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Cold Spring Harbor Laboratory

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.”

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.”

Builds upon revitalization efforts and Connect LI

Suffolk County Executive Steve Bellone, center, along with regional leaders, announced a new regional plan on Tuesday. Photo from the county executive’s office

As the percentage of youth on Long Island declines, regional leaders are determined to entice young people to move in and stay, but their plan comes with a price.

On Tuesday, County Executive Steve Bellone (D) and several regional leaders, including Brookhaven Town Supervisor Ed Romaine (R), announced they are seeking $350 million to fund the Long Island Innovation Zone, I-Zone, plan. I-Zone aims to connect Long Island’s transit-oriented downtown areas, like New Village in Patchogue, the Meadows at Yaphank and the planned Ronkonkoma Hub, to institutions like Stony Brook University, Brookhaven National Laboratory and Cold Spring Harbor Laboratory.

The I-Zone plan emphasizes the use of a bus rapid transit, or BRT, system  that runs north to south and would connect Stony Brook University and Patchogue. There will also be a paralleling hiking and biking trail, and the system will serve as a connection between the Port Jefferson, Ronkonkoma and Montauk Long Island Rail Road lines.

The goal is to make Long Island more appealing to the younger demographic and avoid local economic downturns.

According to the Long Island Index, from 2000 to 2009, the percentage of people aged 25-34 decreased by 15 percent. The majority of these individuals are moving to major cities or places where transportation is readily accessible.

“We must challenge ourselves because if we don’t, we have an Island at risk,” Romaine said. Government officials acknowledged that without younger people living on Long Island the population will be unable to sustain the local economy. Fewer millennials means there are less people who will purchase property and contribute to the success of businesses in the area.

The proposal comes after Governor Andrew Cuomo’s (D) call for regional planning.

The plan also builds upon the Ronkonkoma Hub plan, with the installation of sewers and a new parking area. The I-Zone proposal claims to improve Long Island’s water quality, as funding will help connect sewers through Islip downtown areas to the Southwest Sewer District.

Additionally, the plan calls for the construction of a new airport terminal on the north side of Long Island MacArthur Airport in Islip and for the relocation of the Yaphank train station in closer proximity to Brookhaven National Laboratory.

“We have all that stuff [access to recreational activities, education center and downtown areas] here but we don’t have a connection. We don’t have any linked together,” said Justin Meyers, Suffolk’s assistant deputy county executive for communications.

Bellone and Romaine, as well as Stony Brook University President Samuel Stanley, Islip Town Supervisor Angie Carpenter (R), Suffolk County Legislator Kara Hahn (D-Setauket), Long Island Regional Planning Council Chairman John Cameron, Patchogue Mayor Paul Pontieri, Vice President of Development and Community Relations at CSHL Charles Prizzi, Chief Planning Officer of the Long Island Rail Road Elisa Picca, Director of BNL Doon Gibbs, and founder of Suburban Millennial Institute Jeff Guillot, were involved with the I-Zone proposal.

If funding for the project is received, construction could begin in approximately two years, Meyers said, adding that constructing the BRT and the hiking and biking trial would take as few as five years.

Bellone said that without younger people moving in, the trend could lead to the Island’s economic stagnation.

“We are aging faster than any other region in our country,” he said. “The inevitable result of that will be an ever-growing population that naturally is pulling more social services infrastructure.”

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Doug Fearon. Photo from CSHL

Determined to help develop better treatments and, perhaps even a cure, Douglas Fearon, a medical doctor, decided to conduct research instead of turning to existing remedies. More than two decades later, Fearon joined Cold Spring Harbor Laboratory and is working on ways to help bodies afflicted with cancer heal themselves.

Fearon is focusing on the battle cancer wages with the T lymphocytes cells of human immune systems. Typically, these cells recognize threats to human health and destroy them. The pancreatic cancer cells he’s studying, however, have a protective mechanism that is almost like a shield. “The cancer is killing the T cells before the T cells can kill the cancer,” said Fearon.

The T cells have a complex signaling pathway on their surface that allows them to link up with other objects to determine whether these cells are friend or foe. In pancreatic cancer, Fearon has focused on a receptor that, when attached to the deadly disease, may disarm the T cell.

Researchers had already developed a small molecule that blocks the receptor on the T lymphocytes from linking up with this protein for another disease: the human immunodeficiency virus. When Fearon applied this molecule to a mouse model of pancreatic cancer, the therapy showed promise. “Within 24 hours, T cells were infiltrating the cancer cells,” he said. “Within 48 hours, the tumors had shrunk by 15 percent. This drug overcame the means by which cancer cells were escaping.”

This month, doctors at the University of Cambridge School of Clinical Medicine, where Fearon worked for 20 years, plan to begin Phase I human trials of this treatment for pancreatic cancer. Later this year, doctors at the Weill Cornell Medical College in New York City, where Fearon has a joint appointment, will begin a similar effort.

Scientists are encouraged by the early results from Fearon’s treatment. The Lustgarten Foundation named Fearon one of three inaugural “Distinguished Scholars” last year, awarding him $5 million for his research over the next five years.

The scientific advisory board at the Foundation “expects distinguished scholars to be on the leading edge of breakthrough therapies and understanding for this disease,” said David Tuveson, a professor and director of the Lustgarten Foundation Pancreatic Cancer Center Research Laboratory at CSHL.

During the early stage trials, doctors will increase the dosage to a level HIV patients had received during early experiments with the drug, called AMD 3100 or Plerixafor.

While Fearon is cautiously optimistic about this approach, he recognizes that there are many unknowns in developing this type of therapy. For starters, even if the treatment is effective, he doesn’t know whether the cancer may recur and, if it does, whether it might adapt some way to foil the immune system’s attempt to eradicate it.

Additionally, the receptor the doctors are blocking is required for many other functions in humans and mice. In mice, for example, the receptor on the T cell has a role in the developing nervous system and it also plays a part in a process called chemotaxis, which directs the migration of a cell.

“After giving this drug to HIV patients for 10 days, there were no long-term effects,” Fearon said. Researchers and doctors don’t “know for sure if you continued blocking this receptor what the long-term effects” would be.

Fearon and his wife Clare are renting a cottage in Lloyd Neck and have an apartment on the Upper East Side. Their daughter Elizabeth recently earned her Ph.D. in epidemiology in Cambridge, England while their son Tom, who is working toward a graduate degree in psychology, is interested in a career in counseling.

A native of Park Slope, Brooklyn who was the starting quarterback for Williams College in Massachusetts in his junior and senior years, Fearon feels it’s a “privilege to do something that may have a positive effect” on people’s lives.

Fearon is especially pleased to work at CSHL, where he said he can collaborate with colleagues who often immediately see the benefits of such a partnership. He has worked with Mikala Egeblad on intravital imaging, which is a type of microscope that allows him to look at living tissue. They are sharing the cost of buying a new instrument. Working with her “facilitated my ability to start up a project in my lab using a similar technique,” Fearon said.

A view of the Demerec Laboratory, slated to house a proposed Center for Therapeutics Research. The laboratory, completed in 1953, needs an upgrade. Photo from CSHL

Cold Spring Harbor Laboratory, a research center that has produced eight Nobel Prize winners and is stocked with first-class scientists generating reams of data every year, shared some numbers earlier this week on its economic impact on Long Island.

The facility brought in about $140 million in revenue in 2013 to Long Island from federal grants, private philanthropy, numerous scientific educational programs and the commercialization of technology its scientists have developed, according to a report, “Shaping Long Island’s Bioeconomy: The Economic Impact of Cold Spring Harbor Laboratory,” compiled by Appleseed, a private consulting firm.

At the same time the lab tackles diseases like cancer, autism and Parkinson’s, and employs 1,106 people with 90 percent working full time and 987 living on Long Island.

“We are recognized as being one of the top research institutions throughout the world,” Bruce Stillman, the president and CEO of CSHL said in an interview. The economic impact may help Long Islanders become “aware that such a prestigious institution exists in their backyard.”

Stillman highlighted programs that benefit the community, including public lectures, concerts and the school of education, which includes the DNA Learning Center, a tool to build a greater understanding of genetics.
The financial benefit to the economy extends well beyond Long Island, too.

“The research we do has an enormous impact on the development by others of therapeutics and plant science in agriculture,” Stillman said.

Indeed, Pfizer recently received U.S. Food and Drug Administration approval for a breast cancer drug called Ibrance that is expected to produce $5 billion in annual sales by 2020. The research that helped lead to that drug was conducted at CSHL in 1994.

In its 125-year history, this is the first time the laboratory has provided a breakdown of its financial benefit.
The impetus for this report occurred a few years ago, when Stillman met with Stony Brook University President Dr. Samuel Stanley Jr. and Sam Aronson, who was then the CEO of Brookhaven National Laboratory.

“We were talking about promoting further interactions and seeking state support,” Stillman said.

This year, CSHL will bring online a preclinical experimental therapeutics facility that will build out the nonprofit group’s research capabilities.

At the same time, CSHL is awaiting word on a $25 million grant it is seeking from New York State to support a proposed Center for Therapeutics Research.

The center would cost about $75 million in total, with CSHL raising money through philanthropic donations, partnerships with industry and federal aid. The center would “fit in well with our affiliation with North Shore-LIJ [Health System],” Stillman said.

CSHL plans to create the center in the Demerec Laboratory, which was completed in 1953 and needs an upgrade. Named after Milislav Demerec, a previous director at CSHL who mass-produced penicillin that was shipped overseas to American troops during World War II, the building has been home to four Nobel Prize-winning scientists: Barbara McClintock, Alfred Hershey, Rich Roberts and Carol Greider.

The renovated lab would house a broad range of research strengths, with candidates including a number of cancer drugs that are in the early stages of clinical trials; a therapeutic effort for spinal muscular atrophy, which is the leading genetic cause of death among infants; diabetes; and obesity.

The revenue from CSHL, as well as that from BNL, SBU and North Shore-LIJ, Stillman said, all have a “huge economic benefit to the Long Island community.”

Christopher Fetsch (far left) and Anne Churchland (second from right) with a group of neuroscientists at a conference last month. Photo from Anne Churchland

When she’s having trouble understanding something she’s reading, Anne Churchland will sometimes read the text out loud. Seeing and hearing the words often helps.

An associate professor at Cold Spring Harbor Laboratory, Churchland recently published research in the Journal of Neurophysiology in which she explored how people use different senses when thinking about numbers.

She asked nine participants in her study to determine whether something they saw had a larger or smaller number of flashes of light, sequences of sounds or both compared to another number.

To see whether her subjects were using just the visual or auditory stimuli, she varied the  clarity of the signal, making it harder to decide whether a flash of light or a sound counted.

The people in her study used a combination of the two signals to determine a number compared to a fixed value, rather than relying only on one type of signal. The subjects didn’t just calculate the average of sight and sound clues but took the reliability of that number into account. That suggests they thought of the numbers with each stimuli within a range of numbers, which could be higher or lower depending on other evidence.

Churchland describes this process as the probabilistic method. It would be the equivalent of finding two sources of information online about Gertrude Ederle, the first woman to swim across the English Channel. In the first one, someone might have posted a brief entry on his personal Web page, offering some potentially interesting information. In the second, a prize-winning biographer might have shared an extensive view of her long life. In a probabilistic strategy, people would weigh the second source more heavily.

Funded by an educational branch of the National Science Foundation, Churchland said this is the kind of study that might help teachers better understand how people’s brains represent numbers.

Young children and people with no formal math training have some ability to estimate numbers, she said. This kind of study might help educators understand how people go from an “innate to the more formalized math.”

This study might have implications for disorders in which people have unusual sensory processing. “By understanding the underlying neural circuitry” doctors can “hopefully develop more effective treatments,” Churchland said.

Churchland is generally interested in neural circuits and in putting together a combination of reliable and unreliable signals. Working with rodents, she is hoping to see a signature of those signals in neural responses.

Churchland runs a blog in which she shares developments at her lab. Last month, she attended a conference in which she and other neuroscientists had a panel discussion of correlation versus causation in experiments.

She cautioned that a correlation — the Knicks lose every time a dog tracks mud in the house — doesn’t imply causation.

The group studied a lighthearted example, viewing the relationship between chocolate consumption and the number of Nobel Prizes in various countries, with Switzerland coming out on top of both categories. “In the chocolate case, correlation does imply causation because I like to eat chocolate and was looking for excuses,” she joked.

Christopher Fetsch, a postdoctoral research fellow at the Department of Neuroscience at Columbia University, worked with Churchland for several months in 2010. In addition to teaching him how to do electrical microstimulation and serving as a “terrific role model,” Fetsch described Churchland as “an innovator with a high degree of technical skill and boundless energy.” Fetsch, who attended the same conference last month, lauded Churchland’s ability to bring together experts with a range of strengths.

Churchland created a website, www.Anneslist.net, which is a compilation of women in neuroscience. She said it began for her own purposes, as part of an effort to find speakers for a computational and systems neuroscience meeting. The majority of professors in computational neuroscience are men, she said. “It is important to have a field that is open to all,” she said. “That way, the best scientists [can] come in and do the best work.” The list has since gone viral and people from all over the world send her emails.

A resident of the housing at Cold Spring Harbor Laboratory, Churchland lives with her husband, Michael Brodesky, and their two children.

Churchland has collaborated with her brother Mark, an assistant professor at the Department of Neuroscience at Columbia University. Her parents, Patricia and Paul, are well-known philosophers. Her mother has appeared on “The Colbert Report.” She said her family members can all be contentious when discussing matters of the mind.

“The dinner table is lively,” she said.

Cold Spring Harbor Laboratory and the North Shore-LIJ Health System are partnering up to help cancer patients benefit from new research. File photo

Cold Spring Harbor Laboratory and the North Shore-LIJ Health System say they are partnering up to align research with clinical services in an effort to treat the health system’s nearly 16,000 cancer cases each year.

The partnership, announced last week, will benefit from more than $120 million investment that will be used to accelerate cancer research, diagnosis and treatment. The money will also be used to develop a new clinical research unit at the North Shore-LIJ Cancer Institute in Lake Success, NY. The unit will support the early clinical research of cancer therapies while also being used to train clinicians in oncology, the branch of medicine that deals with cancer. The source of the investment is not being disclosed.

“This is a transformative affiliation for both institutions, bringing the cutting-edge basic discovery science and translational cancer research at CSHL to one of the largest cancer treatment centers in the United States,” Cold Spring Harbor Lab President and CEO Bruce Stillman said in a press release.

As part of the affiliation, clinician-scientists will also be trained to perform preclinical cancer research and conduct early-stage human clinical trials to help further research.

“Cancer patients at North Shore-LIJ are going to benefit from the world’s leading cancer research centers,” Dagnia Zeidlickis, vice president of communications for Cold Spring Harbor Lab said in a phone interview Monday.

The partnership is just the latest move made by North Shore-LIJ to improve cancer care. Over the past two years, the health system invested more than $175 million to expand cancer treatment centers throughout Long Island and New York City.

Recently, North Shore-LIJ completed an $84 million expansion of the institute’s headquarters in Lake Success. It consolidated all cancer services offered by North Shore University Hospital and Long Island Jewish Medical Center in a state-of-the-art 130,000-square-foot facility, including ambulatory hematology/oncology, chemotherapy and radiation medicine, surgical oncology and brain tumor services, according to a press release.

North Shore-LIJ is also building a new $34 million, 45,500-square-foot outpatient cancer center in Bay Shore and is pursuing other major expansions on Long Island and in Manhattan, Queens, Staten Island and Westchester County.

“Bringing the scientists of Cold Spring Harbor Laboratory together with the more than 200 academic oncologists and clinicians of the North Shore-LIJ Cancer Institute will transform our approach to cancer research and treatment throughout the New York area,” North Shore-LIJ President and CEO Michael Dowling said in a statement.

Cold Spring Harbor Lab’s researchers have been studying cancer since the early 70s and have made several discoveries that have helped diagnose and treat cancer patients. In 1982, the lab was part of the discovery of the first human cancer gene. The Cold Spring Harbor Laboratory Cancer Center has been a National Cancer Institute-designated cancer center since 1987, and is the only such center on Long Island, according to the statement.

The lab’s research focuses on many different types of cancers: breast, lung, prostate, pancreas, cervix, ovary and skin, as well as leukemia and lymphoma, carcinoid tumors, sarcomas and more.

The cancer institute is part of the 19 health systems that makes up the North Shore-LIJ Health System. According to Zeidlickis, North Shore-LIJ cares for more than 16,000 new cancer cases each year and is New York State’s largest hospital system.

Under the terms of the partnership, both North Shore-LIJ and Cold Spring Harbor Laboratory will continue as independent organizations governed by their respective boards of trustees.