16-02-2025
On a Mission to Heal Gila Monsters
By any measure, the diabetes drug Ozempic has been a blockbuster, racking up billions of dollars in annual sales. In the United States alone, pharmacies fill millions of prescriptions for Ozempic and related drugs, which have become popular for their weight-loss effects, every month.
But in the beginning, before the celebrity endorsements and the think pieces and the global supply crunch, there was just a strange, venomous lizard with a flair for intermittent fasting. The Gila monster, which is native to the deserts of North America, can survive on just a few meals a year, thanks to a digestion-slowing hormone in its venom.
The discovery of this hormone paved the way for Ozempic, making the Gila monster an enormously profitable gift to modern medicine. And last summer one particular Gila monster, a former pet named Pebbles, needed medicine in return.
Pebbles, a resident at the Creature Conservancy, a wildlife education organization in Ann Arbor, Mich., had been infected with a parasite called Cryptosporidium. Hard to kill, the parasite colonizes the digestive tract and is typically a death sentence for reptiles.
A veterinarian had recommended that Pebbles be humanely euthanized. But the Creature Conservancy wasn't ready to accept that fate for Pebbles, who had at least another decade of life potentially ahead of her.
'If we can fix her,' said Steve Marsh, the founder of the Creature Conservancy, one afternoon last July.
He corrected himself: 'If he can fix her,' he said. He nodded toward a sharply dressed man who was cradling Pebbles in his gloved hands: Tim Cernak, a pharmaceutical chemist at the University of Michigan.
A few minutes later, a veterinarian inserted a tube into the lizard's throat, collecting liquid from her stomach. Later, Dr. Cernak would study this sample in his lab, hoping to isolate the parasite and find a drug that could vanquish it.
Pebbles was not the patient Dr. Cernak had in mind when he began his career. Until 2018, he had worked at the pharmaceutical giant Merck, developing drugs for people with cancer, H.I.V., diabetes and other conditions. Along the way, he had helped develop cutting-edge approaches, involving robots and artificial intelligence, to speed up the invention of new human drugs.
A few years ago, however, Dr. Cernak decided that he wanted to use those tools to make medicines for ailing plants and animals, forging a new field he called 'conservation chemistry.'
Gila monsters weren't the only species that had inspired human drugs. There were antibiotics derived from fungi, anticancer drugs from plants and painkillers from animal venom. Dr. Cernak thought it was time for pharmaceutical chemists to give back. 'To me it's this full circle thing,' he said. 'We're attempting to solve the ultimate health inequity.'
Conservation chemistry
Dr. Cernak, a native Canadian, had grown up catching leopard frogs and crayfish at his grandparents' lakeside cottage in Quebec. When he left his job at Merck, he wanted to use his chemical expertise for a greater environmental good.
'Pharma's rad,' said Dr. Cernak, who has a youthful face and the upbeat energy to match. 'But I wanted to apply my talents to a love of nature.'
Initially, he thought he might do research on methane, a greenhouse gas contributing to climate change. But after Covid-19 hit, he began to think more about the existential, population-level risks posed by disease.
A fungal disease called chytridiomycosis, or chytrid, was driving frogs to extinction. Bald eagles and elephant seals were succumbing to bird flu. And sea turtles were washing ashore with a contagious form of cancer.
Treatment options left much to be desired. There were human medicines that could help some sick frogs and sea turtles, but they could cause severe side effects and were suitable only for certain animal patients.
Dr. Cernak had experience developing targeted anticancer drugs, which were designed to destroy cancer cells while minimizing damage to healthy ones. Would it really be such a stretch to do the same thing for a tumor-riddled sea turtle? 'Precision oncology for a sea turtle — that could totally be done,' he thought.
The same idea could be extended to ecosystems. In some ways, the invasive, sap-sucking insects that were spreading through America's hemlock groves could be considered a cancer of the forest. Perhaps the tools of pharmaceutical chemistry could help him design a precision pesticide that would wipe out the invasive insects while sparing native ones.
Dr. Cernak had a knack for seeing opportunities everywhere and a reluctance to do anything halfway. He began traipsing around hemlock groves at the university's arboretum and asking sea turtle hospitals for samples of tumor tissue. He puzzled over how to get antimalarial drugs to rare birds in Hawaii and wondered, as 'just kind of a fun thought experiment,' whether he could design monoclonal antibodies that selectively ferried poison to different species of invasive fish.
And on a trip to the Creature Conservancy in December 2023, he learned about the plight of Pebbles.
Robo drug discovery
Drug development is a famously failure-prone pursuit. Dr. Cernak has ratcheted up the degree of difficulty by focusing on pathogens and patients that are poorly understood. 'People haven't chosen to look inside of the Gila monster too much,' he said.
But that's exactly what his team was doing one day last July, in a chemistry lab on the University of Michigan's leafy campus.
There are many species of Cryptosporidium, which can infect a wide range of mammals, birds and reptiles. All of them are understudied, Dr. Cernak said, but the reptile pathogens are a particular mystery.
And when the scientists put a sample from Pebbles under the microscope, they were startled by what they saw: a single-celled parasite wrapped in a thick, jellylike coating, an unexpected extra layer of cellular protection. 'It's like this citadel,' Dr. Cernak said.
Soon, they would begin looking for a drug to breach this line of defense. On another lab bench, however, the hunt for a better cure for chytrid, the amphibian fungal disease, was already underway. A modular robot in a transparent box glided back and forth, preparing to dispense minute doses of antifungal drugs into a grid of shallow wells.
The short-term goal was to identify an existing drug that would be more effective and less toxic than one common chytrid treatment. The robots — the largest of which could run more than 1,500 chemical reactions at once — could quickly test a pharmacy's worth of possibilities on lab-grown chytrid cells.
Over the months that followed, the team identified a compound, which Dr. Cernak declined to disclose, that proved promising in both the cells and in the African dwarf frogs that were paddling around in a nearby biology lab. The next step is to test it in additional species.
'The fact that Tim is moving into this from a field of human medicine is really awesome,' said Brian Gratwicke, who leads the amphibian conservation programs at the Smithsonian's National Zoo and Conservation Biology Institute and is collaborating with Dr. Cernak. 'Because that's one of the things that has been missing — that kind of focus, that kind of methodology and the rigor that is being applied to humans.'
Into the wild
Over the longer term, Dr. Cernak is trying to engineer a new drug specifically for chytrid. He is using several A.I.-powered tools — including Google's Nobel-winning software AlphaFold — to visualize the three-dimensional structure of a critical fungal protein and design a drug that binds to it . (He is using the same basic approach in his search for new drugs for bird flu and sea turtle cancer.)
A drug that is sufficiently precise, binding only to that chytrid protein, could potentially be dispensed directly into frog ponds. 'I kind of imagine those pucks that you put in the back of a toilet,' Dr. Cernak said. 'A slow-release type thing.'
It's a vision he shares with some reluctance. 'I just really don't want to appear to be the mad chemist who's sprinkling chemicals all over,' he said. 'Particularly just because I think chemists are so easy to villainize in conservation. And so we're really trying to find the right way to get it to our patient with having the absolute minimal impact on the ecosystem.'
Indeed, the idea of deliberately releasing drugs into the environment is likely to make some conservationists uneasy. 'Pharmaceuticals were never designed to just be sort of broadcast out there,' said Kathryn Arnold, an ecologist at the University of York in Britain.
Human pharmaceuticals, which regularly turn up in the world's waterways, are known pollutants. They can imperil aquatic organisms and fuel the emergence of drug-resistant pathogens.
Even dosing animals individually wouldn't eliminate the risk, said Tomas Brodin, an ecologist at the Swedish University of Agricultural Sciences. Medicated animals could excrete drugs into the environment, he said, or unwittingly poison predators. In India, vultures were nearly driven to extinction after scavenging on the carcasses of cows that had been given a common painkiller.
Dr. Brodin praised Dr. Cernak's optimism. 'His heart is in the right place,' he said. 'But even in drugs in humans, we've seen how hard it is to design drugs that are very specific.'
There are likely to be regulatory and economic hurdles, too: Who, exactly, is going to pay for a precision cancer drug for sea turtles? And while novel drugs can help buy time for critically endangered species, protecting biodiversity will require addressing larger problems, including climate change and habitat loss.
'A lot of these diseases we're seeing are a consequence of changes in the environment, animals' being stressed or their habitats' being degraded,' said David Duffy, a cancer biologist at the University of Florida's Whitney Laboratory for Marine Bioscience, who is also working on cancer treatments for sea turtles. 'What chemists and oncologists can do,' he added, 'is mostly treating the consequences.'
Pills for Pebbles
Dr. Cernak is cleareyed about these challenges.
He has been waiting for more than a year for the federal permits he needs to receive sea turtle tissue. And he has not been able to attract funding for the Pebbles project, even after approaching a drug company profiting from Gila-monster-inspired drugs. 'We have kept the work alive on fumes,' he said.
Without funding, he could not culture Pebbles's parasite in the lab, which he needed to do before he could unleash the robotic drug testers. So his team used A.I.-based tools to scour the scientific literature on Cryptosporidium, looking for potential treatments safe enough to try without extensive laboratory trials. 'My biggest fear was that I would overdose and poison Pebbles,' Dr. Cernak said.
He homed in on a drug that can cure Cryptosporidium infections in livestock but has yielded mixed results in reptiles. In December and January, Pebbles gobbled down seven doses of the drug, which had been secreted inside dead mice and quail.
So far, she has shown no ill effects. But because her digestive system moves so slowly, it could be months before the scientists know whether the drug worked. Dr. Cernak is bracing himself for the possibility that it won't.
And then what? 'We'll try again,' he said.
