Welcome back, everybody.

My next guest is a Harvard medical professor, a biologist, a geneticist, a chemist, and an engineer who's worked with DNA is transforming our biology and our future.

Please welcome George Church.

When it comes to geneting researchers, George Church is the closest person in the field to an actual, real world celebrity.

George Church is a true gentleman scientist wrapped in the cloak of being a madman scientist.

He has a bushy beard.

He wants to bring the wooly mammoth back from extinction.

He talks in this very flamboyant way.

He's just as comfortable at the lab bench as he is on the Colbert TV Show.

For some he's known as the Godfather of synthetic biology for his foundational work on gene editing technology, but for most people today, he's best known as the co founder of Colossal Biosciences, a company that's embarked on the ambitious mission of de extincting species, most recently the dire Wolf.

And so when there's anything exciting happening in the field of gene editing, you can bet George Church has been involved with it in some way.

Isaacson tells me that the development of Crisper was no exception.

He was one of the researchers working on it and a close adviser to Jennifer Dowdner at the time.

He's become this mentor to a lot of people in the biotech world, including Jennifer Dowdner, and I think he started maybe three dozen companies.

So he's not just a great researcher.

He applies it.

He was twenty twelve and now that Dowdner and Charpentier had successfully published their paper on how the Crisper CAST nine mechanism worked, the next challenge for them was to translate their findings from the test tube to the human cell.

Well the end of the piece, they write they hint that this could be used as a tool for editing genes.

But what they've done is only shown that it works in a test tube.

They haven't shown it can work in a human cell.

And so for the next six to seven months you have a great race around the world of scientists trying to show how this new combination of RNA and enzyme a cast enzyme, a little manufactured thing can edit human genes.

And within this global race to figure out how crisper could edit ourselves, one competitor came to the forefront, a competitor who had also been mentored by George Church, a Harvard scientist named Fungjong.

Fung Jang is a great American story.

His mother came over from China on some fellowship to Iowa and just saw how the labs and the universities and the schools and the high schools in Iowa were so good that she ends up bringing her young kid, Fung Jiang, to America, and he becomes sort of a star in high school in Iowa and eventually goes on studies with George Church at Harvard and becomes a great biochemist and microbiologist.

Fun Jong was working at the Broad Institute, a collaboration between Harvard and MIT, when the race to apply crisper and human cells was heating up, and so a triangle of competition was born.

George Church, Jennifer DOWDNA, and Fung Jong.

They were all racing towards the same goal, and Isaacson says that Church, faced with competing with two of his protegees, found himself in a tricky situation.

It's complicated because he's very close to Jennifer Dowdner had been an advisor and mentor, and he was close to Fong Jiang who had worked in his lab, and so he's conflicted a bit.

He ends up wanting to help Jennifer.

Fung Jang is working behind his back, doesn't tell George Church that he's trying to do this, and all three of them at about the same time sort of circle in on how do we prove it can work in a human cell?

What came next would feel one of the most disputed questions around scientific discovery in the past decades.

Who owns Crisper.

I'm Evan Ratliffe and this is on Crisper The Story of Jennifer Dowdner Episode three, Patent Moore's So you have these three labs who are chasing this question will this work in a human cell?

But again you have this kind of competition cooperation because Fong Jiang has previously reached out to Dowdna, been in contact with her because he wants to understand her work.

Phung Jong originally sends an email to Jennifer down to say, I've read your piece.

I want to figure out how it's going to work, but they soon realize the stakes are too high, and they all become more secretive and more competitive.

The question is, is that a bad thing.

Suppose there was no real competition thereby worked together, Well, that would actually be friendlier and nicer.

But maybe we wouldn't have pushed science so far so fast if there weren't an award forgetting their.

First Isaacson tells me that if Dowdner and fun Jong were racing on a track, Jong would have started in the pole position.

Even if Dowda might not have realized.

It, she started off at a disadvantage.

She had never worked in living cells before, she had only done it in a test to now you could have an argument, as they did, about what is the more important way to show something works.

Is it best to be able to show it in a living cell in the real world.

Well, that sounds logical, but actually to be able to show it in a working in a test tube means that you know the exact components.

You know exactly which ingredients are necessary or not which If you're doing it in the human cell, there's also a messy other things happening.

So a Jennifer would say, being able to do with the biochemistry in a test tube, that's actually the big deal, and fong Jiang and others might say, no, no, test tubes are easy.

Doing it in a living cell is the big leap.

But they both knew that it would be a huge discovery whoever got there first in terms of making it work in the human cell.

They both felt it would be a big discovery to be able to do it first in the human cell.

Butjonniffer would argue, and did argue, that's not that big of a leap once you know the ingredients that can work and attest to.

We've always had these things and it's always been pretty ordinary in standard to then apply them in the human cell.

So she would argue the big leap is figuring out the exact ingredients and that every other gene editing tool.

Once she had done that, it wasn't that big of a leap to do it in a cell.

Now I think she's minimizing the importance of doing it in a living cell.

But that's why there was a big dispute afterwards.

But regardless of their starting positions, both Downa and Jung knew that what mattered was who was first of the finish line.

The huge race is to actually be published first, because that's the way you put a stamp on.

I got there first, and Jennifer knew that she was running behind that.

Jennifer for Dowbtne learns in a phone conversation from George Church that not only is George Church trying to make it work in human cells, which is logical, he had done that his whole career, he had made other types of technology work in human cells.

But George Church also says Pong Jang is doing a tiffic, so Jennifer tries to speed up.

She finds a publication that's online only and that will rush it into publication, but she's still She and Martin Yunick have to finish all the experiments and show that it can be made to work, and so over Christmas she's doing it, and then finally at the very beginning of January twenty thirteen, when she's ready to send it in Boom Science magazine, the grandest of all.

The magazine goes online and it has both George Church's paper and Fong Jiang's paper showing how it works in humans.

Before Fong Jang and George church simultaneously a publishing Fong Jang casually sends Jennifer an email saying, hey, my papers about to be published.

So her heart sinks.

She knows she's going to lose the race by about one or two weeks because that's when her paper will be published.

And that may seem pretty you know, close in time, but close doesn't count when it comes to patent surprises.

Yeah, just the idea that it doesn't matter when you knew it.

It matters when that paper appears somewhere in the world.

One of the complexities is the winner of the race is who published it as a paper first.

But the winner of a patent is a slightly more complicated task, which is, even if you haven't published it, if you can show you've made a certain discovery at a certain point and you eventually get it on, it can count in what's called a priority dispute.

And so even now, I mean we're ten years later, there's still a patent war going on, and they're still showing pages in the notebook where they show when they made each experiment.

The notebook, a simple analog object would become a critical piece of evidence in the timeline of Crisper's invention.

Isaacson tells me that Jennifer Downon knew that she could prove that she had discovered the mechanism first just by looking back at her notes each day.

A great scientist who makes any discovery that day will put it in a lab notebook and get two people to witness it on the bottom of the page.

And early on with the first Crisper discoveries, Jennifer Dowdnan did her husband, who's also a BIOCHEMISTY, that's important enough.

You got to go back to the lab, put it in the notebook, and she got two of her graduate students to witness set.

So this is how important this claims of priority can be.

Now you've mentioned patents a couple of times, and I feel like there was, of course a time when if someone made this kind of breakthrough in a lab at university, it wouldn't be patented necessarily.

So what led to these different university associated labs seeking patents on this type of discovery.

In the early nineteen seventies, Herbert Bowyer and others working at Stanford and universities in that area had come up with genetic engineering advances how to do recombinant DNA.

It was called to make new types of organisms.

And at one point the Stanford lawyers helped some of them get a patent, and the other scientists thought, hey, that's not what we're doing here.

We're doing research for the basic good.

But that patent ends up becoming the formation of this multi billion dollar company, Genentech.

So around then patents become more important.

America has a great system of allowing people to patent the type of research they did at universities, even if the government helped fund that research.

And it was two senators, Bob Dole and Birch Buy came up with an act that said, how do we allocate it if the federal government pays for research at the university.

And it's a slightly complicated formula, but the professor gets a stake, the university gets a stake, the government has a right to use the patented material.

And it becomes a great engine for commercializing basic science.

And some people, especially in the old days at Harvard or even in the early seventies, soelth that's not good.

You shouldn't be trying to own this intellectual property.

By the nineteen seventies it was clear, we wanted research labs and research professors to be able to make a buck if they made discoveries.

In order to sort of drive that same competitive spirit.

If you look around the world at where the greatest advance has come in biotech and genetic engineering and the Internet, in searches like Google, which were done at a Stanford university under a government grant, it tends to happen in the US because you're able to get rewarded if you make discoveries, but it also funds them.

It costs a lot of money to build that lab at Berkeley, with all of the not just the benches, but the hoods and the ventilation and the test tubes and the pipeds and the the graduate students being paid to do things.

That's a huge investment.

We'll be right back, coming back to our trio of scientific racers, DAWNA, Young, and Church.

They would all publish their papers close together in twenty thirteen detailing how crisper could work in human cells, and while the patent question was still up in the air, Isaacson says, they began to explore the possibility of linking arms and creating a joint company to share the ownership.

After they all figure out how to make it work in a human cell in this great race, and in January twenty thirteen each published their papers.

Initially they start to work together, with George Church being the Ben Franklin type trying to bring everybody together and starting a company in which all of their intellectual property, any patents they get in anything in the future, will all be part of one consortium and they'll be able to commercialize it and make it work.

And the venture capitalists in Boston in particular, are investing in a big company that's going to do it.

And yet there was a lot of bad feelings, and I think in particular in the book, there's this Jennifer describing that she thought fong Jiang was working with the venture capitalists behind her back, and it turns out he had filed for an expedited patent application without telling her and the group, and she just feels the guys are ganging up on me, and I don't want any part of this, and she pulls out.

And then she thought, well, maybe I'll do it with Emmanuel Sharpentay.

But Emmanuel Sharpentay, she's off in her own world.

She wanted her own thing.

I think eventually they're going to all have to cross license the patents.

But it almost worked at the beginning to have one consortium.

But now if you want to make a treatment for sickle cell anemia for other you know, for type of blindness, and you're using crisper, sometimes you got to figure out which of these patents do I have to license them all?

The field would be better off if they could settle their patent dispute.

And you, as you're reporting the book, you're you are moving as we discussed, you're moving across talking to all the players involved.

Where did you land in terms of pong Jiang's actions pursuing the expedited patent, for example, being machiavellian versus having, you know, purer motives around trying to accelerate the discovery.

I think Pong Jang is a decent, good person and a great scientist.

And what he was doing was in the realm of regular ethical conduct, which is trying to get the patent first, rushing the patent application, and many other things.

And what he also did was keeping it secret.

Well that's not against the ethics rules.

But as George Church said to me, yes, what he did was in the bounds of all the rules of ethics.

But it's not the way I would have had him do it if he had still been part of my lab.

That's not the way we work.

There's a system of honor that goes beyond the ethics of are you supposed to tell the other side?

Or how open do you have to be?

I don't think Fong Xiang is a manipulative or deceitful person, but he did decide toss to his own course a little bit secretively, and that rubbed George Church the wrong way.

And is part of it.

The way that the incentives change when you move from you know, when you're talking about trying to understand bacteria in a salt pool somewhere, there's discovery incentive and there's curiosity that's driving you.

But when you reach this point, you have possible financial incentives that come into play.

These are businesses that are being started.

Did you feel like that played a role in how people responded to the situation.

One of the things that happened at one of these breakfasts in Cambridge or meetings where they're all trying to figure out how to pool together their patents and maybe have one big company is.

Jennifer asked George Church, how big of a deal do you think this is?

This editing genes using Crisper pet and he basically says, grace yourself.

This is one of the biggest things ever to come down the pike.

So when the stakes get to be so big and you realize this may be the biggest discovery of the decade and it may have huge financial implications, and that's a little bit different than trying to share research on exactly how the sequences of Crisper might work in different bacteria.

So let's try to help people understand why it is such a world changing, potentially world changing development because people may know, well, we could sort of edit genes before this, and they've heard of gene editing, So what is the fundamental breakthrough when it comes to human cells and gene editing that Crisper allows that we couldn't do before.

Before when you had to edit, you could do something very tailored and complicated, but it wasn't like programming a microchip, which we can, you know, do in forty second.

If we want to fiddle with a program with Crisper, you can instantly program it to cut wherever you want.

In the gene and then if you decide, well there's some other place you went up, you're just tap tap, tap and you get a new one.

So it's very easy, and with the combined single RNA guide we talked about, it becomes pretty easy to get it into the cell.

So this is the difference between being a monk doing a scribe work on a great manuscript and being able to edit it with a quill pen and having a amazing cut and paste computer programming type thing where you can cut and paste and change.

So Crisper at its foundation using Crisper cast nine, the enzyme and the tool becomes a foundation for even more tools that will allow us to rewrite our genetic code.

At this point in the story, the wider scientific community in the public are becoming aware of the importance of Crisper.

The initial attempt at a consortium has devolved into separate, competing companies, and it's also a point where Isaacson becomes unexpectedly pulled into the dispute over who pioneered Crisper.

It all starts with a paper written by Eric Lander, founding director of the Broad Institute where Fung Jung works.

One of the things that Eric Lander Does, who ran the Broad Institute where Fong Jang was working, decided he wanted to make sure that Fung Jang and his team got credit, and he wrote a scientific paper that got published called The Heroes of Crisper.

It's actually a very good paper, and it takes you through every person involved in the process, starting with Francesco Molika, the guy in Spain who sees it in the original crobes in saltwater ponds, but he minimizes what Jennifer Dowden, Emmanuel Sharpenjay does in sort of a dismissive part of a paragraph saying a good scientist say this, and then paragraph after paragraph on how important it was that Phong Xiang was able to make it work in the human cell.

This causes only the type of controversy that can happen when you combine basic science with Twitter, in which Twitter mobs are accusing Eric Lander are being sexist, and you know, doing to Emmanuel Sharpentjay and Jennifer Dowdner what Jim Watson had done to Rosalind Franklin and writing them out of history, and also not disclosing when he wrote the piece that his institute was in a patent battle with all of them, so it becomes a mini scandal in the world of science.

And then one of the people enlisted to help resolve that scandal is you.

At a certain point, the people at Harvard want to restrain Eric Lander from going too far, and they know it's gotten a bit unseemly.

So I got a call from somebody who said, can you host Eric Lander and a group of science reporters and writers and technicians in Washington and walk them through the Crispers story And we're going to get him prepared to say nice things about Jennifer Downer to try to resolve the controversy.

And Eric couldn't quite do it.

I kept saying, all right, well when the role of Jennifer, and he said, oh yeah, they did okay.

And I could see the person from Harvard who was trying to orchesrate this kind of shrug and roll their eyes.

But I love Eric partly because he's just so competitive.

And was there a part of you that was this did getting involved?

Did you think, well, that's if I'm involved, I'll just write it into the book.

Or did you say I'm trying to stay out of this.

As a reporter.

I was trained to stay out of it, never to put yourself in a story.

And over the years, I realize you're more honest with the reader.

Plus you can make it a better understanding if you hold the reader's hands and say, well, here's what I was doing and how I got involved.

And so with the Jennifer Dowd in a book, I tried not to insert myself in it unnecessarily.

But at one point Jennifer Dowdn and Emmanuel Sharp and Jay just are barely speaking to each other even though that part, and Jennifer says, can you call her up?

And I had a joint session with them on zoom, and I was just trying to see if I could make sure that there was no misunderstandings between them.

And so what I was asked to do this thing Ferick Landra, I said, if I'm upfront with the reader and I plain exactly why I was doing it, and it's actually truer to the situation than if I pretend to have not been involved.

Even when I'm at a crisper conference like in Quebec City and I decide to go out instead of with Jennifer Dowd newsgroup, I decided to go to a restaurant with Fong Jang's group and hear his side of the story.

Instead of just reporting his side of the story, I make it clear they're competing debtors that night, and here's why I decided to go to this one.

You're like an enzyme.

Maybe that's supercharging the competition just by showing up and saying I'm going to write the story about this.

Yeah.

I mean, enzymes are catalysts.

They cause things to happen, and you have to be careful that you're not distorting the narrative by being there, that you're not too much of a catalyst.

On the other hand, when the story is happening around you, when you're a part of it.

When I'm asked to moderate a panel at the Chris Brook one of the later Christopher conferences at Cold Spring Arbor, I want to do which best for the reader in explaining how the tale unfolds.

As of this recording, the dispute over who discovered Crisper Cast nine is ongoing.

In the next episode of On Crisper, we delve into the ethical implications that gene editing technology brings and how Jennifer Dowdner grappled with them, both professionally and personally on Crisper.

The Story of Jennifer DOWDNA is a production of Kaleidoscope and iHeart.

This show is based on the writing and reporting of Walter Isaacson.

It's hosted by me Evan Ratliffe and produced by Adriana Tipia with assistance from Alex Jandenveldt.

He was mixed by Kyle Murdoch and our studio engineer was Thomas Walsh.

Our executive producers are Kate Osborne and my Gaeshatikador from Kaleidoscope and Katrina Dorvel from iHeart Podcasts.

If you enjoy hearing stories about visionaries and science and technology, check out our other seasons based on the biographies that Walter Isaacson has written.

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