Eros Dervishi for STAT

PHILADELPHIA — The search began immediately after breakfast. It was Sunday, the last morning of a conference for patients with Gorlin syndrome, and as Kaylene Sheran finished up her bacon and eggs, Sara Ann Conkling turned the conversation to an experimental drug called patidegib. In this crowd, the medicine was something of a celebrity. Everyone was talking about it: a gel that could potentially shrink existing skin tumors and prevent the growth of new ones without causing the side effects of taking this kind of chemo in pill form. For Gorlin patients — who, in the most extreme cases, needed basal cell carcinomas surgically removed once every few weeks — that sounded too good to pass up.

So, Conkling asked between bites, what did Sheran think? Would she volunteer as a test subject?

The response came as a surprise. Sheran was already so firm, so unmovable in her decision. “I was like, ‘No, and here’s why,’” Sheran recalled: Representatives for the drug company PellePharm had been pleading with patients like her to come forward, but to her, it didn’t seem right to lend them her time and body if they couldn’t say how affordable their medication might eventually be. Yesterday, she’d asked, and they’d given her no details, no guarantees. If they had no answer to her most pressing question, then they could look elsewhere for the 150 recruits they needed; Sheran wasn’t interested.

“I was encouraging her to ask that question,” Conkling said. But she didn’t want her friend to give up prematurely on getting the stuff, either. “I’m concerned about her,” Conkling said. “I’m more concerned about her than about me. I’m older. I’ve lived a lot of life already. It’s more important for her to have treatment.”

They’d met a few years earlier, through a Gorlin support group online. That was how Sheran came to know most of her closest friends. She was bullied in school, and though she liked the other teens with whom she did community radio — on air, she was DJ Diamond — rare illnesses can come with a unique sort of loneliness, a void that can only be filled by people with a visceral understanding of what you’re going through.

Conkling’s Gorlin was milder than Sheran’s. She generally needed carcinomas frozen or cut off only once every three months. But she saw herself in Sheran’s fiery brand of volunteerism, raising money for this, advocating for that — “all that do-goody stuff,” Conkling called it — and they struck up a Facebook correspondence. Now, after years of writing back and forth, they’d finally gotten to meet in person for the first time.

Kaylene Sheran (left) and Sara Ann Conkling pose for a photo in Philadelphia, where they met for the first time after corresponding for years on Facebook. Courtesy

Sheran had been nervous about questioning the company’s leaders. She was 19, one year into her college degree; they were middle-aged executives with M.D.s. There was a time when Conkling would have felt similarly. Now, she was 59. She’d worked as a journalist, a nonprofit director, a corporate vice president, a college instructor, and a public transit advocate. When her local representatives in Florida cut funds to community organizations, she showed up at meetings to call them out. She had no qualms about asking uncomfortable questions. “She was just like, ‘Oh my gosh, I need to talk to these people,’” Sheran recalled.

First, they scanned the hotel mezzanine, thinking their quarry might be here, sipping coffee or nibbling the last of their fruit. But neither the CEO nor the vice president of PellePharm seemed to be there, so Conkling and Sheran set off to find them.

The crowd around them knew all too well how genetic mutations could spiral outward from cells, patterning your finances and relationships, reshaping your life. “I’ve lost a lot of jobs because of this,” said Mark Korschgen, a 39-year-old from Tallahassee, Fla. For a while he’d worked in sales — mostly cars and clothes — but as his need for surgeries burgeoned, he had to stop. “It’s extremely disfiguring,” he said. “It’s hard to be in sales when you have patches all over your face. … I’m going to look like Frankenstein for a couple of weeks — it’s just not practical to be in a customer-facing business.” Sometimes he quit before any issues arose; sometimes his employers let him go.

Even with insurance, medical care cost him thousands every year. Being unemployed could be disastrous. Eventually he’d gotten into junk removal — “we took seven truckloads of clothes out of one person’s house; a lot of dead pets; a lot of falling-apart houses” — and he’d risen through the ranks. But his operations put an end to that, too. Between the time off he needed for surgeries and the post-op activity restrictions, he couldn’t keep pace with the work.

These were the kinds of stories that ran through Sheran’s head as she looked for the PellePharm execs. With Conkling, she descended from the mezzanine to the lobby, eyeing the seats at the hotel bar, peering into meeting rooms, searching the couches by the reception desk. There was no sign of them. All they found were the never-ending rhythms of hotel transience. Sliding doors hissed open and closed. Workers wished guests a pleasant stay. Muzak buzzed, persistent as a fly.

The execs had been here all weekend. They must have stepped briefly into a meeting or out for a break. Conkling and Sheran returned to the windowless ballroom. For Sheran, the thrill of the conference wasn’t totally sapped, but the unsatisfactory answers had left her with a sour aftertaste. Everywhere she looked — on posters, on programs, on speakers’ slides — were reminders that a quiet army of scientists was busy fine-tuning advancements. She tried to focus on the speaker. But she couldn’t keep herself from wondering whether all these glittering technologies would end up within patients’ reach.

Initially, the drug she was after was out of almost everybody’s reach. Its starting ingredient was a chemical extracted from wild cow cabbage roots, which drug manufacturers had found in and around Utah’s Manti-La Sal National Forest, not so far from the mountains where ranchers first noticed their ewes giving birth to one-eyed lambs. Even to some in the drug industry, the provenance can be surprising — as if, under the hood of your Ferrari, there lurked the bones and muscles of a horse.

It all began with a hypothesis: That the biology behind Gorlin might hold the secret to other cancers. After tracing this rare disorder to a mutation in one of the hedgehog genes, which help shape bodies during development, researchers began to look for the same clue elsewhere. They found it in the tumors of patients who didn’t have the syndrome but who grew the same sorts of cancers: A molecular lock was missing, allowing hedgehog proteins to proliferate unchecked. In many other cancers, the signs they found were subtler. There were traces of hedgehog proteins but no telltale mutations, a whiff of smoke but no gun. Still, smoke was smoke, and the news wafted from conference to conference, lab to lab.

Put enough hedgehog inhibitor into a Petri dish with cancer cells and the cells died. Inject enough into a tumor on the flank of a mouse and the tumor shrank. “This was going to be the cure-all for all cancers, or at least 25% of them,” said Tom Curran, executive director of the Children’s Research Institute at Children’s Mercy Kansas City and a former president of the American Association for Cancer Research.

A prime harvest site in the Manti-La Sal National Forest in Utah. Courtesy Dave Mann

Glance at databases like Biomedtracker, clinicaltrials.gov, and PubMed, and you can watch the hedgehog-inhibitor optimism take hold. By 2009, many of the biggest drug makers in the world were beyond convinced about hedgehog inhibitors, and not just for skin tumors. Pfizer, Novartis, Takeda, Eli Lilly, Bristol-Myers Squibb, and Roche all tried them, each one choosing its own litany of cancers to target, which included skin, brain, lung, breast, liver, prostate, bladder, ovarian, colorectal, bone marrow, blood, and bone. “Literally everybody started making hedgehog inhibitors,” said Frédéric de Sauvage, head of molecular oncology at the Roche subsidiary Genentech.

Perhaps the severest outbreak of hedgehog fever — the one that would give rise to PellePharm’s patidegib — emerged at Infinity Pharmaceuticals. The first symptom was an exploratory trip executives made out west with picks and shovels. They collected so much tuber loot they called back to their Massachusetts office, asking for a U-Haul.

Soon, two Infinity chemists were back, traipsing through Manti-La Sal with uniformed Forest Service personnel, buzzing over crags in a helicopter, roaring through vegetation on ranchers’ four-wheelers.

Once they’d found bountiful cow cabbage patches, secured permission from private landowners, and bought permits from the government, the harvest began. They hired a crew of temp workers to hack off the stalks and dig up the roots, rhizomes and all. “I called Home Depot and ordered 100 shovels, maybe I got 20 or 25 machetes,” recalled Joe McPherson, a biochemist-turned-vice-president-turned-harvest-leader. “They said, ‘Oh, the prison put in a big order but they haven’t picked them up.’” McPherson said he’d take them. The pickers formed human chains to pass 50-pound burlap bags of roots up out of the mountain valleys and into the truck.

The roots were a mess, still wet with runoff and easily furred with mold. On a tip from a local, Infinity rented out abandoned turkey coops as a drying-ground. Workers sat on buckets, spreading out a sea of roots where fowls had been fattened for the table. Once moisture-free, the crop could be milled, sieved, and solvent-bathed, going from ginger-like to flour-like to sludge.

A cow cabbage rhizome below the root bulb. Courtesy Dave Mann

Cow cabbage roots drying in an abandoned turkey barn. Courtesy Dave Mann

Gross as it might sound, it was rich with a ready-made hedgehog inhibitor. Like many natural molecules, cyclopamine was a headache for medicine-makers, breaking down in stomach acid, effective only when taken at an impractically high dose. But Infinity had a secret weapon, a rock-star chemist named Julian Adams, whose team finessed the plant goop into a potent anti-cancer pill.

With Genentech already testing a synthetic hedgehog inhibitor against basal cell carcinomas, Infinity focused on cancers of the pancreas, bone marrow, and bone. Hand-gathering cow cabbage was fine for initial experiments, but it wasn’t going to cut it to keep human study participants supplied with pills. So the workers brought tractors up the mountain, mowers to clip the stalks, and lifters like huge underground forks with vibrating tines that could tear up the roots and shake off the clinging earth.

In 2009, Infinity harvested 11 acres, creeping up to 16 the next year. By 2011, it was 25. “That’s probably a couple of semi-truckloads of roots,” said David Mann, another harvest leader. He remembers piling their haul into 10- or 15-foot mounds and clambering to the top, like a muddied mountain king surveying his realm.

For Mann, it was exhilarating, a wonderful departure after years spent in the lab, hands stuck in a fume hood. It was also stressful as hell. At 9,000 feet of elevation, the digging season was breathlessly short, bookended by the snowmelt in July and the squalls in September. “What if there was a fire on the mountain?” said McPherson. “What if the snow never went away?” Ecologists had to survey a site before Infinity harvested it, to make sure the work wouldn’t disturb the nesting of endangered goshawks; afterwards, the team had to reseed the torn up earth with native grasses.

Then, in 2012, as they were preparing for their biggest harvest yet, everything fell apart. Employees remember exactly where they were when they heard each piece of news, the way you might recall where you were when the Twin Towers fell. One had just brought pastries to her colleagues when she was pulled out into the hall. Another was just waking up with coffee the morning after a night out at the Cubs game. “Everyone was devastated. There were tears,” Margaret Read, the project leader, who now works at Vanderbilt University, recalled. “Many of us have never really gotten over it.”

Their drugs weren’t working. Among pancreatic cancer patients — for whom the prognosis was already, as Epstein put it, “horrific, dismal” — those who got Infinity’s treatment fared even worse.

At Infinity, there were layoffs. Elsewhere, too, hedgehog fever subsided. Over 50 clinical trials had begun for similar treatments; now companies began discussing whether to put those drugs aside. There was still promise in basal cell carcinomas, medulloblastomas, and a subset of leukemias — and three hedgehog inhibitors would eventually be FDA-approved — but this kind of chemo was hardly the panacea people had predicted.

“It was so disheartening — almost soul-destroying — that we raised the hope of people with colon, pancreatic, breast, and other cancers,” Curran said.

Why had molecules so highly prized yielded such disappointment? Some say that the understanding of certain tumors was simply incomplete. Others point to shoddy studies done in Petri dishes and mice that never should have been lifted from the lab to the clinic. De Sauvage explains that pretty much any drug, injected directly and at high enough quantities, will kill any cell, but that doesn’t mean it will make a good cancer-specific drug.

In retrospect, the faint haze of hedgehog proteins in many cancers seemed a red herring. As Epstein put it, “Just because you can see something in a tumor doesn’t mean that’s an Achilles’ heel.”

Attendees gather for lunch at the Gorlin Syndrome Alliance conference in Philadelphia. Mark Makela for STAT

Addy Alt-Holland, a professor of endodontics at Tufts University, embraces Tom Sprague, a motivational speaker who has Gorlin syndrome. Mark Makela for STAT

Still, he was willing to bet that Infinity’s drug would work for patients like Sheran. It wasn’t a huge leap. He’d seen clouds of skin tumors like hers vanish under the influence of Erivedge, Genentech’s synthetic hedgehog inhibitor, launched in 2015. He’d also seen how the side effects proved an intolerable torment to some. He was sitting around one morning, having coffee with his colleague Dr. Jean Tang, when they had an epiphany. “Being dermatologists, the answer is, well, duh.” They needed to smear it on as an ointment.

Easier said than done. What they needed was a Goldilocks gel, breaching the skin just enough to treat and prevent tumors but not so much that it caused side effects. The people who could concoct it seemed as elusive as the Gorlin-causing gene, and Epstein searched for them in the same way: by hitting the road. He visited self-proclaimed gel-makers in Connecticut and California, phoned a manufacturer in North Carolina, found labs that turn molecules into dissolve-on-your-tongue tabs.

Only when he got as far as Surrey, England, did he find a company that fit the bill: “They were functioning, they were busy. All the others had dust all over their labs.” He and Tang had already formed PellePharm with Philip Beachy, the biologist who’d helped establish the connection between the one-eyed lambs of Idaho and the hedgehog genes. The trio was ready to start repurposing a different hedgehog inhibitor when Epstein got yet another message out of the blue.

It was from Infinity. As Julian Adams explained later, “Genentech was ahead of us … and won the race.” His team was giving up on the stuff they’d spent years extracting and perfecting. Did Epstein know anyone who might want to take it over?

“My first response was, ‘Uh, oh, we’re going to have a competitor,’” he said. Then, he had a better thought. Why not, with his cronies, take over the cow cabbage patches himself?

Newsletters Sign up for Daily Recap A roundup of STAT's top stories of the day. Please enter a valid email address. Privacy Policy Leave this field empty if you're human:

The deal was sealed with a party in Infinity’s cafeteria. Hands were shaken, papers signed, and then Epstein was asked to make a speech. Instead, after a short burst of “drivel,” he said, he began to perform a kind of circus act.

“He had on a dress shirt, tie, and jacket. He took off the tie and I thought, What is he doing?” recalled Read.

“I didn’t put it in my teeth, like a genuine striptease,” Epstein said.

“And then he unbuttoned his shirt …” Read went on.

“They probably thought I was out of my frigging mind,” Epstein added.

Only when the Infinity T-shirt underneath became visible did the audience start to cheer. The company’s high-mountain drug-making expeditions had cost a fortune; the medication’s failure in three different cancers cost employees their jobs. Now, at least, PellePharm was bringing Operation Cow Cabbage back from the dead. In the upland meadows of Manti-La Sal, a new generation of harvesting machines rumbled to life. The early-stage results were promising. By June 2019, the company just needed 150 patients to volunteer so it could move closer to making the resurrection complete.

Sheran had finally managed to get her mind off her search for the PellePharm execs and onto the talk unfolding in front of her when she was distracted again. To her left, Conkling was scribbling out of time with the rhythm of the lecture, as if she were composing a note so juicy it could overshadow anything going on at the front of the class. She was. While taking a break from the talk, she’d spied someone from PellePharm and walked over.

From elsewhere in the lobby, the encounter would have looked like any other conversation on the sidelines of a conference: pleasantries and polite nods, a snatch of shop talk, an exchange of contact information. Listening in, you would instead have heard Conkling proposing a radical pact. She wanted PellePharm to guarantee that if you volunteered to test the new drug and it ended up making it to market, you’d get the medicine affordably for the rest of your life.

She knew it was an extravagant request. She knew that wasn’t how clinical trials generally work. She knew it upended the economic principles on which drug companies were built. She also thought it was only fair, a long-term safeguard for volunteers who will continue needing cancer treatment for the rest of their lives.

Dr. Sanuj Ravindran, the CEO of PellePharm, responded with a counterproposal. Whether they’d been smearing their faces with a placebo or with the real hedgehog-inhibiting gel, he offered, volunteers would get a year of free treatment after the experiment.

Conkling looked at him: “I said, while that was appreciated, that wasn’t going to solve the problem.” They continued their volley by email the next day. Ravindran wrote that PellePharm might consider extending the offer of free drug beyond a year, right up until the moment when they were ready to start selling it. Again, to Conkling, that wasn’t enough. The moment when they were ready to start selling the drug was exactly what she worried about. (When asked about his conversations with Sheran and Conkling, Ravindran said: “It is premature to discuss pricing considerations. That said, please know that we intend to be thoughtful in our approach to price patidegib fairly and are committed to exploring ways to ensure patients have access to treatment.”)

Sheran at a park near her home in East Boston. Kayana Szymczak for STAT

Back in the hotel ballroom, Conkling tapped Sheran on the shoulder, motioning toward her notepad. In black ink, it said, “They aren’t going to help you.”

That wasn’t entirely fair to PellePharm. The American medical system was not their fault. Conkling said it herself: “These are people who are dedicating their life’s work to a rare disease. By definition, these are good people.” Their study wasn’t even finished recruiting yet. Their drug was nowhere near being approved. They had no control over the headache of the American health insurance system.

Plus, the molecule they’d resurrected was devilishly complex. Coiled within its chemical bonds were traces of one-eyed sheep, distraught ranchers, staid agricultural scientists, fruit fly obsessives, optimistic executives, cow cabbage root-diggers, and devastated cancer patients of every stripe. It was built on the curiosities of basic science, on the weedy bounties of the Manti-La Sal National Forest, on layoffs and reinvestments and breathtaking risks.

In the grand scheme of things, Sheran’s decision was a single data point, an N of one, a quiet protest against American medicine as a whole. Though the reasons were different, the action itself wasn’t entirely new: She’d absented herself from medical interventions before. Recently, she’d found herself choosing between paying for procedures and buying books for school. “It doesn’t sound logical, but the textbook comes first, because I’m always going to have these basal cells,” she said. College, on the other hand, would only last a few years.

She was still thinking about PellePharm’s gel two months after the conference, as she boarded the subway toward an appointment with her ophthalmologist in Boston. Though she’d decided against getting screened for the trial, she hoped the drug would be approved and that she could afford it. The trial was progressing without her. By mid-fall, PellePharm had two-thirds of the volunteers it needed, and expected to find 150 patients by the end of the year.

For now, there was a cloud of more pressing health issues for Sheran: An ever-changing list of prescriptions, a never-ending calendar of appointments. Today’s made her especially nervous: Her father also has Gorlin syndrome, and it was at this same sort of annual visit that the doctor had first noticed, lurking behind his eye, the shadow of a brain tumor.

“Any flashers or floaters?” the ophthalmologist’s technician asked. To measure her eye pressure, the staff pressed something that looked like a thermometer into the whites beside her pupil. They used a camera to reveal the back of her retina, the blood vessels coursing across it like rivers. They ushered her from test to test, from room to room. When she finally saw the ophthalmologist himself, she was relieved: This time, there was no evidence of a brain tumor, no sign of visual deterioration.

As she left, the receptionist asked her to set up another appointment in a year, and she did. Already, she knew she’d go only if she had the $60 to spare for the copay. If not, she’d cancel.