It may be surprising to learn that the credited inventor of the most important workhorse in molecular biology—the polymerase chain reaction or PCR—once claimed he had seen a talking fluorescent raccoon near his cabin, which may or may not have been an alien. He also disagreed with the science on climate change, believed in astrology, and thought HIV was not the cause of AIDS; rather, he hypothesized that AIDS resulted from an overwhelming accumulation of distinct microorganisms that could be harmless on their own.
That this man, Kary Mullis, shared a Nobel Prize for PCR may boggle the mind. How can someone so ingenious be so… unscientific? But Mullis is not alone. Luc Montagnier, who won the Nobel Prize for discovering HIV, became obsessed with homeopathy and the alleged memory of water. Famously, double Nobel winner Linus Pauling developed more and more unconventional ideas as he got older and believed that every disease could be cured by massive doses of vitamin C. This mental slippage of otherwise brilliant scientists even has a name: Nobel disease.
Kary Mullis died on August 7, 2019. In his autobiography published by the Nobel Prize website, he writes that “being a Nobel laureate is a license to be an expert in lots of things as long as you do your homework.” When everyone treats you like intellectual royalty, however, it becomes easier to pass off mere opinions as due diligence. But by brushing aside his controversial positions (as well as the fluorescent raccoon), we can focus on the exquisite beauty and game-changing nature of PCR. “Game-changing” is beloved by the media and certainly overused, but it does apply here.
PCR changed the DNA game. And like many inventions that stand the test of time, it was elegant.
Drowning out a book to focus on a single page
Imagine a book. An old one printed on paper, you remember those? Let’s say Fifty Shades of Grey, the Twilight fan fiction turned worldwide phenomenon. I tear the covers off and pluck each page from its spine (possibly a fantasy of mine). I hand you all the pages and tell you to find the one typo. OK, given that it’s Fifty Shades of Grey, there are quite a few of them, but imagine there’s only one and you don’t know where it is. To find this typo, you’ll probably have to read the dreadful book and subject yourself to ghastly dialogue. It will take time and patience.
But what if instead I took the page that contained the typo and photocopied it one billion times. I then handed you the original pages mixed in with the one billion copies of the one page you needed. You would find the typo much faster.
This is what PCR did to the study of DNA: “photocopying” the bit that mattered so much that it would drown out the rest, making the typo stand out.
You may remember extracting DNA from strawberries and seeing this white, snot-like spaghetti at the end. And that is mostly how DNA was thought of before the invention of PCR. When Kary Mullis went to Berkeley, he attended a seminar that reminded him that DNA wasn’t just a long spaghetti noodle. It was made up of individual building blocks, so-called bases (A, T, C, G), and he decided he wanted to make DNA blocks in the lab. He was hired by a company, Cetus, in 1979, and they bought a machine to assemble these bases together in a pre-determined order. (Fun fact: the first such machine was developed at McGill.) These short segments of DNA bases are known as oligonucleotides. You can think of them as putting a few letters together in the right order to make a short phrase.
Going back to Fifty Shades of Grey, if you search an electronic version of the book for “my subconscious”, you will find many, many matches throughout the book. But what if you could find a unique match each time?
And so it was that on a fateful Friday night, on a drive from Berkeley to Kary Mullis’ cabin in the woods, he had the idea to use two oligonucleotides to frame the region of interest, one before it, one after it. Thus you would only “photocopy” what’s between these two oligonucleotides, like photocopying a single page out of a book.
It may seem like a perfectly obvious solution, but that’s only because my analogy oversimplifies the nature of the problem. Our DNA, though it only contains 4 “letters”, is much more complex than Fifty Shades of Grey. In real life, molecular biologists had to deal with two complementary strands of DNA, with bases that were radioactively labelled and others that weren’t, and with an enzyme that was rendered useless by the high temperatures required for the procedure. So the idea of bracketing a region of interest with bits of DNA and elongating them to create new DNA was not as evident as it is now. But that’s what elegance is: when you see it, you wonder why no one thought of it before.
When I did my first PCR in 2003, the technique had become a simple recipe. Mix the right ingredients in a tube in the right amounts, add your DNA of interest, put in an expensive oven for an hour or so, and voilà. You have now synthesized new DNA. You have photocopied a single page one billion times. PCR is used in hospital laboratories to test for mutations in an effort to diagnose patients and help choose the best treatment. PCR is used in crime labs to help identify perpetrators. And PCR is used extensively in research centres to help us understand the genomes of living organisms and to devise new diagnostic tests and new molecular interventions.
The myth of the genius scientist
There are many more interesting tidbits to be found in Kary Mullis’ life, like his love of LSD and his claim that he chatted with the “non-substantial form” of his recently deceased grandfather one day over beers (Mullis had to drink his granddad’s beer, as the latter’s ghostly form did not take kindly to liquids). The two stories may be tied in some way, it’s hard to tell.
In the minds of many, Mullis was the quintessential genius scientist: eccentric, boundary pushing, and highly gifted. This persistent trope is unfortunate because most scientific advances these days are being done by groups of people. Collaborations and interdisciplinary groups are becoming the norm. The heads of labs are surrounded by staff, post-doctoral fellows, and students who all collectively attempt to reduce the degree of our ignorance.
Twelve years before Mullis invented PCR, a paper was published by Dr. Gobind Khorana’s team that essentially laid the foundation for PCR. Indeed, scientific innovations are not plucked from the void; they are built on the foundation of predecessors. After all, even Fifty Shades of Grey wouldn’t exist without Twilight.
Take-home message:
• Kary Mullis died on August 7, 2019. He shared the 1993 Nobel Prize in Chemistry for the discovery of the polymerase chain reaction, which revolutionized molecular biology
• The polymerase chain reaction allows to make more copies of a specific region of the DNA molecule just like you would make one billion photocopies of a page in a book in order to more quickly spot a typo it contained
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