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Cold Spring Harbor Laboratory

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Pavel Osten. Photo by Joelle Wiggins

By Daniel Dunaief

Male mice, as it turns out, might also be from Mars, while female mice might be from Venus. Looking at specific cells in the brain of rodents, Cold Spring Harbor Laboratory Associate Professor Pavel Osten has found some noteworthy differences in their brain cells.

In the scientific journal Cell, Osten presented data that showed that in 10 out of 11 subcortical regions of the mouse brain, female mice showed greater flexibility and even more cells. These regions of the brain are responsible for reproduction, and social and parenting behaviors. “There were more cells [in these regions] in the female brain, even though the brains tended to be bigger in the males,” Osten said.

These results are part of a multiyear collaboration called the National Institutes of Health’s Brain Initiative Cell Census Network.

In the recent Cell article, Osten indicated that his analysis offered a surprising result in the number of cells of specific types in various regions of the cortex. “Those areas that have higher cognitive functions have different compositions,” he said. The ratios of cell types “vary according to the level of cognitive function.” In retrospect, Osten indicated that he saw the logic in such a cellular organization. “It makes sense that different cortical areas would have different cell type composition tuned to the specific cortical functions,” he explained.

In an email, Hongkui Zeng, the executive director of structured science at the Allen Institute for Brain Science, in Seattle, Washington, suggested that “people never looked at this issue carefully before. She added that the “sexual dimorphism was somewhat expected, but it is still interesting to see the real data.”

Pavel Osten sailing in St. Barts and St. Martin last summer. Photo from Pavel Osten

Osten used a system called qBrain to see and count inhibitory neurons in the mouse brain. Over the next five years, he and his collaborators will build an online resource database for other researchers that will have distribution maps for numerous cell types throughout the mouse brain.

Osten estimates that there could be hundreds or even a thousand cell types within the brain that are largely uncharacterized in their specialized functions. A cell type is defined by its function in terms of its morphology, including dendritic and axonal branches. These cells are also defined by their physiology, which includes spiking properties, and connectivity, which indicates which cell is talking to other cells.

The anatomy and physiology of the cells will validate these transcriptome single-cell RNAseq studies, which probe for the variability between cells based on their gene expression, which includes differences due to day-to-day variability and differences from distinct cell types.

By analyzing the location and modulatory functions of these cell types, Osten would like to determine ways human brains differ from other animal brains. “In the human, we can mainly analyze the location and distribution which includes the ratios of specific cell types and our hypothesis is that fine-tuning the ratios of neuronal cell types may be a powerful evolutionary mechanism for building more efficient circuits and possibly even for distinguishing between human and other animals,” Osten explained in an email.

Humans, he continued, don’t have the largest brains or the most neurons. At one point, spindle neurons were considered unique to humans, but other researchers have shown that great apes, elephants and cetaceans, which is a group that includes whales and dolphins, also have them.

Osten’s hypothesis is that one of the differences is that the ratios of cells of different types built a computational circuit that’s more powerful than the ones in other species.

When he studies mouse brains, Osten collects information across the entire brain. With humans, he explores one cubic centimeter. The human work is just starting in his lab and represents a collaboration with Zsófia Maglóczky from the Hungarian Academy of Sciences at the Institute of Experimental Medicine in Budapest.

Each mouse brain dataset is between 200 gigabytes and 10 terabytes, depending on the resolution Osten uses to image the brain. He can process 10 terabytes of data in about a week.

Osten uses machine learning algorithms that develop with guidance from human experts. This comes from a long-standing collaboration with Sebastian Seung, a professor of computer science at Princeton University.

He suggested that the research has a translational element as well, offering a way to study cellular and wiring elements characteristic of diseases. “We are looking at several of the models that are well established for autism.” He is also planning to write grants to find funds that supports the analysis of brains from people with schizophrenia and Alzheimer’s disease.

The analysis is a promising avenue of research, other scientists said. “It will be extremely interesting to compare the ratio of different cell types in various diseased brains with normal healthy brains, to see if the diseases may preferentially affect certain cell types and why and how,” Zeng explained in an email. “This could be very helpful for us to devise therapeutic means” to treat diseases.

Zeng has known Osten for about seven years. Last year, she began a collaboration using qBrain to quantify cell types.

A current resident of Williamsburg, where his reverse commute is now about 40 minutes, Osten works with a company he and Seung started called Certerra, which provides a rapid analysis of brain activity at different times. The company, located in Farmingdale, has a growing customer base and has a staff of about five people.

As for the recent work, researchers suggested it would help continue to unlock mysteries of the brain. This research is “a basic but important step toward understanding how the brain works,” Zeng added. “This paper provides a new and efficient approach that will be powerful when combined with genetic tools that can label different cell types.”

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Students take samples from Nissequogue River to analyze. Photo by Sara-Megan Walsh

By Sara-Megan Walsh

Hundreds of students from Smithtown to Northport got wet and dirty as they looked at what lurks beneath the surface of the Nissequogue River.

More than 400 students from 11 schools participated in “A Day in the Life” of the Nissequogue River Oct. 6, performing hands-on citizens scientific research and exploring the waterway’s health and ecosystem. The event was coordinated by Brookhaven National Laboratory, Central Pine Barrens Commission, Suffolk County Water Authority and New York State Department of Environmental Conservation.

Northport High School students analyze soil taken from the bottom of Nissequogue River. Photo by Sara-Megan Walsh

“’A Day in the Life’ helps students develop an appreciation for and knowledge of Long Island’s ecosystems and collect useful scientific data,” program coordinator Melissa Parrott said. “It connects students to their natural world to become stewards of water quality and Long Island’s diverse ecosystems.”

More than 50 students from Northport High School chemically analyzed the water conditions, marked tidal flow, and tracked aquatic species found near the headwaters of the Nissequogue in Caleb Smith State Park Preserve in Smithtown. Teens were excited to find and record various species of tadpoles and fish found using seine net, a fishing net that hangs vertically and is weighted to drag along the riverbed.

“It’s an outdoor educational setting that puts forth a tangible opportunity for students to experience science firsthand,” David Storch, chairman of science and technology education at Northport High School, said. “Here they learn how to sample, how to classify, how to organize, and how to develop experimental procedures in an open, inquiry-based environment. It’s the best education we can hope for.”

Kimberly Collins, co-director of the science research program at Northport High School, taught students how to use Oreo cookies and honey to bait ants for Cold Spring Harbor Laboratory’s Barcode Long Island. The project invites students to capture invertebrates, learn how to extract the insects’ DNA then have it sequenced to document and map diversity of different species.

Children from Harbor Country Day School examine a water sample. Photo by Sara-Megan Walsh

Further down river, Harbor Country Day School students explored the riverbed at Landing Avenue Park in Smithtown. Science teacher Kevin Hughes said the day was one of discovery for his fourth- to eighth-grade students.

“It’s all about letting them see and experience the Nissequogue River,” Hughes said. “At first, they’ll be a little hesitant to get their hands dirty, but by the end you’ll see they are completely engrossed and rolling around in it.”

The middle schoolers worked with Eric Young, program director at Sweetbriar Nature Center in Smithtown, to analyze water samples. All the data collected will be used in the classroom to teach students about topics such as salinity and water pollution. Then, it will be sent to BNL as part of a citizens’ research project, measuring the river’s health and water ecosystems.

Smithtown East seniors Aaron Min and Shrey Thaker have participated in this annual scientific study of the Nissequogue River at Short Beach in Smithtown for last three years. Carrying cameras around their necks, they photographed and documented their classmates findings.

“We see a lot of changes from year to year, from different types of animals and critters we get to see, or wildlife and plants,” Thaker said. “It’s really interesting to see how it changes over time and see what stays consistent over time as well. It’s also exciting to see our peers really get into it.”

Maria Zeitlin, a science research and college chemistry teacher at Smithtown High School East, divided students into four groups to test water oxygenation levels, document aquatic life forms, measure air temperature and wind speed, and compile an extensive physical description of wildlife and plants in the area.

Smithtown High School East students take a water and soil sample at Short Beach. Photo by Sara-Megan Walsh

The collected data will be brought back to the classroom and compared against previous years.

In this way, Zeitlin said the hands-on study of Nissequogue River serves as a lesson in live data collection. Students must learn to repeat procedures multiple times and use various scientific instruments to support their findings.

“Troubleshooting data collection is vital as a scientist that they can take into any area,” she said. “Data has to be reliable. So when someone says there’s climate change, someone can’t turn around and say it’s not true.”

The Smithtown East teacher highlighted that while scientific research can be conducted anywhere, there’s a second life lesson she hopes that her students and all others will take away  from their studies of the Nissequogue River.

“This site is their backyard; they live here,” Zeitlin said. “Instead of just coming to the beach, from this point forward they will never see the beach the same again. It’s not just a recreational site, but its teeming with life and science.”

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From left, Zachary Lippman and Dave Jackson, professors at CSHL who are working on ways to alter promoter regions of genes to control traits in tomato and corn. Photo by Ullas Pedmale

By Daniel Dunaief

He works with tomatoes, but what he’s discovered could have applications to food and fuel crops, including corn, rice and wheat.

Using the latest gene editing technique called CRISPR, Zachary Lippman, a professor at Cold Spring Harbor Laboratory, developed ways to fine-tune traits for fruit size, branching architecture and plant shape. Called quantitative variation, these genetic changes act as a dimmer switch, potentially increasing or decreasing specific traits. This could help meet specific agricultural needs. Looking at the so-called promoter region of genes, Lippman was able to “use those genes as proof of principal” for a technique that may enable the fine-tuning of several traits.

For decades, plant breeders have been looking for naturally occurring mutations that allow them to breed those desirable traits, such as a larger fruit on a tomato or more branches on a plant. In some cases, genetic mutations have occurred naturally, altering the cell’s directions. At other times, breeders have sought ways to encourage mutations by treating their seeds with a specific mutagenic agent, like a chemical.

In an article in the journal Cell, Lippman said the results reflect a road map that other researchers or agricultural companies can use to create desirable traits. This article provides a way to “create a new, raw material for breeders to have access to tools they never had before,” he said. Lippman has taken a chunk of the DNA in the promoter region, typically on the order of 2,000 to 4,000 base pairs, and let the CRISPR scissors alter this part of the genetic code. Then, he and his scientific team chose which cuts from the scissors and subsequent repairs by the cell’s machinery gave the desired modifications to the traits they were studying.

Invented only five years ago, CRISPR is a genetic editing technique that uses tools bacteria have developed to fight off viral infections. Once a bacteria is attacked by a virus, it inserts a small piece of the viral gene into its own sequence. If a similar virus attacks again, the bacteria immediately recognizes the invader and cuts the sequence away.

Scientists sometimes use these molecular scissors to trim specific gene sequences in a process called a deletion. They are also working toward ways to take another genetic code and insert a replacement. “Replacement technology is only now starting to become efficient,” Lippman said. Clinical researchers are especially excited about the potential for this technique in treating genetic conditions, potentially removing and replacing an ineffective sequence.

In Lippman’s case, he used the scissors to cut in several places in the promoter regions of the tomato plant. Rather than targeting specific genes, he directed those scissors to change the genome at several places. When he planted the new seeds, he explored their phenotype, or the physical manifestation of their genetic instructions. These phenotypes varied along a continuum, depending on the changes in their genes.

By going backward and then comparing the genes of the altered plants to the original, he could then hone in on the precise changes in the genetic code that enabled that variation. This technique allows for a finer manipulation than turning on or off specific genes in which an organism, in this case a plant, would either follow specific instructions or would go on a transcriptional break, halting production until it was turned on again.

At this point, Lippman has worked with each trait individually but hasn’t done quantitative variation for more than one at a time. “The next question,” he said, “is to do this multitargeting.” He will also use the tool to study how genes are instructed to turn on and off during growth, including exploring the levels and location of expression.

Lippman is talking with agricultural and scientific collaborators and hopes to go beyond the tomato to exploring the application of this approach to other crops. He is working with Dave Jackson, who is also a professor at Cold Spring Harbor Laboratory, on applying this model to corn.

The scientific duo has known each other for 20 years. Jackson taught his collaborator when Lippman was a graduate student at Cold Spring Harbor Laboratory and Jackson was chair of his thesis committee.

They have worked together on and off since Lippman became a faculty member about nine years ago. Last year, the two received a National Science Foundation genome grant to work on using CRISPR to study the effect of changes in promoter regions in their respective plant specialties.

“Unfortunately for us, tomato has a faster life cycle than corn, but we hope to have some results in corn this fall,” Jackson explained in an email. Lippman hopes to continue on the path toward understanding how regulatory DNA is controlling complex traits. “We can use this tool to dissect critical regulatory regions,” he said. “When we create this variation, we can look at how that translates to a phenotypic variation.”

Lippman said he is especially excited about the fundamental biological questions related to plant growth and development. When other scientists or agricultural companies attempt to use this approach, they may run into some challenges, he said. Some plants are “not transformable [genetically] easily.” These plants can be recalcitrant to plant transformation, a step sometimes needed for CRISPR gene editing. Still, it is “likely that CRISPR will work in all organisms,” he said.

Lippman hopes others discuss this technique and see the potential for a system that could help to customize plants. “My hope and my anticipation is that people all over the world will look at this paper and say, ‘Let’s start to try this out in our own systems.’ Hopefully, there will be a grass roots effort to import this tool.”

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Anne Churchland. Photo from CSHL

By Daniel Dunaief

Someone is hungry and is walking through a familiar town. She smells pizza coming from the hot brick oven on her left, she watches someone leaving her favorite Chinese restaurant with the familiar takeout boxes, and she thinks about the fish restaurant with special catches of the day that she usually enjoys around this time of year. How does she make her decision?

While this scenario is a simplified one, it’s a window into the decision-making process people go through when their neurons work together. A team of 21 neuroscientists in Europe and the United States recently created a new collaboration called the International Brain Laboratory to explore how networks of brain cells support learning and decision-making.

“We understand the simple motor reflex,” such as when a doctor taps a knee and a foot kicks out, said Anne Churchland, an associate professor at Cold Spring Harbor Laboratory and the American spokesperson for this new effort. Scientists, however, have only a limited understanding of the cognitive processes that weigh sensory details and a recollection of the outcomes from various courses of action that lead to decision-making, Churchland said.

Scientists likened the structure of the new multilaboratory effort to the circuitry involved in the brain itself. The brain is “massively parallel,” said Alexandre Pouget, a professor at the University of Geneva and the spokesperson for the IBL. “We know it’s working on consensus building across areas so, in that respect, the IBL is similar.”

A greater awareness of the decision-making process could provide a step into understanding the brain network problems involved in mental health disorders.

Churchland’s lab is one of three facilities that will house a new behavioral apparatus to study decision-making in mice. The other sites will be in the United Kingdom and in Portugal. Eventually, other labs will use this same technique and house the same apparatus.

An ongoing challenge in this field of research, Churchland said, is that scientists sometimes create their own models to test the neurological basis of behavior. While these approaches may work in their own labs, they have created a reproducibility problem, making it difficult for others who don’t have expertise in their methods to duplicate the results.

Creating this behavioral apparatus will help ensure that the collaborators are approaching the research with a reliable model that they can repeat, with similar results, in other facilities.

While the scientists will all be exploring the brain, they will each be responsible for studying the activity of circuits in different parts. The researchers will collect a wealth of information and will share it through a developing computer system that allows them to maneuver through the mountains of data.

To address this challenge, the IBL is creating a data architecture working group. Kenneth Harris, a professor of quantitative neuroscience at the University College London, is the chair of the effort. He is currently looking to hire additional outside staff to help develop this process.

Harris suggested that the process of sharing data in neurophysiology has been challenging because of the complex and diverse data these scientists share. “In neuroscience, we have lots of different types of measurements, made simultaneously with lots of different experimental methods, that all have to be integrated together,” he explained in an email.

The IBL collaboration will make his job slightly easier than the generic problem of neurophysiology data sharing because “all the labs will be studying how the brain solves the same decision-making task,” he continued.

Harris is looking to hire a data coordinator, a senior scientific programmer and a scientific MATLAB programmer. He has a data management system already running with his lab that he plans to extend to the IBL.

Pouget said there are two milestones built into the funding from the Wellcome Trust and the Simons Foundation for this new collaboration. After two years, the researchers have to have a data sharing platform in place, which will allow them to share data live as they collect it.

Second, they plan to develop standardized behaviors in all 11 of the experimental labs, where the behavior has to be as indistinguishable from one lab to another as possible.

In addition to the experimentalists involved in this initiative, several theoretical neurobiologists will also contribute and will be critical to unraveling the enormous amounts of data, Pouget suggested. “If you’re going to tackle really hard computational problems, you better have people trained in that area,” he said, adding that he estimates that only about 5 percent of neuroscientists are involved in the theoretical side, which is considerably lower than the percent in an area like physics.

Researchers involved in this project will have the opportunity to move from one lab to another, conducting experiments and gaining expertise and insights. The principal investigators are also in the process of hiring 21 postdoctoral students.

Churchland said each scientist will continue to conduct his or her own research while also contributing to this effort. The IBL is consuming between a quarter and a third of her time.

Pouget suggested that Churchland was “instrumental in representing the International Brain Laboratory to the Simons Foundation,” where she is the principal investigator on that grant. “Her role has been critical to the organization,” he said.

Churchland said the effort is progressing rapidly. “It’s moving way faster” than expected. “This is the right moment, with an incredible team of people, to be working together. Everyone is dedicated to the science.”

Harris indicated that he believes this effort could be transformative for the field. “Neuroscience has lagged behind many other scientific domains” in creating large-scale collaborations, he explained. “If we can show it works, we will change the entire field for good.”

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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.

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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.”

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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.”

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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.

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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!”

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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.

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