Kary Mullis

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[4] 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."[5]

Kary Mullis
Mullis in 2006
Born
Kary Banks Mullis

(1944-12-28)December 28, 1944
Lenoir, North Carolina, U.S.
DiedAugust 7, 2019(2019-08-07) (aged 74)
Newport Beach, California, U.S.[1][2]
NationalityAmerican
Alma materGeorgia Institute of Technology (BS, 1966)
University of California, Berkeley (PhD, 1973)
Known forInvention of polymerase chain reaction
AwardsWilliam Allan Award (1990)
Robert Koch Prize (1992)
Nobel Prize in Chemistry (1993)
Japan Prize (1993)[3]
Scientific career
FieldsMolecular biology
ThesisSchizokinen: structure and synthetic work (1973)
Doctoral advisorJ. B. Neilands

Early life

Mullis was born in Lenoir, North Carolina, near the Blue Ridge Mountains,[6] on December 28, 1944. His family had a background in farming in this rural area. As a child, Mullis said, he was interested in observing organisms in the countryside.[7] He grew up in Columbia, South Carolina,[7] where he attended Dreher High School,[8] graduating in the class of 1962. His interest in chemistry started when he learned how to chemically synthesize and build solid fuel propulsion rockets as a high school student during the 1950s.[9]

He earned a B.S. in chemistry[6] from the Georgia Institute of Technology in Atlanta in 1966, during which time he married his first wife and started a business.[10] He earned his Ph.D. in 1973 in biochemistry at the University of California, Berkeley, in J. B. Neilands' laboratory, which focused on synthesis and structure of bacterial iron transporter molecules.[11] Although he published a sole-author paper in Nature in the field of astrophysics in 1968, he struggled to pass his oral exams (with a colleague recalling that "he didn’t know general biochemistry"), and his dissertation was only accepted after several friends pitched in to "cut all the whacko stuff out of it" while his advisor lobbied the committee to reconsider its initial decision.[12][13]

Following his graduation, Mullis completed postdoctoral fellowships in pediatric cardiology at the University of Kansas Medical Center (1973-1977) and pharmaceutical chemistry at the University of California, San Francisco (1977-1979).[14]

Career

After receiving his doctorate, Mullis briefly left science to write fiction before accepting the University of Kansas fellowship.[10] During his postdoctoral work, he managed a bakery for two years.[5] Mullis returned to science at the encouragement of Berkeley friend and colleague Thomas White, who secured Mullis' UCSF position and later helped Mullis land a position with the biotechnology company Cetus Corporation of Emeryville, California.[7][5] Despite little experience in molecular biology, Mullis worked as a DNA chemist at Cetus for seven years, ultimately serving as head of the DNA synthesis lab under White, then the firm's director of molecular and biological research; it was there, in 1983, that Mullis invented the polymerase chain reaction.[15]

Mullis acquired a reputation for erratic behavior at Cetus, once threatening to bring a gun to work; he also engaged in "frequent lovers' quarrels" with his then-girlfriend (a fellow chemist at the company) and "nearly came to blows with another scientist" at a staff party.[16] According to White, "It definitely put me in a tough spot. His behavior was so outrageous that the other scientists thought that the only reason I didn't fire him outright was that he was a friend of mine."[17]

After resigning from 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.

Thereafter, Mullis worked intermittently as a consultant for multiple corporations and institutions on nucleic acid chemistry and as an expert witness specializing in DNA profiling.[14][5] 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).[18] 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.[19][20] That year, he also founded Atomic Tags in La Jolla, California. The venture 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.[21] In 2014, he was named a distinguished researcher at the Children's Hospital Oakland Research Institute in Oakland, California.[22]

PCR and other inventions
Main articles: Taq Polymerase and History of polymerase chain reaction

In 1983, Mullis was working for Cetus Corporation as a chemist.[10] While driving in the vicinity of his country home in Mendocino County with his girlfriend, who also was 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.[10] Longtime professional benefactor and supervisor Thomas White reassigned Mullis from his usual projects to concentrate on PCR full-time after the technique was met with skepticism by their colleagues.[10][23] Mullis succeeded in demonstrating PCR on December 16, 1983, but the staff remained circumspect as he continued to produce ambiguous results amid alleged methodological problems, including a perceived lack of "appropriate controls and repetition."[10][24] In his Nobel Prize lecture, he remarked that the December 16 breakthrough 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."[10]

Other Cetus scientists who were regarded as "top-notch experimentalists",[25] including Randall Saiki, Henry Erlich, and Norman Arnheim, were placed on parallel 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,[5] while Mullis was still working on the paper that would describe PCR itself.[10] Mullis' 1985 paper with Saiki and 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.[26][27]

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 needed 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. According to University of California, Berkeley biologist David Bilder, "PCR revolutionized everything. It really superpowered molecular biology—which then transformed other fields, even distant ones like ecology and evolution. … It’s impossible to overstate PCR’s impact. The ability to generate as much DNA of a specific sequence as you want, starting from a few simple chemicals and some temperature changes—it’s just magical."[28] Although he received a $10,000 bonus from Cetus for the invention, the company's later sale of the patent to Roche Molecular Systems for $300 million would lead Mullis to condemn White and members of the parallel team as "vultures."[10][29]

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.[30] 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.[6][31]

In a TED Talk, Mullis describes how the US Government paid $500,000 for Mullis to use this new technology against Anthrax, which worked. The treatment was 100% effective, compared to the previous Anthrax treatment which was 40% effective. [31]

Another 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.[32][33] Mullis was inspired to fight this particular strep bacteria because it had killed his friend.[31]

Accreditation of the PCR technique

A concept similar to that of PCR had been described before Mullis' work. Nobel laureate H. Gobind Khorana and Kjell Kleppe, a Norwegian scientist, authored a paper 17 years earlier describing a process they termed "repair replication" in the Journal of Molecular Biology.[34] Using repair replication, Kleppe duplicated and then quadrupled a small synthetic molecule with the help of two primers and DNA polymerase. The method developed by Mullis used repeated thermal cycling, which allowed the rapid and exponential amplification of large quantities of any desired DNA sequence from an extremely complex template. Later a heat-stable DNA polymerase was incorporated into the process.

His co-workers at Cetus, who were embittered by his abrupt departure from the company,[10] contested that Mullis was solely responsible for the idea of using Taq polymerase in PCR. However, other scientists have written that the "full potential [of PCR] was not realized" until Mullis' work in 1983,[35] and that Mullis' colleagues failed to see the potential of the technique when he presented it to them.[19] As a result, some controversy surrounds the balance of credit that should be given to Mullis versus the team at Cetus.[5] In practice, credit has accrued to both the inventor and the company (although not its individual workers) in the form of a Nobel Prize and a $10,000 Cetus bonus for Mullis and $300 million for Cetus when the company sold the patent to Roche Molecular Systems. After DuPont lost out to Roche on that sale, the company unsuccessfully disputed Mullis' patent on the alleged grounds that PCR had been previously described in 1971.[10] Mullis and Erlich took Cetus' side in the case, and Khorana refused to testify for DuPont; the jury upheld Mullis' patent in 1991.[10] However, in February 1999, the patent of Hoffman-La Roche (United States Patent No. 4,889,818) was found by the courts to be unenforceable, after Dr. Thomas Kunkel testified in the case Hoffman-La Roche v. Promega Corporation[36] on behalf of the defendants (Promega Corporation) that "prior art" (i.e. articles on the subject of Taq polymerase published by other groups prior to the work of Gelfand and Stoffel, and their patent application regarding the purification of Taq polymerase) existed, in the form of two articles, published by Alice Chien et al. in 1976,[37] and A. S. Kaledin et al. in 1980.[38]

The anthropologist Paul Rabinow wrote a book on the history of the PCR method in 1996 (titled Making PCR) in which he discussed whether Mullis "invented" PCR or "merely" came up with the concept of it. Rabinow, a Foucault scholar interested in issues of the production of knowledge, used the topic to argue against the idea that scientific discovery is the product of individual work, writing, "Committees and science journalists like the idea of associating a unique idea with a unique person, the lone genius. PCR is thought by some to be an example of teamwork, but by others as the genius of one who was smart enough to put things together which were present to all, but overlooked. For Mullis, the light bulb went off, but for others it did not. This is consistent with the idea, that the prepared (educated) mind who is careful to observe and not overlook, is what separates the genius scientist from his many also smart scientists. The proof is in the fact that the person who has the light bulb go off never forgets the "Ah!" experience, while the others never had this photochemical reaction go off in their brains."[39]

Contrarian scientific views and HIV/AIDS denial

Mullis was quoted saying "the never-ending quest for more grants and staying with established dogmas" has hurt science.[10] He believed that "science is being practiced by people who are dependent on being paid for what they are going to find out," not for what they actually produce.[10] Mullis was described by some as a "diligent and avid researcher" who finds routine laboratory work boring and instead thinks about his research while driving and surfing. He came up with the idea of the polymerase chain reaction while driving along a highway.[40]

A New York Times article listed Mullis as one of several scientists who, after success in their area of research, go on to make unfounded, sometimes bizarre statements in other areas.[41] In his 1998 humorous autobiography proclaiming his maverick viewpoint, Mullis expressed disagreement with the scientific evidence supporting climate change and ozone depletion, the evidence that HIV causes AIDS, and asserted his belief in astrology.[18][42] Mullis claimed climate change and HIV/AIDS theories were promulgated as a form of racketeering by environmentalists, government agencies, and scientists attempting to preserve their careers and earn money, rather than scientific evidence.[18] The medical and scientific consensus considers these hypotheses as pseudoscience , HIV having been conclusively proven to be the cause of AIDS[43][44] and global warming strongly shown to be caused by human activities.[45][46][47]

Mullis wrote that he began to question the AIDS consensus while writing a NIH grant progress report and being unable to find a peer-reviewed reference that HIV was the cause of AIDS.[18][48] He published an alternative theory of AIDS in 1994,[49] and questioned the scientific validity of the link between HIV and AIDS, leading some to label him an "AIDS denialist."[50][51] Mullis has been criticized for his association with HIV skeptic Peter Duesberg,[52] claiming that AIDS is an arbitrary diagnosis used when HIV antibodies are found in a patient's blood.[53] In 2006, Mullis wrote the foreword to the book What If Everything You Thought You Knew About AIDS Was Wrong? by Christine Maggiore,[48] an HIV-positive AIDS denialist whose 3-year-old daughter died of AIDS-related pneumonia in 2005, and herself died of an AIDS-related illness in 2008.[54] According to journalist Coby McDonald, Mullis' HIV skepticism influenced Thabo Mbeki's denialist policymaking throughout his tenure as president of South Africa from 1999 to 2008, contributing to as many as 330,000 unnecessary deaths.[55] An article in the Skeptical Inquirer described Mullis as an "AIDS denialist with scientific credentials [who] has never done any scientific research on HIV or AIDS."[56] However, he consulted for Specialty Labs, in Santa Monica, developing a nucleic acid based HIV test. Seth Kalichman, AIDS researcher and author of Denying AIDS, "[admits] that it seems odd to include a Nobel laureate among the who's who of AIDS pseudoscientists".[57] In 2010, Mullis gave a talk at Google at which he was asked about his controversial views on AIDS and HIV. Mullis said "I'm come to the conclusion... that the thing that causes AIDS is not a species of the retroviridae, it's the whole genus."[58]

Use of hallucinogens

Mullis practiced clandestine chemistry throughout his graduate studies, specializing in the synthesis of LSD; according to White, "I knew he was a good chemist because he'd been synthesizing hallucinogenic drugs at Berkeley."[59] He detailed his experiences synthesizing and testing various psychedelic amphetamines and a difficult trip on DET in his autobiography.[18] In a Q&A interview published in the September 1994 issue of California Monthly, Mullis said, "Back in the 1960s and early 1970s I took plenty of LSD. A lot of people were doing that in Berkeley back then. And I found it to be a mind-opening experience. It was certainly much more important than any courses I ever took."[60] During a symposium held for centenarian Albert Hofmann, Hofmann said Mullis had told him that LSD had "helped him develop the polymerase chain reaction that helps amplify specific DNA sequences".[61]

Personal life

Known for his quick wit and colorful stories, Mullis enjoyed surfing and playing the guitar.[62] He married four times,[10] and had a total of three children by two of his wives. At the time of his death, he had two grandchildren and was survived by his fourth wife, Nancy Cosgrove Mullis.[63] He used profanities to make a point and often said, "Oh, Lord," in response to the absurdities experienced in life.[10] Mullis reported an encounter with a "standard extraterrestrial raccoon" at his cabin in the woods of northern California around midnight one night in 1985; he denied being on psychedelic drugs at the time.[64][18]

Mullis died of pneumonia[1] on August 7, 2019 at age 74 in Newport Beach, California.[2]

Publications and books
  • Mullis, Kary (1968). "Cosmological Significance of Time Reversal". Nature. 218 (5142): 663–664. Bibcode:1968Natur.218..663M. doi:10.1038/218663b0. S2CID 4151884.
  • Mullis, K.F.; Faloona, F.; Scharf, S.; Saiki, R.; Horn, G.; Erlich, H. (1986). "Specific enzymatic amplification of DNA in vitro: The polymerase chain reaction". Cold Spring Harbor Symposia on Quantitative Biology. 51: 263–273. doi:10.1101/sqb.1986.051.01.032. PMID 3472723.
  • K. Mullis, 1990, The unusual origin of the polymerase chain reaction. Scientific American, April 56–65.
  • The Polymerase Chain Reaction, 1994, co-edited Francious Ferre and Richard A. Gibbs (Basel: Birkhauser) ISBN 0817637508 ISBN 978-0817637507.
  • Mullis, Kary B. (1995). "A hypothetical disease of the immune system that may bear some relation to the Acquired Immune Deficiency Syndrome". Genetica. 95 (1–3): 195–197. doi:10.1007/BF01435010. PMID 7744261. S2CID 28158163.
  • Mullis' 1998 humorous autobiography Dancing Naked in the Mind Field (ISBN 978-0679774006), gives his account of the commercial development of PCR, as well as providing insights into his opinions and experiences. In the book, Mullis chronicles his romantic relationships, use of LSD, synthesis and self-testing of novel psychoactive substances, belief in astrology and an encounter with an extraterrestrial in the form of a fluorescent raccoon.

Awards and honors

See also

References
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