Sydney Brenner's most powerful insights on scientific method, experimental strategy, and creative problem-solving. Each quote captures a hard-won principle from his Nobel Prize–winning career, with its practical application explained.
So the which I formulated at the time was, 'There must be an enzyme that breaks the chain, and then unwinds them, and then joins them again'.
Treat missing mechanisms as *latent variables*; proceed when the primary is strong instead of rejecting the whole program.
And so while he... we went to a general store and while Jim was writing postcards to all his friends, you know, in Harvard saying, 'Farewell, we're about to embark on the desert', I who had travelled in deserts, you know, was getting equipped. That is, I bought an extra fan belt. This is the one thing; if you lose your fan belt you've had it. I actually bought water. I mean, Jim was buying ice cream, but I bought water. I bought canisters of water to take with me. I also bought a jar of... I think it was... it was butter, I think, that I got. Anyway, something that you could use on a piece of a shirt which you could coat to make a spare fuel pump. They had diaphragms in fuel pumps. I had been caught once with a collapsed fuel pump in a desert, and of course once that happens you've had it. And we made one out of a shirt and Vaseline, it... it was, which sort of held up. You know, got us to the next place.
Convert vague dread into concrete failure-mode coverage; protect the experiment (or trip) against the small set of catastrophic bottlenecks.
So plans are very unsatisfying and everything was plans, you know – we're going to do the problem.
Plans are not progress; bias toward concrete experiments that bite into the space.
genetics just turned out to be the poor man's way of doing the sequence, or the man's way of doing it with... with his hands tied behind his back.
Use genetics as an information‑extraction instrument when direct measurement (sequencing) is unavailable.
as 1958... the whole of was still thought to be a flash in the pan, not right, you know, not known, not proven.
Important work often begins as "implausible." Even in 1958, five years after Watson-Crick, was still dismissed by many as unproven. Expect a lag between a true idea and field acceptance.
And what was so interesting in those times was you could arrive at a lab and do an experiment.
In the 1950s, you could walk into a lab and start working. Today's approvals, training modules, and committee reviews are friction that slows discovery. The best research environments minimize time from idea to experiment.
We had formulated what had be... what we had come... was the problem. That is, we would investigate the correlation between genes and proteins by getting a on which we could do fine structure analysis, and then its corresponding on which we could do chemical sequencing. And the first question was to prove .
Brenner chose a question that would force a direct comparison between order and order. If they matched (), the connection between and was proven. Pick questions that bridge levels of description.
Francis had come to the conclusion that the code was degenerate, that in fact we can't assign it, we can't deduce it from first principles. We just have to go and find out what it is.
Crick realized the couldn't be derived by pure logic. There were too many possible mappings, and no theoretical reason to prefer one over another. When theory runs out, experiment takes over.
Now the reason to do this was simply that I thought we could just take apart, you know, because it was like a little thing and we could do what we called an of it. Whereas all the other people said, 'No you have to treat it as a mixture of proteins and go on to columns and separate them', so the whole idea that you could actually isolate chunks of it as a preliminary was... was certainly something that no one accepted at the time, and this, we were able to show, could be done, and we did it in very simple ways. For example I discovered that if you put at pH2 – just acidified it – it went into a mass, and when you digested it with a mixture of enzymes you were only left with one little component, namely what came to be called later was the tail sheath.
Prototype a decomposition pipeline by isolating gross parts first; make structure legible before investing in “proper” purification.
Now, one of the interesting things which happened during the time, and actually was a side-effect of all of this work, was the invention of . Now, this is a very remarkable... technology because what it did was it took out of the hands of the elite and gave it to the people, basically. Now Bob Horne said, 'That's a mess, it's a total mess; everything...' But then I saw something, and I knew immediately what it was, and I said, 'This is called '. And how did I know this? Because in my medical course I had learnt to show how you'd look at treponema. Treponema is the age... spirochaetes. Treponema is the agent that causes syphilis, and one of the things you diagnose is you put a drop on a slide and you put Indian ink in it, and you see the treponemas as white objects transmitting the lights, swimming in the sea of ink, and this is called , and this was invented in the 19th century for the optical microscope and we... and I understood that this was the exact image of this, but for the electron microscope, so with this we could produce remarkable images. And it had two effects. One is it allowed at least the of small objects to go. But what happened is it took all the people working in virology and gave them a tool that they could all use and really wiped out the profession of electron microscopist in a biological lab because everybody could just do it.
Break infrastructure monopolies by turning an “elite craft” into a cheap, teachable procedure—often via cross-domain pattern recognition.
The molecular biology of the cell is how bunches of molecules get together and interact
The explanatory object is macromolecular assemblies and interactions; method follows from choosing the right level of description.
And if you have to look at, say, 400 reflections, this means you have two to the four hundred possibilities and so you can't do it in any other way but to determine phase.
Identify the *missing variable* (phase) that makes inference intractable; solve that variable rather than brute‑forcing search.
Max had the fundamental breakthrough in which he showed the method could let you do phase.
“Break” an ambiguity by injecting a controlled perturbation that reveals hidden degrees of freedom.
and what had been developed was this idea of and we had also started some work on this but not... in a desultory way. What was the idea? The idea was not only would we tell the but we'd actually decode the this way you see so if we could get a chemical reagent that we knew changed guanine to adenine, you know that is made that , and we could then see what changed, we will have then been able to work out the . That was the dream.
Use a *spectrum* (pattern over many mutants) to type causal mechanisms and constrain the code.
none of these mutants could be induced to revert by base analogues and none of the mutants could be induced to revert by .
Partition phenomena into equivalence classes by reversible transforms; the partition often *is* the mechanism.
The amazing thing is that when one studied what happened after infection with this , this single accounted for 70% of all the synthesis of the cell.
Choose regimes where the signal overwhelms the background; abundance is an experimental amplifier.
The difficulty was that after infection no new ribosomes are made, there's no synthesis, and so what you had is if you wished to hold the old theory you had to have what I called at that time the paradox of the prodigious rate of synthesis.
Treat contradictions as discriminative constraints; paradox forces a (a separate message layer).
By the afternoon François had come to my house in Cambridge, and we had designed the nature of the experiment that was later to be produced; that is, we realise we have to show... have to show that this new is on old ribosomes and we... I realised very immediately that this could only be done on where we have the switch from old to new synthesis.
Design the one experiment that directly distinguishes the competing causal stories, even if it’s technically harder.
So what I said, 'Well, I'll do a '. That's an... that's an experiment which you'll see if you're on the right grounds because if it is true that new ribosomes are made after infection, my destroying the old ones wouldn't have any... any effect, and they should just take off and do the same thing. Was absolutely... the experiment was beautifully clear because the fewer the ribosomes that you have as they destroy... so you let... you destroy them, you then infect them at different periods, and you ask how much virus can you make, and it goes down, and it goes down, and there comes a point where you don't make anything because of course after infection you don't make any ribosomes. So that said... you know, then I knew I have to be right.
Run cheap “quickies” that would falsify the key alternative before spending months on a hard flagship experiment.
We called it messenger there, but we had another name for it; we called it – it was called that for a short while – just being the idea that the ribosomes were like players, you know, like a tape player, and you fed them with tape. Actually, in my mind that was the old you see. You fed a tape into this machine and it would play out its results, so it was called tape, and it was the whole idea of a message tape, and that of course strikes one now today as obvious that that would be the analogy. But then it was a very... you know, very dramatic thing, and ... I said to François... I said, 'You know we're fine'. He said, 'Why?' I said, 'Max doesn't believe in it'. Because Max was marvellous; he was always wrong.
Import computational metaphors to reframe biology (message vs machine), and use humor/social signals as a lightweight calibration tool.
and then it occurred to me that of course, you see, it is magnesium that stabilises this, and the caesium will compete with the magnesium – not very efficiently, but enough to displace it and unstabilise it. And of course the magnesium we were putting in was a thousandth molar, the caesium we had was 8 molar; therefore the thing to do is to raise the magnesium. We said, 'How much?' I said, 'Let's do a lot', you know because you have three tubes and we said this is the last chance. So I said, 'Put in a lot, can do no harm'.
Identify the single stabilizer/competitor controlling failure and push it hard—often this beats a year of “boring conditions” exploration.
we would use any... we would use anything... any method to try to get to that root.
Brenner and colleagues didn't care which technique solved the - problem. They would use genetics, biochemistry, crystallography, anything. The goal was the answer, not purity of method.
We knew they didn't... they hadn't done the sort of experiments that we had done, because what we had decided to go for was a really definitive one which would demonstrate that new was added to old ribosomes.
When the field is confused, don't run quick suggestive experiments. Run the one that settles the question. A definitive experiment takes longer but ends the debate. Brenner designed an experiment that couldn't be explained away.
And he said... 'Well,' he said, 'either model A is right or model B is right.' And I said, 'You've forgotten there's a '. He said, 'What's that?' I said, 'Both could be wrong', you see.
Scientists love binary debates. But A vs. B often ignores option C: neither is right. Brenner kept his space open. When presented with two competing models, always ask if both might be wrong.
I think that is so necessary to continue, you know, almost hysterical conversation, just constitutive talking, because I think that brings things together that you don't actually see by... logical , because most logical you just go around in the same circle and you need to break out of it.
Pure logic is circular. You start with assumptions and derive conclusions, but the assumptions themselves need checking. Talking with others introduces new perspectives that break the loop. Brenner and Crick talked constantly because conversation produces insights can't.
you could make a machine in which the instructions were separate from the machine, and that's really what the messenger... I mean, of course it got called messenger .
Before messenger , people thought the was both the reader and the message. Brenner realized you could separate the two: a generic machine () that plays different tapes (). This is Turing's insight applied to cells.
Mercury may have been the messenger of the gods, but he was also the god of the thieves
quipped that "messenger" was aptly named because Mercury was both messenger and god of thieves. Science steals from nature. We don't invent; we discover what already works and copy it.
, or Occam's Brush in America, which is that of which the minimum number of facts have to be swept up under the carpet in order to have a consistent theory.
Occam's Razor says prefer the simplest theory. says prefer the theory that requires sweeping the fewest inconvenient facts under the carpet. Every theory has anomalies; the question is how many you need to hide.
I said that, 'What would it be like if there were not only base substitutions but base additions and deletions?'
Everyone assumed mutations were base substitutions. But mutants didn't fit that pattern. Brenner asked: what if bases could be added or deleted entirely? This simple expansion of the space explained everything.
I called the Humpty Dumpty model, which was: how do you get the phase of a message? You start at the beginning and read on in threes till you come to the end.
(phase) is set at the start of the message and never resets. Add or delete a base, and everything downstream is garbled. The name captures the irreversibility: once broken, you can't put it back together.
Now, this I think is the kind of apotheosis of a genetic analysis, because you have to consider what you're doing here. You're taking these viruses and you are just mixing them together and you're simply recording plus, minus. And from this pattern it seems mad that you could deduce the actual triplet nature of the . But that's just simply the logic of how the information is transferred, that it is a non- of these, and of course awoke us, well at least awoke me, to the idea that topology could, you could do these things at the kind of topological level. And formally what we showed that the code is a multiple of three. It's 3n bases, where n is likely to be 1.
Brenner's team proved the code was triplets without any chemistry. Just genetics: cross mutants, record if progeny grow (+) or don't (−). Pure logic deduced molecular structure. Three plusses cancel three minuses; therefore the reading unit is three.
And so when you get something like this, it tells you that all the exceptions, each of which cannot be explained by the coherent theory... that the coherent theory remains, then. And it is... was wise to take all of these exceptions which showed no relationship amongst each other and put them on one... we didn't conceal them; we put them in an appendix.
Scattered anomalies that share no pattern aren't against a theory. Quarantine them in an appendix, don't hide them. If they're unrelated, they're probably noise or special cases. Return to them later once you have more tools.
Kornberg had a monopoly, well, you know, I don't want to put it like that, but really he had a monopoly of because he was the only person who had radioactive triphosphates.
Kornberg could study because only his lab had radioactive triphosphates. The bottleneck wasn't ideas; it was reagents. When one lab controls the materials, they the field. Make your own tools.
you have to open the box. It is not an input/output system, because what's in the box can actually determine your theory of how this can work.
Behaviorists said you only need inputs and outputs. Brenner said that's insufficient for biology. The internal mechanism constrains possible explanations. If you don't know what's inside, you're just curve-fitting.
So we have to have what I call the grammar of the system.
Knowing the parts isn't enough. You need the rules for combining them. Genes are vocabulary; development is grammar. The same words in different orders make different sentences.
the only person that really understands the structure of anything is the person who did that structure.
Reading a paper isn't the same as doing the work. understood hemoglobin because he solved the structure. If you want real understanding, talk to the person who built the thing. Or become that person.
You could only stop its initiation. And of course we did the experiments, they were very simple to do and they worked immediately.
Many processes are easier to block at startup than mid-flow. synthesis can be stopped at initiation, not during elongation. Find the point where intervention is possible.
But that whole concept of conditional lethals opened up genetics in a most remarkable way. And in fact became the basis for a considerable amount of genetics since that time, and gave rise I think to the concept, which became important later, that Seymour used to call .
If you knock out an essential , the organism dies and you learn nothing. But mutants work at one temperature and fail at another. This lets you study essential genes by turning them on and off at will.
It opened up the whole of the concept of how you make elaborate cell structures, and by this hierarchical mode.
Complex structures build themselves in stages. First subunits form, then they assemble into larger units, then those combine further. heads, ribosomes, viruses all work this way. You can test the model by reconstitution: mix purified parts and see if they reassemble.
you can always find a special case that aids you with your experiments.
General questions can be answered in specific systems. Want to study neurons? Find an organism with big ones. Want to study meiosis? Find one where it's slow. The special case makes the experiment possible.
And that you then separate the construction issue, the developmental issue, the building issue, from that of function, and the two are then interlocked, because clearly what organisms do is an output from the machines they have to do things with.
How you build a nervous system is different from how it works once built. Genes specify construction, not behavior directly. The machine's function depends on its structure, which depends on how it developed. Keep these questions separate.
I used to call the European plan versus the American plan.
The "European plan": who your ancestors are matters (lineage). The "American plan": who your neighbors are matters (position). uses mostly lineage. Vertebrates use mostly position. Different organisms, different developmental logics.
genes make proteins and proteins have to do something, so what is it they are doing?
It's not enough to say a "controls" development. Genes make proteins. Proteins do things. What specific molecular activity produces the ? Demand mechanism, not metaphor.
So how does the antibody first of all know what's been published in Beilstein and secondly, a more, a deeper question: how's it going... how does it know what is not yet published in Beilstein but will be in the future?
Beilstein catalogs all known chemicals. The immune system makes antibodies to chemicals not yet synthesized. How? It can't be a lookup table. The antibody repertoire must be generated combinatorially, not encoded directly. One-to-one is impossible at that scale.
if it works do it, if it doesn't work forget about it.
The immune system doesn't understand pathogens. It generates random antibodies, keeps what binds, discards what doesn't. This is "learning" without knowledge. Selection, not instruction. Cheaper and more robust than trying to model the problem.
Many theories are correct in a logical sense but they're untrue because they don't refer to the natural thing we're all interested in.
A theory can be internally consistent yet have no contact with reality. Mathematically coherent models of development might violate physics or chemistry. Logical validity isn't enough; you need .
we should suspect these easy analogies because they are likely to be wrong, because these analogies operate in our conscious minds which are very restricted.
"The brain is like a computer." "The genome is like a blueprint." These analogies come from conscious human experience, which represents a tiny slice of reality. Cells and nervous systems operate on principles we don't intuit. Suspect any analogy that feels too comfortable.
Being able to work without this endless justification that is common today... which I feel is completely stifling to creative work in science... I think made that subject.
The project took 25 years. It couldn't have survived modern grant review cycles demanding quarterly milestones. Some work needs time to mature without constant justification. Research environments that allow this produce breakthroughs.
The connection between genes and behaviour must go through the construction and performance of a nervous system.
You can't skip from to behavior. Genes build cells. Cells wire into circuits. Circuits compute behavior. Each level has its own logic. Shortcuts are illusions.
Gradients would be the analogue way of doing it, and lineage would be the digital way of doing it, so to speak.
Cells can know their identity two ways. Gradients: read a concentration and respond (analogue). Lineage: inherit a state from your parent cell (digital). Vertebrates rely heavily on gradients; relies heavily on lineage.
We would understand the algorithm of how the mouse is built, because we could build it.
The test of understanding is construction. Can you compute a mouse from its ? If not, you don't really understand development. Correlations aren't explanations. The ability to rebuild is.
Routine work itself generates its important problems which you don't see.
Filling in details isn't just cleanup. The "boring" work of characterizing exceptions and edge cases produces the next generation of fundamental problems. Don't mistake "conceptually solved" for "fully understood."
You are doing surgery at the genetic level.
Genes are invisible. You prove function by removing something and seeing what breaks. Mutants make the invisible visible. Loss-of-function is the fundamental assay.
We have now been liberated from the tyranny of the life-cycles of organisms, from their modes of reproduction. We can do genetics now on everything, anything.
Classical genetics required breeding, which required short generation times. freed us from this constraint. Now you pick the organism for the question, not because it breeds fast.
In fact, I thought we could actually do this by having something that was like a bingo hall.
Some scientific tasks are decomposable labor plus good instrumentation; “big science” can be made legible by the right workflow framing.
So I think I like to call the the discount genome, because you get 90% discount on sequencing.
Change the object to change the denominator (cost/time); organism choice can substitute for “tenfold tech.”
Which means that we could characterise genes very quickly.
Compression (less junk) increases throughput; speed is a first-class scientific variable.
Do what you know, but do it here and not there.
Evolution often reuses machinery with new deployment/constraints; search for invariants in parts and variation in .
Daydreaming is terribly important, but the essence of science is to bring it… to realise it, to implement it.
Imagination is only half the loop; the other half is operationalizing into proof-producing experiments.
It is good to be ignorant about a new field and know a lot about the old ones, as you transit from the old to the new.
Cross-field leaps work when you import strong invariants from the old domain while staying unconstrained by the new domain’s “can’t be done” reflexes.
has always appealed to me, largely because I'm convinced that the… that the standard parts of any activity are already petrified at the core.
Default practices harden; method requires periodically rejecting “standard parts” and re-deriving the loop from first principles.
Nobody knows how to connect up all these molecular events to the actual functioning of an organism, or an organ system, so I think physiology will have to be reinvented so that we can grasp how all this molecular stuff is embedded in the function of an organism.
Lists of parts are not explanation; the integrative layer is its own science with its own .
These worlds are lost except through this and I suppose as one gets older one wants to try and preserve something.
"Preservation" is part of the research ecosystem: keeping institutional memory and the lived context that makes methods transferable.
Even if a student comes to me with a first class degree, he has to prove to me he could have got a second class degree if he'd tried.
Academic performance measures conformity to curricula, not intellectual capability. The best researchers often show controlled underperformance in irrelevant areas because they were busy thinking about what matters.
If you want to learn a new subject, I get a book and I start doing it... knowledge is out there; it's available. If you can't buy the book you can always go to the public library and steal it if necessary.
The barrier to learning is not access—it's initiative. Formal instruction is a convenience, not a requirement. Autodidacts often outperform because they're driven by genuine curiosity rather than credential acquisition.
Wordplay is just alternative interpretations of the same thing, and I think that that's a lot of... a lot of science involves that: of... of taking... looking at the thing on the surface and see that there... there's more than one way of looking at it and see there's more than one way of extracting something from it.
Puns and linguistic inversions train the mind to see multiple valid interpretations of the same data—exactly the skill needed for shifts. The cognitive flexibility required for wordplay is the same flexibility required for reconceptualization.
Let the imagination go, guarding it by judgement and principle, but holding it in and directing it by experiment... you've got to really find out.
Speculation is cheap; empirical grounding is expensive but essential. Brenner's scribbled Faraday quote in his copy of Schrödinger's "?" captures the tension: wild theorizing must eventually submit to experimental discipline.
Schrödinger says the chromosomes contain the information to specify the future organism and the means to execute it and that's not true. The chromosomes contain the information to specify the future organisation and a description of the means to implement, but not the means themselves.
This is the deepest insight about biological information: genes encode instructions for building the machinery that reads the instructions, not the machinery itself. got this right; Schrödinger got it wrong. The distinction between program and interpreter is fundamental.
Leó Szilárd used to tell me that the one thing that happened when he went into biology is he couldn't take a nice bath. When he was a physicist, he could go into a bath and he could lie there for three hours and he could think about physics, but he said when he went into biology, no sooner did he get in the bath then he'd have to get out and look up another fact.
Physics permits armchair reasoning; biology is relentlessly particular. Theories must constantly answer to facts. The physicists who entered biology (Delbrück, Schrödinger, Crick) had to learn this the hard way.
This is something you can always do... it's open to you. There's no magic in this and I think the whole of the philosophy that says unless you've gone through this way, if you're an old chap of 25, you can't do it. What you have to be is 18 and naive and go to a course and learn how to do it. This is just absolutely untrue.
Credentialism is gatekeeping dressed as quality . Brenner walked into the Dyson Perrins chemistry lab as an "intruder," synthesized what he needed, and left. Science is about solving problems, not having the right background.
That's when I saw that this was it. In a flash you could just see that everything... you know, this was the fundamental... the curtain had been lifted and everything was now clear what to do. ... This was really the beginning of molecular biology. This was it.
The best theories create clarity rather than complexity. When you see the right framework, the path forward becomes obvious. The Watson-Crick model didn't just explain—it opened an entire research program.
I've always found that the best people to push a science forward are in fact those who come from outside it. Maybe that's the same in culture as well. The émigrés are always the best people to make the new discoveries.
Insiders are captured by their field's assumptions. Outsiders bring fresh perspectives and don't know what's "impossible." Cross-domain transfer is a feature, not a bug.
Computers should be servants and not masters. In fact, that's when I invented something called ad hoc for a style of computing. When someone said what did ad hoc stand for, I said it stood for hands-on computing.
Tools should serve the problem, not dictate it. When the computing center demanded shift schedules and , Brenner demanded a machine they could touch directly. over your instruments is over your thinking.
If you can't compute it you can't understand it. ... I've been much more interested in the way the genomes work, because of course in our brains there's something called consciousness lurking around, but of course in genomes are completely unconscious and that seems to me to offer a much more challenging way of doing things.
Understanding means being able to reconstruct. Verbal descriptions that can't be made precise enough to simulate are probably concealing confusion. The genome offers a cleaner test case than the brain because there's no ghost in the machine.
It learns by being totally ignorant, which is the cheapest way. Which it says, if it works do it, if it doesn't work forget about it. And so I mean, it is learning under the regime of total ignorance that distinguishes the antibody system from what we might speculate as learning.
Evolution and immune systems don't need to understand—they just try things and select what works. This is often faster and more robust than top-down design. Selective retention beats rational planning in complex spaces.
Many theories are correct in a logical sense but they're untrue because they don't refer to the natural thing we're all interested in.
Internal consistency is not enough. A theory can be perfectly coherent yet have no contact with reality. must constrain theoretical possibilities.
We should suspect these easy analogies because they are likely to be wrong, because these analogies operate in our conscious minds which are very restricted. You know, we like to think of the nervous system as something like a general sending commands to an army... But this may not be the way organisms actually operate.
Our intuitions are shaped by social experience and conscious thought, neither of which are good guides to how cells, molecules, or nervous systems actually work. Metaphors that feel right are often systematically misleading.
So we both departed in great mutual ignorance, which is the best way.
Sometimes the most honest outcome of a consultation is recognizing that nobody knows the answer. Pretending otherwise wastes resources and creates false confidence.
This kind of ongoing conversation is so important to science. It's important because I'm not the sort of person that likes to think in isolation... an idea usually forms in my mind, it's at least 50% wrong the first time it appears. There's something wrong with it. And it's only in playing with it... that you can refine it.
First drafts of ideas are almost always flawed. The iterative process of articulation, critique, and refinement through conversation is how raw intuition becomes rigorous insight. Isolation breeds blind spots.
Being able to work without this endless justification that is common today... the endless thing just saying... which I feel is completely stifling to creative work in science... I think made that subject.
Novel research can't be justified in advance because you don't know where it's going. The project took decades to mature. Demanding quarterly milestones kills exactly the kind of work that produces breakthroughs.
I am a strong believer in the value of ignorance... And also, when you get to the age of 60, it's very useful, you begin to forget things... I think people should change their subjects very frequently, and why I think the best scientists do that.
Expertise ossifies. Forgetting clears space for fresh approaches. The same person can bring outsider advantages to serial fields by deliberately moving on before becoming captured by a .
That we thought we didn't want to do, although our laboratory... had all the capability of doing it. If you like, that was a kind of in which you could... a general could, so to speak, plan a campaign and then just get... the cavalry to do this and the artillery to do that. And that didn't seem to me to be what one wants to do in science.
Some problems can be solved by throwing resources at them; those aren't the interesting ones. The deep problems require insight, not campaigns. Organizing science like an army produces incremental results, not breakthroughs.
Reading is not enough. I agreed with him. Reading's not enough. But sometimes thinking isn't enough either, as well, because in the end it's doing what counts.
The three modes of scientific work—reading, thinking, doing—are each necessary but insufficient. Reading informs, thinking connects, but only doing tests. Brenner balanced all three while keeping experimental work primary.
I now divide papers into three classes: those that give me information, those that have no effect, and those that remove information from my head. And the latter is in this class and I'm... I've got very little left and I'm not going to give it over to rubbish like this.
Reading bad papers actively harms your thinking. Memory is limited; every confused framework that enters your head takes space from clear ones. Be ruthless about what you let in.
A modicum of ignorance is... is absolutely essential. Because otherwise you don't try anything. And that's why I think in any line of research people can get saturated very quickly because they just know everything. And when a student comes and says, 'Why don't we try this?' you tend to say 'Oh, don't be silly, you know, that'll never work'.
Experts know all the reasons things won't work—and are therefore paralyzed. The naive student who doesn't know it's impossible sometimes succeeds precisely because of that ignorance. to discovery.
The whole idea of learning by yourself now is absent... I find no, I have to start with chapter seven, then go back and read the first half of chapter one, then go back, then go and read the second half of chapter 10. And in that way I create my own path through this. And I think that is very important, because it's the way you construct your own knowledge which is important to you.
Textbooks present knowledge in a pedagogical order that may not match how your mind works. Creating your own path through material builds deeper understanding than following someone else's sequence. Self-directed learning is active construction.
The nervous system is an organ. It's an organ built out of cells... The connection between genes and behaviour must go through the construction and performance of a nervous system. ... Gradients would be the analogue way of doing it, and lineage would be the digital way of doing it.
You can't skip levels. Genes → proteins → cells → nervous system → behavior. Each level has its own logic that must be understood on its own terms before connecting to adjacent levels.
One day people will be able to compute a mouse from the sequences alone... We would understand the algorithm of how the mouse is built, because we could build it. It's an essential argument... to realise as to the nature of explanation in biology.
This defines what "understanding" means in biology: being able to reconstruct the phenomenon from first principles. If you can't simulate it, you don't really understand it. This is the ultimate test of biological theory.
Like produces like is the oldest biological observation. And of course what science has accomplished is to tell us that this happens because organisms contain genes... And somehow is what we have to explain. We have to say not somehow, but how.
"Somehow" is not an explanation—it's a placeholder for ignorance. The history of biology is replacing "somehow" with mechanism. Every "somehow" in your theory is a confession of incomplete understanding.
It should be in the of the thing being simulated... the of development is in terms of cells and the recognition proteins they carry on them... So the of the object is important and it is, if you like, the task of experimental biologists to define that.
Explanations must be in the vocabulary of the system being explained. Describing worm behavior with trigonometry or development with differential equations may be mathematically elegant but biologically meaningless. Find the native language.
Many people working in experimental biology simply think that when they've got it all... they've got the long list of components... that there will be a blinding insight... the real task of biology will yet remain to be done, which is the integrative aspect.
Parts lists are not understanding. The gave us all the genes; we still can't compute a mouse. Integration—how the parts work together—is the hard problem that remains after enumeration.
Science goes from the heroic... its heroic period into its classical period... being an early Christian must have been exciting, but to be one later is boring, because everybody's converted. The only thing of being an old Jesuit in the church is you know what's wrong with the church basically.
Fields have life cycles. The heroic phase is when foundational discoveries are made by a few visionaries; the classical phase is when armies of workers fill in details. Know which phase your field is in—and consider leaving for a new heroic phase elsewhere.
If you're always doing new things there's always very little competition. ... My people should feel that they're out there alone and they can actually give the problem their big attention... That's the great morale builder in a lab. ... Talleyrand: 'Never do for yourself that which you can get other people to do for you'.
Competition signals you're working on the wrong problems—the ones everyone knows about. The best problems are so new nobody else is working on them. And once you've opened a field, let others populate it while you move on.
It is the reduction of biology to one dimension in terms of information that is the absolute crucial step. Biology... biology had been three-dimensional, and a lot of people wanted it four-dimensional. But the whole idea that you could reduce it to one dimension is a very powerful idea. That you can just have linear sequences. Because it just makes the disentangling of everything so much easier to understand, makes copying easy to understand, it makes expression easy to understand, it makes the mapping easy to understand, and makes easy to understand.
The move from 3D structure to 1D sequence was the conceptual breakthrough that made molecular biology possible. Linear sequences can be copied, compared, mutated, and analyzed. This dimensionality reduction is what made the tractable.
'Don't worry about the energy, energy will look after itself; the important thing is how do you get everything in the correct order? How do you get everything to be specified in this order?' That is, the is the thing.
Brenner and colleagues had to fight the biochemistry establishment who were obsessed with thermodynamics. The insight was that information and , not energetics, were the central problems. This reframing opened molecular biology.
We don't do any statistics... oh, I'm sorry, we do have one test. We plot our results on seven-cycle log paper – that is it goes over 10^7 – and you hold the sheet at one end of the room, and you stand at the other end of the room, and if you can see a difference it's significant. ... Genetics is digital; it's all or none. We didn't have to make any quantitative measurements. And when you think about it, it's very remarkable subject... you can do very remarkable experiments, just on these very simple Boolean primitives.
Digital systems are robust and analyzable. When your signal-to-noise ratio is a million to one, you don't need statistics. The discreteness of genetic enabled clean logical reasoning impossible in messy biochemistry.
I'm a great believer in the . I think you can always know too much... one of the things of being an experienced scientist in a subject is it curtails creativity, because you know too much and you know what won't work. And I think what we should be doing is rather than knowledge, because it's ignorance that allows you to do things.
Expertise is a double-edged sword. Knowing all the reasons things "won't work" is paralyzing. Fresh eyes see possibilities that experts have ruled out. The beginner's mind is a strategic advantage.
You can't prepare yourself, as I mistakenly believed as a young person, equip yourself with a theoretical apparatus for the future... I don't think you can, so to speak, equip yourself, because I think things take you from the back basically and surprise you... 'What mathematics do I need to do biology?' I said, 'The ability to count up to 20, that's all.' ... The best thing to do a heroic voyage is just start. Don't... don't equip yourself.
The urge to prepare comprehensively before starting is a form of procrastination. You can't anticipate what tools you'll need. Start the work; the necessary skills will become obvious and can be learned on demand.
There were always two things that I think were important about our conversations was never restrain yourself; say it, even if it is completely stupid and ridiculous and wrong, because just uttering it gets it out into the open. And someone else will pick up something from it... always try... to materialise the question in the form of: well, if it is like this, how would you go about doing anything about it? ... One of the other things that I learnt through these interactions was to get the scale of everything right... we tried very hard to do: was to within the physical context of everything.
Self-censorship kills discovery. Bad ideas articulated can be corrected; unarticulated intuitions can't be tested. Always ground speculation in experimental possibility and physical reality.
I've always felt that the three things that came together to create the modern period of molecular biology were, first of all, Sanger's proof that proteins had a chemical structure – that is, that there was a defined sequence of amino acids... Secondly, the Watson-Crick structure of , which showed immediately how information could be copied... And thirdly, what Francis called the – that the sequence of bases in determines the sequence of amino acids in a .
Three independent discoveries converged: proteins have specific sequences (Sanger), explains copying (Watson-Crick), and specifies (the code). This triad created a new science.
Cracking the code became the thing... the code was thought to be what we call the genome. Whereas what is the code is... we imagine it was something like the Morse Code, was a table. It said, you know; S dot, dot, dot, O dash, dash, dash... that is wrong. It's the .
Precise language matters. "The " doesn't mean "all the genes." It means the lookup table from nucleotide triplets to amino acids—64 entries, period. Sloppy terminology causes sloppy thinking.
This is called , and this was invented in the 19th century for the optical microscope and we... and I understood that this was the exact image of this, but for the electron microscope... being able to say, 'This picture, I've seen something like this before', and of course now I know it's got to do with syphilis. Of course you can't explain to someone that this is where venereal disease comes in but it's effectively... it's the images that map on to each other.
Pattern recognition across domains drives innovation. The technique for visualizing syphilis spirochetes mapped directly to . Broad training creates a library of patterns waiting to be matched.
Once you've formulated a question, and if it's general enough, it means you can solve it in any biological system. So what you want to do is to find experimentally which is the best one to solve that problem and as long as it's general enough you will find the solution there and the choice of the experimental object remains one of the most important things to do in biology.
General questions can be answered in any system that's experimentally tractable. Choosing the right organism—E. coli, , , yeast—is a strategic decision as important as the question itself.
This is an organism which will have a . So it should be possible to... to do the following: to determine the in an organism of the nerve cells; to also ask whether all organisms have the same if they have the same genes. So therefore we can say genes specify wiring diagrams.
Before , "" was a metaphor. Brenner made it literal: enumerate every connection. This turned neuroscience from hand-waving to engineering.
I thought that there were two steps... you ask the question: how do you build nervous systems? That's one question, and that's what the genes do. And then you ask: how do these nervous systems work to generate behaviour? ... You can't understand how this... how the corresponds to the without understanding the of construction between them, the construction ... So from a genetic point of view the most important question, at least for me, was: how do genes build nervous systems?
There are two separate problems: construction (development) and operation (function). Genes don't specify behavior directly—they specify how to build the machine that generates behavior. Conflating these causes confusion.
They called all the students together and said, 'We want you to do pick and stab, because you have to test each plaque individually, and the first one who finds the mutant we will call this after his mother'... So the first student to find the mutant was a man called Hilliard Bernstein. All right, now you couldn't call them Bernstein mutants, but amber – Bernstein is the German for amber. So these mutants were called amber mutants.
Behind every technical term is a human story. "Amber" sounds scientific but commemorates a mother. Science is done by people with senses of humor.
I came back to find that all they'd done is sat around talking about it, and no one had done the experiment. And I broke my resolve and it didn't take me very long – I think it took me a week – I had... I had 80 phages with this attached.
Discussion without action is sterile. A week of focused experimentation beats months of theorizing. The bias should always be toward doing the experiment.
I did all of these experiments with my own hands, for the simple reason that I loved the . I think I just loved the idea of growing all these strange bacteria... one of the things that I always want... always found interesting to do is in fact to bring it to the stage that in fact other people can take it over and develop all the little tricks... tricks about... about handling the organisms oneself.
Love of the material—the actual organisms, the actual substances—grounds abstract thinking in reality. The feel for cultivation can't be delegated.
One of the things that I think we did rather well in Cambridge... was to have these fields and have people take them and work on them on their own... no one else in the world was working on it. And that's the greatest thing for all morale in the lab... But what is wonderful is to say, you know, this is exclusive... the best thing in science is to work . That is, either half a wavelength ahead or half a wavelength behind. It doesn't matter. But if you're with the fashion you can do new things.
Fashion creates competition and crowds out originality. Working on unfashionable problems means no competition and freedom to think. Being "" is a strategic advantage.
I wrote a little thing which we put into our request for a new building... we will find the position of every cell and its origin in development, and it's quite interesting that when I wrote this thing, some 25 years later, I could actually say, well, we've actually completed everything we said we would do then. We didn't think it would take, you know, 20 years or more, but it's been done. It is complete.
Clear goals, patiently pursued, get achieved. The project took 25 years but delivered exactly what was promised. Long-term commitment to well-defined objectives produces results that seem impossible at the start.
Let me just give a definition of that... you say, there you are, I've simulated the movement of the worm. But I call that an improper simulation... the program is full of sine theta, cos theta... What I would have expected to find in the program were lists of neurones, lists of connections... a proper simulation must be done in the of the object being simulated. And I think that if you do it that way, then I argue the computer program is the explanation... you need a complete ... he says, 'That's very nice, but how do you know there isn't another wire?' And what you need to be able to say is: there are no more wires - we know all the wires.
Curve-fitting is not understanding. A proper model uses the components the system actually uses—neurons, synapses, not trigonometry. And you can only claim completeness if you've enumerated everything.
It was what is called the self-fertilising ... each animal is the result of a cross of itself with itself, and there's no better inbreeding than to cross yourselves with yourself all the time. So this animal then had the property of being completely .
Self-fertilization creates genetically uniform populations—instant pure lines without generations of inbreeding. This made ideal for genetics: every individual is a clone.
It's very easy to put... to freeze things in liquid nitrogen, it's thawing that's the problem... what we found was that when you store cells in liquid nitrogen you're supposed to thaw them very rapidly. And we found that if we froze them slowly and thawed them, then this was the best way to do it.
The obvious approach (fast freeze, fast thaw) was wrong for nematodes. Reversing conventional wisdom (slow freeze) worked. Don't assume the textbook method applies to your system.
We invented the toothpick method of picking up nematodes... people said, how do you pick behavioural mutants?... anything that looks funny or different, you pick it up and you put it on a little petri dish by itself. If its children are different - show the same difference - well, then it's a mutant because it's inherited... I asked people to keep records of their mutant yields... how fast you were learning to discern differences.
Mutant hunts train perception. You learn to see differences you couldn't see before. Track your learning curve—it plateaus when you've trained your eye fully.
Is differentiation a state or a process?... I asked people... what is the difference between laid-back and mellowing out?... Mellowing out is a process, and laid-back is a state. Of course, by mellowing out you hope to reach the laid-back state.
The state/process distinction matters throughout biology. Is a cell "differentiated" (state) or "differentiating" (process)? The vocabulary shapes what questions you can ask.
In those days if you asked for an American machine you never got it... We needed acres of space because in those days this computer had no means of doing anything except... an assembler program... all input and output was done on paper tape. And I can remember lying on the floor with all of this paper tape unwound, going through and editing the single punched holes with... with patches... I think it was the most interesting period in the sense that that is where one got down to the actual essence of computing.
Working at the lowest level—hand-patching paper tape—teaches what computers actually do. Abstraction layers are convenient but hide the machine. Understanding the essence requires going to the metal.
If you stopped work, you... you might as well just stop living. And I think that left... left a deep impression on me... He worked till three, four o'clock in the morning, making shoes.
Work as identity, not obligation. Brenner's father was a cobbler who worked until 4 AM—not from compulsion but because work and life were inseparable. This ethos shaped Brenner's own tireless output.
One of the early memories I have as a child is... getting in there and finding the world of books. And the library in was a Carnegie Library... I remember being thrown out of this public library on more than one occasion, because I was a nuisance to the adults.
Autodidacts find their education in libraries, not classrooms. Young Brenner treated the public library as his university—getting thrown out was the cost of intensity.
There was a lot of bullying and I had some bad experiences... I used to go home by alternative routes and so on... I simply grew up to be a professional coward, which is I think by... by the way the best strategy.
Strategic retreat isn't weakness—it's survival. Brenner avoided fights he couldn't win. The energy saved on losing battles was redirected to battles worth winning.
I think children have an innate kind of scientific curiosity; they have the inquisitiveness, 'Why is this? Why is that?' And then I think it is the formal teaching that destroys this. And I think this is very rare that this is preserved.
Education systems are optimized for compliance, not inquiry. Most people lose their curiosity by age 12. Preserving it requires active resistance to the curriculum.
How things worked seemed to me to be very important. In other words, things had to have... had to have meanings. And I used to be very curious about... about how various things... were constructed.
Mechanism first, names second. Brenner was drawn to understanding construction and function—not classification or taxonomy. This orientation shaped his entire career.
I once criticised him. He asked me a question and I told him he didn't know what he was talking about... Actually, I was right.
Authority doesn't confer correctness. A teenager telling a professor he's wrong requires courage—but more importantly, requires being right. Verify claims regardless of source.
One of the things I've always had is my reluctance to join any organisation. Because I've always felt you compromise if you join an organisation. And that has gone on throughout my life, and I have to say that the only thing I ever joined is I... I did become a Fellow of this Society, that's the only thing... scientific society I've joined.
Organizations demand conformity. Membership trades independence for belonging. Brenner kept his freedom by staying outside—even refusing most scientific societies.
I came across the... the articles of Hopkins, and I realised that my lecturers had never heard of him, but there he was, very important figure... I realised then that these people really didn't know anything about modern science at all. And that was quite a shattering thing.
Teachers don't always know the frontier. Brenner discovered biochemistry's founder (Hopkins) in journals his professors had never read. Original sources beat secondhand knowledge.
I came to the conclusion that you've got to do chemistry and biology, and there's got to be a science that studies the function of cells and something below that, which I called... I thought, chemical embryology. And then I realised there was a subject called biochemistry.
Brenner intuited the need for molecular biology before it existed. He reasoned from first principles: cells exist, they function, therefore there must be a chemistry of that function. The field he predicted became his life's work.
I love pigments, I love colour... Why did I work on pigments? Because you can see them. It is always a good... a good thing in science... if you are working on a that you can see without instrumentation.
Visible phenotypes accelerate discovery. No instrumentation means no calibration errors, no machine breakdowns, no waiting. If you can see the result with your eyes, the feedback loop is instant.
This gives one an eye for country. It gives one an eye that one can look at a... at the topography and see its history in it.
Pattern recognition trained in one domain transfers. Brenner learned to read landscapes; later he read genomes. Both require seeing the history encoded in present structure.
I was interested in languages and in words... wordplay is part of the way one... one learns to think. I think wordplay is just alternative interpretations of the same thing. And that is one of the things that science does.
Punning isn't frivolous—it's cognitive training. Wordplay forces you to see multiple meanings in the same signal. Science requires exactly this: finding alternative interpretations of the same data.
We used to have many discussions... of which we'd come to the conclusion that the fundamental question in philosophy was: 'define define'.
Definitions are circular—you need words to define words. Recognizing this teaches humility about language and forces you to ground abstract terms in operations.
I was very active in hunting around as a naive young man for those sciences that could stand me in good stead for the future, which is a ludicrous activity. Because there's no way of knowing what the future is, and the best thing to do really is to find something that interests you and to try and contribute to it.
You can't predict which fields will matter. Brenner tried to pick "future-proof" subjects—and later realized this was impossible. Better to follow interest than forecast relevance.
It is important to distinguish between chastity and impotence. The outcome is the same, the reasons are fundamentally different.
Two things can look identical yet have opposite causes. "We didn't do X" might mean "we chose not to" or "we couldn't." Diagnosis requires knowing which.
And what you had in Cambridge was, you know, a few old buildings that you could walk through in a... in a few minutes... everything was much smaller than I had imagined it to be... What I knew already was that whatever you read about a subject, when you actually go and see it, the reality is always different.
Reputation inflates perception. The legendary was a few cramped rooms. Great work doesn't require great facilities—it requires great people in close proximity.
In fact, I do believe that the first official use of the term 'molecular biology' in Cambridge was in the list of Part II lecturers... I know because I was one of those lecturers and it was listed under a special... a special heading.
Fields get named when they need to be taught. "Molecular biology" existed as practice before it had a name—the label came from bureaucratic necessity, not theoretical insight.
The difficulty was that after infection no new ribosomes are made, there's no synthesis, and so what you had is if you wished to hold the old theory you had to have what I called at that time the paradox of the prodigious rate of synthesis.
Paradoxes signal wrong models. The "prodigious synthesis" puzzle forced abandonment of the -as-template theory. The resolution was messenger —a new tape for the same player.
We called it messenger there, but we had another name for it; we called it ... the idea that the ribosomes were like players... and you fed them with tape. Actually, in my mind that was the old ... and ... I said to François... I said, 'You know we're fine'. He said, 'Why?' I said, 'Max doesn't believe in it'. Because Max was marvellous; he was always wrong.
Contrarian signals can be informative. was a great physicist but reliably wrong about molecular biology. His skepticism became a positive indicator—if Max disliked it, it was probably right.
Someone got up at a meeting and said, 'I wish to propose two models: model A and model B.' And he said... 'Well,' he said, 'either model A is right or model B is right.' And I said, 'You've forgotten there's a '. He said, 'What's that?' I said, 'Both could be wrong'.
False dichotomies are everywhere. "A or B" assumes exhaustive options. Reality often picks C—a model no one proposed. Keep the space open.
You talk about T4, you get all involved in the intricacies of this, and if you talk about two things simultaneously... sometimes you can just see one set of balls bouncing the same way. And I think that is so necessary to continue, you know, almost hysterical conversation, just constitutive talking, because I think that brings things together that you don't actually see by... logical , because most logical you just go around in the same circle and you need to break out of it.
Logic is circular; conversation is generative. Brenner and Crick talked constantly—not to deduce but to collide ideas. The breakthrough comes from juxtaposition, not syllogism.
You could make a machine in which the instructions were separate from the machine, and that's really what the messenger... I mean, of course it got called messenger .
The messenger concept was computational before it was biochemical. Separating program from processor—this is Turing's insight applied to the cell.
At this meeting at ... we discussed what do we name this thing? And we thought messenger was a perfectly good word for it... immediately said, 'You know, of course, Mercury may have been the messenger of the gods, but he was also the god of the thieves'. And I think it's right to .
Good metaphors carry hidden meanings. The messenger delivers—but also takes. Science steals nature's secrets. Chargaff's quip captured something true about the enterprise.
We all know what I call , or Occam's Brush in America, which is that of which the minimum number of facts have to be swept up under the carpet in order to have a consistent theory.
Occam's Razor is about parsimony of entities. is about parsimony of inconvenient facts. Every theory requires some sweeping—the question is how much.
Talking in the Eagle one time... I said that, 'What would it be like if there were not only base substitutions but base additions and deletions?' And I suddenly realised that you could get that if you stuck into the ...
The frame-shift came from asking "what else could it be?" didn't substitute—it inserted. This single insight explained all the puzzling data.
If you ask how do you do this experiment uniquely... you make a combination A and B. And A and B is mutant... Now, we cross those phages together, there is no way a normal can be produced... But of course you get functional come out, and that must be the triple... the triple showed that the code was phase three... it seems mad that you could deduce the actual triplet nature of the . But that's just simply the logic of how the information is transferred... topology could, you could do these things at the kind of topological level.
You can deduce molecular structure from genetic logic alone. Brenner proved the triplet code without chemistry—just plus/minus genetics. Topology trumps microscopy.
There were many exceptions... what happens to all these exceptions? So you have the ... As it turned out it took about five more years to work through all the exceptions, and the remarkable thing is that each one of them had a different and special explanation... all the exceptions, each of which cannot be explained by the coherent theory... that the coherent theory remains, then. And it is... was wise to take all of these exceptions which showed no relationship amongst each other and put them on one... we didn't conceal them; we put them in an appendix.
Exceptions that share a pattern are dangerous—they suggest a rival theory. Exceptions with unrelated causes are safe—they're noise, not signal. Appendices are honest; omission is not.
It was the real theory; you had to buy everything... Everything was so interlocked. You had to buy the plus minuses, you had to buy the barriers, you had to buy the triplets phase, and all of those remained together... it was all or nothing theory... I think that that is one of the most beautiful... I mean, aesthetically elegant experiences of my life, in which, just by doing these little operations, you land up with this detailed description of the molecular structure of living matter.
Interlocking theories are beautiful but fragile. The frame-shift work was all-or-nothing: reject any piece and the whole collapses. That fragility was its strength—it couldn't be partially wrong.
Our idea was to add viral RNAs to E. coli ribosomes because we thought you should be able to play any tape, and we know that these virus RNAs have information... the people from Ochoa's lab heard this and realised that you could add things to ribosomes.
The messenger concept was liberating: any tape should play on any machine. This idea—tape universality—opened the door to adding synthetic polynucleotides (poly-U) and cracking the code.
The lack of that kind of impetus, that kind of school of biochemistry, really held things back here. In America the... the people emerging from the laboratories of Ochoa, from Kornberg... had by this time, you know, the huge armoury of materials.
Science requires infrastructure. Cambridge had ideas; America had reagents. Kornberg's lab had a monopoly on radioactive triphosphates. Sometimes you can't compete on cleverness alone.
If you take the extreme view that what you'd like to do is to compute organisms from their genome, then you have to understand inside an organism what one can call the... the principle of construction. Let me give you an example... we can look at the head of a virus and we can see it's a perfect icosahedron... so what we want to know is how is the equation for an icosahedron written in .
The ultimate goal is computational: read a genome, output an organism. But you can't get there without understanding how genomes specify geometry. Structure is the intermediate representation.
If we were to unravel all of the structure what we will find is that the equation for an icosahedron is written in little bits and pieces in the genome, in a little sequence of amino acids here, and another little bit there. And we could not disentangle that a priori unless we understood the principle of construction.
Geometry is distributed across the genome. There's no "icosahedron "—just patches of amino acids that form contact angles. You need the construction principle to decode the distribution.
You have to have the genes, the genes then have to work in cells, the cells then have to build a nervous system, the nervous system has to have certain capacities for learning, and that's the way the genes specify: follow Dr Lorenz around. So the argument is very clear; you have to open the box. It is not an input/output system, because what's in the box can actually determine your theory of how this can work.
Black-box behaviorism is insufficient. You can't explain behavior from genes without understanding brains. The mechanism matters—it constrains what theories are even possible.
We have to have what I call the grammar of the system. Part of how you build it up, you construct it, you develop it, is part of that grammar. And unless you include that in the explanation it can't make sense. Hence I think structure at all levels is important.
Development is grammar, not vocabulary. Knowing the genes (words) isn't enough—you need the rules of combination (grammar). Structure at every scale mediates to .
It's... it's to me a most remarkable fact that the only person that really understands the structure of anything is the person who did that structure. So if you want to find out about haemoglobin go and talk to Max. Because Max is the only person who really understands haemoglobin.
Structural knowledge is tacit. solved hemoglobin and understood it in a way no textbook reader ever would. The person who did the work has knowledge that doesn't transfer.
1961 was of course a very exciting year... Of course, that was incredibly exciting, but there was still a lot more work to do... But already I think in 1962, my interests were already turning to different matters. And during that year and I began a long series of conversations... which is: what should we do next?
The hardest question after a triumph is "what's next?" Brenner and Crick didn't rest on the —they immediately asked what new mountain to climb. The answer was nervous systems.
It seemed, as it does happen in all science, that when one gets to this stage there seem to be only what the military people call mopping up operations. And of course such was the thrill of doing molecular biology that one didn't want to be involved in that.
Filling in details is necessary but not exciting. Once the conceptual breakthrough is made, what remains is "mopping up." Brenner left that to others and moved to fresh problems.
defined three units: the ... the muton... and the recon... only one of those has survived, the , and the reason the other two didn't survive was that one should always see what one's units sound like in a different language. And since we had numerous French colleagues, the other two didn't survive because one sounded like a sheep, and the other one sounded like the things Paris taxi drivers call each other.
Names need international road-testing. Technical terms will be spoken by people in many languages. Check how they sound before you publish—"muton" and "recon" failed the French test.
The grand paper of Jacob and Monod really gave you a means for seeing this... that differentiation was the next... the next important problem.
Jacob-Monod showed how genes could be regulated. The obvious next step: how does regulation produce different cell types? Differentiation became the new frontier.
wrote an article saying that as far as he was concerned embryology or development was a solved problem... because Jacob and Monod have already told us what to do. But as in all parts of biology the more general the theory the more vacuous it is.
General theories explain everything and nothing. "Turn genes on and off" is true but useless. Real understanding requires the specific details: which genes, when, where, how.
If you simply say development's just a matter of turning the right genes on in the right place at the right time and that's the answer, that's absolutely true but it's absolutely useless, because somewhere deep down in our cells what we'd like to do is to actually go and make a mouse, to build a mouse.
The criterion for understanding is synthesis. Can you build the thing? A gedanken mouse—one you could compute from sequences—is the test of whether you truly understand development.
The nervous system offered this possibility simply because everything... not only did you have to have cells, not only did you have to have cells in the right place, but they actually had to wire up together accurately. And it is the wiring problem of the nervous system, where things grow for very long distance and hook up at the end... that seemed that you would need very special explanations.
Nervous systems are harder than other tissues. Cells must not only differentiate but find specific partners over long distances. The wiring problem forces you beyond regulation into spatial computation.
I was tremendously impressed by reading in the fly sciara that... which has supernumerary chromosomes which it gets rid of in all but two cells of the 16-cell stage... how does it know that it's got 16 cells and that, you know, 14 + 2 = 16? There must be some kind of cell-counting thing.
Organisms count. They know when they have enough cells, enough organs, enough growth. How? Cell counting is a real computational problem embedded in development.
I remember these pictures of Lorenz being followed around by his ducks... And of course I wanted to know, you know, was there a , so to speak, to put the left foot forward, followed by another that said, 'And having done that put the right foot forward'? In other words, what were the units of behaviour and did they map onto the genetic program?
Behavior must decompose into genetic units somehow. But how? Brenner asked whether the decomposition was obvious (one = one movement) or subtle. Spoiler: it's subtle.
Our work on the mutants had shown us that a lot of the mutations, a lot of the codons had to be sense... we could give a topological proof of – we wouldn't have to do any sequencing. All we showed is that as the mutant moved to the right we got more and more of the .
Topology beats chemistry. Brenner proved genes and proteins were colinear without sequencing either—just by showing truncation points moved together. Logic substituted for measurement.
I was able to prove – knowing that ambers and ochres and UGAs were connected – I was able to say that the nonsense mutants had a U, that one of them had a U and two As, one of them had a U and an A and a G... So only by that experiment, , and a lot of knowledge about what amino acids these were, did we fulfil just even the last bit of the original program of sequencing . So I like to say I did do it, I did sequence three bases in by genetics in this case.
Genetics can substitute for chemistry. Brenner determined UAG, UAA, UGA as stop codons purely from genetic inference—no sequencing machines. The original program wasn't completely abandoned.
This is really our beginnings with genetic engineering; it's what I used to call genetic steam engineering, because we had to do things by .
Before recombinant , genetic engineering was crude and laborious—"steam-powered." But it worked. The elegance of modern cloning grew from these brutal origins.
I was very much imbued with what I'd done with the because I had avoided purification simply by just using something that was a huge amount of the synthesis... as long as everything else is spread over hundreds of species, if yours is a half or even a third you only see yours as the intense thing, because everything else is background.
Amplification beats purification. If your signal dominates the total, background becomes negligible. This principle—overexpress rather than purify—underlies modern molecular biology.
How were we going to study the mutants?... I'd have to look at membranes... an electron microscope can resolve membranes, can resolve small things, and so we said, well, with the electron microscope you could trace the path quite... quite adequately.
Choose the tool that matches the question. Light microscopy couldn't resolve synaptic membranes. The electron microscope could. Tool choice determines what questions become answerable.
To do this even on one neurone of a higher organism would be... would be impossible. That meant for one to do this on a whole organism, we would have to get something that was very, very small in order to fit it into the window of the electron microscope.
Scale constrains ambition. Brenner wanted complete wiring diagrams—but EM windows are tiny. Solution: pick an organism small enough to fit entirely in the window. This drove the choice of .
I've always found that the best people to push a science forward are in fact those who come from outside it. Maybe that's the same in culture as well. The émigrés are always the best people to make the new... make the new discoveries.
Outsiders bring fresh perspectives. Insiders know the rules too well—they can't see past them. Brenner recruited mathematicians, engineers, chemists to do biology. Émigrés don't respect disciplinary boundaries.
When someone said to me once, what is the nature of the organisation in your laboratory? I could only think of one reply, which was, 'Loose gangs'. There were just groups of people who got together and whose aim was to push the subject forward.
Formal hierarchy kills innovation. Brenner's lab was "loose gangs"—self-organizing groups attacking problems. No org charts, no management layers. The science was the organizing principle.
In those days computing was only done in computer centres... we tried to tell them that we don't want to do computing this way, computers should be servants and not masters.
Computer centers enforced batch processing—submit job, wait for results. Brenner wanted interactive computing: the computer serves the scientist, not vice versa. This principle shaped his approach to computational biology.
I actually did write an interpreter for it, and... and became so fascinated by this language that even on my present machines the first thing I've done is write an interpreter for Trac, and my versions of Trac include a whole lot of new constructs... So I think the idea that one has a private computer language seems to me to be rather sophisticated.
Personal tools personal thought. Brenner created his own programming language variant—optimized for how his mind works. The ultimate in tool customization.
If you can't compute it you can't understand it. And... that I... and of course the association with someone like David Marr was very interesting... but of course in genomes are completely unconscious and that seems to me to offer a much more challenging way of doing things.
Computational understanding is the deepest kind. Can you write a program that produces the phenomenon? If not, you don't really understand it. Genomes are unconscious programs—pure information processing without the confounding variable of consciousness.
I used to call the European plan versus the American plan. And I said that in Europe... you don't give a damn who your neighbours are and where you live, the most important thing is who were your ancestors. And so that was a thing in which you had a computation which depended on lineage... As opposed to... the American plan, which is you don't give a damn who your ancestors are, what's most important is who are your neighbours. This I called the spatial computation.
Development uses two logics: lineage (who your ancestors are) and position (who your neighbors are). is mostly lineage; vertebrates are mostly position. Understanding which logic applies is critical to understanding any developmental system.
People have said well, we're sure that if you take a chemical out of Beilstein you can make an antibody to it... this statement will be equally true... a more, a deeper question: how does it know what is not yet published in Beilstein but will be in the future? So what is in fact the landscape of this area of chemical... of molecular recognition? And it becomes very clear that it has to be a rather more complicated thing than... one antigen, one antibody, and it means that everything must be pluralistic.
One-to-one is too expensive. The immune system handles infinite antigens with finite antibodies through pluralism: many-to-many mappings. Recognition is a code, not a lookup table.
It learns by being totally ignorant, which is the cheapest way. Which it says, if it works do it, if it doesn't work forget about it... it is learning under the regime of total ignorance that distinguishes the antibody system from what we might speculate as learning. This is quite important because many people now can't make the clear distinction between selection and acquisition.
Evolution and immune systems "learn" without understanding. They don't model the problem—they just keep what works. This selection-based learning is cheaper than acquisition-based learning. Know which your system uses.
We developed methods for growing large quantities of nematodes, and we actually grew them like you grow bacteria. What we did is we grew fermenters of bacteria, then we threw in nematodes and they ate all the bacteria and so we would then harvest the nematodes.
Scale matters. To do biochemistry you need material. Brenner found a way to grow worms industrially—fermenters of bacteria as food. This unglamorous infrastructure enabled molecular analysis.
You can ask yourself is the genetic program in very general terms, say build this, build this, build this? Or does it say well, there's a big part that says build a sort of a leg, and then we have all this tinkering that goes on which evolution has added, to build a proper leg, an accurate leg? And one's guess is that there will be sort of leg programs and there will be a second level which will be called refining programs. So evolution might actually be viewed as, you know, one step backwards, two steps forward in another direction.
Evolution doesn't start from scratch. It builds rough structures then refines them. The genome contains both "build a leg" routines and "refine the leg" patches. This two-level architecture explains why mutants often "make the same mess."
Apart from looking at the structural changes we could analyse these mutants by putting them in combinations, the so-called . Namely if you put two mutations together and the was like A, then it meant that B had no extra effect and therefore acted after A. And so one could then analyse what came to be called genetic pathways. But the core of it, and it worried me all the time, was how on earth would one ever get down to finding the molecules involved in regulation?
analysis reveals pathway order without knowing the molecules. If A masks B, A acts downstream. This pure logic—combinatorial genetics—established the concept of "genetic pathways" before anyone could clone a .
Francis came in very excited... and he said, 'I've got a new idea and I think that regulation must be carried out by... by single stranded nucleic acid'... At least it had the clarity that if the axiom was wrong everything else would have to be wrong, as I pointed out to him.
Clear theories are falsifiable. Crick's -regulation had the virtue that if the premise failed, the whole structure collapsed. Brenner valued this—theories with escape hatches ("maybe it's different in this case") are worthless.
I wrote a paper myself trying to... which essentially just accounted for it as junk... my only contribution to the junk subject is to differentiate, to make a strong differentiation between junk and garbage. Because very clear is junk is the rubbish you keep and garbage is the rubbish you throw out. So extra by definition cannot be garbage, but only junk, because if it were garbage it wouldn't be there. And I think that's essentially the answer, because junk is just garbage that there's no need to throw out.
Junk persists because it's not costly enough to delete. The genome doesn't optimize aggressively—it tolerates dead weight. This insight frames noncoding correctly: not functional, not actively removed, just accumulated.
Having got to this stage... extensive analysis of the genetics of this beast, an extensive amount of work on the biochemistry beginning, the anatomy going ahead, the development going ahead... one felt the ship was, was at sea but it was very unclear where it was heading.
Strategic uncertainty is normal. Even after years of foundational work on , Brenner felt directionless. The path becomes clear only in retrospect. Keep working through the fog.
I invented a unit which was an Av. An Av of events was 6 x 10²³ events... And of course now we know that experiment wouldn't have had a hope in hell of working. No, not a chance. Zero. For the simple reason, these nematode genes have introns in them. The bacterium wouldn't have known what to do with them... So Francis talked me out of it. He was quite right, because I thought it was, you know, the last desperate experiment.
Good collaborators save you from your worst ideas. Brenner's "put nematode genes in bacteria" experiment was doomed by introns—which no one knew about yet. Crick's skepticism was right for the wrong reasons, but it worked.
I received a letter from the secretary of the MRC enjoining me not to do any of these experiments because of the moratorium which was very easy to obey, because I suddenly realised the great merit of something I had discovered very early, which is the difference between chastity and impotence. So we didn't have to be chaste, we were impotent to do anything. So of course we could agree to the moratorium immediately.
Compliance is easy when you can't do the thing anyway. The recombinant moratorium cost Brenner nothing—he lacked the technology. Distinguishing "won't" from "can't" remains essential for honest self-assessment.
What I predicted they... nobody would cloning all these genes, they would be synthesising them. And I predicted that in fact people would synthesise the for insulin... Now that was pooh-poohed at the time, because you see, it raised the question which no one was willing to ask about, was if a... if your carries the danger from the organism that it comes from, what the hell is an insulin , a synthetic insulin ? It's a piece of chemistry.
Synthetic genes break the "natural source" frame. If danger comes from the organism, what about a that never touched an organism? Brenner saw this logical hole in the biosafety discourse decades early.
At Asilomar, where I gave a talk... I had in fact suggested something called the Book of Man. You have to realise that at that time we still did not know that genes contained introns. And what I'd thought was we would take all the genes and we would glue them down on a page of nitrocellulose and this would be the Book of Man and you could turn to page 48, line 23, word four, and there you'd have the for serum albumin written there... this is on the threshold of the new genetics.
Vision precedes technology. Brenner imagined a complete catalog in 1975—two decades before the Human . The vision was clear even when the method (pre- discovery) was wrong.
The man went berserk, you know. Sort of accused me as a fascist and so on, and then he said: 'Why do you have to do this?'. I said because I believe in the inalienable right of adult scientists to make fools of themselves in private, you see.
Science needs protected spaces for speculation. Public scrutiny of every half-formed idea kills creativity. Scientists must be able to float stupid ideas without journalists reporting them as fact.
The dangers were dependent on where the came from... on that grounds, you see, you would have to clone lion at a much higher category than, say, pussy cat , because clearly lions are more dangerous than pussy cats. And so this kind of uncanny never-neverland which... which just made no sense of anything became the way in which one did these experiments.
Biosafety theater follows vibes, not logic. from a "dangerous" organism isn't more dangerous than from a safe one—danger depends on what the encodes, not its source. Policy often confuses symbolic categories with actual risk.
Science I think is neutral in that sense. If the box can be opened it will be opened. If not now, then later. If not by us, then by other people. And the only thing to do is to forbid the search for any new knowledge. You can't just forbid the search for that kind of new knowledge and not for any other kind, because it's part of the process. Now it seems to me that people had better get on to the real question, which is what do you do with it once you get it?
Suppressing discovery just relocates it. The question isn't whether to discover—that's inevitable—but how to govern what's discovered. Focus on governance, not prevention.
I did create a safe strain... and I had to test it. And of course I tested it on myself. Now, as you know, human experimentation is strictly forbidden, and so I said I'm testing it on an upper primate, I didn't say it was a human being. In fact I don't count myself necessarily as one. I was then told I should consult people before I did this experiment. They couldn't stop me, but I should consult people. So I sort of met odd people in the street and said what do you think about this?... I showed my safe... my strain was 10 million times safer.
Self-experimentation cuts through bureaucracy. When safety testing required proving your strain was safe, Brenner tested it on himself. The result—10 million times safer—was unarguable.
Another remarkable lesson that emerged was, don't worry, if you can think of something dangerous, nature's probably done it... So I surmised of taking cholera toxin and putting it in E. coli... Well, it's been done befo... it's been done. It's called Shiga toxin... nature has done it before. And of course always has priority over us.
Nature is more creative than biosafety committees. Any "dangerous" recombinant you can imagine probably already exists in the wild. This deflates the novelty of engineered risks—nature's had billions of years to try everything.
In fact, I wrote an article... which was for its 10th anniversary... and what I wrote there was that in the history of biological science we can think of two epochs, okay. BC, which stands for Before Cloning and AD, which stands for After . Because at that junction, which dates back now 20 years, 1975... before that point everything seemed hopeless, we'd never get down to the molecular biology of these genes. And now I mean, it's banal. It's commonplace... the explosion of this has made developmental biology into a science.
cloning was biology's phase transition. Before: impossible to connect genes to molecules. After: routine. Brenner lived through this discontinuity and recognized it as the dividing line of the field.
I took over... I then became the Director in 1979. And I think that doing that was at least in my... as I look back on it, I think that was a big mistake, because it's not, it's not a thing that I really like doing. And I realise that people who go into these positions become like windows, that is, where the people above them look through them at the people below them and you become a mediator between two impossible groups, namely the monsters above and the idiots below.
Middle management is a trap for scientists. Directors become transparent conduits—pressed from above, resented from below. Brenner called becoming director his "biggest mistake." Protect your research time.
The new genetics can be differentiated from the old genetics because here we go from the genes outwards rather than in the old genetics we went from the inwards to look for the genes... you are no longer conditioned by experimental constraints. When we did classical experimental genetics we had to go through endless selections to get an organism that fitted into the window of the electron microscope, or that would grow rapidly in a laboratory...
Sequencing inverted genetics. Old genetics: find a , hunt for the . New genetics: read the genome, ask what it does. The constraint shifted from "what can we breed" to "what can we sequence."
Thomas Morgan was an embryologist... who had discovered that he'd come to the end of what he could do with classical embryological techniques. And this is why in the beginning of the century he turned to genetics... now one's come to the end of the genetic deviation and one must go back to the problems of biology that had been left behind, namely those of development.
Fields oscillate. Morgan left embryology for genetics when embryology stalled. Brenner left genetics for development when genetics was "solved." Knowing when to return to abandoned problems is a skill.
The search for the inducer had gone on, lots of people had tried... There was a lot of what I would call theoretical work... ideas that genes really rate processes, but all of this had no body in it, it lacked... it lacked a material content and was simply verbalising our ignorance.
Theory without material substrate is just talk. Pre-molecular developmental biology had words—"inducer," "organizer"—but no molecules. Words without referents are "verbalizing ignorance." Insist on material content.
The units of development are cells. And our job is to ask how do genes get hold of the cells, if I can put it in that way. Because that's the way the genes must go through to the developmental process... They have to get hold of the construction machinery of these... of the organs in order to express their effects.
Genes don't build organisms directly—they work through cells. The cell is the unit of construction. This framing clarifies what developmental genetics must explain: how genes command cells.
Francis got very interested in asking whether you could account for positional information... in terms of a process of diffusion. So one had a very simple model then which was that one had a... a source... and you had a sink at the other end and this molecule distributed itself at a... in the form of a gradient across this. And then the idea was that the cells would read this gradient and decide what it is they were going to be... a diffusible morphogen.
Gradients encode position. Crick formalized the morphogen concept: a source, a sink, diffusion between, and thresholds that cells read. This became the standard model for patterning. Simple physics underlies complex form.
If you could think of Turing as being the archdeacon of digital computation, which he was in his and in everything that followed in computers; this stuff was exactly the opposite. It is essentially an analogue computation, and that's an analogue computation with thresholds, and the sort of thing that cells are, and objects, are very good at doing... biological systems have worked out extremely good ways of doing analogue computation within their scales, and do it exceedingly well. And in fact, they find it very difficult to count things beyond one. They can count the difference between one and nought.
Biology is analogue, not digital. Turing's morphogenesis paper was continuous math, not discrete logic. Cells don't count—they threshold. Understanding this prevents forcing digital metaphors onto continuous processes.
One of the things that we did and which ran through all of our work... I had invented something called . , that's H-A-L, it stood for Have A Look biology. I mean, what's the use of doing a lot of biochemistry when you can just see what happened?
Look before you grind. Brenner's "Have A Look" principle: check with your eyes before running assays. When Spiegelman claimed ribonuclease stopped synthesis, Brenner looked and saw the cells had lysed. Observation trumps measurement.
I noticed that when I wanted to learn a new subject like computation... I got a book and read this book until I found the way to read it, for me. That is, the author thinks he's got the right way of telling you about the subject, but in fact I find no, I have to start with chapter seven, then go back and read the first half of chapter one, then go back, then go and read the second half of chapter 10. And in that way I create my own path through this. And I think that is very important, because it's the way you construct your own knowledge which is important to you.
Textbook order isn't optimal for everyone. Brenner read chapter 7 first, then chapter 1. Find your own path through material. The author's logic isn't your logic. Learning is personal construction.
Owls stayed at the lab till midnight... larks came in early. I was both an owl and a lark. That is, I liked to work late at the lab and then come home, and then quite often go in early: 6 o'clock, 5 o'clock. But as I grew older I had to choose, so these days I'm much more a lark, that is, I like to get up very early in the morning, when the whole world is asleep, 4.30, 5.00am, and then I can read, I can work on my computer... and I can also do quite a lot of daydreaming there. And then... by the time everything came in and all the secretaries and then the usual mess of one's life started, I'd already finished my day's work.
Protect your creative hours. Brenner did his real work before 9 AM when the world was asleep. By the time the "mess" started, he'd already accomplished what mattered. Schedule your best hours for your best work.
A student coming up to me and said: 'Doctor Brenner, what is going to be the next breakthrough in the nervous system?' And I said to him, 'you are 50 years too late, it's already happened, it's called the '. Because of course to that people thought that nervous systems were continua and the triumph of actually showing that they were built of nerve cells connected to each other, that was the breakthrough.
The biggest breakthroughs don't feel like breakthroughs at the time. The doctrine—that brains are made of discrete cells—was the fundamental insight. Everything since is elaboration. Know which foundations already exist.
It's not fraud, this is what I call embezzlement. Because everybody believes that effectively they'll be able to put... one day it'll come right and everything will be put back and no one will know. You see, so that's the embezzler who takes £10 out of the cash till every Friday night and lays it on the horses. What he thinks is, one day the horse will win and he'll put all the money back and no one will know.
Most scientific misconduct isn't malicious fabrication—it's optimistic "embezzlement." Researchers massage data believing they'll eventually get the real result. They never intend to cheat; they just keep betting the data will come good.
Isn't the great thing about science that you can actually solve a problem? You can actually take something which is confused, a mess, and not only find a solution but prove it's the right one. Now, I mean, that to me is really what I think drives us, I mean, should drive us.
The reward of science is resolution. Not prizes, not money, not publications—but taking confusion and replacing it with proven truth. If this doesn't motivate you, you're in the wrong field.
I said had he tried avocado's number. And they said, 'What is avocado's number?'. I said, 'It's the number of molecules in a guacamole.' And I actually managed to get this published in Science, without referees.
Humor deflates pseudoscience. When Benveniste claimed water retained "memory" of antibodies (homeopathy), Brenner mocked it with "avocado's number." Ridicule, deployed correctly, is a legitimate scientific tool.
And of course to jump from 50,000, from 10⁴, to three billion, that is 3 × 10⁹, that's a 10⁵ jump. That's, that was some act, I wouldn't call it of imagination, it's certainly a daring act.
The Human wasn't just ambitious—it was a five-orders-of-magnitude leap. Sequencing jumped from 50kb to 3Gb. "Daring" is the right word. Sometimes you have to bet on scale improvements that don't yet exist.
I thought we could actually do this by having something that was like a bingo hall. That is we could have these machines and we could put up the sequence of the day, people would actually pay to come and operate these machines and we'd have a prize... I think we'd be deluged with people wanting to come and play the machines, and we could put these up in shopping malls and supermarkets...
Crowdsourcing before the internet. Brenner proposed gamifying sequencing—make it a lottery, put machines in malls. The idea was ahead of its time; citizen science projects like Foldit eventually vindicated the instinct.
There's only one map that you need, which is where... how... give us the genes and tell us where they are. That was the task... the map is only required if you wish to operate on that organism in the real world... But if you want to understand human biology you need genes.
Cut through the bureaucratic debates. Physical maps, genetic maps, cytogenetic maps—all distractions. What you need is genes and their locations. Brenner kept focus on the actual goal while others argued methodology.
I would be asked questions at lectures, how do you know there isn't any... there's nothing important in the junk? And aren't you worried? And I would say, no, I'm not worried at all, because I believe in leaving problems to the next generation. So you may be worried, but not me. I'm not worried at all.
Not every problem is yours to solve. Brenner refused to worry about junk 's secrets—that was for later scientists. Strategic neglect of problems outside your scope preserves focus.
I like to call the the discount genome, because you get 90% discount on sequencing. And since I think I've enhanced the job tenfold, then I've fulfilled the great technical requirement which everybody said we should have, a tenfold step in technology every five years, and so I've done that in a few months just by choosing the right organism.
Organism choice is a technology. The puffer fish genome is 8x smaller than human but has the same genes. By choosing , Brenner achieved the "10x improvement" that everyone wanted from technology—through biology, not engineering.
Let us suppose I were to start a new genetic program and I wrote a grant saying I am now really interested in... really interesting mutations; so I want to get a fish, I want to put it in the lab, and I want to make mutants and I want to turn it into a man. Because that's the only really interesting thing... And of course, if I did this no one would give me an absolute penny. But you see, it's already being done for us. Those experiments have been done, we've got the mutants, we've got the human mutants and we still have some representative of the original stock, the fish.
Evolution already ran the experiment. "Fish to human" would never get funded, but nature did it over 500 million years. The "mutants" are the differences between species. Comparative genomics is evolution's grant report.
So I called this rather than genetics by decomposition. And I think that this is going to be the way in which we will tackle all the complex problems... we'll be able to say, this is what happened in this... since the whole of living matter is accessible to this — the whole of living matter is just ... a animal or a cell is just a cross of a genome with a .
Transgenics are crosses. Putting a fish in a mouse is formally the same as a genetic cross—testing whether two things complement. This reframing unified classical and molecular genetics.
And you want to go far away, like fish and mouse, because you want time to have corroded everything that is non-essential. If you do things like mice to man, there hasn't been enough time. We contain mousy features simply because we came from something that also gave rise to mouse. But fish is so far away that effectively we've put enough noise into the rubbish to be able to say, this is the rubbish, this is junk.
Distance reveals essence. Compare close relatives and you see shared accidents. Compare distant relatives and only the essential remains—evolution has randomized everything else. Use deep time as a filter.
I think once one has a complete... once... what one should always have is a complete sense of how ludicrous... not possibly how ludicrous you are, but how ludicrous you can be, and I think that's very important. Pomposity is one of my great fears. I think pompousness in an old man is terrible. Of course, pomposity in a young man is... is absolutely beyond the pale... if one can do what one is interested in and be of benefit to mankind, why not?
Self-awareness prevents pomposity. Know how ridiculous you can be. Old scientists who lose this become insufferable. Young scientists who never had it are worse. Stay humble by remembering your potential for absurdity.
I think one of the things about creativity is not to be afraid of saying the wrong thing... Too many people are brought up, especially in our culture, that everything should be rational, should be worked out... And I think the other answer to creativity is that, I mean... daydreaming is terribly important, but the essence of science is to bring it... to realise it, to implement it.
Creativity requires permission to be wrong. The fear of saying something stupid kills ideas before they form. Daydream freely—but then test ruthlessly. Both halves matter.
One should not fall in love with one's theories. They should be treated as mistresses to be discarded once the pleasure is over. That is what I think is... is a very important thing, and it's one of the characteristics of science that you must be ruthless towards your loved ones. When they go ugly, kill them.
Kill your darlings. Theories are tools, not identities. When they stop working, discard them without sentiment. Too much science is zombie theories kept alive by emotional attachment.
The way I do my thinking is to bounce lots of balls in my head, bounce, bounce, bounce. And if you go on bouncing you begin to notice that sometimes two are bouncing together. Those I think are the connections we have to make, and that means that you've just got to go on thinking about things...
Insight comes from collision. Keep many ideas active simultaneously—"bouncing." When two resonate, that's the connection. This requires cognitive load tolerance: holding multiple threads without resolution.
Looking at my students I've often found that all the characteristics of the one half are in one student, and all the characteristics of the other half are in the other student. So there are brilliant people that can never accomplish anything. And there are people that have no ideas but do things. And if only one could chimerise them — join them into one person — one would have a good scientist. Perhaps that's why science has to operate as a group, as a social unit.
Complete scientists are rare. Some have ideas but can't execute; others execute but lack ideas. The solution: collaboration. Teams can chimerise complementary people into a functional unit.
Since I've spent a lot of time in my life in going from one field to another I've always... always been in this permanent transition between knowledge and ignorance. So maybe I just find it a very natural way to proceed.
Field-switching keeps you in the productive zone. Too much knowledge makes you conservative; too much ignorance makes you naive. Brenner stayed in permanent transition—knowing enough to be dangerous, ignorant enough to be original.
I was assigned to a table with five Afrikaaners, because of my name; they had thought from my name I must be an Afrikaaner... and they refused to speak English, so I learnt Afrikaans. I became fully bilingual... it stood me in great stead, because I could always get a booking on a railway train just by asking for it in Afrikaans.
Constraints become skills. Brenner was assigned to Afrikaans-speakers by bureaucratic accident. Instead of resisting, he became bilingual. The skill proved useful for decades. Turn accidents into advantages.
I discovered the wonders of Puccini's fluid... a preservative that was consisted of... one part of 95% alcohol and one part of glycerine... I decided to have a taste of this stuff... I woke up on the floor of the laboratory Sunday morning, still holding this 100cc measuring cylinder... But it actually is the best way to make lab cocktails.
Curiosity extends to everything. Brenner tasted lab reagents and discovered glycerine smooths alcohol. This playful empiricism—trying things to see what happens—extended from histology to cocktail science.
At 2.00am one morning, I got what I called the Sterkfontein hand, and this was a royal flush. It's the first and only time I got it – I cleaned them out of their toilet paper scrip, but that's the only thing I ever discovered from this excavation, was the Sterkfontein hand, which was a royal flush in hearts.
Not every expedition yields fossils. Brenner's palaeontology dig produced no specimens—but he got a royal flush at poker. The story survives 50 years later. Sometimes the memorable discovery isn't the one you planned.
I was profoundly influenced by Edmund Beecher Wilson's "The Cell in Development and Heredity," particularly the passage stating that "The chromosomes are the bearers... the material bearers of heredity."
One sentence can redirect a life. Wilson's declaration that chromosomes carry heredity—written before was understood—gave Brenner his direction. Great textbooks contain sentences that become careers.
I think I'm the only person who's ever passed medicine who had never seen a patient until his examination because I never went, and in fact one of the great stories is that I failed my medicine because I was asked to smell this patient's breath, incorrectly diagnosed Maclean's toothpaste, where I should have diagnosed acetone...
Expertise has limits. Brenner was a brilliant scientist but a terrible clinician. He confused toothpaste with ketoacidosis. Know what you're not good at. His failure to engage with patients showed he belonged in the lab.
Both my parents had come to South Africa from Russia. My father came from Lithuania... It was a matter of sheer luck that he didn't go to America, 'cause he had a sister in America and his brother was in South Africa... and when he got to London, he only had enough money for the boat to Cape Town, which was half the fare to New York, so he took that.
Contingency shapes everything. Brenner's entire life—and molecular biology's history—depended on a boat fare his father couldn't afford. Major outcomes hinge on trivial causes.
I then discovered that when the immigrants came... there had been a much earlier immigration of Jews from... largely from Germany... The people who had come from Eastern Europe decided to form an organisation which was called in Yiddish the Polnischer und Russischer Yiddische Verein, abbreviated to PERUV... And the people who attended this club came to be called Peruvnics, which later became anglicised... hence the origin of the word Peruvian Jew. It has nothing to do with Peru but with origins in Eastern Europe.
Etymology reveals hidden history. A term of abuse that seemed absurd ("Peruvian Jew" in South Africa?) turns out to encode real social stratification. Always ask why words exist.
We had lived in the back of the shop, and I have this memory of playing on the floor, and still can remember the smell of leather that dominates my entire early life.
Memory is sensory. Brenner's earliest memories aren't ideas—they're smells. The cobbler's shop imprinted on him physically. Embodied experience precedes abstract thought.
I learnt to read at a very early age... she taught me to read from the newspapers that were on the table – which of course in lieu of tablecloths – and this is where I learned to read; so that by the age of four, I could read quite fluently.
Resources don't determine outcomes. Brenner learned to read from newspapers used as tablecloths. Poverty provided motivation; the material was irrelevant.
One of the early books that I read while I went through school which were in the field of science... was a book by a man called Sherwood Taylor, and it gave wonderful recipes for how to do chemistry experiments, and I lost my copy of that unfortunately, but I'd started doing chemistry at the age of 10.
Recipe books beat theory books. Sherwood Taylor's *Young Chemist* gave procedures, not explanations. Doing precedes understanding. Brenner was synthesizing chemicals at 10.
I commuted every day from and that meant getting up at about a quarter to six, cycling to the station which was about two and a half miles – which was quite hard on those cold winter mornings – catching the train, getting into Johannesburg station and then walking to the university and doing this again at night and bringing sandwiches for lunch.
Friction doesn't stop the committed. Brenner cycled 2.5 miles at 5:45 AM, took a train, walked to campus—every day. The path to education was physical labor. No excuses.
I was offered this job which meant coming every morning to the synagogue... and being present for people to come and say the Kaddish... the prayers for the dead... So I spent quite a lot of time also, being the tenth man at prayers for the dead and I must say that I now don't go to funerals... I had enough of funerals for about four years of my life, of having to attend them... as a professional mourner.
Early experiences shape lifelong aversions. Four years as a professional mourner (earning sixpence per ) left Brenner unable to attend funerals. Some quotas fill early.
I spent hours, and this also came my love of just sitting around in the lab till all hours of the night, just talking. And of course it's something that my mother never understood... why have you come home at four o'clock in the morning? And the thing is, well, you can't say – well we got talking, you know, and it just went on.
Conversation is work. Brenner's late nights weren't wasted time—they were where ideas formed. "We got talking" isn't an excuse; it's the process.
We read it at lunchtime, that is, it was one of the things. I brought sandwiches and sat down there and read from this book... three or four pages used to be read at each lunch-time and discussed, it's very talmudic, but nonetheless that's the way I read Biochemistry and Morphogenesis.
Close reading transforms texts. Brenner read Needham's *Biochemistry and Morphogenesis* aloud, three pages at a time, with discussion. Talmudic method applied to biology.
All the students were trying to get into the white maternity hospital... and I didn't care where they sent me, and so I got a hospital right at the bottom of the list... There was nothing else to do except learn how to deliver babies and study obstetrics. So, since I had to do it, I managed to do it extremely well, and I learnt a lot about life that way.
Unwanted assignments become opportunities. Everyone else competed for prestige; Brenner took what was left and mastered it. Constraint forced excellence.
There were no ultracentrifuges, so I decided to use each cell as an and so I built a Beams and King air turbine , took pieces of liver, put them in this and spun them at this high velocity... and then cut sections of them so that each cell was like a little tube.
When you lack equipment, use biology. No ? Spin the tissue, let the cells sediment internally, then them. The organism becomes your instrument.
Schrödinger says the chromosomes contain the information to specify the future organism and the means to execute it and that's not true. The chromosomes contain the information to specify the future organisation and a description of the means to implement, but not the means themselves.
Programs aren't executors. Chromosomes contain instructions, not machinery. The cell provides the machinery. Schrödinger confused the recipe with the kitchen.
The program has to build the machinery to execute the program and in fact he says... when he tries to talk about the biological significance of this abstract theory, he says: "This automaton E has some further attractive sides, which I shall not go into at this time at any length."
got it right. The genome doesn't contain ribosomes—it contains instructions for making ribosomes. This distinction is the foundation of molecular biology.
noted that "the instruction I is roughly effecting the functions of a " and that "the copying mechanism B performs the fundamental act of reproduction, the duplication of the genetic material."
described before was understood. His automaton theory—abstract, mathematical—mapped perfectly onto molecular biology. Theory and biology crossed at 1953.
I needed these intermediates; you couldn't get them anywhere, so the best thing is to go and make them. I mean, how do you make them, you get hold of a paper and it says, you know, take two teaspoonfuls of this compound and stir well in, so I did it... but this is something you can always do... it's open to you. There's no magic in this.
Chemistry is accessible. Brenner wandered into Oxford's organic chemistry lab, made his own intermediates, and left. The gatekeepers are imaginary. If a paper says how, you can do it.
I was visited... by Jerry Donohue... and I just drew one of them and he said, 'Why do you draw it this way?'... it was Jerry that pointed out to the people that they were using the incorrect tautomer and it is a... Most people drew the bases in the OH form. Of course, that's the wrong form, rather than in the Keto form which is the correct form to see the base pairing.
Small details unlock big structures. The keto vs. enol tautomer forms determined whether base pairing made sense. Brenner may have inadvertently contributed to Watson-Crick by drawing it correctly.
Francis was sitting there – it's the first time that I met him – and of course he couldn't stop talking. And he just went on and on and on and on, and it was very inspiring, you see.
Great scientists talk. Crick's verbosity wasn't a flaw—it was his method. Ideas form in speech. The quiet genius is a myth; the talking genius is real.
The model wasn't accepted at all... The establishment were all the biochemists... Chargaff just said that molecular biologists were people who practised biochemistry without a licence.
New fields look illegitimate to old ones. Molecular biology wasn't "real" biochemistry to the establishment. Chargaff's insult became a badge of honor.
Seymour was trained as a physicist; Seymour was in fact an important person in the invention of the Transistor in his early work. He started that... he started working in solid state physics. And Seymour decided he would go into biology...
Field-switching works. Benzer helped invent the transistor, then switched to biology and revolutionized genetics. Outsiders bring tools and perspectives insiders lack.
Milislav Demerec, who was Director of , visited Oxford in 1954 and got very excited about my heretical work on actual mutations. He asked me, "Won't you come to ?" This opportunity led to my Carnegie Corporation Travelling Fellowship.
Heresy attracts the right people. Brenner's "heretical" work—challenging Hinshelwood's adaptation theory—caught Demerec's attention. Orthodoxy doesn't get invitations.
Gamow provided one explanation... He thought... triplets overlapping by two would determine the code... he showed there was a way of arranging these... these three bases, such there were 20 groups of them, and since this 20 came out to be the same as the number of amino acids, the magic number had been reached.
Numerical coincidences seduce. 20 triplet groups matching 20 amino acids seemed too perfect to be wrong. It was wrong—but the question it posed was right.
's work was absolutely critical. His of the ... really demonstrated that the was not indivisible – it had internal structure. This was the end of the classical concept.
Benzer atomized the atom. The "indivisible" turned out to have substructure. You could map mutations within it. The classical bead-on-a-string model died.
Leó Szilárd was at that meeting... I was very impressed by him that with every talk that was given that he didn't like, he would get up; leave the front row. He would stand by the door for a few seconds to give the speaker another chance, and if he didn't, as was usually the case, he would then leave.
Attention is finite. Szilárd's dramatic exits weren't rude—they were honest. Time spent on bad talks is stolen from good ones. The door pause was generous.
Unknown to both of us, the famous hurricane Carolina... Caroline struck this coast, we had no radio, and so we drove into Boston to an appalling storm... We seemed to be the only people driving around. What we were doing is driving around the middle of the hurricane.
Ignorance can be protective. Brenner and Watson drove through Hurricane Carol's eye because they had no radio. Sometimes not knowing saves you from paralysis.
Jim was writing postcards to all his friends... saying, 'Farewell, we're about to embark on the desert', I who had travelled in deserts, you know, was getting equipped. That is, I bought an extra fan belt... I actually bought water. I mean, Jim was buying ice cream, but I bought water.
Experience prepares differently. Watson bought ice cream and wrote postcards; Brenner bought fan belts and water. Both survived. But only one was actually prepared.
I believed that what we had to go is from the genetics. To me that was the open door... and as happened later, you know, genetics just turned out to be the poor man's way of doing the sequence, or the man's way of doing it with... with his hands tied behind his back.
Genetics was sequencing before sequencing. Brenner extracted information from using mutations—reading the sequence indirectly. The poor man's method worked.
He was looking at Gamow's tie pin... 'Oh,' he says, 'I see you looking at my tie pin'. He says, 'It's... it's Alanine there'. He says, 'I'll have to explain it to you'. He says... 'how much do you know about the structure of ?'
Fringe knowledge excludes most people. Gamow's question to a confused bank clerk—"how much do you know about ?"—perfectly captures how esoteric molecular biology was in 1954.
I think my skills are in getting things started... it's the ... I think keeping up the conversation is one of the important roles one can have in science... I think I'm rather good also at brainwashing, which is to persuade people to do things that their upbringing tells them they ought not to be doing.
Know your strengths. Brenner was an opener, not a closer. His gifts: starting fields, maintaining conversation, persuading people to transgress. Self-knowledge guides career choices.
I don't think the Nematode Programme wouldn't have been a failure, but it wouldn't have had the success it had were it not for the invention of cloning... to realise this turned something that might have become just zoology into the centre of molecular biology.
External technology determines internal success. could have remained obscure zoology. Cloning made it molecular biology. Brenner's organism choice was vindicated by technology he didn't invent.
I hope that we had generated — Francis and I did this together — that we had generated a unique atmosphere to do biology. That is, you would work at the... at the edge of the subject, you could do it your own way, and you could... and you could actually make progress in that.
Atmosphere matters more than resources. The 's "unique atmosphere" produced more than better-funded competitors. Culture is infrastructure.
I took the view that the only way to survive is to get young people and let them do what they like. Unfortunately many of my colleagues thought that we should get young people, but they should work for them.
Freedom vs. service. Brenner wanted young scientists to follow their own ideas; colleagues wanted them as labor. This tension killed his directorial vision.
The profession of science will change markedly over the next 25 years because I don't think it can last in its present structure... the present structure is assumed on infinite growth... every student expects to be a post-doc, every post-doc expects to be an assistant professor... that can't last.
The pyramid scheme is unsustainable. Academia assumes everyone advances; mathematics says this is impossible. Brenner predicted the crisis decades early.
I think people will do research for only part of their lives... research — with very few exceptions — is really the job for young people, largely because as I've said they contain the required ignorance that is necessary for this.
Research as phase, not career. Brenner proposed that most scientists should do research for 5-8 years, then become doctors or farmers. The permanent researcher may be an anomaly.
I would like to preserve everything in the form of ... which is to have a treasure house. I like the word 'treasure house', not 'museum', and the idea would be this: is collect the of every living species and just store it... we could have our own Jurassic Park.
Archive before extinction. can be stored; species cannot. Brenner's "treasure house" would preserve genomes against the coming mass extinction. The archive outlasts the organism.
We've now come to realise that more than 90% of the micro-organisms in nature can't be cultivated, but we could retrieve them by their . So there's a whole... whole areas of biology that are waiting to be done.
Most life is unculturable. The vast majority of microbes don't grow in labs. But extraction bypasses cultivation. Metagenomics opened biology's dark matter.
is a great scientific hero to me because it seemed... he seemed to have something. And of course it may be envy rather than admiration, but it's good to envy someone like .
Envy the right people. Brenner distinguished between envying mediocrity (petty) and envying greatness (productive). set a standard worth envying.
What I liked about Leó Szilárd was his complete obliviousness to the conventions and the criteria of this and his complete focus on what came out of his head and that I found was... was admirable.
Ignore conventions. Szilárd didn't care about normal criteria—publications, positions, politeness. He cared about ideas. Convention-blindness enabled originality.
I said, God, he looks like one of my uncles, you know, the rich one... but nevertheless, it is the continuity to past worlds that I found fascinating.
Personal history connects to intellectual history. Brenner saw his Eastern European family in Szilárd's face. The scientific tradition carries ethnic memory. Worlds persist in people.