Meet the Decoders
Dr. Francis Collins
Dr. Francis Collins
Krulwich: There's an analogy I was given that Mozart would sometimes compose
music [such that] you would put the sheet of music in front of you and you read
from the top to the bottom. You'd play a beautiful tune. Then you could take
the music and simply turn it upside down and read it in what is in effect a
mirror image and play another beautiful tune.
Collins: That sounds apocryphal to me, but it's a great story.
Krulwich: Is that the sort of thing? That is, depending upon how you read the
genes you can get different end products?
Collins: Maybe think of it more as if you are reading a mystery novel, and
there are several chapters, and you could pull some out or stick others in.
People actually write novels of this sort. You can make the ending different if
you get sick of that particular one. There's an alternative way to substitute a
few pages here and there.
That's sort of what the gene is doing. You read it one way and you get this
ending; you change around a few chapters, a different guy did it. It's the same
kind of parallel. You have enough information there to code for several
Krulwich: What does folding have to do with it?
Collins: Well, genes are effectively one-dimensional. If you write down the
sequence of A, C, G and T, that's kind of what you need to know about that
gene. But proteins are three-dimensional. They have to be because we are
three-dimensional, and we're made of those proteins. Otherwise we'd all sort of
be linear, unimaginably weird creatures.
So the DNA information, in the process of being translated into proteins, you
end up making a string of amino acids. That's what a protein is. But they're
not going to be happy lying out flat in a long, linear array. They have needs
and reasons to want to be snuggled up against each other in a particular way.
And actually a particular amino acid sequence will almost always fold in a
precise way. Every time you make that one it will fold up in a certain way,
with some help from the cellular machinery.
Krulwich: Shall I think origami-like, an interesting folding?
Collins: It's very elegant, very complicated. And we still do not have from
first principles the ability to precisely predict how that's going to work. But
obviously it does work by a combination of chemistry and a little nudging maybe
from the cell saying, "Oh, don't twist that way, twist that way, and then
you'll get it right." But it does work. You end up with proteins that virtually
always come together in this three-dimensional shape, without which they
couldn't do their work.
Krulwich: Because they want to stick here, land here, point here or what --
shove there or something.
Collins: And if you have a long sequence of amino acids, it may be that this
one over here has to be next to this one over here or the critical thing that
protein has to do can't happen. So they have to hold up just right so that they
actually end up next to each other in the three-dimensional structure, even
though they were far apart in the beginning.
Krulwich: So to identify these different proteins you not only have to know
what they're made of but you have to fold them properly?
Krulwich: And to solve a mistake, to make a bad protein good, sometimes it
would just involve re-folding it?
Collins: Well, cystic fibrosis is a very well-known example where the problem
seems not so much to be that there is a missing amino acid (although there is),
but that the protein as a consequence of that doesn't fold right. So if you
could get it to still fold properly and end up where it was supposed to be, the
fact that that one amino acid wasn't there would have a mild effect but
probably wouldn't be all that severe.
The problem is it gums up the works. Something about that particular
phenylalanine that is supposed to be right there at position 508. If it's not
there, this complicated process of getting this whole thing assembled in the
origami way gets hung up, and it doesn't finish the job. And parts of it that
should have come together in a nice formed, globular way get all strung out
over to the side, and it gets stuck in the machinery that is supposed to
produce that protein in the right place at the right time, and it doesn't
Krulwich: But if you could figure out how to properly re-fold the chemistry,
then you would cure someone with cystic fibrosis, or at least make it so mild
that they wouldn't die.
Collins: There are several drugs already under development that aim to do
exactly this, to sort of cushion that molecule and help it to fold properly,
even in circumstances where it normally wouldn't. We know, by the way, if you
just lower the temperature, it will fold okay. Something about being at body
temperature is just a little too warm for this unstable protein with this
mutation in it to find the right shape, and if you could just cool it down a
little bit -- not so easy to do -- you could probably convince it to end up
Krulwich: Two final questions about this. Why is this such an attractive
business? It seems like everybody we talk to who used to be in the gene
business seems to want to get into the protein business.
Collins: Well, again, I think the proteins are the players that carry out the
action. If you really want to understand a disease, if you want to develop a
therapy -- whether it's replacing the protein or developing some small molecule
that is going to interact with that protein to nudge it along in a way you want
to -- you've got to understand how the protein works.
And, ideally, you want to know all about it. You want to know what is its
structure is in three dimensions, what's its active site, what other proteins
does it bump into, where is it in the cell, what are the kinetics or the
reaction that it's involved in -- all of that stuff. That's proteomics, that's
what everybody is all excited about.
We sort of have the genome and at least a pretty darn good working draft. That
`s great. That allows you to predict what all the proteins are because of this
correspondence. Now it's kind of time to move on and figure out how to use that
information therapeutically, and the proteins are key to that.
Krulwich: Is that another way of saying that we have found -- in fact, you have
helped find the genetic mistake that leads to cystic fibrosis, but all these
years have passed and we can't fix the gene, so let's just go upstairs and see
if we can fix the chemistry that the gene creates? Is that basically the
Collins: I think for every disease you're going to see people pursuing
therapeutic ideas in two different directions. One will be to understand what
is wrong with the gene and try to directly fix it. That is the strategy that we
commonly call "gene therapy." The other is to understand how the gene works,
what protein it makes, what's wrong with that protein in somebody with the
disease, and how to tweak it so that it works after all, even though it wasn't
quite designed right.
And for me, I don't care which of those pathways works for a particular
disease, whether it's Alzheimer's disease or heart disease or schizophrenia. I
just hope one of them does and does so quickly. And I think the betting odds in
many situations are that this pathway that works through an understanding of
the protein may get us there more quickly than the very difficult problem of
how you fix a gene itself when it's not spelled right, and how do you deliver
the nice neat correction of that problem, which has clearly been a big
challenge for research.
Krulwich: So as hard as it may be to learn the art of folding, you might
discover how to be a better folder, you might be able to become a gene fixer.
That's maybe a dumb way of saying it. But if it's caught between here and
there, if there it's called something that helps the patient -- cystic fibrosis
Collins: Yeah, that's where we want to get to.
Krulwich: So did you get a little frustrated after a while when you knew the
name of the cause but there was no way to fix the cause?
Collins: Well, actually when we discovered the cystic fibrosis gene in 1989, I
didn't give much hope that this would have therapeutic consequences for 20
years. It just didn't seem, when we stared at this molecule, that it was
obvious even what direction to go in. So actually I think we've made pretty
good progress, but not good enough. We still have not seen this disease cured
or even particularly benefitted by all of this wonderful molecular biology. You
have to still treat it pretty much the way it was 10 years ago.
But that is going to change. There're now about a dozen drugs in the pipeline
that are based upon a molecular understanding of this gene and its protein
products. And some of the protein therapies are to try to encourage the
molecule to fold correctly and some of the others are actually -- now that we
understand what it does -- to try to get another protein that might be able to
take over the function here, sort of take up the slack, to work a little harder
to compensate for its partner, the cystic fibrosis protein, that isn't doing
its job. I would call that a protein-based therapy as well. It's using a
different strategy, but it still depends on understanding precisely what the
protein problem is.
Krulwich: And could you venture a guess as to how long it might be before
something interesting happens on the protein side with CF?
Collins: Oh, I'd say a lot of interesting things have happened on the protein
Krulwich: Well, let me ask you better, more specifically. Where you could pop
something or inhale something and then you would not have as bad a
Collins: Well, it's always risky to predict timetables. I mean, I am encouraged
that there are a number of these drugs already in Phase 1 trials to try to see
whether they're toxic and whether they might have a hint of benefit. That's a
long pathway. The CF Foundation has also put together, I think, a very
ambitious program using this thing called "combinatorial chemistry," where you
can screen tens of thousands of possible compounds at a rapid pace to try to
find others that tweak the cystic fibrosis protein in the right direction in a
high throughput kind of analysis.
Krulwich: You mean, I can get tugboats, sort of folding tugboats, that
basically shove things together or move them apart, that sort of thing?
Collins: See, the cell has its own system of tugboats to sort of keep things
from getting out of line. They're called things like "chaperones," because they
are chaperoning along this protein so it doesn't misbehave or get drunk on
Saturday night. Sort of make sure that that protein goes to where it's supposed
to and doesn't deviate from the straight and narrow.
So there's a system there already, but maybe it needs a little help. And if you
had the ability to screen a very large number of possible small molecules you
might find one that sort of steps in at just the right moment when the
chaperone was looking the other way, or had a particularly difficult client
that night and had it all turn out okay after all. Got everybody home
Krulwich: New subject and final subject. The movie. Has there been a movie that
has turned your eye a little bit? That raises some of the more interesting
ethical questions for the whole genome project?
Collins: Well, I actually think GATTACA for me was the movie that really
raised some interesting points. I watched that move three times.
Krulwich: Which movie?
Collins: This movie called GATTACA that was in the theater for about a
week and a half. I think I and about four other people went to see it. It was a
little over the top, as any movie would be that deals with science fiction. But
it was provocative. It portrayed a society where genetic determinism had
basically run wild. And society had given up all their civil rights in the
belief that genetics was able to predict everything about you in a very precise
Krulwich: Let me go to the scene -- in the gripping opening scene a baby is
born, and they quickly put some kind of device on his heel, pull out a piece of
blood. Then you watch one globe of blood drop. And it looks like that globe is
fixed. Apparently everything that that blood can tell you will happen. At least
that's the impression the movie gives. And this nurse starts calling off the
precise probabilities of one horrible thing after another. Is that conceivably
an accurate reading of what might happen in 100 years?
Collins: Well, it's like a good Hollywood depiction ought to be. It has a
kernel of truth to it to sort of draw you in, but it's also overstated in order
to make a good yarn. So, yes, a drop of blood contains within it enough cells
to be able to look at the DNA sequence of you or me or a newborn baby. So it
would be realistic, if you decided it was ethical, to actually do this kind of
report card analysis of a newborn. In a matter of another 10 or 20 years that
will be feasible.
Krulwich: Wait a second. I notice that she is making predictions about
near-term diseases and problems, and she even tells the mother and dad when the
baby is going to die and of what.
Collins: That's the part that is really off the wall. Because, in fact, these
kinds of genetic predictions, while they will be possible for common diseases
like heart disease or diabetes, they will be very squishy. They will be able to
say this person's risk of getting heart disease at age 70 is two and a half
times higher than the average. But there will still be a good chance that they
won't get it. So these will be risk factors couched in statistical
And the notion, as the movie portrays, that some of these will be 99 percent --
no way, unless you're talking about something like Huntington's disease, where
the misspelling of the gene is almost certainly going to lead to a certain
result. But that's quite unusual.
Krulwich: She says -- she gets this sort of sad little look on her face, the
nurse does. She says, "Heart disease, 90-something percent." That's the one
where you think, "Uh-huh."
Collins: Genetic predictions, except for strongly inherited disorders like
sickle cell anemia or Huntington's disease, will not be of that sort. And most
of us, when we get this information, will be getting squishy statistical
information that says risk is a little higher, risk is a little lower, but you
still might not get this or you might. We're going to have to deal with that
And why is it ambiguous? Well, because genetics is not deterministic. There's
the environment; it's a big deal. There is free will; that's a big deal, too,
depending on what you decide to do with your own body and your own diet and
whether you smoke. It would seem immediately obvious from those arguments,
which I think most people accept, that it would be ridiculous for somebody to
be able to look at your DNA and say, "Oh, you're going to die at age
That's impossible to accept because we understand that it isn't how it works.
Look at identical twins, our sort of favorite example of nature and how it
interacts with nurture. When you get to know them, they're different people.
When you look at their medical records, they're not identical. Yet their DNA
is. So clearly that kind of prediction that you see in the movies is going to
be couched in all sorts of uncertainties and ambiguities, and I'm just as
Krulwich: But the learning to live with an environment like this, or learning
to live with report cards, is something that's going to happen, right?
Krulwich: Because this little boy and this little boy's parents -- because in
the next scene the little boy falls and you see the anxious look on the mom's
face. Every fall has more meaning to someone who is predicted to be about to
have an illness. This "probably" diagnosis is scary. It's very hard to adjust
Collins: Yeah. So let's step away from the movie and consider the reality. Ten
years from now I think you and I as adults -- I would say probably not as
children; I don't think that's such a great idea, most other people agree --
but as adults we could find out what our susceptibilities are for a dozen
different conditions: cancer, diabetes, etc.
Would that be useful information? Well, in some instances you bet it would. If
you have an intervention -- by lifestyle or diet or medical surveillance -- you
could reduce the risk of dying of a terrible disease? Yeah, that sounds like a
But we have to keep cognizant of the ways in which that might be a bad thing
for some people if it does become a self-fulfilling prophecy, if somebody who
is bound to have a higher risk begins to think of themselves as already ill,
even though they're fine. Or, more diabolically --
Krulwich: Don't you know a lot of people like that; people, who, if there's a
cloud in the sky, they know they just live in the shadow?
Collins: People come in all sorts of flavors. And I'm sure genetic information
will play into whatever dynamics that individual already possesses about how
they view themselves as healthy or not so healthy. And we'll have to deal with
that, that we may be, in fact, adding to the burden that people who already
feel a little shaky about their condition of health will now have more evidence
to feel shaky, and that's something to wrestle with.
And those people, clearly, should never have this information imposed upon them
if they don't want it. They should figure out whether this is something they
want to carry around or not. I think most people will probably say "No thanks"
to the kind of information that doesn't get attached to an intervention that
allows you to do something. Doing something gives you a sense of control. Okay,
it's this. I can make it lower than this.
Krulwich: But what about Glenn Close? Glenn Close, who is not related to this
baby or related to the parent, says, "Sorry, we're not paying your bills
because you introduced an expensive human being into the world, a human being
who we knew was going to have trouble. I don't know who you are, Mr. and Mrs.
X, but you have dome something antisocial."
Collins: This is a serious issue, maybe the most serious one we've talked
about. We do have a promising future here in terms of the applications of
genetics towards individualized preventive medicine that can keep us all
healthy and allow us to live longer, and that's a good thing.
But if that information, as in the movie, gets used to say, "I'm sorry. Your
health insurance has been canceled because you're too big a risk anymore," or,
"You have to take this test because we, your insurer or your employer, need to
know whether we want to support you anymore," then we've done something
This is a fixable problem. It requires effective federal legislation. I'm
sorry, there ought to be a law, and there should already be a law.
Krulwich: So all the villains in this little selection here, Glenn Close is the
one you really don't like?
Collins: I think the scenario of predictive genetic information being used to
discriminate against people is truly scary and one that we ought to put an end
to and we can't.
Krulwich: What about the genetic chemist, that slightly smily guy. He says,
"All right. Do you want a boy or do you want a girl?" And then he said, very
matter-of-factly, "And we've taken care of all those things that might make
your child less than above average." This is a Garrison Keillor world. All the
children apparently have to be above average.
That seems to me almost extremely likely to happen, because what parent
wouldn't want to introduce a child that wouldn't have -- at least be where all
the other kids could be?
Collins: That for me was, in fact, the most compelling theme in the movie,
because it's the closest to a real situation that is right in front of us, or
almost in front of us. The technology that's being described there is, in fact,
quite realistic. It's called "pre-implantation diagnosis," as part of in vitro
fertilization. It's being used to try to prevent the birth of a child with a
terrible genetic disorder, like, say, Tay Sachs disease. But it allows you to
carry out a diagnostic procedure on multiple embryos and then decide which one
you want to reimplant.
That has already been somewhat in the news with the case of Adam Nash, the
little boy who was the product of such a screening procedure, and who is both
free of the disease that his sister has but also a good match for his sister
and has provided her with the transplant which she needed. That has certainly
caused a lot of ethicists to look at this and go, "Wait a minute. Did we just
start down that famous slippery slope?" Because this process has up until now
been limited to the use of trying to prevent a terrible disease. But now we've
actually created a child partly for another purpose --to provide a
Krulwich: You saw that look in the mom's face. You know, she looks at her
husband and says, "Aren't we supposed to say something, because we don't want a
perfect baby; we wanted a baby that was without any horrible diseases. We were
going to stop there." And this fellow has just rolled right past that, as if,
well, any caring parent would feel this way.
Collins: That's why the scenario is chilling. You can sort of see how the
dynamic might develop and how parents might in fact feel that in order to
demonstrate that they are good parents, that they do care about their kids,
that they are going to put them in the best schools and give them music
lessons. But it's also not just a possibility but their obligation to make sure
that they have the best mix of DNA.
And then there is this wonderful line in there about, "We're not doing anything
unnatural here. We're just taking the best of you." There's no new introduction
of genetic material in this process; it is simply screening a large number of
embryos that that couple might produce and trying to pick the one that will
have the most desirable characteristics.
Now, here again there is an element of Hollywood science fiction here. Because
the number of embryos that could actually be produced is not huge, and the
ability, therefore, to select for 10 different things that would all be optimal
in the same one, well, you go through the probabilistic calculations, and it
isn't going to work very well. And, furthermore, it's not going to work very
well because the whole premise of the movie about determinism is wrong.
So if they're promising this couple that this child is going to be a musical
prodigy and is going to do all these other wonderful things, the kid may be a
sullen adolescent who takes drugs. You can't actually count upon the DNA being
that definitive. So when you begin to go down this pathway of the designer
baby, the designer part of it is going to extremely imperfect. And that alone
may make this not very appealing to most couples. Just the same it behooves us
Krulwich: Meaning this is no guarantee here?
Collins: Right, no guarantee. You will not be able to sign a document that
says, "I'm going to bring this one back if it doesn't turn out the way I want."
And a lot of the things that couples might be most interested in asking about,
like intelligence or athletic ability or physical attractiveness, whatever that
is, are not going to be very nicely predictable by this kind of
So the good news might be that this attempt to use this technology for
enhancement of characteristics is so flawed in terms of its effectiveness that
it never really takes off. And then we don't end up with the scene in the
movie. But at the same time I don't think you can entirely count on that, at
least not in a big way.
And so I do think we are at the point now where we ought to begin to consider
whether society has an interest in placing some sort of limits on the use of
genetics for enhancement. I think society in general has smiled upon the use of
genetics for preventing terrible diseases; that's part of a long tradition,
that's what medicine is about, that's what almost every culture believes in.
Alleviating suffering is a good thing.
But when you begin to blur that boundary and move into an arena of making your
kids genetically different than they would have been by the usual roll of the
dice in a way that enhances their performance in some way, that starts to make
most of us uneasy.
Krulwich: At the same time if it's a specific question about your baby, it's
hard to imagine that there could be a law that says, "You can't have the best
baby you can have. We won't allow you" -- this word "best," assuming that such
a thing is possible. It's very hard to imagine people not quickly running off
to Curacao or the Antilles to get that baby.
Collins: I agree with you. We have a collision course here between the usual
principles that couples are the only people who ought to be involved in
deciding about their reproductive decisions and their outcomes, and society's
interest in not having a particular branch of science run off in a direction
that most people in the society are uncomfortable with.
There are consequences if we turn our head and completely look the other way.
The technology won't be available to everybody. It will probably be available
to those with lots of resources. You can imagine --
Krulwich: Money, you mean?
Collins: Money, yes, money. And education and access to sophisticated medical
technology. And this might further distance the haves from the have nots. It
might further add to the ways in which people look at disabled individuals as
though it was their fault, which very much came across in the movie. There are
consequences for just saying, "Oh, well, let's see how this turns out." So I
don't think we can afford to say, "It's inevitable. We better just turn our
head And walk away." I think we really have to engage in this debate.
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