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Cold Spring Harbor Laboratory

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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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Benjamin Cowley. Photo courtesy of CSHL Communications

By Daniel Dunaief

Most behaviors involve a combination of cues and reactions. That’s as true for humans awaiting a response to a gesture like buying flowers as it is for a male fruit fly watching for visual cues from a female during courtship. 

The process is often a combination of behaviors and signals, which the visual system often processes as a way of determining the next move in a courtship ritual.

At Cold Spring Harbor Laboratory, Assistant Professor Benjamin Cowley recently published research in the prestigious journal Nature in which he used a so-called deep neural network to mirror the neurons involved in a male fly’s vision as it interacts with a potential female mate.

Working with a deep neural network that reflects the fly’s nerve cells, Cowley created a knockout training process, in which he altered one set of neurons in the model at a time and determined their effect on the model and, with partners who conduct experiments with flies, on the flies themselves.

Cowley’s lab group, which includes from left to right, Rabia Gondur, computational research assistant, Filip Vercuysse, postdoctoral researcher, Benjamin Cowley, and Yaman Thapa, graduate student. Photo by Sue Weil-Kazzaz, CSHl Commnications.

Cowley worked closely with his former colleagues at the Princeton Neuroscience Institute, including Professor Jonathan Pillow and Professor Mala Murthy. His collaborators genetically silenced a fruit fly’s neuron type, observing the changes in behavior. Cowley, meanwhile, trained his deep neural network on this silenced behavior while also “knocking out” model neurons, teaching the model by perturbing it in a similar way to the changes in the fruit fly circuitry.

This approach proved effective, enhancing the ability of these models not only to understand the wiring involved in processing visual information and translating that into behavior, but also to provide potential clues in future experiments about similar cellular dysfunction that could be involved in visual problems for humans.

What researchers can infer about the human visual system is limited because it has hundreds of millions of neurons. The field has taken decades to build artificial visual systems that recognize objects in images. The systems are complex, containing millions of parameters that make them as difficult to explain as the brain itself.

The fly visual system, which is the dominant focus of the fly’s brain, occupying about 70 percent of its 130,000 neurons, provides a model system that could reveal details about how these systems work. By comparison, the human retina has 100 million neurons.

“To build a better artificial visual system, we need to know the underlying mechanisms,” which could start with the fly, Cowley said. “That’s why the fruit fly is so amenable.”

Researchers need to know the step-by-step computations going from an image to neural response and, eventually, behavior. They can use these same computations in the artificial visual system.

‘A suite of tools’

The fly’s visual system is still robust and capable, contributing to a range of behaviors from courtship to aggression to foraging for food and navigating on a surface or through the air as it flies.

The fly “gives us a whole suite of tools we can use to dissect these circuits,” Cowley said.

The fly visual system looks similar to what the human eye has, albeit through fewer neurons and circuits. The fruit fly visual system has strong similarities to the early processing of the human visual system, from the human eye to the thalamus, before it reaches the visual cortex in the occipital lobe.

Interpreting the visual system for the fly will “help us in understanding disorders and diseases in human visual systems,” Cowley said. “Blindness, for the most part, occurs in the retina.”

Blindness may have many causes; a large part of them affect the retina and optic nerve. This could include macular degeneration, cataracts, diabetic retinopathy and glaucoma.

In its own right, understanding the way the visual processing system works in the fly could also prove beneficial in reacting to the threat of invasive species like mosquitoes, which pass along diseases such as malaria to humans.

Visual channels

Anatomists had mapped the fly’s 50 visual channels, called optical glomeruli. In the past decade, researchers have started to record from them. Except in limited cases, such as for escape reflex behaviors, it was unknown what each channel encoded.

Cowley started the research while a postdoctoral researcher at Princeton Neuroscience Institute in Jonathan Pillow’s lab and finished the work while he was starting his own lab at CSHL. Mala Murthy’s lab, who is also at Princeton, performed the silencing experiments on fruit flies, while Cowley modeled the data.

Through hundreds of interactions between the flies in which some part of the fly’s visual system was silenced, Cowley created a model that predicted neuronal response and the behavior of the fly.

The deep neural network model he used deploys a new, flexible algorithm that can learn its rules based on data. This approach can be particularly helpful in situations when researchers have the tools to perturb the system, but they can’t recover or observe every working part.

In some of the experiments, the males became super courters, continuing to engage in courtship activities for 30 minutes, which, given that the fly lives only three weeks, is akin to a date that lasts 25 days.

It is unclear why these flies become super courters. The scientists speculate that silencing a neuron type may keep the male from being distracted by other visual features.

In the experimental part of the experiments, the researchers, including Dr. Adam Calhoun and Nivedita Rangarajan, who both work in Murthy’s lab, tried to control for as many variables as possible, keeping the temperature at 72 degrees throughout the experiment.

“These flies live in nature, they are encountering so much more” than another fly for potential courtship, said Cowley, including the search for food and water.

This research addressed one small part of a behavioral repertoire that reveals details about the way the fly’s visual system works.

A resident of Huntington, Cowley grew up in West Virginia and completed his undergraduate work and PhD at Carnegie Mellon in Pittsburgh.

An avid chess player, which is a field that has included artificial intelligence, Cowley, who spent much of his life in a city, appreciates having a backyard. He has learned to do some landscaping and gardening.

Cowley had been interested in robotics in college, until he listened to some lectures about neuroscience.

As for the next steps in his work, Cowley hopes to add more complex information to his computational system, suppressing combinations of cells to gather a more complete understanding of a complex system in action.

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Gov. Kathy Hochul speaking with Cold Spring Harbor Laboratory CEO Bruce Stillman during a recent visit. Photo courtesy of Darren McGee/ Office of Governor Kathy Hochul

By Daniel Dunaief

The transition from studying pancreatic cancer’s playbook to attempting new moves to wrestle it into submission is getting closer at Cold Spring Harbor Laboratory, thanks to support from New York State.

Recently, Governor Kathy Hochul (D) announced that the Empire State would contribute $15 million to a new Pancreatic Cancer Center at Cold Spring Harbor Laboratory as a part of the lab’s Foundations for the Future Expansion.

The funds will support the construction of a new center that will continue to try to defeat this insidious type of cancer as CSHL aims to develop new treatments.

“Patients should not feel there’s no chance and no hope” after a pancreatic cancer diagnosis, said David Tuveson, Director of the CSHL Cancer Center and a researcher whose lab has taken innovative approaches to pancreatic cancer. “They are watching the evolution of an area in a disease that previously has been challenging to treat. Through fundamental research, we are coming up with new approaches.”

As CSHL works with human organoids, which are tissues grown from a patient’s own cancer cells that can be used to test the effectiveness of various treatments and any resistance from cancer, animal models, and other techniques, they have moved closer to finding targets that could lead to new therapies.

Any novel treatment would likely involve creating new companies, likely on Long Island, that could develop these treatments, file for patents, and build a commercial presence and infrastructure.

“It’s an investment by the state to accelerate our translational research so we can go from preclinical to clinical,” said Tuveson. “Part of that will be to generate private entities that can focus on turning a lead to first-in-class, first-in-human products. It allows us to build that infrastructure.”

Tuveson has been working on a potential treatment for several years. Other potential treatments are also in the earlier stages of development.

Governor Hochul suggested that the state’s investment fits in the context of an overall goal to boost the local economy with new biotechnology companies.

“New York State is leading on innovative healthcare space, and this funding will advance research to better understand pancreatic cancer – one of the most devastating forms of cancer,” Governor Hochul said in a statement.

Big Picture

The Pancreatic Cancer Center will take a wide range of approaches to this particular type of cancer.

The Center will be, along with Northwell Health, a “pipeline from fundamental discovery science” to clinical trials conducted with hospital partners, explained Bruce Stillman, CEO of Cold Spring Harbor Laboratory.

The center will address early detection as well.

For Tobias Janowitz, Associate Professor and Cancer Center Program Co-Leader at CSHL, the investment means “we can strengthen collaborations between experts in metabolism, immunology, cancer cell biology, and whole body effects of cancer, all of them interconnected and relevant to therapy development in pancreatic cancer.”

Janowitz explained that patients with pancreatic cancer have the highest incidence of cachexia, in which chronic illness causes a reduction in muscle and fat, lowers people’s interest in food and causes extreme and potentially terminal weight loss. Pancreatic cancer patients almost universally experience a loss of appetite and profound weight and muscle loss.

Understanding cachexia in the context of pancreatic cancer will “enable care for patients with other cancers, too,” Janowitz added.

From that perspective, Janowitz hopes the New York State funds could enable discoveries that reach beyond pancreatic cancer.

As an MD/PhD, Janowitz could be involved in the translation of fundamental discoveries into clinical research and, ultimately, clinical care.

Janowitz has a specific interest in optimizing the therapeutic window for patients with pancreatic cancer.

“We are looking for management options that intensify the anti-cancer effect,” while, at the same time, protecting or reconditioning the whole body, Janowitz added.

Janowitz is using special transcriptomics on clinical samples in collaboration with Jon Preall, who leads the genomics core facility.

In a statement, Cold Spring Harbor Laboratory Chair Marilyn Simons described the state funding as a “catalyst to mobilize further private investment in pancreatic cancer research at CSHL.”

Simons added that her father was diagnosed with pancreatic cancer at the age of 75. A doctor offered him an exploratory operation, which enabled him to live another 14 years.

“Few people are so lucky,” Simons added in a statement. “Our wonderful scientists at Cold Spring Harbor are working with Northwell Health and the Feinstein Institutes to help more people get access to the latest biomedical advances.”

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Camila dos Santos Photo courtesy of CSHL

By Daniel Dunaief

People often think of and study systems or organs in the body as discrete units. 

In a healthy human body, however, these organs and systems work together, sometimes producing signals that affect other areas.

Recently, Cold Spring Harbor Laboratory Associate Professor Camila dos Santos and graduate students Samantha Henry and Steven Lewis, along with former postdoctoral researcher Samantha Cyrill, published a study in the journal Nature Communications that showed a link in a mouse model between persistent bacterial urinary tract infections and changes in breast tissue.

The study provides information about how a response in one area of the body could affect another far from an infection and could provide women with the kind of information that could inform the way they monitor their health.

To be sure, dos Santos and her graduate students didn’t study the processes in humans, which could be different than they are in mice.

Indeed, they are in the process of establishing clinical studies to check if UTIs in women drive breast alterations.

The body’s response

In this research, the scientists demonstrated that an unresolved urinary tract infection itself wasn’t causing changes in breast tissue, but that the body’s reaction to the presence of the bacteria triggered these changes.

By treating the urinary tract infections, Henry and Lewis showed that breast cells returned to their normal state.

Further, when they didn’t treat the UTI but blocked the molecule TIMP1, which causes collagen deposits and milk duct enlargements, the breast cells returned to their normal state.

The TIMP1 role is “probably the main eureka moment,” said Lewis, who is an MD/ PhD student at Stony Brook University. “It explains how an infection in the bladder can change a faraway tissue.”

Lewis suggested that collagen, among other factors, changes the density of breast tissue. When women get a mammography, doctors are looking for changes in the density of their breasts.

Taking a step back from the link, these graduate students and dos Santos considered whether changes in the breast tissue during an infection could provide an evolutionary benefit.

“From an evolutionary standpoint, there should be some adaptive advantage,” suggested Henry, who is earning her PhD in genetics at Stony Brook University and will defend her thesis in July. Speculating on what this might be, she suggested the mammary gland might change in response to an infection to protect milk production during lactation, enabling a mother to feed her young.

Epidemiological studies

A link between persistent UTIs and breast cancer could show up in epidemiological studies.

Dos Santos and collaborators are exploring such questions in the context of European data and are working with US collaborators to collect this information.

In addition, dos Santos believes women should consider how other ongoing threats to their overall health impact their bodies. Women with clinical depression, for example, have worse prognoses in terms of disease. Humans have health threats beyond UTIs that could predispose them to developing cancer, dos Santos said.

Division of labor

Henry and Lewis took over a study that Samantha Cyrill, the third co-first author on the paper started. When Cyrill finished her postdoctoral work, Henry and Lewis “put on their capes and said, ‘We are going to take this to the end line.’ They are incredible people,” said dos Santos.

They each contributed to the considerable work involved.

Henry primarily analyzed the single cell RNA sequencing data, specifically identifying changes in the epithelial compartment. Gina Jones, a visiting CSHL undergraduate research program student, and Lewis also contributed to this.

Henry also participated in TIMP1 neutralizing antibody treatment in post-lactation involution mice, contributing to tissue collection and staining.

Working with Cyrill and Henry, Lewis contributed to the mouse work, including experiments like neutralizing TIMP1 and CSF3. Lewis also worked with Cyrill on the UTI infections in the animals and with Henry in processing tissues for single cell RNA sequencing and assisted Henry on the sequencing analysis.

While this result is compelling and offers an opportunity to study how an infection in an area of the body can trigger changes in another, dos Santos recognized the inherent risk in a new project and direction that could have either been disconnected or a been a dead end.

“It was an incredible risk,” said dos Santos. She was rejected from at least four different funding opportunities because the research is “so out there,” she said. She tapped into foundations and to CSHL for support.

Back stories

A resident of Brooklyn, Lewis was born in Queens and raised in Scarsdale. He joined the dos Santos lab in March of 2021. One of the appeals of the dos Santos lab was that he wanted to understand how life history events drive disease, especially breast cancer.

A big Mets fan, Lewis, whose current favorite payer is Pete Alonso, is planning to run his third marathon this fall.

Lewis is dating Sofia Manfredi, who writes for Last Week Tonight with John Oliver and accepted an Emmy award on behalf of the staff.

Lewis considers himself Manfredi’s “biggest cheerleader,” while he appreciates how well she listens to him and asks important questions about his work.

As for Henry, she grew up in Greenport. She joined the lab in May of 2020 and is planning to defend her thesis in July.

Her father Joseph Henry owns JR Home Improvements and her mother Christine Thompson worked as a waitress and a bartender in various restaurants.

Henry is married to Owen Roberts, who is a civil engineer and works in the Empire State Building for HNTB as a civil engineer, where he focuses on traffic.

Henry hopes to live in Boston after she graduates. She’s adopted the rooting interests of her husband, who is a fan of Beantown teams, and will support the Bruins and the Celtics. A lifelong Yankees fan, however, Henry, who watched the Bronx Bombers with her father growing up, draws the line at supporting the “Sawx.”

As for the work, Henry and Lewis are excited to see what the lab discovers in the next steps.

“I do think this work is extremely informative, defining a relationship between an infection, UTI, and the mammary gland that has not previously been appreciated,” Henry explained.

“This provides information to the public,” said Henry. “I always think it is worth knowing how different events may impact your body.”

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Gabrielle Pouchelon with technician Sam Liebman. Photo by Constance Brukin/CSHL

By Daniel Dunaief

Gabrielle Pouchelon doesn’t need to answer the age-old debate about heredity vs. environment. When it comes to the development of the brain, she’s studying the response both to sensory cues and genetics.

Gabrielle Pouchelon.
Photo courtesy of CSHL

An Assistant Professor who joined Cold Spring Harbor Laboratory in March of 2022, Pouchelon studies the interplay between sensory and neuromodulatory inputs and genetic programs in circuit maturation. She also studies other neuromodulatory inputs, usually associated with states of adulthood, which could control development.

A combination of genetics and environment shapes the way neurons connect in a healthy brain. In people who develop non-neurotypical behaviors, through autism, schizophrenia or other conditions, the development of neurological connections and architecture is likely different.

Researchers have associated genes of susceptibility with schizophrenia and autism spectrum disorders. Scientists believe environmental cues provide the brain with activity that interact with these genetic components.

“We are trying to understand whether we can [intervene] earlier that can have different outcomes at later times,” said Pouchelon. “We are studying ways to intervene with these transient processes and examine whether dysfunctions associated with the disorders are improved.”

During critical periods of development, the brain has a high level of plasticity, where various inputs can alter neurons and their connections. This not only involves building connections, but sometimes breaking them down and rebuilding other ones. As people age, that plasticity decreases, which is why children learn faster than adults in areas such as the acquisition and development of language skills.

While the timing of critical periods is less well-defined in humans and language is a complex function, the ability to learn new languages at a young age reflects the high plasticity of the brain.

Scientists are studying language processes, which are specific to humans, with functional magnetic resonance imaging.

Pouchelon, who isn’t studying language skills, hopes that understanding the architecture of developing brains and how they respond to sensory and neuromodulatory cues could shed light on the studies performed in humans. Since behavioral therapy and pharmaceutical treatments can help children with autism, she believes understanding how external cues affect genetic elements could uncover drug targets to alleviate symptoms of neurodevelopmental disorders at an early age.

Neurons & the environment

From left, technician Sam Liebman, Gabrielle Pouchelon and postdoctoral researcher Dimitri Dumontier. Photo courtesy of Gabrielle Pouchelon

In her lab, which currently includes three researchers but she expects to double within a month, Pouchelon uses sophisticated tools to target not only the effect of the environment, but also to look at the specific neurons that transmit information.

She is trying to “understand at a very precise level what a sensory input means and what are the neurons that integrate that sensory input.”

Sam Liebman, who became a technician in Pouchelon’s lab two years ago after graduating from the University of Vermont, appreciates the work they’re doing and her mentorship.

The lab is “unique and special” because he has that “close relationship” in what is now a smaller lab with Pouchelon, Liebman said.

Growing up in Huntington, Liebman, who hopes to go to graduate school in the fall of 2025, came to Cold Spring Harbor Laboratory for field trips in middle school and high school.

“I idolized this place and this campus,” said Liebman.

Pouchelon has asked for Liebman’s opinion on potential candidates to join the lab, even summer interns.

Fragile X Syndrome

Most of the work Pouchelon conducts is done on animal models. She is mainly studying animals with a mutation linked to Fragile X Syndrome. 

In Fragile X Syndrome, which can affect boys and girls, children can have developmental delays, learning disabilities and social and behavioral problems. Boys, according to the Centers for Disease Control and Prevention, typically have some degree of intellectual disability, while girls can have normal intelligence or some degree of intellectual disability.

Other models for autism exist, such as genetic mutations in the gene Shank3. “We are trying to utilize these models to apply what we understand of development in brains that are healthy and compare them” to the mutated models, Pouchelon explained.

While clinical trials are exploring receptors as drug targets for Fragile X Syndrome, she hopes to find new ones that are selective in early stages of the disease to modify their use depending on the stages of development.

An annoying nerd

Born and raised in Paris, France to a family that showed considerably more artistic talent than she, Pouchelon struggled with games she and her sisters played when they listened to music on the radio and they had to guess the composer.

“I was the one always losing,” said Pouchelon. Her family, including her two older sisters who currently live in France, knew “way more about art and history than I did. I was the nerd scientist.”

When she was young, she was curious and asked a lot of “annoying questions” because she was interested in the “mystery of everything.” In high school, she became interested in the brain.

Pouchelon, who isn’t actively searching for French food but finds the baguettes at the Duck Island Bakery exceptional, lives on the Cold Spring Harbor Laboratory campus with her husband Djeckby “DJ” Joseph, a naturalized American citizen originally from Haiti who works in law enforcement at the VA Hospital in Manhattan, and their two-year old son Theo.

Eager to ensure her son benefits from a multicultural identity, Pouchelon speaks to Theo in French. He also attends on campus day care, where he learns English.

As for the decision to come to Cold Spring Harbor Laboratory, Pouchelon, who conducted her PhD research at the University of Geneva in Switzerland and completed her postdoctoral research at New York University and at Harvard Medical School, is thrilled to discuss her work with the talented and collegial staff at the lab.

Cold Spring Harbor Laboratory, which is known internationally for meetings and courses, is an “exciting place” where scientists conduct cutting edge research.

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Joshua Homer. Photo by Constance Burkin

By Daniel Dunaief

Even as some antibiotics and anti cancer treatments help beat back infections and diseases such as cancer, pathogens and diseases can develop resistance that render these treatments less effective.

Researchers at pharmaceutical companies and universities spend considerable time trying to ensure therapies continue to work. Companies make derivatives of existing drugs or they combine drugs to reduce resistance. They also develop new agents to combat drug-resistant tumors.

Using a chemical process that won his mentor K. Barry Sharpless a Nobel Prize, John Moses, a Professor at Cold Spring Harbor Laboratory, has deployed a new version of click chemistry to assemble biologically active compounds quickly and effectively, which could be used for further development into potential therapies.

Akin to fastening a seatbelt or assembling LEGO blocks, click chemistry benefits from an efficient system to create reliable end products, with the additional advantage of minimizing waste products or impurities.

Recently, Research Investigator Joshua Homer, who has been in Moses’s lab for over three years, published a paper in Chemical Science in which he created several libraries of over 150 compounds. He screened these for activity in anticancer or antibiotic assays.

The newer click process, called Accelerated SuFEx Click Chemistry, or ASCC, involves “less synthetic steps,” said Homer. ASCC can use functional groups like alcohols, that are naturally found in numerous commercially available compounds, directly. Homer can and has used commercially available alkyl and aryl alcohols as fragments in this application of ASCC.

This approach “allows us to explore chemical space so much faster,” Homer said.

In an email, Moses suggested that the paper “demonstrates that SuFEx chemistry can be a feasible and speedy approach compared to traditional methods.”

To be sure, the products could still be a long way from concept to bedside benefit.

“It’s important to note that while the chemistry itself shows promise, the actual application in drug development is complex and can take many years,” Moses added.

The research contributed to finding compounds that may be promising in treating various conditions and represent initial findings and potential starting points for further development, Homer added.

Specifically, Homer took inspiration from the structure of combrestastatin A4 when developing microtubule targeting agents.

The chemicals he produced had good activity against drug-resistant cancer cell lines that resist other treatment options.

Homer also modified the structure of dapsone, generating a derivative with greater activity against a strain of M. tuberculosis that is otherwise resistant to dapsone. 

“Strains of bacteria develop resistance to antibiotics,” said Homer. Derivatization of antibiotic structures can generate compounds that maintain activity.

Breast cancer

In creating these compounds, Homer bolted on different commercially available fragments and developed potential nano-molar treatments that could be effective against triple-negative breast cancer.

At this point, he has evaluated two lead agents in two dimensional cell culture and against patient-derived organoids. Homer did this work in collaboration with the lab of CSHL Cancer Center director David Tuveson.

Organoids can help gauge the potential response of a patient’s tumor to various treatments.

Homer found that eight of the microtubule targeting agents were more potent than colchicine against HCT-15. This cancer cell line, he explained, is known to have upregulated efflux, which is a major cause of drug resistance in cancer cells.

His compounds maintained a similar potency between two dimensional cell lines and organoids. Often, compounds are less potent in organoids, which makes this a promising discovery.

Making molecules and screening them for function to discover lead candidates is one of the first steps in the drug discovery process, with considerable optimization and regulatory steps necessary to generate a drug for the clinic.

Promising treatments sometimes also cause cellular damage in healthy tissue, which reduces the potential benefit of any new treatment. Effective cancer drugs are selective for cancer cells over normal cells.

At this point, the molecules Homer creates involve a search for function, he said. “Once we identify the reaction, we can remake our molecule to confirm it is our compound that is causing a reaction.”

Click chemistry doesn’t necessarily lead to solutions, but it enables scientists and drug companies to create and test molecules more rapidly and with considerably less financial investment.

Click solutions

Click chemistry has affected the way Homer thinks about problems outside the lab.

“I think more about doing things quickly and how to tackle the issues we face, rather than using brute force in one direction,” he said. “We can go in lots of directions and probe. We should be looking at all sorts of baskets at once to solve the issues we have.”

Originally from Tauranga, New Zealand, Homer enjoys traveling around the country, visiting new cities and interacting with different people. A resident of Huntington, Homer is looking forward to an upcoming visit from his parents Dave and Debbie and his aunt Carol, who are making their first trip to the continental United States.

“One of my favorite things about being a scientist is that I can bring my parents out of their comfort zone,” he said. His parents live on a small lifestyle block with several sheep and chickens.

Moses lauded the contributions Homer has made to the lab, including providing mentorship to other students.

As for click chemistry, Homer appreciates how the reactions create opportunities even for those without advanced backgrounds in chemistry.

Click chemistry creates the opportunity to help non-scientists understand scientific concepts more easily.

“I can give a high school student the reagents and substrates and they can reliably make biologically active anticancer agents or antibiotics,” he said. “That helps connect science and drug discovery with the community.”

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