Biochemist Kary Mullis says he was driving from the Bay Area to his cabin in Mendocino in 1983 when suddenly, like a bolt of lightning out of the California sky, he came up with a way to pinpoint a particular stretch of DNA and synthesize an enormous amount of copies.
“The simple technique would make as many copies as I wanted of any DNA sequence I chose, and everybody on Earth who cared about DNA would want to use it,” Mullis recounts in his colorfully titled 1998 memoir Dancing Naked in the Mind Field. “It would spread into every biology lab in the world. I would be famous. I would get the Nobel Prize.
Before PCR, studying DNA was tough. Lots of genetic information is packed into DNA molecules and isolating exactly the right small snippet to study was tricky. Even if a scientist could isolate a section of interest, the amount of material was often so minuscule that there just wasn’t much available for experiments.
To get around this, the state-of-the-art in the 1980s was DNA cloning. In this process, scientists put their desired genetic sequence into the genomes of bacteria, which then divided and replicated both themselves and the introduced genetic code. It’s a powerful but laborious process, which is why something simpler and faster would be such a windfall.
After that fateful weekend in his cabin, Mullis returned to work at Cetus Corporation in Emeryville, California. Cetus was one of the first biotechnology companies in the world, and the culture at the time was closer to what you might find today at a tech startup in Silicon Valley. There, various teams were playing with exciting new tools to clone genes and express proteins that could be used for medical applications.
Mullis’ main job at Cetus was to make little strips of genetic material for other scientists in the company to use in their experiments. While his bombastic personality led to personal conflicts with his colleagues, including fisticuffs on one occasion, his work was useful to Cetus.
It was “an unusual group of young scientists, and they tolerated Kary,” says Paul Rabinow, an anthropologist at the University of California, Berkeley, and author of Making PCR, A Story of Biotechnology.
In Rabinow’s telling, Mullis brought the PCR idea to his colleagues. The process was elegant and simple: Heat a DNA molecule to separate the double helix into two strands, and use each strand as a template for making a copy—much like how DNA unspools and copies itself inside our cells. Then you let the sample cool; this would normally cause the two DNA strands to click back into place, but you can hijack the process with lots of short stretches of DNA called primers—just the type of genetic fragments Mullis was working with for other projects.
If you start with just one piece of DNA, you’ll have two copies of your target sequence after one PCR cycle. Each copy can again be unwound to make more templates. After just 30 cycles, you’ll have over a billion copies—all from one molecule of DNA.
Mullis was known for his eccentric ideas, many of which had basic biology mistakes according to his colleagues, so people initially either didn’t think it would work or didn’t care. But Mullis kept tinkering with the idea, and the following year he was able to bring them some experimental data that seemed to show the chain reaction was working. This caught the attention of several Cetus colleagues, especially biochemist Thomas White.
White had had a soft spot for Mullis ever since they’d became close friends in graduate school at UC Berkeley. Mullis helped White rebuild his car engine and ordained White as a Universal Life minister. White returned the favor by presiding over Mullis’s wedding to his second wife. White had recruited Mullis to work at Cetus and ended up being his boss, helping diffuse tensions when Mullis’s ego would grate on coworkers.
White asked Mullis to focus exclusively on getting PCR to work. By the end of 1984, White and other company leaders still didn’t think he had enough evidence, so the company kept adding experimental scientists to parallel his efforts. The skilled work of many colleagues—in particular Stephen Scharf, Fred Faloona, and Randall Saiki—finally yielded enough replicable data to declare PCR a success.
Since then, PCR usage has multiplied exponentially, with numerous adaptations for various applications. Medical diagnosis, forensics, food safety, crop development, even the search for the origin of humanity—the boundaries of all these fields and more were busted wide open with the power of PCR.
“There is just no way the Human Genome Project could have been successful without PCR,” says Green, who is now the head of the National Human Genome Research Institute.
And of course, many of the COVID-19 tests being conducted today use PCR to amplify bits of the genetic code of the SARS-CoV-2 virus from swabbed samples, allowing the tests to detect its presence.
Today it’s clear that, despite their contentious relationships, Mullis and his colleagues made an amazing contribution to science—one that will likely inspire generations of researchers for decades to come.
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Wouldn't it be a good idea to create a course?
