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Cold Spring Harbor Laboratory

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Olaf Kleingbeil at the Pezcoller24 Symposium in Italy in June, 2024. Photo by Claudia Tonelli

By Daniel Dunaief

The wreck-and-check method sometimes works, providing the kind of clues that lead to cures.

In the case of cancer, however, taking out one gene or one protein may not be enough, particularly when a combination contributes to cancer growth or to inactivating the body’s defenses against the disease.

Olaf Klingbeil. Photo courtesy of CSHL

Over the course of seven years, first developing a technique, then searching for possible clues about what the work might reveal, Olaf Klingbeil, a postdoctoral researcher in the lab of Professor Chris Vakoc at Cold Spring Harbor Laboratory, discovered two proteins that work together to do cancer’s bidding.

Called Mark 1 and Mark 2, these two proteins in combination keep a tumor suppressor called Hippo from doing its job, enabling a wide range of cancers from continuing to grow.

The Hippo pathway is one of the most dysfunctional in all human cancer biology.

The journey to this discovery is as compelling as the finding itself.

Klingbeil honed a technique that took out a series of genes, hoping to find out how more than one protein might be involved in the kind of on-off switch geneticists are often seeking to slow or squelch cancer.

Indeed, disrupting either of the proteins on its own would not have been enough, as the disease would have progressed with a singular inhibitor.

“When you manipulate A or B individually” you don’t see much difference in the cancer cells, Vakoc said. “When you manipulate A plus B, you get a massive effect.”

Vakoc suggested that his lab developed a new technology to find cancer targets, enabling them to search for processes and contributors that were otherwise invisible. Klingbeil used lentiviruses to introduce CRISPR gene editing into cancer cells.

“What [Klingbeil] developed, a method where you can introduce two [changes] at the same time, can be engineered to target combinations of genes,” Vakoc said. “It took years to figure out how to do this.”

Klingbeil explored the effect of making these double knockouts through many perturbations.

“It was the largest project in my lab to this point,” said Vakoc.

A eureka moment

Klingbeil examined several potential leads that might provide clues about how to attack cancer cells. He published 1,719 single gene knockouts and 2,529 paralog double knockouts and expected to find a few jewels. 

Christopher Vakoc. Photo courtesy of CSHL

He likens the process to panning for gold at a creek, which involves getting rid of numerous stones before discovering that gold nugget, which, in this case came in the form of two kinases, which add phosphate labels to macromolecules.

When Klingbeil honed in on Mark 2 and Mark 3, he couldn’t immediately understand why inhibiting these enzymes affected some forms of cancer, but not all of them. 

The postdoctoral researcher read a study in which the researchers looked at the tumor suppressive function of Yap/Taz in leukemia and neuroendocrine cancers and realized that these were the cancer types that didn’t show a reaction to inhibiting these kinases.

This was the first hint that Marks 2 and 3 and Yap/Taz might work together, Klingbeil explained.

The affected cancers include liver, lung, colorectal, ovarian, triple negative breast cancer, pancreatic cancer and prostate cancer. That list also includes rhabdomyosarcoma, a rare form of pediatric cancer for which Vakoc, in particular, is eager to develop new treatments.

While numerous scientists are seeking ways to block this pathway directly, the focus on Mark 2 and Mark 3 presents a new potential opportunity.

Marks are “totally overlooked in the community” and are “not a known target,” said Vakoc. “This is the first paper that announces these as cancer targets in a compelling way.”

An existing drug

Once he discovered this link, Klingbeil searched for existing drugs that might target Marks 2 and 3. Fortunately, he found one that Merck had tried to develop for Alzheimer’s disease.

While that didn’t work as well as the pharmaceutical company had hoped, the CSHL researchers are looking to use it as a starting point for a future therapy.

“We are excited that there’s a chemical matter” that might help treat cancer, Vakoc said, adding that such a treatment will likely require “a lot of love by chemists to give them the ideal attributes” for any therapeutic approach.

The drug Merck produced inhibited Marks 1 and 4 as well as 2 and 3, which provides opportunities to tailor it for the most relevant enzymes. By increasing the specificity of the drug for two of the four proteins, researchers and pharmaceutical companies could reduce the side effects of inhibition.

To be sure, Vakoc and Klingbeil cautioned that this discovery, while encouraging, wouldn’t likely provide a magic bullet for cancer, which has a way of becoming resistant to treatments and to tapping into other unknown or unseen pathways to continue to cause harm.

Effective future treatments that involve inhibiting Marks 2 and 3 could require the use of a combination of therapies, which might outmaneuver or slow the progression of cancer.

A personal message

Earlier this year, Klingbeil learned that the journal Cancer Discovery had accepted the paper for publication in an unusual way. He was attending a dinner one night at a conference in Italy when Elizabeth McKenna, the Executive Editor of the journal, approached him.

“She told me she was about to send an email” to Vakoc that the paper was accepted, Klingbeil said. “I was very excited. I’m happy to publish it and that I could convince the most critical reviewers about the value of the work.”

After a productive and rewarding collaboration with Vakoc, Klingbeil is preparing for the next steps in his career. He is speaking with various institutions, particularly in Europe, where he can be closer to his family and his native Berlin, Germany while continuing to advance his scientific career. He plans to continue to work with Vakoc after he leaves.

“The discovery was big enough to carve out a piece for him and me,” Klingbeil said and suggested he would study Mark function in pancreatic cancer in more detail.

On the personal front, fate lent a hand when Klingbeil first arrived on Long Island.

He started his life here in the middle of the winter, without a car or a driver’s license. The lab provided temporary housing on campus. He had a choice to share an apartment with either a French or an Italian postdoctoral researcher.

He chose to live with postdoctoral researcher Claudia Tonelli, who works in the lab of Cancer Center Director David Tuveson and is now his partner. The two researchers, who started dating a few months after living together, have a daughter Lily.

As for his work, he is cautiously optimistic that this discovery may one day help with new and effective therapies.

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Bottom row, from left, Andrew Whitely, VP Business Development and Technology Transfer at CSHL; Dr Susan Poser, President of Hofstra University; students Dimitri Dumontier; Charlie Chung, Yong Lin, Stephen Staklinski and Javier Anduaga; Dr. Janet A. Lenaghan, Dean of the Frank G. Zarb School of Business at Hofstra University; and Erick Hunt, Director of the Institute of Innovation and Entrepreneurship at Hofstra University Top row, from left, students Zifei Wang, Viet Hang Lee, Yujia Li, Jed de Ruiter-Swain, and Eva Lentsch. Photo courtesy of Hofstra University

By Daniel Dunaief

Ten graduate students and postdoctoral researchers stepped outside their familiar surroundings at Cold Spring Harbor Laboratory into a different campus and discipline recently.

As a part of the inaugural Bioscience Business Innovation Program, these developing scientists spent a week working with a collection of business professors at the Frank G. Zarb School of Business at Hofstra University, where they learned a range of subjects such as financial planning, intellectual property, leadership and project management.

The program, which will include a second week of training in March, is designed to teach developing scientists about market validation, Food and Drug Administration processes, and the creation of business models. The program also teaches leadership, team building and communications, which could help researchers who enter the pharmaceutical or biotechnology fields after they leave CSHL.

The goal is to “familiarize these new researchers on several aspects of business, marketing, finance, and management” which will help them consider the potential commercial application of their work, said Anoop Rai, Finance Professor at Zarb and one of the instructors in the Bioscience Business effort.

Indeed, in applying for some grants for startups from agencies like the National Science Foundation, researchers need to answer questions relating to growth, profitability and a target market.

“A knowledge of business is probably very important in that sense,” added Rai.

Scientists often have an interest in developing an innovation that could be useful for society, whether that’s a drug to treat a disease, a test to monitor health, or a new product. Such efforts need to “be marketed to become successful,” Rai said. “This group may, at some point, try and make [their findings] into a successful venture.”

Scientists would benefit from knowing about business in case they move to the next stage in their research or business development. To be sure, a two-week course offers an opportunity to learn and to develop an awareness of the business world, but doesn’t provide a comprehensive formula for success. The students will “get a feel more on the venture funding side, not so much on the complete running of a business,” said Rai.

Still, at the end of the program, the CSHL researchers will have an opportunity to make a pitch alongside a law student and a MBA candidate that a group of experts will evaluate. These pitches will require a basic understanding of business.

Student experience

Some of the students, who put most of their research aside for a week to immerse themselves in intensive training from a host of lecturers and experts, felt they have already benefited from such instruction.

Stephen Staklinski

One of the biggest take-home messages for PhD candidate Stephen Staklinski, who works in the lab of Professor Adam Siepel, involved understanding the consumers of any future product.

In research, Staklinski reads papers and looks for information that’s missing in the field. He rarely communicates directly with people who might be affected by any future discovery until a project is well under way. With a business viewpoint, he gained a new perspective he feels he can integrate effectively into his research.

Staklinski recognized the value of talking to physicians and cancer patients about some of their biggest issues. He sees the benefit of these open communications about how to serve patients who are battling various conditions.

In his current research, Staklinski builds statistical probabilistic models around the human genome. Specifically, he’s looking at molecular sites in RNA and is searching for targets that lead to metastatic processes. In working with experimental collaborator, Staklinski said he can “think about therapeutics to block this.”

Viet Hang Le, a postdoctoral researchers in the lab of Professor Linda Van Aelst, felt she received an introduction on how to develop fundamental research findings towards making new therapies.

“We got to learn about the laws and policies involved” in creating a new company, said Le. On the clinical safety side, she also learned how new products maneuver through health care and reach patients.

Her original curiosity was to see how research findings could lead to real-life treatments. Understanding business fundamentals opens more career options.

Indeed, even if Le and her colleagues continue to conduct research, she feels she can communicate more effectively with industry partners. It also whet her appetite for more business learning.

“It really bridges the gap between our background in fundamental science and the requirement for an MBA course,” Le explained. 

She is working on two projects in Van Aelst’s lab. In the first, she is studying early onset epilepsy, which is a symptom of an X-linked intellectual disability in patients carrying a mutation in the gene Oligophrenin 1.

In the second, she is exploring how the nervous system influences the progression of cancer in main tumors and metastatic tumors.

“We built a hypothesis on how different branches of nerves might increase the growth of cancer,” said Le. In Van Aelst’s lab, they are working with primary breast cancer and liver metastasis.

Originally from Dan Nang, Vietnam, Le spent a number of weeks during several summers as a part of the US Navy Pacific Partnership delivering medical treatment to medically underdeveloped areas in the country.

Through her lab work and any budding business interest, she would like to figure out how to deliver medical care to patients who might struggle with the financial or logistical challenge of affording care.

By connecting with experts who’ve negotiated various obstacles, “I’m gaining a clearer sense of how to streamline the path from discovery to patient care, cutting down unnecessary costs and time without compromising safety,” she said.

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Cold Spring Harbor Laboratory. Photo courtesy Cold Sping Harbor Laboratory website

By Daniel Dunaief

A stock fund is taking a page out of the Newman’s Own playbook.

The food company which was started by the late actor Paul Newman and author A.E. Hotchner donates its after tax profits to charity through the Newman’s Own Foundation, enabling consumers to feel that they aren’t just covering their salad with tasty dressing but are helping the world through their consumer choices.

Range Cancer Therapeutics, an exchange-traded fund that purchases a broad basket of cancer therapeutic stocks, created a new partnership with Cold Spring Harbor Laboratory to contribute to cancer research.

The fund, which was started in 2015, plans to contribute 23 percent of its revenues, reflecting the 23 pairs of chromosomes in the human genome, each quarter to Cold Spring Harbor Laboratory.

“The contribution from Range will directly benefit the research efforts at CSHL, underscoring our commitment to advancing scientific innovation in oncology therapeutics,” Range ETF’s founder and CSHL Association Board Member Tim Rotolo, said in a statement. The ETF provides “exposure to nearly the entire lifecycle of drug development and distribution, and this new collaboration with CSHL provides an opportunity for investors to also see their money go toward the earliest stages of cancer breakthroughs.”

Revenues collected by the fund are likely to vary by quarter, depending on the amount of money the fund manages. With an estimated $12.1 million in assets under management as of the end of September and an expense ratio of 0.79%, the fund could contribute about $21,850.

“Hopefully, people will feel when they’re buying the ETF that they are in some ways supporting cancer research,” said Charles Prizzi, Senior Vice President for Advancement & Special Advisor to CSHL President Bruce Stillman.

Prizzi anticipates that the funding could support the lab’s efforts to conduct a broad range of research as CSHL’s staff, who come to the site from all over the world, seek to address the kinds of questions that can lead to advancements in a basic understanding of processes as well as to translational breakthroughs that can help in the prevention, diagnosis and treatment of various diseases.

Prizzi hopes this partnership will attract attention and inspire other fund managers or businesses to contribute to the lab, particularly amid periods when the budgets for federal funding agencies that support research rise and fall.

Borrowing from the language of genetics, Prizzi hoped that this kind of arrangement will be “replicated” by others.

 NASDAQ event

The NASDAQ stock market, which is where the Range Cancer Therapeutics Fund trades under the ticker CNCR, will celebrate the partnership on November 14th in New York City.

The Nasdaq tower will feature a visual display, while Range ETFs and CSHL leadership and guests come together at the Nasdaq podium to mark the ongoing contribution.

Dave Tuveson, head of the Cancer Center, Professor Adrian Krainer, who developed an effective treatment for spinal muscular atrophy using antisense oligonucleotide to affect gene splicing, Vice Chair Howard Morgan, and Goldman Sachs’s Roy Zuckerberg, and others will attend the event.

d Spring Harbor Laboratory President Bruce Stillman. File photo

“Cold Spring Harbor Laboratory is one of only seven national basic biological research cancer centers designated by the National Cancer Institute in Washington, DC,” Bruce Stillman, CEO of the lab said in a statement. “The institution is investing heavily in the growth of our cancer program, specifically in multidisciplinary, collaborative ventures as part of our new brain-body physiology initiative.”

Prizzi is often searching for novel ways to support research and was pleased with the contribution and hopeful that it would spur other creative donations and support.

“I hope people will learn from it and copy it,” Prizzi said. “It will benefit the lab for many years to come.”

Rotolo joined the board at CSHL earlier this year and has supported the lab for about a decade.

Rotolo had approached the lab to establish this financial commitment.

The laboratory is a 501c3 nonprofit institution, which means that donations to the lab are tax deductible.

Prizzi suggested that interested donors often reach out to him towards the end of December.

“We would love to have more people support what we’re doing,” said Prizzi.

CSHL is home to eight Nobel Prize winners and employs 1,000 people, including 600 scientists, students and technicians.

The Meetings & Courses Program bring in more than 12,000 scientists from around the world each year, offering opportunities for researchers to meet and establish collaborations and to learn about the latest scientific breakthroughs.

CSHL is in the first phase of a Foundations for the Future project, which is a seven-acre expansion effort that will tackle research in neuroscience, neuro-AI and the brain-body. Scientists will pursue better patient outcomes by exploring cancer’s whole-body impacts.

In the second phase of the project, the lab will create a new conference center and collaborative research center.

As for the connection with Range, Prizzi added that CSHL is a “lab, we like experiments. This is like an experiment. I hope it goes well and other people build off of it.”

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Kate Alexander. Photo courtesy of CSHL

By Daniel Dunaief

In the nucleus of the cell, researchers often focus on the genetic machinery, as the double-helical DNA sends signals that enable the creation of everything from my fingers that are typing these words to your brain that is processing what you’ve read.

But DNA, which occupies most of the nucleus, is not alone. Scattered through the nucleus are protein and RNA filled structures that have an influence on their important gene-bearing nuclear cohabitants, including speckles.

One of the newest members of the Cold Spring Harbor Laboratory team, Assistant Professor Kate Alexander, who joined the lab in August, is focused on a range of questions about these speckles, which represent about 10 to 30 percent of the nuclear volume.

Preliminary data from Alexander’s lab support the idea that speckles can signal how a person responds to various types of therapy, although careful extensive follow up studies are needed, Alexander explained. She would like to know how the speckles are affecting the genetic machinery.

While speckles have been known since 1910, the ways they affect healthy cells and diseased cells remains a mystery. In some cases, normal or aberrant speckles can signal how a person responds to various types of therapy.

Normal speckles are in the center of the cell nucleus, while aberrant speckles are more scattered. Aberrant speckles can activate some of the surrounding DNA.

At this point, Alexander and her colleagues have “found that normal or aberrant speckle states correlate with survival of clear cell renal cell carcinoma. This accounts for over 80 percent of all kidney cancers.”

Medical choices

After a patient with clear cell renal cell carcinoma receives a cancer diagnosis, the first line of treatment is usually surgery to remove the tumor in the kidney. In addition, doctors could treat the tumor with a systematic anti-cancer therapy. The treatments themselves can and often do cause difficult side effects, as therapies can harm healthy cells and can disrupt normal biological functioning.

Normal speckles look something like the face of the man on the moon and are more centrally located.

Alexander is hoping speckles will help predict the state of the tumor, offering clues about how it might respond to different types of treatments. She could envision how aberrant speckles could correlate with better responses to one drug, while normal speckles might correlate with better responses to another treatment.

In her research, Alexander is exploring how DNA is organized around speckles, as well as how the speckles affect DNA.

“Speckles can change and impact what’s happening to all the DNA that’s surrounding them,” she said. 

Over 20 tumor types show evidence for both normal and aberrant speckles. Aberrant tumors can occur in many types of cancer.

“The consequence of [speckles] becoming normal or aberrant are starting to become more clear,” she said, although there is “still a lot to learn.”

Alexander is trying to figure out how to alter the conformation of these speckles. During cancer, she suspects these speckles may get trapped in a particular state.

In one of the first experiments in her lab, she’s culturing cells in an incubator and is trying to predict what cues may cause speckles in those cells to switch states. 

‘Speckle club’ leader

Alexander previously did postdoctoral research at the University of Pennsylvania in the laboratory of Shelley Berger, where she was also a Research Associate. She led a subgroup in the lab known as the “speckle club.”

Charly Good, who is now Senior Research Investigator in Berger’s lab, worked with Alexander at Penn from 2017 until this summer.

Aberrant speckles are scattered throughout the nucleus.

Alexander “helped recruit me to the postdoc I ended up doing,” said Good who appreciated Alexander’s computational skills in analyzing big data sets. Speckles represent an “up and coming area” for research, which Alexander and Berger are helping lead, Good suggested.

Alexander’s quick thinking meant she would go to a talk and would email the speaker as soon as she got back to her desk. “Her brain is always spinning,” said Good.

Alexander is building her lab at CSHL. Sana Mir is working as a technician and is helping manage the lab. Recently, Hiroe Namba joined the group as a postdoctoral researcher. In the next few years, Alexander would like to add a few graduate students and, within five years, have about eight people.

Originally from Tigard, Oregon, Alexander attended Carleton College in Northfield, Minnesota. In her freshman year, she tried to get into a physics class that was full and wound up taking a biology class. She was concerned that biology classes were mostly memorization. When she started the course, she appreciated how the science involved searching for missing pieces of information.

Cold Spring Harbor Laboratory appealed to her because she could go in whatever direction the research took her.

For Alexander, scientific questions are like a layer of cloth with a few threads sticking out.

“You see one sticking out and you start to pull,” Alexander said. “You don’t necessarily know what’s going to come out, but you keep getting the urge to pull at that thread. You realize that it is connected to all these other things and you can look at those, too.”

She is excited to cross numerous disciplines in her work and is eager to think about how her research might “interplay across those fields and boundaries.”

Speckle origins

As for speckles, Alexander observed during her postdoctoral research how one factor seemed to influence a neighborhood of genes.

For that to occur, she realized that something had to affect those genes at the same time in the physical space. She hadn’t known about speckles before. A few of her colleagues, including Good, came across speckles in their analysis. That made Alexander curious about what these speckles might be doing.

She saw an opening to pursue connections between changes in these potential gene activators and illnesses.

Researchers know that viruses can use speckles to help them copy themselves.

If they are used by viruses “they must be important” and they “probably go wrong in a lot of diseases,” Alexander said. There are a series of neurodevelopmental disorders called “speckleopathies” that involve mutations in proteins found inside speckles.

“We have the computational and experimental tools to start investigating them across a wide variety of conditions,” she said.

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Shushan Toneyan and Peter Koo at Cold Spring Harbor Laboratory. Photo by Gina Motisi/CSHL

By Daniel Dunaief

The real and virtual world are filled with so-called “black boxes,” which are often impenetrable to light and contain mysteries, secrets, and information that is not available to the outside world.

Sometimes, people design these black boxes to keep concepts, ideas or tools outside the public realm. Other times, they are a part of a process, such as the thinking behind why we do certain things even when they cause us harm, that would benefit from an opening or a better understanding.

In the world of artificial intelligence, programs learn from a collection of information, often compiling and comparing enormous collections of data, to make a host of predictions.

Companies and programmers have written numerous types of code to analyze genetic data, trying to determine which specific mutations or genetic alterations might lead to conditions or diseases.

Left on their own, these programs develop associations and correlations in the data, without providing any insights into what they may have learned.

That’s where Peter Koo, Assistant Professor at Cold Spring Harbor Laboratory, and his former graduate student Shushan Toneyan come in.

The duo recently published a paper in Nature Genetics in which they explain a new AI-powered tool they designed called CREME, which explored the genetic analysis tool Enformer.

A collaboration between Deep Mind and Calico, which is a unit of Google owner Alphabet, Enformer takes DNA sequences and predicts gene expression, without explaining what and how it’s learning.

CREME is “a tool that performs like large-scale experiments in silico [through computer modeling] on a neural network model that’s already been trained,” said Koo. 

“There are a lot of these models already in existence, but it’s a mystery why they are making their predictions. CREME is bridging that gap.”

Award winning research

Indeed, for her work in Koo’s lab, including developing CREME, Toneyan recently was named a recipient of the International Birnstiel Award for Doctoral Research in Molecular Life Sciences.

“I was genuinely surprised and happy that they selected my thesis and I would get to represent CSHL and the Koo lab at the ceremony in Vienna,” Toneyan, who graduated from the School of Biological Sciences, explained. 

Toneyan, who grew up in Yerevan, Armenia, is currently a researcher in The Roche Postdoctoral Fellowship Programme in Zurich, Switzerland.

She said that the most challenging parts of designing this tool was to focus on the “interesting and impactful experiments and not getting sidetracked by more minor points more likely to lead to a dead end.”

She credits Koo with providing insights into the bigger picture.

New knowledge

Without taking DNA, running samples in a wet lab, or looking at the combination of base pairs that make up a genetic code from a live sample, CREME can serve as a way to uncover new biological knowledge.

CREME interrogates AI models that predict gene expression levels from DNA sequences.

“It essentially replicates biological or genetic experiments in silico through the lens of the model to answer targeted questions about genetic mechanisms,” Toneyan explained. “We mainly focused on analyzing the changes in models outputs depending on various perturbations to the input.”

By using computers, scientists can save considerable time and effort in the lab, enabling those who conduct these experiments to focus on the areas of the genome that are involved in various processes and, when corrupted, diseases.

If scientists conducted these experiments one mutation at a time, even a smaller length sequence would require many experiments to analyze.

The tool Koo and Toneyan created can deduce precise claims of what the model has learned.

CREME perturbs large chunks of input sequence to see how model predictions change. It interrogates the model by measuring how changes in the input affect model outputs.

“We need to interpret AI models to trust their deployment,” Toneyan said. “In the context of biological applications, we are also very interested in why they make a certain prediction so that we learn about the underlying biology.”

Using ineffective and untested predictive models will cause “more harm than good,” added Koo.  “You need to interpret [the AI model’s] programs to trust them for their reliable deployment” in the context of genetic studies

Enhancers

Named for Cis Regulatory Element Model Explanations, CREME can find on and off switches near genetic codes called enhancers or silencers, respectively.

It is not clear where these switches are, how many there are per gene and how they interact. CREME can help explore these questions, Toneyan suggested.

Cis regulatory elements are parts of non-coding DNA that regulate the transcription of nearby genes, altering whether these genes manufacture or stop producing proteins.

By combining an AI powered model such as Enformer with CREME, researchers can narrow down the possible list of enhancers that might play an important genetic role.

Additionally, a series of enhancers can sometimes contribute to transcription. A wet lab experiment that only knocked one out might not reveal the potential role of this genetic code if other nearby areas can rescue the genetic behavior.

Ideally, these models would mimic the processes in a cell. At this point, they are still going through improvements and are not in perfect agreement with each other or with live cells, Toneyan added.

Scientists can use the AI model to aid in the search for enhancers, but they can’t blindly trust them because of their black box nature.

Still, tools like CREME help design genetic perturbation experiments for more efficient discovery.

At this point, the program doesn’t have a graphical user interface. Researchers could use python scripts released as packages for different models.

In the longer term, Koo is hoping to build on the work he and Toneyan did to develop CREME.

“This is just opening the initial doors,” he said. “One could do it more efficiently in the future. We’re working on those methods.”

Koo is pleased with the contribution Toneyan made to his lab. The first graduate student who worked with him after he came to Cold Spring Harbor Laboratory, Koo suggested that Toneyan “shaped my lab into what it is.”

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Assistant Professor Michael Lukey and postdoctoral researcher Yijian 'Evan' Qiu. Photo courtesy of Michael Lukey lab

By Daniel Dunaief

Cancer is a dangerous and wily adversary. Just when researchers think they have come up with a plan to defeat a deadly disease that takes many forms and that attacks different organs, cancer can figure out a way to persist.

Researchers have known that breast cancer uses the amino acid glutamine to power its high energy needs. To their disappointment, when they’ve blocked glutamine or reduced its availability, cancer somehow carries on.

An adaptable foe, cancer has figured out how to find an alternative metabolic pathway that can use the same energy or carbon source when its level gets low.

Cold Spring Harbor Laboratory Assistant Professor Michael Lukey and postdoctoral researcher Yijian “Evan” Qiu have discovered how a form of breast cancer has a back up plan, enabling it to survive despite glutamine deprivation.

“Analysis of tumor samples has revealed that glutamine is often depleted within the tumor microenvironment, so we were interested in understanding how seemingly ‘glutamine addicted’ cancer cells adapt to this challenge,” Lukey explained..

In research published last week in the journal Nature Metabolism, the Cold Spring Harbor Laboratory researchers discovered and quieted a type of breast cancer’s alternate energy source.

This form of breast cancer typically uses glutamine, which is one of the most common amino acids, to power its disease-driven machinery. When Qiu and Lukey blocked the formation of alpha-ketoglutarate, which is a metabolite normally derived from glutamine and then glutamate, they significantly repressed the growth of tumors in animal models of the disease.

Cancer cells turn on this alternative pathway that can catalyze glutamate into alpha-ketoglutarate.

“Cancer is always evolving and adapting,” said Qiu. “We need to stay ahead as scientists.”

The results of this research suggest a possible approach to treating cancer, depriving the disease of ingredients it needs to feed the kind of runaway growth that threatens human health. Limiting key ingredients could come from applying specific inhibitors, extracellular enzymes or antimetabolites.

Their work could have implications and applications in other forms of cancer.

The time between observing a promising result in the lab and a new therapy typically takes years. In this case, however, treatments that use inhibitors of glutamine have been well-tolerated in animals and humans. Qiu also did not observe any side effects in animal models in his study, which could potentially accelerate the process of creating a new therapy.

To be sure, developing treatments that cut off cancer’s primary and back up energy supply may not be sufficient, as cancer may have other metabolic moves up its figurative sleeves.

“Cancer cells typically exhibit metabolic flexibility, such that they can adapt to a variety of metabolic stresses,” said Lukey. “It remains to be seen if they can ultimately adapt to long-term blockade of the axis that we identified, but so far we have not seen this happen.”

A search for the back up plan

Qiu and Lukey speculated at the beginning of Qiu’s Cold Spring Harbor Laboratory experience in August of 2020 that cancer cells likely had another energy option.

“The fact that cancer cells that should be dependent on glutamine adapted in glutamine-free media in weeks made me believe that the cancer cells must have such a plan B,” Qiu explained.

To figure out why glutamine inhibitors weren’t shrinking tumors in animal models or humans, Qiu removed glutamine from cancer cells, causing over 99.9 percent of the cells to die. A few, however, survived and started proliferating in weeks.

Qiu used RNA-seq analysis to compare the parental and adaptive cells and found that the cells that are glutamine independent upregulated a serine synthesis pathway. These adaptive cells used PSAT1, or phosphoserine aminotransferase 1, to produce alpha-ketoglutarate.

As for human patients, the scientists don’t know what kind of stress is activating a Plan B for metabolism, which they are currently exploring.

A ‘passion’ for the field

Lukey and Qiu submitted the paper for publication about a year ago. After conducting additional experiments to verify their findings, including confirming that some of the metabolite entered the cell, these researchers received word that Nature Metabolism would publish the research.

Lukey appreciated Qiu’s passion for science and suggested his postdoctoral researcher combines his technical proficiency with good ideas to generate promising results.

Lukey suggested that researchers in the field have developed a growing consensus that effective strategies to target tumor metabolism will likely involve combination therapies that disrupt a critical metabolic pathway in cancer cells and simultaneously block the adaptive response to that intervention.

From China to Buffalo to LI

Born in Yiyang, Hunan province in China, Qiu moved several times during his childhood, to Sanya, Hainan and Changsha, Hunan.

Qiu knew he wanted to be a scientist when he was young. He enjoyed watching ants, observing the types of food they carried with them. He earned his PhD from Clemson University in South Carolina, where he built his knowledge about metabolism-related research and benefited from the guidance of his mentor James Morris.

Qiu and his wife Peipei Wu, who is a postdoctoral researcher in Chris Hammell’s lab and focuses on epigenetic gene regulation in skin stem cell development, live in Oyster Bay.

The scientific couple don’t have much overlap in their work, but they do get “lots of inspiration from each other, during our discussion outside of work,” said Qiu.

Qiu enjoys fishing and caught and ate a catfish from the Hudson River. He appreciates drawing scenery, animals and a range of other visuals, including cartoon characters. He designed T-shirts for his department during his PhD.

As for his research, Qiu hopes the metabolism finding may lead to new treatments for cancer. He also suggested that this approach may help with other cancers.

“What I have found in my study can be applied for many other cancer types that are also dependent on glutamine, such as lung and kidney cancer,” he said. He also can not rule out “the possibility that the treatment may help reduce metastasis.”

An important topic for follow up studies, Lukey suggested, is to address how the metabolic interventions Qiu used might affect immune cells and the anticancer immune response.

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Hiro Furukawa Photo courtesy of CSHL

By Daniel Dunaief

Following a relentless drive to succeed, scientists have a great deal in common with athletes.

In addition to putting in long hours and dedicating considerable energy to improving their results, these talented professionals also enjoy moments of success — large and small — as opportunities to appreciate the victories and then build to greater challenges.

And so it is for Hiro Furukawa, a Professor at Cold Spring Harbor Laboratory.

Hiro Furukawa. Photo courtesy of JMSA

Working with a team of scientists including at Emory University, Furukawa recently published a paper in the prestigious journal Nature in which he demonstrated the long-sought structural process that leads to the opening of an important channel in the brain, called the NMDAR receptor.

When this cellular channel doesn’t function correctly, it can lead to numerous diseases, including Alzheimer’s and depression. Understanding the structural details of this channel could, at some point in future research, lead to breakthrough treatments.

“Each moment of discovery is exciting and priceless,” Furukawa explained. “When I finally see what I have sought for many years — in this case, the mechanism of NMDAR channel opening — it fills me with immense euphoria, followed by a sense of satisfaction.”

That sounds like the kind of mountaintop moment that star athletes whose achievements people applaud share once they’ve reached a long-desire milestone, like, perhaps, winning a gold medal in the Olympics.

The thirst for more for Furukawa, as it is for those with a passion for success in other fields beyond science and athletics, is unquenchable and unrelenting.

“This feeling is fleeting,” he added. “Within a few hours, a flurry of new questions arising from the discovery begins to occupy my mind.”

Indeed, Furukawa suggested that he expects that many other scientists share this experience.

Forming a winning team

Furukawa and Stephen Traynelis, Professor and Director in the Department of Pharmacology and Chemical Biology at Emory University School of Medicine in Atlanta, started to work together on a series of modulators for the NMDAR protein about eight years ago.

Hiro Furukawa. Photo courtesy of JMSA

This particular protein binds to the neurotransmitter glutamate and to glycine, which is another compound. Once bound to both, the channel, as if responding to the correct combination in a garage door, opens, creating electrical signals that contribute to brain functions.

To study the way the binding of these molecules opened the channel, the researchers needed to figure out how to keep the receptor in the open position.

That’s where a combination of work in the labs of Traynelis and Dennis Liotta, also a Professor at Emory, came in. Liotta’s lab made over 400 analogs that Traynelis ran in his lab.

Liotta created a compound called EU-1622-A, which is now known as EU-1622-240, that upregulates NMDAR activity, Furukawa explained.

“We used cryo-EM [electron microscopy] to capture the NMDAR structure with the compound, validated its conformation through electrophysiology and elucidated the activation mechanism,” he said.

Incorporating EU-1622-240 along with glycine and glutamate into the GluN1-2B NMDAR sample, which is a specific subtype and is the easiest to work with, enabled a visualization of the open channel.

Furukawa described the compound Traynelis created at Emory as the “key factor in capturing the open channel conformation.”

Determining the structure of a functioning protein can provide clues about how to alter those that may be contributing to the onset or progression of a disease.

To be sure, Furukawa recognizes the work as one step in what’s likely to involve an extensive research journey.

“We still have a long way to go, but we’ve made progress,” Furukawa said. “In this study, a compound bound to NMDAR gave us a clue on how to control the frequency of ion channel openings. Both hyperactive and hypoactive functions of NMDAR ion channels have been implicated in Alzheimer’s disease, so being able to regulate NMDAR activity would be significant.”

Furukawa can’t say for sure if this compound could alleviate the symptoms of certain diseases, but it serves as a new series of potentially clinically relevant options to test.

The researchers are developing a method to purify NMDAR proteins from animal tissues. Once they accomplish that task, they should be able to isolate NMDAR from Alzheimer’s brains to compare them to a normally functioning protein.

Furukawa suggested that it’s probable that specific NMDAR conformations are stabilized to different extents in various diseases compared to normal brains.

The researchers have not yet presented this work at meetings. First author Tsung-Han Chou, who is a postdoctoral fellow in Furukawa’s lab, plans to present the work at upcoming conferences, such as the Biophysical Society Meeting.

The review process for the research proceeded quickly, as the team submitted the paper in February of this year. 

Next steps

As for what’s next, Furukawa suggested that the team planned to solidify their findings.

“We must determine if the channel opening mechanism applies to other types of NMDARs,” he said. “Although we observed that EU1622-A compound binds to NMDAR, its structure was not sufficient resolved.”

To facilitate the re-design of EU1622-240, the scientists will need to improve the cryo-EM map resolution.

Traynelis, meanwhile, said that he and Liotta are synthesizing new modulators in this class and related classes and are working on mechanisms of action for this series at all NMDA receptors as well as actions in neuronal systems.

“We have a robust synthetic program with our collaborator [Liotta], whose laboratory is synthesizing many new modulators in this class and related classes,” Traynelis explained.

Traynelis added that his goal is to “develop new medicines to address unmet clinical needs. We want to find new and effective therapeutic treatments that help patients.”

The Emory professor is excited about the “potential development of positive NMDA receptor allosteric modulators that could enhance NMDA receptor function.”

Broader perspective

Furukawa, who lives in Cold Spring Harbor and whose sons Ryoma, 16 and Rin, 13, attend senior and junior high school, respectively, was interested in international politics and economics when he attended Tufts University as an undergraduate.

These non-science topics provide additional perspective that enrich his life.

“I remain very interested in understanding history and the reasons behind current events in Europe, the Middle East, and the U.S.,” he said. “This endeavor is far more challenging than decoding NMDAR structures and functions.”

As for his collaborations, Furukawa suggested that the findings from this research inspire him to continue to search for more answers and greater scientific achievements.

“We will continue to unravel these mysteries in future studies,” Furukawa said. “The best is yet to come.”

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Qingtao Sun, postdoctoral researcher at CSHL, presents a poster of the cachexia research taken at a Society for Neuroscience meeting in 2023 in Washington, DC. Photo by Dr. Wenqiang Zheng

By Daniel Dunaief

Cancer acts as a thief, robbing people of time, energy, and quality of life. In the end, cancer can trigger the painful wasting condition known as cachexia, in which a beloved relative, friend or neighbor loses far too much weight, leaving them in an emaciated, weakened condition.

A team of researchers at Cold Spring Harbor Laboratory has been studying various triggers and mechanisms involved in cachexia, hoping to find the signals that enable this process.

Recently, CSHL scientists collaborated on a discovery published in the journal Nature Communications that connected a molecule called interleukin-6, or IL-6, to the area postrema in the brain, triggering cachexia.

By deleting the receptors in this part of the brain for IL-6, “we can prevent animals from developing cachexia,” said Qingtao Sun, a postdoctoral researcher in the laboratory of Professor Bo Li.

Through additional experiments, scientists hope to build on this discovery to develop new therapeutic treatments when doctors have no current remedy for a condition that is often the cause of death for people who develop cancer.

To be sure, the promising research results at this point have been in an animal model. Any new treatment for people would not only require additional research, but would also need to minimize the potential side effects of reducing IL-6.

Like so many other molecules in the body, IL-6 plays an important role in a healthy system, promoting anti- and pro-inflammatory responses among immune cells, which can help fight off infections and even prevent cancer.

“Our study suggests we need to specifically target IL-6 or its receptors only in the area prostrema,” explained Li in an email.

Tobias Janowitz, Associate Professor at CSHL and a collaborator on this project, recognized that balancing therapeutic effects with potential side effects is a “big challenge in general and also is here.”

Additionally, Li added that it is possible that the progression of cachexia could involve other mechanistic steps in humans, which could mean reducing IL-6 alone might not be sufficient to slow or stop this process.

“Cachexia is the consequence of multi-organ interactions and progressive changes, so the underlying mechanisms have to be multifactorial, too,” Miriam Ferrer Gonzalez, a co-first author and former PhD student in Janowitz’s lab, explained in an email.

Nonetheless, this research result offers a promising potential target to develop future stand alone or cocktail treatments.

The power of collaborations

Working in a neuroscience lab, Sun explained that this discovery depended on several collaborations throughout Cold Spring Harbor Laboratory. 

“This progress wouldn’t be possible if it’s only done in our own lab,” said Sun. “We are a neuroscience lab. Before this study, we mainly focused on how the brain works. We have no experience in studying cachexia.”

This paper is the first in Li’s lab that studied cachexia. Before Li’s postdoc started this project, Sun had focused on how the brain works and had no experience with cachexia.

When Sun first joined Li’s lab three years ago, Li asked his postdoctoral researcher to conduct an experiment to see whether circulating IL-6 could enter the brain and, if so where.

Sun discovered that it could only enter one area, which took Li’s research “in an exciting direction,” Li said.

CSHL Collaborators included Janowitz, Ferrer Gonzalez, Associate Professor Jessica Tolkhun, and Cancer Center Director David Tuveson and former CSHL Professor and current Principal Investigator in Neurobiology at Duke University School of Medicine Z. Josh Huang.

Tollkuhn’s lab provided the genetic tool to help delete the IL-6 receptor.

The combination of expertise is “what made this collaboration a success,” Ferrer Gonzalez, who is now Program Manager for the Weill Cornell Medicine partnership with the Parker Institute for Cancer Immunotherapy, explained in an email.

Tuveson added that pancreatic cancer is often accompanied by severe cachexia.

“Identifying a specific area in the brain that participates in sensing IL-6 levels is fascinating as it suggests new ways to understand physiological responses to elevated inflammation and to intervene to blunt this response,” Tuveson explained. “Work in the field supports the concept that slowing or reversing cachexia would improve the fitness of cancer patients to thereby improve the quality and quantity of life and enable therapeutic interventions to proceed.”

Tuveson described his lab’s role as “modest” in promoting this research program by providing cancer model systems and advising senior authors Li and Janowitz.

Co-leading an effort to develop new treatments for cachexia that received a $25 million grant from the Cancer Grand Challenge, Janowitz helped Sun understand the processes involved in the wasting disease. 

Connecting the tumor biology to the brain is an “important step” for cachexia research, Janowitz added. He believes this step is likely not the only causative process for cachexia.

Cutting the signal

After discovering that IL-6 affected the brain in the area postrema, Sun sought to determine its relevance in the context of cachexia.

After he deleted receptors for this molecule, the survival period for the test animals was double that for those who had interleukin 6 receptors in this part of the brain. Some of the test animals still died of cachexia, which Sun suggested may be due to technical issues. The virus they used may not have affected enough neurons in the area postrema.

In the Nature Communications research, Sun studied cachexia for colon cancer, lung cancer and pancreatic cancer.

Sun expects that he will look at cancer models for other types of the disease as well.

“In the future, we will probably focus on different types” of cancer, he added.

Long journey

Born and raised in Henan province in the town of Weihui, China, Sun currently lives in Syosset. When he’s not in the lab, he enjoyed playing basketball and fishing for flounder.

When he was growing up, he showed a particular interest in science.

As for the next steps in the research, Sun is collaborating with other labs to develop new strategies to treat cancer cachexia.

He is eager to contribute to efforts that will lead to future remedies for cachexia.

“We are trying to develop some therapeutic treatment,” Sun said.

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Daniel Marx in front of one of the magnets at the Relativistic Heavy Ion Collider at Brookhaven National Laboratory. Photo courtesy of BNL

By Daniel Dunaief

In a world filled with disagreements over everything from presidential politics to parking places, numbers — and particularly constants — can offer immutable comfort, as people across borders and political parties can find the kind of common ground that make discoveries and innovations possible.

Many of these numbers aren’t simple, as anyone who has taken a geometry class would know. Pi, for example, which describes the ratio of the circumference of a circle to its diameter, isn’t just 3 or 3.14.

In classes around the world, people challenge their memory of numbers and sequences by reciting as many digits of this irrational number as possible. An irrational number can’t be expressed as a fraction.

These irrational numbers can and do inform the world well outside of textbooks and math tests, making it possible for, say, electromagnetic radiation to share information across a parallel world or, in earlier parlance, the ether.

“All electronic communication is made up of waves, sines and cosines, that are defined and evaluated using pi,” said Alan Tucker, Toll Distinguished Teaching Professor in the Department of Applied Mathematics and Statistics at Stony Brook University. The circuits that send and receive information are “based on calculations using pi.”

Scientists can receive signals from the Voyager spacecraft, launched in 1977 and now over seven billion miles away, thanks to the ability to tune a circuit using math that relies on pi and numerous mathematical formulas where the sensitivity to the signal is infinite.

The signal from the spacecraft, which is over 16 years older than the average-aged person on the planet, takes about 10 hours to travel back and forth.

“Think of 1/x, where x goes to 0,” explained Tucker. “Scientists have taken that infinity to be an infinite multiplier of weak signals that can be understood.”

Closer to Earth, the internet, radio waves and TV, among myriad other electronic devices, all use generated and decoded calculations using pi.

“All space has an unseen mathematical existence that nobody can see,” said Tucker. “These are heavily based on calculations involving pi.”

Properties of nature

Constants reflect the realities of the world. They have “a property that is fundamental and absolute and that no one could change,” said Steve Skiena, Distinguished Teaching Professor of Computer Science at Stony Brook University. “The reason people discovered these constants as being important is because they are relating things that arise in the world.”

While pi may be among the best known and most oft-discussed constant, it’s not alone in measuring and understanding the world and in helping scientists anticipate, calculate and understand their experiments.

Chemists, for example, design reactions using a standard unit of measure called the mole, which is also called Avogadro’s number for the Italian physicist Amedeo Avogadro.

The mole provides a way to balance equations, enabling chemists to determine exactly how much of each reactant to combine to get a specific amount of product.

This huge number, which is often expressed as 6.022 times 10 to the 23rd power, represents the number of atoms in 12 grams of carbon 12. The units can be electrons, ions, atoms or molecules.

“Without Avogadro’s number, it would be impossible to determine the ratio of particular reactants,” said Elliot Smith, a postdoctoral researcher at Cold Spring Harbor Laboratory who works in John Moses’s lab. “You could take an educated guess, but you wouldn’t get good results.”

Smith often uses millimoles, or 1/1000th of a mole, in the chemical reactions he does.

“If we know the millimoles of each reactant, we can calculate the expected yield,” said Smith. “Without that, you’re fumbling in the dark.”

Indeed, efficient chemical reactions make it possible to synthesize greater amounts of some of the pharmaceutical products that protect human health.

Moles, or millimoles, in a reaction also make it possible to question why a result deviated from expectations. 

Almost the speed of light

Physicists use numerous constants.

“In physics, it is inescapable that you will have to deal with some of the fundamental constants,” said Alan Calder, Professor of Physics and Astronomy at Stony Brook University.

When he models stellar explosions, he uses the speed of light and Newton’s gravitational constant, which relates the gravitational force between two objects to the product of their masses divided by the square of the distance between them.

The stars Calder studies are gas ball reactions that also involve constants.

Stars have thermonuclear reactions going on in them as they evolve. Calder uses reaction rates that depend on local conditions like temperature, but there are constants in these.

Calder’s favorite number is e, or Euler’s constant. This number, which is about 2.71828, is useful in calculating interest in a bank account as well as in understanding the width of successive layers in a snail shell among many other phenomena in nature.

Electron Ion Collider

The speed of light figures prominently in the development and calculations at Brookhaven National Laboratory as the lab prepares to build the unique Electron Ion Collider, which is expected to cost between $1.7 billion and $2.8 billion.

The EIC, which will take about 10 years to construct, will collide a beam of electrons with a beam of ions to answer basic questions about the atomic nucleus.

“It’s one of the most exciting projects in the world,” said Daniel Marx, an accelerator physicist in the Electron Ion Collider accelerator design group at BNL.

At the EIC, physicists expect to propel the electrons, which are 2,000 times lighter than protons, extremely close to the speed of light. In fact, they will travel at 99.999999 (yes, that’s six nines after the decimal point) of the speed of light, which, by the way, is 186,282 miles per second. That means that light can circle the globe 7.48 times per second.

The EIC will increase the energy of ions to 99.999% of the speed of light. With only three nines after the decimal, the protons will be traveling at a slower enough speed that the designers of the collider will make the proton ring about 4 inches shorter over 2.4 miles to ensure that the protons and electrons arrive at exactly the same time.

The EIC will attempt to answer questions about the mass and spin of the nucleus. They hope to understand what happens with dense systems of gluons. By accelerating nuclei or protons to higher energies, they will get more gluons and will look for evidence of gluon saturation.

“The speed of light is absolutely fundamental to everything we do,” said Marx because it is fundamental to relativity and the particles in the accelerator are relativistic.

As for constants, Marx suggested that its value might look like a row of random numbers, but if those numbers are a bit different, that could “revolutionize” an understanding of physics.

In addition to a detailed understanding of atomic nuclei, the EIC could also lead to new technologies.

When JJ Thomson discovered the electron, he toasted it by saying, “may it never be of use to anyone.” That, however, is far from the case, as the electron is at the heart of electronics.

As for pi, Marx, like many of his STEM colleagues, appreciates this constant.

“Once you look at the mathematical statement of pi, and how it relates in various ways to other quantities in math and physics, it deepens your appreciation of how beautiful the whole universe is,” Marx said.

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From left, Adrian Krainer and Danilo Segovia with the Breakthrough Prize, which Krainer won in 2018. Photo from Danilo Segovia

By Daniel Dunaief

For many young children, the ideal peanut butter and jelly sandwich doesn’t include any crust, as an accommodating parent will trim off the unwanted parts before packing a lunch for that day.

Similarly, the genetic machinery that takes an RNA blueprint and turns it into proteins includes a so-called “spliceosome,” which cuts out the unwanted bits of genetic material, called introns, and pulls together exons.

Adrian Krainer. Photo from CSHL

When the machinery works correctly, cells produce proteins important in routine metabolism and everyday function. When it doesn’t function correctly, people can contract diseases.

Danilo Segovia, a PhD student at Stony Brook University who has been working in the laboratory of Cold Spring Harbor Laboratory Professor Adrian Krainer for seven years, recently published a study in the Proceedings of the National Academy of Sciences about an important partner, called DDX23, that works with the key protein SRSF1 in the spliceosome.

“We obtained new insights into the splicing process,” said Krainer, who is the co-leader of the Gene Regulation & Inheritance program in the Cancer Center at CSHL. “The spliceosome is clearly important for every gene that has introns and every cell type that can have mutations.”

Krainer’s lab has worked with the regulator protein SRSF1 since 1990. Building on the extensive work he and members of his lab performed, Krainer was able to develop an effective treatment for Spinal Muscular Atrophy, which is a progressive disease that impacts the muscles used for breathing, eating, crawling and walking.

In children with SMA, Krainer created an antisense oligonucleotide, which enables the production of a key protein at a back up gene through more efficient splicing. The treatment, which is one of three on the market, has changed the prognosis for people with SMA.

At this point, the way DDX23 and SRSF1 work together is unclear, but the connection is likely important to prepare the spliceosome to do the important work of reading RNA sequences and assembling proteins.

Needle in a protein haystack

Thanks to the work of Krainer and others, scientists knew that SRSF1 performed an important regulatory role in the spliceosome.

What they didn’t know, however, was how other protein worked together with this regulator to keep the machinery on track.

Danilo Segovia in the lab at Cold Spring Harbor Laboratory. Photo by Constance Burkin/CSHL

Using a new screening technology developed in other labs that enabled Segovia to see proteins that come in proximity with or interact with SRSF1, he came up with a list of 190 potential candidates.

Through a lengthy and detailed set of experiments, Segovia screened around 30 potential proteins that might play a role in the spliceosome.

One experiment after another enabled him to check proteins off the list, the way prospective college students who visit a school that is too hilly, too close to a city, too far from a city, or too cold in the winter do amid an intense selection process.

Then, on Feb. 15 of last year, about six years after he started his work in Krainer’s lab, Segovia had a eureka moment.

“After doing the PhD for so long, you get that result you were waiting for,” Segovia recalled.

The PhD candidate didn’t tell anyone at first because he wanted to be sure the interaction between the proteins was relevant and real.

“Lucky for us, the story makes sense,” Segovia said.

Krainer appreciated Segovia’s perseverance and patience as well as his willingness to help other members of his lab with structural work.

Krainer described Segovia as the “resident structural expert who would help everybody else who needed to get that insight.”

Krainer suggested that each of these factors had been studied separately in the process, without the realization that they work together.

This is the beginning of the story, as numerous questions remain.

“We reported this interaction and now we have to try to understand its implications,” said Krainer. “How is it driving or contributing to splice assembly.”

Other factors also likely play an important role in this process as well.

Krainer explained that Segovia’s workflow allowed him to prioritize interacting proteins for further study. Krainer expects that many of the others on the list are worth further analysis.

At some point, Krainer’s lab or others will also work to crystallize the combination of these proteins as the structure of such units often reveals details about how these pieces function.

Segovia and Krainer worked together with Cold Spring Harbor Laboratory Professor Leemor Joshua-Tor, who does considerably more biochemistry work in her research than the members of Krainer’s lab.

When a cowboy met a witch

A native of Montevideo, Uruguay, Segovia came to Stony Brook in part because he was conducting research on the gene P53, which is often mutated in forms of human cancer.

Segovia had read the research of Ute Moll, Endowed Renaissance Professor of Cancer Biology at Stony Brook University, who had conducted important P53 research.

“I really liked the paper she did,” said Segovia. “When I was applying for college in the United States for my PhD, I decided I’m for sure going to apply to Stony Brook.”

Even though Segovia hasn’t met Moll, he has benefited from his journey to Long Island.

During rotations at CSHL, Segovia realized he wanted to work with RNA. He found a scientific connection as well as a cultural one when he discovered that Krainer is from the same city in Uruguay.

Krainer said his lab has had a wide range of international researchers, with as many as 25 countries represented. “The whole institution is like that. People who go into science are naturally curious about a lot of things, including cultures.”

Segovia not only found a productive setting in which to conduct his PhD research, but also met his wife Polona Šafarič Tepeš, a former researcher at Cold Spring Harbor Laboratory who currently works at the Feinstein Institute for Medical Research. Tepeš is originally from Slovenia.

The couple met at a Halloween party, where Segovia came as a cowboy and Tepeš dressed as a witch. They eloped on November 6, 2020 and were the first couple married after the Covid lockdown at the town hall in Portland, Maine.

Outside of the lab, Segovia enjoys playing the clarinet, which he has been doing since he was 11.

As for science, Segovia grew up enjoying superhero movies that involve mutations and had considered careers as a musician, scientist or detective.

“Science is universal,” he said. “You can work wherever you want in the world. I knew I wanted to travel, so it all worked out.”

As for the next steps, after Segovia defends his thesis in July, he is considering doing post doctoral research or joining a biotechnology company.

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