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Benjamin Martin

From left, Evan Sohn, co-founder of the Sohn Conference Foundation; Benjamin Martin, associate professor at Stony Brook University; and Bill Ackman, co-founder of the Pershing Square Foundation and CEO of Pershing Square Capital Management at an awards dinner. Photo by Melanie Einzig/PSSCRA

By Daniel Dunaief

Up and coming scientists are often stuck in the same position as promising professionals in other fields. To get the funding for research they’d like to do, they need to show results, but to get results, they need funding. Joseph Heller, author of “Catch 22,” would certainly relate.

A New York-based philanthropy called the Pershing Square Sohn Cancer Research Alliance is seeking to fill that gap, providing seven New York scientists with $600,000 each over the course of three years.

In the fifth annual competition, Benjamin Martin, an associate professor in the Department of Biochemistry & Cell Biology at Stony Brook University, won an award for his study of zebrafish models of metastatic cancer. Martin is the first Stony Brook researcher to win the prize.

Working with Assistant Professor David Matus, whose lab is across the hall and whose research team conducts weekly group meetings with Martin’s lab, Martin is able to see in real time the way grafted human tumor cells spread through blood vessels to other organs in the transparent zebrafish.

“It’s been very challenging to understand what process cancer cells are using to metastasize and leave the blood vessels,” said Olivia Tournay Flatto, the president of the Pershing Square Foundation. “With this technology, he can see what’s happening. It’s a really powerful tool.”

The work Martin presented was “really appealing to the whole board, and everybody felt this kind of project” had the potential to bring data and insights about a process researchers hope one day to slow down or stop, said Flatto.

This year, about 60 early-stage investigators applied for an award given specifically to researchers in the New York City area. When he learned that he won, Martin said, “There was some dancing going on in the living room.” He suggested that the award is a “validation” of his research work.

The process of a cancer cell leaving a blood vessel is “basically a black box” in terms of the mechanism, Martin said. It’s one of the least understood aspects of metastasis, he added.

Indeed, a developmental biologist by training, Martin is hoping to discover basics about this cancer-spreading process, such as an understanding of how long it takes for cancer cells to leave blood vessels. The process can take hours, although it’s unclear whether what he’s seen is typical or abnormal.

Martin would like to identify how the cancer cells adhere to the blood vessel walls and how and why they leave once they’ve reached their target.

Metastatic cancer is likely using the same mechanism the immune system uses to travel to the sites of infection, although researchers still need to confirm several aspects of this model.

Moving in involves interactions with white blood cells, including macrophages. With white blood cells, an area of infection or inflammation becomes activated, which triggers a reaction of adhesion molecules called selectins.

By watching a similar transport process in cancer, Martin and Matus can “see things people haven’t seen before” and can explore way to inhibit the process, Martin suggested.

He is hoping to find ways to stop this process, forcing cancer cells to remain in the blood vessels. While he doesn’t know the outcome of a cancer cell’s prolonged stay in the vessel, he predicts it might end up dying after a while. This approach could be combined with other therapies to force the cancer cells to die, while preventing them from spreading.

Through this grant, Martin will also study how drugs or mutations in selectins generate a loss of function in these proteins, which affects the ability of cancers to leave the blood vessel.

Martin plans to use the funds he will receive to hire more postdoctoral researchers and graduate students. He will also purchase additional imaging equipment to enhance the ability to gather information.

Martin appreciates that this kind of research, while promising, doesn’t often receive funding through traditional federal agencies. This type of work is often done on a mouse, which is, like humans, a mammal. The enormous advantage to the zebrafish, however, is that it allows researchers to observe the movement of these cancer cells, which they couldn’t do in the hair-covered rodent, which has opaque tissues.

“There’s a risk that these experiments may not work out as we planned,” Martin said. He is hopeful that the experiments will succeed, but even if they don’t, the researchers will “learn a great deal just from seeing behaviors that have not been observed before.”

Indeed, this is exactly the kind of project the Pershing Square Sohn Cancer Research Alliance seeks to fund. They want scientists to “put forward the riskiest projects,” Flatto said. “We are ready to take a chance” on them.

One of the benefits of securing the funding is that the alliance offers researchers a chance to connect with venture capitalists and commercial efforts. These projects could take 20 years or more to go from the initial concept to a product doctors or scientists could use with human patients.

“We are not necessarily focused on them starting a company,” Flatto said. “We think some of those projects will be able to be translated into something for the patient,” which could be through a diagnosis, prevention or treatment. “This platform is helpful for young investigators to be well positioned to find the right partners,” he added.

Aaron Neiman, the chairman of the Department of Biochemistry & Cell Biology at SBU, suggested that this award was beneficial to his department and the university.

“It definitely helps with the visibility of the department,” Neiman said. The approach Matus and Martin are taking is a “paradigm shift” because it involves tackling cells that aren’t dividing, while many other cancer fighting research focuses on halting cancer cells that are dividing.

Neiman praised the work Martin and Matus are doing, suggesting that “they can see things that they couldn’t see before, and that’s going to create new questions and new ideas,” and that their work creates the opportunity to “find something no one knew about before.”

Benjamin Martin in his lab at Stony Brook University. Photo courtesy of SBU

By Daniel Dunaief

Last week, the Times Beacon Record Newspapers profiled the work of David Matus, an assistant professor in the Department of Biochemistry and Cell Biology. Matus and Benjamin Martin, who has the same title in the same department, are working together on a new cancer study.

While neither Matus nor Martin are cancer biologists, these researchers have experience in developmental biology with different organisms that could contribute to insights in cancer. Specifically, they are exploring the processes that lead to cell division or invasion. Matus is working with the transparent roundworm, while Martin is focusing on the zebrafish.

The duo recently won the 2017 Damon Runyon–Rachleff Innovation Award, which includes a grant of $300,000. Martin got involved in the research “based on learning more about [Matus’] work and the general hypothesis” about division and invasion, Martin said. The overall perspective is that the cell doesn’t “invade through tissues and divide at the same time.”

Martin has done innovative work with a neuromesodermal progenitor in the zebrafish. These cells are highly plastic and can give rise to numerous other cell types. Martin is focused on trying to understand the basic biology of these cells.

From left, David Matus and Benjamin Martin in the lab where they investigate metastatic cancer. Photo courtesy of SBU

Martin is known for the “very original discovery that a signaling protein called Wnt can regulate the decision between these progenitor cells becoming muscle or neurons,” explained David Kimelman, a professor of Biochemistry at the University of Washington who oversaw Martin’s research when he was a postdoctoral student.

“What is very nice is that [Martin’s] discovery in zebrafish has since been replicated in other organisms such as the mouse and even in human stem cells, showing that this is a fundamental property of vertebrates,” Kimelman explained in an email.

Similar to Matus’ work with the worm, Martin has been working with cells that go through invasive behavior and don’t engage in cell proliferative activities. “We already knew that notochord progenitors are not proliferating when they undergo convergence and extension” from other published works, explained Martin in an email. “Since notochord progenitors exist in the tailbud and we were already studying them, it was a natural jumping off point to address the same question.”

Martin is testing a transcription factor, called brachyury, which drives metasasis-like behavior in human cancer cells. He has studied this transcription factor in the context of early zebrafish development and will see if it helps drive metastasis through inhibition of the cell cycle. At this point, Martin said, there is some “evidence that it does arrest the cell cycle” using human cells in another lab.

So far, the work he has done with brachyury and the cell cycle/invasion in zebrafish is preliminary. Their hypothesis is that halting the cell cycle is a prerequisite for invasive behavior. Like the roundworm, the embryonic zebrafish is transparent, which makes it easier to observe cellular changes.

One of the goals of the project is “to observe the cell cycle of human cancer as it invades through tissues in the fish embryo,” Martin said. In the long term, he hopes to see whether the overexpression of a transcription factor Matus has found in the worm is sufficient to drive metastasis in the zebrafish.

Martin described winning the Damon Runyon–Rachleff Award as “exciting,” and suggested that it “pushes back a little bit of the worry phase” of finding funding for compelling scientific projects. Kimelman said Martin is an “exceptional scientist” and one of the “best I have had the privilege to train.”

Kimelman believes the work Martin and Matus are doing has the potential to provide “important insight into the basic changes that occur during cancer as cells become metastatic,” he explained in an email. “While it doesn’t immediately lead to a therapeutic, understanding the basic biology of cancer is the first step to defining new ways of affecting it.”

Kimelman particularly appreciated the way Matus and Martin combined two different model systems, which offers the potential to provide insight into the basic changes that occur during cancer as cells become metastatic.

Martin learned about science and research during his formative years. His father Presley Martin was a graduate student at Johns Hopkins in Baltimore when the younger Martin was born. Presley Martin recently retired from Hamline University in St. Paul, Minnesota, where he studied the genetics of the fruit fly Drosophila. “At a young age, I was exposed to a lot of the lab and experiments and it was certainly appealing to me,” said Martin.

Benjamin Martin with his son Calvin. Photo by Richard Row

Martin is married to Jin Bae, whom he met at the University of California at Berkeley, where he was studying the molecular control of how muscle precursor cells move to distant parts of the embryo in frogs and fish. Bae is a registered nurse at Stony Brook Hospital. The couple’s son Calvin, who enjoys visiting the lab, will be four in April.

Matus and Martin are collaborating with Scott Powers, a professor in the Department of Pathology at Stony Brook, and Eric Brouzes, an assistant professor in the Department of Biomedical Engineering at Stony Brook.

Powers said the work Martin and Matus are doing is a “basic discovery but an important one,” he explained in an email. “Conceivably, further research could lead to translation but as of right now, any thoughts along those lines are speculative.”

Martin appreciates the opportunity to work on these cells that are so important in development and that might lead to insights about cancer. “It seems like in the past few years” these discoveries have “opened up a subfield of developmental biology,” he said. “It’s exciting to see.”

David Matus in his lab at Stony Brook University. Photo courtesy of SBU

By Daniel Dunaief

At first look, the connection between a roundworm, a zebrafish and cancer appears distant. After all, what can a transparent worm or a tropical fish native to India and the surrounding areas reveal about a disease that ravages its victims and devastates their families each year?

Plenty, when talking to David Matus and Benjamin Martin, assistant professors in the Department of Biochemistry and Cell Biology at Stony Brook University whose labs are next door to each other. The scientific tandem recently received the 2017 Damon Runyon–Rachleff Innovation Award, which includes a two-year grant of $300,000, followed by another renewable grant of $300,000 to continue this work.

In the first of a two-part series, Times Beacon Record Newspapers will profile the work of Matus this week. Next week the Power of Three will feature Martin’s research on zebrafish.

Long ago a scientist studying dolphin cognition in Hawaii, Matus has since delved into the world of genetic development, studying the roundworm, or, as its known by its scientific name, Caenorhabditis elegans. An adult of this worm, which lives in temperate soil environments, measures about 1 millimeter, which means it would take about 70 of them lined up end to end to equal the length of an average earthworm.

From left, David Matus and Benjamin Martin. Photo courtesy of SBU

Matus specifically is interested in exploring how a cell called the anchor cell in a roundworm invades through the basement membrane, initiating a uterine-vulval connection that allows adult roundworms to pass eggs to the outside environment. He is searching for the signals and genetic changes that give the anchor cell its invasive properties.

Indeed, it was through a serendipitous discovery that he observed that the loss of a single gene results in anchor cells that divide but don’t invade. These dividing cells are still anchor cells, but they have lost the capacity to breach the basement membrane. That, Matus said, has led the team to explore the ways cancer has to decide whether to become metastatic and invade other cells or proliferate, producing more copies of itself. In some cancers, their hypothesis suggests, the cells either divide or invade and can’t do both at the same time. It could be a cancer multitasking bottleneck.

Mark Martindale, the director of the Whitney Laboratory at the University of Florida in Gainesville who was Matus’ doctoral advisor, said a cell’s decision about when to attach to other cells and when to let go involves cell polarity, the energetics of motility and a host of other factors that are impossible to study in a mammal.

The roundworm presents a system “in which it is possible to manipulate gene expression, and their clear optical properties make them ideal for imaging living cell behavior,” Martindale explained in an email. Seeing these developmental steps allows one to “understand a variety of biomedical issues.”

Last year, Matus and Martin were finalists for the Runyon–Rachleff prize. In between almost getting the award and this year, the team conducted imaging experiments in collaboration with Eric Betzig, a group leader at the Janelia Research Campus of the Howard Hughes Medical Institute in Ashburn, Virginia. Betzig not only brings expertise in optical imaging technologies but also has won a Nobel Prize.

“We really appreciate the opportunity to work with [Betzig] and his lab members on this project,” said Matus, who also published a review paper in Trends in Cell Biology that explored the link between cell cycle regulation and invasion. He and his graduate student Abraham Kohrman explored the literature to find cases that showed the same switching that he has been exploring with the roundworm.

Yusuf Hannun, the director of the Stony Brook Cancer Center, said the work is highly relevant to cancer as it explores fundamental issues about how cells behave when they invade, which is a key property of cancer cells. Hannun said the tandem’s hypothesis about division and invasion is “consistent with previous understandings but I believe this is the first time it is proposed formally,” he suggested in an email.

Their work could apply to invasive epithelial cancers, suggested Scott Powers, a professor in the Department of Pathology at Stony Brook and the director of Clinical Cancer Genomics at the Cancer Center. That could include breast, colon, prostate, lung and pancreatic cancers, noted Powers, who is a recent collaborator with Matus and Martin.

The additional funding allows Matus and Martin to focus more of their time on their research and less on applying for other grants, Matus said.

Back row from left, David Matus and his father in law Doug Killebrew; front row from left, Maile 9, Bria, 7, and Matus’ wife Deirdre Killebrew. Photo by Richard Row

Matus lives in East Setauket with his wife Deirdre Killebrew, who works for Applied DNA Sciences. The couple met when they were working with dolphins in Hawaii. Matus’ first paper was on dolphin cognition, although he switched to evolutionary and developmental biology when he worked in Martindale’s lab at the University of Hawaii.

Martindale described Matus as prolific during his time in his lab, publishing numerous papers that were “profoundly important in our continued understanding of the relationship between genotype and phenotype and the evolution of biological complexity,” Martindale wrote in an email.

Following in Martindale’s footsteps, Matus replaced his middle name, Samuel, in publications with a Q. Martindale said several of his colleagues adopted the phony Q to pay homage to the attitude that drove them to pursue careers in science. Matus has now passed that Q on to Korhman, who is his first graduate student.

Matus and Killibrew have two daughters, Bria and Maille, who are 7 and 9 years old. Their children have a last name that combines each of their surnames, Matubrew. Matus said he feels “fortunate when I got here three years ago that they had me set up my lab next to [Martin]. That gave us an instantaneous atmosphere for collaboration.”