A cancer scare helped encourage stem cell researcher Paul Knoepfler to become an outspoken watchdog over his field.

Carl Costas

The rise of unproven stem cell therapies turned this obscure scientist into an industry watchdog

SACRAMENTO—Back in his lab after a week of vacation, Paul Knoepfler slogs through backlogged emails: A 71-year-old woman with arthritic knees would like to know whether a stem cell clinic she researched can give her relief. The parents of a 12-year-old with a degenerative eye disease wonder whether there's any hope of averting blindness with a stem cell injection. "Kindly apprise us of expenses and chance of success," they ask.

Knoepfler, though housed in the Shriners Hospitals for Children here, isn't a physician. And his University of California (UC), Davis, lab doesn't study arthritis or eye disease, nor does he have any experience developing a stem cell therapy. He mostly uses stem cells to study cancer-causing gene mutations. But thanks to The Niche, a blog he has run since 2010, Knoepfler has become an unlikely authority—and a dogged voice of caution—on the clinical use of stem cells.

The blog, which now averages more than 4000 daily visits, has elevated him from an obscure bench scientist to an international spokesperson on all things stem cell. "It's one of the major sources of information [for the] layperson, and also for stem cell researchers," says Jeanne Loring of Scripps Research Institute in San Diego, California, an occasional commenter and guest writer on the blog.

It also has turned Knoepfler, a softspoken, unimposing presence in person, into a divisive figure. He has sounded the alarm on hundreds of U.S. physicians and clinics advertising stem cells to treat everything from sore knees to spinal cord injury. These offerings haven't been through the approval process at the U.S. Food and Drug Administration (FDA), and most aren't supported by evidence from randomized clinical trials.

"They were just saying, ‘Screw the rules, we're just going to set up shop and put up a website and start injecting people with stem cells,'" says Knoepfler, who co-wrote a paper last year documenting the scope of this industry. "I saw that as a threat, first to patients, but to the field as well."

Stem cell researchers largely applaud his efforts. "He's been a reliable voice of reason in the field," says George Daley, a stem cell researcher at Boston Children's Hospital and dean of Harvard Medical School in Boston. Academics are "often more comfortable being provincial and insular, and not … mixing it up in the public debates."

But even people who have expressed concern about predatory and fraudulent clinics contend Knoepfler has sometimes painted potential stem cell therapies with too broad a brush. "There are clinicians in the United States that are practicing forms of regenerative medicine that are legal and that are having good results for their patients," says Bernard Siegel, executive director of the nonprofit Regenerative Medicine Foundation in Wellington, Florida. "We can't tar everyone."

Siegel says he admires Knoepfler, and his foundation honored the blogger with its national advocacy award in 2013. But in Siegel's view, Knoepfler has at times acted as "almost a bit of a societal scold."

On The Niche's discussion thread, patients who believe they have benefited from unapproved stem cell treatments are harsher. "You and I will never agree on this issue," wrote one commenter, Barbara Hanson, who has sought stem cell treatment overseas for chronic obstructive pulmonary disease and runs an online forum for patients, in a discussion about the value of FDA approval. "I have experienced a much better quality of life after having stem cell treatment than I could ever have expected from prescription medications and conventional treatment."

Seven years into the conversation, Knoepfler accepts criticism in stride. But with FDA looking unlikely to tighten its grip on such clinics, and strong pressure from some patients, advocates, and companies to keep stem cell treatments outside regulators' grasp, he admits the impact of his outreach is hard to measure. "A few individuals can't really necessarily rein in a whole industry."

Finding his Niche

Paul Knoepfler's blog, The Niche, steadily gained readers in its early years, but saw a spike in 2014 with his skeptical coverage of stimulus-triggered acquisition of pluripotency (STAP) stem cell claims.

(Graphic) G. Grullón/science; (Data) Paul Knoepfler

Knoepfler's fascination with stem cells grew out of science, but his willingness to speak out started with a life-changing personal event. A college English major, he didn't commit to science until he landed a postgraduation job as a research technician at UC San Diego, where his wife was starting medical school. "Being in the lab setting felt like I was at home," he says.

While working on a doctorate there and a postdoc at the Fred Hutchinson Cancer Research Center in Seattle, Washington, Knoepfler explored the proteins and genes that act up in some childhood cancers. To understand why variations in the gene MYC and its relatives lead to childhood brain tumors, Knoepfler realized he would have to detail their normal role in the growth and differentiation of neural stem cells.

Just as he set out to establish his own lab, the state of California launched a grand experiment in stem cell funding. Motivated in part by then-President George W. Bush's ban on federal funding for embryonic stem (ES) cell research, which antiabortion groups opposed, California voters approved the $3 billion California Institute for Regenerative Medicine (CIRM). In 2006, a $2 million "new faculty" grant from CIRM helped get Knoepfler's UC Davis lab off the ground.

It had been running for 3 years when, at age 42, he was diagnosed with prostate cancer and given roughly 50-50 survival odds. Knoepfler found himself a patient at the same cancer center he frequented for research meetings and seminars. "This time, I walked straight past the auditorium for the clinic. That was a freaky moment."

Surgery led to a remission that has now lasted for 7 years. But the medical scare emboldened him "to try to expand how I had impact, beyond just the pure science," he says. Weeks after the operation, Knoepfler published the first official post on The Niche, named after a defunct stem cell blog once hosted on Nature.com that he admired. (Stem cells often reside and grow in specific niches in the body, such as bone marrow, which houses blood-forming cells.)

Early on, Knoepfler was an impassioned and partisan advocate for ES cell research. Many Republicans "are in favor of executing prisoners who might be innocent, taking away women's rights, cutting aid to poor children, eliminating Social Security," he wrote after Mississippi lawmakers introduced an amendment to give embryos constitutional protections, "but when it comes to fertilized eggs or few-days-old blastocysts, they start carrying pitchforks and torches."

As the threat to ES cell research began to feel less serious under former President Barack Obama's administration, Knoepfler's attention shifted. His periodic Google searches for "stem cells" began to turn up unfamiliar treatment centers in the United States advertising poorly validated therapies. Many clinics isolated adult stem cells from a patient's own fat or bone marrow and reinjected them, promising to heal injured joints, rejuvenate aging skin, or even repair damage from neurological disorders and autoimmune disease.

Recently, Knoepfler and bioethicist Leigh Turner of the University of Minnesota in Minneapolis set out to compile U.S. stem cell clinics marketing directly to consumers online. In a paper in Cell Stem Cell, they revealed a marketplace of 351 businesses operating at 570 clinics. "That was a tremendous piece of work," says David Jensen, a retired newspaper journalist in Paso Robles, California, who runs a blog monitoring CIRM. "You could see it was a problem if you looked out your window. The question was how big it is."

Knoepfler believes that new stem cell treatments will eventually help patients, but he has long fretted about their safety. In 2012, his team published a paper pointing out similarities between tumor cells and induced pluripotent stem (iPS) cells—adult cells reprogrammed to a more primitive state in the lab. In part because iPS cells don't face religious objections, they are an appealing alternative to ES cells. But the paper concluded that iPS cells' potential for cancerous growth could stand in the way of using them therapeutically.

The adult stem cells used in most of the emerging clinics didn't undergo the same reprogramming process, but Knoepfler still worried about their potential for uncontrolled growth. "I guess I just had this deep concern that someone was going to get cancer, maybe because of my own experience with cancer, in retrospect."

Knoepfler acknowledges that few stem cell-induced cancers and other serious side effects have been reported. But he maintains that the risk is still there, noting the case of stroke patient Jim Gass, who ended up with a tumor along his spine after a series of stem cell injections at clinics outside the United States. A report this year in The New England Journal of Medicine also documented three women who were blinded after a Florida clinic injected them with stem cells to treat macular degeneration. And even patients not physically harmed might spend thousands of dollars on useless treatments that insurers often refuse to cover.

At first, Knoepfler thought FDA would crack down on the emerging industry—an expectation he now calls naïve. The only FDA-approved stem cell therapies involve transplants of umbilical cord blood-derived stem cells for blood cancers and certain metabolic and immune disorders. But the agency classifies other uses of stem cells as medical procedures and exempts them from its drug approval process, provided they meet certain criteria, including "minimal manipulation" of the cells and "homologous use"—using the cells for the same function they naturally perform in the body. Some uncertainty remains about which products are exempted—particularly when it comes to fat-derived stem cells. Draft guidances FDA issued in 2014 and 2015 seemed to narrow the set of exempted therapies, but those have yet to be finalized.

Meanwhile, Knoepfler pursues his own grassroots effort with unlikely passion. "He's a sweetheart," Jensen says. "Personally, I find him sort of shy and diffident sometimes," but Knoepfler "doesn't shy away from contact with the mainstream media." He has picked apart stem cell claims that seem too good to be true, requested details from clinics, and complained about uncritical press coverage of treatments.

Even after a recent redesign of The Niche, Knoepfler's corner of the internet feels homespun and unadorned. He often illustrates his posts with corny clip art, appropriated Hollywood movie posters ("A Nightmare on Stem Street"), and cartoons he draws himself. The blog yo-yos between audiences, dissecting a technical research paper one day, raising questions about a celebrity's stem cell boob job the next. Its most visited page in the past year is a Spanish translation of his layperson-friendly explainer, "What are stem cells?"

In 2014, Knoepfler found himself fielding midnight calls from Japanese reporters after he blogged his doubts about a paper from a Kobe-based research team describing stimulus-triggered acquisition of pluripotency (STAP) stem cells, allegedly created from adult cells by simple measures such as exposure to acid. He published some of the earliest skepticism of the claim, which swiftly fell apart through failed replication attempts, a misconduct investigation, and the paper's retraction. Knoepfler chronicled the downfall of STAP stem cells blow by blow.

Other moves drew more criticism. Knoepfler took to The Sacramento Bee last June to decry what he saw as a dangerous shift in CIRM's agenda. In a Fox News oped, CIRM's then-President C. Randal Mills and Senator Bill Frist (R-TN) criticized FDA's regulatory process as too rigid. The comments came as the Senate considered legislation that would let FDA conditionally approve stem cell therapies without largescale clinical trials. CIRM "should refocus its efforts on the science and medicine of stem cells," Knoepfler wrote, "instead of lobbying for high-risk weakening of federal stem cell oversight."

The affront to the head of a major funding organization that had supported Knoepfler's own lab struck some colleagues as reckless. "I advised him not to do it," says Loring, adding, "it doesn't mean I agreed with [Mills]."

Asked about Knoepfler's criticism the next week, Mills called him "fairly self-interested" in his push for more basic research and suggested that critics of FDA reform "live with a horrible disease" before defending the agency's slow and expensive process for approving new treatments.

Knoepfler's unyielding skepticism has also turned some patients against him. In a three-part series of posts this spring, he questioned the ethics of a center at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, that is attempting to treat autoimmune diseases such as multiple sclerosis (MS) by eliminating patients' immune cells and then using their bone marrow stem cells to replenish them. The principal investigator, Richard Burt, has run clinical trials, but has also provided treatment outside of trials under an FDA-sanctioned protocol known as expanded access.

After hearing that some MS patients were asked to pay as much as $150,000 to participate in a trial or receive off-study treatment, Knoepfler took to his blog. Although careful not to equate Burt's operation with for-profit clinics, Knoepfler suggested that testimonials on the center's website painted too rosy a picture of the experimental therapy and that its patient handbook encouraged fundraising efforts that might force patients to share private health information.

"It was astonishing, what he wrote," says Heather Burke of Orlando, Florida, who credits treatment at Northwestern with putting her MS into permanent remission and runs a Facebook group for patients. She says Burt tells patients that the procedure is potentially fatal and never promises improvements in their symptoms. Knoepfler's suggestion that Northwestern endorses fundraising is unfair, she adds, because for most patients, the procedure is fully covered by insurance. (Burt declined a request for comment.)

Burke shares Knoepfler's concerns about stem cell clinics that peddle shoddy science. But "Northwestern is not a popsicle stand in Mexico," she says. "When you have bloggers like Paul putting things out there like this, the only thing that they're doing is halting a possible really big breakthrough for treatments for MS."

One patient threatened to file an ethics complaint with his university. Others have accused Knoepfler of being a shill for Big Pharma, intent on suppressing alternatives to traditional drugs. (Knoepfler says he receives no funding from pharmaceutical companies.)

Knoepfler's online jabs at high-profile figures, companies, and doctors have never led to a libel lawsuit—though he says there have been a few threats. He has had tenure since 2011, and higher-ups at the university have never reprimanded him for voicing his opinions online, he says. But the stream of negativity has made him question how much longer he will continue blogging, even if he has no immediate plans to stop. "It takes a certain amount of energy just to deal with that."

He also admits that "I haven't necessarily made much headway" in convincing advocates of unfettered stem cell access that careful oversight is important, too. In recent years, nearly 40 states have passed controversial "right to try" laws, meant to allow dying patients easier access to experimental treatments without FDA oversight. And in June, Texas enacted a law that allows clinics to offer stem cell interventions without the testing and approval required under federal law. Knoepfler has predicted the change will be a boon to predatory clinics.

Still, he believes his handful of weekly email exchanges with conflicted patients is a chance to make a difference. He encourages them to get advice from their doctors, then explains why he's skeptical of approaches not proven in randomized trials. Some, he knows, will decide to go through with treatments anyway. Rarely do they write back to tell him about their decision. "That's kind of a hard part for me," he says. "I don't know the end of the story."