In this episode of the Making Sense podcast, Sam Harris speaks with Jennifer Doudna about the gene-editing technology CRISPR/cas9. They talk about the biology of gene editing, how specific tissues in the body can be targeted, the ethical implications of changing the human genome, the importance of curiosity-driven science, and other topics.
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This is an unofficial transcript meant for reference. Accuracy is not guaranteed.
Today, I am speaking with Jennifer Loudness Jennifer's biochemist, professor
chemistry, the molecular and sell biology Department of the universe in California at Berkeley, she's off
investigator with Howard Hughes, Medical Institute and a real
search and they molecular biophysics an integrated, vile imaging division at the Lawrence Berkeley, national laboratory. She is one of the world's exe
is on RNA protein, biochemistry and in particular, crisper biology,
and she's the author, along with Samuel Sternberg of the book, a crack and creation
Jeanne at a Dane and the unthinkable power to control evolution and Jennifer
is credited as one of the inventors of the crisper CAS nine Jean editing technology, which is the topic of today's conversation.
We get into all the details and the ethics
That time is short, Jennifer's aim a rock star scientist end
I can only schedule about an hour with her, but I will take. It was great to have her walk me through the details of crisper
and I trust you will leave this package as I did Know- and much more about where this technology
is at present and where it's all likely to head so without further delay. I bring you Jennifer
I am here with you,
Four downer Jennifer thanks are come on the broadcast great to be here, SAM, so you
or a co inventor of crisper, cast, nine of which was a gene, editing technology that we'll talk about before we get into this. Perhaps you can just give a car potted summary of your background scientifically. Well, I I am a bio chemist son, somebody who studies molecules and how they work and I've always been interested in evolution and the way they did. Cells have evolved to use their genetic information in precise ways and that's actually how we got into the whole area of gene, editing and you're. You see Berkeley right, I don't you see, Berkeley Correct
now I know there is some controversy about who should get credit for inventing crisper cast nine, and we don't really have to go into that. I think there is clearly no controversy that you are one of the world's experts on this. Is there anything you want to say about the controversy or as a kind of a distraction as well?
This conversation concern. Well, I guess I would say is that my work with a manual sharpened here was, you know, going on to really. I would call it a curiosity driven a project that was aimed at discovering how bacteria fight viral infection, so neither of us were aiming to create a a technology, but but the work that we did uncovered the activity of a protein that can be programmed to find and cut dna sequences, and with that without understanding, it was pretty obvious that this was going to be a great, a great technology, and that was work that was published in two thousand twelve. I don't think anybody argues about that. Wrote, ok
Let's talk about crisper in and that protein, but before we do, it might be good to give a very quick remedial summary of some basic molecular biology. I think we have a fairly educated audience here, but every
I think, can do with a primer on dna
to our native protein, and because we would be talking about just the mechanics of gene editing here. So can you give us a few minutes of basic biology, her shirt? Absolutely so I guess we could start by by pointing out that people probably are familiar with the idea that DNA encodes genetic information. So it's it's really that chemical that stores information
in cells and allows cells to grow and develop and become tissues or or whole organisms, and the way that sells use that information is mostly in the form of proteins. So the information in the dna is converted into into proteins by a process that creates the pros,
molecules by reading the code in the dna and the intermediaries in that processes is, is kind of what I like
The call a throwaway a copy of the genetic information, which is our molecules of irony and what has emerged over the last probably two decades is that are in a molecules, are not just throw away copies of of the genome, but they are actually molecules that have a lot of interest.
Its functions in their own right and that's actually what I've always been interested in my own laboratories. The role of RNA molecules that are involved in controlling the flow of genetic information and helping cells decide when and how to use the information that stored in the genome in the DNA and that the story of course,
for the story of this gene. Editing technology is kind of interesting because it really involves all three of those types of fundamental molecule is DNA, RNA and protein, because it's a protein that is involved in the this is really responsible for cutting dna in a precise positions. The places in the dna that get cut are defined by molecules of RNA that
all that the protein which is called cast nine holds onto and the places in the dna they get cut. Are the sites in the genome, where editing occurs, where permanent changes are made to the genetic code, and so you discovered this bacteria.
Crisper has been described as part of their bacterial immune system. That's correct! Take me, there is what happens. Viruses periodically infect bacteria, and what is the crisper sequence do in that context? Rights of viruses, infect bacteria, actually all the time in nature, and so bacteria have a very effective way of defending against viruses by storing pieces of viral dna in their own chromosome, and then they use that they use that stored viral dna sequence. There actually are multiple multiple sequences, coming NOS one representing each virus that pisses infected the cell over time, so that you can think of it. Sort of
a genetic vaccination card and then those those stored viral dna sequences are copied into our any and then those are in a molecules assemble with they cast nine protein to direct it to sequences that match. The irony sequence, in other words, sequences that are belong to viruses and when that match occurs than the they cast nine protein works like a
molecular scalpel and cuts the the viral dna and and and basically allows the seldom too to destroy it? So again, this is semi,
pants material and you don't have the benefit of visual aids here. So I just wanted to make another pass on this. Just to make sure everyone has a picture of what's happening here, so you have this little machine really, if it's a combination,
protein molecule and rna, which is really informing its behalf
if you're right, you have an orange sequence that matches a sequence in the dna which determines what part of the dna
it will bind to and edit or cut- and this is something you ve discovered in bacterial, but which can be used as a kind of molecular scalpel in you carry out like mammals such as ourselves, and this then becomes a way of targeting with a precision that we didn't have before spots in the human genome that can be edited. You nailed it. That's perfect, ok, so I guess I'm interested in a little more than the canopy of this. So what are the chances that the crisper CAS nine
technology will cut in the wrong place in the genome? Does there have to be a complete complementarity between the irony in the dna or there's some potential for error here? Sure there's always
so for error
think the amazing thing about the crisper cast nine technology. Is that it's? It's really
the accurate and it's not perfect, but it's it's it's it's close to. So I think I think, what's emerged over the last few years that people have been using this, and you know it's probably worth mentioning that this technology took off incredibly quickly was adopted very very rapidly after after
twenty twelve publication and you own there. Now, probably thousands of people around the world using this as a tool in all sorts of systems, and the good thing about that or one of them is that is that it's meant that there's been were very rapid development of of the technology as well as understanding of how it works, and one of the things that emerged is that this this tool is
you know it's accurate enough to make precise changes in even very large genomes like the human genome, more plants, plant genomes
the wind, when people of have sort of, as I think as people have become more sophisticated about using at ensuring that the cast nine protein is used in limiting amounts in cells. Not not not press
in huge quantities and not hanging around for too long bet it's actually
markedly accurate, add to generating those kinds of edits, it's possible to find off targets, but it's you have to look pretty hard and can you edit a single base pair? Nor does it do you have to deal with longer sequences and that you can edit a single based their yeah. Well, so you have described this
they scalpel now what happened after the dna is cut. Is it always a matter of inserting,
Dna variant sequence, or can you,
Blake caught and remove parts of the DNA. Yes
you can cut and remove or or you can cut and replace the the removal
part Is- is turned out to be easier technically to do then, the replacing part but but both are possible so against this is so counter intuitive and waves. When you actually picture what's happening here, because you know anyone who's taken biology.
In recent memory, will know that the genetic material inside ourselves in the nucleus and its found very tight
crammed in theirs at the chromosomes, aren't laid out in the pretty way that they are when we picture them in textbooks, and now you ve sent crisper this little machine in to the cell will talk about how you can target tissues later on. For you, this goes
to the cell and moves all over the genome and is searching for the sequence to which it is the mate and so that it can find the place to cut. How does it search the whole
No, how do you get full coverage of a genome and how quickly does this happen? But if we could take a video
camera inside a cell. What would we be seen there? Well, we ve sort of done add that quite a video camera, but it's been possible to make fluorescent labelled versions of the
ass, nine protein that can be visualized in live cells, so you can watch. You can basically watch these little dots of late
moving around in the nucleus and when you do that kind of experiment, what what emerges is that this is a protein that is has very fast kinetic. So it's moving around the nucleus incredibly quickly, much more quickly than what you see for other kinds of proteins that r l you know existing in the in the nucleus and, what's what's a thought to happen, is that this protein
rapidly sampling, different sections along the the sequence of dna and its. It is quite remarkable to think about it, because you know we're talking about billions of of base pairs of dna in the cell, but but somehow this this protein very quickly samples alive
The dna sequence looking for a match to the guide, rna sequence and
One thing that's important to keep in mind is that it's not a single a protein that would be in the nucleus, but instead many many copies of this. There might be in a thousands or tens of thousands of copies that are all
searching, and when one finds its target site, then it makes a cut in the edit occurs.
Now are? The sequence
of DNA, unique enough.
So that we're not getting redundant cuts
So maybe someday. You know a ten nuclear tied sequence as Europe Search code. Are we expecting that to be the only place in there?
You know that would get modified or just by dint of numbers, you're going to be altering something you didn't expect alter. If you do that well in one of those interesting serendipity of science, this casts nine protein actually uses at twenty nucleotides. Rna sequence has twenty letters that it's looking for twenty letters in a row and if you do the math, that's just about what you need to unite
we define a sequence in the in the the human genome. For example, good numbers were on our side effect. Rape, what's back
now we have a human being. Who has.
Variety of genes that are not as perfect as they might be and we'll talk about the conditions for which we have
some understanding of the underlying genetics and what could be modified here, but
Let's say we know what genes we want to alter. How would we target crisper too
specific sites in the body, and presumably these insertions would sometimes need to be tissue specific. You wouldn't want to send this everywhere right
and I think, you're putting your finger on what I think is one of the critical challenges for gene editing in the clinic going forwarded witches just what you said
are we deliver the these editing molecules into the right cells at the right time, one
the ways that this can be done today is actually by delivering into cells that are temporarily taken out of the body. So, for example, people are working hard on correcting mutations that cause blood disorders, because the blood cells can actually be taken out edited and
replaced so that's it. I think that's a that's one, a strategy that gets around the issue of trying to deliver something like this in two specific tissues in in a person. That's it
that's a much bigger challenge, and why is it a challenged on the wall? What would be the mechanism would use and viral vector to deliver it if you wanted to get into every cell in the body? What would be the methodology I'll be hard?
if even for even using a virus, because viruses tend to target particular kinds of cells, so you might have to use a cocktail of viruses that are able to get into many different types of cells, but I think what what is typically envisioned is that you might be able to use viruses that would deliver into specific parts of the body, for example, into the into the liver, or
or into the brain and create at its that would alleviate disease in cases where the the gene edit is necessary. Just in those kinds of cells.
And what is the timeframe over which this would occur? Images so again it will talk about how difficult this might be in practice, but-
Let's say we know the gene, we want to add it and we have the way to target they relevant tissue, and some one has a disease born of this malfunctioning Jean. How quickly would.
Spur change their genome and cancel the disease.
In principle very quickly, I you I've seen some data in animal models of disease, for example in mice, where mice get in
Jackson and, within a matter of you know a couple of days. You can start to detect edits in the dna of the cells that have been targeted in the treatment. So I think the idea in principle- and I think this is something that field is work
towards doing is that gene editing would be a fairly fast kind of treatment. And furthermore- and this is actually very important to Appreciate- is that it is a different kind of
repeat because it's really a one in done. Treatment is, in principle, rent the ideas. You would do this once
and then you don't have to do it again. Here am I going to the ethics?
I would like to continue with neither the twentieth you'll need to subscribe at San Aristotle, eugenics.
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Transcript generated on 2020-03-23.