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Cold Spring Harbor Laboratory

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Ride For Life presents CSHL with $300,000 for ALS research: from left, CSHL Director of Annual Giving and Donor Relations Karen Orzel, CSHL Assistant Professor Molly Hammell, Ride for Life Founder Chris Pendergast, Stony Brook Associate Professor Josh Dubnau and Ride for Life board member Frank Verdone. Photo by Jessa Giordano, Cold Spring Harbor Laboratory

By Daniel Dunaief

The past can come back to haunt us, even in the world of genetics. Over the course of millions of years, plants and animals have battled against viruses, some of which inserted their genes into the host. Through those genetic struggles, explained Molly Hammell, an assistant professor at Cold Spring Harbor Laboratory, cells develop “elaborate ways to fight back,” even as they continue to make copies of these pieces of DNA.

Sometimes, when our defenses break down, these retrotransposons, or jumping genes, can become active again. Indeed, that appears to be the case in a fly model of amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.

Working on a fruit fly model of ALS, Joshua Dubnau, an associate professor at Stony Brook University, Lisa Krug, who earned her doctorate at Cold Spring Harbor Laboratory and is now working at Kallyope in New York, and Hammell showed that these ancient genetic invaders play an important role in the disease amid activation by a protein often linked to ALS called TDP-43.

A recent study, published in PLOS Genetics, “really proves that retroviral reactivation (as a consequence of TDP-activity) is … central to either causing or accelerating neuronal cell death when TDP-43 inclusions are present,” explained Hammell in an email. If TDP-43 plays the same role for humans, this would suggest that targeting this protein or the jumping genes, it activates could lead to potential treatment for ALS.

These collaborators showed that an aggregation of this protein turned on jumping genes. These genes can make copies of themselves and insert themselves in other parts of the genetic code. In this case, TDP-43 expression disrupts the normal immune-like system that silences retrotransposons such as gypsy, which is a particular type of jumping gene in the fruit fly.

When gypsy was activated, the fruit fly exhibited many of the features of ALS, including protein pathology, problems with movement, shortened life span and cell death or glia and neurons in the brain. The scientists were also able to turn gypsy off, which improved the health and extended the life span of the fly.

Mimicking this protein results in broad activation of several retrotransposons. If this also occurs in people, the disease may activate a retrotransposon that is the human analog to gypsy, called HERV-K, as well as other retrotransposons. The study also suggests that DNA damage caused by retrotransposons may active a cell suicide mechanism. Finally, this effort showed a means by which the protein disrupts the normal immune surveillance that keeps retrotransposons quiet.

To be sure, Dubnau cautioned that animal models of a disease may not translate when returning to people. Researchers need to look at more patients at all the retrotransposons in the human genome to monitor its prevalence, Dubnau suggested. If the link between retrotransposon activation and the development of ALS is as evident in humans as it is in the fruit fly, scientists may take an approach similar to that which they took to battle the human immuno-deficiency virus, or HIV. Retrotransposons have an RNA genome that needs to be copied to DNA. This, Dubnau explained, is the step in the process where researchers attacked the virus.

In a small subset of HIV patients who have motor neuron symptoms that are similar to ALS, Avi Nath, a senior investigator at the National Institutes of Health discovered that treating patients with the typical HIV medication cocktail helped relieve their ALS symptoms as well.

“What is not known is whether, for some reason, this subset of patients had an ALS syndrome caused by HIV or they were curing them” by treating HIV, Dubnau said. Nath is currently involved in one of two clinical trials to see if HIV medications help ALS patients. The next step for Dubnau and Hammell is to screen the tissue of numerous ALS patients after their death to see if their retrotransposons were elevated.

In addition to NIH funding, the scientists received financial support from Ride for Life, which is a not-for-profit organization started in 1997 that raises funds for research to find a cure for ALS, supports patients and their families through patient services and raises awareness of ALS. Every May, Ride for Life conducts a 12-day, 100-mile patient wheelchair ride across Long Island. Dubnau and Hammell, who received a $300,000 grant from Ride for Life in 2015, said they have been inspired by Ride for Life founder Chris Pendergast.

Meeting Pendergast “has had a big impact,” Dubnau said. “He’s a force of nature. He’s an incredibly strong and intelligent person.” Receiving funds from Ride for Life created a sense of personal obligation to Pendergast and many other people who “had raised that money through sweat and effort.”

Without funding from the Ride for Life Foundation, “We would not have the resources to obtain these samples and do the sequencing experiments necessary to prove that this is a clinically relevant phenomenon in a large number of ALS patients,” Hammell said.

Through an email, Pendergast explained that Ride for Life chose to fund the work by Dubnau and Hammell because the research met several criteria, including that it might lead to new strategies to treat ALS and the research was on Long Island, which is a “powerful affirmation for our generous donors.”

Pendergast emphasized the importance of funding basic ALS research. “We need to know why it develops, how it progresses [and] how it can be diagnosed and monitored,” he urged.

A resident of Huntington, Dubnau and his wife Nicole Maher, who works at the Nature Conservancy as a climate scientist, have a nine-year-old daughter, Caitlin. Reflecting both of her parents’ professional interests, Caitlin is going to a statewide science fair, where she is presenting her work on how temperature affects the life span of insects.

As for his research, Dubnau hopes a further exploration of TDP-43 might reveal an important step in the progression of ALS. He hopes this discovery may suggest a strategy researchers and clinicians can take that might “stop the cascade of events” in ALS.

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Above, members of the New York Chapter of The Children’s Heart Foundation present CSHL Research Assistant Professor Michael Ronemus with a $50,000 check from The Children’s Heart Foundation for his recently funded research grant on Feb. 23. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

By Daniel Dunaief

Just before he took a holiday break in December, Michael Ronemus received a welcome surprise. “In the last afternoon before the holidays, I got a call from William Foley. He said, ‘Congratulations,’” recalled Ronemus, a research assistant professor at Cold Spring Harbor Laboratory. “I submitted the application in May and I didn’t know what to expect.”

Foley, the executive director at the Children’s Heart Foundation, was reaching out to Ronemus to let him know he was one of seven researchers — six in North America and one in Europe — to receive funding for his research. Ronemus received a check for $50,000 at a presentation ceremony on Feb. 23.

Scientists are seeking out private foundations more as they search for sources of funding, said Ronemus. The funds will help Ronemus use next-generation sequencing to look closely at 120 families for evidence of copy number variation in their genes.

 

When a person has a different number of copies of a part of a specific gene, that can be a positive, neutral or negative event, depending on the consequence for the individual. Most copy number variations are neutral, which is why people have hundreds of them in their genes. Copy number variations can contribute, however, to de novo mutations, presenting changes in a genetic code that can make the genes of an offspring different from those of his or her parents. If these mutations damage a gene that’s essential for normal development of the heart, they can contribute to congenital heart defects.

Michael Ronemus explains the relevance of his research to the community at the check presentation event on Feb. 23. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

Indeed, the Children’s Heart Foundation has contributed $8.7 million to research, hoping to improve the ability to prevent, diagnose and treat the 40,000 people born each year in the United States with a heart defect. Of the children born with a heart defect, about one in four, has a form of critical congenital heart disease, said Jon Kaltman, the chief in the Heart Development and Structures Diseases Branch of the National Heart, Lung and Blood Institute. That means he or she will most likely require surgery within the first year of life, although most have it within the first month.

At this point, doctors and researchers understand the genetic cause of congenital heart disease for a small percent of people. The work of the Pediatric Cardiac Genomics Consortium hopes to make this true for a larger number of people with a congenital heart defect, Kaltman said.

Knowing the genetics of a patient and his or her family could be “helpful for that family to understand what might have caused the congenital heart disease” said Kaltman, who has been a pediatric cardiologist since 2005. “If that family were to have another child” the genetics could help assess the “risk that a second child will also have a congenital heart defect.”

A greater awareness of the genes involved in heart disease could also provide a guide for the way the defect might react to treatment. “We see patients with identical looking hearts [on an echocardiogram] from different families in which they undergo surgery” and have different reactions, Kaltman said. “One does well and has few complications and the other develops arrhythmias at 15 and heart failure at 25.”

The differences in respones to treatment for those patients may be genetic. “For the patient with the genetic signal for the complicated course, we can do more interventions early on,” Kaltman said, which could include earlier valve replacements or more aggressive arrhythmia surveillance.

Working with Bruce Gelb, a professor in pediatrics and cardiology at Mount Sinai Hospital, Ronemus is focusing on a group of patients with a condition called tetralogy of Fallot. Children with this defect develop a bluish color in their skin and can have trouble breathing when they exercise.

New York Chapter president of the Children’s Heart Foundation Jackie Pecora speaks at the check presentation event. Photo courtesy of ©C. Brukin, 2017/Cold Spring Harbor Laboratory

Doctors treat people with this condition with open heart surgery, which fixes a hole between the ventricles and opens up a narrowed right ventricular outflow tract. “Early diagnosis can lead to a straightforward procedure and good outcome,” Ronemus said. “If there is any reason to suspect [that a developing fetus has this condition], we’d like to know.”

By studying copy number variation, Gelb and Ronemus can search for signatures or markers in prenatal screening, which doctors can do through amniocentesis or cell-free fetal DNA analysis, which is a noninvasive form of prenatal testing. A definitive diagnosis even before birth could help doctors prepare for quick intervention that could be more effective, Ronemus said. If not diagnosed, a third of the children with the condition die within the first year and 50 percent in the first three years, Ronemus explained. If doctors know a child has the condition, they can take precautions, like have supplementary oxygen or drugs nearby.

Ronemus, who started his career in plant genetics and then became involved in the study of autism, is applying a genetic technique he co-developed at CSHL for copy number variation detection called SMASH. He applied for the Children’s Heart Foundation grant because of a meeting at CSHL with Jackie Pecora, a resident of East Northport, who is New York Chapter president of the Children’s Heart Foundation. The foundation has 11 chapters throughout the country and raises funds through events like the Long Island Congenital Heart Walk, which will take place on May 21 in Sunken Meadow State Park. Ronemus will be an honorary co-chair for the walk.

Foley said Ronemus’ approach is a “unique way” of looking at congenital heart defects. During the medical advisory board’s discussion of which projects to fund “there was a lot of enthusiasm” for this project. Ronemus is the first New York researcher to receive CHF funds since 2009.

A resident of East Meadow, Ronemus lives with his wife Ana Rodriguez-Fernandez, who is an associate professor of microbiology at the NYU School of Medicine. The couple has three children, Martin, 14, Silvia, 12, and Daniel, 11.

Pecora has family experience with congenital heart disease. After she gave birth to twins 18 years ago, doctors discovered that her daughter Chloe had a heart defect that required surgery. Nine days after she was born, Chloe died from an infection. Pecora got involved because of a bumper sticker for another grassroots fundraiser for a baby with the same heart condition as Chloe. That led her to the Children’s Heart Foundation. While the awareness among the public is improving, there’s still a way to go to combat a prevalent condition, Pecora said. “Look at the clock: Every 15 minutes a baby is born with congenital heart disease. People don’t realize the magnitude.”

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By Daniel Dunaief

 

Adrian Krainer with Emma Larson earlier this year. Photo from Dianne Larson

The prognosis hit Dianne Larson of Middle Island hard. Within three weeks, anxiety attacks, a lack of sleep and fear caused her weight to plummet from 135 to 120 pounds. She found out her daughter Emma, who was 17 months old at the time, had a potentially fatal genetic condition called spinal muscular atrophy in which the motor nerve cells of the spinal cord progressively weaken. Normally, the SMN1 gene produces the survival of motor neuron protein, which, as its name suggests, helps maintain motor neurons. People with SMA, which has four types and severity, produce a lower amount of the functional protein.

“My mind went to the darkest of dark places,” said Larson, whose daughter couldn’t crawl or sit up to eat. “There was no hope. There was nothing I could do.”

At the time of Emma’s diagnosis, there was no treatment for a disease that is the leading genetic cause of death among infants and affects about 1 in 10,000 newborns. Thanks to the work of Adrian Krainer, a professor and program chair of cancer and molecular biology at Cold Spring Harbor Laboratory, that changed early enough to alter the expectations for Emma and children around the world battling a genetic condition that causes progressive weakness and can make moving and even breathing difficult.

Turning to a back up gene called SMN2, Krainer hoped to fix a problem with the way that gene is spliced. On SMN2, exon 7 is normally skipped and the resulting protein has a different sequence at the end. Krainer developed an antisense olignocleotide that binds to a sequence in the intro following exon 7, blocking the splicing receptor. The treatment, which is called Spinraza, helps guide the splicing machinery, which carries out one of the steps in gene expression that is necessary to build a functional protein.

The Larson family of Middle Island, from left, Dianne, Emma and Matthew. Photo from Dianne Larson

Larson had heard of Krainer’s work and was eager to see if his success with animal models of the disease would translate for humans. As soon as Emma reached her second birthday, Larson enrolled her daughter in a clinical trial for Spinraza. After her daughter had a few shots, Larson was stunned by the change. “I was in the master bedroom and she was in the den and I heard a voice getting closer,” Larson recalls. “Next thing I know, she was in my bedroom. I couldn’t believe she crawled from the den to the bedroom. I put her in the den and told her to do it again,” which she did.

The SMA community and Krainer received an early holiday present in late December when the Food and Drug Administration not only approved the treatment, but it also gave doctors the green light to prescribe it for all types of SMA and for patients of all ages. While the SMA community, doctors and Krainer have been delighted with the FDA approval, the excitement has been tempered by concerns about the price tag Biogen, which manufactures and commercializes Spinraza and funded the drug’s development, has placed on the treatment.

For the first full year of injections, the drug costs $750,000. Every year after that will cost $375,000, which Biogen has said publicly is consistent with the pricing for other drugs for so-called orphan diseases, which affect a much smaller percentage of the population.

Knowledge Ecology International, a nonprofit advocate for affordable medicines, sent a letter to the Office of the Inspector General at the Department of Health and Human Services, seeking an investigation. The letter claims that the inventor and maker of Spinraza failed to disclose that the treatment received federal funding. KEI urges the government to use that alleged disclosure failure to end the patent and authorize a generic manufacture of the treatment.

Biogen didn’t return a call and email for comment. Patients and their families, meanwhile, are looking for immediate access to a life-altering treatment. “To be honest, I really don’t know what we’re going to do,” said Larson, whose daughter has four injections left as part of the extension trial soon. “I’m hoping insurance will cover it.”

Insurer Anthem announced late in January that the treatment was only medically necessary for patients with Type 1 SMA, which include people diagnosed with the disease within six months of birth. Anthem created a pay for performance model, which will require patients or their families to prove that the treatment is improving the lives of the recipients.

Larson said she has been in touch with a personal liaison at Biogen, which has been “helpful and supportive,” she said. “They have been going out of their way to reach out to the community to make sure everyone gets access.”

Larson, who is a financial advisor, said she understands the need for the company to generate a profit. “A lot of money goes into” research and development Larson said. “If they’re not gong to make money, they’re not going to” support the efforts to create a treatment.

Emma Larson will be turning 4 this month. Photo from Dianne Larson

Joe Slay, who is the chairman of FightSMA, a group he and his wife Martha founded in 1991 after they learned their son Andrew had Type 2 SMA, sounded hopeful that people who need this treatment will receive it. “I understand there’s constructive, good conversations between insurance companies and Biogen,” Slay said. “We’re monitoring that.”

While Andrew, who is now 30, considers the potential benefits of Spinraza, Slay is pleased the treatment is an option for people and is proud of Krainer’s work.Krainer is “by any definition of the word a hero,” Slay said. “He’s taken his natural gifts, his brilliance in science, his discipline year in and year out approach to his work and has applied himself 100 percent.”

Slay and FightSMA, which has raised over $8 million since its founding, helped provide seed money to Krainer more than 15 years ago, attracting a promising scientist to what was then an intractable medical challenge.

Tom Maniatis, who is the chairman of the Department of Biochemistry and Molecular Biophysics at Columbia University, said Krainer, who did his doctoral work in Maniatis’s lab, showed considerable scientific promise early in his career. Krainer “clearly had the intelligence, drive and experimental skills to make important contributions,” Maniatis said. His work is “a perfect example of how deep basic science studies can lead to profound understanding of a disease mechanism and that, in turn to the development of a treatment,” explained Maniatis in an email.

Within Krainer’s own family, there is a connection to patient care. Krainer’s daughter Emily, who is a pediatric neurology resident at Rochester, may one day prescribe a treatment her father developed. “It will be quite something for me if she eventually prescribes Spinraza to one of her patients,” Krainer said. Even as other scientists and companies like AveXis continue to search for ways to treat SMA, Krainer enhances and refines his research.

“We continue to work on understanding aspects of SMA pathophysiology, the role of SMN levels outside the central nervous system and the potential for prenatal therapy,” he explained in an email. “We are also working on antisense therapies for other genetic diseases and cancer.”

Larson, who is overjoyed with her daughter’s progress, calls Krainer her “superhero” who “saved my daughter’s life.” “It’s such a different feeling when you know you can do something,” she said. When she found out that the FDA approved the treatment, it was “the best day.”

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From left, David Tuveson with Kerri Kaplan, the executive director and chief operating officer of the Lustgarten Foundation, and Sung Poblete, the CEO of Stand Up to Cancer. Photo courtesy of the Lustgarten Foundation

By Daniel Dunaief

Even as David Tuveson was recently fishing for tautog for dinner, he conducted conference calls on a cellphone while watching the clock before an afternoon meeting. A professor at Cold Spring Harbor Laboratory and a world-renowned expert in pancreatic cancer, Tuveson describes the research of some of the students in his laboratory as having considerable bait in the water.

The director of research for the Lustgarten Foundation, Tuveson recently assumed greater responsibility for a larger boat, when he was named director of the Cancer Center at Cold Spring Harbor Laboratory, taking over a role the lab’s president Bruce Stillman held for 25 years. The Cancer Center, which is one part of CSHL, will be in “great hands since Dave Tuveson has wide respect int he cancer community because of his research accomplishments and his talents in leading others,” Stillman explained in an email.

Stillman, who will continue to run his own lab and serve as the President and CEO of CSHL, described Tuveson as a “thought leader” and a “great scientist.” Tuveson and his team of 20 in his laboratory are approaching pancreatic cancer in several directions. They are searching for biomarkers for early detection, developing and testing drugs that preferentially target cancer cells and seeking to uncover the molecular pathways that turn a mutated gene, inflammation, or an illness into a tumor.

Tuveson, who has MD and PhD degrees, focuses on finding ways to use science to help patients. He will continue the Cancer Center’s mission to understand the fundamental causes of the disease, while adding some new strategies. He plans to develop nutrition and metabolism as new areas for the Cancer Center and will recruit “ a few outstanding faculty,” he explained in an email.

CSHL will also expand its skills in immunology and chemistry. Tuveson has dedicated himself and his laboratory to taking innovative approaches to a disease that had received only one-half of 1 percent of the National Cancer Institute’s annual research budget in 1999. That is up to 2 percent today, according to the Lustgarten Foundation, which is the largest private funder of pancreatic cancer research.

Tuveson and his team have become leaders in the developing field of organoids. By taking cells from a tumor or cyst, scientists can produce a smaller copy of the tumor from inside a partial, reproduced patient pancreas. The painstaking work enables researchers to look for the specific type of tumor in a patient, while it also provides a model for testing drugs that might treat the cancer. The technique of growing organoids has become so refined that researchers can create a structure that’s a mix of normal, healthy cells blended with the tumor.

Scientists can then take the resulting structure, called a chimera, and test the effectiveness of therapies in destroying cancers, while monitoring the side effects on healthy cells. Stillman believes Tuveson’s work with pancreas cancer organoids “is at the cutting edge of research in this area.” Tuveson’s lab is using organoids to study what Tuveson, for whom metaphors roll off the tongue as often as characters break into song in Disney movies, describes as kelp-like projections. Each cell has parts that project out from the membrane. His staff is looking for changes in the kelp.

Tuveson is encouraged by work that might help find a subtle protein shift, or changes in the structure of the kelp, as a telltale sign about the type of tumor a patient who is otherwise asymptomatic might have. Doctors might one day screen for these during annual physical exams. Other scientists are so interested in the potential benefits of these organoids that they are attending a training session in Tuveson’s lab that started early this month.

A post doctoral candidate in Tuveson’s lab, Christine Chio, is studying how reactive oxygen affects the growth and stability of cancer. In general, medical professionals have recommended antioxidants to protect health and prevent disease. In pancreatic cancer, however, antioxidants are necessary to keep cancer cells alive. An abundance of reactive oxygen can cause cancer cells to shut down.

“The irony is that cancer cells make their own anti-oxidants and are very sensitive to reactive oxygen — thus we use reactive oxygen to kill cancer cells,” Tuveson explained. Chio, Darryl Pappin, a research professor at CSHL, and several other scientists published their work this summer, in which they identified protein translation as the pathway protected from reactive oxygen species in cancer cells.

At the same time that Tuveson is overseeing the work searching for biomarkers and treatments in his lab, he is also encouraging other research efforts through his work with the Lustgarten Foundation. Started in 1998 when former Cablevision executive Marc Lustgarten developed pancreatic cancer, the Foundation invested $19.4 million in 2015 to pancreatic cancer research and is projected to invest $21 million in 2016.

The mission of the Foundation is to advance research related to the diagnosis, treatment and cure of pancreatic cancer. It also offers patient advice, information and a sense of community through events. Indeed, recently, as a part of a phase 2 clinical trial at Johns Hopkins Kimmel Center, the Foundation offered to provide a free genetic test for microsatellite instability, or MSI, to anyone who might benefit from it as a part of a diagnosis and treatment. MSI occurs in about 2 percent of pancreatic cancer patients. Those with this genetic characteristic responded to a particular type of treatment, called pembrolizumab. The study is still seeking to increase enrollment.

The Foundation is encouraged by the progress scientists like Tuveson have made. “We are hopeful about the future because we know that we have the most talented cancer researchers working on this devastating disease,” Kerri Kaplan, the President and Chief Operating Officer at the Lustgarten Foundation, explained in an email. “We are particularly optimistic about the organoid project and the implications it has for more effective treatments and the work being done on our ‘earlier’ detection program.”

Still, Tuveson and the Foundation, which received donations from 62,000 people in 2015, realize there’s a long way to go. “Pancreatic cancer is an incredibly complex and difficult disease which is why we need to stay focused on funding the most promising research,” Kaplan said.

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Raffaella Sordella. Photo from the laboratory of Raffaella Sordella

By Daniel Dunaief

Raffaella Sordella, whose lyrical name reflects her upbringing in Italy, takes the fight against cancer personally. That’s because she underwent surgery for a tumor in her pancreas a few years ago when she, her husband Manuel Barriola and their young daughters Victoria and Alicia were living in Boston.

“The past few years I have made friends with many people who share firsthand experience with cancer,” she recalled in an email. “I have witnessed their strength and courage and they have been an incredible source of inspiration for our work, especially at times when the glass looked half-empty.”

Indeed, while she fought cancer herself, Sordella and the lab she leads as an associate professor at Cold Spring Harbor Laboratory battle against the deadly disease every day. Recently, she made a discovery about a gene that has been among the most studied and carefully combed genetic regions of the human genome. A tumor suppressor gene, p53 protects against tumor growth. An increasing number of findings, however, point toward the possibility of p53 mutants that promote tumors.

In research published in eLife, Sordella found just such a mutant. Looking at a variation in which the gene is truncated, or cut short, a range of cancers can develop and can cause greater threats to a patient’s health. “Despite four decades and all these papers, this is completely new,” Sordella said.

As many as 10 to 15 percent of tumors of the pancreas, ovaries, melanoma, head and neck and small cell lung carcinoma have this truncated version of p53, according to Sordella. “If you have these mutations, your colon cancer tends to become more metastatic,” she said.

Sordella and her colleagues studied the signaling pathway that regulates the activity of this gene. They have found a path that may become a target for drugs. Her lab is in discussions with a pharmaceutical company to start clinical trials. Sordella suggested that this type of finding addresses the notion of individualized medicine, in which doctors and scientists search for the specific genetic regions that contribute to cancer, looking for ways to block them, turn them off or slow them down.

In this truncated version of p53, the genes are active in the mitochondria, or the powerhouse of the cell, where the energy molecule adenosine triphosphate, or ATP, is produced. Sordella is studying how this mutant p53 can affect metabolism.

“The result is exciting because it was so unexpected,” Scott Lowe, the chair of the Cancer Biology & Genetics Program at the Memorial Sloan Kettering Cancer Center, wrote in an email. “The current work shows that these mutations can act as an ‘accelerator’ of tumorigenesis as well.” Lowe was a co-author on the study, who described his lab’s contributions as providing human data on the prevalence of truncated mutations in p53 in human tumors.

Researchers have dedicated considerable effort to understanding the tumor microenvironment. They are seeking to understand what a cancer might need from its immediate surroundings. Scientists studying other diseases, such as fibrosis, tissue chronic injuries, Alzheimer’s and Parkinson’s are also dedicating considerable resources to understanding the microenvironment. The recent discovery has encouraged Sordella and her colleagues to explore the role of cancer cell metabolism, cancer cells and their interaction with the tumor microenvironment, while also exploring the druggability of downstream pathways. This form of the gene is interacting with cyclophilin D, which is an inner pore permeability regulatory. Cyclophilin D, as a result, could become the target for future drug treatments.

Lowe suggested that the “current study raises the possibility that cancers with truncating mutations in p53 would be susceptible to agents that block cyclophilin D,” but added that it “should be clear that this will require much further testing.” Still, he concluded that it “is exciting as the possibility of this approach was not previously appreciated.”

Sordella came upon the discovery of the role of this form of the gene by chance. The focus of her lab is to understand the mechanism of resistance in small cell lung cancers. She generated a model in which there was resistance to a particular inhibitor. When she conducted an expression profile, she found a shift in the molecular weight of p53. Cloning and sequencing the gene demonstrated an alternative splicing, or cutting, that nobody had described.

Sordella credits partners including Edward Kastenhuber, Marc Ladanyi and Lowe at Sloan Kettering with assisting in the analysis of the gene. Sordella appreciates the financial support of Swim Across America, an organization that raises money for cancer research and that has supported her research for several years. Swim Across America takes “great pride in each new finding as these are the building blocks for achieving the ultimate goal,” Daniel Cavallo III, the beneficiary chair of the Nassau-Suffolk Chapter of Swim Across America, wrote in an email. “All you need to do is speak with Dr. Sordella for a short time and it is so clearly evident just how passionate she is about her work,” Cavallo said. “Her hard work, dedication and commitment to the cause are extraordinary — this along with her achievements are part of why we continue to fund her research.”

As a child, Sordella said she had an interest in becoming a physicist. After witnessing the suffering and strain cancer inflicted on her family, including an uncle and grandfather who succumbed to the disease when she was 13, Sordella decided that battling this disease would be her mission. Her family, she said, instilled in her the sense of finding purpose beyond the accumulation of wealth and has established a foundation with the goal of caring for the elderly and promoting education. She hopes her work contributes to her family’s legacy. “Hopefully one day soon, I will be able to celebrate with them a new great victory in the fight against cancer,” she said.

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Dave Jackson. Photo courtesy of CSHL

By Daniel Dunaief

If we get a text message that our son just gained admission to his first choice for college, we might throw our arms in the air, pick up the phone and call him, or stand on the top of our desk and shout our joy to the room. We might feel, in that instant, as if he can achieve anything and, as a result, so can we.

While plants don’t send and receive text messages, they process and react to a range of signals, some of which can determine how and when they grow, which can be key parts of determining how much food they produce.

Recently, David Jackson, a professor at Cold Spring Harbor Laboratory, explored a mutation that causes corn, or maize, to experience growth that is so out-of-control that the corn becomes a disorganized mess. Jackson wondered what caused this growth and disrupted the creation of succulent rows of juicy, yellow bits ready to explode off the cob.

Stem cells can grow to become any type of cell. In this pathway, which was disrupted in the mutant and caused the uncontrolled growth, Jackson showed that the signal came from the leaves, which is likely responding to its surroundings. He discovered that fine tuning that mutation — or weakening the “grow-out-of-control” signal — was enough to cause a regular ear of corn to include as much as 50 percent more food. “What was surprising about our work is that we found this new stem cell pathway that had not been discovered in Arabidopsis,” which is, as Jackson described, considered the equivalent of the well-studied fruit fly in the plant world. “We had gone on to show that it was also present in Arabidopsis.”

At this point, he’s hoping to introduce these mutations or alleles into breeding lines to try to generate a similar increase in yields that he’s seen in the lab. He’s collaborating with DuPont Pioneer on that testing. “As in all areas of science, we make a basic discovery and hope it’ll be applicable,” he said. “We can’t guarantee it’ll work until” it’s checked in the field. “People cure cancer in mice, but find it’s more complicated in people. We’re hoping cumulative knowledge will lead to breakthroughs,” he added.

Sarah Hake, the director of the USDA Plant Gene Expression Center at the University of California at Berkeley, described the work as “important.” In an email, she suggested that “translation to more corn yield can take time, but this information will be crucial for thinking about breeding.”

Jackson received the mutated maize from a breeder in Russia. He then altered a wild type, or normal plant, to cause a similar mutation that produced more food. Jackson is excited about the potential to use the gene-altering technique called CRISPR, in which researchers can edit a genome, changing one or multiple base pairs at a time.

Above left, normal corn and, right, corn with a weakened Fea3 mutation. The mutated corn has up to 50 percent more yield. Photo by Byoung Il Je
Above left, normal corn and, right, corn with a weakened Fea3 mutation. The mutated corn has up to 50 percent more yield. Photo by Byoung Il Je

Jackson is not adding new genes but, rather, is “tweaking” the ones that are already there. He said agricultural companies can use CRISPR instead of dumping in a foreign DNA. In past experiments, Jackson has worked to produce a greater number of seeds in his experimental plants. In that work, however, he increased the number of seeds, although the size of the seeds was smaller, so the overall yield didn’t increase. In this study, however, he and his postdoctoral student Byoung Il Je produced more seeds that generated greater yield. The gene involved in this signaling pathway is called Fea3. It is part of the signaling network that tells the plant to pump more into the ear of the corn to produce more yield. Jackson named the gene Fea because of the way the corn looked. Fea stands for fasciated ear. He and the members of his lab had already characterized another gene, called Fea2.

Jackson has been working on this gene for 20 years, although the intensive work occurred more in the last four or five years. He said he’s benefited from the ability to take a mutant and identify the gene. When he started out 25 years ago, a graduate student could take five years to characterize a mutation and find a gene. “It was like looking for a needle in a haystack,” he said. Now, genome sequencing and fast mapping enables researchers to find a gene in as little as a few months. When he first produced the weaker mutation, Jackson wasn’t anticipating a higher yield but, rather, was hoping to prove that this gene was the one responsible for this uncontrolled growth that created a pulpy mess of corn. Jackson said he is “excited about the stem cell pathway” his lab discovered. He hopes this finding can lead to a better understanding of the signals that determine how a plant uses its resources.

A resident of Brooklyn, Jackson lives with his wife Kiyomi Tanigawa, an interior designer, and their eight-year-old son Toma.

Jackson, whose lab has seven postdoctoral researchers and one lab manager, plans to start experiments on tomatoes and rice to see how this gene is involved in similar signals in other food crops. He is also working on similar mutations to other genes like Fea3, which also might affect a plant’s decision to produce more food.

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Tony Zador. Photo courtesy of Cold Spring Harbor Laboratory

By Daniel Dunaief

For some people, the frontier lies deep in space, further than the eye can see. For others, the frontier resides at tremendous pressure beneath the surface of the ocean. For Tony Zador, the chair of neuroscience and professor of biology at Cold Spring Harbor Laboratory, the frontier is much closer to home, in the collection of signals in our brains that enable thought and direct our actions.

Recently, Zador and his research team helped explore that frontier, developing a technological innovation that allowed them to see where nervous system cells from one important region projected into other areas.

About six years ago, Zador came up with the idea to barcode the brain. Zador and his former graduate student Justus Kebschull explored the connections between the locus coeruleus (LC) and other parts of a rodent brain. The LC is responsible for reacting to stressful situations, allowing an animal to stimulate areas that might help save its life, including those responsible for visual or auditory processing.

Researchers believed that the intercom system that connected the LC to the rest of the brain could stimulate all areas at once, like a building-wide announcement coming over the public address system. What scientists didn’t know, however, was whether that communication system could send messages to individual areas.

“People knew before our work that neurons in the locus coeruleus broadcast their signals throughout the cortex,” Zador said. “What was not known was whether there was any specificity. It was always assumed.”

Zador found that individual neurons had precise connections to different parts of the brain. While this doesn’t prove that the LC can selectively activate one area, the way a superintendent might send a signal to one wing of a building, it demonstrates the specificity of the connections, which “raises the possibility” of selective signals.

Indeed, if each neuron diffusely spread out across the entire cortex, there would be no way to achieve localized control over cortical functions through the LC system. The visual cortex, for example, would be alerted at the same time as the auditory and frontal cortex.

Ultimately, Zador is interested in the brain’s neuronal network. The way nervous system cells communicate in our brains can help us understand how we process and interact with the world around us. Down the road, he is hoping to help create something called a connectome, which will provide a map of that network.

This information, at a basic level, could provide a better understanding of neurological conditions such as autism, schizophrenia, depression and addiction.

At this stage, however, Zador is building a network called the projectome, which provides a map of the specific regions neurons go in the brain. He collects this information by inserting a deactivated virus with a unique genetic code into the brain. These viruses act as a label, allowing Zador and his colleagues to trace the areas where individual neurons go. This technique, he said, doesn’t indicate whether neuron one is connected to neuron two, three or four, but, rather, it indicates whether neuron one is connected to a bunch of neurons in regions one and two but not in three and four.

Zador “had to develop a method of bar coding each neuron so that it is unique and a technique of detecting each bar code individually,” said Bruce Stillman, the president and chief executive officer of Cold Spring Harbor Laboratory. By collecting numerous samples of where these neurons go, Zador, his collaborators and other scientists can determine the natural range of variability for animal models of individuals with typical behaviors and reactions. Once they establish that range of typical wiring, they can compare that to animal models of neurological challenges, like autism. Zador wants to “create a baseline against which we can compare neuropsychiatric models of disease.”

Stillman explained that Zador’s focus at CSHL has been on cognition — how the brain makes decisions, retains memory and pays attention to tasks at hand. Zador, Stillman suggested, is “one of the pioneers in establishing the rodent cognition area.”

To understand cognition, however, Zador needed to see what regions of the brain are connected to other areas, providing a road map of the brain. Even though he didn’t have a background in molecular biology, Zador benefited from working with specialists at CSHL to create this bar coding, Stillman explained. Stillman described Zador as “bright” and “broad thinking.”

Zador said the next step in his work will be to relate the projections to the individual cells’ function in the brain. He would also like to see their neuron-to-neuron connectivity. He said he is pursuing both goals and hopes to submit a paper in the next month or two describing such a method for the first time.

“Although we can sequence the codes” from neighboring neurons, “we still have work to do to figure out connectivity,” Zador said. “That involves significant molecular tricks that we’re refining.”

Georgio Ascoli, a collaborator with Zador and the director of the Center for Neural Informatics at the Krasnow Institute of Advanced Study at George Mason University, described Zador as an “internationally renowned, highly respected scientist,” whose best known contributions relate to the challenge of understanding how the brain can seamlessly decide which stimuli in a varied environment like a cocktail party to listen to among numerous choices.

A resident of Laurel Hollow, Zador lives with his wife Kathy Shamoun, who practices Chinese medicine at CSHL and is a childbirth educator and doula. The couple has two sons, Ronin, 10, and Bowie, 6.

As for the benefits of this bar-coding approach, Ascoli explained that the technique is “potentially revolutionary because of its inherent scalability to full mammalian brain mapping, which is currently out of reach for alternative approaches.”

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Gaofeng Fan
Gaofeng Fan at Cold Spring Harbor Laboratory. Photo by Siwei Zhang

The terror in the opening of the horror movie “When a Stranger Calls” comes when the police tell an anxious babysitter that threatening calls are “coming from inside the house.”

With the killer disease cancer, researchers spend considerable energy and time focusing on signals that might be coming from outside the cell. Many of those signals bind to a receptor in the membrane that corrupt a cell’s normal pathways, leading the cell to uncontrolled growth, the production of tumors or other unhealthy consequences.

Working in the laboratory of Nicholas Tonks, a professor at Cold Spring Harbor Laboratory, postdoctoral researcher Gaofeng Fan has spent over four and a half years studying a particular signal that comes from inside the cell. I

n a recent study published in Genes & Development, Fan demonstrated that a protein called FER, which adds a phosphate group to the inside part of a receptor called MET, plays a role in the ability of ovarian cancer to spread or metastasize. Already the target of drug development, MET is overexpressed in 60 percent of ovarian tumors. Thus far, developing drugs that block MET alone has not been particularly effective. Indeed, a humanized antibody that prevents human growth factor from binding to this receptor has shown “weak anti-tumor effect” in clinical trials, Fan suggested. In his research in cells, cultures and animal models, Fan demonstrated that ovarian cancer doesn’t spread and may have a different prognosis without FER.

“We found that the ligand [the human growth factor] is not necessary for the activation of the MET,” Fan said. “In the presence of FER, without the ligand, MET can be activated.” Understanding the role of FER in ovarian cancer may offer some clues about why only preventing signals from the outside aren’t enough to protect the cell. While Fan worked with ovarian cancer, he explained other scientists have shown that FER activation has been reported in lung, hepatic, prostate, breast and ovarian cancer. FER plays a part in cell motility and invasion, drug resistance and programmed cell death.

Fan’s work with FER started with a genetic experiment. Taking FER out of a cell, through a process called a loss-of-function assay, Fan found that the cell motility, or its ability to move, decreases. Once he took out FER, he also looked closely at MET activation. If the receptor required only human growth factor, which he included in his experiment, the removal of FER shouldn’t have any effect on its activity. “We found the opposite result,” Fan said.

Gaofeng Fan with his son Ruihan at Tall Ships America in Greenport in 2015. Photo by Xan Xu
Gaofeng Fan with his son Ruihan at Tall Ships America in Greenport in 2015. Photo by Xan Xu

A set of experiments with mice provided stronger evidence to support his belief that FER played a role in the spread of ovarian cancer. One of the mice had normal FER expression, while the other was missing the FER protein. When he compared the ability of cancer to metastasize, he found that cancer spread in a more limited way in the mice without the protein. “This confirmed the in vitro data and all the cell-based assays,” he said.

After six and a half years as a postdoctoral researcher, Fan is now looking for opportunities to teach and, perhaps, start his own lab in his native China. Fan hopes to continue to work on this system and would like to be a part of the discovery process that might find a small molecule inhibitor for FER. Once he and others find a FER inhibitor, they might be able to use it in combination with other drugs, including small molecules that inhibit human growth factor’s effect on the MET receptor.

Fewer than one in four women with Stage 3 ovarian cancer, which is typically the stage at which doctors find the disease, survive for five years.

Fan said he feels driven to help find a way to slow down the progression of this disease. “There’s an urgency to find a good, effective treatment.” To be sure, Fan cautioned that these studies, while encouraging and an important step in learning about ovarian cancer metastasis, require considerable work to become a part of any new treatment.

In his work, Fan was grateful for the support of Peter A. Greer, a principal investigator at the Cancer Research Institute at Queen’s University at Kingston in Ontario, Canada. Greer “is the leading scientist in research of FER proteins and he opened up all his toolbooks to me,” Fan said.

In an email, Greer described Fan as a “very gifted scientist with an outstanding training experience.” He hopes to “continue our collaboration in the area of ovarian cancer after [Fan] establishes his independent research program” in China. Greer, who spoke with Fan regularly through the process, said he is hopeful that the publication of the study in Genes & Development, in addition to other studies he and other labs have published, will “encourage drug development aimed at FER inhibitors suitable for clinical use.”

Fan also appreciated the guidance and flexibility of his CSHL mentor Nicholas Tonks, famous for his work on tyrosine phosphatase in which he studies the effect of removing phosphate groups. Fan’s research, however, involved understanding adding a phosphate group, through a kinase. “I got humongous support” from Tonks. “Without his help, I couldn’t come this far.”

A resident of Port Jefferson, Fan lives with his wife Yan Xu, who is earning her Ph.D. in materials science at Stony Brook. The couple has a six-year old son, Ruihan, who has enjoyed the Summer Sunday opportunities at Brookhaven National Laboratory, where Ruihan spent hours viewing and constructing the structure of DNA. As for his work, Fan sees opportunities to help people battling this disease.“If we can collect more evidence from this story, we can propose” a way to boost the outcome of treatment, he said.

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When they work as they should, they become a part of a process that helps us remember the Amendments to the Constitution, the Pythagorean Theorem, or the words to a love poem by Elizabeth Barrett Browning. When they don’t work correctly, we can run into all kinds of problems, some of which can get worse over time.

The N-methyl-D-aspartate receptor, also known as the NMDA receptor, which has parts that are bound in the membrane of brain cells, or neurons, is at the center of learning and memory.

Up until last year, only parts of the NMDA receptors sticking out of the membrane were known. A lack of a three-dimensional understanding made it difficult to see how this receptor works. Hiro Furukawa, an associate professor at Cold Spring Harbor Laboratory, and his postdoctoral researcher, Erkan Karakas, provided considerably more structural details of this receptor.

“The structures of the full-length NMDA receptor that [Furukawa’s] lab generated last year are seminal,” said Lonnie Wollmuth, a professor in the Department of Neurobiology and Behavior at Stony Brook University and a collaborator with Furukawa on other work. “They are fundamental to understanding how the NMDA receptor operates and how it can be modified in the clinic.”

Wollmuth suggested Furukawa has an “outstanding” reputation and said the structure of the receptor will “drive the field in new directions.”

Furukawa cautioned that scientists are still missing a structural understanding of a piece of the receptor that protrudes into the cell. Seeing the structure of this receptor will “provide clues for developing new compounds and for redesigning existing compounds to minimize side effects associated with nonspecific targeting,” Furukawa explained.

When NMDA receptors open, sodium and calcium ions flow into the cells. Too much calcium in the cells can cause toxicity that results in the neurodegeneration observed in Alzheimer’s disease and injuries related to strokes. Changes in the concentration of these ions can excite the neuron and cause symptoms such as epilepsy.

Seeing the structure of this receptor can provide a road map to find places on it that can become too active or inactive. Researchers typically look for binding sites, where they can send in a drug that can affect the function of the receptor. The more binding pockets scientists like Furukawa find, the greater the opportunity to regulate the NMDA receptor function.

Furukawa’s lab includes two graduate students, four postdocs and a technician. He is collaborating with scientists at Emory University to design and synthesize novel compounds based on the protein structures. As he gets more research funding, Furukawa would like to add more expertise in bioinformatics, which involves using computer science and statistics to understand and interpret large collections of data.

Experts in this field can go through a database of compounds quickly, enabling scientists to conduct the equivalent of thousands of virtual experiments and screen out candidates that, for one reason or another, wouldn’t likely work.

Furukawa is also studying autoimmune disorders in which immune cells attack these important receptors. One of these diseases is called anti-NMDA receptor encephalitis. Susannah Cahalan wrote an autobiographical account of her struggle with the disease in a New York Times Best Selling Book called “Brain on Fire: My Month of Madness” in 2012.

Furukawa is collaborating with a group at the University of Pennsylvania to find a way to detect the autoimmune antibodies that causes encephalitis. He is working to find a way to quench autoimmune antibodies for an anti-NMDA receptor.

Furukawa lives in Cold Spring Harbor with his wife, Megumi, who used to be an elementary school teacher but is now taking care of their sons Ryoma, 7, and Rin, 4.

Furukawa, who moved from Japan to Boston in fifth grade, then back to Japan for junior high school and finished high school in Missouri, is enjoying an opportunity to grow his own vegetables on Long Island.

As an undergraduate at Tufts, Furukawa was more interested in international politics and economics than in science. When he took chemistry and physics classes, he said the work “clicked comfortably” and he wound up majoring in chemistry. As an eight-year-old, he recalled watching the stars at night through a telescope. When he saw a ring of Saturn for the first time, he was so excited that he couldn’t sleep.

Furukawa’s colleagues appreciate his dedication to his work.

“He is certainly driven,” said Wollmuth. “He is in an extremely competitive field, so he must work efficiently and hard.”

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Camila dos Santos photo from the scientist

By Daniel Dunaief

Mothers of more than one child have blogged about it for years. When they have their second child, the breastfeeding process is often quicker, with milk available sooner than for the first child. Camila dos Santos, who became an assistant professor at Cold Spring Harbor Laboratory in February, has found a reason.

Cells in the mammary gland go through something called epigenetic changes. That means something affects the genetic machinery, causing them to react differently under the same circumstances. In mouse models, dos Santos discovered changes in cell proliferation and milk production genes to the hormones estrogen and progesterone.

When she was a postdoctoral student in Greg Hannon’s laboratory at CSHL, dos Santos said they “decided to profile the epigenome before and after pregnancy.” At first, she was looking for changes associated with the effects of pregnancy on breast cancer development. The recent work, however, described the presence of epigenetic memory of past pregnancies, which influences milk production in the next pregnancy.

The message from these studies was that those areas where she saw changes “are associated with the genes responsible for lactation and the proliferation of the mammary gland during pregnancy,” said dos Santos.

The implications of this research extend from the potential to enhance breastfeeding in women who struggle during lactation to breast cancer.

Indeed, other studies have shown that women who become pregnant before 25 have a lower risk for all types of breast cancer.

“We believe that such strong protective effect must have an epigenetic basis,” dos Santos said. She would like to “understand how this stable, pregnancy-induced epigenome prevents cancer development,” she continued.

Hannon believes the kind of research dos Santos is conducting holds promise.

“The world of breast cancer prevention is badly in need of very solid underlying molecular biology and I think there’s a fair chance that what [dos Santos] is doing will eventually get us there,” said Hannon, who recently left Cold Spring Harbor Laboratory and is now the Royal Society Wolfson Research Professor at the Cancer Research UK Cambridge Institute at the University of Cambridge.

Dos Santos said her research is exploring ways to turn the changes that occur during pregnancies before the age of 25 into a “preventive strategy to treat women that are high risk and even those that are not.”

To be sure, Hannon and dos Santos cautioned, it’s difficult to know how quickly or even whether this kind of research will lead to any treatment or prevention options.

“The main goal of my lab is to try to understand the effects of pregnancy on normal cells, to devise a strategy to prevent breast cancer from arising,” dos Santos said. She recently published her work in the journal Cell Reports.

Dos Santos and Andrew Smith, a computational biologist from the University of Southern California, along with his postdoctoral fellow Egor Dolzhenko discovered that mice that had been through a single pregnancy had methylation marks that were different from mice of the same age that hadn’t been pregnant. The group connected the changes in the genome to a transcription factor called Stat5a. A transcription factor is a protein that acts like a genetic traffic light, turning on or off genes.

When she joined Hannon’s lab in 2008, dos Santos wanted to study gene regulation throughout cell development. It took her three years to purify stem cells.

Hannon credits dos Santos for developing new techniques.

“She had to build the tools she needed to ask” these questions, Hannon said.

Dos Santos lives in campus housing with her husband, Christopher Vakoc, who is an assistant professor at CSHL. The couple take their young sons hiking and can’t wait for the spring and summer because they hike, swim and kayak. Vakoc and dos Santos met when they were in adjoining labs in Philadelphia.

“We used to have joint lab meetings and one day he asked me on a date,” she recalled.

This summer, dos Santos’ lab will include a premed undergraduate student from Hofstra and high school students from Cold Spring Harbor High School and  Southampton High School. She recently hired a postdoctoral fellow.

“I envision my lab growing according to my needs,” she said. “Right now, I want to continue to work at the bench while training students and postdocs.”

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