The Man Who Took LSD and Changed The World

DNA can be extracted from your mouth by gargling salt water, then mixing with soap and rubbing alcohol to get a gooey mass at the top containing DNA, bacteria, and proteins.

At 100 times magnification, you can see coiled up DNA, proteins, and debris clumped together, but it remains essentially useless for reading genetic information.

Even with a million dollar electron microscope, you cannot actually see the genetic code that makes you you.

For the vast majority of human history, reading DNA has been completely impossible and illegible.

In the 1960s at Berkeley, biochemistry student Kary Mullis was more interested in taking LSD than attending classes, and his PhD dissertation was filled with jokes that the committee refused to approve until he removed the 'wacko stuff'.

LSD fueled Mullis's eccentric genius, leading him to write a letter to Nature journal chronicled the entire universe from beginning to end at age 22, which was published.

• After graduating, he worked briefly in a cardiology lab but was horrified by rat killings • He then worked in a bakery where he met Tom White from biotech startup Cetus • White recommended him based on his chemistry skills, including synthesizing hallucinogenic drugs

Mullis was obnoxious, picked fights with receptionists and colleagues, was a womanizer while married, and once threatened to bring a gun to work.

Cetus was founded in 1971 as one of the first biotech companies and wanted to develop commercial DNA tests that hospitals could use to quickly diagnose diseases.

Scientists discovered that bacteria evolved defensive molecules that scan DNA for specific sequences and cut them, leading to the creation of restriction enzymes that work like nanoscopic scissors.

Detecting mutations like sickle cell disease in a sample of six billion letters of DNA was equivalent to reading a license plate on Interstate 5 in the dark from the Moon.

• The Southern Blot technique worked but took days or weeks • Every step was difficult, inefficient, and cumbersome • Technicians had to work with radioactive materials • The method was not commercially feasible

Restriction enzymes cut DNA into pieces of different lengths, and gel electrophoresis separates them by placing the sample in porous material and applying voltage, with shorter pieces navigating faster than longer ones.

• Heat and alkaline solutions break hydrogen bonds between nucleotides, causing DNA to unzip • Unzipped strands can pair with complementary DNA sequences (A pairs with T, G pairs with C) • Scientists synthesize short DNA probes designed to match specific sequences

Synthetic probes are made radioactive and added to the sample; if they pair with target DNA they stick, otherwise they rinse away, leaving radioactivity only where the mutation exists.

The Southern Blot method was so slow and cumbersome that it wasn't commercially feasible, taking days or weeks to complete a single test.

Mullis's job at Cetus was making short radioactive bits of DNA to be used as probes, which was a slow, repetitive, and extremely boring task.

• Mullis was obnoxious and didn't get along with anybody • He picked fights with receptionists, security guards, and colleagues • He was a womanizer and hit on people while married • He once threatened to bring a gun to work

A new machine was introduced that could synthesize DNA snippets in a day, doing a month of Mullis's work automatically, leaving him with free time and access to many DNA snippets to experiment with.

Without much work to do and unpopular at the office, Mullis started taking weekends in Mendocino County to relax at his cabin.

While driving to his cabin on a Friday night in spring 1983, Mullis realized instead of inventing a more powerful telescope to read a single license plate from the Moon, he could create a billion copies of that same license plate.

Mullis experienced vivid visualizations of DNA molecules with blue and pink images of electric molecules, describing his mind as having learned how to get to the LSD state without taking the drug itself.

• Heat DNA to separate strands, then design short DNA primers that pair to both strands • Use DNA polymerase to extend primers, creating identical copies of the double helix • Repeat the cycle: unzip DNA, pair primers, and extend them • Each cycle doubles the DNA copies, creating exponential growth

Mullis later stated: 'What if I had not taken LSD ever? Would I have invented PCR? I don't know. I seriously doubt it.'

Mullis named his discovery the polymerase chain reaction (PCR), a DNA photocopier that could make exponential copies of any DNA segment after just 30 cycles, creating over a billion copies of a specific sequence.

• Monday morning, Mullis pitched his idea as a DNA Xerox machine to Cetus • People started leaving before he finished his presentation • Many were skeptical, thinking such a simple idea must have been tried before • They believed there must be a reason why PCR wasn't already being used

Mullis started his first PCR experiment in September 1983, initially trying to replicate a 400 base pair fragment of human DNA, but switched to a smaller 25 base pair bacterial DNA fragment after months of failure.

By summer 1984, Mullis thought he had proof PCR worked, but colleagues said his work was sloppy with no controls or experimental repetitions, and colleagues stated no one but Kary believed the data.

Tom White argued PCR had potential, so Mullis was given a one year probationary period, but would not work alone. White, Arnheim, and Henry Ehrlich assigned other technicians to develop PCR alongside Mullis.

By spring 1985, after months of painstaking trial and error, the group finally cracked it and had definitive proof that PCR was possible.

• PCR required heating DNA to 95 degrees Celsius to unzip it, then cooling to 30 degrees for primers to pair • DNA polymerase from E. coli bacteria was destroyed at high temperatures • Scientists had to manually add more polymerase every cycle, making it expensive and time consuming • This process needed to repeat 30 times, adding difficulty and inefficiency

The new sickle cell diagnostic method using PCR worked like a charm and could be completed in under 10 hours.

In 1964, microbiologist Tom Brock visited Yellowstone National Park and observed vivid yellow and orange colors in boiling hot springs, suspecting they were bacteria living at extreme temperatures.

Undergraduate student Hudson Freeze collected samples from the springs and after a few days observed small organisms growing in test tubes, which under a microscope revealed worms crawling around.

The organism was named Thermus Aquaticus (hot water), and it revealed that all essential enzymes could adapt to boiling water temperatures, with no applications imagined at the time.

Brock and Hudson published their findings and stored a culture of Taq at the American Type Culture Collection, a database preserving microbial samples for future use.

In spring 1985, 16 years after Taq's discovery, Kary Mullis was looking for a polymerase that could survive high heat and found Thermus Aquaticus in the scientific literature.

The group isolated polymerase from Taq and tested it in PCR; the results were breathtaking, and scientist David Gelfand remarked 'The holy grail had been achieved.'

• Taq polymerase thrived at high temperatures unlike E. coli polymerase • With Taq, primers would virtually only bind to their target region • Background noise was completely erased from results • The process became 'set it and forget it' for 30 cycles

PCR now worked effortlessly, allowing amplification of any piece of DNA no matter how small the sample, fundamentally transforming DNA diagnostics.

Cetus realized they had a golden goose, but competitors like Perkin Elmer and Kodak were catching onto the PCR idea, so they had to go public quickly before losing patent rights.

• The PCR group urged Mullis to publish a solo paper first since PCR was his idea • Mullis procrastinated on writing his paper • The group published their own PCR research article in Science Magazine in December 1985 • Mullis was listed as the fourth author, which made him furious

By the time Mullis had his own paper ready, no reputable journal wanted it. He remarked that Nature and Science rejected his work, claiming the PCR group stole his work.

The group worked to get Mullis proper recognition, and he became the face of PCR after giving a talk at a microbiology symposium in 1986, though it was too late.

Still fueled by anger toward the group, Mullis left Cetus shortly after gaining recognition, and work on PCR continued without him.

• New PCR machines were developed that automated the entire process • These machines became standard equipment in every lab doing DNA work • PCR machines are now ubiquitous in laboratories worldwide

• DNA cloning and vaccine development • Cancer and HIV detection • DNA cloning and vaccines to detecting cancer and HIV saved lives • Forensic analysis and criminal investigations

PCR supercharged forensics by amplifying tiny DNA samples, freeing hundreds of wrongfully convicted people and catching thousands of criminals, allowing families separated by war to reunite.

In 1993, Kary Mullis was awarded both the Japan Prize and the Nobel Prize in Chemistry for inventing the polymerase chain reaction, despite PCR's development depending on many colleagues.

• Mullis made PCR his story and his story only • Colleagues felt he was a 'fame hog' and didn't give credit • He completely rewrote history to portray himself as the sole inventor • Others at Cetus Corp who helped him received no recognition

• He talked about seeing glowing raccoons and being abducted by aliens • He made shocking claims like 'Distrust your fellow man' and 'We're an arrogant little bunch of naked apes' • He wrote a book called 'Dancing Naked in the Mind Field' • He was an expert witness in the OJ Simpson trial

• He didn't believe in global warming or the ozone hole • He denied that HIV caused AIDS, claiming 'HIV is not deadly' and 'There's not something called AIDS' • His AIDS denialism influenced President Thabo Mbeki of South Africa during an epidemic • Over 330,000 people died in South Africa due to denial of treatment under Mbeki's leadership

Kary Mullis passed away in August 2019 at age 74 due to complications from pneumonia, leaving behind a complex legacy.

Despite Mullis's departure from science, the work on PCR continued and evolved into automated machines now found in every DNA laboratory worldwide.

Just a year after Mullis's death, PCR reached perhaps its most significant use yet when PCR COVID tests helped keep billions of people safe throughout the pandemic.

• Mullis discovered PCR partly because his job was taken over by a machine, forcing him to think bigger and more creatively • Automation might open minds to breakthroughs and discoveries that change the world • The takeaway is that automation, though scary, could lead to major innovations like it did for Mullis