The tiny microbe that changed molecular biology forever

Posted: January 10, 2024

If you fell sick in 2020 or early 2021, you might have done a PCR (polymerase chain reaction) test to check if you had COVID-19. A gowned and masked health worker would have collected a sample of your mucus by inserting a long swab into your nose or throat. You might still remember that uncomfortable sensation.

Once collected, the sample would have been sent to a laboratory equipped with a PCR machine and SARS-CoV-2 primers, which are specific segments of DNA that match the genetic material of the coronavirus. If the virus was present in your sample, the PCR reaction would have used these primers to create many small copies of DNA, which serve as indicators of the disease.

The test became a crucial part of the global fight against the pandemic, but its applications go way beyond detecting pathogens in people’s airways. PCR is one of the most important, powerful and widely used techniques in modern biology, allowing scientists to amplify segments of DNA and produce millions or even billions of copies. This process makes it possible to analyze even minute amounts of DNA, and it has completely revolutionized any field in which experts study DNA.

“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,” American biochemist Kary Mullis, the inventor of PCR, wrote in his 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.”

While credit is due to Mullis, scientists who care about DNA also owe some gratitude to a tiny microorganism called Thermus aquaticus.

Thermus aquaticus: Yellowstone’s hidden treasure

In 1983, Mullis was working at Cetus Corporation, one of the first biotechnology companies in the country, located in Emeryville, California, when he came up with a way to pinpoint a particular stretch of DNA and synthesize a large number of copies.

The technique involves a series of temperature changes that separate the two strands of a DNA molecule, allowing each strand to function as a template for making more copies. A major challenge that Mullis faced was that the high temperatures required to separate the DNA strands typically damaged most DNA polymerase enzymes. For instance, human DNA polymerase works best at body temperature (around 98 °F) and cannot withstand the elevated temperatures needed for PCR. To solve this issue, Mullis needed to find a polymerase from a heat-resistant organism.

Seventeen years earlier, American microbiologist Thomas Brock had been studying^[1] microbes in the hot springs, geysers, fumaroles, and thermal basins of Yellowstone National Park to understand how these creatures lived and performed photosynthesis in such harsh environments.

In samples collected from Mushroom Spring in the Lower Geyser Basin of Yellowstone, he discovered a previously unknown microbe^[2] that he named Thermus aquaticus, or “Taq.” Brock kept samples of this heat-loving bacterium and sent some to the American Type Culture Collection (ATCC), a non-profit organization established in the 1920s to serve as a repository for microorganisms that scientists could use for research. Today, ATCC is one of the largest and most diverse collections of biological resources, which includes microorganisms, cell lines, molecular genomics tools, and nucleic acids.

Years after Brock collected his Mushroom Spring microbe samples, Mullis bought one^[3] for $35. Brock’s freeze-dried samples remain at ATCC to this day, and can now be purchased for $418.

How does PCR work?

Legacy of Taq: Science’s gift to humanity

Because Taq thrives in hot springs, its DNA polymerase is uniquely suited to endure the high temperatures used in PCR, making it an ideal enzyme for this process.  As a result, Taq polymerase has had a profound impact, both scientifically and commercially. It has become an essential technique for many applications where only small amounts of DNA are available, such as in forensic investigations or when analyzing ancient samples. It helps identify genetic disorders, detect pathogens like viruses and bacteria, and analyze genetic markers for paternity tests. It is a foundational tool for many advanced molecular biology techniques, including DNA sequencing, gene cloning, understanding genetics and developing new therapies. Whenever scientists work with DNA, they will, at some point, use PCR.

In 1991,^[4] Cetus Corporation sold the rights to Mullis’s Taq polymerase technique to Swiss pharmaceutical giant F. Hoffmann-LaRoche for $300 million. Today, Hoffmann-LaRoche's yearly sales of related licenses and equipment for the process exceed $200 million.

The success of PCR has been so impressive that in 2013 the U.S. National Park Service implemented a benefit-sharing policy^[5]. Under this agreement, researchers must sign a contract before collecting samples from parklands, ensuring that the Park Service will receive a portion of the profits if their findings result in commercial success.

The policy came too late for Yellowstone National Park, and despite Taq's groundbreaking role, the park never received any financial benefit from its discovery.

Mullis did in fact receive the Nobel Prize in Chemistry in 1993. Brock, however, did not profit. Yet, he expressed no regret. In a 2007 Time magazine interview, he said, “Yellowstone didn’t get any money from it. I didn’t get any money either, and I’m not complaining. The Taq culture was provided for public research use, and it has given great benefits to mankind.”

^{[1] Discovering Life in Yellowstone Where Nobody Thought it Could Exist, Yellowstone National Park.
[2] Life at High Temperatures: Evolutionary, ecological, and biochemical significance of organisms living in hot springs is discussed, Science, Nov 1967, Vol 158, Issue 3804
[3] The Gold in Yellowstone’s Microbes, Time, Nov 2007
[4] The Gold in Yellowstone’s Microbes, Time, Nov 2007
[5] National Park Service Benefits Sharing Program}