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Cold Spring Harbor Laboratory

Lloyd Harbor resident Frank D’Amelio, Jr. , CEO of Nature’s Answer in Hauppauge, cuts a pink ribbon to celebrate the formation of the company’s Nature’s Answer Foundation. Photo by Sara-Megan Walsh

By Sara-Megan Walsh

A Hauppauge company’s employees are heading out on a cross-country tour to raise funds for cancer research and awareness inspired by the memory of a Kings Park woman.

Nature’s Answer, a family-owned manufacturer of nutritional supplements, will celebrate the formation of its charitable arm, Nature’s Answer Foundation, with six employees embarking on a more than 4,000-mile motorcycle ride beginning Oct. 1.

“We are a health-oriented company and this ties closely in with the company’s mission of promoting well-being,” said vice president of operations Tom Connelly, of Stony Brook.

The Road 2 Wellness Tour motorcycle ride came together as part coincidence and part in loving memory, said Nature’s Answer CEO Frank D’Amelio, Jr.

The Road 2 Wellness Tour motorcycle ride came together as part coincidence and part in loving memory, said Nature’s Answer CEO Frank D’Amelio Jr. Photo by Sara-Megan Walsh

D’Amelio, of Lloyd Harbor, said an employee asked for the company to participate in Making Strides Against Breast Cancer, an American Cancer Society fundraising event Oct. 15 at Jones Beach. Nature’s Answer general counsel Scott Seedall, an avid motorcycle enthusiast, then asked D’Amelio if he would join him for a motorcycle ride after the company’s annual trade show in California.

“When it was suggested we ride, I connected the events together,” said Nature’s Answer CEO. “I said let’s do it for [the] cause and that Monday is Breast Cancer Awareness Month.”

D’Amelio said his sister-in-law, Maria Bellock, 46, of Kings Park, died of breast cancer in July 2016. He witnessed firsthand how devastating cancer can be.

“Riding 4,200 miles is child’s play compared to what she went through,” he said.

Bellock’s brother Larry Chiarenza, of Commack, is Nature’s Answer vice president of sales and will be riding cross country.

“Cancer is very taxing on the caregivers as well as on the patient,” he said. “It’s a very difficult process to go through.”

A former motorcyclist, Chiarenza said the two-week ride will be a challenge as he’s never ridden further than 100 miles before.

“[Maria] would probably think I’m nuts because I haven’t ridden in 30 years,” he said. “I never had any intention of riding again but it’s for such a good cause. How could I not?”

Other riders include Kasra Hosmand, of Bay Shore; Tom Mandelo, of Lake Ronkonkoma; and John Hank, of Huntington.

“Riding 4,200 miles is child’s play compared to what she went through.”

— Frank D’Amelio , Jr.

Father Anthony Asir of St. Thomas More Parish in Hauppauge blessed the bikes Sept. 18 at a kickoff event held at the company’s Hauppauge location.

“I hope this can help bring people out of the darkness into the light, from ignorance into awareness,” Father Asir said. “May they go as your ministers bringing cancer awareness where they ride.”

The two-week tour will include stops in numerous cities to raise awareness with highlights including several American Cancer Society Hope Lodges, St. Jude Children’s Research Hospital in Memphis, and Cold Spring Harbor Laboratory before ending at the Jones Beach walkathon Oct. 15.

Money will be raised through donations from sponsors and the sale of promotional items. In addition, the company will donate 10 percent of its total sale proceeds for the month of October. Overall funds raised will go to charities including the American Cancer Society, Cold Spring Harbor Laboratory and St. Jude hospital.

“With that funding, we can start new research projects which are risky, too risky for the government to support,” said Diane Fagiola, senior director of philanthropy for CSH Lab. “This fundraising is huge for us.”

Camila dos Santos, a junior faculty at the lab, said these funds allow researchers, like her, to get an initial data set to help support “out-of-the-box” research ideas and be more competitive for federal grants.

Those interested can visit www.road2wellnesstour.com to learn more, follow the riders on their trip and donate money.

Also, the Road 2 Wellness Tour can be followed on Twitter through #Road2Wellness.

Organizers of the 3rd annual Genome Engineering: The CRISPR-Cas Revolution event, from left, Maria Jasin, Jonathan Weissman, Jennifer Doudna and Stanley Qi. Photo courtesy of CSHL

By Daniel Dunaief

One day, the tool 375 people from 29 countries came to discuss in late July at Cold Spring Harbor Laboratory may help eradicate malaria, develop treatments for cancer and help understand the role various proteins play in turning on and off genes.

Eager to interact with colleagues about the technical advances and challenges, medical applications and model organisms, the participants in Cold Spring Harbor Laboratory’s third meeting on the CRISPR-Cas9 gene editing system filled the seats at Grace Auditorium.

Jason Sheltzer. Photo from CSHL

“It’s amazing all the ways that people are pushing the envelope with CRISPR-Cas9 technology,” said Jason Sheltzer, an independent fellow from Cold Spring Harbor Laboratory who presented his research on a breast cancer treatment.

The technology comes from a close study of the battle between bacteria and viruses. Constantly under assault from viruses bent on commandeering their genetic machinery, bacteria figured out a way of developing a memory of viruses, sending out enzymes that recognize and destroy familiar invaders.

By tapping into this evolutionary machinery, scientists have found that this system not only recognizes genes but can also be used to slice out and replace an errant code.

“This is a rapidly evolving field and we continue to see new research such as how Cas1 and Cas2 recognize their target, which opens the door for modification of the proteins themselves, and the recent discovery of anti-CRISPR proteins that decrease off-target effects by as much as a factor of four,” explained Jennifer Doudna, professor of chemistry and molecular and cell biology at the University of California at Berkeley and a meeting organizer for the last three years, in an email.

Austin Burt, a professor of evolutionary genetics at the Imperial College in London, has been working on ways to alter the genes of malaria-carrying mosquitoes, which cause over 430,000 deaths each year, primarily in Africa.

“To wipe out malaria would be a huge deal,” Bruce Conklin, a professor and senior investigator at the Gladstone Institute of Cardiovascular Disease at the University of California in San Francisco and a presenter at the conference, said in an interview. “It’s killed millions of people.”

Carolyn Brokowski. Photo by Eugene Brokowski

This approach is a part of an international effort called Target Malaria, which received support from the Bill and Melinda Gates Foundation.

To be sure, this effort needs considerable testing before scientists bring it to the field. “It is a promising approach but we must be mindful of the unintended consequences of altering species and impacting ecosystems,” Doudna cautioned.

In an email, Burt suggested that deploying CRISPR in mosquitoes across a country was “at least 10 years” away.

CSHL’s Sheltzer, meanwhile, used CRISPR to show that a drug treatment for breast cancer isn’t working as scientists had thought. Researchers believed a drug that inhibited the function of a protein called maternal embryonic leucine zipper kinase, or MELK, was halting the spread of cancer. When Sheltzer knocked out the gene for MELK, however, he discovered that breast cancer continued to grow or divide. While this doesn’t invalidate a drug that may be effective in halting cancer, it suggests that the mechanism researchers believed was involved was inaccurate.

Researchers recognize an array of unanswered questions. “It’s premature to tell just how predictable genome modification might be at certain levels in development and in certain kinds of diseases,” said Carolyn Brokowski, a bioethicist who will begin a position as research associate in the Emergency Medicine Department at the Yale School of Medicine next week. “In many cases, there is considerable uncertainty about the causal relationship between gene expression and modification.”

Brokowski suggested that policy makers need to appreciate the “serious reasons to consider limitations on nontherapeutic uses for CRISPR.”

Like so many other technologies, CRISPR presents opportunities to benefit mankind and to cause destruction. “We can’t be blind to the conditions in which we live,” said Brokowski.

Indeed, Doudna recently was one of seven recipients of a $65 million Defense Advanced Research Projects Agency award to improve the safety and accuracy of gene editing.

The funding, which is for $65 million over four years, supports a greater understanding of how gene editing technologies work and monitors health and security concerns for their intentional or accidental misuse. Doudna, who is credited with co-creating the CRISPR-Cas9 system with Emmanuelle Charpentier a scientific member and director of the Max Planck Institute for Infection Biology in Berlin, will explore safe gene editing tools to use in animal models and will specifically target Zika and Ebola viruses.

“Like most misunderstood disruptive technologies, CRISPR outpaced the necessary policy and regulatory discussions,” Doudna explained. The scientific community, however, “continued to advance the technology in a transparent manner, helping to build public awareness, trust and dialogue. As a result, CRISPR is becoming a mainstream topic and the public understanding that it can be a beneficial tool to help solve some of our most important challenges continues to grow.”

Visitors enjoyed a wine and cheese party on the Airslie lawn during the event. Photo from CSHL

Cold Spring Harbor Laboratory plans to host its fourth CRISPR meeting next August, when many of the same scientists hope to return. “It’s great that you can see how the field and scientific community as a whole is evolving,” Sheltzer said.

Doudna appreciates the history of Cold Spring Harbor Laboratory, including her own experiences. As a graduate student in 1987, Doudna came across an unassuming woman walking the campus in a tee-shirt: Nobel Prize winner Barbara McClintock. “I thought, ‘Oh my gosh, this is someone I revere,” Doudna recalled. “That’s what life is like” at the lab.

Brokowski also plans to attend the conference next year. “I’m very interested in learning about all the promises CRISPR will offer,” she said. She is curious to see “whether there might be more discussion about ethical and regulatory aspects of this technology.”

Alexander Krasnitz. Photo from CSHL

By Daniel Dunaief

If homeowners could find insects in their home, confirm that they were termites and locate nests before the termites damaged a house, they’d save themselves numerous problems. The same holds true for cancer.

Using the latest molecular biology techniques, researchers at Cold Spring Harbor Laboratory including Associate Professor Alexander Krasnitz and Professor Michael Wigler have explored ways to detect cancer earlier.

Unlike other scientists, who have created tests that reveal the genetic probability of developing cancer, Krasnitz and Wigler developed a blood test to reveal the presence of a tumor that might be hard to spot. Such a test could be particularly valuable for cancers such as ovarian and pancreatic cancer, which can be inoperable by the time they present clinical symptoms.

Urging what Wigler described as a “call to arms,” Krasnitz said they created a blood test, called copy number variation, that they hope will be economically feasible. In copy number variation, sections of genes are repeated. While healthy cells have copy number variation, cancer cells use them like a Jack Nicholson mantra in “The Shining,” where the repetition of “all work and no play makes Jack a dull boy” becomes a calling card for a killing spree.

In cancer, chromosomes or chromosome arms are duplicated or deleted. Sometimes, a narrow region of the genome undergoes amplification, creating multiple copies of the region. Other times, a region of the genome may be lost. Genome-wide copy number variation is a hallmark of cancer. Copy number variation occurs often amid the disruption of DNA repair mechanisms and the breakdown in the way DNA separates into daughter cells during division.

In a recent article in Trends in Molecular Medicine, Krasnitz, Jude Kendall, Joan Alexander, Dan Levy and Wigler — all scientists at CSHL — suggest the potential for single-cell genomic analysis that searches for the presence of copy number variations could raise the alert level for cancer, signaling the need to search more closely for developing tumors.

In most massive cancers in the population, including breast, ovarian and prostate cancer, copy number variation is “ubiquitous,” Krasnitz said. Screening for these changes could provide “evidence for the presence of something abnormal,” which can be validated through other tests, Krasnitz said.

Copy number variation, on its own, is not sufficient to detect cancer, Krasnitz said. Researchers need evidence of similar abnormal copy number profiles in multiple cells. For this test to have clinical relevance, it would need to minimize false positives, which could create alarm and lead to future tests that might not be warranted, while also avoiding false negatives, which would miss the presence of cancer.

The main sources of false positives could come from copy number variation that’s already in cells in the blood that randomly look like a tumor. Cells with partially degraded DNA can have high copy number variation, which the researchers have observed. These profiles, however, arise from random processes and typically look different from each other. Cells from a cancer clone, however, have similar copy number profile.

Cancers with low copy number variation were a minority among the 11 cancers the scientists studied and include a type of colorectal cancer called microsatellite-unstable. If these CSHL researchers developed a preclinical test, they would look for additional ways to detect such cancers.

While numerous technological innovations required for the test exist, including copy number profiling of single cells and methods to enrich specimens from blood for suspected tumors, Krasnitz explained that considerable work remains before its clinical use, including establishing tumor cell counts in the blood of early patients, making single-cell profiling cheaper and finding optimal ways to identify the tissue of origin.

They are planning to study newly diagnosed patients to observe the presence of circulating cells from tumors. Once the scientists prove that the test has some predictive value, they need to ensure that it is economical and that they can follow up with patients to find tumors.

At this point, it’s unclear what the presence of copy number variation might reveal about the type of tumor, which could be a slowly growing or an aggressive type. Additionally, an abnormal indication from this type of analysis wouldn’t reveal anything about the type of cancer. Further tests, including on RNA, would help direct doctors to a specific organ or system.

Apart from his work with Wigler, Krasnitz also has numerous collaborations, including one with CSHL Cancer Center Director David Tuveson.

In his work with Tuveson, Krasnitz is ensuring that the organoid models Tuveson’s lab creates, which are living replicas of tumors taken from patients, faithfully reflect the genetic make up of the tumors. That, Tuveson said, is a significant undertaking because it can validate the organoid model for exploring the biology of tumors.

“This is a deliverable that many people are waiting for,” Tuveson said. The researchers want to make sure “what we grew is what the patient had in the first place.” So far, Tuveson said, the data looks good and the scientists don’t have any examples of the genetics of the organoids differing from that of the tumor.

Krasnitz also attempts to predict an organoid’s response to drugs that haven’t been tested yet based on the organoid’s reaction to other drugs. Tuveson reached out to Krasnitz to work with his group. He said Krasnitz is “a major player” and is “very skilled” in the type of analysis of big data his group generates through the genome, the transcriptome and drug screens. “He’s able to look at those three types of information and make sense of it,” Tuveson said.

Krasnitz is grateful for the support of the Simons Foundation, the National Institutes of Health and the Breast Cancer Research Foundation for his work with Wigler. The most recent article with Wigler is an “invitation for the [research] community to join in the effort,” Krasnitz said. “We want collaborators and more competition in this area.”

Priya Sridevi with her golden doodle Henry. Photo by Ullas Pedmale

By Daniel Dunaief

Priya Sridevi started out working with plants but has since branched out to study human cancer. Indeed, the research investigator in Cold Spring Harbor Laboratory Cancer Center Director David Tuveson’s lab recently became the project manager for an ambitious effort coordinating cancer research among labs in three countries.

The National Cancer Institute is funding the creation of a Cancer Model Development Center, which supports the establishment of cancer models for pancreatic, breast, colorectal, lung, liver and other upper-gastrointestinal cancers. The models will be available to other interested researchers. Tuveson is leading the collaboration and CSHL Research Director David Spector is a co-principal investigator.

The team plans to create a biobank of organoids, which are three-dimensional models derived from human cancers and which mirror the genetic and cellular characteristics of tumors. Over the next 18 months, labs in Italy, the Netherlands and the United States, at Cold Spring Harbor Laboratory, expect to produce up to 150 organoid models.

The project officially started in January and the labs have been setting up the process through June. Sridevi is working with Hans Clevers of the Hubrecht Institute, who pioneered the development of organoids, and with Vincenzo Corbo and Aldo Scarpa at the University and Hospital Trust of Verona.

Sridevi’s former doctoral advisor Stephen Alexander, a professor of biological sciences at the University of Missouri, said Sridevi has had responsibilities beyond her own research. She was in charge of day-to-day operations in his lab, like ordering and regulatory reporting on radioactive material storage and usage, while he and his wife Hannah Alexander, who was Sridevi’s co-advisor, were on sabbatical. “She is hard working and determined,” said Alexander. “She knows how to get things done.”

In total, the project will likely include 25 people in the three centers. CSHL will hire an additional two or three scientists, including a postdoctoral researcher and a technician, while the Italian and Netherlands groups will also likely add another few scientists to each of their groups.

Each lab will be responsible for specific organoids. Tuveson’s lab, which has done considerable work in creating pancreatic cancer organoids, will create colorectal tumors and a few pancreatic cancer models, while Spector’s lab will create breast cancer organoids.

Clevers’ lab, meanwhile, will be responsible for creating breast and colorectal organoids, and the Italian team will create pancreatic cancer organoids. In addition, each of the teams will try to create organoids for other model systems, in areas like lung, cholangiocarcinomas, stomach cancer, neuroendocrine tumors and other cancers of the gastrointestinal tract.

For those additional cancers, there are no standard operating procedures, so technicians will need to develop new procedures to generate these models, Sridevi said. “We’ll be learning so much more” through those processes, Sridevi added. They might also learn about the dependencies of these cancers during the process of culturing them.

Sridevi was particularly grateful to the patients who donated their cells to these efforts. These patients are making significant contributions to medical research even though they, themselves, likely won’t benefit from these efforts, she said. In the United States, the patient samples will come from Northwell Health and the Tissue Donation Program of Northwell’s Feinstein Institute of Medical Research. “It’s remarkable that so many people are willing to do this,” Sridevi said. “Without them, there is no cancer model.”

Sridevi also appreciates the support of the philanthropists and foundations that provide funds to back these projects. Sridevi came to Tuveson’s lab last year, when she was seeking opportunities to contribute to translational efforts to help patients. She was involved in making drought and salinity resistant rice and transgenic tomato plants in her native India before earning her doctorate at the University of Missouri in Columbia.

Alexander recalled how Sridevi, who was recruited to join another department at the University of Missouri, showed up in his office unannounced and said she wanted to work in his lab. He said his lab was full and that she would have to be a teaching assistant to earn a stipend. He also suggested this wasn’t the optimal way to conduct research for a doctorate in molecular biology, which is a labor-intensive effort. “She was intelligent and determined,” Alexander marveled, adding that she was a teaching assistant seven times and obtained a wealth of knowledge about cell biology.

Sridevi, who lives on campus at CSHL with her husband Ullas Pedmale, an assistant professor at CSHL who studies the mechanisms involved in the response of plants to the environment, said the transition to Long Island was initially difficult after living for six years in San Diego.

“The weather spoiled us,” she said, although they and their goldendoodle Henry have become accustomed to life on Long Island. She appreciates the “wonderful colleagues” she works with who have made the couple feel welcome.

Sridevi believes the efforts she is involved with will play a role in understanding the biology of cancer and therapeutic opportunities researchers can pursue, which is one of the reasons she shifted her attention from plants. In Tuveson’s lab, she said she “feels more closely connected to patients” and is more “directly impacting their therapy.” She said the lab members don’t get to know the patients, but they hope to be involved in designing personalized therapy for them. In the Cancer Model Development Center, the scientists won a subcontract from Leidos Biomedical Research. If the study progresses as the scientists believe it should, it can be extended for another 18 months.

As for her work, Sridevi doesn’t look back on her decision to shift from plants to people. While she enjoyed her initial studies, she said she is “glad she made this transition” to modeling and understanding cancer.

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!”

Sen. Kenneth LaValle, wearing hat, sits with Brookhaven National Laboratory beamline scientist Dieter Schneider. Looking on from left, BNL Director Doon Gibbs; vice president for development at Cold Spring Harbor Laboratory, Charles Prizzi; NSLS-II director John Hill; and Stony Brook University associate vice president for Brookhaven affairs, Richard Reeder. Photo from Brookhaven National Laboratory

Thanks to the persistent support of state Sen. Ken LaValle (R-Port Jefferson), Brookhaven National Laboratory secured $15 million from New York State to add a state-of-the-art microscope that could contribute to advances in basic science and medicine.

The national laboratory will purchase a new cryo-electron microscope and will use the funds to create a building attached to its National Synchrotron Light Source II.

“Cryo-electron microscopy is an advanced imaging technology that will significantly accelerate scientists’ understanding of molecular structures and processes generally, including many impacts in understanding disease and in aiding drug discovery,” Doon Gibbs, the laboratory director of BNL, said in an email.

BNL will use the funds to purchase the first of what they hope will be four such new microscopes. The lab is finalizing a bid, which is due by June 30 for funds from the National Institutes of Health for three additional microscopes.

“There is an exponentially increasing demand for the type of bio-structural information that such machines provide, and so we are competing to become an East Coast based national facility to serve this rapidly growing community,” James Misewich, the associate director for energy and photon sciences at BNL said in an email.

Having a suite of microscopes would enable BNL to have a spectrum of capabilities to serve the needs of its scientists and of researchers from around the world who flock to the Upton-based lab to conduct their research.

The new facility will create jobs associated with running the cryo-EM, Misewich said. If BNL wins the NIH proposal to become a national cryo-EM facility, it would also employ additional scientists, engineers, technicians and administrators to run the user program.

Misewich said he hopes scientists at nearby Stony Brook University and Cold Spring Harbor Laboratory will benefit from the opportunity to use a combination of its X-ray and electron microscope probes.

Senior members of the BNL team credit LaValle for helping to secure the funds.

“The $15 million in New York State funding is the culmination of a two-year effort led by the senator to bring a cryo-EM to Brookhaven and jump-start this important effort,” Gibbs said.

LaValle suggested that the funds were well worth the investment.

“It is critically important for government to embrace and support the work of the organizations that make life-altering discoveries and better our lives, health and environment,” LaValle said in an email. “This investment will further establish world-leading prominence in the field of medical research, and position the region for additional major investments by the National Institutes of Health and the U.S. Department of Energy.”

Misewich envisions configuring one of the microscopes to allow for electron tomography, which will generate three-dimensional images of cells.

“The approach will be complementary to the X-ray imaging work we can undertake with the NSLS-II beamlines,” Misewich said.

Gibbs explained that the cryo-EM is complementary to X-ray crystallography, which is the traditional method for determining structures, which scientists already do at BNL.

“Few prescription drugs have been approved by the [Food and Drug Administration] for use in the U.S. in the last 20 years without a crystallographic study of their structure by X-rays,” Gibbs continued.

Misewich expects the new microscope could lead to new methods of detection, diagnosis and treatment for diseases like cancer or for medical challenges like antibiotic resistance.

Combining the technological tools of the new cryo-EM with the insights from the NSLS II and the nine-year-old Center for Functional Nanomaterials will enable researchers to “provide much more rapid bio-structure determination in response to needs like the ability to rapidly characterize a virus,” Misewich said.

LaValle sited this effort as a part of his ongoing commitment to build Long Island’s new high-tech economy.

The combination of BNL, SBU and CSHL “will provide a significant boost to the competitiveness of the biosciences and biotechnology communities across Long Island,” LaValle said.

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.

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.”

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.”

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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