Gordon Gribble has had little time for rest this summer, between finishing two books, running experiments, and teaching an undergraduate course in environmental chemistry. At 85, the professor emeritus of chemistry is determined to tie up the loose ends of a long and productive career.
Why he’s still at it has as much to do with his lifelong love affair with organic chemistry as an unusually fruitful collaboration with the late Michael Sporn, a cancer researcher at Dartmouth’s Geisel School of Medicine. Together, Gribble and Sporn developed two anti-cancer compounds that made it to clinical trials. One of them, sold as Skyclarys, became the first FDA-approved treatment in 2023 for a rare neurodegenerative disorder called Friedreich’s ataxia.
Sporn died before he could see their discovery make it to market, but the royalties the drug generated helped support Gribble’s return to research. He retired in 2017 but never fully stepped away, continuing to teach environmental chemistry each summer while pursuing his own work. He recently recruited two of his former students, Gary Jaycox, Guarini ’88, and Steve Wright ’81, both now visiting scholars at Dartmouth, to continue the hunt for cancer-fighting compounds. Both retired to New Hampshire after successful careers at DuPont and Pfizer, respectively, and jumped at the chance to join Gribble in the lab.
“We’re just really getting started,” says Gribble. “Our goal is to make something that will benefit humanity.”
Common cause
At a larger or more siloed institution, a synthetic organic chemist and a cancer pharmacologist might never have met. But at Dartmouth, Gribble and Sporn found common cause almost instantly and launched what would become a 25-year partnership. Their proximity on campus allowed Gribble to work up a compound at Burke Hall, walk it over to Sporn at Geisel for testing, discuss the results, and iterate, often in the same day.
Michael Sporn (Photo by Jon Gilbert Fox)
But the relationship flourished not just because of their favorable locations. They were bench scientists with an untiring work ethic. They were also independent thinkers willing to champion unpopular causes.
For Gribble, who came of age during the environmental movement, the cause was society’s irrational fear of chemicals. To combat what he called “chemophobia,” he made it his mission to explain the difference between safe and dangerous chemical exposures. In lectures and review articles, he repeated the mantra: “the dose makes the poison.”
Sporn had a different message. He thought cancer treatment should begin with chemoprevention, a term he coined in the 1970s. Cancer was a chronic disease that developed slowly, and should be treated, he believed, with preventive measures rather than toxic drugs. For 17 years, Sporn led the chemoprevention lab at the National Institutes of Health, where he showed, among other things, how a class of vitamin A derivatives called retinoids could prevent and treat breast, colon, and other cancers in mice.
'My door was open’
Gribble arrived at Dartmouth first, in 1968, after an invitation to give a job talk. When his prepared notes and slides were lost with his luggage on the flight from Los Angeles, he was forced to wing it. “I gave a blackboard talk on my research and it seemed to work because I was offered a job,” he says.
Dartmouth turned out to be a natural fit for someone who cared as much about teaching organic chemistry (the chemistry of carbon compounds) as improving on chemical structures found in nature. Students sought out Gribble for his willingness to take on projects outside his immediate interests.
“I had some ideas about designing molecules that would bind to DNA, maybe for their anti-cancer properties,” says Jaycox. “I talked to Gordon and he was one of the few professors I’d ever met who gave me the freedom to pursue my own work.”
Gribble became a magnet for other creative minds. “Gordon was always willing to try ideas that seemed reasonable, whether or not they fit some pre-existing framework,“ says Wright. “If it’s chemistry, Gordon is interested.”
Gribble’s unusual openness, and perhaps his habit of working on weekends, meant he was in the right place when Sporn dropped by the chemistry department one morning in 1994. Dartmouth at the time was recruiting Sporn, and Sporn had expressed interest in working with a synthetic chemist to develop new anti-cancer drugs. The head of the biology department introduced them. “I happened to be in my office, and my door was open,” Gribble remembers. “We had a great chat.”
Gribble had lost his first wife to brain cancer a decade earlier and Sporn’s preventive message resonated. The meeting went so well that Sporn followed up with a letter typed on NIH letterhead, with a handwritten note at the bottom. “Terpenes from peony root would still be my first choice for a starter project.”
Terpenoids are ubiquitous in the plant world, and Sporn thought they could have properties that might explain why sequoias and some other trees lived so long. “It’s kind of a simple idea, but that’s what got us started,” Gribble told Dartmouth Medicine in 2006.
When Sporn arrived in Hanover in 1995, they got to work. When the peony extract didn’t pan out, they turned to a larger, heavier class of relatives known for their anti-inflammatory properties: triterpenoids. The starter compound they settled on next, oleanolic acid, was an extract found in olives, a mainstay of the Mediterranean diet.
In its pure form, oleanolic acid looks like table salt or sugar, and Gribble and his postdoc, Tadashi Honda, synthesized hundreds of variations in the search for one with real therapeutic power. Sporn would test each one on protein targets to measure its potency. “The big hit was the 151st compound, which came to be known as bardoxolone methyl,” says Gribble. “It was 40,000 times, maybe even 400,000 times, more active in inflammatory assays than oleanolic acid.”
It took three years to accomplish the 10-step synthesis, “going from the stuff we get from olive oil to a compound that made it through phase three of clinical trials [for cancer and chronic kidney disease],“ he told the Dartmouth Undergraduate Journal of Science in 2017.
They went on to make 400 more compounds, including some even more potent. One was omaveloxolone, also based on bardoxolone, but with a slightly different side chain. The molecule was synthesized at Reata Pharmaceuticals, a startup Sporn founded after growing frustrated by the difficulty of getting promising molecules commercialized. Reata took omaveloxolone through clinical trials, and after receiving FDA approval, was sold to Biogen.
A year shy of seeing his project to completion, Sporn died of natural causes in 2022, at age 89.
Gribble with former Dartmouth professor Hadashi Honda in 2006 (Photo by Jon Gilbert Fox)
From pyrotechnics to practical compounds
Gribble’s interest in chemistry dates back to the 1950s. His parents gave him a chemistry set for Christmas one year, and he remembers doing experiments with his father in their kitchen in San Francisco. “I really loved the idea of making something new, noticing how chemicals react to form colors, smoke, things like that,” he said in an earlier interview. By 14, he was setting off fireworks for the neighborhood kids and handing out business cards advertising his services.
He majored in chemistry at the University of California, Berkeley. At the University of Oregon, where he earned his PhD, he was introduced to nitroindoles, a class of compounds found in everything from plant oils to tryptophan to the brain chemical serotonin. Many common drugs are based on the indole chemical structure and used to treat migraines, among other conditions.
A synthetic organic chemist does two main things: modifying the structure of molecules found in nature to enhance a desired property and devising methods to produce these artificial compounds. Gribble excelled at both. In his early years at Dartmouth, he developed anti-bacterial and anti-cancer compounds. He also invented a one-step process to produce a fly pheromone that could be applied to sticky tape. He came up with many new ways to produce reducing agents from sodium borohydride, including sodium triacetoxyborohydride, which is today widely used in commercial labs.
“It’s cheap, safe, predictable, reliable, and green,” says Wright.
‘You have to love organic chemistry’
Gribble’s enthusiasm for his subject comes across vividly in lectures, as he connects carbon-based compounds to topics in the news and everyday life. There are more molecules of H2O in a drop of water, he likes to tell students, than there are grains of sand on Earth. In Chem 63, the course he taught this summer, his lectures range from chemical weapons to bug and weed killers to the wrinkle-concealing agent Botox.
“Too many professors lecture from their own level and never manage to reach people with less expertise and it’s unfortunate,” says Jaycox. “He’s one of the best I’ve seen at shaping his lectures to a general audience.”
Gribble’s gift for translating chemistry for non-chemists helped him counteract the misinformation that spread as the harmful effects of pesticides, PCBs, and other synthetic chemicals became more widely known. When Greenpeace launched a campaign in the 1980s to ban chlorine, an active ingredient in PCBs and DDT, he became vocal. These chemicals posed a legitimate threat to public health and the environment, but in trying to simplify the message, Greenpeace had made the claim that nature would never produce such toxic and long-lasting chemicals.
“I knew these statements weren’t true and that there were several well-known chlorinated, brominated, and iodinated natural compounds,“ he says. “So, I started writing about it!”
And he didn’t stop there. He has so far written three books on “organohalogenated“ compounds and is at work on his fourth. Meanwhile, his tally has grown to 8,400 compounds that are mainly used by seaweed, sponges, corals, and other marine life to ward off predators. “If you go to Cape Cod or New Hampshire beaches, you’re smelling these organohalogens,” he says.
“Gordon is a true champion of chemistry,” says Ekaterina Pletneva, chair of the chemistry department, “and we are grateful for his continued involvement in the life of the department.”
“Gordon and Michael’s collaboration is a perfect illustration of how scientists at Geisel and in the Science Division have found critical overlaps and amplified their research impact, which is a key path to success in an institution built of smaller individual communities,” adds Jane Lipson, associate dean for the sciences. “Their discoveries, and the researchers now aimed at continuing the forward progress, are a testament to Gordon’s work with Michael Sporn, and also to his ongoing energy and vision.”
If Sporn could see his successors now, he would no doubt be pleased. “He was always so enthusiastic about our project and had a deep desire to find a cure for cancer and other diseases,” says Gribble.
In addition to helping Gribble with his projects, Jaycox and Wright returned to unfinished business from their student days, which includes work on compounds that structurally resemble ellipticine, found in the bark of evergreen trees. Jaycox contributes to teaching organic chemistry and serves on the safety committee. Wright and senior lecturer Cathy Welder recently authored an article detailing safer solvent solutions that drew national attention.
Like Gribble, they feel overjoyed to be back at the bench.
“I fell in love with chemistry in the third grade and just can’t walk away from it,” says Wright. “I didn’t need to be convinced to come out of retirement. I was eager to get in the lab again.”
To date, Gribble has authored more than 500 scientific articles and books. Ask him about the secret to his productivity, and he shrugs: “You have to love organic chemistry."