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Cold Spring Harbor Laboratory

Tim Sommerville. Photo by Brian Stallard, 2018/ CSHL

By Daniel Dunaief

Many research efforts search for clues about the signals or processes that turn healthy cells into something far worse. Scientists look at everything from different genes that are active to signs of inflammation to the presence of proteins that aren’t typically found in a system or organ.

Tim Somerville, a postdoctoral researcher in Chris Vakoc’s laboratory at Cold Spring Harbor Laboratory, recently took a close look at a specific protein whose presence in a high concentration in pancreatic cancer typically worsens the expectations for a disease with an already grim prognosis.

This protein, called P63, has a normal, healthy function in skin cells for embryos and in maintaining normal skin for adults, but it doesn’t perform any important tasks in the pancreas.

Tim Somerville at Cold Spring Harbor Laboratory. Photo by Brian Stallard, 2018/ CSHL

Somerville wanted to know whether the protein appeared as a side effect of the developing cancer, like the appearance of skinny jeans someone wears after a diet starts working, or whether it might be a contributing cause of the cancer’s growth and development.

“What was unclear was whether [the higher amount of P63] was a correlation, which emerges as the disease progresses, or something more causal,” he said, adding that he wanted to find out whether “P63 was driving the more aggressive features” of pancreatic cancer.

Somerville increased and decreased the concentration of P63 in tissue cells and organoids, which are copies of human tumors, hoping to see whether the change had any effect on the cancer cells.

The postdoctoral researcher knocked out the amount of P63 through the use of CRISPR, a gene-editing technique. He also overexpressed P63, which is also a transcription factor.

“From those complementary experiments, we were able to show that P63 is driving a lot of the aggressive features of cancer cells,” Somerville concluded. “Rather than being a correlation that’s observed, it is functionally driving the cancer itself.”

Somerville recently published his research in the journal Cell Reports.

As a transcription factor, P63 recognizes specific DNA sequences and binds to them. With P63, Somerville observed that it can bind to DNA and switch on many genes that are active in the worse form of pancreatic cancer. He and his collaborators describe P63 as a master regulator of the gene program.

Pancreatic cancer is often discovered after the irreversible conversion of normal, functional cells into a cancerous tumor that can spread to other organs. It also resists chemotherapy. Research teams in the labs of Vakoc and Dave Tuveson, the director of the Cancer Center at CSHL, and other principal investigators at CSHL and elsewhere are seeking to understand it better so they can develop more effective treatments.

Tim Somerville. Photo by Yali Xu

Vakoc was impressed with the work his postdoctoral researcher performed in his lab. Somerville is “one of the most scholarly young scientists I have ever met,” Vakoc explained in an email. “He is simply brilliant and thinks deeply about his project and is also driven to find cures for this deadly disease.”

At this point, Somerville is pursuing why P63 is activated in the pancreas. If he can figure out what triggers it in the first place, he might be able to interfere with that process in a targeted way. He also might be able to think about ways to slow it down or stop the disease.

The form of P63 that is active in the pancreas is not a mutated version of the protein that functions in the skin. If scientists tried to reduce P63, they would need to develop ways to suppress the cancer promoting functions of P63 without suppressing its normal function in the skin.

Many of the genes and proteins P63 activates are secreted factors and some of them contribute to inflammation. Indeed, researchers are exploring numerous ways inflammation might be exacerbating the progression of cancer.

P63 is also active in other types of cancer, including lung, head and neck cancers. Frequently, elevated levels of P63 in these other forms of cancer also lead to a worse prognosis.

Somerville explained that the changes P63 makes in a pancreatic cancer cell may expose new weaknesses. By studying cells in which he has overexpressed the protein, he hopes to see what other addictions the cells may have, which could include a reliance on other proteins that he could make compounds to target.

A resident of Huntington, Somerville has worked in Vakoc’s lab for three years. While he has spent considerable time studying P63, he is also looking at other transcription factors that are involved in pancreatic cancer.

Somerville wants to contribute to the discovery of why one form of pancreatic cancer is so much worse than the other. “If we can understand it, we can find new ways to stop it,” he said.

Originally from Manchester, England, Somerville is working in the United States on a five-year visa and plans to continue contributing to Vakoc’s lab for the next couple of years. At that point, he will consider his options, including a potential return to the United Kingdom.

Tim Somerville. Photo by Gina Motisi, 2018/CSHL

Somerville appreciates the opportunity to work on pancreatic cancer with Vakoc and with Tuveson, whose lab is next door. The researcher is enjoying his time on Long Island, where he takes walks, enjoys local restaurants and, until recently, had been playing on a Long Island soccer team, which played its matches in Glen Cove.

For Somerville, Cold Spring Harbor Laboratory has exceeded his high expectations. “The research that goes on here and the interactions you can have at meetings” have all contributed to a “great experience,” he said.

Somerville is excited to be a part of the pancreatic cancer team.

“With the work from [Tuveson’s] lab and ours, we’re finding new things we didn’t know,” he said. “It’s only when you understand those different things and the complexity that you can start thinking about how to tackle this in a more successful way. If the research carries on, we’ll make improvements in this disease.”

Photo by Ela Elyada

By Daniel Dunaief

What if, instead of defeating or removing enemy soldiers from the battlefield, a leader could convince them to join the fight, sending them back out to defeat the side they previously supported? That’s the question Giulia Biffi, a postdoctoral researcher at Cold Spring Harbor Laboratory, is asking about a particular type of cells, called fibroblasts, that are involved in pancreatic cancer.

Fibroblasts activated by cancer cells secrete a matrix that surrounds cancer cells and makes up about 90 percent of pancreatic tumors.

Giulia Biffi. Photo by ©Gina Motisi, 2018/CSHL

Responding to a molecule called IL-1, an inflammatory potential tumor-promoting fibroblast may enhance the opportunity for cancer to grow and spread. Another type of fibroblast responds to TGF-beta, which potentially enables them to restrain tumors.

Researchers had suggested that the inflammatory fibroblasts are tumor promoting, while the myofibroblasts are tumor defeating, although at this point, that still hasn’t been confirmed experimentally.

Researchers knew TGF-beta was important in biology, but they didn’t know that it was involved in preventing the activation of an inflammatory tumor-promoting version.

Biffi, however, recently found that IL-1 promotes the formation of inflammatory fibroblasts. She believes these fibroblast promote tumor growth and create an immunosuppressive environment.

In an article published in the journal Cancer Discovery, Biffi showed that it’s “not only possible to delete the population, but it’s also possible to convert [the fibroblasts] into the other type, which could be more beneficial than just getting rid of the tumor-promoting cells,” she said.

Biffi works in Director Dave Tuveson’s CSHL Cancer Center laboratory, which is approaching pancreatic cancer from numerous perspectives.

Her doctoral adviser, Sir Shankar Balasubramanian, the Herchel Smith Professor of Medicinal Chemistry at the University of Cambridge, suggested that the work she did in Tuveson’s lab is an extension of her successful research in England.

“It is evident that [Biffi] is continuing to make penetrating and important advances with a deep and sophisticated approach to research,” Balasubramanian explained in an email. “She is without a doubt a scientist to watch out for in the future.”

To be sure, at this stage, Biffi has performed her studies on a mouse model of the disease and she and others studying fibroblasts and the tumor microenvironment that dictates specific molecular pathways have considerable work to do to extend this research to human treatment.

She doesn’t have similar information from human patients, but the mouse models show that targeting some subsets of fibroblasts impairs cancer growth.

“One of the goals we have is trying to be able to better classify the stroma from pancreatic cancer in humans,” Biffi said. The stroma is mixed in with the cancer cells, all around and in between clusters of cells.

The results with mice, however, suggest that approaching cancer by understanding the molecular signals from fibroblasts could offer a promising additional resource to a future treatment. In a 10-day study of mice using a specific inhibitor involved in the pathway of inflammatory fibroblasts, Biffi saw a reduction in tumor growth.

If Biffi can figure out a way to affect the signals produced by fibroblasts, she might be able to make the stroma and the cancer cells more accessible to drugs. One potential reason other drugs failed in mouse models is that there’s increased collagen, which is a barrier to drug delivery. Drugs that might have failed in earlier clinical efforts could be reevaluated in combination with other treatments, Biffi suggested, adding if scientists can manage to target the inflammatory path, they might mitigate some of this effect.

A native of Bergamo, Italy, which is near Milan, Biffi earned her doctorate at the Cancer Research UK Cambridge Institute. Biffi lives on a Cold Spring Harbor property which is five minutes from the lab.

When she was young, Biffi wanted to be a vet. In high school, she was fascinated by the study of animal behavior and considered Dian Fossey from “Gorillas in the Mist” an inspiration. When she’s not working in the lab, she enjoys the opportunity to see Broadway shows and to hike around a trail on the Cold Spring Harbor campus.

Biffi started working on fibroblasts three years ago in Tuveson’s lab. “I really wanted to understand how fibroblasts become one population or the other when they were starting from the same cell type,” she said. “If they have different functions, I wanted to target them selectively to understand their role in pancreatic cancer to see if one might have a tumor restraining role.”

A postdoctoral researcher for over four years, Biffi is starting to look for the next step in her career and hopes to have her own lab by the end of 2019 or the beginning of 2020.

When she was transitioning from her doctoral to a postdoctoral job, she was looking for someone who shared her idealistic view about curing cancer. Several other researchers in Cambridge suggested that she’d find a welcome research setting in Tuveson’s lab. Tuveson was “popular” among principal investigators in her institute, Biffi said. “I wanted to work on a hard cancer to treat and I wanted to work with [Tuveson].”

Biffi hopes that targeting the inflammatory pro-tumorigenic fibroblasts and reprogramming them to the potentially tumor-restraining population may become a part of a pancreatic cancer treatment.

She remains optimistic that she and others will make a difference. “This can be a frustrating job,” she said. “If you didn’t have hope you can change things, you wouldn’t do it. “I’m optimistic.”

Biffi points to the hard work that led to treatments for the flu and for AIDS. “Years back, both diseases were lethal and now therapeutic advances made them manageable,” she explained in an email. “That is where I want to go with pancreatic cancer.”

Adrian Krainer in his lab. Photo by ©Kathy Kmonicek, 2016/CSHL

By Daniel Dunaief

This Sunday, Adrian Krainer is traveling to California to visit with Emma Larson, a Middle Island girl whose life he helped save, and to see an actor who played the fictional super spy James Bond.

A professor at Cold Spring Harbor Laboratory, Krainer is the recipient of the Breakthrough Prize in Life Sciences, which noted Silicon Valley benefactors including Facebook’s Mark Zuckerberg and Google’s Sergey Brin financed seven years ago. Pierce Brosnan will host the event, which National Geographic will broadcast live starting at 10 p.m. Eastern time.

Dr. Adrian Krainer and Emma Larson. Photo from Diane Larson

Krainer will split the $3 million prize money with Frank Bennett, a senior vice president of research and a founding member of Ionis Pharmaceuticals. The duo helped develop the first treatment for spinal muscular atrophy, the leading genetic cause of death among infants, which affects 1 in 10,000 births.

Prior to the Food and Drug Administration’s approval of Ionis and Biogen’s treatment, which is called Spinraza, people with the most severe cases of this disease lost the ability to use their muscles and even to breathe or swallow. Many children born with the most severe symptoms died before they were 2 years old.

“No one deserves it more,” said Dianne Larson, whose 5-year-old daughter Emma has been in a trial for the drug Krainer helped develop since 2015. When Emma started the trial as a 2-year-old, she couldn’t crawl anymore. Now, she’s able to push herself in a wheelchair, stand and take steps while holding onto something. Emma refers to Krainer as the person who helped make “my magic medicine.”

People with medical needs “kind of take for granted that there’s a medicine out there,” Larson said. “You don’t think about the years of dedication and research and hours and hours and money it costs to do this.”

Bruce Stillman, president and chief executive officer at Cold Spring Harbor Laboratory, said that this award was well deserved and was rooted in basic science. Krainer’s “insights were substantial and he realized that he could apply this unique knowledge to tackle SMA,” Stillman wrote in an email. “He did this with spectacular results.”

Dr. Adrian Krainer with the Larson family, Matthew, Diane and Emma. Photo from Diane Larson

Children with the most severe case of this disease had faced a grim diagnosis. “Now those children have a treatment that will keep them alive and greatly improve the prospects for a normal life,” Stillman added.

New York recently added SMA to its newborn screening test.

Krainer, who specialized in a process called RNA splicing during his research training, began searching for ways to help people with spinal muscular atrophy in 2000.

SMA mostly originates when the gene SMN1 has a defect that prevents it from producing the SMN protein,  called survival of motor neuron. This protein is important for the motor neurons, the nerve cells that control voluntary muscles.

As it turns out, people have a backup gene, called SMN2, which produces that important protein. The problem with this backup gene, however, is that it produces the protein in lower amounts. Additionally, RNA gene splicing leaves out a segment that’s important for the stability of the protein.

Looking at the backup gene, Krainer began his SMA work by seeking to understand what caused this splicing inefficiency, hoping to find a way to fix the process so that more function protein could be made from the SMN2 gene.

Collaborating with Bennett since 2004, Krainer developed and tested an antisense olignucleotide, or ASO. This molecule effectively blocked the binding of a repressor protein to the SMN2 transcript. By blocking this repressor’s action, the ASO enabled the correct splicing of the survival of motor neuron protein.

Emma Larson standing during her Mandarin lesson at Middle Country Public Library. Photo from Diane Larson

At first, Krainer tested the cells in a test tube and then in culture cells. When that worked, he went on to try this molecule in an SMA mouse model. He then worked with Ionis Pharmaceuticals and Biogen to perform the tests with patients. These tests went through hundreds of patients in numerous countries, as diseases like SMA aren’t limited by geographic boundaries.

“Everything worked” in the drug process, which is why it took a “relatively short time” to bring the treatment to market, Krainer said.

People who have worked with Krainer for years admire his character and commitment to his work.

Joe and Martha Slay, who founded the nonprofit group FightSMA, helped recruit Krainer to join the search for a treatment.

Joe Slay recalls how Krainer made an effort to meet with children with SMA. He recalls seeing Krainer during a pickup football game, running alongside children in wheelchairs, handing them the ball and tossing it with them.

Krainer brought his family, including his three children, to meet with the SMA community. The trip had a positive effect on his daughter Emily, who said it “subliminally had an impact on wanting to work in this field.” 

Currently a third-year resident in a combined pediatric neurology residency and fellowship program, his daughter is “very excited for him and proud.” She recalls spending Christmas holidays and New Years celebrations at the lab, where she met with his friends and co-workers.

Emily Krainer said a few people in her residency know about the role her father played in developing a treatment the hospital is employing.

The treatment is the “talk of child neurology right now,” she said.

Researchers hope the recognition for the value of basic research that comes with the breakthrough prize will have an inspirational effect on the next generation.

“The idea of prizes like this is to highlight to the public that scientists spend many years working without public recognition but make really important contributions to society,” Stillman suggested.

For Larson, the research Krainer did was key to a life change.

“To me, science is hope,” Larson said. “If we didn’t have this science, we wouldn’t have any hope,” adding that she would like her daughter to become a scientist someday.

Michael Schatz. Photo courtesy of Cold Spring Harbor Laboratory

By Daniel Dunaief

What if an enormous collection of Scrabble letters were spread out across the floor? What if several letters came together to form the word “victory”? Would that mean something? On its own, the word might be encouraging, depending on the context.

Genetic researchers are constantly looking at letters for the nucleotides adenine, guanine, cytosine and tyrosine, searching for combinations that might lead to health problems or, eventually, diseases like cancer.

For many of these diseases, seeing the equivalent of words like “cancer,” “victory” and “predisposition” are helpful, but they are missing a key element: context.

W. Richard McCombie

Michael Schatz, an adjunct associate professor at Cold Spring Harbor Laboratory who is also the Bloomberg distinguished associate professor at Johns Hopkins, and W. Richard McCombie, a professor at Cold Spring Harbor Laboratory, use long-read sequencing technology developed by Pacific Biosciences to find genetic variants that short-read sequencing missed.

The two scientists recently teamed up to publish their work on the cover of the August issue of the journal Genome Research. They provided a highly detailed map of the structural variations in the genes of a breast cancer cell.

“This is one of many covers [of scientific journals] that we are pleased and proud of,” said Jonas Korlach, the chief scientific officer at Menlo Park, California-based Pacific Biosciences. 

“This is another example of how long-read sequencing can give you a more complete picture of the genome and allow researchers to get a more complete understanding of the underlying biology and here, specifically, that underlies the transition from a health to a cancer disease state,” he said.

Schatz and McCombie were able to see fine detail and the context for those specific sequences. They were able to see about 20,000 structural variations in the cancer genome. “It’s like using Google maps,” explained Schatz in a recent interview. “You can see the overall picture of the country and then you can see roads and zoom out.”

In the context of their genetics work, this means they could see large and small changes in the genome. Only about a quarter of the variants they found could be detected without long-read technology.

In breast cancer, scientists currently know about a family of genes that could be involved in the disease. At this point, however, they may be unaware of other variants that are in those genes. Schatz is hoping to develop more sensitive diagnostics to identify more women at risk.

People like actress and advocate Angelina Jolie have used their genetic screens to make informed decisions about their health care even before signs of any problems arise. Jolie had a double mastectomy after she learned she had the mutation in the BRCA1 gene that put her at an 87 percent risk of developing breast cancer.

By studying the sequence of genes involved in breast cancer, researchers may be able to identify other people that are “at high risk based on their genetics,” Schatz said.

Knowing what’s in your genome can help people decide on potentially prophylactic treatments. 

When people discover that they have breast cancer, they typically choose a specific type of treatment, depending on the subtype of cancer.

“There’s a lot of interest to divide [the genetic subtypes] down into even finer detail,” said Schatz, adding, “There’s also interest in transferring those categories into other types of cancer, to give [patients] better treatments if and when the disease occurs.”

The reduced cost of sequencing has made these kinds of studies more feasible. In 2012, this study of the breast cancer genome would have cost about $100,000. To do this kind of research today costs closer to $10,000 and there’s even newer sequencing technology that promises to be even less expensive, he said.

Pacific Biosciences continues to see a reduction in the cost of its technology. The company plans to introduce a new chip next year that has an eightfold higher capacity, Korlach said.

Schatz said the long-term goal is to apply this technique to thousands of patients, which could help detect and understand genetic patterns. He and McCombie are following up on this research by looking at patients at Northwell Health.

In this work, Schatz’s group wrote software that helped decipher the code and the context for the genetic sequence.

“The instrument doesn’t know anything about genes or cancer,” he said. “It produces raw data. We write software that can take those sequences and compare them to the genome and look for patterns to evaluate what this raw data tells us.”

Schatz described McCombie, with whom he speaks every day or so, as his “perfect complement.” He suggested that McCombie was one of the world’s leaders on the experimental side, adding, “There’s a lot of artwork that goes into running the instruments. My lab doesn’t have that, but his lab does.”

Working with his team at CSHL and Johns Hopkins has presented Schatz with numerous opportunities for growth and advancement.

“Cold Spring Harbor is an internationally recognized institute for basic science, while Johns Hopkins is also an internationally recognized research hospital and university,” he explained. He’s living in the “best of both worlds,” which allows him to “tap into amazing people and resources and capacities.”

Korlach has known Schatz for at least a decade. He said he’s been “really impressed with his approach,” and that Schatz is “highly regarded by his peers and in the community.”

Schatz is also a “terrific mentor” who has helped guide the development of the careers of several of his former students, Korlach said.

Down the road, Schatz also hopes to explore the genetic signature that might lead to specific changes in a cancer, transforming it from an organ-specific disease into a metastatic condition.

Camila dos Santos speaks at the Pershing Square Research Alliance’s Fifth Annual Prize Dinner at the Park Avenue Armory on May 23 with Bill Ackman, co-founder of the Pershing Square Sohn Foundation and CEO of Pershing Square Capital Management, and Olivia Tournay Flatto, the President of the Pershing Square Foundation.

By Daniel Dunaief

They aren’t quite wonder twins, but some day the dedicated work of husband and wife scientists Christopher Vakoc and Camila dos Santos may help people batting against a range of cancers, from leukemia to breast cancer.

An assistant professor at Cold Spring Harbor Laboratory, dos Santos recently won the prestigious and highly coveted Pershing Square Sohn prize. Dos Santos, who studies breast cancer, will receive $200,000 in funds per year for the next three years. She won the same prize her husband, an associate professor at Cold Spring Harbor Laboratory, collected two years earlier for his work using the gene-editing technique CRISPR to study the molecular pathways involved in leukemia.

Dos Santos and Vakoc are the first family of prize winners in the Pershing Square Foundation’s five years of supporting research in the New York area.“The board was very much taken by how original her approach is and how thoughtful she is about it,” said Olivia Tournay Flatto, president of the foundation. “There was a lot of early stage data that would say that the observations she’s making are interesting to pursue, but that the National Institutes of Health would not fund. We felt this was something we wanted to be a part of.”

Dos Santos is studying so-called epigenetic changes that protect women from breast cancer if they become pregnant before they are 25. Women who have pregnancies before that cut-off age have a 30 to 40 percent decrease in breast cancer, even decades after their pregnancy.

Dos Santos has been digging into this process, looking at why some women who are pregnant before this age still develop breast cancer later in life.

The Cold Spring Harbor scientist is exploring how infections block the protective effects of pregnancy. She hasn’t defined the panel of infections that could influence cancer risk before or after pregnancy. The hypothesis in her work is that “the whole process that is fighting inflammation could change the breast cells,” which could “take away the advantage that pregnancy brings.”

If she proves her theory — that changes to inflammation could take away benefits of an early pregnancy — she could define changes to proteins and genes as biomarkers to predict the risk of breast cancer, even in the event of an early pregnancy. One of the challenges in the three-step application process for this prize was to explain to a group of experts how what she’s doing was different from what others are pursuing. Her approach is to look at cells before and during the process of turning into cancer cells. That strategy led to the current hypothesis, which was the basis for her application for this prize.

To study breast cancer, dos Santos recently developed a mouse model in her lab, to see how pregnancy changes pre-malignant lesions. When the mice they are studying have a gene that would turn into cancer, some of them don’t develop cancer if they’ve already been pregnant. Those mice that haven’t been pregnant develop cancer. She uses this mouse model to ask questions about how pregnancy changes a cell such that oncogenes cannot operate to change a cell into a cancer.

“We are not only investigating how prevention works, but we are also learning what signals break that prevention,” dos Santos said.

Dos Santos has used the mouse model experiments to test an unusual element to human breast cancer resistance. Women who reach their second trimester before 25, but don’t give birth to a child, have the same resistance, decades later, to breast cancer. Mice whose pregnancies last through the equivalent of the second trimester also experience similar epigenetic benefits.

She has tested mice who have a pseudo-pregnancy —who have higher pregnancy hormone levels without being pregnant — to see if a similar pregnancy environment would convey the same resistance. “Even in those cases, with no fetus, no embryo, no birth and no nursing, we see that the epigenetics changes,” dos Santos said. The scientist plans to use the funds from this award to perform high-tech experiments, such as single-cell, multiple mouse models and human tissue analysis that she wouldn’t have been able to tackle without the funding.

Dos Santos is grateful for the funding, which she said she wouldn’t have been able to secure through other means based on “the stage we are right now,” she said. The work is “risky” and “provocative,” but it’s also “outside of the box ideas and experiments and approaches.”

When she puts all the variants together, the risky outcome could be beneficial, leading to a better understanding of how to copy or, perhaps, understand nature to try to cure or prevent cancer.

Dos Santos said she learned about the award when she was on a train on the way to Jamaica, where she was catching a flight to Washington, D.C. She said she turned into a “texting machine,” sharing the good news with everyone, including her husband Vakoc, who called her as soon as he saw the news. “He was super happy,” she recalled.

She said Vakoc was particularly helpful in discussing the work and in watching their sons Lucas and Marcus who are 8 and 5, respectively. She also received some unexpected help from him before an extensive seven- to eight-minute finalist screening process.

She asked him about the interview, and he remembered that there were five people in the audience and that he didn’t get that many questions. When she appeared for her interview, she saw about 25 people in the audience and received numerous questions. In a way, she said, his memory of his experience may have helped her, because she didn’t have time to worry about the size of the audience or the number of questions.

Dos Santos said their sons are proud of their parents for winning awards for their work on cancer.

When her sons are upset with dos Santos, they sometimes warn, reflecting their parents’ threat to take away TV, that they’re going to “take your epigenetics away.”

Dos Santos said the couple maintains a healthy work-life balance. She is grateful for her husband’s support, as well as for the environment and expertise at Cold Spring Harbor Laboratory.

“Here at the lab, we not only have the technology to move this forward, but we also have a pretty outstanding body of scientists that are very collaborative,” she said.

Hervé Tiriac during a recent visit to the University of Nebraska Cancer Center. Photo by Dannielle Engel

By Daniel Dunaief

What if doctors could copy human cancers, test drugs on the copies to find the most effective treatment, and then decide on a therapy based on that work?

Hervé Tiriac, a research investigator at Cold Spring Harbor Laboratory, moved an important step closer to that possibility with pancreatic cancer recently.

Tiriac, who works in the Cancer Center Director Dave Tuveson’s lab, used so-called organoids from 66 patients with pancreatic ductal adenocarcinoma tumors. These organoids reacted to chemotherapy in the same way that patients had. 

“This is a huge step forward,” Tiriac said, because of the potential to use organoids to identify the best treatments for patients.

Hervé Tiriac. Photo by Dannielle Engel

Tuveson’s lab has been developing an expertise in growing these organoids from a biopsy of human tumors. The hope throughout the process has been that these models would become an effective tool in understanding the fourth most common type of cancer death in men and women. The survival rate five years after diagnosis is 8 percent, according to the American Cancer Society.

The study, which was published in the journal Cancer Discovery, “shows real promise that the organoids can be used to identify therapies that are active for pancreatic cancer patients,” Tuveson explained in an email. “This may be a meaningful advance for our field and likely will have effects on other cancer types.”

Kerri Kaplan, the president and CEO of the Lustgarten Foundation, which has provided $150 million in financial support to research including in Tuveson’s lab, is pleased with the progress in the field.

“There’s so much momentum,” Kaplan said. “The work is translational and it’s going to make a difference in patients’ lives. We couldn’t ask for a better return on investment.”

Tiriac cautions that, while the work he and his collaborators performed on these organoids provides an important and encouraging sign, the work was not a clinical trial. Instead, the researchers retrospectively analyzed the drug screening data from the organoids and compared them to patient outcomes.

“We were able to show there were parallels,” he said. “That was satisfying and good for the field” as organoids recapitulated outcomes from chemotherapy.

Additionally, Tiriac’s research showed a molecular signature that represents a sensitivity to chemotherapy. A combination of RNA sequences showed patterns that reflected the sensitivity for the two dominant chemotherapeutic treatments. “It was part of the intended goal to try to identify a biomarker,” which would show treatment sensitivity, he said.

While these are promising results and encourage further study, researchers remain cautious about their use in the short term because several technical hurdles remain.

For starters, the cells in the organoids take time to grow. At best right now, researchers can grow them in two to four weeks. Drug testing would take another few weeks.

That is too slow to identify the best first-line treatment for patients with advanced pancreatic cancer, Tiriac explained. “We have to try to see if the organoids could identify these biomarkers that could be used on a much shorter time frame,” he added.

Tuveson’s lab is working on parallel studies to accelerate the growth and miniature the assays. These efforts may reduce the time frame to allow patients to make informed clinical decisions about their specific type of cancer.

As for the RNA signatures, Tiriac believes this is a first step in searching for a biomarker. They could be used in clinical trials as is, but ideally would be refined to the minimal core gene signatures to provide a quick and robust assay. It is faster to screen for a few genes than for hundreds of them. He is studying some of these genes in the lab.

Researchers in Tuveson’s lab will also continue to explore biochemistry and metabolism of the organoids, hoping to gain a better insight into the mechanisms involved in pancreatic cancer.

Going forward, Tiriac suggested that his main goal is to take the gene signatures he published and refine them to the point where they are usable in clinical trials. “I would like to see if we can use the same approach to identify biomarkers for clinical trial agents or targets that may have a greater chance of impact on the patients,” he said.

The research investigator has been working at Tuveson’s lab in Cold Spring Harbor since the summer of 2012.

Tuveson applauded Tiriac’s commitment to the work. Without Tiriac’s dedication, “there would be no Organoid Profiling project,” Tuveson said. “He deserves full credit for this accomplishment.”

Tiriac lives in Huntington Station with his wife Dannielle Engle, who is a postdoctoral researcher in the same lab. He “really enjoyed his time on Long Island,” and suggested that “Cold Spring Harbor has been a fantastic place to work. It’s probably the best institution I’ve worked at so far.”

He appreciates the chance to share the excitement of his work with Engle. “You share a professional passion with your loved one that is beyond the relationship. We’re able to communicate on a scientific level that is very stimulating intellectually.”

Born in Romania, Tiriac moved to France when his family fled communism. He eventually wound up studying in California, where he met Engle.

Tuveson is appreciative of the contributions the tandem has made to his lab and to pancreatic cancer research. 

“Although I could not have imagined their meritorious accomplishments when I interviewed them, [Tiriac and Engle] are rising stars in the cancer research field,” he said. “They will go far in their next chapter, and humanity will benefit.”

Kaplan suggested that this kind of research has enormous potential. “I feel like it’s a new time,” she said. “I feel very different coming into work than I did five years ago.”

What do the signs tell us?

In Hawaii, numerous small earthquakes caused parts of Big Island to shake. Geologists, who monitor the islands regularly, warned of a pending volcanic eruption. They were right, clearing people away from lava flows.

How did they know?

It’s a combination of history and science. Researchers in the area point to specific signs that are reflections of patterns that have developed in past years. The small earthquakes, like the feel of the ground trembling as a herd of elephants is approaching in the Serengeti, suggest the movement of magma underneath the ground.

Higher volumes of lava flows could come later on, as in 1955 and 1960, say USGS scientists in the archipelago.

The science involves regular monitoring of events, looking for evidence of what’s going on below the surface. “Hopefully we’ll get smart enough that we can see [tremors] coming or at least be able to use that as a proxy for having people on the ground watching these things,” Tina Neal, scientist-in-charge at USGS Hawaiian Volcano Observatory, explained to KHON2 News in Honolulu.

People look for signs in everything they do, hoping to learn from history and to use whatever evidence is
available to make predictions and react accordingly.

Your doctor does it during your annual physical, monitoring your blood chemistry, checking your heart and lungs, and asking basic questions about your lifestyle.

Scientists around Long Island are involved in a broad range of studies. Geneticists, for example, try to see what the sequence of base pairs might mean for you. Their information, like the data the geologists gather in
Hawaii, doesn’t indicate exactly what will happen and when, but it can suggest developments that might affect you.

Cancer researchers at Cold Spring Harbor Laboratory and Stony Brook University are using tools like the gene editing system called CRISPR to see how changing the genetic code affects the course of development or the pathway for a disease. Gene editing can help localize the regions responsible for the equivalent of destructive events in our own bodies, showing where they are and what sequences cause progression.

Scientists, often working six or seven days a week, push the frontiers of our ability to make sense of
whatever signs they collect. Once they gather that information, they can use it to help create more accurate diagnoses and to develop therapies that have individualized benefits.

Indeed, not all breast cancers are the same, which means that not all treatments will have the same effect. Some cancers will respond to one type of therapy, while others will barely react to the same treatment.

Fundamental, or basic, research is critical to the understanding of translational challenges like treating
Alzheimer’s patients or curing potentially deadly fungal infections.

Indeed, most scientists who “discover” a treatment will recognize the seminal studies that helped them finish a job started years — and in some cases decades — before they developed cures. Treatments often start long before the clinical stages, when scientists want to know how or why something happens. The pursuit of knowledge for its own sake can lead to unexpected and important benefits.

Outside the realm of medicine, researchers on Long Island are working on areas like understanding the climate and weather, and the effect on energy production.

Numerous scientists at SBU and Brookhaven National Laboratory study the climate, hoping to understand how one of the most problematic parts of predicting the weather — clouds — affects what could happen tomorrow or in the next decade.

The research all these scientists do helps us live longer and better lives, offering us early warnings of
developing possibilities.

Scientists not only interpret what the signs tell us, but can also help us figure out the right signs to study.

Gholson Lyon. Photo courtesy of Cold Spring Harbor Laboratory

By Daniel Dunaief

With the cost of determining the order of base pairs in the human genome decreasing, scientists are increasingly looking for ways to understand how mutations lead to specific characteristics. Gholson Lyon, an assistant professor at Cold Spring Harbor Laboratory, recently made such a discovery in a gene called NAA15.

People with mutations in this gene had intellectual disability, developmental delay, autism spectrum disorder, abnormal facial features and, in some cases, congenital cardiac anomalies.

In a recent interview, Lyon explained that he is trying to understand how certain mutations influence the expression of specific traits of interest, such as intelligence, motor development and heart development. He’s reached out to researchers scattered around the world to find evidence of people who had similar symptoms, to see if they shared specific genetic mutations in NAA15 and found 37 people from 32 families with this condition.

“I really scoured the planet and asked a lot of people about this,” said Lyon, who recently published his research in The American Journal of Human Genetics. The benefit of this kind of work, he explained, is that it can help screen for specific conditions for families at birth, giving them an ability to get an earlier diagnosis and, potentially, earlier treatment. “Being able to identify children at birth and to know that they are at risk of developing these disorders would, in a perfect world” allow doctors to dedicate resources to help people with this condition, he said.

Lyon published a similar study on a condition he named Ogden syndrome seven years ago, in which five boys in a single family died before they reached the age of 3. A mutation in a similar gene, called NAA10, led to these symptoms, which is linked to the X chromosome and was only found in boys.

Lyon found the genes responsible on NAA15 by comparing people with these symptoms to the average genome. The large database, which comes from ExAC and gnomAD, made it possible to do a “statistical calculation,” he said. The next steps in the research is to look for protein changes in the pathway in which these genes are involved. The people he studied in this paper are all heterozygous, which means they have one gene that has a mutation and the other that does not.

With this condition, they have something called haploinsufficiency. In these circumstances, they need both copies of the fully functioning gene to produce the necessary proteins. These mutations likely decrease the function of the protein. Lyon would like to study each of these cases more carefully to understand how much the mutation contributes to the various conditions. He looked for evidence of homozygous mutations but didn’t find any. “We don’t know if they don’t exist” because the defective gene may cause spontaneous miscarriages or if they just didn’t find them yet, he said.

Lyon plans on reaching out to geneticist Fowzan Alkuraya, who was trained in the United States and is working at King Faisal Specialist Hospital and Research Centre clinic in Saudi Arabia. The geneticist has studied the genes responsible for a higher rate of genetic disorders linked to the more common practice of people having children with cousins in what are called consanguineous marriages. 

Alkuraya works on the Saudi Human Genome Program, which studies the inherited diseases that have a higher incidence in Saudi Arabia.

For Lyon, finding the people who carry this mutation was challenging, in part because it hasn’t run in the family for multiple generations. Instead, Lyon and his colleagues, including Holly Stessman of Creighton University in Omaha, Nebraska and Linyan Meng at Baylor College of Medicine in Houston, Texas, found 32 unrelated families. In some of these families, one or two siblings carried this mutation in a single mutation.

By defining a new genetic disease, the scientists could help families seeking a diagnosis, encourage the start of early intervention such as speech therapy and connect patients with the same diagnosis. This can provide a support network in which people with this condition and their families know they are not battling this genetic challenge alone, Meng, the assistant laboratory director at Baylor Genetics and assistant professor at Baylor College of Medicine, explained in an email.

Every patient with an NAA15 mutation won’t have the same symptoms. “We see a range of phenotypes in these patients, even though they carry the same diagnosis with defects in the same disease,” Meng added. “Early intervention could potentially make a difference for NAA15 patients.”

Lyon works as a psychiatrist in Queens providing medication management. During his undergraduate years at Dartmouth College, in Hanover, New Hampshire, Lyon said he was interested in neurology and psychology. As he went through his residency at NYU, Columbia and New York State Psychiatric Institute, he gravitated toward understanding the genetic basis of autism, which he said is easier than conditions like schizophrenia because autism is more apparent in the first few years of life.

Lyon recently started working part time at the Institute for Basic Research in Developmental Disabilities on Staten Island. While Lyon appreciates the opportunity to work there, he is concerned about a potential loss of funding. “These services are vital” on a clinical and research level, he said. He is concerned that Gov. Andrew Cuomo (D) is thinking about decreasing the budget for this work. Reducing financial support for this institution could cause New York to lose its premiere status in working with people with developmental disabilities, he said.

“It has this amazing history, with an enormous number of interesting discoveries in Down syndrome, Alzheimer’s disease and Fragile X,” he said. “I don’t think it gets enough credit.”

As for his work with NAA, Lyon plans to continue to search for other people whose symptoms are linked to these genes. “I am looking for additional patients with mutations in NAA10 or NAA15,” he said.

First Row from Left to Right: Kapeel Chougule, Computational Science Developer II; Mariana Neves Dos Santos Leite, Lab Aide (no longer at CSHL); Sharon Wei, Computational Science Analyst II; Andrew Olson, Computational Science Analyst II Second Row from Left to Right: Joshua Stein, Computational Science Manager III; Christos Noutsos, Postdoctoral Fellow (no longer at CSHL); Vivek Kumar, Computer Scientist; Doreen Ware, CSHL Adjunct Associate Professor & USDA/ARS Research Scientist; Yinping Jiao, Post Doc Computational; Sunita Kumari, Computational Science Analyst III; Marcela Tello-Ruiz, Computational Science Manager II; Young Koung Lee, Post Doc 11; Jerry Lu, Computational Science Developer III; Michael Regulski, Research Investigator Third Row from Left to Right: Christophe Liseron-Monfils, Post Doc Computational (no longer at CSHL); Bo Wang, Post Doc Computational; Liya Wang, Computational Science Manager III; Joseph Mulvaney, Computational Science Analyst III (no longer at CSHL); Lifang Zhang, Research Associate; James Thomason, Computational Science Developer III; Peter Van Buren, Systems Engineer III Not Pictured but in Ware Lab: Nicholas Gladman, Post Doc III; Fangle Hu, Research Technician II; Demitri Muna, Computational Science Analyst III; Pragati Muthukumar, Lab Intern, High School; Xiaofei Wang, Computational Science Analyst I; George Wang, Lab Intern, College; Christy Bedell, Senior Scientific Administrator. Photo by William Ware

By Daniel Dunaief

In a two-month span, members of Doreen Ware’s lab at Cold Spring Harbor Laboratory have published three articles that address fundamental properties of plants. 

Doreen Ware. Photo by Gina Motisi, Cold Spring Harbor Laboratory

Printed in the journal Nature Genetics, researchers in her lab studied the genes involved in conferring disease resistance across a range of species of rice. Another study, featured in Nature Communications, found the genes and the molecular pathway that determines the number of fertile flowers in the cereal crop sorghum.

In Frontiers in Plant Science, her productive team identified the causal genes that enable sorghum to develop a waxy outer layer that allows it to resist drought by containing water vapor.

 

“I am pleased with the recent publications from the laboratory,” Ware, who is also a computational biologist for the U. S. Department of Agriculture, explained in an email. “This is a sign of productivity, as well as the impact [technological] advances and drop in sequencing [costs] that is supporting these science advancements.”

Her lab is interested in the link between the genes in a plant and the way it develops.

“I want to understand mechanistically how the outputs in a genome interact with one another to produce a product,” Ware said. This will allow the lab to inform breeding models. “We would like to use the biological mechanism to support predictive modeling.”

In the rice article, Ware, informatics manager Joshua Stein at Cold Spring Harbor Laboratory and University of Arizona plant scientist Rod Wing searched for the specific genetic sequences different species of rice around the world use to develop resistance to infections by fungi, bacteria and other pathogens.

They used wild varieties of rice that had not been domesticated and looked for signals in the DNA. These were selected by their collaborators based on phenotypes that may be of value to introduce into domesticated varieties.

Stein looked at rice in areas including Asia, Africa, South America and Australia. Through this analysis, he was able to focus on specific genetic sequences that helped these species survive local threats.

As a first step, Stein explained, they have identified all of the genes in these species, but do not yet know which are important for local adaption. This article could provide information on the region of the genome that had disease genes that have been successful over time against threats in the environment.

One potential route to reducing dependency on pesticides is to introduce natural resistance or tolerance. By providing multiple ways of defending itself, a plant can reduce the chance that a pathogen can overcome all of these defenses.

“This is a similar strategy that is used to address both viral diseases and cancer treatment,” Ware explained.

Boosting the defenses of some of these crops with genes that have worked in the past is one strategy toward sustainability, although the scientists would need to work on the specifics to see how they were deployed.

Stein explained that his role in this specific study was to annotate the genes by using computer programs to look at DNA sequences. Stein used a process called comparative genomics, in which he studied the genes of numerous species of rice and compared them to look for similarities and differences.

“Because these different species grow in different climates and geographical ranges, they will be locally adapted to those regions,” Stein said. “Those genes might be important to improve cultivated rice.”

As climates change and people and materials such as seed crops move around the world, rice may need to develop a resistance to a bacteria or fungi it hasn’t encountered much through its history. Indeed, even those species of rice that haven’t moved to new areas may face threats from new challenges, such as insects, fungi, bacteria and viruses, that have moved into the area.

By understanding successful adaptive strategies, researchers like Ware and Stein can look for ways to transfer these defenses to other rice varieties.

Stein likens the process to an arms race that pits pathogens against food crops. “There are real examples of where a resistance gene has been transferred from a wild species to a cultivated species using traditional approaches,” he said. This includes knocking out specific genes in wheat that provide powdery mildew resistance.

Ware’s lab also produced an article in which they explored the genetic pathway that tripled the grain number of sorghum. The grain is produced on the panicle, which has many branches. In a normal plant, more than half of the flowers are not fertile, producing fewer grains.

“We have recently published a paper on a variety of sorghum where nearly all of the flowers are fertile, increasing the grain number on each head,” said Ware.

The work was led by Yinping Jiao and Young Koung Lee, postdoctoral researchers in Ware’s lab. Jiao focused on the computational analysis while Lee explored the development.

The researchers reduced the level of a hormone, which generated more flowers and more seeds. Other researchers could take a similar approach to boost yield in other grain crops.

Employing a commonly used technique to introduce new variation to support trait development, Department of Agriculture plant biologist Zhanguo Xin created a new variant that resulted in a change in a protein. This plant had a lower level of the hormone jasmonic acid in the developing flower. The researchers believe a reduction in the activity of a transcription factor that controls gene regulation caused this.

“We are currently exploring if this is associated with a direct or indirect interaction with biosynthetic genes required to make the plant hormone,” Ware said.

Early in January, Ware’s lab also produced a study in which they used mutations in sorghum to reveal the genetic mechanism that enables the plant to produce a wax that helps with its drought resistance.

Ware suggested these studies are linked to an underlying goal. “In human health, genomics and mechanism support the development of management of disease and in some cases cures,” she explained. “In agriculture, it leads to improved germplasm development and sustained agriculture.”

From left, Jason Sheltzer, Nicole Sayles (who is a former lab technician and a co-author of an earlier MELK paper) and SBU undergraduates Chris Giuliano and Ann Lin. Photo by Constance Brukin

By Daniel Dunaief

If eating macaroni and cheese made Joe sick, he might conclude he was allergic to dairy. But he could just as easily have been allergic to the gluten in the macaroni, rendering the dairy-free diet unnecessary.

Scientists try to connect two events, linking the presence of a protein, the appearance of a mutation or the change in the metabolic activity of a cell with a disease. That research often leads to targeted efforts to block or prevent that protein. Sometimes, however, that protein may not play as prominent a role as originally suspected. That is what happened with a gene called MELK, which is present in many types of cancer cells. Researchers concluded that the high level of MELK contributed to cancer.

Jason Sheltzer, a fellow at Cold Spring Harbor Laboratory, and Ann Lin and Christopher Giuliano, undergraduates at Stony Brook University who work in Sheltzer’s lab, proved that wasn’t the case. By rendering MELK nonfunctional, Sheltzer and his team expected to block cancer. When they knocked out MELK, however, they didn’t change anything about the cancer, despite the damage to the gene. But, Sheltzer wondered, might there be some link between MELK and cancer that he was missing? After all, scientists had found a drug called OTS167 that was believed to block MELK function.

To test this drug’s importance for MELK and cancer, Sheltzer used this drug on cancer cells that didn’t have a functioning MELK gene or protein. Even without MELK, the drug “killed cancer cells,” regardless of the disappearance of a gene that researchers believed was important for cancer’s survival, he said.

“We showed for the first time that [the drug] was killing cells that didn’t express MELK,” Sheltzer said. The drug had to have another, unknown target.

Sheltzer suggested that this is the first time someone had used CRISPR, a gene-editing technique, to take a “deep dive” into what a drug is targeting. This drug, he said, has a different mechanism of action from the one most people believed.

Sheltzer, whose work was published in early February in eLife, expanded the research from a petri dish, where researchers grow and study cells, to mouse models, which are often more similar to the kinds of conditions in human cancers. In those experiments, he found no difference between the tumors that grew with a MELK gene and those that didn’t have the MELK protein, continuing to confirm the original conclusion. “The tumors that formed in cells that had MELK and the tumors that formed in cells that didn’t have MELK were the same size,” he said.

Originally, Sheltzer believed the MELK protein might be involved in chemotherapy resistance. His lab found, however, that no matter what they did to MELK in these cells, the cancer appeared indifferent. Other researchers suggested that Sheltzer’s work would be instructive in a broader way for scientists.

Sheltzer’s research on MELK “will motivate a new set of standards for target discovery and validation in the field going forward,” Christopher Vakoc, an associate professor at CSHL, explained in an email. Sheltzer “brings a rigorous approach to cancer research and an impressive courage to challenge prevailing paradigms.” Sheltzer’s work highlights the challenge of understanding the mechanism of action of new medicines, Vakoc added.

Sheltzer plans to explore several other genes in which a high concentration of a specific protein coded by that gene correlates with a poor prognosis.

Using CRISPR, Sheltzer believes his lab can get precise information about drug targets and their effect on cancer. He’s also tracing a number of other types of cancer drugs that he thinks might have compelling properties and will use CRISPR to study the action of these drugs. “We want to know not just that a drug kills cancer cells: We want to know how and why,” he said.

By figuring out what a drug targets, he might be able to identify the patients who are most likely to respond to a particular drug. So far, the finding that a drug doesn’t work by interfering with a specific gene, in this case MELK, has been easier than finding the gene that is the effective target, he explained.

One of Sheltzer’s goals is to search for a cancer cell that is resistant to the drug, so that he can compare the genes of the vulnerable one with those of the cell that’s harder to treat. Detecting the difference in the resistant cell can enable him to localize the region critical for a drug’s success.

Sheltzer said finding that MELK was not involved in a cancer’s effectiveness was initially “depressing” because researchers believed they had found a cancer target. “We hope that by publishing these techniques and walking through the experiments in the paper that other labs can learn from this and can use some of the approaches we used to improve their drug discovery pipelines,” he said.

Sheltzer is pleased that Lin and Giuliano made such important contributions to this paper. CRISPR has made it possible for these undergraduates to “make these really important discoveries,” he said. Lin, who has worked in Sheltzer’s lab for two and a half years, was pleased. “It is very exciting to share my knowledge of MELK in regards to its role in cancer biology,” she wrote in an email. “Authoring a paper requires a great deal of work and I am super thrilled” to see it published.

Sheltzer, who lives with his partner Joan Smith, who is a software engineer at Google, said he was interested in science during his formative years growing up in Wayne, Pennsylvania, which is just outside of Philadelphia, and appreciates the position he has at Cold Spring Harbor Laboratory. Soon after earning his doctorate at MIT, Sheltzer set up his own lab, rather than conducting research for several years as a postdoctoral researcher. “I was really fortunate to be given that opportunity,” he said.

As for his work with MELK, Sheltzer hopes he’s saved other labs from pursuing clinical dead ends.

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