Loose Ends ... False Starts

Sydney Brenner

• Publisher: WSPC
• Year: 2019
• eBook ISBN: 9789811208195
• Topic: Business
• Subtopic: Leadership
• Index: Business

Sydney Brenner was born in South Africa and educated at the University of Witwatersrand, Johannesburg (Medicine and Science). He then moved to Oxford and received a D.Phil in 1952, before joining the MRC Unit in the Cavendish Laboratory in Cambridge in 1956. His various accomplishments include serving as the Director of MRC Laboratory of Molecular Biology in Cambridge, founding the Molecular Science Institute in Berkeley, holding the position of Distinguished Professor at the Salk Institute, La Jolla. And during his last years, Sydney Brenner played a key role in shaping research and development in the biomedical sector in Singapore as A*Star Senior Fellow.

He was one of the greatest biologists of the 20th century and was awarded the Nobel Prize in 2002 for his pioneering work in the field of molecular biology. He was also known for his boundless curiosity, sharp intellect and courage to speak with clarity and characteristic wit as evident in this delightful book which is a compilation of the columns that he wrote for Current Biology in the late '90s.

Contents:

• Loose Ends
• All the World's a Lab...
• Molecular Biology by Numbers
• The Seven Deadly Curs'd Sins...
• False Starts

Readership: Students and researchers in biological sciences or anyone interested in a witty commentary on science in general. Molecular Biology;Loose Ends;False Starts;Uncle Syd00

Loose Ends

1. Loose Ends

When Current Biology invited me to write a monthly column in the journal, I quickly accepted, thinking that I would be able to dash it off easily. I have the freedom to write on anything I choose, subject only to some gentle editorial guidance and also of course to the laws of libel. Writing the column has turned out to be much more difficult than I expected, and the freedom of choice has made matters worse. When I was younger I wrote much more easily than I do now, when I can spend hours, days, even weeks, contemplating first sentences and feeling more and more like a paralysed rabbit as the terrible tiger of publication deadlines approaches.

A good deal of the difficulty comes from the compression of style imposed on us by the editors of scientific journals and the years of writing papers which have to be concise, cautious, impersonal and totally boring. We scientists are discouraged from talking and writing about ideas, and what would be called theory in other areas is dismissed as unbased speculation by the factomania that grips our subject. Some editors allow others to act as commentators on papers published in the journal, and provide them with more freedom of style. Commentators have more opportunity to be clever, witty and to bring some novel insight to the work. Above all, however, they need to be accurate and clear.

Which brings me to the issue of Science of the 22nd October 1993, in which there are two very good papers on the identification of genes in Arabidopsis and yeast that specify proteins of the ‘two-component’ signal pathway that had previously been found only in bacteria. This pathway operates by phosphorylation. But the kinase, which is modulated by a receptor, phosphorylates a response regulator on a carboxylic acid group, rather than the tyrosine or serine/threonine phosphorylation that is already very well known in eukaryote cells. The kinase transfers the phosphate from an autophosphorylated histidine and thus (why thus?) is often reversible, with the kinase acting as a phosphatase as well.

The same issue of Science has a commentary on this work by Dan Koshland, whose own analysis of this pathway in bacterial chemotaxis is a classic piece of research. Dan is also the Editor-in-Chief of Science. I anticipated that I would be served up with fine thoughts that had been kept bottled up for years. Instead, I could not believe what I read. Here are opening sentences:

“Two simplifying principles of biology are what might be called “the principle of redundancy” and “the principle of diversity.” Mother Nature follows the principle of redundancy by selecting a simple mechanism or module as a building block for a complex system and then using that module over and over again in other systems. The principle of diversity utilizes the concept that there are many ways of achieving the same goal, for example, creating a living organism or generating motility.”

There are certainly some original thoughts here but they are totally wrong. My dictionary defines redundant as “superabundant, superfluous, excessive” and redundancy therefore means that there is more than is actually required. It is indeed a principle, and in engineering it is deliberately used to allow complex systems to preserve their integrity in the face of faulty components. Thus when two, or even three, computers were used in space vehicles this redundancy ensured that everything would continue to work in the event of failure or errors. Redundancy is well known in biology — it is the bane of developmental geneticists. Many genes have been found that, when mutated, show no visible phenotypic effects under laboratory conditions. Such redundancy cannot be deliberate in organisms as there is no Great Engineer in the sky; rather, they must be a consequence of how the system evolved.

Thus, in a simple example, one can imagine a gene product that performs two functions, A and B. If the gene then duplicates and the copy mutates, the product of the copy may perform functions B and C, creating redundancy for the function B. One cannot, therefore, say that the presence of similar schemes in different organisms is a consequence of the principle of redundancy. As for the “principle of diversity”, neither is it a principle nor does it use “the concept that there are many ways of achieving the same goal”. This is more a question of fact: there may or may not be more than one way of implementing a function or a device.

So what “principles” can these papers illuminate? Koshland uses the term module and he could have lighted on the “principle of modularity” — that is, the construction of complex systems from modules each of which has a closed function and can be assembled independently of other modules. But even this is not exemplified here, and the only principle that is illustrated here is “the principle of genetic continuity”. All organisms are connected by descent, and functions evolved by our predecessors are preserved and handed on. Once Nature finds a good device it will have to go on using it because it is impossible to go back to the drawing board and design another one. We owe everything to our prokaryotic ancestors and so it is not surprising that we continue to find prokaryotic systems in eukaryotes; in fact, it would be surprising if we did not.

What still needs to be explained is how the more typical eukaryotic phosphorylation cascades evolved and came to replace the bacterial systems. The principle of continuity demands that there are no unbridgeable chasms to cross in evolution; therefore, the two systems may have existed side by side for some time before one gained ascendancy. That, of course, could be the real exemplar of the “principle of redundancy”.

© Current Biology 1994, Vol 4 No 1

2. Loose Ends

When I retired from the Medical Research Council in 1992, I took the view that retirement should be symmetrical and that, like divorce, it was a question of who was leaving whom. I still have money left over from my Jeantet Prize and this, together with some other private funds, has allowed me to stay on in my laboratory and support a group of scientists. Outside my laboratory there is a plaque that reads “Medical Research Council Unit of Molecular Genetics opened by Dr D. A. Rees on May 11, 1989”. ‘When the unit disappeared in May 1991 some wit added a sign that began “and closed by...”, but this is no longer there. There was some discussion about what we should call ourselves and, after discussing Sidneyland and BMW (Brenner’s Molecular Works), we deleted MRC Unit and remain simply as Molecular Genetics. This is the term invented by Francis Crick and myself in 1958 to describe our work and was the name of our division for many years in the newly founded Laboratory of Molecular Biology. These days, of course, everything is molecular and everybody is a molecular biologist of some kind.

It was molecular genetics, particular of cancer cells, that opened up the field of cellular regulation and identified the components of signal transduction pathways. This has been so productive that those who looked to experimental models such as Drosophila and the nematode to provide the basis for understanding complex processes in higher organisms, such as men and mice, have had the tables turned on them. In most cases, when genes that are involved in development in Drosophila or the nematode are finally cloned and sequenced it is found that they have already been discovered as oncogenes in mammalian tumours, and that the same tyrosine kinases and ras proteins are at work in both. Except, of course, the outcomes are different, and what is used to make an eye in a fly or a vulva in a worm makes lymphocytes in a mouse.

Like many others, I find it difficult to follow this field in the detail it deserves given that the uncovering of the mechanisms of signal transduction is revealing the molecular basis for cellular processes. My problem is I just cannot remember which three-letter expletive is which; I would not be surprised if at least half of these characters — ras, rac, rib, rob, ref, raf, roc, rol — are not genuine members of the cast. I had the same problem reading War and Peace, and had to compile a list of the characters to remind me who they were.

Perhaps somebody will print a handy guide, preferably in luminous ink, so I can take it to seminars. Every one of them that I have attended starts with a slide showing the signal transduction pathway soon to be explained by the speaker. This begins at a receptor at the membrane, pursues its way through the cytoplasm, from second messengers to kinases and kinase kinases and even kinase kinase kinases, with jak and jil, grk and trk, to end in the nucleus with transcription, which is also mediated by a bunch of three-letter factors. There is a puzzling set of activations and inactivations, and everything seems to interact with everything else.

As seminar succeeds seminar, you come to realize that the unique transduction pathway of Dr X crosses, and shares a node with, the equally unique transduction pathway of Dr Y. It dawns on one that this is not a collection of pathways but a network, and that many of the interactions are not required for the explicit transmission of the signal but only to service the network. For example, after stimulation, the network must obviously be restored to its initial state or else it could only be used once and would be useless.

We actually know quite a lot about molecular signalling in other systems and it is useful to look at some cases. For example, an axon conveys messages by modulating the frequency of electrical signals of fixed amplitude. A chemical is then released at the synapse in proportion to this frequency and interacts with its receptor causing some change. If nothing else happened the postsynaptic cell would go into a spasm and would take a long time to relax. Instead, there is either a mechanism for transmitter uptake or an enzyme that destroys the transmitter to ensure that it is delivered as a short pulse with a height that records the frequency of impulses. The G-proteins signal with pulses; not only do they have a builtin decay mechanism but this can be accelerated by GAP proteins, which may be activated by a side branch of the initial pathway to apply this negative feedback.

Another method of signalling is linked to changes in the steady-state level of, in particular, a metabolic intermediate. This method is widely used in bacteria to control the rate of synthesis of metabolites, and allosteric mechanisms ensure that the response is sharply tuned to a narrow range of fluctuations. This requires a reversible interaction of the protein with the ligand, with an association constant corresponding to the critical level. As protein–protein interactions are usually of very high affinity, it is unlikely that this mechanism will be much used in eukaryotes. Steroid receptor proteins probably respond to their effectors in this way, but for molecules such as insulin this is unlikely. Indeed, these act very much like the transmitters; the essentially irreversible interaction of the ligand with its receptor is terminated by the endocytosis of the receptor complex, followed by the proteolytic destruction of both.

If we are to understand how all of this works we will need something more than merely lists of components and binary interactions. As someone once remarked, the great difference between the telephone directory and a Shakespeare play is that, while both have a grand cast of characters, only the play has a plot.

© Current Biology 1994, Vol 4 No 2

3. Loose Ends

On my visits to universities in America I am often asked to meet the graduate students at what is usually a sandwich lunch session. The faculty carefully exclude themselves, explaining that this allows the students to speak more freely, but my guess is that they want to get rid of the visitor for a few hours and go and have a better lunch elsewhere. We begin by introducing ourselves and our interests. With experience this can be made to take 20 minutes. There follow some penetrating scientific questions such as “What is going to be the next breakthrough in developmental neurobiology?”.

Conversation then turns to matters of greater importance — careers, jobs, research opportunities and funding. Finally, we reach a subject much loved by ageing scientists — the good old days. In the good old days we not only did science without any money but, paradoxically, we also came by the money quite easily; a half page was usually enough to get support for a research programme but, if you wanted a building, you might have had to stretch it to a page. Editors of journals were polite, even quite charming in some cases, and they and their referees had not yet become the fanatic guardians of scientific purity that they are today. Elderly scientists were treated with some respect and were not dispatched so easily by grant committees and study sections as they now are.

I have to remind the students that the research community was very small in the good old days and that most of the stresses and strains of the present system come simply from the enormous growth in the number of bio-medical research scientists and in their resources and expectations. A large bureaucracy has grown up with administrators, assessors, planners, strategists, palm readers and soothsayers employed to manage the scientific enterprise, so that today we resemble a mediaeval North Indian army with its few thousand soldiers accompanied to war by a few hundred thousand camp followers. Science is a product of human minds, and the essence of research is creative innovation; neither can be produced by committees.

Bemoaning our state and indulging in nostalgia for the past is not a constructive way of dealing with the problem. For some years, Instead, I have quietly been conducting research in the fields of science politics and administration. Recently, I have made some remarkable discoveries that not only explain what is going on but also offer some hope for the future. Luckily, this column is not subjected to professional refereeing and I can therefore pub...

Table of contents

• Cover
• Halftitle
• Title
• Copyright
• Preface
• Editorial
• Contents
• LOOSE ENDS
• FALSE STARTS
• Biography for Sydney Brenner