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Bruce Stillman

Photo by © Kevin P. Coughlin/Office of Governor Andrew M. Cuomo

After two years of extensive renovation and with generous support from New York State, Cold Spring Harbor Laboratory’s historic Demerec Laboratory was reborn as a state-of-the-art research facility. Governor Andrew Cuomo cut the ribbon for the building’s reopening on Oct. 30, celebrating how the state will benefit from this new chapter in CSHL research.

“It’s good for Long Island, it’s good for the economy, but also it is doing work that I believe will improve the quality of life for thousands and thousands of people. I believe this work will actually save lives and there is nothing more important than that,” Governor Cuomo said during his visit. “That is the work that the people in this facility are dedicated to and God bless them for that. The state is honored to be playing a small role today.”

The Demerec Laboratory, home to four Nobel laureates, has been both a bastion and compass point for genetics research in New York and the world. Its new research will focus on taking a more holistic approach to treating cancer and the disease’s impact on the entire body.

According to the CSHL’s website, the new center “will enable newly developed compounds to be refined by world-leading chemists to develop next-generation therapies. This research will form a basis for collaboration with private foundations and pharmaceutical companies, while advancing the development of new drugs. 

In addition, the center will support ongoing research activities aimed to develop therapeutics for breast cancer, leukemia, autism, obesity, diabetes and lung cancer. The primary goal of such research activities will include the development of advanced drug compounds targeting underlying biological pathways.” 

To prepare the Demerec building for 21st-century science, it had to be gutted, with extensive renovations of the basement and interior, while leaving the historic 1950s brutalist exterior largely unchanged.

“We really challenged ourselves to preserve the history of the building as much as possible,” said Centerbrook design firm architect Todd E. Andrews, who planned the renovation.

The result is a modern facility uniquely designed for a scientific approach that considers disease not as a stand-alone subject of study but as a complex system that focuses on the patient.

“Too often [scientists] are not looking at the patient and the system of the patient … even though there are obvious signs that we should be looking,” said Dr. Tobias Janowitz, one of the next generation of Demerec Lab scientists and research-clinicians dedicated to rethinking cancer medicine.

Other Demerec researchers will include Nicholas Tonks, who investigates relationships between diabetes, obesity and cancer, and Linda Van Aelst, a neuroscientist who is interested in how sleep and signals from the brain may be impacted by cancer. Semir Beyaz, who studies how a patient’s nutrition can affect cancer treatment, will also join the team.

While the Demerec Laboratory’s faculty hasn’t been finalized, the researchers will be working alongside the rest of the CSHL community — including 600 scientists, students and technicians — to create a distinctly collaborative and cross-disciplinary culture.

Governor Cuomo called the Demerec building and the larger CSHL campus “hallowed ground for scientific research,” after dedicating $25 million in 2017 toward the $75 million renovation and said he is confident the space and its scientists will deliver a new wave of scientific progress.

“We invested over $620 million statewide in life sciences with $250 million in Long Island alone in biotech. Why? Because we believe that is an economic cluster that is going to grow and that is going to create jobs and it already is,” the governor said. “I believe Long Island is going to be the next Research Triangle.“

Renovating a single research facility may seem like a small step toward the state’s goal, but this particular building has made Long Island a scientific hot spot once again.

“While the Demerec building is comparatively smaller than larger projects that the governor has initiated … it is arguably one of the most productive buildings in all of science,” said CSHL President and CEO Bruce Stillman. “This renovation allows us to really think about where the Lab will take things next. It will have, I hope, a global impact on the research community, especially in the biomedical sciences.

Pictured from left: Laurel Hollow Mayor Daniel DeVita, President of Long Island Association Kevin Law, Northwell Health CEO Michael Dowling, President of Empire State Development Eric Gertler, Commissioner of Health for NYS Dr. Howard Zucker, CSHL President and CEO Bruce Stillman, Governor Andrew M. Cuomo, CSHL Honorary Trustee Jim Simons, CSHL Chair of the Board of Trustees Marilyn Simons, Nassau County Supervisor Laura Curran, NYS State Assemblyman Chuck Lavine, NYS Assemblyman Steve Stern, NYS Senator Jim Gaughran and CSHL COO John Tuke.   Photo by © Kevin P. Coughlin/Office of Governor Andrew M. Cuomo

 

Bruce Stillman. Photo courtesy of CSHL

By Daniel Dunaief

Bruce Stillman, the president and CEO of Cold Spring Harbor Laboratory, was recently awarded the prestigious Canada Gairdner International Award for his contributions to research about the way DNA copies itself. The 60-year-old prize, which Stillman will receive in a ceremony in October and that he shares with his former postdoctoral fellow John Diffley, includes a financial award of $100,000 Canadian dollars that he can spend however he’d like.

A native Australian, Stillman, who has been at Cold Spring Harbor Laboratory since 1979, recently shared his thoughts about the award, research at the lab and his concerns about science in society with Times Beacon Record News Media. 

How does it feel winning the Gairdner Award?

It’s one of the most prestigious awards in the life sciences in the world and it’s certainly a great honor to win it and to join the list of spectacular scientists in the history of the award. There are some really fantastic scientists who I very much admire who have received this award.

How does it relate to the research you’ve conducted?

The field of DNA replication and chromosome inheritance was recognized. It is something I’ve devoted my entire career to. There are a lot of people that have made important contributions to this field. I’m pleased to be recognized with [Diffley] who was my former postdoc. [It’s validating] that the field was recognized.

Has CSH Laboratory been at the cutting edge of discoveries using the gene-editing tool CRISPR?

Cold Spring Harbor didn’t discover CRISPR. Like many institutions, we’ve been at the forefront of applying CRISPR and gene editing. The most spectacular application of that has been in the plant field. Zachary Lippman, Dave Jackson and Rob Martienssen are using genetic engineering to understand plant morphogenesis and development, thereby increasing the yield of fruit. Hopefully, this will be expanded into grains and have another green revolution.

CSHL has also been making strides in cancer research, particularly in Dave Tuveson’s lab, with organoids.

Organoids came out of people studying development. Hans Clevers [developed organoids] in the Netherlands … Tuveson is at the forefront of that. The full promise hasn’t been realized yet. From what I’ve seen, we are quite excited about the possibility of using organoids as a tool to get real feedback to patients. It is rapidly moving forward with the Lustgarten Foundation and with Northwell Health.

What are some of the other major initiatives at CSHL?

The laboratory’s investment about 10 or 15 years ago in understanding cognition in the brain has paid off enormously. Neuroscientists here are at the forefront of understanding cognition and how the brain does computation in complicated decisions. [Scientists are also] mapping circuits in the brain. It took a lot of investment and kind of the belief that studying rodent cognition could have an impact on human cognition, which was controversial when we started it here, but has paid out quite well. At the same time, we are studying cognitive dysfunction particularly in autism. 

Any other technological advances?

There’s been a real revolution in the field of structural biology… [Researchers] have the ability to look at single biological molecules in the electron microscope. It shoots electrons through a grid that has individual biological molecules. The revolution, which was done elsewhere by many people actually, led to the ability to get atomic resolution structures of macro molecular complexes. 

Cold Spring Harbor invested a lot of money, well over $10 million to build a facility and staff a facility to operate this new technology. I’ve been working on this area for about 12, 13 years now … Our structural biologists here in neuroscience, including neuroscientists Hiro Furukawa and Leemor Joshua-Tor have really helped introduce a lot of new biology into CSHL.

What are some of the newer efforts at the lab?

One of the big new initiatives we started is in the field of cancer. As you know by looking around, there’s an obesity epidemic in the Western world. We started a fairly large initiative, understanding the relationship between obesity and cancer and nutrition, and we’re not unique in this. We’re going to have some significant contributions in this area. 

Cancer cells and the tumor affect the whole body physiology. The most severe [consequence] is that advanced cancer patients lose weight through a process called cachexia. We hired [new staff] in this new initiative, renovated a historic building, the Demerec building at a fairly substantial expense, which was supported by New York State. 

What will CSHL researchers study related to obesity?

We’re absolutely going to be focusing on understanding mostly how obesity impacts cancer and the immune system, then how cancer impacts the whole body physiology. Hopefully, once we start to understand the circuits, [we] will be able to intervene. If we can control obesity, we will by logic reduce cancer impact.

What worries you about society?

What worries me is that there is a tendency in this country to ignore science in policy decisions … The number of people not getting vaccinated for measles is ridiculous. There is this kind of pervasive anti-science, anti-technology view that a lot of Americans have. They want the benefits of science and everything that can profit for them. 

There are certain groups of people who misuse data, deliberately abuse misinformation on science to promote agendas that are completely irrational. One of the worst is anti-vaccination. … We should as a society have severe penalties for those who choose to go that route. They shouldn’t send their children to schools, participate in public areas where they could spread a disease that effectively was controlled. Imagine if polio or tuberculosis came back?

How is the lab contributing to education?

People need to act like scientists. It’s one of the reasons we have the DNA Learning Center, to teach people to think like scientists. If 99.99 percent of the evidence suggests [something specific] and 0.01 percent suggest something [else], you have to wonder whether those very small and vocal minority are correct.

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.

Leemor Joshua-Tor. Photo from CSHL

By Daniel Dunaief

Like many of the other talented and driven professionals at Cold Spring Harbor Laboratory, Leemor Joshua-Tor often works far from the kind of spotlight that follows well-known actors or authors.

That changed in April and early May. First, the American Academy of Arts and Sciences elected her a member on April 11. Other members joining the academy this year include Carol Burnett, New York Times columnist Nicholas Kristof, actor Ian McKellen, who played Gandalf in the Hobbit films and Magneto in the X-Men movies, and Israeli writer David Grossman.

Then, on May 2, the National Science Foundation elected the Cold Spring Harbor Laboratory professor and Howard Hughes medical investigator to join its ranks. “I got a huge amount of congratulatory emails from many friends, some of which I haven’t been in touch with for a while,” Joshua-Tor said. “It’s humbling.”

Joshua-Tor’s research covers a range of areas in structural and molecular biology. She works with RNA interference, where she focuses on how small molecules regulate gene expression or translation. She has also worked with Cold Spring Harbor Laboratory President Bruce Stillman on the early stages of DNA replication.

Early this year, Joshua-Tor and Stillman published a paper in eLife Sciences in which they offered more details about the human origin recognition complex. Stillman suggested that Joshua-Tor was the “main driver” for the research, studying the structure of a protein he had isolated years ago. “I am not a structural biologist, but she is an outstanding one and together, we came up with a very satisfying result.”

The origin recognition complex begins the process of replication, recruiting a helicase, which unwinds DNA. It also brings in regulatory factors that ensure smooth timing and then other factors such as polymerase and a clamp that keeps the process flowing and ensures accurate copying of the genetic code. “We don’t know how ORC’s motor activity is used,” Joshua-Tor explained. “We don’t really know what it is on the DNA that the ORC likes to bind to.”

In the recent work, the scientists explored the ORC’s structure and tinkered with it biochemically to understand it. The ORC binds and hydrolyzes the energy molecule adenosine triphosphate, or ATP, in the same way a motor would, although it probably isn’t continuous. “It might use ATP hydrolysis to perform one sort of movement, perhaps a detachment,” Joshua-Tor suggested.

In the early stages of replication, ATP is necessary for the integrity of the ORC complex, as well as the helicase that gets recruited. “We knew from biochemistry that ORC bounds multiple ATP molecules, but we did not know precisely how,” Stillman explained in an email. “The structure told us. ORC does not open the DNA by itself, but loads a protein complex onto the DNA that, when activated, can open the DNA.” Stillman is working on that process now. The next step for the CSHL collaborators is to get a structure of human ORC bound to DNA.

In their recent work, the researchers characterized how mutations involved in ATP hydrolysis affect a condition called Meier-Gorlin syndrome. Of the mutations they characterized, one affects the ability to hydrolyze ATP. Patients with this syndrome have one copy of the gene with typical function and the other that doesn’t. This likely leaves the patient with half of the molecules to do the required job.

The misregulation of replication is often associated with cancer and is something Joshua-Tor and others consider when they conduct these studies.

ATP, meanwhile, is associated with all kinds of activities, including cell adhesion and taking down misfolded proteins. Many processes in the cell connect to these types of molecular machines.

In her research with RNA interference, she is studying how a microRNA called Let7 is produced. Let7 is involved in development. Before cells differentiate when they are stem cells, they make Let7 continuously and then destroy it. She is studying the pathway for this process. Let7 is absent from stem cells and in some cancers.

Interested in science and theater when she was young, Joshua-Tor grew up in Israel, where she participated in activities at the Weizmann Institute of Science. The institute has biology, biochemistry, chemistry, math, computer science and physics, as well as an archeology unit that didn’t exist when she was there. Later, when she was a graduate student, Joshua-Tor returned to the institute and became an instructor.

An important moment in her scientific development occurred when she was in seventh grade. She was learning about elements and she put each one on a card. She brought these cards to class to study them. Her mother gave her a container that had housed her perfumes, which created a positive association for chemistry every time she studied the elements.

Joshua-Tor was also interested in theater, where she was initially in shows and then became an assistant director. The researcher lives with her daughter Avery, who is 8 and attends the Jack Abrams Magnet School. The tandem have a Schnauzer named Charles Darwin. Her daughter is proud of her mother and tells “anyone that would listen” about the awards her mother recently won, Joshua-Tor said.

Joshua-Tor, whose lab now has 11 people, said she is excited for the opportunity to meet some of her fellow honorees this fall.

Stillman expressed pride in “all our scientists and especially when they make major discoveries and they receive such peer recognition,” he wrote in an email. Joshua-Tor is “one of our best, but we have many scientists who will go on to gain substantial peer recognition. This is her turn, at least for these two awards!”

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.