BY ALICE PARK
Dr. Carl June’s lab at the University of Pennsylvania looks like any other biology research hub. There are tidy rows of black-topped workbenches flanked by shelves bearing boxes of pipettes and test tubes. There’s ad hoc signage marking the different workstations. And there are postdocs buzzing around, calibrating scales, checking incubators and smearing solutions and samples onto small glass slides.
Appearances aside, what June is attempting to do here, on the eighth floor of the glass-encased Smilow Center for Translational Research in Philadelphia, is anything but ordinary. He’s built a career trying to improve the odds for people with intractable end-stage disease, and now, in the university’s brand-new cell-processing lab, he’s preparing to launch his most ambitious study yet: he’s going to try to treat 18 people with stubborn cancers, and he’s going to do it using CRISPR, the most controversial new tool in medicine.
Developed just four short years ago by two groups—Jennifer Doudna, a molecular and cell biologist at the University of California, Berkeley, together with Emmanuelle Charpentier, now at the Max Planck Institute in Berlin; and Feng Zhang, a biomedical engineer at the Broad Institute of Harvard and MIT—CRISPR allows scientists to easily and inexpensively find and alter virtually any piece of DNA in any species. In 2016 alone it was used to edit the genes of vegetables, sheep, mosquitoes and all kinds of cell samples in labs. Now, even as some scientists call for patience and extreme caution, there’s a worldwide race to push the limits of CRISPR’s capabilities.
June’s ultimate goal is to test CRISPR’s greatest potential: its ability to treat diseases in humans. “Before we were kind of flying in the dark when we were making gene changes,” he says of earlier attempts at genetic tinkering. “With CRISPR, I came to the conclusion that this technology needs to be tested in humans.” The trial, which will start treating patients in a few months, is the first to use this powerful technique in this way. It represents the most extensive manipulation of the human genome ever attempted.
Soon, June’s 18 trial patients will become the first people in the world to be treated with CRISPR’d cells—in this case, cells genetically edited to fight cancer. Like many people with cancer, the patients have run out of options. So, building on work by Doudna, Charpentier and Zhang, June’s team will extract their T cells, a kind of immune cell, and use CRISPR to alter three genes in those cells, essentially transforming them into superfighters. The patients will then be reinfused with the cancer-fighting T cells to see if they do what they’re supposed to do: seek and destroy cancerous tumors.
A lot of hope hangs on the outcome of the trial, but whether it succeeds or fails, it will provide scientists with critical information about what can go right and wrong when they try to rewrite the genetic code in humans. The hope is that studies like June’s will bear out CRISPR’s therapeutic potential, leading to the development of radical new therapies not just for people with the cancers being studied but for all of them, as well as for genetic diseases such as sickle-cell anemia and cystic fibrosis, and chronic conditions like Type 2 diabetes and Alzheimer’s. It may sound far-fetched, but studies like this one are an enormous first step in that direction.
Using CRISPR on humans is still hugely controversial, in part because it’s so easy. The fact that it allows scientists to efficiently edit any gene—for some cancers, but also potentially for a predisposition for red hair, for being overweight, for being good at math—worries ethicists because of what could happen if it gets into the wrong hands. As of now, the National Institutes of Health (NIH), by far the world’s largest sponsor of scientific research, will not fund studies using CRISPR on human embryos. And any new way of altering genes in human cells must get ethics and safety approval by the NIH, regardless of who is paying for it. (The NIH also opposes the use of CRISPR on so-called germ-line cells—those in an egg, sperm or embryo—since any such changes would be permanent and heritable.)
To fund his study, June was able to attract support from Sean Parker, the former Facebook executive and Silicon Valley entrepreneur behind Napster. Parker recently founded the $250 million Parker Institute for Cancer Immunotherapy, a collaboration among six major cancer centers, and June’s study is its first ambitious undertaking. “We need to take big, ambitious bets to advance cancer treatment,” says Parker. “We’re trying to lead the way in doing more aggressive, cutting-edge stuff that couldn’t get funded if we weren’t around.”
That’s not to say June’s study will necessarily cure these cancers. “Either it’s back to the drawing board,” he says, “or everyone goes forward and studies a wide variety of other diseases that could potentially be fixed.” In reality, both things are probably true.
Even if June’s study doesn’t work as he hopes, experts still agree it will be a matter of months—not years—before other privately funded human studies get launched in the U.S. and abroad. An ongoing patent battle over who owns the lucrative technology hasn’t stopped investors from pouring millions into CRISPR companies. So simple and inexpensive is the technique, and so frenzied is the medical community about its potential, that it would be foolish to bet on anything else. “With a technology like CRISPR,” says Doudna, “you’ve lit a fire.”
A Year of Progress
CRISPR’s journey from lab bench to cancer treatment may seem quick. After all, as recently as a couple of years ago only a minuscule number of people even knew what clustered regularly interspaced short palindromic repeats—that’s longhand for CRISPR—was. But the technology is at least hundreds of millions of years old. It was bacteria that originally used CRISPR, as a survival mechanism to fend off infection by viruses. The ultimate freeloaders, viruses never bothered developing their own reproductive system, preferring instead to insert their genetic material into that of other cells—including bacteria. Bacteria fought back, holding on to snippets of a virus’ genes when they were infected. The bacteria would then surround these viral DNA fragments with a genetic sequence that effectively cut them out altogether.
Bacteria have been performing that clever evolutionary stunt for millennia, but it wasn’t until the early 2000s that food scientists at a Danish yogurt company realized just how clever the bacterial system was when they noticed that their cultures were turning too sour. They discovered that the cultures were CRISPRing invaders, altering the taste considerably. It made for bad dairy, but the scientific discovery was immediately recognized as a big one.
About a decade later, in 2012, Doudna and Charpentier tweaked the system to make it more standardized and user-friendly, and showed that not just bacterial DNA but any piece of DNA has this ability. That was a game changer. Scientists have been mucking with plant, animal and human DNA since its structure was first discovered by James Watson and Francis Crick in 1953. But altering genes, especially in deliberate, directed ways, has never been easy. “The idea of gene correction is not new at all,” says June. “But before CRISPR it just never worked well enough so that people could do it routinely.”
Within months of Doudna’s and Charpentier’s discovery, Zhang showed that the technique worked to cut human DNA at specified places. With that, genetics changed overnight. Now scientists had a tool allowing them, at least in theory, to wield unprecedented control over any genome, making it possible to delete bits of DNA, add snippets of genetic material and even insert entirely new pieces of code.
Now, that theoretical potential took shape in a remarkable array of real-world applications. CRISPR produced the first mushroom that doesn’t brown, the first dogs with DNA-boosted cells giving them a comic-book-like musculature, and a slew of nutritionally superior crops that are already on their way to market. There are even efforts to use CRISPR’d mosquitoes to fight Zika and malaria.
On the human side, progress has been even more dramatic. In a lab, scientists have successfully snipped out HIV from infected human cells and demonstrated that the process works in infected mice and rats as well. They’re making headway in correcting the genetic defect behind sickle-cell anemia, which stands to actually cure the disease. They’re making equally promising progress in treating rare forms of genetic blindness and muscular dystrophy. And in perhaps the most controversial application of CRISPR to date, in 2016 the U.K. approved the first use of the technology in healthy human embryos for research.
At the Francis Crick Institute in London, developmental biologist Kathy Niakan is using CRISPR to try to understand one of the more enduring mysteries of human development: what goes wrong at the earliest stages, causing an embryo to die and a pregnancy to fail. To be clear, Niakan will not attempt to implant the embryos in a human; her research is experimental, and the embryos are destroyed seven days after the studies begin.
Like Niakan, June is looking for answers to one of human biology’s more vexing problems: why the immune system, designed to fight disease, is nearly useless against cancer. It’s an issue that’s kept him up at night since 2001, when his wife, not responding to the many treatments she tried, died of ovarian cancer.
“This trial is about two things: safety and feasibility,” he says. It’s about testing whether it’s even possible to successfully edit these immune cells to make them do—in human bodies, not a petri dish—what he wants them to do. Either way, the study will yield critical information, paving the way for eventual new treatment options that are more targeted, less brutal and far smarter against tumors than systemwide chemotherapy will ever be.
As much as has been done in 2016, this is only the beginning of a kind of medicine that stands to effectively change the course of human history. “CRISPR is an empowering technology with broad applications in both basic science and clinical medicine,” says Dr. Francis Collins, director of the NIH. “It will allow us to tackle problems that for a long time we probably felt were out of our reach.”
The Hurdles Ahead
Because it’s so easy to use, Zhang, along with the other CRISPR pioneers, says careful thought should be given to where and how it gets employed. “For the most part I don’t think we are getting ahead of ourselves with the CRISPR applications,” he says. “What we need to do is really engage the public, to make sure people understand what are the really exciting potential applications and what are the immediate limitations of the technology, so we really are applying it and supporting it in the right way.”
Regulatory scrutiny is a given with CRISPR, and any new tool for rewriting human DNA requires federal approval. For the current Penn trial, June got the green light from the NIH Recombinant DNA Advisory Committee, established in the 1980s to assess the safety of any first-in-humans gene-therapy trials. While there are still dangers involved in any kind of gene therapy—the changes may happen in unexpected places, for example, or the edits may have unanticipated side effects—scientists have learned more about the best way to make the genetic changes, and how to deliver them more safely. So far, animal studies show CRISPR provides enough control that unexpected negative effects are rare—at least so far.
The role of regulatory oversight is less clear when the technique is used to alter food crops. Even before June’s patients get infused with CRISPR’d T cells, farmers in Argentina and Minnesota will plant the world’s first gene-edited crops for market. CRISPR provides an unparalleled ability to insert almost any trait into plants—drought or pest resistance, more of this vitamin or less of that nutritional villain du jour. Dupont, for instance, is putting the finishing touches on its first drought-resistant corn, and biotech company Calyxt has created a potato that doesn’t produce cancerous compounds when fried; it’s also planting its first crop of soy plants modified to produce higher amounts of healthy oleic-acid fats.
These edits involve deleting or amping up existing genes—not adding new ones from other species—and the U.S. Department of Agriculture has said this kind of gene-edited food crop is not significantly different from unaltered crops and therefore does not need to be regulated differently.
In the coming months, the National Academy of Sciences is expected to issue guidelines that might address some of the challenges posed by CRISPR, focusing on how and when to proceed with developing new disease treatments. The report is expected to launch much-needed discussion in the scientific community and among the public as well. Whether more regulation will eventually be required likely depends on how far scientists push the limits of their editing—and how comfortable consumers and advocacy groups are with those studies.
As CRISPR goes mainstream in medicine and agriculture, profound moral and ethical questions will arise. Few would argue against using CRISPR to treat terminal cancer patients, but what about treating chronic diseases? Or disabilities? If sickle-cell anemia can be corrected with CRISPR, should obesity, which drives so many life-threatening illnesses? Who decides where that line ought to be drawn?
Questions like these weigh heavily on June and all of CRISPR’s pioneering scientists. “Having this technology enables humans to alter human evolution,” says Doudna. “Thinking about all the different ways it can be employed, both for good and potentially not for very good, I felt it would be irresponsible as someone involved in the earliest stages of the technology not to get out and talk about it.”
Last year, Doudna invited other leaders in genetics to a summit to address the immediate concerns about applying CRISPR to human genes. The group agreed to a voluntary temporary moratorium on using CRISPR to edit the genes of human embryos that would be inserted into a woman and brought to term, since the full array of CRISPR’s consequences isn’t known yet. (Any current research using human embryos, including Niakan’s, is lab-only.)
For researchers like June and Niakan, Doudna and Zhang, and others, proceeding carefully with CRISPR is the only way forward. But proceed they will. The sooner more answers emerge, the sooner CRISPR can mature and begin to deliver on its promise. “There are thousands of applications for CRISPR,” says June. “The sky is the limit. But we have to be careful.”