The dirty dance of a fruitful lab investigation often goes this way: One step back, two steps forward.
Numerous scientific leaps, in fact, looked for a time like basic blunders or even full flops.
Linus Pauling’s DNA model contained the wrong number of strands. Albert Einstein’s equations on general relativity weren’t quite airtight. And the elusive hunt for an HIV vaccine still spurs one of the effort’s leaders, Fred Hutchinson Cancer Research Center’s Dr. Jim Kublin, to repeat a famous quote on scientific perseverance:
“We are like sailors who have to rebuild their ship on the open sea without ever being able to dismantle it in dry dock and reconstruct it from the best components.” — Otto Neurath, social scientist
Kublin, executive director of the Hutch-based HIV Vaccine Trials Network, said recent findings about the gut microbiome — which are offering HIV vaccine researchers several new directions — grew from past setbacks in the lab.
“Most of our experience in the HVTN is really encountering negative results when trying to develop an HIV vaccine,” Kublin said. “But those negative results are certainly ripe with a lot of opportunities for discovery.”
One stinging example: In 2007, a major trial was halted when HVTN researchers found that a potential vaccine neither prevented HIV infection nor reduced the amount of virus in the blood among vaccine recipients who became infected. The vaccine also made some recipients more susceptible to the virus.
That news brought tears to Kublin. He had moved to sub-Saharan Africa with his family in 1998 to run a research program. In Malawi, he saw entire villages ravaged by HIV. Kublin used expired U.S. drugs to treat the ill. His son, Gus, befriended many touched by the epidemic.
The night of the 2007 trial halt, Gus, then 9, told his dad: “But you’re not going to give up, are you? It’s too important.” The next day, Kublin relayed Gus’ plea to his team. “We needed to hear that,” recalled Niles Eaton, HVTN director of site operations.
“Gus saw me in distress and wanted to see me get back on the horse,” Kublin said. “He valued and values the work we do here because it’s addressing something that’s affected him personally.”
Eight years later, researchers at Duke University suggested for the first time that a healthy gut microbiome may interfere with an HIV vaccine. That study, published July 30 in Science, gives scientists new paths to follow to perhaps develop a working HIV vaccine. Kublin was not an author of the microbiome study. But he said those findings are a byproduct of the HVTN’s progress — work once inspired by a failed trial that made him cry.
Like many scientists, Kublin draws a sharp distinction between “negative results” and failed research that’s doomed by human errors like lab contaminations or blinded studies that are compromised by poor designs.
“Some mistakes, we shouldn’t embrace — the mistakes done because somebody is being sloppy or not thoughtful enough,” said Dr. Mario Livio, an astrophysicist and author of a book exploring scientific boons that emerged from initially flawed hypotheses.
In addition to the missteps made by Pauling and Einstein, Livio’s book outlines the “brilliant blunders” of Fred Hoyle on the cosmos as well as lapses by luminaries like Charles Darwin and Lord Kelvin.
Darwin created the first scientific theory of evolution, recognizing that certain variations in species made those creatures better suited to thrive in their environments — and that those traits could be passed to their offspring. His core concept, natural selection, was a game changer. But Darwin also tried and failed to explain the genetics at play. He adopted a later-disproven hypothesis — “pangenesis” — asserting that a reproductive cell contains gemmules (invisible germs) obtained from individual cells all over the organism and that these gemmules carried hereditary attributes.
“Darwin used a completely wrong theory of genetics,” Livio said. “He’s not to blame for that, no better theory was known at his time. But he didn’t realize that with that theory natural selection would never have worked.”
Another science giant, William Thomson, Lord Kelvin, used physics to calculate, for the first time, the ages of the sun and Earth. Unfortunately, his estimates were off — he pegged the two bodies as being about 50 times younger than scientists now calculate. But Kelvin’s findings are still considered historic.
“All of these mistakes eventually developed or led to real breakthroughs,” Livio said. “Failures are really part and parcel of scientific progress. They are really inevitable and, in some sense, even essential.”
“This is the best part of science,” agreed Hutch Deputy Director and Executive Vice President Dr. Fred Appelbaum. “For basic science, you set up these experiments and, yes, the world doesn’t work necessarily the way you thought it worked. And finding that out is wonderful.”
Appelbaum was centrally involved in a temporary setback that, soon, propelled cancer treatment forward. In his lab, he and Fred Hutch colleague Dr. Irv Bernstein sought to develop a more efficient way to deliver radiation to leukemia patients to prepare their bodies for bone marrow transplants.
Their idea was to intravenously deliver monoclonal antibodies (small proteins) coupled with radioisotopes into the body where they’d seek out and hook onto leukemic cells. The radioactive molecules would then directly emit their cancer-killing energy, sparing the rest of the body from radiation toxicity.
The experiment had worked in models in the lab. Then, Appelbaum and Bernstein tried the procedure in their first human patient who had a case of relapsed leukemia and was being prepared for a bone marrow transplant.
“We were all, literally, at the patient’s side while the patient was under the gamma camera so we could see images of where the monoclonal antibody was going. Just as we’d hoped, it went right to the bone marrow and the lymph nodes. We were ecstatic. We thought: This is a home run; this is going to be spectacular,” Appelbaum said.
The key to success, however: The antibody would need to stay on that spot for a few days to properly irradiate the disease. But the next morning, when the team took a picture of the patient, they saw no isotope left in the bone marrow.
“It was all gone. Empty. We were so bitterly disappointed,” Appelbaum said. “So it was a real failure. “
Back in the lab, the team began dissecting what had happened. They realized that when the antibody attached to the leukemic cell, it was rapidly taken into the cell where enzymes cleaved off the radioactive material then spit it out, Appelbaum said.
That fueled a brainstorm: Instead of a radioisotope, researchers could try attaching a potent toxin that would kill the cancer cell after it was ingested. New experiments worked. They led to the development of a chemotherapy drug that remains in use in Japan and Europe. Meanwhile, a Seattle biotechnology company is working on a version of another drug based on the same principle, Appelbaum said.
Researchers must, by nature, accept some setbacks — and have the innate ability to interrogate their errors. But, in a culture that tends to fear failure, could that resilient mindset benefit non-scientists, too?
That may depend on your job.
"I do think failure can benefit many other professions, but (and it is a big but) you have to construct the experiments in ways that protect people from being injured (physically, financially, emotionally), and you hopefully have the opportunity to learn the reasons for failure," Appelbaum wrote in an email. "It's OK to fail when you build a bridge, as long as it is a model and not the real thing."
“This is critical for all types of creative thinking,” Livio added. “We want people to think in unconventional ways. And we have to accept the fact that when they do that, occasionally, they will make a blunder.”
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Bill Briggs is a former Fred Hutch News Service staff writer. Follow him at @writerdude. Previously, he was a contributing writer for NBCNews.com and TODAY.com, covering breaking news, health and the military. Prior, he was a staff writer for The Denver Post, part of the newspaper's team that earned the Pulitzer Prize for coverage of the Columbine High School massacre. He has authored two books, including "The Third Miracle: an Ordinary Man, a medical Mystery, and a Trial of Faith."