Now that a federal biosafety and bioethics committee has approved what would be the first use of the trailblazing genome-editing technology CRISPR-Cas9 in people, the obvious question arises: Could anything go wrong?

The purpose of such a Phase 1 clinical trial is to assess safety, so problems wouldn’t come as a total shock. The fact that the trial in cancer patients (which still needs OKs from the Food and Drug Administration, among others) would be funded by the new cancer institute founded this year by tech mogul Sean Parker adds a wild card. Four potential snafus:

1. CRISPR edits DNA it isn’t supposed to

Soon after scientists reported in 2012 that CRISPR can edit DNA, experts raised concerns about “off-target effects,” meaning genes that scientists didn’t intend to change inadvertently got deleted or altered. That can happen because one molecule in the CRISPR system acts as a molecular bloodhound, sniffing around the genome until it finds a match to its own sequence of A’s, T’s, C’s, and G’s; unfortunately, in the 6 billion such letters of the human genome, there can be more than one match. The proposed CRISPR experiment, which would be led by scientists at the University of Pennsylvania, would use three of these molecular bloodhounds, tripling the risk of off-target effects.

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The experiment would alter the immune system’s T cells only after they’re removed from a patient. That gives scientists the chance to screen the CRISPR’d cells to make sure only the three intended genes, all involved in making T cells find and destroy tumor cells, are altered. But after those T cells are infused back into a patient to fight melanoma, sarcoma, or myeloma, the CRISPR system can keep editing DNA, and tracking such edits becomes like following a polar bear in a snowstorm.

“How will you identify off-target editing?” asked Dr. Michael Atkins of the Georgetown Lombardi Comprehensive Cancer Center, a member of the federal Recombinant DNA Advisory Committee that approved the experiment.

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Penn’s data on cells growing in lab dishes showed low off-target effects: Of 148 genes they thought might be inadvertently hit by CRISPR, only ANK1, a gene that is active in the brain and red blood cells, was. “But we can’t be sure that will be maintained over time,” Atkins said — meaning, whether CRISPR will edit the wrong DNA once the T cells are back in a patient.

Hitting the wrong DNA target in a gene therapy experiment has caused tragedy in the past. In 2002, a little boy developed leukemia after a gene he received landed at a spot in his DNA that activated cancer-causing DNA.

Scientists have made “tremendous progress” in minimizing CRISPR’s off-target effects, said Dr. J. Keith Joung of Massachusetts General Hospital. But some of that progress has come from benching CRISPR’s standard DNA-cutting enzyme and substituting one called Cas9-HF1, as Joung’s team has reported. The Penn team is not using HF1. Penn’s Dr. Carl June, who will lead the study, told STAT that CRISPR science is “rapidly evolving,” so they “will use the state-of-the-art technology at the time the [study] opens. At this point, we have compelling preclinical data with standard Cas9.”

2. CRISPR hits its targets, but then genetic hell breaks loose

When CRISPR’s DNA-cutting enzyme snips the genome, the severed DNA strands don’t just smoothly reconnect like an electronic document that closes up the space between “just” and “reconnect” if “smoothly” is deleted from this sentence. No. Random DNA floating around rushes into the gap.

If the DNA equivalent of, say, “politically” or “misanthropically” scoots in, the result could be as nonsensical as putting those adverbs into the sentence above. The problem is serious enough that scientists are racing to solve it, and no one knows the biological consequences if Penn’s system doesn’t. Only a safety study like the one Penn is proposing “can determine if there is acceptable feasibility and safety of this approach,” June said. But since all the study volunteers will have incurable cancer, “these risks would seem to be acceptable.”

3. The Energizer Bunny problem

The components of CRISPR usually don’t just slip into T cells on their own. That requires a virus, since viruses are adept at infiltrating cells. A spokesman for Penn said the scientists were not available to answer questions about their proposed procedure, but if they do use viruses, they run the risk that virus-infected cells will keep cranking out the DNA-snipping Cas9 — by one estimate, for 10 or 20 years. That leaves lots of time for unintended genome-editing to occur.

4. Dollars triumph over data

If Penn’s experiment goes well, larger clinical trials would follow. But “well” is subjective. Measures such as whether a patient is alive or dead are, of course, tough to fudge. How bad side effects are, less so. Judgment calls can even enter into assessments of how significantly and for how long tumors have shrunk.

Study after study has shown that when clinical trials involve entities with a financial interest in the outcome, as the Parker Institute for Cancer Immunotherapy and Penn have in this one, the reported outcomes are more likely to be favorable than when the trial is sponsored by, say, the National Institutes of Health. In studies where the sponsor has a profit motive, scientists are also less likely to adhere to best practices, research has shown. “If you really believe in a [bio]technology and it’s not completely clear whether a side effect is the fault of the disease or the technology, your bias could influence how you interpret that,” said Atkins.

In 1999, members of the Recombinant DNA Advisory Committee pointed out, a young man died in a now-infamous gene therapy trial at Penn in which the lead scientist had a multimillion-dollar financial stake in the technology. That conflict of interest, scholars have argued, may have led him to make dangerous decisions. Although the Parker Institute will handle patents for any discoveries that emerge from the research it funds, “each site owns its intellectual property,” said chief legal counsel Melinda Griffith. “If you invent it, you own it.”

Or, everything could go well and CRISPR cures cancer.