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Cold Spring Harbor Laboratory

Stony Brook University: Entrance sign

By Daniel Dunaief

In anticipation of a nor’easter on Tuesday, Feb, 13 that has triggered a National Weather Service Winter Storm Warning, Stony Brook University announced that it was canceling classes and events scheduled for Tuesday.

The canceled classes and events apply to the Stony Brook main campus, SB Southampton and SB Manhattan campuses and includes the School of Medicine, School of Nursing, School of Health Professions, School of Social Welfare, and the Dental School.

In a note from Jason Casale, Director of Emergency Management, Stony Brook urged students with clinical obligations to make every effort to attend rotations and contact their clinical coordinators with questions or concerns.

During emergencies, non-essential employees can request supervisory approval to charge their accruals when offices are open, according to the campus e-mail blast. Essential employees have to report to work according to their scheduled hours.

University Hospital and the Long Island State Veterans Home employees are considered “essential” and are expected to work according to their regular schedule.

Brookhaven National Laboratory is also closed to everyone but essential personnel from 6 a.m. Tuesday to 6 a.m. Wednesday.

Cold Spring Harbor Laboratory, meanwhile, announced it is closing on Tuesday until 5 pm.

As of Monday evening, the National Weather Service issued a winter storm warning, predicting Suffolk County could receive snow accumulations of 5 inches to 10 inches and wind gusts of 40 miles per hour.

Zhe Qian

By Daniel Dunaief

Addition and subtraction aren’t just important during elementary school math class or to help prepare tax returns.

As it turns out, they are also important in the molecular biological world of healthy or diseased cells.

Some diseases add or subtract methyl groups, with a chemical formula of CH3, or phosphate groups, which has a phosphorous molecule attached to four oxygen molecules.

Nicholas Tonks. Photo courtesy of CSHL

Adding or taking away these groups can contribute to the progression of a disease that can mean the difference between sitting comfortably and watching a child’s performance of The Wizard of Oz or sitting in a hospital oncology unit, waiting for treatment for cancer.

Given the importance of these units, which can affect the function of cells, researchers have spent considerable time studying enzymes such as kinases, which add phosphates to proteins.

Protein tyrosine phosphatases, which Professor Nicholas Tonks at Cold Spring Harbor Laboratory purified when he was a postdoctoral researcher, removes these phosphate groups.

Recent PhD graduate Zhe Qian, who conducted research for six years in Tonks’s lab while a student at Stony Brook University, published a paper in the journal Genes & Development demonstrating how an antibody that interferes with a specific type of protein tyrosine phosphatase called PTPRD alters the way breast cancer spreads in cell cultures.

“The PTPs are important regulators of the process of signal transduction — the mechanisms by which cells respond to changes in their environment,” explained Tonks. “Disruption of these signal transduction mechanisms frequently underlies human disease.”

To be sure, Tonks cautioned that the study, which provides a proof of concept for the use of antibodies to manipulate signaling output in a cancer cell, is a long way from providing another tool to combat the development or spread of breast cancer.

The research, which formed the basis for Qian’s PhD project, offers an encouraging start on which to add more information.

Blocking the receptor

Qian, who goes by the name “Changer,” suggested that developing a compound or small molecule to inhibit or target the receptor for this enzyme was difficult, which is “why we chose to use an antibody-based method,” he said.

By tying up a receptor on the outside of the cell membrane, the antibody also doesn’t need to enter the cell to reach its target.

The Antibody Shared Resource, led by Research Associate Professor Johannes Yeh, created antibodies to this particular receptor. Yeh created an antibody is shaped like a Y, with two arms with specific attachments for the PTPD receptor.

Once the antibody attaches, it grabs two of these receptors at the same time, causing a dimerization of the protein. Binding to these proteins causes them to lose their functionality and, ultimately, destroys them.

Cell cultures of breast cancer treated with this antibody became less invasive.

Limited presence

One of the potential complications of finding a new target for any treatment is the side effects from such an approach.

If, for example, these receptors also had normal metabolic functions in a healthy cell, inhibiting or killing those receptors could create problematic side effect.

In this case, however,  the targeted receptor is expressed in the spine and the brain. Antibodies normally don’t cross the blood-brain barrier.

Qian and Tonks don’t know if the antibody would affect the normal function of the brain. Further research would help address this and other questions.

Additionally, as with any possible treatment, future research would also need to address whether cancer cells developed resistance to such an approach.

In the time frame Qian explored, the cells in culture didn’t become resistant.

If the potential therapeutic use of this antibody becomes viable, future researchers and clinicians might combine several treatments to develop ways to contain breast cancer.

Eureka moment

In his research, Qian studied the effect of these antibodies on fixed cell, which are dead but still have the biochemical features of a living cell He also studied living cells.

When the antibody attaches to the receptor, it becomes visible through a staining process. Most antibody candidates stain living cells. Only the successful one showed loss-of-signal in living staining.

The antibody Qian used not only limited the ability of the receptor to send a signal, but also killed the receptor. The important moment in his research occurred when he discovered the antibody suppressed cancer cell invasion in cell culture.

Outside of the lab, Qian enjoys swimming, which he does between four and five times per week. Indeed, he combined his athletic and professional pursuits when he recently raised funds for Swim Across America.

“I not only want to do research, but I also want to call more attention to cancer research in the public,” said Qian.

The Swim Across America slogan suggests that each stroke is for someone who “couldn’t be with us” because of cancer. In the lab, Qian thinks each time he pipettes liquids during one of his many experiments it is for someone who couldn’t make it as well.

Qian, who currently lives in Hicksville, grew up in Suchow City, which is a village west of Shanghai and where Cold Spring Harbor Asia is located. 

Qian has been living on Long Island since he arrived in the United States. Qian graduated from Stony Brook University in October and is currently looking for a job in industry.

Looking back, Qian is pleased with the work he’s done and the contribution he’s made to breast cancer research. He believes the antibody approach offers a viable alternative or complement to searching for small molecules that could target or inhibit proteins or enzymes important in the development of cancer.

The 2023 Double Helix Medals Dinner was once again held under the American Museum of Natural History's iconic blue whale model. Photo from CSHL

By Nick Wurm

On November 15, Cold Spring Harbor Laboratory (CSHL) held its 18th annual Double Helix Medals dinner (DHMD) at the American Museum of Natural History in New York City. CBS journalist Lesley Stahl returned to emcee the awards dinner, which honored Neri Oxman & William Ackman and 2018 Nobel laureate Jim Allison. Thanks to the event chairs and donors, the event raised more than $10 million. After receiving the Double Helix Medal, Oxman and Ackman announced an extraordinary gift, further breaking the event’s fundraising record to support scientific research and education at CSHL.

William Ackman & Neri Oxman

Neri Oxman & William Ackman are co-trustees of the Pershing Square Foundation. The organization empowers scientists to take on important social causes, including the environment, cancer, and cognitive health. Ackman is also the CEO of Pershing Square Capital Management and chairman of the Howard Hughes Corporation. Oxman is an innovative designer whose fusions of technology and biology have been featured in museums around the world. Her work has yielded over 150 scientific publications and inventions.

“Something we continue to this day is backing young, talented entrepreneurs who are on a mission to solve an important societal problem,” Ackman says. “We believe in taking risks with incredible scientists who have the ability to tackle these complex problems,” Oxman adds.

Dr. Jim Allison

Dr. Jim Allison is regental professor and chair of the MD Anderson Cancer Center’s Department of Immunology. He won the 2018 Nobel Prize in Physiology or Medicine for pioneering the field of cancer immunotherapy. Since then, his research has led to the development of ipilimumab, an FDA-approved therapy for metastatic melanoma, renal cell carcinoma, and lung cancer.

“The perception of immunology has shifted,” Dr. Allison says. “People used to say, ‘Will immunotherapy ever work?’ We now know it works. Immunotherapy is going to be a part of all cancer therapies for almost every kind of cancer.”

The 2023 DHMD was chaired by Ms. Jamie Nicholls and Mr. O. Francis Biondi, Ms. Barbara Amonson and Dr. Vincent Della Pietra, Drs. Pamela Hurst-Della Pietra and Stephen Della Pietra, Mr. and Mrs. John M. Desmarais, Mr. and Mrs. Jonathan Gray, Mr. and Mrs. Jeffrey E. Kelter, Dr. and Mrs. Tomislav Kundic, Mr. and Mrs. Robert D. Lindsay, Ms. Ivana Stolnik-Lourie and Dr. Robert Lourie, Dr. Marcia Kramer Mayer, Dr. and Mrs. Howard L. Morgan, Drs. Marilyn and James Simons, and Mr. and Mrs. Paul J. Taubman.

Since the inaugural gala in 2006 honoring Muhammed Ali, the DHMD has raised over $60 million to support CSHL’s biological research and education programs.

Author Nick Wurm is a Communications Specialist at Cold Spring Harbor Laboratory.

A Jamaican fruit bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

By Daniel Dunaief

Popular in late October as Halloween props and the answer to trivia questions about the only flying mammals, bats may also provide clues about something far more significant.

Despite their long lives and a lifestyle that includes living in close social groups, bats tend to be resistant to viruses and cancer, which is a disease that can and does affect other mammals with a longer life span.

Armin Scheben

In recent work published in the journal Genome Biology and Evolution, scientists including postdoctoral researcher at Cold Spring Harbor Laboratory and first author Armin Scheben, CSHL Professor and Chair of the Simons Center for Quantitative Biology Adam Siepel, and CSHL Professor W. Richard McCombie explored the genetics of the Jamaican fruit bat and the Mesoamerican mustached bat.

By comparing the complete genomes for these bats and 13 others to other mammals, including mice, dogs, horses, pigs and humans, these scientists discovered key differences in several genes.

The lower copy number of interferon alpha and higher number of interferon omega, which are inflammatory protein-coding genes, may explain a bat’s resistance to viruses. As for cancer, they discovered that bat genomes have six DNA repair and 33 tumor suppressor genes that show signs of genetic changes.

These differences offer potential future targets for research and, down the road, therapeutic work.

“In the case of bats, we were really interested in the immune system and cancer resistance traits,” said Scheben. “We lined up those genomes with other mammals that didn’t have these traits” to compare them.

Scheben described the work as a “jumping off point for experimental validation that can test whether what we think is true: that having more omega than alpha will develop a more potent anti-viral response.”

Follow up studies

This study provides valuable potential targets that could help explain a bat’s immunological superpowers that will require further studies.

“This work gives us strong hints as to which genes are involved, but fully understanding the molecular biology will require more work” explained Siepel.

In Siepel’s lab, where Scheben has been conducting his postdoctoral research since 2019, he is using human cell lines to see whether adding genetic bat elements makes them more effective in fighting off viral infections and cancer. He plans to do more of this work with mice, testing whether these bat variants help convey the same advantages in live mice.

Armin Scheben won the German Academic International Network Science Slam competition with his presentation on bat genomics.

Siepel and Scheben have discussed improving the comparative analysis by collecting information across bats and other mammals of tissue-specific gene expression and epigenetic marks which would help reveal changes not only in the content of DNA, but also in how genes are being turned on and off in different cell types and tissues. That could allow them to focus more directly on key genes to test in mice or other systems.

Scheben has been collaborating with CSHL Professor Alea Mills, whose lab has “excellent capabilities for doing genome editing in mice,” Scheben said.

Scheben’s PhD thesis advisor at the University of Western Australia, Dave Edwards described his former lab member’s work as “exciting.”

Edwards, who is Director of the UWA Centre for Applied Bioinformatics in the School of Biological Sciences, suggested that Scheben stood out for his “ability to strike up successful collaborations” as well as his willingness to mentor other trainees.

Other possible explanations

While these genetic differences could reveal a molecular biological mechanism that explains the bat’s enviable ability to stave off infections and cancer, researchers have proposed other ways the bat might have developed these virus and cancer fighting assets.

When a bat flies, it raises its body temperature. Viruses likely prefer a normal body temperature to operate optimally. 

Bats are “getting fevers without getting infections,” Scheben said.

Additionally, flight increases the creation of reactive oxygen species, which the bat needs to control on an ongoing basis.

At the same time, bats produce fewer inflammatory cytokines, which helps prevent them from having a runaway immune reaction. Some researchers have hypothesized that bats clear reactive oxygen species more effectively than humans.

A ‘eureka’ moment

The process of puzzling together all the pieces of DNA into individual chromosomes took considerable time and effort.

A Mesoamerican mustached bat, one of two bat species Scheben studied as a part of his comparative genomic work. Photo by Brock & Sherri Fenton

Scheben spent over 280,000 CPU hours chewing through thousands of genes in dozens of species on the CSHL supercomputer called Elzar, named for the chef from the cartoon “Futurama.” Such an effort would have taken eight years on a modern day personal computer.

During this effort, Scheben saw this “stark effect,” he said. “We had known that bats had lost some interferon alpha. What astounded me was that some bats had lost all alpha” while they had also raised interferon omega. That was the moment when he realized he found something novel and bat specific.

Scheben recognized that this finding could be one of many that lead to a better understanding of the processes that lead to cancer.

“We know that it’s unlikely that a single set of genes or a small set of genes such as we identified can fully explain the diversity of outcomes when it comes to a complex disease like cancer,” said Scheben.

A long journey

A resident of Northport, Scheben grew up in Frankfurt, Germany. He moved to London for several years, which explains his use of words like “chuffed” to describe the excitement he felt when he received a postdoctoral research offer at Cold Spring Harbor Laboratory.

When he was young, Scheben was interested in science despite the fact that classes were challenging for him.

“I was pretty poor in math and biology, but I liked doing it,” he said.

Outside of work, Scheben enjoys baking dense, whole wheat German-style bread, which he consumes with cheese or with apple, pear and nuts, and also hiking.

As for his work, which includes collaborating with CSHL Professor Rob Martienssen to study the genomes of plants like maize that make them resilient amid challenging environmental conditions, Scheben suggested it was the “best time to be alive and be a biologist” because of the combination of new data and the computational ability to study and analyze it.

Scheben recognized that graduate students in the future may scoff at this study, as they might be able to compare a wider range of mammalian genomes in a shorter amount of time.

Such a study could include mammals like naked mole rats, whales and elephants, which also have low cancer incidence and long lifespans.

A scene from 'Oppenheimer'

By Daniel Dunaief

Researchers at Brookhaven National Laboratory, Cold Spring Harbor Laboratory and Stony Brook University joined the chorus of moviegoers who enjoyed and appreciated the Universal film Oppenheimer.

“I thought the movie was excellent,” said Leemor Joshua-Tor, Professor and HHMI Investigator at Cold Spring Harbor Laboratory. “It made me think, which is always a good sign.”

Yusuf Hannun, Vice Dean for Cancer Medicine at Stony Brook University, thought the movie was “terrific” and had anticipated the film would be a “simpler” movie.

Jeff Keister, leader of the Detector and Research Equipment Pool at NSLS-II at Brookhaven National Laboratory, described the movie as “interesting” and “well acted.”

Joshua-Tor indicated she didn’t know anything about Robert Oppenheimer, the title character and leader of the Manhattan Project that built the atomic bomb. She “learned lots of new things” about him, she wrote. “I knew he was targeted by McCarthy-ism, but didn’t realize how that came about and the details.”

Keister also didn’t know much about Oppenheimer, who was played by actor Cillian Murphy in the film. “Oppenheimer seemed to quietly struggle with finding his role in the story of the development of the atomic bomb,” Keister said. “At times, he wore the uniform, then later seemed to express regret.”

Like other researchers, particularly those involved in large projects that bring together people with different skills and from various cultural backgrounds, Oppenheimer led a diverse team of scientists amid the heightened tension of World War II.

Oppenheimer was “shown to have been granted an extremely powerful position and was able to form a relatively diverse team, although he was not able to win over all the brightest minds,” Keister wrote.

Joshua-Tor suggested Oppenheimer “charmed” the other scientists, who were so driven by the science and the goal that they “accepted him. The leader of the team should be a great scientist, but doesn’t necessarily have to be the biggest genius. There is a genius in being able to herd the cats in the right way.”

Joel Hurowitz, Associate Professor in the Department of Geosciences at Stony Brook University, “loved” the movie. Hurowitz has worked with large projects with NASA teams as a part of his research effort.

Hurowitz suggested that the work that goes into coordinating these large projects is “huge” and it requires “a well laid out organizational structure, effective leadership, and a team that is happy working hard towards a common goal.”

‘Stunning’ first bomb test

Keister described the first nuclear bomb test as “stunning” in the movie. “I have to wonder how the environmental and health impacts of such a test came to be judged as inconsequential.”

Some local scientists would have appreciated and enjoyed the opportunity to see more of the science that led to the creation of the bomb.

Science is the “only place the movie fell short,” Hannun said. “They could have spent a bit more time to indicate the basic science behind the project and maybe a bit more about the scientific accomplishments of the various participants.”

Given the focus of the movie on Oppenheimer and his leadership and ultimate ambivalence about the creation of the atomic bomb, Keister suggested that scientists “could be better encouraged to understand the impacts of applied uses of new discoveries. Scientists can learn to broaden their view to include means of mitigating potential negative impacts.”

Research sponsors, including taxpayers and their representatives, have an “ethical responsibility to incorporate scientists’ views of the full impacts into their decisions regarding applications and deployment of new technology,” Keister said.

Joshua-Tor thinks there “always has to be an ongoing conversation between scientists and the citizenry” which has to be an “informed, somewhat dispassionate conversation.”

Recommended movies about scientists

Local researchers also shared some of their film recommendations about scientists.

Hurowitz wrote that his favorite these days is Arrival, a science fiction film starring Amy Adams. If Hurowitz is looking for more lighthearted fare, he writes that “you can’t go wrong with Ghostbusters,” although he’s not sure the main characters Egon, Ray and Peter could be called scientists.

Keister also enjoys science fiction, as it “often challenges us with ethical dilemmas which need to be addressed.” While he isn’t sure he has a favorite, he recommended the sci-fi thriller Ex Machina starring Alicia Vikander as a humanoid robot with artificial intelligence,.

Joshua-Tor recalls liking the film A Beautiful Mind starring Russell Crowe and Jennifer Connelly as John and Alicia Nash. She also loved the film Hidden Figures, starring Taraji P Henson, Octavia Spencer and Janelle Monáe.

Jasmine Moss. Photo by Susan Anderson

By Daniel Dunaief

As the first chemist in the history of Cold Spring Harbor Laboratory, Professor John Moses has forged new connections at the lab, even as he maintains his affinity for and appreciation of his native Wrexham in Wales.

Indeed, Moses recently created and funded a fellowship for disadvantaged students in Wales, giving them an opportunity to visit the lab, learn about the science he and others do, and, perhaps, spark an interest in various science, technology, engineering and math fields.

Called Harbwr y Ffynnon Oer Scholarship, which means “Cold Spring Harbor” in Welsh, Moses’s laboratory recently welcomed Jasmine Moss, the first recipient, in early August.

“I hope it broadens” the horizons of those who travel to the lab, explained Moses in an email. “Wales is a small country” with a population of about three million. Coming to New York — a city with a much bigger population than Wales — “can only be an eye-opening experience.”

Jasmine Moss with postdoctoral fellow Dharmendra Vishwakarma. Photo by Theresa Morales

For Moss, who is studying for an integrated masters degree in biomedical engineering, the opportunity proved exciting and rewarding.

“I was expecting to feel intimidated” with everyone knowing so much more than she, Moss said during an interview on the morning of her third day in the lab. “I was expecting maybe a little bit not to understand everything. Everyone is amazing” and made her feel welcome.

The experience started with a walk around the campus, which included considerable information not only about the science but also about the history of the 133-year old laboratory.

Moss, who said this was the first time she’d been in a professional chemistry lab, helped conduct an experiment in which a reaction caused a liquid to change color because of the presence of copper.

“I did the measuring and putting it together,” said Moss, who added that she was “heavily supervised.” She did some calculations as well.

Moss suggested that her interest in science originated with a proficiency in math.

If she were having a bad day in secondary school, she could turn her mood and her mentality around by spending an hour in math class.

Beyond the science

Theresa Morales, a senior scientific administrator, created a schedule of activities and coordinated Moss’s visit.

“We want to do the same thing for any scholarship awardee,” Morales said. “We want to give them the overall experience. It’s not just about the science. We invite the person to realize the culture of Cold Spring Harbor Laboratory” which has a “beautiful campus and great people” who occupy its labs, attend meetings, and share scientific insights and experiences.

A postdoctoral researcher in Moss’s lab, Josh Homer suggested that Morales did “the heavy lifting” in coordinating three days of activities and opportunities for Moss. Homer, who is collaborating with Professor Bo Li to develop new opiates that are non addictive for pain treatment, appreciated Moss’s reactions to the opportunities in the lab.

“I thought [Moss’s] face lit up,” he said. When people are exposed to science in a “manageable and digestible way, they learn that they can do it.”

Indeed, Homer, who grew up in New Zealand, recalled how a high school teacher inspired his interest in science.

“My journey genuinely kick started from one good teacher” who sparked an “inquisitiveness” within him, Homer said. 

Coming from a smaller country, Homer can relate to the opportunities science has provided for him.

“Chemistry has been a fantastic way to see the world and explore,” said Homer, who conducted his PhD research at the University of Oxford in the United Kingdom. “Science is a universal language. Chemistry is the same in India, China” and all over the world.

A family experience

Jasmine Moss with her dad, Stephen Moss, front, with members of John Moses’s lab. Photo by Lorraine Baldwin

Moss traveled to New York for the first time with her parents Stephen and Emma, who stayed with her on campus, toured the grounds and library and attended a picnic.

While the library tour was less interesting to Moss, she said her father “really enjoyed it.”

Morales suggested that the lab “wants parents to feel just as good” and that the parents will have “the same enthusiasm for science and the experience as the scholar if they can feel they are a part” of the visit.

In addition to getting an inside look at Cold Spring Harbor Laboratory, Moss and her parents ventured into the city, where she ate her first pizza and visited the Empire State Building and the Statue of Liberty. She was particularly impressed with the speed at which the Empire State Building was constructed, which took a year and 45 days.

Prior to her visit, Moss’s understanding of the city of New York came from the version she observed through the sitcom “Friends.”

As for the next phase of her life, she expressed an interest in helping people, which could be through medical engineering, biology or in some other field.

“I want to do something meaningful,” Moss said.

Next steps

Moses hopes to bring students to the lab each year, particularly those who might have had problems or difficulties or are from a disadvantaged background. Moss suffers from anxiety and feels every new experience makes similar opportunities easier.

“The team really put me at ease almost immediately,” said Moss.

Moss was surprised by the similarities between Long Island and the United Kingdom. She suggested the best parts of Wales are the countryside and beaches. If she returned the favor and hosted guests in her native Wales, she would take them to an international rugby match in Cardiff.

As for other area sports, Moses comes from the little soccer town that could in Wrexham, which is now famous for the purchase of the local team by actor Ryan Reynolds and co-owner Rob McElhenney. While the actors have brought soccer dreams to life, Moses hopes Cold Spring Harbor Laboratory might help young students realize their science dreams.

By Daniel Dunaief

This is part 2 of a two-part series.

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

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

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

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

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

Starting with the data

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Long standing partnership

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

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

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

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

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

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

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

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

By Daniel Dunaief

This part one of a two part series.

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

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

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

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

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

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

Miriam Ferrer Gonzalez

Miriam Ferrer Gonzalez. Photo by Caryn Koza/CSHL

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

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

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

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

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

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

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

Ferrer recently published her paper in the journal Cell Metabolism.

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

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

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

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

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

Next steps

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

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

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

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

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

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

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

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

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

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

The hand off

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

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

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

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

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

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

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

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

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

 

John Moses. Photo courtesy of CSHL

By Daniel Dunaief

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

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

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

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

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

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

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

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

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

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

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

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

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

The shape shifting star

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

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

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

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

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

Welcoming back a familiar face

Adam Moorhouse
Photo by Rebecca Koelln

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

By Tara Mae

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

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

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

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

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

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

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

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

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

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