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Jason Sheltzer

Jason Sheltzer. Photo by ©Gina Motisi, 2018/CSHL

By Daniel Dunaief

A diagnosis of cancer brings uncertainty and anxiety, as a patient and his or her family confront a new reality. But not all cancers are the same and not all patients are the same, making it difficult to know the severity of the disease.

As doctors increasingly focus on individual patient care, researchers are looking to use a wealth of information available through new technology to assist with everything from determining cancer risks, to making early diagnoses, to providing treatment and aftercare.

Jason Sheltzer, a fellow at Cold Spring Harbor Laboratory, and his partner Joan Smith, a senior software engineer at Google, have sought to use the genetic fingerprints of cancer to determine the likely course of the disease.

By looking at genes from 20,000 cancer patients, Sheltzer and Smith found that a phenomenon called copy number variation, in which genes add copies of specific long or short sequences, is often a good indicator of the aggressiveness of the cancer. Those cancers that have higher copy number variation are also likely to be the most aggressive. They recently published their research in the journal eLife.

While the investigation, which involved work over the course of four years, is in a preliminary stage, this kind of prognostic biomarker could offer doctors and patients more information from which to make decisions about treatment. It could also provide a better understanding of the course of a disease, as copy number variation changes as cancer progresses.

“The main finding is simply that copy number variation is a much more potent prognostic biomarker than people had realized,” Sheltzer said. “It appears to be more informative than mutations in most single genes.”

Additionally, despite having data from those thousands of patients, Sheltzer and Smith don’t yet know if there’s a tipping point, beyond which a cancer reaches a critical threshold.

Some copy number changes also were more problematic than others. “Our analysis suggested that copy number alterations affecting a few key oncogenes and tumor suppressors seemed to be particularly bad news for patient prognosis,” Sheltzer said, adding that they weren’t able to do a clinical follow-up to determine how genes changed as the cancer progressed. 

“Hopefully, we can follow up this study, where we can do a longitudinal analysis,” he said.

Joan Smith. Photo by Seo-young Silvia Kim

Smith, who has written computer code for Twitter, Oracle and now Google, wrote code that’s specific to this project. “The analysis we’ve done here is new and is on a much more significant scale than the analysis we did in the past,” she said.

Within the paper, Smith was able to reuse parts of code that were necessary for different related experiments. Some of the reusable code cleaned up the data and provided a useful format, while some of the code searched for genetic patterns.

“There is considerable refinement that went into writing this code, and into writing code in general,” she explained in an email.

Smith has a full-time job at Google, where she has to clear any work she does with Sheltzer with the search engine. Before publication, she sent the paper to Google for approval. She works with Sheltzer “on her personal time,” and her efforts have “nothing to do with Google or Google Tools.”

The search engine company “tends to be supportive of employees doing interesting and valuable external work, as long as it doesn’t make use of any Google confidential information or Google owned resources,” including equipment supplies or facilities, she explained in an email.

The phenomenon of copy number variation occurs frequently in people in somatic cells, including those who aren’t battling a deadly disease Sheltzer said. “People in general harbor a lot of normal copy number variation,” he added.

Indeed, other types of repetitive changes in the genome have played a role in various conditions.

Some copy number variations, coupled with deletions, can be especially problematic. A tumor suppressor gene called P53, which is widely studied in research labs around the world, can accumulate copy number variations.

“Patients who have deletions in P53 tend to accumulate more copy number alterations than patients who don’t,” Sheltzer said. “A surprising result from our paper is that copy number variation goes above and beyond P53 mutations. You can control for P53 status and still find copy number variations that act as significant prognostic biomarkers.”

The copy number variations Sheltzer and Smith were examining were affecting whole genes, of about 10,000 bases or longer.

“We think that is because cancers are Darwinian,” explained Sheltzer. “The cells are competing against one another to grow the fastest and be the most aggressive. If a cancer amplifies one potent oncogene, it’s good for the cancer. If the cancer amplifies 200 others, it conveys a fitness penalty in the context of cancer.”

Smith is incredibly pleased to have the opportunity to contribute her informatics expertise to Sheltzer’s research, bringing together skill sets that are becoming increasingly important to link as technology makes it possible to accumulate a wealth of data in a much shorter term and at considerably lower expense.

Smith has a physics degree from MIT and has been in the technology world ever since.

“It’s been super wonderful and inspiring to get to do both” technology work and cancer research, she said.

The dynamic scientific duo live in Mineola. They chose the location because it’s equidistant between their two commutes, which are about 35 minutes. When they are not working, the couple, who have been together for eight years and have been collaborating in their research for almost all of them, enjoy biking, usually between 30 to 60 miles at a time.

Sheltzer greatly appreciates Smith’s expertise in using computer programs to mine through enormous amounts of data.

They are working on the next steps in exploring patient data.

From left, Jason Sheltzer, Nicole Sayles (who is a former lab technician and a co-author of an earlier MELK paper) and SBU undergraduates Chris Giuliano and Ann Lin. Photo by Constance Brukin

By Daniel Dunaief

If eating macaroni and cheese made Joe sick, he might conclude he was allergic to dairy. But he could just as easily have been allergic to the gluten in the macaroni, rendering the dairy-free diet unnecessary.

Scientists try to connect two events, linking the presence of a protein, the appearance of a mutation or the change in the metabolic activity of a cell with a disease. That research often leads to targeted efforts to block or prevent that protein. Sometimes, however, that protein may not play as prominent a role as originally suspected. That is what happened with a gene called MELK, which is present in many types of cancer cells. Researchers concluded that the high level of MELK contributed to cancer.

Jason Sheltzer, a fellow at Cold Spring Harbor Laboratory, and Ann Lin and Christopher Giuliano, undergraduates at Stony Brook University who work in Sheltzer’s lab, proved that wasn’t the case. By rendering MELK nonfunctional, Sheltzer and his team expected to block cancer. When they knocked out MELK, however, they didn’t change anything about the cancer, despite the damage to the gene. But, Sheltzer wondered, might there be some link between MELK and cancer that he was missing? After all, scientists had found a drug called OTS167 that was believed to block MELK function.

To test this drug’s importance for MELK and cancer, Sheltzer used this drug on cancer cells that didn’t have a functioning MELK gene or protein. Even without MELK, the drug “killed cancer cells,” regardless of the disappearance of a gene that researchers believed was important for cancer’s survival, he said.

“We showed for the first time that [the drug] was killing cells that didn’t express MELK,” Sheltzer said. The drug had to have another, unknown target.

Sheltzer suggested that this is the first time someone had used CRISPR, a gene-editing technique, to take a “deep dive” into what a drug is targeting. This drug, he said, has a different mechanism of action from the one most people believed.

Sheltzer, whose work was published in early February in eLife, expanded the research from a petri dish, where researchers grow and study cells, to mouse models, which are often more similar to the kinds of conditions in human cancers. In those experiments, he found no difference between the tumors that grew with a MELK gene and those that didn’t have the MELK protein, continuing to confirm the original conclusion. “The tumors that formed in cells that had MELK and the tumors that formed in cells that didn’t have MELK were the same size,” he said.

Originally, Sheltzer believed the MELK protein might be involved in chemotherapy resistance. His lab found, however, that no matter what they did to MELK in these cells, the cancer appeared indifferent. Other researchers suggested that Sheltzer’s work would be instructive in a broader way for scientists.

Sheltzer’s research on MELK “will motivate a new set of standards for target discovery and validation in the field going forward,” Christopher Vakoc, an associate professor at CSHL, explained in an email. Sheltzer “brings a rigorous approach to cancer research and an impressive courage to challenge prevailing paradigms.” Sheltzer’s work highlights the challenge of understanding the mechanism of action of new medicines, Vakoc added.

Sheltzer plans to explore several other genes in which a high concentration of a specific protein coded by that gene correlates with a poor prognosis.

Using CRISPR, Sheltzer believes his lab can get precise information about drug targets and their effect on cancer. He’s also tracing a number of other types of cancer drugs that he thinks might have compelling properties and will use CRISPR to study the action of these drugs. “We want to know not just that a drug kills cancer cells: We want to know how and why,” he said.

By figuring out what a drug targets, he might be able to identify the patients who are most likely to respond to a particular drug. So far, the finding that a drug doesn’t work by interfering with a specific gene, in this case MELK, has been easier than finding the gene that is the effective target, he explained.

One of Sheltzer’s goals is to search for a cancer cell that is resistant to the drug, so that he can compare the genes of the vulnerable one with those of the cell that’s harder to treat. Detecting the difference in the resistant cell can enable him to localize the region critical for a drug’s success.

Sheltzer said finding that MELK was not involved in a cancer’s effectiveness was initially “depressing” because researchers believed they had found a cancer target. “We hope that by publishing these techniques and walking through the experiments in the paper that other labs can learn from this and can use some of the approaches we used to improve their drug discovery pipelines,” he said.

Sheltzer is pleased that Lin and Giuliano made such important contributions to this paper. CRISPR has made it possible for these undergraduates to “make these really important discoveries,” he said. Lin, who has worked in Sheltzer’s lab for two and a half years, was pleased. “It is very exciting to share my knowledge of MELK in regards to its role in cancer biology,” she wrote in an email. “Authoring a paper requires a great deal of work and I am super thrilled” to see it published.

Sheltzer, who lives with his partner Joan Smith, who is a software engineer at Google, said he was interested in science during his formative years growing up in Wayne, Pennsylvania, which is just outside of Philadelphia, and appreciates the position he has at Cold Spring Harbor Laboratory. Soon after earning his doctorate at MIT, Sheltzer set up his own lab, rather than conducting research for several years as a postdoctoral researcher. “I was really fortunate to be given that opportunity,” he said.

As for his work with MELK, Sheltzer hopes he’s saved other labs from pursuing clinical dead ends.

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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