On Genome Editing With Fyodor Urnov, A Pioneer

Recorded 11 October 2023

Beyond being a brilliant scientist, Fyodor is an extraordinary communicator as you will hear/see with his automotive metaphors to explain genome editing and gene therapy. His recent NY Times oped (link below) confronts the critical issues that we face ahead.

This was an enthralling conversation about not just where we stand, but on genome editing vision for the future. I hope you enjoy it as much as I did.

Transcript with key links

Eric Topol (00:00):

Well for me, this is really a special conversation with a friend, Professor Fyodor Urnov , someone who I had a chance to work with for several years on genome editing of induced pluripotent stem cells --a joint project while he was the Chief Scientific Officer at Sangamo Therapeutics, one of the pioneering genome editing companies. Before I get into it, I just want to mention a couple of things. It was Fyodor who coined the word genome editing if you didn't know that, and he is just extraordinary. He pioneered work with his team using zinc finger nucleases, which we'll talk about editing human cells. And his background is he grew up in Moscow. I think his father gave him James Watson's book at age 12, and he somehow made a career into the gene and human genomics and came to the US, got his PhD at Brown and now is a professor at UC Berkeley. So welcome Fyodor.

Fyodor Urnov (01:07):

What an absolute treat to be here and speak with you.

Eric Topol (01:11):

Well, we're going to get into this topic on a day or a week that's been yet another jump forward with the chickens that were made with genome editing to be partially resistant to avian flu. That was yesterday. Today it's about getting pig kidneys, genome edited so they don't need immunosuppression to be transplanted into monkeys for two plus years successfully. And this is just never ending, extraordinary stuff. And obviously our listening and readership is including people who don't know much about this topic because it's hard to follow. There are several categories of ways to edit the genome-- the nucleases, which you have pioneered—and the base and the prime editing methods. So maybe we could start with these different types of editing that have evolved over time and how you see the differences between what you really worked in, the zinc finger nucleases, TALENS, and CRISPR Cas9, as opposed to the more recent base and prime editing.

Fyodor Urnov (02:32):

Yeah, I think a good analogy would be with transportation. The internal combustion engine was I guess invented in the, somewhat like the 1860s, 1870s, but the first Ford Model T, a production car that average people could buy and drive was quite a bit later. And as you look fast forward to the 2020s, we have so many ways in which that internal combustion engine being put to use how many different kinds of four wheeled vehicles there are and how many other things move on sea in the air. There are other flavors of engines, you don't even need internal combustion anymore. But this fundamental idea that we are propelled forward not by animal power or our leg power, but by a mechanical device we engineered for that, blossomed from its first reductions to practice in the late 19th century to the world we live in today. The dream of changing human DNA on demand is actually quite an old one.

(03:31):

We've wanted to change DNA for some time and largely to treat inborn errors of ourselves. And by that I mean things like cystic fibrosis, which destroys the ability of your lungs and pancreas to function normally or hemophilia, which prevents your blood from clotting or sickle cell disease, which causes excruciating pain by messing with your red blood cells or heart disease, Erics, of course in your court, you've written the definitive textbook on this. Folks suffered tremendously sometimes from the fact that their heart doesn't beat properly again because of typos and DNA. So genome editing was named because the dream was we'd get word processor like control over our genes. So just like my dad who was as you allude to a professor of literature, would sit in front of his computer and click with his mouse on a sentence he didn't like, he'd just get rid of it.

(04:25):

We named genome editing because we dreamt of a technology that would ultimately allow us that level of control about over our sequence. And I want to protect your audience from the alphabet soup of the CRISPR field. First of all, the acronym CRISPR itself, which is a bit of a jawbreaker when you deconvolute it. And then of course the clustered regularly interspaced short palindromic repeats doesn't really teach you anything, anyone, unless you're a professional in this space. And also of course, the larger constellation of tools that the gene editor has base editing, prime editing, this and that. And I just want to say one key thing. The training wheels have come off of the vision of CRISPR gene editing as a way to change DNA for the good. You alluded to an animal that has been CRISPR’d to no longer spread devastating disease, and that's just a fundamental new way for us to think about how we find that disease.

(05:25):

The list of people who are waiting for an organ transplant is enormous and growing. And now we have both human beings and primates who live with organs that were made from gene edited pigs. Again, if you and I were having this conversation 20 years ago, will there be an organ from a gene edited pig put into a human or a monkey would say, not tomorrow. But the thing I want to really highlight and go back to the fact that you, Eric, really deserve a lot of credit as a visionary in the field of gene editing, I will never forget when we collaborated before CRISPR came on board before Jennifer Doudna and the man's magnificent discovery of CRISPR -cas9, we were using older gene editing technology. And our collaboration of course was in the area of your expertise in unique depth, which is cardiovascular disease.

(06:17):

And we were able to use these relatively simple tools to change DNA at genes that make us susceptible to heart disease. And you said to me, I will never forget this, Fyodor. What I