What Kary Mullis says about PCR testing – some take away lessons for #COVID19
Kary Banks Mullis (December 28, 1944 – August 7, 2019) was an American biochemist. In recognition of his invention of the polymerase chain reaction (PCR) technique, he shared the 1993 Nobel Prize in Chemistry with Michael Smith and was awarded the Japan Prize in the same year. His invention became a central technique in biochemistry and molecular biology, described by The New York Times as “highly original and significant, virtually dividing biology into the two epochs of before PCR and after PCR.”
After receiving his doctorate, Mullis briefly left science to write fiction before accepting the University of Kansas fellowship. During his postdoctoral work, he managed a bakery for two years. Mullis returned to science at the encouragement of friend Thomas White, who later helped Mullis land a position with the biotechnology company Cetus Corporation of Emeryville, California. Mullis worked as a DNA chemist at Cetus for seven years; it was there, in 1983, that Mullis invented the polymerase chain reaction. After leaving Cetus in 1986, Mullis served as director of molecular biology for Xytronyx, Inc. in San Diego for two years. While inventing a UV-sensitive ink at Xytronyx, he became skeptical of the existence of the ozone hole.
Mullis served as a consultant for multiple corporations on nucleic acid chemistry. While writing a National Institutes of Health grant progress report on the development of a human immunodeficiency virus (HIV) test for Specialty Labs, he became skeptical that HIV was the cause of acquired immunodeficiency syndrome (AIDS). In 1992, Mullis founded a business to sell pieces of jewelry containing the amplified DNA of deceased famous people such as Elvis Presley and Marilyn Monroe. Also in 1992 he founded Atomic Tags, in La Jolla, California. Atomic Tags sought to develop technology using atomic-force microscopy and bar-coded antibodies tagged with heavy metals to create highly multiplexed, parallel immunoassays.
Mullis was a member of the USA Science and Engineering Festival‘s Advisory Board. In 2014, he was named a distinguished researcher at the Children’s Hospital Oakland Research Institute in Oakland, California.
In 1983, Mullis was working for Cetus Corporation as a chemist. Late one night while driving with his girlfriend, who was also a chemist at Cetus, he had the idea to use a pair of primers to bracket the desired DNA sequence and to copy it using DNA polymerase; a technique that would allow rapid amplification of a small stretch of DNA and become a standard procedure in molecular biology laboratories. Cetus took Mullis off his usual projects to concentrate on PCR full-time. Mullis succeeded in demonstrating PCR December 16, 1983. In his Nobel Prize lecture, he remarked that the success did not make up for his girlfriend breaking up with him. “I was sagging as I walked out to my little silver Honda Civic. Neither [assistant] Fred, empty Beck’s bottles, nor the sweet smell of the dawn of the age of PCR could replace Jenny. I was lonesome.” He received a $10,000 bonus from Cetus for the invention.
Other Cetus scientists, including Randall Saiki and Henry Erlich, were placed on PCR projects to work on determining if PCR could amplify a specific human gene (betaglobin) from genomic DNA. Saiki generated the needed data and Erlich authored the first paper to include utilization of the technique, while Mullis was still working on a paper that would describe PCR itself. Mullis’ 1985 paper with R. K. Saiki and H. A. Erlich, “Enzymatic Amplification of β-globin Genomic Sequences and Restriction Site Analysis for Diagnosis of Sickle Cell Anemia”—the polymerase chain reaction invention (PCR) — was honored by a Citation for Chemical Breakthrough Award from the Division of History of Chemistry of the American Chemical Society in 2017.
A drawback of the technique was that the DNA polymerase in the reaction was destroyed by the high heat used at the start of each replication cycle and had to be replaced. In 1986, Saiki started to use Thermophilus aquaticus (Taq) DNA polymerase to amplify segments of DNA. The Taq polymerase was heat resistant and only need to be added to the reaction once, making the technique dramatically more affordable and subject to automation. This modification of Mullis’ invention revolutionized biochemistry, molecular biology, genetics, medicine, and forensics.
Mullis also invented a UV-sensitive plastic that changes color in response to light.
He founded Altermune LLC in 2011 to pursue new ideas on the immune system. Mullis described the company’s novel technology in a presentation:
It is a method using specific synthetic chemical linkers to divert an immune response from its nominal target to something completely different which you would right now like to be temporarily immune to. Let’s say you just got exposed to a new strain of the flu. You’re already immune to alpha-1,3-galactosyl-galactose bonds. All humans are. Why not divert a fraction of those antibodies to the influenza strain you just picked up? A chemical linker synthesized with an alpha-1,3-gal-gal bond on one end and a DNA aptamer devised to bind specifically to the strain of influenza you have on the other end will link anti-alpha-Gal antibodies to the influenza virus and presto!–you have fooled your immune system into attacking the new virus.
The first proof-of-principle of this technology, re-targeting pre-existing antibodies to the surface of a pathogenic strep bacteria using an alpha-gal modified aptamer (“alphamer”), was published in 2015 in collaboration with scientists at the University of California, San Diego.