Studies in History and Philosophy of Biological and Biomedical Sciences 40 (2009) 65–71

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Studies in History and Philosophy of Biological andBiomedical Sciences

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Interview with Sydney Brenner1

Soraya de ChadarevianDepartment of History, University of California Los Angeles, 6265 Bunche Hall, box 951473, Los Angeles, CA 90095-1473, USA

a r t i c l e i n f o

Keywords:Molecular biologySystems biologyInverse problemsEvolutionReductionismHuman Genome Project

1369-8486/$ - see front matter � 2009 Elsevier Ltd. Adoi:10.1016/j.shpsc.2008.12.008

E-mail address: chadarevian@history.ucla.edu1 Sydney Brenner is widely regarded as one of the p

career see his autobiography (Brenner, 2001).

a b s t r a c t

The following text is an edited version of a recent interview with Sydney Brenner who has been at theforefront of many developments in molecular biology since the 1950s. It provides a participant’s viewon current issues in the history and epistemology of molecular biology. The main issue raised by Bren-ner regards the relation of molecular biology to the new field of systems biology. Brenner defendsthe original programme of molecular biology—the molecular explanation of living processes—that inhis view has yet to be completed. The programme of systems biology in contrast he views as either trivialor as not achievable since it purports to deal with inverse problems that are impossible to solve in com-plex living systems. Other issues covered in the conversation concern the impact of the human genomesequencing project, the commercial turn in molecular biology and the contested disciplinary status of thescience.

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When citing this paper, please use the full journal title Studies in History and Philosophy of Biological and Biomedical Sciences

SdC: I would like to start with a very general question. What, inyour view, are the main issues for molecular biology today?

SB: I don’t think there are any issues. I think people have created alot of problems, and what still remains I think is the path for expla-nation. I think this puts molecular biology in contrast with what iscalled systems biology which is the opposing thing basically, as thetwo cannot be compared, because systems biology isn’t science.

SdC: Systems biology is not science?

SB: We can forget about the claims of systems biology because theycannot be achieved, and I will explain why in a moment. If you saywe have to study the system, of course we agree with that. We usedto call this physiology. So to me it seems pretty straightforward thatthe programme of molecular biology just continues to its comple-tion. There’s no new path to follow, in my opinion.

SdC: Systems biology was of course one of the topics I hoped to getto.

SB: Of course. Let me try and explain now why I think its pro-gramme cannot be achieved, right? So the first thing, it is looking

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ioneers of molecular biology. He sh

at inverse problems. And these are extremely difficult to deal withbut we know the conditions under which they can be solved. Let megive you a classic example of an inverse problem. It’s the one incrystallography; most people know about the issues there so theycan see it pretty quickly. Right, so the question is: can you go fromthe diffraction pattern to the molecular structure? We know if wehave the molecular structure, we can calculate the forward prob-lem. Can you calculate the diffraction pattern? Sure we can becausewe’ve got a whole lot of physics and Bragg’s law, and all of thatstuff. But could we reverse the issue and go backwards? That wouldbe solving crystal structures directly. Now, you can’t do it for thesimple reason that information is lost. What’s the information loss?It’s the phase information because all you are measuring is theintensity, and the intensity is the amplitude squared, and if it is‘� 4’ or ‘+ 4’ you can’t tell the difference because both squared are16. So there is a clear-cut case of a real typical inverse problem.

Alright, how can you solve inverse problems? Well, the firstthing you can do is basically to get more information. But youmight say, ‘Well, why don’t we try all the phases and see whichone works?’ And of course we know that with big molecules youcan’t do it. You can do it with small molecules. You can do it if

ared the 2002 Nobel Prize for Physiology and Medicine. For a detailed account of his

66 S. Chadarevian / Studies in History and Philosophy of Biological and Biomedical Sciences 40 (2009) 65–71

you have large computers. You can calculate everything and seethe right one that will work. But there’s the wonder of mole-cules—the size of the molecules increases and the number of dif-fraction spots goes up. It’s one of these problems that nocomputer can solve. We’d be calculating from the beginning ofthe universe until the end of the universe. Okay. Another thingyou could do is inject a priori information—which is exactly whatWatson and Crick did. What they did is, they made a theory. Andof course, the theory was based on other information and so on.And when they put that into the machinery, they got the right an-swer. So, if you can define the model—in terms of a theory—you canprove that it’s correct. But of course, to get to that model, what youhave is essentially a statistical distribution of all models, which isenormous. And you cannot treat all possible structures in muchthe same way. Now, systems biology purports to be able to solvethe inverse question. What it intends to do is make enormousnumbers of measurements with micro-arrays and everything likethat, and then it says that by putting all of this information to-gether, it’ll form a model of how the system is working, and that’llbe the theory. And this is not achievable. It’s not achievable for allthe reasons I’ve given. One, you cannot make the measurementsaccurately enough, you lose information in making the measure-ments, just in terms of what you can do. And there is anotherfrightening thing in biology, which is that if you suppose that allthose numbers that you measure are fixed numbers—that is theyare valid, and you’ve made accurate measurements of them—youstill have to understand that in an evolutionary system, not every-thing becomes fixed because there are ‘don’t-care conditions’. Soyou could have things that fluctuate because by the theorem ofnatural selection, if it has no effect on the organism or its reproduc-tion, nothing will be selected. If you wish to fix the number in abiological system, whether it is an affinity constant or not, it hasto be encoded in some form. And that’s the cost in evolution. Itall has to be encoded in such a way that it doesn’t confuse withanything else. So if you want to do things specifically in biologyyou have to pay for it in sequence information. But if it doesn’tmatter, why bother to pay for it? Now that means that many ofthe numbers that we think we are measuring, which we think willhave validity, probably have no validity at all.

SdC: But isn’t that a problem that molecular biologists would alsorun against?

SB: No, no. Molecular biologists actually solve the forward problem.That is, they can find out what each of the components is doing, andthen compute the whole from this. Now of course people say, ‘No,you can’t get that information about a system from the individualcomponents’.

SdC: Because of emergent properties—.

SB: That’s another thing that I raise my gun against.

SdC: (Laughs)

SB: So, let me tell you that the correct quotation is that ‘the whole isgreater than the sum of the parts studied in isolation’. The wholecannot be greater than the sum of the parts and their interactions.In fact, it is the interactions of the parts that compute the whole. Ijust put it in form of ‘compute’ but what is the nature of this com-putation? This depends on the way you look at so-called elaboratesystems and some other problems. I believe that people hold theirhands up in horror over ‘we’ve got twenty thousand genes express-ing, and everything is a mishmash, and how are we going to sortthis out?’ Well, that’s a problem biology would have to solve. AndI believe that biology never solves many problems because they’reall like income tax. Namely, it is criminal to evade, but legal toavoid. So biology has no molecular tricks. Instead of measuring

concentration, for example—which of course has to be fixed in allof these models, and people scratch their heads about it—it countsmolecules. I can give you all the detailed molecular mechanisms asto how molecules are counted, because they are by the actual struc-ture of the thing itself. So basically, the task of molecular biology isto just get on with finding out what the pieces do, what they inter-act with, and putting that into the equation. So it is not a system of alot of things interacting and running around. That’s nonsense.Because if it were, we wouldn’t be here basically, because those sys-tems are metastable; they either explode or collapse. They cannotmaintain such a state. So by the evidence of our existence, and bythe existence of other complex structures, we know that cannotbe the case. And some solution has had to be found. So I thinkyou’ve just got to see what there is. Now, why do I still say mole-cular biology? Actually, the actual unit to look at, in biology, isnot the molecule, or the gene, it’s the cell.

SdC: So that’s where systems biologists and molecular biologistscould actually meet, because they would both say that.

SB: Yeah. Of course they both say that. But we say that it has to bedone at the level of the cell, as it is the useful intermediate level ofall analysis. And then you have something that effectively can coverthe whole of living matter because it’s all based on cells, whetherthere’s one cell or many cells. And you can consider the cell as anetwork of molecules (using network in a general sense). And youcan consider the body as a network of cells. So it’s all now to beexplained as a sort of branch of communication. And that’s theway I think we’ve got to look at it. All these units send messagesto each other.

SdC: So would you still want to speak about systems? Or do you notneed the term system?

SB: No, I don’t need the term ‘systems biology’. I want to explain thebrain. I know that it is a very complicated system. I know that thereis behaviour of the entire system. I’m not going to explain it bysystems biology. I’m going to say that the brain is a network ofneurons. So first I find out about neurons and then—it is what I callmiddle-out as opposed to top-down and bottom-out. You go fromneurons or cells to the organisms and from cells downwards tothe molecules. And our task is simply to formulate this in thecorrect way.

SdC: How would you respond to the argument that the molecularlevel is too reductive? I have in mind the example of the tableand the atoms. If we want to explain the table, and speak aboutatoms, we don’t get very far because what a table is can’t beexplained on the level of atoms.

SB: That’s okay, but biology is different. The whole basis of what weare, and what we do, and how we grow and develop, die, perform,act is encoded at the molecular level. At the end of the day ourfundamental problem is to understand exactly what this geneticscript really means. That’s why we have to stay at the molecularlevel. Because, we know that if we would go through all of theselevels and we would find that this interaction between two proteinswas this little strip of this gene, and a little strip of that gene—. Andthis change can then be amplified throughout all the levels of inter-pretation. So I see no difficulty. I mean, I wouldn’t want to explaineverything in terms of molecular motion. So people say, ‘Well,how do you account for stochastic things?’ You see, we can lookat stochastic things, but at the end of the day, there must be someway of ignoring all the problems or using them. That’s the otherthing, biology learns to use various things. So that’s all our task is.And I see all the people say, ‘We don’t need molecular biology.We make measurements of the output and we will deduce thenature of what’s in the box’. I think it’s not achievable. Hadamard

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wrote a paper on this in 1902 for mathematics: the solution of in-verse problems.2 He showed that some things could only be solvedin one direction. If you take differentiation, the opposite of differen-tiation is integration. Now there are many things you can differenti-ate, but it’s very difficult to integrate, to do the reverse operation, forexample. And he then found that these things have to have certainproperties in order to do this. There’s a tremendous amount of workin this, and if you want to read about it, it’s very interesting becauseit all wraps up from the questions of causality, as well. Fundamen-tally, systems biology wants to avoid detailed questions of causality.They think they can just cover it all. And you can’t, because causalityis the key to what we are doing. There is a huge body of informationin solving inverse questions that exists in the social sciences. I meanquestions like what can we deduce about an economic system fromits outputs, from the observations of it? And can we deduce causalfeatures from it? I’ve discovered a huge literature on this. It tookme a while to realize that’s what systems biologists are claimingthey can do, but they have not shown me under what conditionsthey would be able to do it.

SdC: Do you see a difference between the systems biology thathappens now, and the systems biology of the 1920s and 1930s?

SB: Well, you have to be very careful about that because the wholeof what we call general systems theory, I think is different becausetoday’s systems biology is couched in very different terms. This islargely because of the ability to make lots of measurements, yousee. I mean, I haven’t read Bertalanffy for forty, fifty years. But Ithink it’s interesting to ask this. Because I think, you see, it lies atthe heart of what we are doing with complex systems. There is aCIBA symposium on this a few years ago, on reductionism. If youread that, you’ll see that I claim to be a pragmatic reductionist.3

That is, I’ll reduce to the level at which the explanation suffices.For biology I don’t have to go much beyond the molecular structureof the whole protein because I know that somewhere else there willbe another group of specialists worrying about the motion of elec-trons in this protein. That’s fine. As long as I’m assured about conti-nuity of explanation, even by example, then I know the programmeof reductionism can be completed in stages. That is, I don’t have togo from thought to molecule, to quantum mechanics in one leap.But I can go that way if they allow me to say, well, quantum mechan-ics, I can tell you about atoms, from atoms I can tell you about mol-ecules, molecules I can tell you about biological molecules. Then Ican tell you about their interactions, and then ultimately I’ll tellyou how they build brains. And so we have to go through that.You cannot go in one leap.

SdC: Are these the ‘levels’ you have been talking about earlier?

SB: These are the levels. It suffices not to iterate the whole explana-tion, but to take it that it can be done.

SdC: Of course the question is how molecular explanations relate tothe next level of explanations.

SB: Correct. In my opinion, it’s very easy. Let me give you a goodexample, one in which I think I can see a programme to be com-pleted. Let me give it to you from the point of view of someoneapproaching the cell. People will say there are twenty thousandgenes expressed; how are we ever going to explain hundreds ofthousands of interactions? Now one part of systems biology pro-poses to measure all the interactions, which is a matrix of twentythousand by twenty thousand, which is a pretty big matrix. Butwe know it’s going to be very sparsely occupied. So, you don’t need

2 Hadamard (1902).3 Brenner (1998).

to do this, correct? So now we sit down and we just ask whathappens to all these molecules? We can give an account of howthey’re produced, how they folded up, and then of course they havea function. So we now look to see, in the cell, how do moleculeswork? We discover they hardly ever work on their own. They formassemblages with other molecules, the proteins. I can give youexamples of these assemblages, some of which are very big, but justfor purposes of discussion, we’ll say that on average it containsabout ten molecules. If you want to work in octal, we’ll say eight.But—we give it an order of magnitude. So then immediately, thetwenty thousand disappear and we have got two thousand ‘devices’,as I call them. These two thousand devices then are not distributedall throughout the cell. Cells divide into compartments: the mito-chondria, cell membrane, etc.; allow me ten compartments. So thismeans that when I focus on one compartment, I’m talking abouttwo hundred entities. Alright? So I now have to define—the key isto define, what are these entities? Well, that’s just a matter ofmolecular biology investigation, who is stuck to who, how do theystick? This data is beginning to be produced.

It is very interesting to ask, what do these little things do? I’llgive you an example, which I think is very instructive. It’s a littlegadget that you find inside your heart cells, and it turns out tobe how cyclic AMP, which is generated, effectively stimulates therelease of calcium. It’s a very interesting gadget. It’s made up ofat least eight different gene products. So first, there is somethingcalled the ryanodine receptor, which is the element that containsa channel for calcium. It sits onto a thing called an anchor proteinwhich binds the regulating subunit of the cyclic AMP kinase. At-tached to the cyclic AMP kinase there is the catalytic unit, the unitthat phosphorylates. And then also on this gadget, there is an en-zyme, which destroys cyclic AMP, which you think is odd, butyou see it has a very beautiful little molecular function. And thenthere are several other proteins, which I can mention later. Whathappens is that when a wave of diffusion of cyclic AMP hits this,you would think it’s destroyed. No. Because in this state of the sys-tem, the phosphodiesterase has very little activity. Cyclic AMP goesand releases the catalytic subunit, and the catalytic subunit thenphosphorylates the phosphodiesterase, on the one hand, and phos-phorylates the channel to then open it. What happens then is thatas the phosphodiesterase is phosphorylated, it is activated and de-stroys the cyclic AMP. So a wave is turned into a pulse. Cyclic AMPceases, the enzyme can go back and then there are two proteinphosphatases on this, which can restore both proteins to their rest-ing position.

I’ve given you that example in some detail. The point is that allthis can be worked out. We can formulate the device as a new en-tity. We can say if you put cyclic AMP in this way, so much calciumwill come out. So we can see it’s just as executing a transfer func-tion. It means that eight proteins, or whatever it is, are now con-densed into one node in the graph. There is an output that wecan compute exactly, the output of calcium according to the inputof cyclic AMP. Then of course, the calcium goes in many directions.The cyclic AMP goes in other directions. So, eventually, stepwise,by understanding how each of these devices work, we could workout not only qualitative, not only by description, but we couldactually provide a computation of what happens to the rate ofbeating of the heart when you put something on the receptor onthe outside of the heart, and it would’ve been translated. So wecan compute the forward answer.

That’s what I think our programme is. Finished. I mean, there’snothing else. And to go and do a lot of measurements of cyclicAMP—, and of course, all of the measurements that they make in

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systems biology are static. We would have to make measurementsover time periods of parts of seconds for these reactions. We couldcompute them. So that’s why I believe that the whole of systemsbiology is a waste of time. And in my opinion, it has now becomea great gimmick to get support and so on, but it doesn’t tackle theproblems, the scientific questions you see, which people have for-gotten. And the reason it doesn’t tackle them is that we’ve gener-ated the belief we can describe everything in full detail, at anylevel we like, because of the power of the tools we have for inves-tigation. As someone once said, the slogan is, ‘More is better’. But ofcourse, science is, ‘The least is best’. We calculate the rest, predictthe rest. But I’ve given you a causal analysis of what happens whena molecule hits the receptor, and how it can generate something atthe physiological level. It seems to me this is the way to do it.

SdC: Just to finish off on the systems biology, do you have an expla-nation for why systems biology came along now, after the humangenome project?

SB: It’s post-genome. It came from the fact, you see, that we sud-denly realized that we could collect lots of information and handleit, because of the sequencing machines and the computers. But, yousee, I believe that all this data that is being collected should obeywhat I call the CAP principle—Complete, Accurate, and Permanent.And only sequencing information has that. We never have to do itagain. What systems biologists don’t realize is that they can collecta lot of information, but they are also collecting a lot of noise. Andthey have no idea how much is noise. And noise is just a contami-nant of all this data, it should all be thrown out basically.

SdC: Are the people who were involved in the sequencing now thesystems biologists? Or who are the systems biologists?

SB: Well, let me tell you what happened with the systems biolo-gists. They came out of the people who did the sequencing, theycame out of people working with yeast. You know, we used to domultiple experiments, we used to make ten thousand crosses, itwas all done by hand. But then there were machines and many par-allel executions were technologized. So what used to be called a‘gridded’ library, which someone may have put out by hand on aPetri dish is now made by a machine and reduced in size. It isnow called a chip array. Sure, you can make a lot of observationsin parallel, but most of them are absolutely useless. There are pub-lished papers showing that if you take the same sample and usethree different methods, three different chips, from three differentpeople, your results overlap in only ten percent of the cases, forall three, and those are the abundant expressions anyway. So I thinkit came from that.

SdC: So is systems biology technology driven?

SB: It is technology driven, it also does not have to pose any hypo-thesis. In other words, it claims to release people from thinking. Youdo not have to think, you just make an array and get a lot ofnumbers. And then you do cluster analysis, you see.

SdC: Are systems biologists biologically trained?

SB: They are, but the whole thing has changed so rapidly. In fiveyears it’s all gone. Nobody knows how to do an experiment any-more. Nobody understands what proof is in biology. How do youprove something? I take this so seriously, I’m getting to start run-ning master classes in methododogy in Singapore. You know, likethey have for opera singers, and I’ll just show students how you dealwith experiments.

SdC: This used to be done in the laboratory?

SB: Of course it was done, because you would sit and say, ‘Show meyour results’. And say, ‘This is a lot of rubbish’, and why, and he

would learn. He would learn on the job. But it is the rise of biggergroups. It is getting out of the medieval guild of the journeymanand a few apprentices, which is what experimental science was,into this industrial structure. And I think that’s been the big change,and I think it’s very interesting to look at the psychology of this. Imean, it’s amazing because I really feel that I’m becoming the voicefrom another century. It’s the students, they have no idea—it hashappened very fast, because factory science has come to dominate.And you know, now people feel they can’t do anything on their ownbecause they have things like Lander’s Institute, which is a big fac-tory, which can do all of these experiments. The whole art is now toreally try and get students to think of what it would take to proveanything, but they can’t do it!

SdC: It’s very difficult not just to be seen as old fashioned.

SB: It’s all rubbish. That’s what it is. You see, I’m not scared to say sobecause it’s also very bad, in the sense that students now do not seehow to solve a problem, how to say, ‘Well, what is the problem youare studying?’ They want to know how the whole cell works. Ofcourse, you can’t know how the whole cell works. You’ll only knowit when you’ve done this analysis. This is what I think has got to bethe program. It still is an anatomy program; it’s a structure program.It’s based on the molecular gene products. And you know, we will beable to understand much more about this. I also find now that I leanvery heavily on the basic principles of evolution. Someone said, ‘It isthe chaos in biology’. I said, ‘If you mean by chaos, you cannot pre-dict the answer from the initial conditions, that genotypes wouldnot be specific, no. The answer is natural selection wouldn’t work’.Those things, if they were to be the case, would have been lost a longtime ago. So I think we really have to make these arguments now.What is the cost of specific information?

SdC: Are you such a lone voice? Is systems biology really sodominant?

SB: It has become a very dominating thing. I mean, a lot of peopleare neither and are just going along investigating their favorite dis-ease, or their favorite tissue, or doing embryology and so on. But I’monly speaking of the kind of avant-garde that wants to claim theyare going to lead us to paradise.

SdC: It is interesting because there was a time when molecular biol-ogists were presenting themselves as the avant-garde.

SB: We were the avant-garde. My line is: we still are the avant-garde. The revolution hasn’t been completed. And we do not needanother revolution, you see? That is not the right revolution.

SdC: If we consider the effects of the human genome project onmolecular biology—is the rise of sytems biology the main effect?

SB: It’s one of the outputs. I think the human genome project had anenormous benefit in the fact that we now know all the genes. Butvery little has been done to do any detailed analysis of what thereis in our genomes. It is true, there are people with big computerswho are comparing genomes. They found ultraconserved regions,so the question arises what these might be. I mean, the only thingI believe to do is to take one piece of this, and try and analyze itin detail. Once you do that, once you get away from this global viewof the whole genome, and whole genome analysis, and you reallyask what does this really mean?—then, I think you can come tosome sort of understanding. Of course everybody wants to under-stand how things work, and understanding is the same as doing sci-ence I believe. It’s not description. Description is not understanding.

SdC: Am I wrong if I remember that originally you were against theproject of sequencing the whole human genome? You wanted onlyto do the functional sequencing?

S. Chadarevian / Studies in History and Philosophy of Biological and Biomedical Sciences 40 (2009) 65–71 69

SB: No, no, you aren’t wrong. See, what I said at the time was thetechnology wasn’t up to it. The technology only got up to it, not be-cause of technological advances, but simply because of factories.

SdC: And sequencing machines.

SB: Yeah. Wally Gilbert saw that immediately because he realizedthat the scale had to go up by a factor of a thousand, and that maybeyou could expect a factor of ten from the technology that’s there. Soyou just have to have a hundred machines. And so, he wanted tobuild a factory as early as 1986, but of course everybody said, ‘That’snot science’, and so on. However, the factories were built and therewere multiple ones of them. And they accomplished that. And theyaccomplished that simply by just having a lot of machines. And nowthere might be a further increase in ten, in sequencing capacity andso on. That doesn’t matter. One of the things that has now hap-pened, is, because of this, people can only do human genetics if theylink to one of these vast centers, and the ordinary investigator is outof this. So I think we’ve just got to develop tools to say, ‘Well, youtoo can study human beings with a modest sequencing resourcethat you can have in any lab’. So I think it is necessary to democra-tize the study of human biology.

SdC: So not by giving everyone access to these machines?

SB: You give access, you give them access to a machine. You don’tgive them access to a factory because they don’t need a factory. Ifyou can avoid having a factory, then I think you can actually stim-ulate people to ask real questions. I’ve got a small company in Cam-bridge called Population Genetics Technology. We hope with this togive everybody a little machine. They’ll have to buy it, but still, toprovide a machine that will simplify the problems for people. Andyou know, we can reduce costs by several orders of magnitude.

SdC: Is that for clinical use as well?

SB: No, only for research uses. Because, what I believe now, thegreat thing that has happened with all of this technology is wecan study human beings directly. We do not need mice or othermodel organisms.

SdC: So that’s what you see as the impact of the human genomeproject?

SB: Yes, I think that is the impact. The lack of impact is—I was talk-ing to someone in a pharmaceutical company, and not a singleinteresting topic that hadn’t been known before came out of the hu-man genome. There was nothing surprising saying, ‘Oh, we’ve got tohave that’. You can now see a gene, and you can see its protein tar-get, but you don’t know what it does. You must put it in its contextor function, and that’s what was lacking. So nobody knows—. Thereare many receptors that people are still studying to find out whatthey’re doing. That’s the great thing, that we’re finding that out inman.

SdC: And what about junk DNA? Don’t people now rethink thatconcept?

SB: Oh no, I think you see, people keep on writing to me and saying,‘So there you are, we’ve now got micro-RNA’. It’s the small RNAs,and they’re going to be the important things. To me that’s just an-other gene product. It doesn’t go through this interpretation mode.It goes through another one. So it’s a good thing we’ve found it. Justtell me what they do; I will add them to the list. But junk remains.One person asked me for a public confession, that I was wrongabout junk, I wrote back and said, ‘I am prepared to reduce it from96% to 95.8%’.

SdC: But you also distinguished between junk and garbage. Junk isuseful—potentially useful.

SB: No, no. Maybe useful. There are two kinds of rubbish. [Junk is]maybe useful. You could plan to use junk as a human being butthe genome cannot. Now of course, various uses have been as-cribed. And you can see some has been assimilated, just as to beexpected. But it cannot be by design. And it cannot be by planning,which is the mistake that people make. They say, ‘Isn’t this junkgoing to be useful?’ And it’s kept there. The trouble is people don’trealize—this, to me, is amazing, that no one has tried to scale gen-ome evolutionary rates to real time. So I’ve been trying to do thisnow. Genomes of vertebrates evolve incredibly slowly, incrediblyslowly. The genome of drosophila appears to have evolved muchfaster. In other words, five hundred million years on the vertebratescale is about equivalent to fifty million years on the drosophilascale. They are evolving ten times more rapidly. We absolutelydon’t know about bacteria. You know, when did salmonella splitoff? We know that they are related. I can order them now, but Ican’t pinpoint and say, ‘That happened on December the 14th’,you know? I just have absolutely no idea about how to measurethe sidereal time, except by assuming a molecular clock, but that’sgot to be wrong. The clock runs at different speeds, if there is aclock. So there, you see, is a challenging problem. I point it outto students; anybody could sit down and try to solve this. Youdon’t need anything. All the data is accessible on the Internet.You just need some good ideas. You don’t need any money todo it, you can just do it. You don’t need a big lab, and so on. Ifyou need the genome to be filled in, don’t worry, it will be done.Sooner or later, people will do it.

SdC: Okay, so maybe we should talk about the commercial turn. Ithas been going on since the 1980s. Do you see any impact of thaton how molecular biology has developed?

SB: Well, no, I think there’s been very little impact. No, let me re-move that. There hasn’t been any impact on the science. That’s forcertain. I mean, science has been steadily moving forward, youknow, with the two big drivers of technology, which is cloningand sequencing in the mid ’70s. That’s what really lifted it. Andthat clearly made embryology into a real science, into a causal sci-ence, if I may use that dirty word today. But what happened is ofcourse that it changed the kind of social structure of science. Look-ing at that time in perspective—with the distance of thirty yearssince cloning and sequencing began—I’d say that what happenedwas understandable, in that people could see that there could bethis impact on all the biotech industries. You could make things;where previously you had to purify them, now you could makethem. All the things that we use now in the lab, as a way of ana-lyzing things, could actually be turned to useful production. And itwas a technology which was very different from the kind of stan-dard biochemistry and physiology being done in industry. As a re-sult, the people who were skilled at this all formed companies,and the big pharmaceutical companies made agreements withthem because they needed access to this technology and neededto get on board. And of course, there were all those things aboutpeople playing dual existences, you know. You have your com-pany, and then you have your lab, and you use your students, yourpost-docs. It’s totally unclear what’s going on there with all of this.The universities were keen on this, because it was something theythought they could sell and enhance their income with. And so allof these controversies about patenting, and then of course, withthe human side now we have problems raised by alternativemodes of reproduction and genetic therapies and so on, and therise of the whole industry of bioethics. Now, I personally thinkthat some of us wasted a lot of our time trying to deal with this,because it did threaten, at one stage you know, to really compressthe science and try to control it and so on. But I think in the end, ithas worked out properly.

70 S. Chadarevian / Studies in History and Philosophy of Biological and Biomedical Sciences 40 (2009) 65–71

SdC: In the sense?

SB: In the sense that—nobody believes—to say it in the extreme fun-damentalist view—, that you shouldn’t tamper with nature; thatthis is God’s work, so only God should know the human genome;that it is forbidden knowledge; that we open Pandora’s box, all ofthat language. It ranges from that, to doing it with guidelines, andthe whole of the apparatus essentially to make a social contract be-tween science and society for the conditions under which societywill fund the science. I mean, society could stop science tomorrow,instantly. There would only be people like me working with PCs, butthey could close the Internet as well. (Laughs) That might beheavenly.

So basically, there’s a social contract. And there are expectationsnow on both sides. I think that in terms of what the human genomedid in the health business, that I think has not had any of the im-pact in the pharmaceutical companies that was expected. It gaverise to a huge boom in sequence, patents, and so on. None of thathas turned out to be relevant at all. And it’s gone through all thesephases. Now the big thing is disease association, and we will mapthese diseases, and we’ll find out about a lot of things. And now wehave all kinds of issues of excluding, discriminating against peopleon genetic grounds, and so on. But I think what is missing now, is akind of—it’s not missing, but what I think is the wrong posing ofhow to deal with a problem. The situation is assumed by every-body in the game to be as follows, roughly speaking: that all thesevery clever scientists are finding out all sorts of things about every-thing. And we need to have that knowledge applied to medicine, tohealth problems, to food problems, to fuel problems. And in med-icine, what we need is being proposed, we need to have a transla-tional research. We need to take that basic research findings andmove that from the bench, as they say, to the bedside; from thebench to the clinic. Now, what you find is that basic scientists don’tnecessarily want to do that. However, if you will pay to have, whatare called, translational units, they will tackle these questions; theygo as far as developing drugs, try them out with clinical trials andso on. So that’s translational research.

Now I think we should take a completely opposite view. Weshould leave those people in their labs and let them get on with it.What we should do is, we should ask ourselves what are the prob-lems in the clinic that we can solve directly with all this new science.In other words, what I want to do is go from bedside to bench. I wantto know what the physician has to do when faced with a clinicalproblem. In many cases, it’s therapeutic selection. What drug do Igive him? How can we inform that process so that the expectationis much more scientific and not just kind of mixing up a cocktail.So the science should start in the clinic. And the science should actu-ally become part of the operation of medicine. I think that’s probablymuch more difficult to accomplish, but the other approach has thedanger of turning labs, academic labs, into pharmaceutical compa-nies. They start to do drug discovery. The students are then em-ployed on high throughput screening and all this stuff.

SdC: So that is going on?

SB: That is going on. It is going on more or less in some places. Thereare a lot of institutes of cancer research that effectively engage intrying to develop drugs in the research environment, for cancer. Imean they are funded by the charities, their object is that. But dowe need to have it done as a kind of translational effort? It seemsto me, we should do what we did in Singapore, which is just makea state funded biotech company. In other words, we have giventhem money and said, ‘Get on with it. Your job is now not to doresearch, not to further knowledge, but get on and do this’. Andyou are now free of the worries of the persecution by venturecapitalists and investors saying, ‘I’ve got to have a return’. Becausethat’s what destroys all innovation.

SdC: You said the turn to commercialisation had no impact on thescience itself but on the social structure. Yet according to whatyou are just saying it seems there has been an impact on the scienceafter all.

SB: Yeah. I now speak from a programmatic point of view of what Ithink we still need to solve, what we still need to understand andwork on. The reason is that this is technology. I think I’ve foundthe essential difference between technology and science. In scienceyou’ve got to support the individual. It’s an intellectual thing. Ifsomething goes wrong, in his job to find a cure, that’s the end ofhim. In technology, you support the project. And if they’re not mak-ing headway, you stop the project and start another one. And youuse the same people of course, they are skilled now, skilled people,and they need management and so on. And technology then be-comes very much goal-directed, but it needs a different environ-ment. It needs the discipline of focus, it needs to be industrial, ithas its own rewards for some people. You know, it’s different—but to try and run a research lab now, like you run a mini-industry,that’s not going to work.

SdC: To come back to our earlier discussion, is systems biology ofany interest to industry? Is the industry making investments in thatfield or is it still more interested in molecular biology?

SB: No, they call it systems biology in industry, they also caught thefad.

SdC: Can systems biology be put to use for products which they canthen sell?

SB: I think they work through this, you see. They all adopted bioin-formatics. I’ll tell you a very interesting little thing. When they se-quenced all these bacteria, they said, ‘My God, there will be millionsof targets’, and sure enough then lots of enzymes for the synthesisof this and the synthesis of that. And so a lot of companies juststarted to count all these enzymes and express them; they made as-says, found chemicals that inhibited them, and then put the bacteriain these chemicals and they didn’t work. Bacteria just grew happilyon. See, nature has worked very hard to produce antibiotics thatwork. And of course, they forgot about that, that bacteria have adap-tive proteins. It’s not true in us. Bacteria can amplify a protein, so ifyou inhibit the pathway, they just compensate. So in fact, from theliterature, which I actually did trace back, you could calculate that ifyou inhibited one enzyme in a pathway by as much as 97%, it wouldstill grow as fast as wildtype because it’d just make thirty timesmore enzyme and escape from it. So, that of course, is basically for-getting what’s already lying around in the literature and not beingproperly informed. So that’s what happened there. They alwaysclaim they have done systems biology all the time because they’vebeen looking for biomarkers in people and in animals, for theirdrugs. So I think you have to ask when is it just a name. They’vebeen watching for years how drugs work, now the new name to callit is systems biology.

SdC: One last question: there has always been a controversy ifmolecular biology was a discipline. Some people claim it was a dis-cipline for fifteen years after the double helix. Other people claimthat the whole of biology is molecular biology and that it doesnot make sense any more to call it a discipline. Do you think thisis still a relevant question? And if so, how and why?

SB: It’s a discipline, I believe, if there’s a department in the univer-sity and you give degrees.

SdC: That’s the classical definition.

SB: Yes, and I think it has become a discipline, and systems biologyhas become a discipline as well, in that sense. You then ask, is it

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different from all other disciplines? And I think that the one thingthat it has done, is that every pharmaceutical company has adepartment of molecular biology now. You can then ask: is cancerbiology a discipline because they use molecular biology, cell biol-ogy, and so on? I think the only thing you can really define is whatsome people call a program, but what I call a manifesto. What wasthe manifesto of molecular biology? Its manifesto was that we canexplain biological behavior through the properties of the large mol-ecules within them, mainly the nucleic acids and proteins. That wasthe manifesto. And of course, it got into detailed questions aboutthe structure of DNA, how do genes work, and so on. But that wasits manifesto. And I think at each stage problems were really wellposed. They were hard to solve for technical reasons, but advanceswere made and I think it came through. And basically, we haven’tyet completed that program.

SdC: So the manifesto is still there?

SB: The manifesto is still there.

Acknowledgements

The interview with Sydney Brenner was held in Ely (UK) on 25August 2007. The text reproduced here is a slightly edited andshortened version of the original transcript. We thank SydneyBrenner for permission to reproduce the text. We are also gratefulto Nathasha Thomas (UC San Diego) for expert help with the tran-scription. The original tape and a full transcript of the interview aredeposited in the archives of the Medical Research Council Labora-tory of Molecular Biology in Cambridge, UK.

References

Brenner, S. (1998). Biological computation. In G. R. Bock, & J. A. Goode (Eds.), Thelimits of reductionism in biology (pp. 106–111). Novartis Foundation Symposium,213. Chichester: J. Wiley & Sons.

Brenner, S. (2001). A life in science, as told to Lewis Wolpert (E. C. Friedberg, & E.Lawrence, Eds.). London: Biomed Central.

Hadamard, J. (1902). Sur les problèmes aux derivées partielles et leur significationphysique. Princeton University Bulletin, 13, 49–52.