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Unraveling CRISPR-Cas9 with Jennifer Doudna – Conversations with History

(logo whooshing) (mouse clicking)
(computer beeping) (soft music) – Hello, I’m Harry Kreisler, of the Institute of International Studies. Welcome to Conversations with History. Our guest today is Dr. Jennifer Doudna, who is professor in the
Department of Chemistry, in the Department of
Molecular and Cell Biology at UC Berkeley, and Li Ka
Shing Chancellor’s Professor in Biomedical and Health Research. She is also the director of the Innovative Genomics
Institute at Berkeley. Jennifer, welcome to our program. – Thank you for having me. – What led you to go
into science as a career? – I grew up on a small island
in the middle of the Pacific, the island of Hawaii, and it was there that I think I really gained my desire to study the chemistry of life. I was fascinated by the
evolutionary process that led to all of the
diverse animals and plants that we see in that environment, and I wanted to understand
how they got there. – And neither of your
parents were scientists. – No, no, my parents were academics, but they were in the humanities. My dad was a American literature professor at the university in Hawaii, and my mom was a history lecturer. – And your father, at some
point early in your life gave you a copy of The Double Helix. – He did, yeah. I was probably 12 years old. – My god, and you read it. – Eventually. (both laughing) – Oh, a secret revealed. What led you to want to
focus on biochemistry and the structure, biological structures? – I got very excited about
chemistry in high school. I had a wonderful chemistry
teacher, Miss Wang, who showed us kids that science was about the process of discovery, and I somehow got fascinated with the idea that you could understand the details of molecules in living systems, and that’s what I wanted
to do for my career. You were educated, your
undergraduate work was at– – Pomona.
– Pomona. And where did you do your doctorate? – So, from Pomona, I went to Boston. I went and worked at
Harvard Medical School, where I was in the Department
of Biological Chemistry and Molecular Pharmacology,
a big mouthful, but it was a wonderful place that had a lot of classical biochemists as well as people thinking
about the chemistry of life in biomedical settings. – And I read it in your
book that at some point, you, looking back at
your own life, you saw that the common thread was
correcting defective genes? Is that a fair statement, restatement? – Not exactly. I think the common thread always, for me, has been understanding
the evolution of the, sort of the fundamental
molecules that we see in modern biology, and that’s
a big topic, obviously. But for me, it was always about thinking about life’s origins, and
what can we learn about the history of life on our planet from studying how things work today. And I’ve always been fascinated by the flow of genetic information, again, kind of stemming from the story described in The Double Helix, actually. – And who did you work under
at the Harvard Medical School? That’s really kind of the first step in the trajectory of your education toward the discovery you were to make. – Yeah, well, I worked
with three scientists in the first year I was
there, as typically happens in graduate programs like that, we had rotations that we did as students. So we were working in
several different labs to get a flavor of
different kinds of science. So I worked in, first, for a professor named Roberto Kolter,
who studies how bacteria produce toxins that poison other bacteria in their environment, so
that was a fascinating sort of introduction to the biology of what’s happening out in,
sort of, in the environment. Second, I worked with a
guy named Richard Kolodner, very well known for his work on DNA repair and actually, interestingly,
that came back to me later, in my later work. And third was Jack Szostak, whose lab I actually ended up
joining and worked under for my PhD, who also, at that time, was studying the process of DNA repair. But in his lab, I actually
took on a new project to understand how RNA molecules
might have played a role in the origin of life. – And so this is where, the
origin of your focus on RNA? – [Jennifer] Yes. – And was that a hot topic at the time? Was that, initially, it was thought that RNA didn’t do much, right? That it was primarily a messenger,
is that a fair statement? – I think that’s a fair statement. Certainly, when I was
going through school, RNA seemed like the least interesting of the major macromolecules
in living systems. Proteins were exciting because they do a lot of interesting things in the cell. DNA, of course, is the
important repository of genetic information and responsible for passing it on to future generations, and then RNA was, we were sort of taught that it was an intermediary
and a messenger, and maybe not a molecule
playing an active role in biology, and what was happening, when I was in grad school, and my advisor, Jack Szostak, was a big player in this, was the fundamental change in thinking, across biological scientists that in fact, RNA molecules do a lot of very active and important things in cells, and they can also give us hints about how life might have come to be. – And so, your focus
initially was on biochemistry, and what sorts of things did you look at beyond what your mentors were doing? – Well, in my graduate
work, I was studying how RNA molecules might be
capable of self-replication, in other words, making
copies of themselves, something that we think is a
fundamental definition of life is having, organisms
are able to replicate, they’re able to divide and
make more of themselves. And so I was investigating
that at a molecular level by studying RNA molecules that
have some of those properties that we can investigate in the laboratory. But beyond that, I think I really learned from my graduate advisor,
Dr. Szostak, that science is, he was so passionate about his work, and he was a very big thinker. He was always, I’d go into his office in the afternoon, and he would
be reading journal articles about applied mathematics,
things like that. So the things very far afield
from what we were researching in the laboratory, but
he had so many interests, and that was really infectious, to see such a wise person who was working on very detailed problems
in his research lab, but had such broad based interests. – So this raises an important
point about science. A lot of it is interdisciplinary. – It is, yeah. – And you learn from each other’s, and not just the others
in your particular– – Absolutely, yeah. – And I read somewhere
that you learned from him how to identify the
problem and focus on it and how, therefore, to
frame the right questions. – Well, I admired that greatly
about him, I have to say. When I, and this was something I observed when I was a student in his lab, and I couldn’t imagine how he did it, but somehow, he seemed to always be asking the right question, and he could frame these very big questions, like, how did life evolve on earth? That sounds like a huge problem. How would you ever
investigate it in the lab, but he had the ability
to frame that question in a way that you could
actually break it down as a studiable problem
that you could investigate with experiments, and I thought that was an incredible skill that he had. – Does one learn to do that from a mentor, or do you self-teach
yourself as you go along? – I think it’s a combination. I think when I was a
student in Szostak’s lab, of course, I learned a lot from him and watching him in
action, and also directly through his mentorship, but frankly, he had, he put together
a lab of brilliant people who were colleagues of mine, and every day in the laboratory, we would be talking about experiments and about questions that
we were investigating, papers we were reading,
things we just wondered about, and so it was a really exciting sort of intellectual melting pot of people from different backgrounds who were interested in similar questions. – And this is a theme that
recurs again and again, sort of, groups of
scientists and of students, actually, interacting on a regular basis, and each sharing where they were going. – Right, right. And I think that’s a theme that I’ve always enjoyed in science. It’s not, honestly, it’s
not something I imagined would be a part of my
professional life as a scientist back when I was first being trained, because I imagined sort
of the media presentation of scientists as being
people in white lab coats with black-rimmed glasses and very geeky and working, maybe, in isolation. And I discovered in graduate
school that it’s very, science is a very different
process than that. It’s actually all about people. – You then went to Colorado
to fill in your knowledge about the world you wanted to explore. What is it you wanted to do there? Study the how, the structure of RNA? – Exactly, so when I
was in graduate school, and as I was wrapping
up my research there, I realized that to really understand how these RNA molecules
I was studying operated in a biological setting,
we really had to understand their three-dimensional shapes, because that would explain
the kind of chemistry, and the chemical reactions
that they could be involved in. And so, at the time,
there was only one type of RNA structure, molecular structure that was known, and in fact, nobody had really seriously
investigated RNA structures for about 10 or 12 years at that point. And I decided that I needed
to, I wanted to go after that as a next direction in my work, and to do so, I decided I would pick the very best RNA biochemist
that I could find, and that was Tom Cech, who was a professor at the University of Colorado Boulder. – So what’s interesting here
is that you were on a path of understanding RNA
in its many dimensions, but you encountered
problems, plus curiosity, which define the next step.
– Yeah. Yeah, exactly. – And so as a result of
your work in Colorado, you were then positioned to think about the structure of
RNA and how it interacted with the biochemistry, is
that a fair way to state that? – Yeah, I think that’s very fair, yeah. Yeah, looking at, I
mean, it’s sort of like thinking about form, sort
of establishing function. And we think about this,
and it’s a principle in architecture, for example, right? Well, it’s very similar all the way down at the molecular level
that form, basically, establishes function and you
can, form follows function. And so by understanding
the shapes of molecules and how they’re put
together, you can understand a lot about their functions and purpose in biological settings. – So you go back to
Yale, or you’re at Yale, now after Colorado, continuing this work, but then you come to Berkeley. – Yeah, yep. So I got hired, my first job was at Yale. I got hired there as a professor in 1994. I was stunned that they
would hire me, but they did, and it was a remarkable experience to go to the Molecular, Biophysics and Biochemistry Department at Yale, where it’s some of the most eminent people in the country, probably in the world, working on molecular structures
and properties of molecules and some of the most
fundamental pathways in biology, were researching there,
doing their work at the time. But then, eight years later, I made the very, kind
of bittersweet decision at the time to move to UC Berkeley, and why did I do that? Well, I was offered a
position at Berkeley, and although I had been
extremely happy at Yale and very well supported
there, I could also see exciting opportunities that
would be special to Berkeley. For example, being embedded in a much larger university system, adjacent to a national laboratory, right across the Bay from an
outstanding medical school and Stanford right down the street. It just seemed like a wonderful
intellectual environment in the Bay area, and it didn’t hurt that it’s a pretty nice place to live. – That’s true, and to raise a family. – [Jennifer] And to raise a family. – Right, so you’re working here now. You’ve established your
credentials in RNA, and then one day, you
get a call from professor in another department, I believe, and what does she tell
you, and how does that lead on a trail to your discovery? – Well, I was, when I
moved the lab to Berkeley, we started studying something
that I had not worked on up until that point, which
was how very small pieces of RNA in mammalian
cells, even human cells, are able to control how and
when certain proteins are made. And we were fascinated by that process, how had it evolved and how did it work, and we were studying
the molecules involved in that pathway, which is called
RNA interference, or RNAi, and then, I was sitting
innocently in my office one day at Berkeley, and Jillian Banfield, a professor here in earth
and planetary science contacted me and she
said that she had seen my work on RNA interference
and she wanted to meet because she had an interesting
observation in her work about the possibility that bacteria were also using an RNA
interference kind of mechanism, but with entirely different
molecular machinery. And of course, I was fascinated. – And she googled you.
– She did. – Right, and it was clear
that your background and what you were working on related. So this, together with a meeting you had with your co-discoverer
on a walk at a conference in San Juan–
– Right. – And she was, essentially,
working on the same problem, Emmanuelle Charpentier.
– Yeah, exactly. Yeah, Emmanuelle Charpentier. So, and this is another
great instance of how, there’s an interesting
serendipity in science. So Emmanuelle Charpentier
and I met for the first time at a meeting in San Juan, Puerto Rico, and we recognized that we were working on different aspects of
the same bacterial pathway, a bacterial immune system known as CRISPR. And at that conference,
we decided to team up to investigate a particular protein that’s part of that pathway,
that Emmanuelle’s lab was starting to investigate at the time, a protein called Cas9. – And there was some sense
in the broader community that something was going on, but no one, with Cas9, but no one had yet figured out exactly what it did, and how it did it. – Right.
– Okay. And so the discovery
that was revolutionary by you and your collaborator
and your teams was what? – Well, it was fundamentally figuring out how this protein, Cas9,
uses an RNA molecule to identify the segment
of DNA and cut it, right? So it’s just, you can imagine it like DNA is sort of like a ropy
molecule in the cell. You got this very, very, very long rope that encodes all of
the genetic information necessary for the cell to function, and what Cas9 does is to
find a place in that rope, which is put together by
letters of the DNA code, so it’s a programmable kind of code, and what Cas9 does with its RNA guide is to find a place in that
coded sequence and make a break. And why was this so exciting? Well, first of all, we
had set out to figure out how to, sort of a,
somewhat modest question, how does this protein function as part of a bacterial immune system. And what our work revealed
was that in bacteria, this protein is programmed
with molecules of RNA that give it the information
to find and cut virus DNA. So it’s a way that bacteria
can destroy virus particles that might try to infect the cell. But in the course of doing
that fundamental research and answering that
question of how it works, we realized that it could be harnessed for a different purpose,
because of its ability to easily find and cut
any sequence of DNA, and because we knew how it worked, we could reprogram it
in the laboratory to, for example, cut a gene that leads to cystic fibrosis
development and trigger cells to make a change in the
DNA sequence at precisely that place that could correct a disease causing mutation like that. – So in effect, your teams
were identifying the scissors, so to speak, and then also the GPS system, which is the tracer RNA,
if I have this right, which together make
this revolution possible in understanding how the
place in the DNA is found, how it’s cut, and it’s
replaced with something else. And what, when Banfield called you, she was saying, well,
we’re looking at this DNA, and there are these strips, pieces, of RNA in the DNA, what is this? We don’t understand. And you were the one who
was positioned, in a way, because of the work we just discussed, to begin the analysis of that. – Well, just a little,
a little revision there to what you just said. So what Banfield had found
was that there’s no RNA directly in the DNA,
but the important thing that she identified was
that there was evidence from her research that bacteria
had a programmable system. So they had this GPS,
as you’re alluding to. And the question was, how does it work. She suspected that it might
be an RNA-based system, which was the reason she googled me and contacted me, and that’s
exactly what we figured out, was that it’s an RNA-guided system that can be reprogrammed easily, once you understand how to program it. You can do that in the laboratory, it can be introduced into
different kinds of cells, where it then functions as a tool that scientists can use to
reprogram the DNA in cells. – And you’ve, team, figured out a way to combine these two functions
in one unit, is that? – Yes, so yes, so this is kind of getting a little bit into the
weeds about how it works, but it’s actually
important, so it turns out that in nature there are
two separate molecules of RNA necessary to create the GPS, right, that do the actual
programming of the Cas9 protein, and our team figured out
how you could combine them into one single piece of RNA that could be easily reprogrammed by scientists anywhere
to target DNA sequences in animals, plants, fungi,
basically any kind of cell. – And so, briefly, the revolution here is what this discovery means
is that it can be applied across the board in all sorts
of living things and domains. So biomedicine, agriculture, where changes that are very precise can be made in the DNA to
create a positive revolution, but also possibly, a negative one. – Exactly, yeah. So it’s a very powerful technology that is widely applicable across biology, as you just described, and importantly, it became very quickly
adopted by labs globally, and the reason was that it was easy. It was easy to use. We found that we could have
students come to the laboratory over the summertime,
and within a few weeks, we had them using Cas9
to edit human cells. Imagine, it’s just sort of,
incredible opening the door of opportunity for scientists,
and I think what’s happened over the last six years is that we’ve seen increasing applications of
this technology, as you said, and for biomedical
purposes, in agriculture, in what we call synthetic biology. And so there’s been a tremendous increase in the pace of science, and
just the number of publications that are coming out in
the scientific literature because of this tool that’s so enabling. Now, importantly, as we’ve
looked at your career and the problems that
you were interested in, you weren’t going for this result. You were following a
path of pure research. Your curiosity was leading
you to the next problem, and then, wow, you came upon this insight that has all sorts of
revolutionary implications. Now, let’s move to the whole realization which then, you turn into
something of a public advocate to help all sorts of
constituencies understand the implications of this. Because it has policy implications, it has ethical implications, it has potential national
security implications. – Correct, yeah. So it’s been a profound evolution for me, over the last few years,
recognizing that this project that, as you said, began as a
fundamental research project, kind of a very focused question that we were asking in our work, but once this technology was born, it really quickly was clear
that this was going to be, first of all, kind of revolutionary, and secondly, that it would
have a lot of implications beyond scientists working in their, sort of sequestered away
in their laboratories. And so I had to make a decision about how I would manage that, and I have to tell you that initially, I felt very uncomfortable with
the idea of speaking publicly about some of these broader implications, because like many scientists, I felt, first of all, that I’m not
trained, professionally in bioethics, and so who was
I to be speaking about this, and secondly, that I had a lab to run and I had classes to teach, and
I had a pretty full-time job at Berkeley, but I really came to see that I had to step up
to the plate on this, because I had been involved in the genesis of this technology, and it came with a lot of responsibility. – There’s a sense here that this has to have a profound effect on
the way we train students. So in the future, science students may have to think about the
implications of the work, on the one hand, although
they want to go for discovery, they wanna fulfill their curiosity, but also, students in the social science or in policy studies are
gonna have to know some of the science, because we’ve
got ethical issues here, we’ve got policy issues.
– Right, yeah, yeah. No, I agree. – And do you see that as
part of your advocacy role, to say, hey, let’s think
about our curriculums? – I do, and maybe I should be, I’m feeling a little bit guilty when I hear you saying that,
because maybe I should be doing more of that, but I would– – [Harry] You’re doing enough. – I would say at the
moment, I’m probably leading more by example than anything else. I have not put in place particular policy or curriculum changes, for example, here at my university, at Berkeley. But what I definitely do is I feel that a lot of the kinds
of speaking engagements that I have right now are, frankly, with groups of students, often
they’re younger students, even high school students,
and what I try to do in those forums is to tell students that my experience exemplifies
what can happen in science, where you start off
with one particular goal or set of questions, and science, being the kind of process that it is, it goes naturally in
unexpected directions, and that we all have to be prepared for the broader implications of our work and be prepared to step out of the lab and discuss the implications,
the significance of our work, and explain how that
affects societal decisions. – And there’s an
education role here, also, for the general public,
and I should point out that you have co-written a
book, A Crack in Creation, where you talk about the
evolution of your science and of your thinking about this set of problems we’re addressing. Now, let’s talk a minute about some of the negative consequences of this, ’cause there’s, in
genetics, there’s a history of going down the wrong
path in the early history of that discipline, going toward genetics. In the case of what you’ve discovered, one can envision states
using this technology with the hope of creating a super race, on the one hand, or eliminating
populations on the other. Talk a little about that. – Well, it sounds pretty scary when you describe it that way. I think the reality is that
both of those scenarios, right now, remain in the
realm of science fiction– – Thankfully.
– Thankfully, right? For many reasons, but what I do think is now on the table,
frankly, is the potential to alter individual
human beings genetically, and to do that, not just
in a way that affects an individual, but in a way that affects that individual and all
of their future children and grandchildren and so, in other words, it creates a heritable change to DNA. And that really is a profound
thing when you think about it, because it means that
we now have the power to control evolution,
as our book discusses. And not only of other
organisms in our environment, but of ourselves, and
so that really makes us have to think very hard
about, first of all, whether to do that, and I
think the answer will be yes, whether we want it to be or not. I think there will be people
that want to use it this way, and then we have to ask
how and when and why would one want to do this, and I think most people would say, well, if there’s an unmet medical need that necessitates correction to DNA, there might be an argument to be made that we should actually do that in people so we could remove a
disease-causing mutation from maybe an entire family. And you could imagine that could be very beneficial from a health perspective. There’s also, though, the potential for what we call enhancements, and changes to be made to
DNA that are maybe perceived to be desirable in some way,
but don’t actually impact someone’s health directly, so. – We should make an
important distinction here, as part of our public education role here, between a somatic cell and a germ cell. – Yes.
– Do a brief– – Yes, and we talked about
this in Elberg Lecture, right, but you raise a very important point, and that is that when we edit, when we use genome editing,
this technology CRISPR-Cas9 in what we call somatic cells, that means we’re making changes to cells that are fully developed. They’re not cells that can
lead to a new organism, whether it’s a human being
or a plant or anything else, right, so it’s, somatic
cell changes affect just an individual and not their progeny, but if we make changes in germ cells, whether that’s in the form of embryos or eggs or sperm, those genetic changes can become part of an individual and be passed on to future generations, so that’s a much more
profound kind of editing. – One of the ways for getting the world to think about how we should
regulate the implications of all of this is the notion
of the international community of scientists, so in this recent incident, where a Chinese scientist did work that affected the germ line and seemed to not know what he was
doing, he presented this at an international conference,
but there was really an uproar from the scientific community that this was a step too
far, without careful thought. – Exactly, yeah, that’s
right, that’s right. And I think what you’re referring to is an announcement from last November, November of 2018, by a Chinese scientist at a meeting in Hong
Kong that was, actually, a meeting organized, I was
on the organizing committee, organized to discuss human genome editing and this issue of human germ line editing. And what was announced
there was that in fact, a team of scientists had done this already and not in, just in a research setting, but they had actually
implanted edited embryos to achieve a pregnancy
and children, twin girls, had been born with
reported edits to the DNA. So this really, I think, shook up the international scientific
community profoundly, because it emerged, as the details of the work were unveiled,
that the particular edits that were made to those two girls were, in fact, changes to DNA
that had never been observed in humans, and in fact,
never been tested in animals. So it really had the
feeling of doing research on people, and without appropriate consent or a plan for following
their health in the future. So it was really quite
shocking, I would say. – Another constituency, it seems to me, that needs to be educated
are our political leaders, because they’re gonna have to define the rules, the legislation, the laws that, on the one hand,
regulate, moderate, control, without interfering
with the work of science and the creativity that will
lead to great discoveries. Any thoughts on that,
besides reading your book, which they do. – Well, I think that, I’ve
been actually very pleased that there’s been quite a lot of interest on the part of various governments, including here in the United States, but also in other countries. And over the last several years, I’ve had the opportunity to visit with a number of government delegations who have been on fact-finding missions, trying to understand what’s
happening on the research front, and how they should be
addressing any regulatory needs that are arising due to new technology, including genome editing. So there’s attention being
paid to this, for sure. I think the devil is in the details. How do we think about this? And it’s almost a rhetorical question, because, and I’d love to
hear your thoughts on it too, because there’s no easy
answer, in my opinion. I don’t think that we
would want a situation where non-scientists are
placing a large number of regulations on the scientific community that might, frankly, impair the ability to develop new ideas and creative work that will solve real
problems and help people with their healthcare and
other kinds of situations that they’re facing, I feel
very deeply about that. But at the same time,
one does not want to see technologies being
utilized, as we observed in this announcement from last November, where people are being experimented on, perhaps without their real understanding of what’s happening,
and certainly, in ways that I would consider to be unethical. – It’s interesting, ’cause it strikes me that, although the science
is moving very quickly, that you almost have to do
this on a case by case basis, and that the case of
the Chinese scientists, there clearly was a mobilization by the scientific, the
international scientific community about the implications of this, because some of this
seems to be about alerting the political leaders
and alerting the public about the implications. I think of nuclear weapons
and the important role that things like Pugwash, these
meetings between scientists on both sides, and how it shaped the actual political negotiation with regard to the control
of nuclear weapons. Unfortunately, the one caveat here is, goes back to a point you
made in your lecture, which is, the tool we now have
is one of democratization. Anybody can do it.
– Yeah, yeah. That’s both a blessing and a curse. – Well, one last question. If students were to
watch this and look back at your career, what should they learn about creativity in science and the road to great discoveries? – I think keeping an open
mind is very important, and I also think that it’s very valuable to follow your passions, and pay attention to what each of us finds exciting. What I’ve learned over the
years from my students, my many students that have
worked in the lab with me, is that each person that
comes to the laboratory comes with their own cultural background, their own intellectual
interests, their own skillset, and I think for each of us, we have to discover about ourselves what kinds of questions
we most want to answer in science, and for me, it’s always been about paying attention to
that kind of inner voice, things that I find real
exciting and interesting, and coupling that with working
with people smarter than me, just trying to find people
that are really going to help build a team
that can ask questions and do science in a way that’s both intellectually
stimulating and fun. – And this path is a vehicle
for building self confidence, which, I think I’ve read
you feel is very important. – Very important. I often think back to a story, I can’t remember if I told it in the book or not, but I was a, I think I was a second-year
graduate student, and I had joined Szostak’s lab at Harvard. It was very clear that I
was working for somebody who was kind of a creative
genius in the lab, and I was so amazed that
he would have accepted me into his lab, and I remember one day, I was sitting at my desk
and I was planning out an experiment that I
was gonna do that day, and he came down the hall
and he came over to me, and he said, “Hey,
Jennifer, I’ve been thinking “about an idea for an experiment, “and I wanted to bounce it off of you “to see what you think, and see “if you think it’s a good idea.” And I can’t tell you how stunned I was. This brilliant professor is asking for my, little second-year
graduate student’s opinion about his idea, and it was
that kind of interaction that I had with my, a number of mentors, but certainly with Szostak over the years that I think helped me really build my confidence in the beginning. – Well, on that positive note, thank you very much, Jennifer. Being with us, and sharing the trajectory of your career with us, and leading to this wonderful discovery, thank you. – Thanks so much for hosting me. – Yeah, and thank you
very much for joining us for this Conversation with History. (soft music)

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