Here's what happens when you put your DNA under a microscope. You can extract some from your mouth, just gargle salt water and mix this with soap and rubbing alcohol. You'll get a gooey mass at the top.
This is DNA. Most of it is yours, but some of it actually comes from bacteria living in your mouth. At 100 times magnification, you'll see these strings, which are coiled up DNA, proteins and debris, all clumped together.
But looking at them is pretty much useless. I mean, even with a million dollar electron microscope, you can't actually see the genetic code that makes you you. So how do you read DNA?
DNA. DNA evidence. DNA.
Your family secrets. You are not the father. Diseases you haven't been diagnosed with yet.
Predicting or even diagnosing cancers. The tiny quirks of what makes you you. But for the vast majority of human history, we have not been able to read it.
It is completely illegible. All of this might still be impossible today, if not for one man who took a lot of drugs and stumbled upon a discovery that unlocked DNA forever. Also, he was kind of a jerk.
In the 1960s as a biochemistry student at Berkeley, Kary Mullis wasn't interested in going to his classes. He was too busy taking LSD and lots of it. Mullis didn't take university very seriously.
His PhD dissertation was filled with jokes and the committee refused to approve it until he, quote, cut all the wacko stuff out. But LSD fueled his eccentric genius, sparking all sorts of interesting ideas. It did trickle into his science.
So for example, he wrote a letter to the journal Nature, which chronicled the, quote, entire universe from the beginning to the end, and they published it, which is amazing. He was like 22 years old, they published that. After graduating, Mullis just bummed around for a bit.
First, he gets a job in a cardiology lab, but he's just kind of so horrified at how many rats are being killed. So he starts writing fiction, he gets a job in a bakery. One day he's working in this bakery, and this guy, Tom White, walks in and it turns out Tom White works at this company.
It's a biotech startup called Cetus. They sort of get to talking, and this guy offers Kary Mullis, he offers him a job. White recommended Mullis to his higher-ups, saying "Hire this guy Mullis, he's an excellent synthetic chemist.
I knew he was a good chemist because he'd been synthesizing hallucinogenic drugs at Berkeley. " Cetus was one of the first biotech companies in the world. It was founded in 1971.
An exciting time when scientists were starting to figure out how to manipulate DNA. One of the most important discoveries was actually made that year while researchers at Johns Hopkins were studying the bacteriophage. The phage is a virus that hijacks bacteria by injecting its DNA into the cell.
The bacteria is then forced to create copies of the phage until it explodes. But the researchers realized that some bacteria evolved defenses that make them more resistant to the virus. Their defensive molecules would scan the phage DNA, looking for a specific sequence, and when they found a match, they would cut the DNA, turning it into useless strings.
Scientists called these little scissor molecules restriction enzymes, and different types of restriction enzymes cut DNA at different places and they work on human DNA too. So the researchers extracted the enzymes to essentially create a toolbox of nanoscopic scissors that would allow them to cut DNA at will. Cetus was trying to use biotech like this to develop commercial DNA tests that hospitals could use to quickly diagnose diseases.
But at the time, simple DNA tests like this were impossible. Say you want to detect sickle cell disease. I mean, you could just look at the blood cells under a microscope, but Cetus wanted to prove that they could do it with a genetic test.
And for one of those, you would start off with a sample of DNA. In each of your cells, there are 23 pairs of chromosomes, and if you zoom into the tip of the 11th chromosome, you'll find the beta globin gene. This sequence of adenine, thymine, guanine, and cytosine nucleotides controls the shape of your red blood cells.
And if you inherit a T instead of an A here from both of your parents, well, you're born with sickle cell anemia. But, you can't see any of this under a microscope. So how do you check these single letter mutations against DNA that's over six billion letters long?
Mullis said that this was the equivalent to reading a license plate on interstate five in the dark from the Moon But luckily there was a way to do it. The first step is to separate the beta globin gene from the rest of the DNA. So you can use restriction enzymes on your sample to cut the DNA into little pieces, all of different lengths, and the sickle cell mutation will be on one of these ribbons.
But how does that help? Well, DNA is negatively charged so if you place your cut up sample into a porous material like a gel and apply a voltage across it, the DNA pieces will flow from the negative end to the positive end. But because they're all different lengths, shorter pieces of DNA will navigate the gel pores quicker than longer ones.
This is called gel electrophoresis, and it lets you separate DNA out by length. Its results are consistent enough that after the DNA is spread across the gel, you can see where different length strands end up. Near the start, you'll see DNA strands that are 10,000 base pairs followed by shorter ones, 3000, 1000, and so on.
And because you used specific restriction enzymes, you can predict that the sickle cell mutation was sliced into a 2000 base pair segment. So it's in here. And now that we know where the target DNA is, we can move on to step two, checking whether our sample actually has that mutation or not.
If you soak the sample in an alkaline solution or heat it up to over 90 degrees, the hydrogen bonds between nucleotides will break and the DNA will unzip. Now, the two strands will be able to pair to any other DNA as long as it's a match. As only pair to Ts and Gs only pair to Cs.
You need a complimentary sequence. Scientists could take advantage of this by synthesizing short pieces of DNA in a lab. These are called probes, and they can be designed to have any specific sequence.
So if the sickle cell mutation is CTGTG, you can create a probe that has the complimentary sequence, GACAC, that will stick to it. And because normal DNA is supposed to be CTGAG, your custom probe won't be a good match. Now, the trick is to make these synthetic probes radioactive and add them in.
So after a while, your probes will either pair to the DNA or just keep floating around. And if you wash your sample, any probes that didn't pair will rinse off. So the final step is to check the sample for radioactivity.
You can see that with sickle cell blood, there's a radioactive signal on the right. The probe found the mutation and stuck to it. But in the case of normal blood, there's no signal.
None of the probes paired, so there must be no mutation. There is also this other huge signal in both cases. That's because the probes will match to other parts of the DNA too, not just to the sickle cell region.
This is why you need to separate the mutation out using the gel first. This technique was known as the Southern Blot, and it worked, but there was a problem. It took days or even weeks.
Every step of it is difficult and every step of it, it's like super inefficient. The matching is inefficient. The radio-sensitive paper is really inefficient, and you have these technicians having to work with radioactive stuff.
And it happened in a way that it was so slow and cumbersome that it wasn't commercially feasible in any way. Cetus wanted a DNA test that could be done in a day in a single test tube, and they were close. They developed a method that could test for sickle cell disease in just seven hours.
But this new test suffered from a different problem. The signal was just too faint. You could hardly tell whether the sample had the sickle cell mutation or not because it would barely return any results.
Now, Kary Mullis didn't work on these cutting edge DNA tests. His job was to make those short radioactive bits of DNA that would be used as probes. He wasn't even doing the interesting part.
So he's just making these snippets. That's his job, and it is a slow, repetitive, extremely boring job. So while he's working there, maybe in part because he is bored, he's just obnoxious, he's like a really annoying person.
He doesn't get along with anybody. He picks fights with like receptionists and security guards and his colleagues. He also was a womanizer, so he would be hitting on people all the time, which was at the same time he was also married.
There was one time where he threatened to bring a gun to work. Really like not someone you would wanna work with. But, one day they bring in this new machine into the workplace.
This machine basically could synthesize these snippets all by itself. It's basically doing, you know, a month of his work in like a day. Mullis, he's like, now I both have free time and I have a lot of these little DNA snippets I can sort of play with and figure out like, what can I do with them?
And now he doesn't really have a lot of work to do. And also people don't like him at work. So he basically starts taking weekends in Mendocino County to just relax.
As he was driving up to his cabin on a Friday night in the spring of 1983, Mullis let his mind wander. He thought about that new DNA test and was trying to think of a way to fix it. Then a thought struck him.
What if instead of inventing a more powerful telescope to read a single license plate from the Moon, he just created more of that same license plate. His mind raced. Mullis could see DNA chains floating all around him.
"Blue and pink images of electric molecules injected themselves between the mountain and my eyes. " He wasn't on LSD, but his mind by then had learned how to get there. He could sit on a DNA molecule watching the reactions unwind.
See, the whole DNA sequence around the sickle cell mutation was known. And because Mullis knew one strand, by complementarity, he knew the other as well. So if he heated up the DNA and separated the strands, he could design short bits of DNA that would pair to both strands anywhere on the sequence.
These would be his primers. Then, Mullis could use something called DNA polymerase. It's a special protein that attaches itself to sites like these where primers are paired to the original DNA.
The polymerase basically grabs nucleotides floating around and extends the primer. And the primer is built as a perfect complimentary pair to the strand of DNA it's attached to. This creates an identical copy of the initial double helix.
Polymerase exists in every cell of every living thing. It is what's responsible for replicating DNA during cell division. But it will only ever build out a primer in one direction.
It's kind of like a one-way street. You see each DNA strand starts with a phosphate molecule. This is called the five prime end.
That phosphate is attached to a sugar molecule called deoxyribose, which holds one of the four nucleotides. And deoxyribose also connects to the next phosphate, and so this pattern repeats. But the last deoxyribose molecule doesn't have another phosphate connected to it.
So it ends with an OH group instead. This is the three prime end, our street exit. The three prime end on one DNA strand is always connected to the five prime end on the other.
The second DNA strand always points the other way. And DNA polymerase needs an OH group to attach the next nucleotide. So it always builds on the three prime end.
But that wasn't a limitation, it was an advantage, and Mullis knew exactly how to use it. He could create two primers that would bind to the DNA before the sickle cell mutation, each on a different strand pointing at each other. And if he added polymerase along with some spare nucleotides, it would have to extend both primers toward and over the sickle cell mutation.
This would create two separate DNA segments, both with the mutation. A few miles down the road, he had another eureka. He could just do these three steps again, Unzip the DNA, pair the primers, and use polymerase to extend them.
He now had four DNA sequences with the mutation and he could make that eight and then 16, 32, 64. And he realized that if he repeated this chain reaction 30 times, he would have over a billion copies of that specific DNA segment, all with the sickle cell mutation. He could cover the entire Earth with identical copies of the license plate.
And if he designed different primers, he could change the length of the DNA section that would get replicated. This didn't only work for the sickle cell mutation. As long as you knew the sequence for any part of any DNA, human, plant, bacterial, you could make copies of that exact segment and the copies would grow exponentially, like a nuclear chain reaction.
(upbeat music) Mullis had invented a DNA photocopier. He named it the polymerase chain reaction, or PCR for short. Immediately he stopped the car and scribbled his idea on the back of a gas receipt.
PCR consumed his thoughts for the rest of the weekend. "It was difficult for me to sleep with DNA bombs exploding in my brain. What if I had not taken LSD ever?
Would I have invented PCR? I don't know. I doubt it.
I seriously doubt it. " Monday morning, he bursts into the office at Cetus Corp, and he pitches his idea. He's like, basically, look, hey, I came up with a DNA Xerox machine.
Like, we are working so hard to read this tiny tiny thing. What if we made a billion copies of it? It would be so much easier.
Mullis presented his idea at a company-wide seminar, but people started leaving before he was done. A lot of them are skeptical. They've heard him pitch cockamamie ideas before.
The other thing is that they were like, that's so simple. It had to have been tried before and it can't possibly work. Like, there must be a reason why this is not the way we're doing this.
But Mullis was undeterred. He started his first experiment in September, 1983, trying to replicate a 400 base pair fragment of human DNA. After months of trying, he couldn't get PCR to work.
Human DNA was just too complicated. So he set his sights on a smaller fragment of bacterial DNA, just 25 base pairs. For months, he'd separate the strands, attach the primers, add the polymerase, hoping to amplify that small section of bacterial DNA.
By the summer of 1984, Mullis thought he had it — indisputable proof that PCR worked. But others at Cetus weren't convinced. His work was sloppy.
He didn't have any controls or do repetitions of his experiments. Tom White and Norman Arnheim, another colleague at Cetus said that "No one but Kary believed the data he showed demonstrated what he said it did. " "Any independent scientist looking at the data today would come to the same conclusion.
" Mullis took these comments personally. He constantly argued with his colleagues about these results and even started a fist fight at one point. He was losing credibility fast and everyone wanted him out.
But White argued that PCR had potential, so Mullis was given a one year probationary period to prove that PCR could work, but he wouldn't be doing it alone. White, Arnheim and Henry Ehrlich assigned other technicians to develop PCR along with Mullis. And from there on out, this group of scientists worked overtime to make PCR a reality.
And by spring 1985, after months of painstaking trial and error, the group finally cracked it. They had definitive proof that PCR was possible. With it, their new sickle cell diagnostic method worked like a charm and could be done in under 10 hours.
But PCR was still just a concept with a huge problem. For each cycle, you needed to raise the temperature to 95 degrees Celsius to unzip the DNA, and then lower it to around 30 degrees to allow the primers to pair and the polymerase to extend them. And then you would repeat that cycle, heating back up to 95 degrees.
The problem was that the polymerase would get destroyed when it was heated up. It was extracted from E. coli bacteria and E.
coli can only survive up to around 50 degrees Celsius. So you would have to stand there and manually add in more polymerase every time you cycled the temperature. And that was expensive and time consuming.
You have to do this loop like maybe 30 times for a piece of DNA you're looking at, and every time you gotta stop, you gotta add more polymerase. It was just getting in the way of the vision and of the efficacy. This was like, yeah, it was adding more time.
It was adding more difficulty to the process. But, it turns out a solution had been bubbling away in the background for over 20 years. In 1964, a microbiologist named Tom Brock was visiting Yellowstone National Park.
He'd never been before, but when he got to the boiling hot springs, immediately the vivid hues of the yellow and orange water caught his eye. Are these colors bacteria? Nobody thought that something could live at higher than 60 degrees Celsius.
But this professor Thomas Brock, this microbiologist, he was like, no, no, no, no, no. I think not only can things live at that temperature, I think things can live above 100 degrees Celsius. I think things can live in boiling water.
Brock set up a lab next to one of the springs and asked his undergraduate student, Hudson Freeze, to tag along. I mean, I wasn't even old enough to drink. So, we would go to the spring and collect the samples there, and then bring them back to the laboratory for the analysis.
So every day, oh, over about three or four days, I would go in and I would pick up this tube. So, a standard looking test tube. And I would go like that, and I'd flick it just to see if there was anything growing in there.
Didn't see anything. You know, this is never gonna work. Third day, nothing, fourth day, ooh, look at this.
There's a little something on the bottom. So I picked up the tube and shook it. And this time there was this this stuff that was going (whistles) like this.
And I, well, that's interesting. So I got a little pipette out, took a little drop, put it under a microscope. I still get goosebumps, man, I'll tell you.
I still get goosebumps. I looked at it, and here are all these worms just crawling around. I thought, my god, I'm the first person to the world that ever sees this.
There was a graduate student in the lab. And so this graduate student said, well, I think we ought to call it 'Hudsoniae Freeziensis'. I mean, you do have a great name.
And Tom said, no, no, you can't name it after a person, we're gonna call it Thermus Aquaticus. And the graduate student and I both looked at each other - hot water? Man, that's not very creative.
So it meant that if an organism was gonna live out there, it had to have all of its essential enzymes adapted, living at that temperature. So it was clear, boiling water is not going to knock these guys off, but we thought it had no applications. Brock and Hudson published their findings and stored a culture of Taq at the American Type Culture Collection, a database that preserves microbial samples.
16 years later, in the spring of 1985, Kary Mullis stumbled upon their discovery. He was looking for a polymerase that could survive the high heat of the PCR cycle and he had found it. At his suggestion, the group isolated the polymerase out of Taq and tried it in a PCR test.
The results were breathtaking. David Gelfand, the Cetus scientist who purified the new polymerase said, "It worked like a charm. It worked better than anything we have ever fantasized.
The holy grail had been achieved. " Not only was Taq able to survive the high temperature of PCR, it thrived in it. These are the results with the old E.
coli polymerase. You can see that it amplified the sickle cell DNA, but it amplified a lot of the background DNA too. So it was messy.
That's because primers can actually attach to DNA even if they aren't a perfect match, they just need a low enough temperature, otherwise the high kinetic energy peels them off. But with Taq, you never had to lower the temperature below 50 degrees, so the primers would virtually only ever bind to their target region. These were the results with Taq.
It completely erased all of the background noise. You could sort of set it and forget it and come back, you know, 30 cycles later, a couple hours later and all of a sudden you have a billion of the thing you're looking for. PCR worked and it worked effortlessly.
They could amplify any piece of DNA they wanted, no matter how small the sample. Cetus realized they had a golden goose. But other companies like Perkin Elmer and Kodak were starting to catch onto their idea.
And if anyone else even briefly mentioned the concept of PCR in their paper, Cetus would lose all rights to the patent. So they had to go public and they had to do it quickly. The PCR group urged Mullis to publish a solo paper first, since PCR was his idea.
But Mullis procrastinated. Afraid they would lose credit for PCR, the rest of the group was forced to publish an article on their own PCR research. So the first paper on PCR that came out in Science Magazine in December of 1985 listed Mullis as the fourth author.
He was furious. By the time he got his own paper ready, no reputable journal wanted it. He remarked, "Nature didn't call me.
I wasn't one of the good old boys. Science rejected it too. " He claimed the PCR group stole his work.
"My God, they're going to get away with their little trick. " But the group scrambled together to get Mullis the proper recognition. He became the face of PCR after giving a talk at a microbiology symposium in 1986.
But, it was too late. Shortly after, still fueled by his anger for the group, Mullis left Cetus. However, the work on PCR continued without him.
And after he leaves, they come up with like, basically there are new PCR machines that do the whole thing for you. And basically these machines are now in like every lab that does any kind of work with DNA anywhere. PCR was a huge success.
Polymerase chain reaction test. PCR, PCR. It's a DNA photocopier.
Measure remaining blood cancer cells that other tests can't detect. Everyone was using it. From DNA cloning and vaccines to detecting cancer and HIV, PCR was saving lives.
It completely opened up everything, it revolutionized everything. P-P-P-PCR. PCR could amplify the tiniest sample of DNA.
It supercharged forensics. Texas man should be freed from prison because new DNA evidence does not link him to the crime. Hundreds of wrongfully convicted people were freed and thousands of criminals were caught.
Families separated by war could be reunited. We use PCR all the time, all the time. Everybody in our institute.
Scientists even tried to use PCR on ancient DNA from insects fossilized in amber. Sound familiar? Like it's completely taken over so much of our world.
And right at the center of this takeover, Kary Mullis. Dr Kary Mullis, a surfer, a scientist who proved that science can be fun. The world renowned inventor of polymerase chain reaction.
What inspired you to invent this? It wasn't people, it was. .
. Drgs, drug, drug, drugs, I'm experienced with drugs. In 1993, Mullis was awarded both the Japan Prize and the Nobel Prize in chemistry for his invention of the polymerase chain reaction method.
Although it wouldn't have existed without his colleagues, Mullis made PCR his story and his story only. There were a lot of people who were like, he's such a fame hog. Like, he completely didn't give any of us credit.
I invented PCR. After I had invented PCR. And now it's like they bought into his version of the story where he did this solo.
Whereas there were a lot of people at Cetus Corp who helped him. As Erlich remarked, "To Kary, rewriting history was more important than writing papers. " "He seems to have viewed PCR as a means to a celebrity.
" He left Cetus and as far as I could tell, really stopped being a scientist. . .
. realized, I had in my hands the thing that would make me famous, 'cause I knew that night I was gonna get a Nobel Prize for that. He used his publicity to springboard his eccentric views.
He talked about seeing glowing raccoons and being abducted by aliens. He would go around saying kind of crazy, shocking stuff. Distrust your fellow man.
We're an arrogant little bunch of naked apes. He wrote this book called "Dancing Naked in the Mind Field", which the blurb on the book is amazing. It's from the Washington Post, and it's like: "The strangest guy to ever win the Nobel Prize in chemistry.
He just would do like weird stuff. Did you see me eating those leaves? Was that a drug?
He was an expert witness in the OJ Simpson trial. He started a company where he would PCR DNA from famous dead celebrities like Marilyn Monroe. And then he would make like little trinkets out of them and sell them.
But not all of his ideas were as harmless. He didn't believe in global warming. He didn't believe in the ozone hole.
He didn't believe that HIV caused AIDS. HIV is not deadly. There's not something called AIDS.
In the early 2000s, HIV denialism in South Africa was at a high, while the country was battling a crippling AIDS epidemic. What we are facing is a catastrophe, which is indescribable. President Thabo Mbeki was under the influence of AIDS denialists.
Does HIV cause AIDS? How does the virus cause a syndrome? It can't.
An even invited Nobel Prize winner, Kary Mullis, to weigh in on the issue. Under Mbeki's leadership, the government refused to provide adequate treatment for those affected. And more than 330,000 people died.
Kary Mullis passed away in August, 2019 at the age of 74 due to complications from pneumonia. Nonetheless, the legacy of PCR lives on. Just a year later, the method reached perhaps its most significant use yet, as PCR COVID tests helped keep billions of people safe throughout the pandemic.
Sometimes he's like, he's very funny and charming and a good storyteller, but he's also, you feel like he's a very sleazy guy. He's like not a person you'd want to be around. He did have a sort of, a sparky mind.
He was not being forced by some company to discover something. He was playing. It was like imaginative play.
He was like, I have these snippets and what could I do with them? And to me, he invented the solution, and then like a huge field of problems emerged to fit. But maybe the real takeaway from Mullis's story is about automation.
I mean, he discovered PCR partly because his day-to-day job was taken over by a machine. And this is a pretty important point because all of us are maybe staring down the barrel of a future where machines take over our jobs, especially now with the surge of AI and generative models. And that's pretty scary.
But it could also force us to come up with bigger, more creative ideas, just like it did for Kary Mullis. Automation might open our minds to breakthroughs and discoveries that could change the world. (upbeat music) Of course, making breakthroughs like PCR take more than just opportunity.
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