TRANSCRIPT: Meeting 2, Session 8

Reflections for the Future

Date

September 14, 2010

Location

Philadelphia, Penn.

Presenters

Sydney Brenner, M.D., D.Phil.
Senior Distinguished Fellow of the Crick-Jacobs Center, The Salk Institute

Transcript

Jim Wagner:
Actually, our next panel is a panel of one, who can certainly hold his own. I have the pleasure actually of introducing to you Sydney Brenner, who is a geneticist and winner of the Nobel Prize in Physiology and Medicine in 2002. He continues to be one of the world’s leading pioneers in genetics and molecular biology. He established the existence of messenger RNA with Francis Crick back in 1961 discovered the triplet nature of the code approaching translation which provided critical insights into the nature of genetic code. His recent work involving new ways to analyze gene sequences has led to fresh insights into vertebrate evolution.
 
He is a Fellow of the World Society, a Foreign Associate of the National Academy of Sciences, a recipient of the Lasker Award in Medical Research and currently a Distinguished Fellow at the Salk Institute. We learned last evening that as a mentor and master, he is demanding, but the results seem to be well worth it. He told us last evening that five of his post-docs are also Nobel Laureates. I asked if he had any open slots.
 
Sydney Brenner:
Too late.
 
Jim Wagner:
That’s what he told me. It’s too late.
 
Amy Gutmann:
Too late.
 
Jim Wagner:
We are delighted to have you with us today, Sydney.
 
Sydney Brenner:
Yes. Well, I thought I would begin at the beginning because I think there is a lot of confusion about this synthetic biology. So let me begin by saying that the most important thing to understand about the living world is that it is the only complex, natural system which contains an internal description of itself.
 
And I can illustrate this by a story, which I think is important to understand.
 
I once attended a long and boring discussion by a Buddhist priest. And at the end of this, someone said, "What is the Buddhist definition of life?" And he said that many Buddhists believe that everything is alive; the rivers are alive, and mountains are alive. I interrupted him and I said, "Mountains are not alive." And he said, "How do you know?" I said, "You can’t clone a mountain," which is a title I’ve patented for a book.
 
You can’t clone a mountain because the mountain does not contain this internal description which, of course, are the genes because that’s what you hand down from generation to generation. That is what changes. That is what differentiates one organism from another.
 
So DNA by itself is useless, and it will probably just fall to pieces in the laboratory.
 
You must be able to express what is in the DNA. And if you want to do anything with it, you need to copy it. That’s what organisms have learned how to do. So if we were to ask how should we treat all of this, we have to ask, "Well, what are we synthesizing?"
 
So let me now let me go to another area of synthetic which is chemistry. Now we know that in chemistry you can start to study natural products and you can try to find out what their structure by degradation. That’s the way by all chemists. But the proof that you’ve got the right structure is that you can make it. You can synthesize it.
 
Now in that case, these people have to put elements together in a way which is not the way they were put together inside the natural product. And so they learn an alternative way of making that which, of course, is then deployed in making entirely novel compounds. So I think there is a very important place for what I will call synthesizing DNA or synthesizing genes, which is to prove that you really know how it works.
 
Today we live in a period where we think we can describe everything in the world at atomic resolution, so we don’t have to bother to understand or prove anything. But if we are going to understand living things, we need to prove that we know how this gene is turned on or what disease does. It’s not enough to give just a description. That’s not science. That is something else.
 
So I believe that one has to start with this fundamental thing, that of the DNA which then has to be interpreted by a living system in order to do anything. It has no function as such. It has promise, but it only has promise by itself.
 
So if you take that point of view, I would like to add one other very general thing.
 
About 60 years ago, John von Neumann, a very great man whom everybody knows from other things in this country was concerned with how you would build self?reproducing machines and he produced a very interesting, a very interesting, set of theorems, if you like, that there were conditions for constructing such self?reproducing machines.
 
I read his article in 1950, and I was astounded by this because later it turned out he predicted the whole of the DNA, the DNA and the structure of living systems. So it is one thing -- and, indeed, in fact, this was unknown to all of the people working who seemed to be more influenced by Schrodinger, though Schrodinger can be shown to have been wrong. He said that the chromosomes contain the program for the organism and the means to execute them. They do not contain the means. They contain a description of the means. You have to read that.
 
So we have to distinguish inheriting things between two things. On the proposition of continuity, you first have to make something using the machinery of one and then you have to using the description. So you must already have the reader. So it’s a moot point if you synthesize a whole genome. If the genes there were incompatible with being read by the machinery of the recipient, you would not get anything.
 
His experiment ?? I tried to do his experiment many years ago just by standard mating, which was the question, whether if you put E. coli into salmonella ?? it was a favorite question we used to ask students, what do you think the outcome would be, and everybody thought it would be sort of in between, you see. The safe answer is wrong because then you find it doesn’t work because there is one failure in the reading mechanism because you can’t get that out of salmonella, the DNA, until you have it.
 
Okay, so there should be one gene that you would then have to put an E. coli promoter there so you could read it and so it could go on and read itself. So there are very strong conditions for moving DNA extraneously. So I really think we need to see this.
 
And just in the last discussion we had, I think the nightmare, the nightmare incident which I think we could think about, is the suicide-infector who gives himself smallpox, travels to a country and goes around to movie houses and can create an epidemic today when nobody is vaccinated. And I think we should look at the natural way in which infection is moved like the SARS epidemic. And you can see that those which are the product of nature’s genetic engineering simply because you have a lot of people and ducks or people and other animals living together, viruses will exchange things and you create novel pathogens.
 
The other thing I would like to say that you need to have fairly in perspective is the following. It used to be argued, especially at the Asilomar that the dangerous thing, the dangerous thing, was to cross natural genetic barriers; in other words, to put DNA. We always considered cloning orange DNA and duck DNA together and what that might could be, you know, thought of. It resulted in a completely distorted view of pathogenicity. The view was, the more pathogenic the organism, the higher the level of containment. So in a sense, lions should be cloned at a much higher level on containment than pussycats. Clearly lions are more dangerous than pussycats. But that took no account into the reconstitution of the pathogenicity. In order to get an effect, as I said, the DNA is useless. You must reconstitute the actual pathogenic mechanism.
 
And so I think when we do this we need to keep all of these things in parallel because what Venter has done is, he’s a forger. He’s created counterfeit genomes. That’s exactly what he’s done. He’s copied another genome. I mean, he’s also -- I mean, like most forgers he actually has signed the forgery, you see, so we know it’s him. [Laughter.] But this is not -- this is not a little thing. He has synthesized nothing. He has created a counterfeit which just does what nature does, and so he has proved that nature can be emulated in that way, just by copying. And I think that’s fine. I mean, we knew it anyway from the normal one.
 
So I believe that there is still a very important area of misunderstanding of what the technology can do. And, I mean, even in the example if I may mention it of the bioterrorrist who orders a pathogenic sequence from this, he will have to amplify it in some way, which means he will have to protect himself from it or else he will be like those Irish bombers who would blow themselves up at the wrong time in the streets of Birmingham. But he will have to have much more than just a garage in order to create a real public hazard. So I think we would really have to know, as someone said, who is ordering the DNA.
 
Now I would just like to finish off by saying that really what are the visions for all of this technology that can come? So we’ve heard of all of the applications. None of them are really novel in the sense that they hadn’t been already thought of with ordinary genetic engineering.
 
I think that personally that the most important thing we can understand is the discovery of how devices work at the molecular level. We have three classes of devices in the world -- or gadgets if you like. You heard about all of this. Nature is making little gadgets here, and so there are devices.
 
There are the devices that come out of synthetic organic chemistry. There are the devices that come out of what is called nanotechnology, and there are the devices that can come out of biological systems.
 
Now, if you look at the character of all of these, they have different modes of specification. They have different modes of fabrication. And the area that is completely missing is how we put this all together to make things that are of use and that function in the real world.
 
So how can we employ the great specificity of biological recognition at the molecular level when we only have very crude methods of putting that into a device like making an array and so on. We can’t read directly from a sequence into a computer. We have to go through a lot of other machinery.
 
I think that’s an area of technology ?? in fact, when I started a new lab recently, which you have to be under 30 to enter and in which you have to know what you want to do ?? I’m not going to tell them when they want to do and, so this is a lab where we train real scientists. And so I had to find a name for it. So since for the last 50 years all we’ve done is pen the name "molecular" to everything, and so we have molecular gynecology and molecular medicine and what-you-want -- I believe even molecular psychiatry, which sounds like something we should use for the DNA of apogamic sequences. However, so I thought, "What about molecular engineering?" I had never heard this before. So just for desultory I actually looked for it in one of these literature abstracts.
 
There was a paper written in 1980-81, I think by Drexler, the same man who has propagated nanotechnology, in which everything, synthetic biology, says more and, of course, less because the technology didn’t actually exist, he has written there in that paper. It’s inspired him to do the things in nanotechnology as well. So I think that that presaged, and I think that is the way really to think about the technology. It is the technology of engineering at the level of molecules. And I think if we develop that, it becomes sensible area, which I think is really full of promise for us.
 
So I just will finish off on one last thing. It is the whole business of saying, well, if it doesn’t occur in nature, we really need to control the scientific population of people who work in laboratories because that could fire it off. So I want to tell you a true story. I was very keen at one stage, really, to do a dangerous experiment just really to see what’s the limit, because, you know, nobody knew what you had to do. If you want to contain it in a lab, we should do a dangerous ?? we actually did one at NIH finally, but it took years to it get going.
 
You want to really know, can animals be infected with DNA? Can they be infected with DNA in a plasmid? Of course, as I said, all of those experiments were doomed to success. They were going to work because the barriers as we conceived them at the time were nonexistent.
 
So I conceived of the following experiment. I would take ricin which is the thing that the KGB used to knock off people in the London train -- a very poisonous material. I would get the sequence for ricin which was known at the time, and I would clone it in lambda and I would put it in E. coli. Little did I know at the time that nature has already done it because the toxin of shigellosis is exactly a homologue of ricin. It is cloned in epsilon which is a phage. The phage is defective, which I believe the successful bacteria don’t want to give it to someone else basically, so it’s a defective phage. And it’s in shigella, which is a close relative of E. coli. And now that we understand so much about the evolution of genomes and know of many cases, DNA moves freely in the world.
 
And so I will just finish by telling you that at the time when everybody was saying the recombinant in science is the Pandora’s Box, if we keep it closed we can stop it, kill it before it’s born, that idea that controlled the scientists and you will be safe didn’t work.
 
But in the same page of your Federal Register, there is the previous one calling for meetings on how to deal with antibiotic resistance. What caused antibiotic resistance? We know where the genes come from. We know that it was caused by us loading into animals a huge excess of antibiotics. So selection is an important rule. And if you like, that was an environmental change. It had nothing to do ?? nature provided the bits and pieces, but we provided the conditions for these to survive.
 
So I think it is extremely important to understand about transmission, to understand about how the environment can be in that case unwittingly used in order to create or increase something which was really undesirable and threatens our control of infectious disease. So that, I think, if you put that into perspective, that you need something more than DNA, you need actually to create a public hazard, then I think that that is the thing.
 
And, in conclusion, I do agree with what one of the speakers said: Watch out! You need to watch for the technology that can make things, not only worse, but also better. So I think, for example, those are the warning signs that I think is there.
 
Jim Wagner:
Dr. Brenner, thank you for that summary and some provocative thoughts as a matter of fact. I will turn now to our chair who, I believe, has a ?? no, no, stay put.
 
Amy Gutmann:
I have a question for you, Sydney.
 
Sydney Brenner:
Okay.
 
Amy Gutmann:
We’ve talked about and we’ve used the phrase among the commissioners and yesterday in the public session of "responsible stewardship," of the responsibility basically of the human species to be stewards, of the environment, and of future generations and to make sure the world has a future and, ideally, a future at least as good if not better than the present. We’ve also heard a lot of people concerned about not only synthetic biology but about genetic engineering and a lot of what the biosciences do.
 
And I heard you say that the proof ?? and I think this is a very succinct way of saying it and leads to my question. The proof that you have the right structure is that you can synthesize it. Now, how do you address the concerns of individuals in groups who think that this ability of the human species to synthesize in order to prove things is destructive of our stewardship of nature?
 
Sydney Brenner:
Well, I think that that’s a question which can only be addressed by education. So I think we live in a world where increasingly people are suspicious of all technologies. And I think the only thing we can do is, I think, to educate the public.
 
And I think it does require -? it does require careful thinking about what their own sight should be and also a realization.
 
If I can you give you one example? I was giving a lecture on cloning and someone in the audience stood up and said, "Why can’t I clone myself and keep the copies for spare parts?" My answer was, "Be careful. One of the copies might keep you for spare parts."
 
[AUDIENCE LAUGHTER]
 
See? Now I tell you that is something we are guilty of. What we don’t realize is in the way we talk we begin to view people just as genomes -- I think all of this, whereas you are much more than a genome. You are your memories. Your immune system is different and I think to guard against the individuality. I think that also everybody who has practiced medicine will realize that people have no notion of probability. If you say to a patient, "If you take my treatment, you have 60 percent of being cured." They say, "Am I in the 60 or the 40 percent?"
 
So I think we have to address the public really as individuals, and I think we really need a way to educate, to educate people into acknowledging that the best way they can look after themselves is to look after other people. So it means we must take -- and I think that is one thing that can be done because our perspective of adding all of these things has been to depersonalize the individual. But as long as we say we are dealing with persons and not just genomes or bodies, I think it’s a very important to start from that point of view.
 
I think that’s just an attitude and a broad philosophical attitude that I think needs to be corrected in the way we talk about this, just the language we use. That is why I urged Drew Endy not to use the words "synthetic biology," because I said, "Well, one day he will be called a synthetic biologist, and that puts him in the class of plastic surgeons, [laughter] animal behaviorists, and all of the other fat bio?chemists -- I believe they are called lipid bio?chemists. We used to call them fat bio?chemists; however, but I think it’s a bad choice of words.
 
The same with genetic manipulation or modification. It should have been called genetic enhancement. It would just have carried a different context to the public.
 
So I think when we do this, we really need to think of always identifying what --
 
Amy Gutmann:
The terms. So organic chemistry got it right even though it does synthesis over and over again. Because it’s called organic chemistry, it threatens nobody.
 
Sydney Brenner:
Correct, correct. But "synthesis" threatens people.
 
Jim Wagner:
The microphone is open and also the table is open if there are questions. Oh, okay. Go ahead.
 
Anita Allen:
I loved your, I guess somewhat playful, characterization of the invention that got us here last spring as a forgery.
 
Sydney Brenner:
Yeah.
 
Anita Allen:
I’m wondering if you were challenged to put those discoveries or those innovations in the most positive light, what language would you use? It’s not a forgery, but instead [gasping]. Now what is the real innovation there?
 
Sydney Brenner:
I think that you have to communicate first that the DNA is just a description of that, that, in fact, in all of science what we would really like to do is to be able, not to read it just as a string of letters, but to understand it. So I take the view that this is a script like an ancient script, which I need to decode and I need to understand it because I will not understand evolution until I understand what is said in this. So that is the essence.
 
Now, of course, in order to do that, what Venter has done is he has shown you can substitute one genome by another. But we have to -- and that’s okay. He has also shown by the way, a much more dramatic ?? because in the course of this he revealed that the big problem is, could you synthesize a million base pairs accurately? In fact, the thing didn’t work firstly because there were mistakes in the synthesis which he had to go back and correct. So in a technological sense he shows it can be done.
 
But I think when cast in the way of, you know, we have synthesized a new life form, it isn’t. It’s a counterfeit of something that already exists and it’s, of course, guaranteed to work because the two things are related. But it shows in principle or in practice that it actually can be done and will provide a tool, though not many people are going to have the million dollars required to synthesize the sequences.
 
Jim Wagner:
Sydney, your line of reasoning that the DNA is this script as an ancient script matched to, at most, a very narrow set of readers that could do anything with it and the two things it needs to do presumably is to replicate it and to implement its code. It seems to put more distance between where we are today and where we should be worried about ??
 
Sydney Brenner:
I think so.
 
Jim Wagner:
Well, talk to me about that.
 
Sydney Brenner:
Well, I think my own experience is that it is extremely difficult to make something new. It’s extremely difficult to make something new by design, intent, and so on because we just do not understand it.
 
Now, about two levels of this, which is how proteins ?? because what we really want to design are proteins that do the work because, if we are given a protein, I can write down the DNA script retrospectively. It’s not to sit and play with the DNA sequence, but to play with the protein sequence. So that has that technology. It has to be developed, understood, what are the possibilities? And I think that we are very far from being able to do this -- very far, very far, very distant. And that’s just one thing, because the other thing is ?? and anybody who will tell you this -- that if you use other microorganisms even to express these sequences, the microorganisms don’t like them, because if it’s not useful to the microorganism, they will throw it out because they can grow faster without having this added burden.
 
And that is very important because all attempts are made to make sure that your production strains don’t lose the gene. And even dilution would help because microorganisms are just organized to grow as fast as they can and anything that grows even slightly faster ??
 
Jim Wagner:
Has an advantage.
 
Amy Gutmann:
Yes.
 
Sydney Brenner:
-- will win out in the end, will win out.
 
And I think I can make just one other addition, the perspective. Half the genes we see in bacteria, we don’t know what they do. That is because many of the organisms have two lives. They actually have two genomes. They have the genome that they use to live out in the wild here. Then they have the genome that they use to live in you or on a plant or somewhere else. So if you take this, you find about half of it is devoted to basically being out there in the wild and just growing and the other half is to gain from doing this.
 
So we have lots of genes that allow bacteria to stick in you, to do things so they can actually live on the food. They get a lot of free food inside us. And, of course, some of them even decline and become essentially parasites -- really, dependent only. They’ve lost their free?living character.
 
So I think we need to have a perspective of the whole of this microbial life when we start to think it’s going to get out into the environment. It’s hard work surviving out there.
 
And as the famous remark ?? it’s called the Red Queen’s hypothesis, a very famous remark -- that the Red Queen makes to Alice, she says, "It takes all the running to stay in the same place," because you’re competing against everybody outside.
 
So, I think those perspectives need to be understood if we really are to treat this as a serious thing.
 
Jim Wagner:
And we must. Lonnie, did you have a comment?
 
Lonnie Ali:
I just want to ask you, sir -- I’m not a scientist or anything.
 
Amy Gutmann:
Lonnie, use the mike.
 
Lonnie Ali:
Oh, I’m sorry. Just to be clear, sir, what you think is that synbio doesn’t really present the danger or the urgency of danger that we have discussed and that we have been discussing but more of a natural danger of people infecting themselves with natural pathogens and such presents a bigger danger?
 
Sydney Brenner:
Well, I think the world is dangerous as it is, and I think there are things that go on simply because of development. For example, the flu epidemic at the end of the First World War, it took 20 million lives. But it took nearly a year, more than a year, to go around the world. And today, that is shortened to 24 hours is all you need for an epidemic to move and we can trace it in all of the events. We have viruses now moving in at least three cases and recombining ?flu is one- between animals and humans.
 
And I think that we are offering by not changes in genetic engineering, not of the DNA, we are offering now the possibility of the way the world has developed and so on of creating new infectious agents just by letting nature invade us, so to speak, and so I think that that is the important thing.
 
I think that what one mustn’t get, one must avoid, is taking ?? I mean, to become a techno freak. A lot of that comes out of thinking about scenarios, worst?case scenarios, the existentialist. By the way, those people who are thinking about the nanobots that will invade the world should also start to think, could they be made accurately, could they copy themselves accurately. When they start attacking each other, because one group might have a mutation -- it’s the things we have to understand about complex things.
 
And maybe I can finish off with one more true story. I was at Asilomar. One of the journalists said, "The trouble with you scientists is you want to make people." So I said, "Well, look, I can think of much more pleasant and even cheaper methods of making people than messing around with DNA in a lab."
 
[AUDIENCE LAUGHTER]
 
And so I think that is the reality principal.
 
Jim Wagner:
Sydney, thank you very much, and let that be the last word.
 
[AUDIENCE APPLAUSE]
 
Amy Gutmann:
Thank you all for being an extremely attentive and indeed impressive audience. And I want to thank my fellow commission members and Dr. Brenner once again.
 
We are adjourned. We will reconvene in November at Emory University in Atlanta. But one final thank you to the staff of the bioethics commission headed by Valerie Bonham, our executive director, for really enabling all of this to happen. Thank you so very, very much.
 
[AUDIENCE APPLAUSE]

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