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Cold Spring Harbor Laboratory

Photo courtesy of CSHL

By Daniel Dunaief

Cold Spring Harbor Laboratory’s DNA Learning Center and the Red Cloud Indian School recently launched a program called Students Talk Science in which high school students could ask questions from several senior scientists about the vaccine for COVID-19 and healthcare disparities in minority communities.

Dr. Eliseo Pérez-Stable

 

The talks are a component of a program called STARS, for Science, Technology & Research Scholars, an effort the group started in 2019 to build interest and experience in STEM for minority students. The Students Talk Science program engaged the STARS participants and students from the Red Cloud Indian School on the Pine Ridge Indian Reservation.

Jason Williams, Assistant Director of Inclusion and Research Readiness at the DNA Learning at CSHL; Brittany Johnson, an educator at the DNA Learning Center; Katie Montez, a teacher at the Red Cloud Indian School ;and Carol Carter, Professor in the Department of Microbiology and Immunology at the Renaissance School of Medicine at Stony Brook University, wanted to connect minority students with practicing physicians and scientists in leadership positions at the National Institutes of Health to allow them to ask questions of concern regarding the vaccines.

Dr. Monica Webb-Hooper

“We did this to empower them to function as trusted resources for their families, friends and network,” Carter, who participated as an individual rather than as a formal representative of Stony Brook University, explained in an email.

The conversations included interactions with Dr. Eliseo Pérez-Stable, Director of the National Institute on Minority Health and Health Disparities, or NIMHD at the National Institutes of Health; Dr. Monica Webb Hooper, Deputy Director of the NIMHD; Dr. Gary Gibbons, Director of the National Heat, Lung and Blood Institute; and Dr. Eugenia South, Assistant Professor in Emergency Medicine at the Hospital of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia.

The high school students prepared informed questions.

Dr. Gary Gibbons

“The students were encouraged to do their own research” on the interview subjects, Williams explained. “We asked students not to look just at [each] interviewee’s science work, but also any personal background/ biography they could find. Students had multiple opportunities for follow up and were largely independent on their choices of questions.”

Samantha Gonzalez, a student at Walter G. O’Connell Copiague High School, asked South about her initial skepticism for the vaccine.

South acknowledged that she had no interest in taking the vaccine when she first learned she was eligible. “I almost surprised myself with the fierceness with which I said, ‘No,’” South said. “I had to step back and say, ‘Why did I have this reaction?’”

Some of the reasons had to do with mistrust, which includes her own experiences and the experiences of her patients, whom she said have had to confront racism in health care. In addition, she was unsure of the speed at which the vaccine was developed. She had never heard of the mRNA technology that made the vaccines from Moderna and Pfizer/ BioNTech possible.

“I had to do my own research to understand that this wasn’t a new technology,” she said.

Dr. Eugenia South

South went through a learning process, in which she read information and talked to experts. After she received answers to her questions and with the urging of her mother, she decided to get the vaccine.

“I’m so thankful that I was able to do that,” South said.

The team behind Students Talk Science not only wanted to empower students to make informed decisions, but also wanted to give them the opportunity to interact with scientists who might serve as personal and professional role models, providing a pathway of information and access that developed amid an extraordinary period.

“We wanted to engage high school students in something unique going on in their lifetime,” Carter said.

To be sure, Carter and Williams said the scientific interactions weren’t designed to convince students to take the vaccine or to urge their parents or families to get a shot. Rather, they wanted to provide an opportunity for students to ask questions and gather information.

“We purposely did not participate in the discussions because our goal was not to convince or ‘preach,’ but to enable students and their networks to make informed decisions,” Carter said.

Parents had to read and sign off on the process for students to participate. The organizers didn’t want a situation where they were doing something that conflicts with a parents’ decisions or views.

Williams added that the purpose of the conversations was never to say, “you must get the vaccine. Our purpose is to talk about information.”

The objective of these interactions is to help minority students find a track for a productive career in ten years.

In addition to questions about hesitancy, Williams said some of the high school students expressed concerns about access to vaccines. He is pleased with the result of this effort to connect students with scientists and doctors.

The group was “able to get some of the most important scientists in the country to sit with high school students,” he said. “It was very powerful to give students access to these role models.”

The goal is to stay with these students, mentor them and stay in touch with them until they graduate from college and, perhaps, return as research scientists.

Even for students who do not return, this type of interaction could provide an “impactful experience that prepares them for other opportunities,” Williams explained, adding that the STARS program would incorporate the Students Talk Science Series into the program more formally in the future, with new students and topics most likely during the school year.

The interviews are available at the following website: https://dnalc.cshl.edu/resources/students-talk-science/.

From left, John Inglis and Richard Sever. Photo from CSHL

By Daniel Dunaief

Scientists rarely have people standing at their lab door, waiting eagerly for the results of their studies the way the public awaits high-profile verdicts.

That, however, changed over the last 16 months, as researchers, public health officials, school administrators and a host of others struggled to understand every aspect of the basic and translational science involved in the Sars-Cov2 virus, which caused the COVID-19 pandemic.

With people becoming infected, hospitalized and dying at an alarming rate, businesses closing and travel, entertainment and sporting events grinding to a halt, society looked to scientists for quick answers. One challenge, particularly in the world of scientific publishing, is that quick and answers don’t often mesh well in the deliberate, careful and complicated world of scientific publishing.

The scientific method involves considerable checking, rechecking and careful statistically relevant analysis, which is not typically designed for the sharing of information until other researchers have reviewed it and questioned the approach, methodology and interpretation.

The pandemic changed that last year, increasing the importance of preprint servers like bioRxiv and medRxiv at Cold Spring Harbor Laboratory, which provide a way for researchers to share unfiltered and unchecked information quicker than a scientific review and publishing process that can take months or even years.

The pandemic increased the importance of these preprint servers, enabling scientists from all over the world to exchange updated research with each other, in the hopes of leading to better basic understanding, diagnosis, treatment and prevention of the spread of the deadly virus.

The importance of these servers left those running them in a bind, as they wanted to balance between honoring their mission of sharing information quickly and remaining responsible about the kinds of information, speculation or data that might prove dangerous to the public.

Richard Sever and John Inglis, Assistant Director and Executive Director of Cold Spring Harbor Laboratory Press, created pandemic-specific criteria for work reporting potential Covid-19 therapies.

“Manuscripts making computational predictions of COVID-19 therapies are accepted only if they also include in vitro [studies in test tubes or with live cells] or in vivo [studies in live subjects] work,” the preprint directors wrote in a recent blog. “This restriction does not apply to non-covid-19 work.”

Inglis and Sever continue to decline research papers that might cause people to behave in ways that compromise public health.

“We are simply doing our best to tread carefully in the early days of clinical preprints, as we gain experience and bias our actions toward doing no harm” the authors wrote in their blog.

In the first few months after the pandemic hit the United States, the pace at which scientists, many of whom pivoted from their primary work to direct their expertise to the public health threat, was the highest bioRxiv, which was founded in November of 2013, and medRxiv, which was started in June of 2019, had ever experienced.

These preprint servers published papers that wound up leading to standards of care for COVID-19, including a June research report that appeared on June 22nd in medRxiv on the use of the steroid dexamethasone, which was one of the treatments former President Donald Trump received when he contracted the virus.

The rush to publish information related to the virus has slowed, although researchers have still posted over 16,000 papers related to the virus through the two pre-print servers. MedRxiv published 12,400 pandemic-related papers since January of 2020, while bioRxiv published over 3,600.

At its peak in late March of 2020, medRxiv’s abstract views reached 10.9 million, while downloads of the articles were close to five million.

Currently, bioRxiv is publishing about 3,500 papers a month, while medRxiv put up about 1,300 during a month. Close to 60 percent of the medRxiv papers continue to cover medical issues related to the pandemic.

The numbers of page views are “not anywhere near the frenzy of last year,” Inglis said in an interview. 

With the volume of papers still high, people can receive alerts from the preprint servers using parameters like their field of interest or word searches.

“The real question is how to sort out the gold from the dross,” Inglis said. While some people have suggested a star system akin to the one shopping services use, Inglis remained skeptical about the benefit of a scientific popularity contest.

“Have you looked at the stuff [with four or five stars] on Amazon? It’s one thing if you’re buying a widget, but it’s different if you’re trying to figure out what’s worthwhile science,” he said.

Other organizations have reviewed preprints, including the Bloomberg School of Public Health at Johns Hopkins.

“By sheer diligence, the [Johns Hopkins team] go into medRxiv mostly and simply pick out things they think are striking,” Inglis said. 

At the same time, a team of researchers led by Nicolas Vabret, Robert Samstein, Nicolas Fernandez, and Miriam Merad created the Sinai Immunology Review Project, which provides critical reviews of articles from the Cold Spring Harbor Laboratory preprint sites. The effort ranks COVID-related preprints according to their immunological relevance. Fernandez created a dedicated website to host and integrate the reviews. The group also worked with Nature Reviews Immunology to publish short weekly summaries of preprints, according to a comment piece in that journal.

BioRxiv and medRxiv were founded on the belief that early sharing of results as preprints would speed progress in biomedical research, better equipping scientists to build on each other’s work.

“My team is proud to have contributed to the response to this worldwide human tragedy,” Inglis said. “We’re also glad we made the decision to set up a separate server for health science, in which the screening requirements are different and more stringent.”

Inglis explained that the pre-print servers have “learned a lot in the past year” about providing information during a crisis like the pandemic. “If another pandemic arose, we’d apply these learnings and respond immediately in the same way.”

Linda Van Aelst. Photo from CSHL

By Daniel Dunaief

Different people respond to the same level of stress in a variety of ways. For some, a rainy Tuesday that cancels a picnic can be a minor inconvenience that interrupts a plan, while others might find such a disruption almost completely intolerable, developing a feeling of helplessness.

Scientists and clinicians have been working from a variety of perspectives to determine the cause of these different responses to stress.

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Cold Spring Harbor Laboratory Professor Linda Van Aelst and a post doctoral researcher in her lab, Minghui Wang, recently published a collaborative work that also included graduate student Nicholas Gallo, postdoctoral researcher Yilin Tai and Professor Bo Li in the journal Neuron that focused on the gene Oligophrenin-1, which is also implicated in intellectual disability.

As with most X-linked diseases, the OPHN1 mutation primarily affects boys, who have a single X chromosome and a Y chromosome. Girls have two X chromosomes, giving them a backup gene to overcome the effect of an X-linked mutation.

In addition to cognitive difficulties, people with a mutation in this gene also develop behavioral challenges, including difficulty responding to stress.

In a mouse model, Wang and Van Aelst showed that the effect of mutations in this gene mirrored the stress response for humans. Additionally, they showed that rescuing the phenotype enabled the mouse to respond more effectively to stress.

“For me and [Wang], it’s very exciting,” Van Aelst said. “We came up with this mouse model” and with ways to counteract the effect of this mutated analogous gene.

As with many other neurological and biological systems, Oligophrenin1 is involved in a balancing act in the brain, creating the right mix of excitation and inhibition.

When oligophrenin1 was removed from the prelimbic region of the medical prefrontal cortex, a specific brain area that influences behavioral responses and emotion, mice expressed depression-like helpless behaviors in response to stress. They then uncovered two brain cell types critical for such behavior: the inhibitory neurons and excitatory pyramidal neurons. The excitatory neurons integrate many signals to determine the activity levels in the medial prefrontal cortex.

The inhibitory neurons, meanwhile, dampen the excitatory signal so they don’t fire too much. Deleting oligophrenin1 leads to a decrease in these inhibitory neurons, which Van Aelst found resulted from elevated activity of a protein called Rho kinase.

“The inhibitor keeps the excitatory neurons in check,” Van Aelst said. “If you have a silencing of the inhibitory neurons, you’re going to have too much excitatory response. We know that contributes to this maladaptive behavior.”

Indeed, Wang and Van Aelst can put their metaphorical finger on the scale, restoring the balance between excitation and inhibition with three different techniques.

The scientists used an inhibitor specific for a RhoA kinase, which mimicked the effect of the missing Oligophrenin1. They also used a drug that had the same effect as oligophrenin1, reducing excess pyramidal neuron activity. A third drug activated interneurons that inhibited pyramidal neurons, which also restored the missing inhibitory signal. All three agents reversed the helpless phenotype completely.

Japanese doctors have used the Rho-kinase inhibitor fasudil to treat cerebral vasospasm. which Van Aelst said does not appear to produce major adverse side effects. It could be a “promising drug for the stress-related behavioral problems” of oligophrenin1 patients, Van Aelst explained in an email. “It has not been described for people with intellectual disabilities and who also suffer from high levels of stress.”

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Van Aelst said she has been studying this gene for several years. Initially, she found that it is a regulator of rho proteins and has linked it to a form of intellectual disability. People with a mutation in this gene had a deficit in cognitive function that affected learning and memory.

From other studies, scientists learned that people who had this mutation also had behavioral problems, such as struggling with stressful situations.

People with intellectual difficulties have a range of stressors that include issues related to controlling their environment, such as making decisions about the clothing they wear or the food they eat.

“People underestimate how many [others] with intellectual disabilities suffer with behavioral problems in response to stress,” Van Aelst said. “They are way more exposed to stress than the general population.”

Van Aelst said she and Wang focused on this gene in connection with a stress response.

Van Aelst wanted to study the underlying cellular and molecular mechanism that might link the loss of function of oligophrenin1 with the behavioral response to stress.

At this point, Van Aelst hasn’t yet studied how the mutation in this gene might affect stress hormones, like cortisol, which typically increase when people or mice are experiencing discomfort related to stress. She plans to explore that linkage in future studies.

Van Aelst also plans to look at some other genes that have shown mutations in people who battle depression or other stress-related conditions. She hopes to explore a genetic link in the brain’s circuitry to see if they can “extend the findings.” She would also like to connect with clinicians who are studying depression among the population with intellectual disabilities. Prevalence studies estimate that 10 to 50 percent of individuals with intellectual disability have some level of behavioral problems and/or mood disorders.

Reflecting the reality of the modern world, in which people with various conditions or diseases can sequence the genes of their relatives, Van Aelst said some families have contacted her because their children have mutations in oligophrenin1.

“It’s always a bit tricky,” she said. “I don’t want to advise them yet” without any clinical studies.

A resident of Huntington, Van Aelst arrived at CSHL in the summer of 1993 as a post doctoral researcher in the lab of Michael Wigler. She met Wigler when he was giving a talk in Spain.

After her post doctoral research ended, she had planned to return to her native Belgium, but James Watson, who was then the president of the lab, convinced her to stay.

Outside of work, Van Aelst enjoys hiking, swimming and running. Van Aelst speaks Flemish, which is the same as Dutch, French, English and a “bit of German.” 

She is hopeful that this work may eventually lead to ways to provide a clinical benefit to those people with intellectual disabilities who might be suffering from stress disorders.

Peter Koo Photo from CSHL

By Daniel Dunaief

The goal sounds like a dystopian version of a future in which computers make critical decisions that may or may not help humanity.

Peter Koo, Assistant Professor and Cancer Center Member at Cold Spring Harbor Laboratory, would like to learn how to design neural networks so they are more interpretable, which will help build trust in the networks.

The neural networks he’s describing are artificial intelligence programs designed to link a molecular function to DNA sequences, which can then inform how mutations to the DNA sequences alter the molecular function. This can help “propose a potential mechanism that plays a causal role” for a mutation in a given disease, he explained in an email.

Researchers have created numerous programs that learn a range of tasks. Indeed, scientists can and have developed neural networks in computer vision that can perform a range of tasks, including object recognition that might differentiate between a wolf and a dog.

Koo when he received a COVID vaccination.

With the pictures, people can double check the accuracy of these programs by comparing the program’s results to their own observations about different objects they see.

While the artificial intelligence might get most or even all of the head-to-head comparisons between dogs and wolves correct, the program might arrive at the right answer for the wrong reason. The pictures of wolves, for example, might have all been taken during the winter, with snow in the background The photos of dogs, on the other hand, might have cues that include green grass.

The neural network program can arrive at the right answer for the wrong reason if it is focused on snow and grass rather than on the features of the animal in a picture.

Extending this example to the world of disease, researchers would like computer programs to process information at a pace far quicker than the human brain as it looks for mutations or genetic variability that suggests a predisposition for a disease.

The problem is that the programs are learning in the same way as their programmers, developing an understanding of patterns based on so-called black box thinking. Even when people have designed the programs, they don’t necessarily know how the machine learned to emphasize one alteration over another, which might mean that the machine is focused on the snow instead of the wolf.

Koo, however, would like to understand the artificial intelligence processes that lead to these conclusions.

In research presented in the journal Nature Machine Intelligence, Koo provides a way to access one level of information learned by the network, particularly DNA patterns called motifs, which are sites associated with proteins. It also makes the current tools that look inside black boxes more reliable.

“My research shows that just because the model’s predictions are good doesn’t mean that you should trust the network,” Koo said. “When you start adding mutations, it can give you wildly different results, even though its predictions were good on some benchmark test set.”

Indeed, a performance benchmark is usually how scientists evaluate networks. Some of the data is held out so the network has never seen these during training. This allows researchers to evaluate how well the network can generalize to data it’s never seen before.

When Koo tests how well the predictions do with mutations, they can “vary significantly,” he said. They are “given arbitrary DNA positions important scores, but those aren’t [necessarily] important. They are just really noisy.”

Through something Koo calls an “exponential activation trick,” he reduces the network’s false positive predictions, cutting back the noise dramatically.

“What it’s showing you is that you can’t only use performance metrics like how accurate you are on examples that you’ve never seen before as a way to evaluate the model’s ability to predict the importance of mutations,” he explained.

Like using the snow to choose between a wolf and a dog, some models are using shortcuts to make predictions.

“While these shortcuts can help them make predictions that [seem more] accurate, like with the data you trained it on, it may not necessarily have learned the true essence of what the underlying biology is,” Koo said.

By learning the essence of the underlying biology, the predictions become more reliable, which means that the neural networks will be making predictions for the right reason.

The exponential activation is a noise suppressor, allowing the artificial intelligence program to focus on the biological signal.

The data Koo trains the program on come from ENCODE, which is the ENCyclopedia Of DNA Elements.

“In my lab, we want to use these deep neural networks on cancer,” Koo said. “This is one of the major goals of my lab’s research at the early stages: to develop methods to interpret these things to trust their predictions so we can apply them in a cancer setting.”

At this point, the work he’s doing is more theoretical than practical.

“We’re still looking at developing further tools to help us interpret these networks down the road so there are additional ways we can perform quality control checks,” he said.

Koo feels well-supported by others who want to understand what these networks are learning and why they are making a prediction.

From here, Koo would like to move to the next stage of looking into specific human diseases, such as breast cancer and autism spectrum disorder, using techniques his lab has developed.

He hopes to link disease-associated variance with a molecular function, which can help understand the disease and provide potential therapeutic targets.

While he’s not a doctor and doesn’t conduct clinical experiments, Koo hopes his impact will involve enabling more trustworthy and useful artificial intelligence programs.

Artificial intelligence is “becoming bigger and it’s undoubtedly impactful already,” he said. “Moving forward, we want to have transparent artificial intelligence we can trust. That’s what my research is working towards.”

He hopes the methods he develops in making the models for artificial intelligence more interpretable and trustworthy will help doctors learn more about diseases.

Koo has increased the size and scope of his lab amid the pandemic. He current has eight people in his lab who are postdoctoral students, graduate students, undergraduates and a master’s candidate.

Some people in his lab have never met in person, Koo said. “I am definitely looking forward to a normal life.”

Stem cell growth, required for kernel development, is controlled in corn by a set of genes called CLEs. But how these genes change the corn is complicated. Using CRISPR genome editing, CSHL researchers found they could change kernel yield and ear size by fine-tuning the activity of one of the CLE genes, ZmCLE7. In the image: an unmodified corn cob with normal ZmCLE7 gene activity (1) is packed with regular rows of kernels. Shutting off ZmCLE7 (2) shortened the cob, disrupted row patterns, and lowered kernel yield. However, decreasing the same gene’s activity (3) led to an increase in kernel yield, while increasing the gene’s activity (4) decreased the kernel yield. Jackson Lab/CSHL 2021

By Daniel Dunaief

The current signal works, but not as well as it might. No signal makes everything worse. Something in the middle, with a weak signal, is just right.

By using the gene-editing tool CRISPR, Cold Spring Harbor Laboratory Professor Dave Jackson has fine-tuned a developmental signal for maize, or corn, producing ears that have 15 to 26 percent more kernels. 

Dave Jackson. Photo from CSHL

Working with postdoctoral fellow Lei Liu in his lab, and Madelaine Bartlett, who is an Associate Professor at the University of Massachusetts Amherst, Jackson and his collaborators published their work earlier this week in the prestigious journal Nature Plants.

Jackson calls the ideal weakening of the CLE7 gene in the maize genome the “Goldilocks spot.” He also created a null allele (a nonfunctional variant of a gene caused by a genetic mutation) of a newly identified, partially redundant compensating CLE gene.

Indeed, the CLE7 gene is involved in a process that slows the growth of stem cells, which, in development, are cells that can become any type of cell. Jackson also mutated another CLE gene, CLE1E5.

Several members of the plant community praised the work, suggesting that it could lead to important advances with corn and other crops and might provide the kind of agricultural and technological tools that, down the road, reduce food shortages, particularly in developing nations.

“This paper provides the first example of using CRISPR to alter promoters in cereal crops,” Cristobal Uauy, Professor and Group Leader at the John Innes Centre in the United Kingdom, explained in an email. “The research is really fascinating and will be very impactful.”

While using CRISPR (whose co-creators won the Nobel Prize in Chemistry in October) has worked with tomatoes, the fact that it is possible and successful in cereal “means that it opens a new approach for the crops that provide over 60% of the world’s calories,” Uauy continued.

Uauy said he is following a similar approach in wheat, although for different target genes.

Recognizing the need to provide a subtle tweaking of the genes involved in the growth of corn that enabled this result, Uauy explained that the variation in these crops does not come from an on/off switch or a black and white trait, but rather from a gradient.

In Jackson’s research, turning off the CLE7 gene reduced the size of the cob and the overall amount of corn. Similarly, increasing the activity of that gene also reduced the yield. By lowering the gene’s activity, Jackson and his colleagues generated more kernels that were less rounded, narrower and deeper.

Uauy said that the plant genetics community will likely be intrigued by the methods, the biology uncovered and the possibility to use this approach to improve yield in cereals.

“I expect many researchers and breeders will be excited to read this paper,” he wrote.

In potentially extending this approach to other desirable characteristics, Uauy cautioned that multiple genes control traits such as drought, flood or disease resistance, which would mean that changes in the promoter of a few genes would likely improve these other traits.

“This approach will definitely have a huge role to play going forward, but it is important to state that some traits will still remain difficult to improve,” Uauy explained.

Jackson believes gene editing has considerable agricultural potential.

“The prospect of using CRISPR to improve agriculture will be a revolution,” Jackson said.

Other scientists recognized the benefits of fine-tuning gene expression.

“The most used type/ thought of mutation is deletion and therefore applied for gene knockout,” Kate Creasey Krainer, president and founder of Grow More Foundation, explained in an email. “Gene modulation is not what you expect.”

While Jackson said he was pleased with the results this time, he plans to continue to refine this technique, looking for smaller regions in the promoters of this gene as well as in other genes.

“The approach we used so far is a little like a hammer,” Jackson said. “We hope to go in with more of a scalpel to mutate specific regions of the promoters.”

Creasey Krainer, whose foundation hopes to develop capacity-building scientific resources in developing countries, believes this approach could save decades in creating viable crops to enhance food yield.

She wrote that this is “amazing and could be the green revolution for orphan staple crops.”

In the United States, the Food and Drug Administration is currently debating whether to classify food as a genetically modified organism, or GMO, if a food producer used CRISPR to alter one or more of its ingredients, rather than using genes from other species to enhance a particular trait.

To be sure, the corn Jackson used as a part of his research isn’t the same line as the elite breeding stock that the major agricultural businesses use to produce food and feedstock. In fact, the varieties they used were a part of breeding programs 20 or more years ago. It’s unclear what effect, if any, such gene editing changes might have on those crops, which companies have maximized for yield.

Nonetheless, as a proof of concept, the research Jackson’s team conducted will open the door to additional scientific efforts and, down the road, to agricultural opportunities.

“There will undoubtedly be equivalent regions which can be engineered in a whole set of crops,” Uauy wrote. “We are pursuing other genes using this methodology and are very excited by the prospect it holds to improve crop yields across diverse environments.”

Feinstein Institutes’ Drs. Kevin Tracey and Christina Brennan break down the current COVID-19 clinical trials and treatments. Photo courtesy of The Feinstein Institutes for Medical Research

By Daniel Dunaief

In a collaboration between Cold Spring Harbor Laboratory and Northwell Health’s Feinstein Institutes for Medical Research, doctors and researchers are seeking patients with mild to moderate symptoms of COVID-19 for an at-home, over-the-counter treatment.

The two-week trial, which will include 84 people who are 18 years old and older, will use a high, but safe dose of Famotidine, or PEPCID, in a double-blind study. That means that some of the participants will receive a placebo while others will get the Famotidine.

Volunteers will receive the dosage of the medicine or the placebo at home and will also get equipment such as pulse oximeters, which measure the oxygen in their blood, and spirometers, which measure the amount of air in their lungs. They will also receive a scale, a thermometer, a fitness tracker and an iPad.

Dr. Christina Brennan. Photo courtesy of The Feinstein Institutes for Medical Research

Northwell Health will send a certified phlebotomist — someone licensed to draw blood — to the participants’ homes to collect blood samples on the first, 7th, 14th, and 28th day of the study.

The study is the first time CSHL and Northwell Health have designed a virtual clinical trial that connects these two institutions.

“What is very powerful with our work with Cold Spring Harbor Laboratory is the ability to do a virtual trial and utilize patient-recorded outcome measures,” said Christina Brennan, a co-investigator on the study and Vice President for Clinical Research for Northwell Health. “I’m thrilled that we’re doing this type of virtual trial. It’s very patient-centric.”

While reports about the potential benefits of Famotidine have circulated around the country over the last year, this study will provide a data-driven analysis.

“If we study this in the outpatient population, then we might have an opportunity to see if [Famotidine] really does play a role in the reduction of the immune overreaction,” Brennan said.

At this point, researchers believe the drug may help reduce the so-called cytokine storm, in which the immune system becomes so active that it starts attacking healthy cells, potentially causing damage to organs and systems.

In an email, Principal Investigator Tobias Janowitz, Assistant Professor and Cancer Center Member at Cold Spring Harbor Laboratory, wrote that “there are some retrospective cohort studies” that suggest this treatment might work, although “not all studies agree on this point.”

In the event that a trial participant developed more severe symptoms, Janowitz said the collaborators would escalate the care plan appropriately, which could include interrupting the use of the medication.

In addition to Janowitz, the medical team includes Sandeep Nadella, gastroenterologist at Northwell, and Joseph Conigliaro, Professor of the Feinstein Institutes for Medical Research.

Janowitz said he does not know how any changes in the virus could affect the response to famotidine.

In the trial, volunteers will receive 80 milligrams of famotidine three times a day.

The dosage of famotidine that people typically take for gastric difficulties is about 20 milligrams. The larger amount per day meant that the researchers had to get Food and Drug Administration approval for an Investigational New Drug.

“This has gone through the eyes of the highest regulatory review,” Brennan said. “We were given the green light to begin recruitment, which we did on January 13th.”

Volunteers are eligible to join the study if they have symptoms for one to seven days prior to entering the trial and have tested positive for the virus within 72 hours.

Potential volunteers will not be allowed in the trial if they have had other medications targeting COVID-19, if they have already used Famotidine in the past 30 days for any reason, if they have severe COVID that requires hospitalization, have a history of Stage 3 severe chronic disease, or if they are immunocompromised by the treatment of other conditions.

Brennan said Northwell has been actively engaged in treatment trials since the surge of thousands of patients throughout 2020.

Northwell participated in trials for remdesivir and also provided the steroid dexamethasone to some of its patients. The hospital system transfused over 650 patients with convalescent plasma. Northwell is also infusing up to 80 patients a day with monoclonal antibodies. The hospital system has an outpatient remdesivir trial.

“Based on all our experience we’ve had for almost a year, we are continuously meeting and deciding what’s the best treatment we have available today for patients,” Brennan said.

Janowitz hopes this trial serves as a model for other virtual clinical trials and is already exploring several potential follow up studies.

Brennan said the best way to recruit patients is to have the support of local physicians and providers. 

People interested in participating in the trial can send an email to [email protected] or call 516-881-7067.

When the study concludes, the researchers will analyze the data and are “aware that information on potential treatments for COVID-19, no matter if the data show that a drug works or does not work, should be made available to the community swiftly,” Janowitz wrote in an email.

The decision to test this medicine as a potential treatment for COVID-19 arose out of a conversation between Director of the Cold Spring Harbor Laboratory Cancer Center Dave Tuveson and CEO of the Feinstein Institute Kevin Tracey.

“I got involved because I proposed and developed the quantitative symptom tracking,” Janowitz explained.

Dr. Christopher Vakoc. Photo from CSHL

On January 23, the Christina Renna Foundation (CRF), together with Cold Spring Harbor Laboratory, will host a free virtual celebration and sarcoma update to mark their 14th Annual Angel’s Wish Gala. Join us in celebrating 14 years of funding cutting edge research into rare pediatric cancer.

The gala will honor Christopher Vakoc, MD., Ph.D., Professor, Cold Spring Harbor Laboratory, 2020 CRF Research Award recipient for the Sarcoma Research Project

The Christina Renna Foundation is a 501(c)(3) public charity supporting children’s cancer research and furthering awareness and education through the support of cancer groups and outreach programs for the direct support of those in need. Funds raised through this event will go to continued research into rhabdomyosarcoma (RMS), a rare and often fatal form of pediatric cancer. In total, CRF has donated over $350,000 to research at CSHL. For more information, please visit: www.crf4acure.org

What: CRF Angel’s Wish Virtual Gala and Sarcoma Research Update

When: January 23, 2021 – 6 p.m. to 7 p.m.

RSVP: https://www.cshl.edu/mc-events/crf-angels-wish-virtual-gala-and-sarcoma-research-update/

From left, Research Assistant Onur Eskiocak, CSHL Fellow Semir Beyaz and graduate student Ilgin Ergin. Photo by Gina Motisi, 2019/CSHL.

By Daniel Dunaief

It’s a catch-22: some promising scientific projects can’t get national funding without enough data, but the projects can’t get data without funding.

That’s where private efforts like The Mark Foundation for Cancer Research come in, providing coveted funding for promising high-risk, high-reward ideas. Founded and funded by Pamplona Capital Management CEO Alex Knaster in 2017, the Foundation has provided over $117 million in grants for various cancer research efforts.

Tobias Janowitz

This year, The Mark Foundation, which was named after Knaster’s father Mark who died in 2014 after contracting kidney cancer, has provided inaugural multi-million dollar grants through the Endeavor Awards, which were granted to three institutions that bring scientists with different backgrounds together to address questions in cancer research. 

In addition to teams from the University of California at San Francisco and a multi-lab effort from Columbia University, Memorial Sloan Kettering Cancer Center and Johns Hopkins University School of Medicine, Cold Spring Harbor Laboratory scientists Tobias Janowitz and Semir Beyaz received this award.

“We are absolutely delighted,” Janowitz wrote in an email. “It is a great honor and we are excited about the work.” He also indicated that the tandem has started the first set of experiments, which have produced “interesting results.”

The award provides $2.5 million for three years and, according to Janowitz, the researchers would use the funds to hire staff and to pay for their experimental work.

Having earned an MD and a PhD, Janowitz takes a whole body approach to cancer. He would like to address how the body’s response to a tumor can be used to improve treatment for patients. He explores such issues as how tumors interact with the biology of the host.

Semir Beyaz

Semir Beyaz, who explores how environmental factors like nutrients affect gene expression, metabolic programs and immune responses to cancer, was grateful for the support of the Mark Foundation.

Beyaz initially spoke with the foundation about potential funding several months before Janowitz arrived at Cold Spring Harbor Laboratory. When the researchers, whose labs are next door to each other, teamed up, they put together a multi-disciplinary proposal.

“If the risks [of the proposals] can be mitigated by the innovation, it may yield important resources or new paradigms that can be incorporated into research proposals that can be funded by the [National Institutes of Health] and other government agencies,” Beyaz said.

Janowitz wrote that he had a lunch together in a small group with Knaster, who highlighted the importance of “high-quality data and high-quality data analysis to advance care for patients with cancer.”

Michele Cleary, the CEO of The Mark Foundation, explained that the first year of the Endeavor program didn’t involve the typical competitive process, but, rather came from the Foundation’s knowledge of the research efforts at the award-winning institutions.

“We wanted to fund this concept of not just studying cancer at the level of the tumor or tumor cells themselves, but also studying the interaction of the host or patient and their [interactions] with cancer,” Cleary said. “We thought this was a fantastic project.”

With five people on the Scientific Advisory Committee who have PhDs at the Foundation, the group felt confident in its ability to assess the value of each scientific plan.

Scientists around the world have taken an effective reductionistic approach to cancer, exploring metabolism, neuroendocrinology and the microbiome. The appeal of the CSHL effort came from its effort to explore how having cancer changes the status of bacteria in the gut, as well as the interplay between cancer and the host that affects the course of the disease.

From left, Becky Bish, Senior Scientific Director, Ryan Schoenfeld, Chief Scientific Officer and Michele Cleary, CEO of The Mark Foundation at a workshop held at the Banbury Center at Cold Spring Harbor Laboratory in September 2019. Photo by Constance Brukin.

These are “reasonable concepts to pursue, [but] someone has to start somewhere,” Cleary said. “Getting funding to dive in, and launch into it, is hard to do if you can’t tell a story that’s based on a mountain of preliminary data.”

Beyaz said pulling together all the information from different fields requires coordinating with computational scientists at CSHL and other institutions to develop the necessary analytical frameworks and models. This includes Cold Spring Harbor Laboratory Fellow Hannah Meyer and Associate Professor Jesse Gillis.

“This is not a simple task,” Beyaz said. The researchers will “collaborate with computational scientists to engage currently available state-of-the-art tools to perform data integration and analysis and develop models [and] come up with new ways of handling this multi-dimensional data.”

Cleary is confident Janowitz and Beyaz will develop novel and unexpected insights about the science. “We’ll allow these researchers to take what they learn in the lab and go into the human system and explore it,” she said.

The researchers will start with animal models of the disease and will progress into studies of patients with cancer. The ongoing collaboration between CSHL and Northwell Health gives the scientists access to samples from patients.

With the Endeavor award, smaller teams of scientists can graduate to become Mark Foundation Centers in the future. The goal for the research the Foundation funds is to move towards the clinic. “We are trying to join some dots between seemingly distinct, but heavily interconnected, fields,” Beyaz said.

Beyaz has research experience with several cancers, including colorectal cancer, while Janowitz has studied colorectal and pancreatic cancer. The tandem will start with those cancers, but they anticipate that they will “apply similar kinds of experimental pipelines” to other cancer types, such as renal, liver and endometrial, to define the shared mechanisms of cancer and how it reprograms and takes hostage the whole body, Beyaz said. 

“It’s important to understand what are the common denominators of cancer, so you might hopefully find the Achilles Heel of that process.”

While Cleary takes personal satisfaction at seeing some of the funding go to CSHL, where she and Mark Foundation Senior Scientific Director Becky Bish conducted their graduate research, she said she and the scientific team at the foundation were passionate to support projects that investigated the science of the patient.

“No one has tried to see what is the cross-talk between the disease and the host and how does that actually play out in looking at cancer,” said Cleary, who earned her PhD from Stony Brook University. “It’s a bonus that an institution that [she has] the utmost respect for was doing something in the same space we cared” to support.

The CSHL research will contribute to an understanding of cachexia, when people with cancer lose muscle mass, weight, and their appetite. Introducing additional nutrition to people with this condition doesn’t help them gain weight or restore their appetite.

Janowitz and Beyaz will explore what happens to the body physiologically when the patient has cachexia, which can “help us understand where we can intervene before it’s too late,” Cleary said.

The CSHL scientists will also study the interaction between the tumor and the immune system. Initially, the immune system recognizes the tumor as foreign. Over time, however, the immune system becomes exhausted.

Researchers believe there might be a “tipping point” in which the immune system transitions from being active to becoming overwhelmed, Cleary said. People “don’t understand where [the tipping point] occurs, but if we can figure it out, we can figure out where to intervene.”

Scientists interested in applying for the award for next year can find information at the web site: https://themarkfoundation.org/endeavor/. Researchers can receive up to $1 million per year for three years. The Mark Foundation is currently considering launching an Endeavor call for proposals every other year.

 

Michael Schatz and Aspyn Palatnick. Photo by Lauryl Palatnick

By Daniel Dunaief

Michael Schatz, Adjunct Associate Professor at Cold Spring Harbor Laboratory, saw some similarities to his own life when he met the then 14-year old Aspyn Palatnick.

Palatnick, who was a student at Cold Spring Harbor High School, had been developing games for the iPhone. When he was that age, Schatz, who is also a Bloomberg Distinguished Associate Professor of Computer Science and Biology at Johns Hopkins University, stayed up late into the evening programming his home computer and building new software systems.

Meeting Palatnick eight years ago was a “really special happenstance,” Schatz said. He was “super impressed” with his would-be young apprentice.

When he first met Schatz, Palatnick explained in an email that he “realized early on that he would be an invaluable mentor across research, computer science, and innovation.”

Palatnick was looking for the opportunity to apply some of the skills he had developed in making about 10 iPhone games, including a turtle racing game, to real-world problems.

Knowing that Palatnick had no formal training in computer science or genetics, Schatz spent the first several years at the white board, teaching him core ideas and algorithms.

“I was teaching him out of graduate student lecture notes,” Schatz said.

Schatz and Palatnick, who graduated with a bachelors and master’s from the University of Pennsylvania and works at Facebook, have produced a device which they liken to a “tricorder” from Star Trek. Using a smart phone or other portable technology, the free app they created called iGenomics is a mobile genome sequence analyzer.

The iPhone app complements sequencing devices Oxford Nanopore manufactures. A mobile genetic sequencer not only could help ecologists in the field who are studying the genetic codes for a wide range of organisms, but it could also be used in areas like public health to study the specific gene sequences of viruses like SARS-CoV-2, which causes COVID-19.

In a paper published in GigaScience, Schatz and Palatnick describe how to use iGenomics to study flu genomes extracted from patients. They also have a tutorial on how to use iGenomics for COVID-19 research.

While developing the mobile sequencing device wasn’t the primary focus of Schatz’s work, he said he and others across numerous departments at Johns Hopkins University spent considerable time on it this summer, as an increasing number of people around the world contracted the virus.

“It very rapidly became how I was spending the majority of my time,” said Schatz.

Palatnick is pleased with the finished product.

“We’ve made DNA sequence analysis portable for the first time,” he explained in an email.

Palatnick said the app had to use the same algorithms as traditional genomics software running on supercomputers to ensure that iGenomics was accurate and practical. Building algorithms capable of rendering DNA alignments and mutations as users tapped, scrolled and pinched the views presented a technical hurdle, Palatnick wrote.

While Schatz is optimistic about the vaccinations that health care workers are now receiving, he said a mass vaccination program introduces new pressure on the virus.

“We and everyone else are watching with great interest to see if [the vaccinations] cause the virus to mutate,” Schatz said. “That’s the big fear.”

Working with the sequences from Nanopore technology, iGenomics can compare the entire genome to known problematic sequences quickly. Users need to get the data off the Oxford Nanopore device and onto the app. They can do that using email, from Dropbox or the web. 

In prior viral outbreaks, epidemiologists traveled with heavier equipment to places like West Africa to monitor the genome of Ebola or to South and Central America to study the Zika virus genome.

“There’s clearly a strong need to have this capability,” Schatz said.

Another iGenomics feature is that it allows users to airdrop any information to people, even when they don’t have internet access.

Schatz urged users to ensure that they use a cloud-based system with strong privacy policies before considering such approaches, particularly with proprietary data or information for which privacy is critical.

As for COVID-19, people with the disease have shown enough viral mutations that researchers can say whether the strain originated in Europe or China.

“It’s kind of like spelling mistakes,” Schatz said. “There are enough spelling mistakes where [researchers] could know where it came from.”

Palatnick described iGenomics as an “impactful” tool because the app has increased the population of people who can explore the genome from institutional researchers to anyone with an iPhone or iPad.

In the bigger picture, Schatz is broadly interested in learning how the genome creates differences.

“It’s important to understand these messages for the foods we eat, the fuels we use, the medicines we take,” Schatz said. “The next frontier is all about interpretation. One of the most powerful techniques is comparing one genome to another.”

Schatz seeks out collaborators in a range of fields and at numerous institutions, including Cold Spring Harbor Laboratory.

Schatz and W. Richard McCombie, Professor at CSHL, are studying the genomes of living fossils. These are species that haven’t evolved much over millions of years. They are focusing on ancient trees in Australia that have, more or less, the same genetic make up they did 100 million years ago.

As for Palatnick, Schatz described his former intern and tricorder creating partner as a “superstar in every way.” Schatz said it takes considerable fortitude in science, in part because it takes years to go from an initial idea on a napkin to something real.

Down the road, Schatz wouldn’t be surprised if Palatnick took what he learned and developed and contributed to the founding of the next Twitter or Facebook.

“He has that kind of personality,” Schatz said.

Dennis Plenker Photo by Bob Giglione, 2020/ CSHL

By Daniel Dunaief

If the job is too easy, Dennis Plenker isn’t interested.

He’s found the right place, as the research investigator in Cold Spring Harbor Laboratory Cancer Center Director Dave Tuveson’s lab is tackling pancreatic cancer, one of the more intractable forms of cancer.

Plenker joined Tuveson’s lab in 2017 and is the technical manager of a new organoid facility.

Organoids offer hope for a type of cancer that often carries a poor prognosis. Researchers can use them to find better and more effective treatments or to develop molecular signatures that can be used as a biomarker towards a specific treatment.

Scientists can take cells from an organoid, put them in miniature dishes and treat them with a range of drugs to see how they respond.

The drugs that work on the organoids offer potential promise for patients. When some of these treatments don’t work, doctors and researchers can continue to search for other medical solutions without running the risk of making patients ill from potentially unnecessary side effects.

“Challenges are important and there is a sweet spot to step out of my comfort zone,” Plenker explained in an email.

Dennis Plenker Photo by Bob Giglione, 2020/ CSHL

In an email, Tuveson described Plenker as a “pioneer” who “likes seemingly impossible challenges and we are all counting on him to make breakthroughs.”

Specifically, Tuveson would like Plenker to develop a one-week organoid test, where tissue is processed into organoids and tested in this time frame.

Organoids present a cutting edge way to take the modern approach to personalized medicine into the realm of cancer treatments designed to offer specific guidance to doctors and researchers about the likely effectiveness of remedies before patients try them.

Plenker and others in Tuveson’s lab have trained researchers from more than 50 institutions worldwide on how to produce and use organoids.

“It’s complicated compared to conventional tissue culture,” said Plenker, who indicated that considerably more experience, resource and time is involved in organoid work. “We put a lot of effort into training people.”

Tuveson explained that the current focus with organoids is on cancer, but that they may be useful for other conditions including neurological and infectious diseases.

The way organoids are created, scientists such as Plenker receive a biopsy or a surgical specimen. These researchers digest the cells with enzymes into singular cells or clumps of single cells and are embedded. Once inside the matrix, they form organoids.

When they “have enough cells, we can break these down and put them into multi-well plates,” Plenker explained. In these plates, the scientists test different concentrations and types of drugs for the same patient.

It’s a version of trial and error, deploying a range of potential medical solutions against cells to see what weakens or kills cells.

“If you do that exercise 100 times, you can see how many times compound A scores vs. C, E and F. You get a sense of what the options are versus what is not working,” Plenker said.

While scientists like Plenker and Tuveson use targeted drugs to weaken, cripple or kill cancer, they recognize that cancer cells themselves represent something of a molecular moving target.

“There is a very dynamic shift that can happen between these subtypes” of cancer, Plenker said. “That can happen during treatment. If you start with what’s considered a good prognosis, you can end up with a higher fraction of basal cancer cells” which are more problematic and have a worse prognosis. “We and others have shown that you have a mixture of cell types in your tumor all the time.”

Part of what Plenker hopes to discover as the director of the organoid center is the best combination of ingredients to foster the growth of these versatile and useful out-of-body cancer models.

The gel that helps the cells grow is something Plenker can buy that is an extracellular matrix rich matter that is of murine, or rodent, origin. He hopes to develop a better understanding of some of these proprietary products so he can modify protocols to boost the efficiency of the experiments.

Plenker is “trying to innovate the organoids, and so he may need to adjust conditions and that would include inventing his own recipes,” Tuveson explained.

The facility, which received support from the Lustgarten Foundation, will engage in future clinical trials.

The type of treatments for pancreatic cancer patients typically fall into two arenas. In the first, a patient who is doing well would get an aggressive dose of chemotherapy. In the second, a patient who is already sick would get a milder dose. Determining which regimen is based on the current diagnostic techniques.

Plenker and his wife Juliane Dassler-Plenker, who works as a post-doctoral fellow in the lab of Mikala Egeblad at Cold Spring Harbor Laboratory, live in Huntington. The pair met in Germany and moved to the United States together.

Plenker calls himself a “foodie” and appreciates the hard work that goes into creating specific dishes.

In his career, Plenker always “wanted to help people.” He has appreciated the latest technology and has disassembled and put back together devices to understand how they work.

Prior to the pandemic, Plenker had gone on short trips to Germany to visit with friends and relatives. He is grateful for that time, especially now that he is much more limited in where he can go. He appreciates his landlord and a second American family which helps the couple feel welcomed and grateful.

In 2017, Plenker recalls attending a talk Tuveson gave in Washington, D.C. in which he invited anyone in the audience who wanted to improve a test to come and talk to him after the presentation.

“I was the only one in that regard who talked to him” after that lecture, Plenker said.