantitatively predict a binding affinity, that’s amazing,” Seeliger said. “It’s extremely hard to calculate kinetics, and he got that right.”
Tiwary, who started talking with Seeliger about five years ago and has been actively collaborating for about three years, uses experimental data to inform the dynamics that affect his simulations.
Seeliger “had done the experiments of the dissociation rates beforehand, but did not have a way to explain why they were what they were,” Tiwary explained in an email. “Our simulations gave him insights into why this was the case and … insight into how to think about drugs that might dissociate further.”
Drug discovery
Tiwary hopes the work enables researchers to look at structural and kinetic intermediates in reactions, which could provide clues about drug design and delivery. While he worked with a single mutation, he said he could conduct such an analysis on alterations that affect drug interactions in other diseases.
He wrote that the computations, while expensive, were not prohibitive. He used the equivalent of 16 independent 64 CPUs for one to two weeks. He suggested that computing advances could cut this down by a factor of 10, which would enable the exploration of different mutations.
“The methods are now so easy to automate that we could run many, many simulations in parallel,” Tiwary explained. Machine learning makes the automation possible.
Given what he’s learned, Tiwary hopes to contribute to future drug begin that addresses mutation or resistance to treatment in other cancers. He also plans to continue to work with Seeliger to address other questions.
Next steps
Seeliger said he plans to extend this work beyond the realm of this specific type of cancer.
He will explore “how common these kinetic mutations are in other systems, other diseases and other kinases,” Seeliger said.
He would also like to understand whether other proteins in the cell help with the release of drugs or, alternatively, prevent the release of drugs from their target. The cell could have “other accessory proteins that help kick out the drug from the receptor,” Seeliger said.
The concept of drug resistance time comes from infectious disease, where microbes develop numerous mutations.
Seeliger, who is originally from Hanover, Germany, said he enjoys seeing details in any scene, even outside work, that others might not notice.
He described how he was driving with postdoctoral fellows in Colorado when he spotted a moose. While the group stopped to take a picture, he noticed that the moose had an ear tag, which is something others didn’t immediately notice.
As for the research collaboration, Seeliger is pleased with the findings and the potential of the ongoing collaboration between experimental and computational biologists.
“The computational paper, aside from using interesting new methodology, describes why things are happening the way they are on a molecular level,” he said.
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