Peer Review Reform

"Which areas of researchis the "quick fix" mentality driving, and which researchers aredeemed worthy of funding support? Are scientists forced to engagein unethical practices to ensure continuity of funding? Does therace for funds risk alienating young and talented scientists fromthe research enterprise? These are some of the questions thatbiochemist Donald Forsdyke seeks toaddress."

"This is an important and timely book. It examines how health and medical research is conducted and by whom. The tragedy of funded and unfunded scientists alike, who are unable to pursue their novel ideas, comes through clearly. It is compellingly written, and the book contains a wealth of examples and insights on what ails health research, as well as some useful suggestions on what might be done."

Definitions

Peer review is the name of a process by which the work and ideas of an individual or group is assessed by another individual or group considered to have a level of expertise near to that of the assessed. Thus the reviewers are deemed to be the "peers" of the assessed.

The purposes of peer review are to inform decisions either on the allocation of funds among a number of applicants ("research grant agency peer review "), or on the publication of the results of research ("editorial peer review"). This web-page is concerned primarily with grant peer review, and advocates extensive reform.

Sadly, the quest for excellence in research has not been accompanied by a quest for excellence in the evaluation of that excellence. To prevent further deterioration, it is proposed that conventional peer review be replaced by a new form of peer review, called "bicameral review".

In the sense that our justice system declares it better the guilty go free than that the innocent be condemned, we believe it better that poor research be supported than that excellent research be condemned to zero support.

Donald Forsdyke

The Argument in a Nut-Shell

Despite lip-service to the contrary, the grant agencies assess projects, not people. In the final analysis they hold it is better that a less able researcher carry out an approved project, than that a more able researcher carry out an unapproved project. Indeed, they hope with the funding carrot to coerce the more able researchers to carry out approved projects.

For the less able researchers this is not a problem. They just have to write an honest application stating what they want to do and why they want to do it. On the other hand, the more able researchers, who can see beyond the conventional wisdom, have serious difficulties. Grant writing is a marketing exercise that, more often than not, requires that that their "best" ideas be discarded, since, by definition, these ideas are difficult to understand and communicate (if not, the less able researchers would have already thought of them).

Thus, the more able researchers are tested, not on their abilities to come up with innovative ideas, but on their abilities to tune in to the conventional wisdom, and write an application with an appropriate degree of marketing spin. Many able researchers, and especially the most able, find this, not only distasteful, but impossible to do.

People find this difficult to understand. Why can't the researchers just write a simple application, and then, when they have the money, use it to do the work they want to do? Unfortunately (or fortunately, depending on your perspective) the most able researchers, although they come in all shapes and sizes, have one common attribute - integrity. They can no more discard this than a tortoise can discard its shell, or a giraffe its neck!

Thus, the major premise here is that peer review, as currently practiced in North America and many other places, is highly error-prone. It discriminates against the most able, so achieving the very opposite of what is desired. This means that over several decades peer-review has "dummed down" the Professoriat, decreased the quality of available "expert" advice, and impaired the process of scientific discovery. What is the remedy?

Decision-making in uncertain environments (as any Wall Street analyst will tell you), should be guided by two cardinal rules:

1. Use the most objective parameters.

2. Hedge your bets (i.e. diversify).

In the context of research funding this translates into:

1. Emphasize track record.
2. Avoid sharp cut-off points by using a sliding scale of fund allocation.

There are four reasons why such obvious reforms have not been made:

1.Premise of impossibility not accepted. It is very difficult for those in Western culture systems to accept that some things are virtually impossible. If you have a problem, just appoint a committee of informed, well-intentioned, persons, and the best solution will emerge! When the resulting solution is attacked, the response is to shrug and declare no feasible alternative: "Like democracy it’s a terrible system, but it’s the best we have".

2.Winners do not want change. Those best placed to bring about reforms are the "winners" who have been supported by current peer review procedures. It is hard for them not to accept the syllogism: "I am an excellent researcher, the system recognizes that I am excellent, therefore the system must be excellent".

3. Losers think they see losers. It is difficult to win public support for reform because, admit it or not, the average member of the public is a "loser" (in the sense that only one person can be top of the class). All-to-readily we invent face-saving excuses, and all-to-readily we think we recognize the excuses of others. Why should the bleating, disenchanted researchers who are not funded be any different?

4. To compete needs big bucks. To keep up with top laboratories in other countries the "best" must be funded. This argument has much weight if one could really predict the "best". In practice, as funds get tighter, it translates into progressively moving the funding cut-off point higher. The ad absurdum argument is that ultimately there will be just one laboratory in a country with funds sufficient to compete with top laboratories elsewhere. This argument ignores the fact that there are many low-cost research projects where a country can compete very well. Somewhere along the line it has to be recognized that:
- (i) great damage is inflicted at many levels by not funding more projects, and
- (ii) it may not be in the best interests of a country to put all its eggs in a few, very expensive, baskets.

Experts

To compound the problem the "baskets" often come to be labelled "experts." By default, the "non-baskets," are "non-experts." Of course, Government and Society only listen to "experts." The "experts" following the Thrasybulus principle (see below), seize the high ground. Further securing their careers and retirement years, they push the careers of their graduate students and post-docs. Inward-looking dynasties come to control the agenda of science.

There is nothing strange about this. This is the way human beings behave, and it is the responsibility of those designing organizational systems to take human behaviour into account. If there are not appropriate "traffic lights," free rein is given to the most basic instincts. A willingness to push the ethical and moral constraints on one's actions to, and beyond, the legal limits, can become a requirement for survival.

Thus, as the history of the twentieth century shows so well, the ultimate test of a political system is not its ideology, but the extent to which it can restrain those who would subvert it for their own ends. Despite their many faults, democratic Capitalist systems proved less corruptible than totalitarian Communist systems. Yet, in vain, we await the falling of the peer-review equivalent of the Berlin wall.

Excellence Adjudicated

The quest for excellence in research has not been accompanied by a quest for excellence in the evaluation of that excellence. Can excellence be evaluated, and with what degree of precision?

If it cannot be evaluated, then we should just toss a coin and save ourselves a lot of trouble.
If it can be evaluated with precision then we should just fine-tune the present system.
If our evaluation system is error-prone then we must redesign the system taking error-proneness into account.

The system is likely to be error-prone prone for two reasons.

1. Novel ideas are usually both difficult to understand (even by their creator) and difficult to communicate (that's one reason why they they tend to be labelled "novel").
2. The historical record clearly shows that great scientific discoveries have often been achieved with minimal support of, and/or despite active hindrance by, the discoverer's "peers." This evidence should not be dismissed as "anecdotal." That excellence is ignored, opposed, or unfunded, is as much a fact as that the sun riseth in the east and setteth in the west (see Bernard Barber's study in Science (1966) 134, 596-602).
Gregor Mendel's work, funded from monastery coffers, provided the basis for the modern revolution in biotechnology, but was not appreciated for 35 years.
Charles Darwin's work was self-funded and initially was much opposed by the religious establishment and by many in the scientific establishment.
George Romanes' work was self-funded and opposed by the scientific establishment (see these web-pages).
William Bateson's work was largely self-funded and opposed by the scientific establishment (see these web-pages).
Albert Einstein's special theory of relativity was funded by working for the local patent office.
Schaudinn's discover of the bacterium causing syphilis was greeted with scorn (see below).
Watson & Crick discovered DNA structure "on the side", while being funded for other work. ...
Peter Mitchell's studies of novel ideas on energy formation in mitochondria were largely self-funded.
Helena Czajkowski (Robinson) when working as a technician, at her own initiative discovered that periwinkle leaf extracts depressed white blood cell counts, opening the way for cancer therapy with vinca alkaloids (Duffin, J. 2000).
Stephan Jay Gould's promotion of Richard Goldschmidt's work is still held in scorn by the evolution establishment (New York Review of Books 42, 17-19).

Some of the above eventually received Nobel Prizes, but too many died before they were recognized, or were not recognized at all. From the very beginnings, to the modern era, the list goes on and on and on ....

Grant agency administrators point with pride to the power of "DNA evidence" in judicial settings. Too often for comfort, decisions which appeared clear cut at the time, have since been overthrown. Yes, a triumph for our medical research system in exposing defects in our legal system. However, in some cases it was too late. The accused had been found guilty and a death sentence administered.

Yet, these very same agency administrators will defend to the last ditch their own judicial practices with respect to peer review. The halls and corridors of our universities and research institutes are awash with academic blood, yet they still will not admit how flawed the system is!

In most areas where creativity is at a premium (the stage, literature, etc.) the administrators recognize that high creativity is often divorced from marketing skills and expect applicants to have agents. Not so with the biomedical research agencies! This is not an argument for agents. It is an argument for the biomedical research agencies profoundly changing the way they go about their business.

The Two Competitions

One of the many ironies of the peer review system as it currently operates is that it is believed to stimulate competition, and hence high achievement. It certainly stimulates competition for funds. But what are the funds for?

There is another competition, - the competition to discover. Here the competition for funds works as a weapon. By eliminating the majority of your potential competitors using the weapon of non-funding, you decrease the competition to a level that can be managed by politics and trade-offs. Thus, you can move along at a leisurely pace, playing politics for all its worth, and even creaming off your unfunded potential competitors ideas as their grant applications, year after year, cross your desk. And of course, the more expensive the project, the less likely there are to be competitors, and the greater the scope for politics.

An alternative is bicameral review as proposed in these web-pages. This retains some of the competition for funds, but also increases the competition to discover. Watch out! At the moment of elation when you arrive at a critical �break- through,� you may find that another laboratory, albeit working on a shoe-string budget, has just published the same finding!

For those who need the "spur" of competition (as if curiosity and a desire to help humankind were insufficient), this pressure, the pressure to be first to make a discovery, is the real competition. This is the competition which the current peer-review system destroys, but which bicameral review promotes.

Shuffling Deckchairs

Modern political campaigns are expensive. Successful politicians are usually those who are most successful at campaign fund-raising. Indeed, quite often it is success at fund-raising, rather than ability in skills which make for wise governance, which decides whether a politician will be elected.

So, in the hope of future favours, special interests move in. Thus, public pressures mount for the reform of campaign financing. In Canada we had Bill C2 (Feb. 2000), and there were similar calls for legislation in the USA and elsewhere. However, despite much lip-service, such reforms never seem to be implemented. Why?

Because those who have most to lose from the reforms are those who decide whether the reforms will be implemented.

As indicated above ("Winners do not want change") this is precisely the situation that prevails in the medical research funding system. In response to pressures for reform the twentieth century Canadian Medical Research Council engaged in another round of rearranging deckchairs. The cosmetic offered for the twenty first century was to rename itself The Canadian Institutes for Health Research.

There is another political agenda to consider. The ultimate track record is a investigator's genes. Of course, the author of these web-pages is not advocating that agencies seek to know an applicant's genetic background! But one of the major issues in 20th century politics was the struggle between Communism and Capitalism. Lysenkoist genetics was supported by Stalin and Kruschev in part because it suggested that "nurture" (environment) rather than "nature" (genes) was of major importance. It was only a question of giving the proletariat an equal opportunity (i.e. a "level playing field"), and they could do just as well as the bourgeois middle and upper classes.

The granting agency equivalent is to look at the applicant as he/she is at the time of the application. Are his/her ideas better than those of the others? Asking about his/her track-record is perhaps asking about what may have been unfair advantages (e.g. having gone to an "ivy-league" university, having had better teachers, etc...). With arguments such as this, those with leftward political leanings in decision-making positions in grant agencies may be preventing necessary reforms. Under the system of "bicameral review" proposed here, track-record is carefully defined for evaluative purposes as the ratio of performance to dollars received. From those to whom much has been given much is expected.

Against the CIHR (MRC) juggernaut, a few lone voices speak out. They call themselves CARRF, the Canadian Association for Responsible Research Funding. Some examples of their attempts to get government support for the reforms which the CIHR (MRC) itself is unwilling to implement are documented in these pages. First, some background papers by people who have thought long and hard about peer review are provided. We begin with President Nixon's plan to achieve a cure of cancer by 1976 (Click Here if you want to skip the papers).

CARRF.

In Canada an organization of researchers called Canadians Association for Responsible Research Funding (CARRF) has been seeking reform of the research system for many years. For the CARRF response when, after a period of devastating cut-backs, the Canadian Government promised to increase total research funding: (Click Here)

"On the other hand, I will say you deserve this and worse, for you have been disarming by steps those who have control of the sciences, and they have nothing left but to run back to holy ground"

Archbishop Piccolomini to Galileo 1633 concerning the outcry over the Dialogue

"I am attacked by two very opposite sects - the scientists and the know-nothings. Both laugh at me - calling me 'the frog's dancing-master.' Yet I know that I have discovered one of the greatest forces in nature."

LUIGI GALVANI (1737 - 1798)
Italian physician, discoverer of electric current

"Our own more direct way of calling a spade a spade, ... with the intention that everyone should understand it as a spade, seems more satisfactory.... However this may be, the fear-of-giving- themselves-away disease was fatal to the intelligence of those infected by it, and almost everyone ... had caught it to a greater or less degree. After a few years, atrophy of the opinions invariably supervened.... The expression on the faces of these peoples was repellent; they did not, however, seem particularly unhappy, for they none of them had the faintest idea that they were in reality more dead than alive. No cure for this disgusting fear-of-giving- themselves-away disease has yet been discovered."

Samuel Butler (1872) On the Colleges of Unreason in Erewhon

"Original thought is much more common than is generally believed. Most people, if only they knew it, could write a good book or play, paint a good picture, compose a fine oratorio; but it takes an unusually able person to get the book well reviewed, persuade a manager to bring the play out, sell the picture, or compass the performance of the oratorio.

Indeed, the more vigorous and original any one of these things may be, the more difficult will it prove to even bring it before the notice of the public. The error of most original people is in being just a trifle too original."

Samuel Butler (1887) in Luck or Cunning, Cape, London. Or, to paraphrase H. G. Wells - "In the land of the intellectually blind, the one-eyed man should be king, but is not." John Maynard Smith made essentially the same point in 1952 (see below).

[John Burden Sanderson] "would say ... that he is very tolerant about theories -- [but] that what really tells is facts. But then what are facts that are essential? It's the theory that determines that. I would simply disregard as trivial and misleading heaps of things which he considers essential, and vice-versa. And even the simplest 'facts' are expressed, - perceived - through theory."

John Scott Haldane on his Uncle's aversion to theory in science. [Kant wrote similarly]. Letter to Louisa K. Trotter. 3 December 1891. [Their son, J.B.S. Haldane was born the following Guy Fawkes' day.]

"I have got to know another sad specimen of this kind - one of the foremost physicists in Germany. To two pertinent objections which I raised against one of his theories and which demonstrate a direct defect in his conclusions, he responds by pointing out that another (infallible) colleague of his shares his opinion. ... Authority gone to one's head is the greatest enemy of truth."

Albert Einstein (on his controversy with Drude 1901. Collected Papers).

"The really depressing thing ... is that, the evil being of slow maturation and coming to no obvious crisis, there will never be anything in the nature of a panic. And as recent events only too clearly show, it is only in moments of panic that anything gets done. Foresight is one thing: but acting on foresight and getting large bodies of men and women to accept such action ... are very different matters."

Aldous Huxley to Ronald Fisher (1931)

"Any report of famine in Russia today is an exaggeration or malignant propaganda."

Walter Duranty of the New York Times (circa 1932) who prostituted high literary skills to win a Pulitzer prize for reporting of Stalin's purges in the Ukraine.

"There does not exist, and cannot exist in the world, a science divorced from politics. The fundamental question is with what kind of politics is science connected, whose interests it serves - the interests of the people or the interests of the exploiters."

Response of the Lenin All-Union Academy of Agricultural Sciences to the attack of the great US geneticist H. J. Muller on its endorsement of Lysenkoism. Pravda 14th Dec. 1938

"The mass trials have been a great success, comrades. In the future there will be fewer but better Russians"

GRETA GARBO, in Ninotchka, 1939

"The situation of research is different. Actually, almost anyone who makes a scientific advance of almost any kind is bound to be exposing, as erroneous or obsolete, views and methods formerly taught and trusted. The teacher especially who is accustomed to pontificate is decidedly reluctant to eat his words or to recast his courses. He therefore finds some excuse for not doing so by ignoring or, failing that, belittling and criticizing, with more or less astuteness, views which threaten his current stock of ideas. This temperamental factor is almost always in evidence in the earlier reactions to any new notion, and of course the publication of new findings and the discussion of their relevance is not really carried out in logical terms."

Ronald Fisher, pioneer in the field of statistics (1940)

"When in 1916, Dampier-Whetham ... submitted a screed of mine, on the genetical interpretation of the biometrical work Galton had inspired, to the Royal Society, the referees appointed are rumoured to have been Karl Pearson and Reginald Punnett. The Society's action was impeccable; these were two leading lights in statistics and genetics respectively, with the additional advantage ... that they were not very likely to agree. In fact, I suspect the rejection of my paper was the only point in two long lives on which they were ever heartily at one. Lest this sad story seem depressing, it has the point that the author of the paper was chosen to succeed each pundit in turn."

Ronald Fisher, pioneer in the field of statistics (1943)

"Of all the passions, the passion for the Inner Ring is most skillful in making a man who is not yet a very bad man do very bad things....Until you conquer the fear of being an outsider, an outsider you will remain. ...The quest of the Inner Ring will break your hearts unless you break it. But if you break it, a surprising result will follow. If in your working hours you make the work your end, you will presently find yourself all unawares inside the only circle in your profession that really matters. You will be one of the sound craftsmen, and other sound craftsmen will know it. ... And if in your spare time you consort simply with the people you like, you will again find that you have come unawares to a real inside, that you are indeed snug and safe at the centre of something which, seen from without, would look exactly like an Inner Ring. But the difference is that the secrecy is accidental, and its exclusiveness a by-product, and no one was led thither by the lure of the esoteric, for it is only four or five people who like one another meeting to do things that they like. This is friendship. Aristotle placed it among the virtues. It causes perhaps half of all the happiness in the world, and no Inner Ring can ever have it."

C. S. Lewis (1944) Address given at King's College, London. The Weight of Glory & Other Addresses. Macmillan, 1980

"This story has a simple moral,

With which the wise will hardly quarrel;

Remember, Prof, it hardly ever,

Pays to be too bloody clever."

J. Maynard Smith et al. (1952). An ode entitled "The Folly of Being Too Clever" to J. B. S. Haldane on his 60th birthday

Edward R. Murrow to Jonas Salk (April 12th 1955):

"Who owns the patent on this vaccine?"

"Well, the people, I would say. There is no patent. Could you patent the sun?"

Salk's discovery of a safe and effective vaccine against polio was largely financed by the March of Dimes Foundation, and built on the work of generations of scientists and doctors.

"Once work had ... started, it took Schaudinn only a single day to discover the hardly visible germ, the Spirochaeta pallida. He was absolutely sure of his discovery, but when he announced it at a meeting of the medical society the chairman, von Leyden, rose after the paper was finished and said in effect:

'Gentlemen, you have listened in this hall already to one hundred announcements of the discovery of the syphilis germ. This was the hundred and first.'

Accompanied by the laughter of the hostile meeting, Schaudinn left. For many weeks attacks and insults were heaped upon him, and in the front line stood his former chief, F. E. Schultz. ... Meanwhile, Neisser, Levaditi, and Metchnikoff had come out for Schaudinn, his discovery was accepted all over the world, and the way was open for Paul Ehrlich's discovery of Salvarsan."

Richard Goldschmidt (1960) In and Out of the Ivory Tower. University of Washington Press, p. 60.

"The instruments produced graphs, which Bose explained as recording the heartbeat of the plant... Bose became a famous man, was knighted, and considered himself the great Indian scientist.. The whole thing was a joke, and I wonder how he could get away with it and be feted all over Europe as a great man."

Richard Goldschmidt (1960) In and Out of the Ivory Tower. University of Washington Press, p. 260-1.

"The cure for boredom is curiosity.

There is no cure for curiosity."

Dorothy Parker (1893-1967)

"Only the Prof. could have done it. If he had been killed it is impossible to imagine any other scientist to whom Winston would have listened. ... He had fought at Winston's side at a time when no one had a good word to say for the man who was 'spreading alarm and preventing an understanding with Germany'. ... Winston would recount ..."We were losing some of our best young pilots. Their aircraft would stall and go into a nose-dive, and the pilot was always killed. The Prof., with his mathematics, worked it all out on paper. To come out of the spin safely, the pilot must pick up enough speed in a vertical dive. No one took him seriously. So the Prof. learnt to fly, and then one morning ... he went up alone.... He put his craft into a spinning nose-dive. Those watching him held their breath. ... His theory worked."

Remarks concerning Frederick Lindemann (Lord Cherwell) from The Dairies of Lord Moran (Churchill's physician) 1966.

"I sought the guidance of two Fellows of the Royal Society. One of those I consulted said that Cherwell completely changed the attitude of those at the top towards scientific developments. 'Modern war ... is probably won by ideas, and the real enemy of new ideas is always the expert'. Sir Winston, with the Prof. as tutor, would not allow the expert to kill new ideas or technical innovations. Lord Swinton, who was Air Minister at the time spoke in support. No project was too far fetched, too novel, to be rejected outright by Lord Cherwell."

Remarks concerning Frederick Lindemann (Lord Cherwell) from The Dairies of Lord Moran (Churchill's physician) 1966.

"In nine cases out of ten large teams and expensive apparatus are a substitute for really accurate observation and really deep thinking.

One can't order a Faraday and a von Frisch, with a Laplace to do their mathematics for them.

One can order a hundred graduates, a cyclotron, a computer, two electron microscopes, and so on. Such apparatus also impresses visiting journalists; whereas great scientists are often shy or rude, and sometimes both."

J. B. S. HALDANE, in Science and Life (1969)

"I consider it desirable that a man's or woman's major research work should be in a subject in which he or she has not taken a degree. To get a degree one has to learn a lot of facts and theories in a somewhat parrot-like manner....It is rather hard to be highly original in a subject which one has learned with a view to obtaining first-class honours in an examination."

J. B. S. HALDANE, in Science and Life (1969)

"In the nature of the case, an explorer can never know what he is exploring until it has been explored. He carries no Baedeker in his pocket, no guidebook which tells him which churches he should visit or at which hotels he should stay. He has only the ambiguous folklore of others who have passed that way. No doubt deeper levels of the mind guide the scientist or the artist towards experiences and thoughts which are relevant to those problems which are somehow his, and this guidance seems to operate long before the scientist has any conscious knowledge of his goals."

Gregory Bateson 1971 in Steps to an Ecology of Mind

"I also learnt at an early age the great truth that the twentieth century is an age of almost inconceivable credulity, in which critical faculties are stifled by a plethora of public persuasion and information so that, literally, anyone will believe anything."

"For resident journalists in Moscow the arrival of the distinguished visitors was ... our best - almost our only - comic relief. ... We used to run a little contest among ourselves to see who could produce the most striking example of credulity among this fine flower of our western intelligensia. ... I got an honourable mention by pursuading Lord Marley that the queueing at food shops was permitted by the authorities because it provided a means of inducing the workers to take a rest when otherwise their zeal for completing the Five-Year Plan in record time was such that they would keep at it all the time."

"No other foreign journalist had been into the famine areas in the USSR except under official ... supervision, so my account was by way of being exclusive. This brought me no kudos, and many accusations of being a liar, in the Guardian correspondence columns and elsewhere... Shaw's picture of Stalin as the Good Fabian ... continued to carry more conviction than mine of a bloodthirsty tyrant.... People, after all, believe lies ... because they want to believe them."

Malcolm Muggeridge (1972) Chronicles of Wasted Time

"I feel that much of the work is done because one wants to impose an answer on it. They have the answer ready, and they [know what they] want the material to tell them. ... [Anything else it tells them] they don't really recognize as there, or they think it's a mistake and throw it out. ... If you'd only just let the material tell you."

Barbara McClintock, circa 1980.

"Barbara McClintock belongs to a rare genre of scientist; on the short-term view of the mood and tenor of modern biological laboratories, hers is an endangered species. Recently, ... she met informally with a group of graduate and postdoctoral students. They were responsive to her exhortation that they "take time and look," but they were also troubled. Where does one get the time to look and think? They argued that the new technology of molecular biology is self-propelling. It does not leave time. There is always the next experiment, the next sequencing to do. The pace of current research seems to preclude such a contemplative stance."

Evelyn Fox Keller (1983) The Feeling for the Organism. The Life and Work of Barbara McClintock. Freeman, San Francisco.

"The National Academic of Science made what looked like a prudent response. It put together a high level committee of scientists who worked with DNA in the hope that they would do more than throw dice, [and] that somehow their past experiences would equip them for a logical response. The truth in such situations, however, is often just the opposite. But no one likes to advertise that we may have no meaningful guide for what tomorrow may bring. Psychologically, this is hard to accept, and our sanity almost demands placing more faith in experts than the facts warrant."

James D. Watson (1978) on the debate about the potential dangers of recombinant DNA research. Reprinted in A Passion for DNA (2000) Cold Spring Harbor Laboratory Press p. 62.

"Three new values:

Focus on original sources instead of textbooks - read the great books themselves, not the interpretations of others.
The importance of theory. Of course, you have to know some facts, but much more important is how to put them together in some rational scheme.
Concentrate on learning how to think as opposed to memorization skills"

James D. Watson (1993) on his early education. From A Passion for DNA p. 4.

"The elucidation of the full genomic sequence of humans ... has been referred to as the Rosetta Stone of human biology, which implies that it will allow us to elucidate all of the information encapsulated in this DNA sequence. However, it might be more appropriate to liken the human genomic sequence to the Phaestos Disk: an as yet undeciphered set of glyphs from a Minoan palace on the island of Crete. With regard to understanding the A's, T's, G's, and C's of genomic sequence, by and large, we are functional illiterates."

Molecular Biologist William M. Gelbart (1998) Databases in genome research. Science 282, 659-61.

"Research aiming for a rapid, practical and commercial outcome has become almost a necessity for survival because of the increasingly severe reduction in government funding for universities and research institutes. We [can] ... illustrate the value of curiosity-based research with ... examples from our own fields ... none initiated with a commercial goal in mind. Benjamin Franklin, when asked about the importance of some research, replied 'Of what use is a a baby?'"

Gordon L. Ada & Frank Fenner
(2002; Medical Journal of Australia 176, 244)

"Science has always been a communal effort, but its ability to spawn technological innovation has transformed it into Big Business. That's certainly true of biochemistry and other branches of molecular biology, which offer the promise of blockbuster drugs and a host of other medical revolutions. The biomedical sciences have become expensive, busy, manipulative, political, and harshly competitive. Worse yet, their practitioners are being forced to fiddle with the truth. When they describe their work, they must gloss over uncertainties, or their manuscript won't get published. If they apply for grants, they must make wild claims, or they won't get funded. If they write letters of recommendation, they must tell white lies, or their letters will be counterproductive. And if they shoptalk with colleagues, they must hold back information, or they might get scooped. Today's science is too much dominated by efficient people with cold eyes."

Gottfried Schatz

Letter to a young student

FEBS Letters
(2004) 558,1-2

Case Histories in Innovative Science

William Donald Hamilton
Born August 1 1936; died March 7 2000

Biologist who died of malaria after an expedition in the Congo was a leading Darwinian theorist who explained how natural selection acts on social behaviour. His work was popularized in Richard Dawkins' book, The Selfish Gene. Although the full obituary appeared in UK papers, the part about peer review was not included in the Toronto Globe & Mail version.

Obituary by Alan Grafen

Thursday March 9, 2000

Bill Hamilton, who has died aged 63 after weeks in intensive care following a biological expedition to the Congo, was the primary theoretical innovator in modern Darwinian biology, responsible for the shape of the subject today.

Educated at Tonbridge school, he came across RA Fisher's Genetical Theory of Natural Selection while a Cambridge university undergraduate. When he prompted one of his tutors about the book, he was told it was mistaken and that the author, still then lecturing in Cambridge, had "no standing to write about biology".

Bill was captured by the intellectual excitement of this remarkable book, and spent his working life pursuing its line. In so doing, he provided the conceptual foundation for our understanding of how natural selection acts on social behaviour, opened up the area of "extraordinary" (that is, unequal) sex ratios, transformed thinking on sexual selection and produced a corpus of work that demonstrates the capacity of parasite-host interactions to support the maintenance of sexual reproduction. These are the primary Darwinian themes of the second half of the 20th century, and can be understood only in the context of Bill's contributions. He, like Fisher before him, took many steps at once away from conventional paths, and found that eventually biologists would change their conventions.

The career of a typical Hamilton paper can be caricatured as follows. In review, it is panned by referees who demand shortenings and revisions. Immediately after publication, it attracts criticism for obscurity. Its significance slowly emerges through secondary works, further work is inspired, and one or more literatures develop around its themes. Later more mathematical work may even be rather patronising about the paper, and emphasise discrepancies, while the primary finding is that the original idea is abundantly confirmed. The original paper is frequently, indeed often obligatorily, cited in papers in the new literatures, but is not read nearly as often as it deserves to be, since it retains a reputation for obscurity. The joy of reading the original paper is becoming aware of remaining steps.

We can look forward to decades of catching up with Bill's biological thoughts. He fused mathematics and natural history. He had a vast personal knowledge of insects and was pretty good on plants too. He kept a vast card index system. He once led an expedition through Wytham Woods, near the village where he lived, and showed an entranced audience the range of organisms that lived in rotting wood in which, he believed, most important events in insect evolution had occurred.

He loved living in Wytham, latterly with his partner Luisa, an Italian journalist. He gave dinner parties during the periods Luisa was in Oxford to spare guests his own cooking, and they were charming hosts.

Much of his thinking was mathematical in nature. He covered pages in algebra, and often drew scribbled diagrams to help his line of thought. His grasp of biological theory was extremely firm, and all his major works draw on mathematical structures. There are many biologists who are better mathematicians, but Bill more than made up in vision and purpose for any lack of formal skills. To take one example that will appeal to recreational mathematicians, his paper Geometry For The Selfish Herd is based on the idea that herds of animals are arranged on the principle that each individual tries to maximise the chance that, if a predator appears at random and strikes at the nearest prey, somebody else gets eaten.

    He saw genes everywhere. On a train in New England in 1980, he pointed out clumps of sumac trees. Some had smooth crowns over the whole clump, while others had furrows between individual trees. He was sure that furrows existed between genetically different trees, while trees from the same clone had a smooth crown. Everything he saw in nature was viewed through a genetic lens.

    He was a lecturer in genetics at London university's Imperial college from 1964-77, a professor at Michigan university from 1978 to 1984, and then became a fellow and later a research professor of the Royal Society and fellow of New College Oxford. He received many international scientific prizes, but the time-scale of recognition led to difficulties.

    In his early life, when none of his work was properly recognised, he even doubted his sanity, as he reports in the first volume of his collected papers (Narrow Roads Of Gene Land). Later, he had difficulty obtaining grants and publishing papers. The time-lag could have entertaining consequences, which occasionally gratified Bill.

The authors of one paper who made rather patronising comments waited 15 years to find the criticised theory accepted as commonplace by their own graduate students. Bill's world had different theoretical presuppositions to the worlds of those around him, and a far-seeing prophet can be a poor teacher. He would often speak so quietly that only the front couple of rows could hear properly. If supplied with a microphone, he would often speak more quietly to maintain the same level of general inaudibility. More than once, I have seen him stop in front of a slide with a graph on it, and become so engaged in contemplation of a particular data point that he grew oblivious of the audience. On the other hand, even these talks were inspiring to the few. And sometimes Bill would prepare a lecture that inspired everyone.

    At the end of one such talk at the Royal Society, he showed a slide with a male and female parrot, one bright red and one bright green. Conventional theories could explain why one sex was bright, but not why both were. He ended: "When I understand why one sex is red and the other green, I will be ready to die," and seemed to mean every word.

    He often referred to his own death. He said to me that he would not grow old, both in discussions of his paper on senescence ("I feel bucked when anyone refers to that paper") and discussions touching on personal safety. He refused to wear a cycle-helmet, even once they became fashionable and he had been thrown from his bike through a car windscreen. He fantasised in print about being buried by one of his favourite organisms, burying beetles, in his favourite place, the Amazonian rain forest.

    In late 1999, Fisher's Genetical Theory was republished, and Bill supplied three paragraphs for the back dust-jacket. After blaming the book for his second class degree, he moves on to ask whether "by the time of my ultimate graduation, will I have understood all that is true in this book, and will I get a first?".

    The circumstances of his last fatal expedition are characteristic. He became interested in the theory that HIV arose through poorly conducted vaccination trials in Africa in the 1950s, and felt this theory received less attention than it deserved because of entrenched interests in the medical establishment. The implications of this theory for xenotransplantation are very serious. He went to the jungle to collect chimpanzee faeces with the aim of finding a related virus, and testing whether it was very close to the human virus. While there he contracted malaria, and then collapsed after returning to London. He lived for ideas, was especially partial to unpopular ideas, and thought little of his own safety. His focus of interest was always genes, and it was genes he went to collect.

    He was separated from his wife Christine, who he married in 1967. She and their three daughters survive him, together with his partner Luisa.

Harmon Craig

Geochemistry pioneer. In 1998 he was awarded the Balzan Prize... considered the equivalent of the Nobel Prize in the fields of earth sciences.

Page, D. (2000) An interview with Harmon Craig. Science Spectra 20, 14-18 (with copyright permission from the editor)

"'I think of science as very similar to a chess game. There is the

opening game (discovery),
middle game (enlarging a subject), and
end game (tidying up).

My style and preference are the opening game. Of course, one has to play the middle game to get funding for research, because it is difficult to get funded for exploring new ideas, generally because proposal reviewers and program managers are playing the middle game. So, I generally write middle-game proposals to keep working on a subject I have started. This keeps the lab running and one can use part of the funding for exploring new ideas.'"

"...he's recently been rejected twice by Marine Geology in NSF Ocean Sciences for a proposal to dredge some newly-discovered seamounts in a high-helium 3 gap in the Austral islands at the point where the Austral fracture zone intersects the chain. 'The tenor of the review is 'Craig doesn't follow the scientific method. He doesn't lay out exactly what he expects to find and what it will mean,'' Craig says.

'I wrote the Program Director and said, 'I've never used the scientific method in my life'. I don't know any good scientist who ever worked with the scientific method.'"

Adolfo J. de Bold

Discoverer of Atrial Natriuretic Factor

"The 1981 article by de Bold and colleagues triggered a revolution in our thinking about sodium homeostasis and stimulated a blizzard of papers that together educated a generation of investigators in the topic of volume homeostasis [relevant to high blood pressure].

De Bold had noticed that atrial myocytes contained what seemed to him to be secretory granules. He also had shown that the volume status of the animal had an impact on the number of these granules. In a superb marriage of anatomy and physiology, he collaborated with a leading renal physiologist, Harald Sonnenberg, to determine whether extracts from atrial muscle had any impact on volume homeostasis."

M. L. Zeidel (2001)

Adolfo J. de Bold. Reproduced from the Journal of the American Society for Nephrology with permission of Adolfo de Bold.

A Retrospective by Adolfo J. de Bold

Journal of the American Society of Nephrology
Volume 12 February 2001

[With the permission of A. J. de Bold]

The discovery of an endocrine link between the heart and the kidneys has its basis in the electron microscopic finding that the striated muscle cells of the cardiac atria in mammals are differentiated both as contractile and as endocrine cells. The demonstration that atria produce polypeptide hormones was established with the discovery of atrial natriuretic factor (ANF). ANF is the founder member of the ANF family of natriuretic peptides that have very important functions in the modulation of volume regulation and cardiovascular growth.

The unfolding of this discovery, as many others, has a great deal of human content that often is lost in our technical writings. I hope that students and investigators who are just starting out will find inspiration (and consolation) in the informal account of the ANF discovery that follows.

When I arrived to the pathology department at Queen's University [Kingston] in 1968, fresh from obtaining a degree in clinical biochemistry from the Faculty of Chemical Sciences in Cordoba, Argentina, my supervisor, Sergio Bencosme, was interested in the functional morphology of the endocrine pancreas. As an aside, Bencosme had taken up the question of secretory-like differentiations found in atrial cardiocytes, a fact known since the early days of electron microscopy and manifesting itself most notably by the presence of storage granules known as "specific atrial granules" whose function was a mystery. He and many other notables, including George Palade then at the Rockefeller Institute in New York, could not advance past their morphologic description. Others considered the atrial granules as an evolutionary remnant.

I found myself unable to ignore a secretory phenotype and made it a personal challenge to demonstrate that a combination of morphologic and biochemical techniques would unravel the functional nature of the atrial granules. Perhaps I was influenced by the great endocrine work of Argentinean Nobel Prize laureate B. Houssay, who is an icon of academic excellence for anyone born in Argentina. And so the ANF saga began. It would take 12 yr of investigations (with only 1 month of holidays) before the nature and function of the dual secretory-contractile nature of atrial cardiocytes would become apparent (for a review, see reference ^[1] ).

I began my studies on the possible secretory function of the heart by trying to isolate the atrial granules armed with the papers produced by Christian De Duve on isolation of subcellular organelles and the paper by Blascho on isolation of adrenal chromaffin granules. There were literature data that hinted that the atrial granules were a storage site for catecholamines, but a careful read of the literature was not very convincing in that sense. At any rate, this was a hypothesis to test and this turned into my project for my master of science project.

The isolation of the granules was particularly difficult because they were immersed in the great tangle of myofibrils and connective tissue that represents a homogenate of the heart muscle. Therefore, it took me 2 yr and quite a few 20- to 60-rat ultracentrifugation runs to obtain the purified granules. Bigger animals (cow hearts were suggested many times) were of no use because there is an inverse relationship between the number of atrial granules found in atrial cardiocytes and the size of the animal. Because I had no biochemical marker for the granules, the most tedious job that I found was to look at every fraction by electron microscopy to see where the granules went with the many variations to the isolation technique ^[2] . For this purpose I developed an electron microscopy embedding technique to deal with subcellular fractions. After many trials, I was able to isolate and purify the granules and proved by biochemical means that the granules did not contain catecholamines ^[3] . This was success in one sense, but it also meant that I had no hypothesis left to test.

I set out to develop techniques to visualize specifically the atrial granules at the light microscopic level. I reasoned that with such a technique, one could correlate the distribution of the granules with histochemical reaction products. It helped me enormously that, by intervention of Divine Providence I am sure, I had managed twice during my undergraduate years to end up working as a research assistant in pathology departments, where I learned many histologic techniques.

I developed the first method to stain specifically the granules at the microscopic level using lead-hematoxylin following a paper that my wife had found to stain cells in the pituitary gland ^[4]. The stain aldehyde-fuchsin also provided a visualization of the granules. With these techniques at hand, I carried out a whole battery of histochemical investigations ^[5]. A number of cytochemical properties of the atrial granules thus were uncovered. These investigations would later help me to isolate and purify ANF. For example, the poor stainability of the atrial granules following Bouin's fixative (a fixative that contains acetic acid) suggested that the granules' content was soluble in acetic acid. Indeed, ANF and brain natriuretic peptide are highly soluble in acetic acid, which is the basis for extractants of these hormones.

Altogether, these cytochemical studies plus the ones that I carried out later as an independent investigator provided evidence that the atrial granules stored a random-coiled, basic polypeptide that contained cystine and tryptophan. Autoradiographic studies with radiolabeled leucine showed that the content of the granules had a high turnover in a manner similar to secretory cells ^[6]. All of these properties were confirmed later by biochemical means following the isolation of ANF.

By this time (1973), I had finished my doctoral thesis, my first of our five children had been born, and we had purchased our first home. I was then offered a position to continue at Queen's, moving to the Pathology Laboratory at Hotel Dieu Hospital, a teaching hospital associated with Queen's University, as an assistant professor of pathology. I was to help develop research at this hospital, and it was a leap of faith of the chairman of pathology, Nathan Kaufman, to put me there and for which I am very grateful. Years later, after the discovery of ANF, Nate reminded me that during my thesis defense, I had guessed that the atrial granules, because of their location, might be involved in sensing changes in volume load. I had forgotten that.

A service-oriented hospital, Hotel Dieu was not the most propitious place for a young scientist. I was given an office, half a lab bench, an old incubator, and a microscope to start. Mine was a windowless office in the basement, across from the autopsy room. The smell of formalin was a constant companion. Looking back, this isolation helped me in continuing with the goal of establishing the endocrine function of the heart.

My first grant application to the Medical Research Council as an independent researcher was on the status of the cardiac adrenergic innervation in heart failure. This is the reason that I have a publication on a new model for inducing heart failure in the guinea pig. This theme was really a safety net in case the atrial granule business did not work out. As it turned out, the reverse occurred.

I secured funding from the Heart and Stroke Foundation to continue my graduate studies on atrial granules, but I knew that their patience was wearing thin on this theme. I also collaborated with Jack Kraicer of the physiology department at Queen's on the morphology of the pars intermedia of the pituitary gland. My wife, who had started working with me, and I were able to define a system of canaliculi in this avascular gland using extracellular space markers. In the process, we discovered a new cell type for which my wife developed a silver impregnation technique to demonstrate it at the light microscopic level ^[7].

Although the nature of the granule's content seemed reasonably well defined by the histochemical studies, there was still no hint as to their function. However, we now had something that was not available previously. Namely, a stain that could demonstrate the granules at the light microscopic level; therefore, we could develop a quantitation procedure to assess changes in the number of granules after different experimental procedures using the light microscope. The difference between a morphometric procedure at the light microscopic level and procedures at the electron microscopic level is that the sample size is made much larger at the light microscopic level. This was particularly important for quantitation of atrial granules because of their irregular distribution in the atria and even within the same cell.

We developed a morphometric procedure using the light microscopic staining developed during the histochemical studies using embedding in plastic to obtain uniformly thin sections of atrial tissue. Such a procedure then was tested statistically ^[8] and was used later to test claims that previous researchers had made regarding the ability of certain experimental maneuvers to change the number of granules. There were many such claims and counter claims, and I tested most. I found unequivocal, statistically significant changes in the number of granules after some procedures that were known to alter water and electrolyte balance as previously suggested in electron microscopic studies by Bencosme and Hatt (reviewed in reference ^[9]). The difference afforded by the light microscopic quantitation of granules was that one could be confident that the changes were not the result of biased sampling, and therefore one really could commit one's time to further the study without the feeling of being wasteful.

The hypothesis thus developed was that the atria produced and stored a polypeptide that helped regulate water and electrolyte balance given the nature of the contents revealed by histochemistry and the changes in the number of granules revealed by the morphometric technique after procedures that were known to alter water and electrolyte balance. I thought that the easiest way for a cardiac hormone to modify water and electrolyte balance was to target the prominent role of the kidneys in maintaining water and electrolyte homeostasis. Besides, the atria were in an ideal spot to sense changes in venous return. Looking for a bioassay for diuretic substances, I found that Harald Sonnenberg of the Department of Physiology at the University of Toronto, whom I did not know, was searching for a natriuretic hormone and had a rat bioassay for that purpose. I phoned him and related to him my quest and hypothesis.

Because the existence of atrial granules was not widely known, even by morphologists, it was specially generous of Harald to accept my invitation "to take a shot in the dark." He invited me to give a seminar in Toronto, and we agreed that I would send him atrial extracts. The first extracts were, in fact, atrial granule extracts that contained a high concentration of potassium chloride because of the composition of the solutions used for isolation. This promptly killed the bioassay rats upon injection. I then more or less supplicated Harald to be patient and please to try just crude extracts of atria, and of ventricles as a control, prepared in simple phosphate-buffered saline.

Some weeks went by, and then, to my unbelieving ears, Harald phoned me to say that the injection of atrial extracts produced a diuresis and natriuresis that was immediate and incredibly strong, just like furosemide. Always a worrier, I started to wonder about what contamination would produce such effects. We repeated the experiments many times in my lab, and the results were equally impressive. Also, proteinase destroyed the activity, which went right along with the hypothesis that the atrial granules contained a polypeptide hormone.

The potential importance of the finding prompted us to send our findings to the prestigious Journal of Clinical Investigation. It was tersely rejected in a letter dated May 28, 1980, because the finding "was not thought to be suitable for publication." Because I had disclosed the findings previously at a meeting of the Canadian Society for Clinical Investigation, we decided to publish the findings as quickly as possible. For this reason, it was sent to Life Sciences, where it was quickly accepted and published in 1981 ^[10]. By 1983, the first publications on ANF from other centers started to appear. Not a single laboratory failed to confirm our findings, given that the natriuretic and diuretic activities of atrial extracts were so powerful that nothing short of a dead bioassay rat could stop such action.

The article in Life Sciences [1981] spurred a flurry of activity and went on to become a Citation Classic as qualified by the Institute of Scientific Information. Needless to say, the researchers in the hypertension field were ready to exploit the finding of a hormone that was diuretic, natriuretic, and hypotensive. It is of interest to note the different reactions by different groups of investigators.

Some invited me to present my work and recognized the discovery in one way or another. Others embarked on ANF in furious research and in public relations campaigns, some including televised speeches, to convince the world that they had discovered ANF. It was never clear to me how they planned to claim a discovery for which we had an indisputable 3-yr precedence in publishing. I guess that a discovery that came from a basement of an obscure hospital was deemed easy prey. At any rate, it seems that all discoveries follow the same libretto. The Japanese authors, although they also invented a new name (ANP) and thus disregarded an international nomenclature agreement reached in New York and still existing, truly did contribute to the natriuretic peptide field by demonstrating the occurrence of brain natriuretic peptide and C-type natriuretic peptide based on the ANF discovery.

Our laboratory also was the first to isolate, purify, and sequence ANF ^[11] ^[12] ^[13]. The way that this was accomplished was not less heroic than the 12 yr of work that preceded the ANF discovery. It was very opportune for me to find in the United States a company that provided us with rat atria. In total, approximately 200,000 rat atria were used. It was also fortunate that the techniques for isolation of peptides by HPLC were coming into use. The only problem was that I did not have an HPLC. The clinical laboratory in our hospital, however, had just purchased one to measure theophylline in serum. Luckily, I was put in charge of that technique, so it was not very noticeable that I came during the night to reconfigure the machine and fitted it with a chromatographic column to purify peptides.

Three people essentially did the isolation and purification of ANF in my laboratory: my wife would extract the atria, I would purify the extracts, and a technician would test the different fractions obtained during purification in the bioassay rat. No other resource or person was involved in this effort.

Once the peptide was purified to chemical homogeneity, my next problem was to sequence it. The only person at Queen's involved in amino acid analysis and protein sequencing was Geoff Flynn, to whom I offered collaboration. We had various false starts because of antiquated equipment, both in the amino acid analysis and in the sequence results. The problems were resolved when we obtained funding from the government of Ontario to purchase a gas phase sequencer; thus, we were the first laboratory to produce a sequence in 1983 ^[13]. The Japanese workers produced the human sequence the following year.

Students often ask for advice to succeed in research, and my standard answer is, "Have a dream, don't think small, work hard, and believe in yourself." I finish this in my mind with, "...and pray that you are right."

References

1. de Bold AJ, Bruneau BG: Natriuretic peptides. In: Handbook of Physiology, Section 7: The Endocrine System, Volume III: Endocrine Regulation of Water and Electrolyte Balance, edited by Fray JCS, Goodman MH, New York, American Physiological Society by Oxford University Press, 2000, pp 377-409

2. de Bold AJ, Bencosme SA: Studies on the relationship between the catecholamine distribution in the atrium and the specific granules present in atrial muscle cells; 1. Isolation of a purified specific granule subfraction. Cardiovasc Res 7; 351-363, 1973

3. de Bold AJ, Bencosme SA: Studies on the relationship between the catecholamine distribution in the atrium and the specific granules present in atrial muscle cells: 2. Studies on the sedimentation pattern of atrial noradrenaline and adrenaline. Cardiovasc Res 7: 364-369, 1973

4. de Bold AJ, Bencosme SA: Selective light microscopic demonstration of the specific granulation of the rat atrial myocardium by lead-hematoxylin-tartrazine. Stain Technol 50: 203-205, 1975

5. de Bold AJ, Raymond JJ, Bencosme SA; Atrial specific granules of the rat heart: Light microscopic staining and histochemical reactions. J Histochem Cytochem 26: 1094-1102, 1978

6. de Bold AJ, Bencosme SA: Autoradiographic analysis of label distribution in mammalian atrial and ventricular cardiocytes after exposure to tritiated leucine. In: Recent Advances in Studies on Cardiac Structure and Metabolism. The Cardiac Sarcoplasm, edited by Roy PE, Harris P, Baltimore, University Park Press, 1975, pp 129-138

7. de Bold ML, de Bold AJ, Kraicer J: Demonstration of stellate cells of the pars intermedia of the pituitary gland using a new silver impregnation technique. Stain Technol 59: 49-52, 1984

8. de Bold AJ: Morphometric assessment of granulation in rat atrial cardiocytes: Effect of age. J Mol Cell Cardiol 10: 717-724, 1978

9. de Bold AJ: Heart atria granularity effects of changes in water-electrolyte balance, Proc Soc Exp Biol Med 161: 508-511, 1979

10. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H: A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci 28: 89-94, 1981

11. de Bold AJ, Flynn TG: Cardionatrin I--A novel heart peptide with potent diuretic and natriuretic properties. Life Sci 33: 297-302, 1983

12. Flynn TG, Davies PL, Kennedy BP, de Bold ML, de Bold AJ: Alignment of rat cardionatrin sequences with the preprocardionatrin sequences from complementary DNA. Science 228: 323-325, 1985

13. Flynn TG, de Bold ML, de Bold AJ: The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 117: 859-865, 1983

Figure. Reproduction of a typical chromatographic run showing the final purification step of what later sequencing demonstrated to be ANF_99-126.

This particular run was completed on July 7, 1982, and represents the peptide obtained from a pool of several hundred rat atria extracts. The absorbance unit at full scale is 0.02 at 280 nm. A small amount of peptide was recovered because our isolation procedure prevented peptide breakdown; thus, most of the tissue ANF was present as proANF, which eluted in another, higher molecular weight fraction. The technician has written that the test to confirm natriuretic activity in the bioassay rat was carried out on July 8, 1982. He wrote "with Strong R," meaning strong response after injection of 0.2 ml of sample eluate mixed with 0.3 ml of phosphate- buffered saline.

The peak shows good symmetry, suggesting that purification had been taken to homogeneity. Samples such as this then were sent for amino acid analysis and sequencing.

In 1986 a Gairdner Foundation International award was given "for the discovery and characterization of atrial natriuretic factor" to Adolfo J. de Bold, T. Geoffrey Flynn and Harald Sonnenberg.

The Toronto-based "Gairdner Foundation is a non-profit corporation devoted to the recognition of outstanding achievement in biomedical research worldwide.... The purpose of these awards is the recognition of individuals whose work or contribution constitutes tangible achievement in the field of medical science."

"An award of $30,000 CAD (each) payable in Canadian funds to individual winners from a diversity of fields for outstanding discoveries or contributions to medical science. A joint award for the same discovery or contribution may be given, usually to no more than two individuals."

In 1994 a Ciba Foundation award was given to Adolfo J. De Bold "for his discovery of atrial natriuretic factor."

Periander sent a messenger to Thrasybulus to ask for advice on ruling Corinth. Thrasybulus did not answer, but took the messenger out for a walk in the corn field. As they strolled along, Thrasybulus idly swatted the corn with his stick, so cutting back the stems that stuck out above the rest. The messenger returned and told Periander what had happened. Periander deduced that Thrasybulus's advice was to kill the most outstanding citizens. Any student of modern tyranny knows that Thrasybulus's advice is followed to this day. The most outstanding citizens are likely to be the prime challengers of the tyrant's power.

For more of the significance of this is the present context (Click Here)

Election 2000 - Just Ice

Those inclined to believe in the probity of high councils, such as those that disburse a nation’s health research funds, were driven from complacency in the fall of 2000 when one of the highest councils, the Supreme Court of the United States of America, handed the Presidency to the republican son of a previous republican President.

The republicans had discarded their most competent candidate, Senator John McCain, who strongly advocated reform of campaign financing (see above), and selected George Bush, the Governor of Texas. The democrats selected the Vice-President, Albert Gore. In a time of "unprecedented prosperity" things looked good for Gore, whose 8 year understudy had amply prepared him to assume the highest office in the land. Yet, his style was somewhat "stiff," and his mentor, Clinton, had erred in his private life. By pressing for Clinton’s impeachment on this matter, the republicans had attempting to cripple the Presidency (and hence the important role it had to play in a dangerous world) in support of their own political interests. Bush played the "integrity" card for all it was worth, and the election became "too close to call." Everything came to depend on the vote in Florida, whose 25 electoral college votes would give victory.

In the initial count, Bush had a slight lead. However, malfunctioning voting machines in certain democratic counties had rejected large numbers of votes ("undercounts"). The voters in those counties had thus been denied "the equal protection of the law" that the US Constitution’s 14^th Amendment required. Gore appealed to the Supreme Court of Florida, which has final authority in state matters, requesting a recount in these counties, and called upon Bush to join him and press for a rapid hand recount of all rejected votes in Florida, so that "the will of the people" would become apparent, and the future President would be legitimized. Bush decline to do this and the matter went to the Supreme Court of the USA.

Meanwhile, the State Supreme Court, under pressure from the Federal Supreme Court not to "make new law" gave the go-ahead for the recount, which under existing Florida Law required that the counters manually examine the voting cards to discern "the clear intent" of the voter. While this criterion might differ from counter to counter, an individual counter would use the same criterion whether judging an undercount for Bush or for Gore. So the counting was essentially fair, and could be made fairer by group evaluation of every undercounted ballot. The Florida Law did not elaborate, in advance, what would constitute "the clear intent," thus, wisely leaving the door open to the unexpected (such as a voter leaving the card untouched, except for writing, say, "I vote for George Bush"). In any case, changing that law was a legislative, not a judicial, task. Furthermore, all parties knew the rules when the "game" began and, however imperfect the rules, it was not appropriate to change them when the game was in progress.

Amazingly, on Saturday 9^th December, the Federal Supreme Court, issued a ruling that the counting be stopped, on the grounds that it would do "irreparable harm" to Bush in that there would be a "cloud" over "the legitimacy of the election". As pointed out by Ronald Dworkin (NY Review of Books Vol 48, no. 1. p. 53-55): This

"bizarre claim not only assumes that Bush would have lost the recount, but also that the public is not to be trusted. Public knowledge that Gore would have won, if the recounts had been continued and been accepted, would produce doubt about a Bush election only if the public disagreed with the Court’s judgement that the recount was illegal; and it is constitutionally improper for the Court to keep truthful information from the public just because that information might lead it to conclude that the election was a mistake or that the Court was wrong."

Even more amazing was the further Federal Supreme Court adjudication that the Florida Supreme Court’s "clear intention of the voter" standard for manual recounts violated the equal protection clause. Given this, it was still possible for the Florida Supreme Court (i) to define a new standard (an essentially legislative act, which the Federal Supreme Count now countenanced) and (ii) to have the manual recount completed by 18^th December, when the Electoral College voted.

However, the Federal Supreme Court considered that the Florida legislature would want to take advantage of the Federal "safe harbor" law that guarantees immunity against the unlikely event of a Congressional challenge to the Florida result, if the counting is completed by 12^th December. Dworkin pointed out:

"It goes far beyond that safe [harbor] assumption to declare, as the five [Federal] Supreme Court conservatives did, that the Florida legislature meant to insist that the optional deadline be met at all costs, even if it was necessary to ignore the principles of accuracy and fair treatment that underlie the rest of the election code. That would be a bizarre interpretation of any state’s election law – what legislature would wish to be understood as purchasing an immunity it would almost certainly never need at the cost of sacrificing its basic commitments to justice?"

Knowing that there were time limits, the republicans took every opportunity to delay. The Federal Supreme Court gave its final judgement only 2 hours before the 12^th December "safe harbor" deadline expired, stating that the recount would have to be completed by that date. This was, or course, impossible, so that the Presidency was handed to Bush. A dissenting Supreme Court judge observed that the decision "can only lend confidence to the most cynical appraisal of judges throughout the land." Another dissenting judge considered this "self-inflicted wound … may harm not just the court, but the nation".

Naked power had won over principle. "Justice" was revealed as just ice, which melts when the political temperature rises. When Gore conceded, many sighed that at least there had been a peaceful transition. But what is a "peaceful transition"? Did they really imagine that there would be a military coup in the USA?

Events of the last few decades have shown that small groups, with an imaginary or real sense of injustice and a little technical know-how, can disrupt peace in powerful ways. As antidote to imaginary injustice we must bolster our mental health system (Click Here) . But the only antidote to real injustice is to ensure that such injustice does not occur.

A political transition that leads Ronald Dworkin, Professor of Law at New York University and of Jurisprudence at University College, London, to write as quoted above, may turn out to be far from peaceful. This lack of peace may not be confined to North America. A clear signal has been sent to those who have power, but hesitate to use it. Winning is more important than justice. The ends justify the means.

Tuesday 7th November. Election Day

Tuesday 21st November. Florida Supreme Court lets recounts proceed in four counties.

Wednesday 22nd November. Bush appeals to US Supreme Court.

Friday 24th November. US Supreme Court accepts appeal.

Friday 1st December. Case is argued to US Supreme Court.

Monday 4th December. US Supreme Court unanimously decides to vacate the Florida Supreme Court's decision, asking for a better explanation of the ruling.

Friday 8th December. Florida Supreme Court overturns a lower court decision and order a statewide recount of ballots for which machines had registered no choice for president.

Saturday 9th December. Justices accept Bush appeal and, by 5-4 vote, also grant the Bush request to stop the recount in the meantime.

Sunday 10th December. Both sides file briefs.

Monday 11th December. Cases are argued before the US Supreme Court.

Tuesday 12th December. The US Supreme Court rules, 5-4, that the recount as structured by the Florida Supreme Court is unconstitutional and there is no time to fix it.

Wednesday 13th December. Gore concedes.

In the final hours of his administration the out-going President took an important step to improve the legitimacy of Bush. The NY Times declared on 24th Jan:

"Bill Clinton's last-minute pardon of Marc Rich, the shadowy commodities trader who fled to Switzerland in 1983 to avoid American justice, was a shocking abuse of presidential power and a reminder of why George W. Bush's vow to restore integrity to the Oval Office resonates with millions of Americans who otherwise disagree with the new president's politics."

Casualties: First Justice, then Truth?

In January 2001 The New York Times, The Washington Post, The Wall Street Journal, Associated Press, Newsweek, CNN and several other news organizations commissioned Chicago's National Opinion Research Center to conduct a comprehensive examination of the 180,000 ballots not officially counted in Florida. It seemed that the press was fulfilling its constitutional responsibility to search out the truth.

Weeks turned into months. It took until August 2001 to complete the survey. Then, on September 11th came a terrorist attack on the World Trade Center in New York, and the Pentagon in Washington. Shortly thereafter, cases of anthrax were reported in individuals who received letters in the post containing a strange powder. The USA was placed on a war footing.

On October 12th the Globe & Mail of Toronto (John Ibbitson) reported that "A consortium of major U.S. news organizations had decided unanimously not to analyze and report the results ... of the audit they commissioned to identify which presidential candidate received the most votes in Florida ...". The following day a lead editorial stated:

"Executives of the five major U.S. television networks have met and decided, on the advice of the U.S. government, that there are some things it would be best for the American people not to know. This is a startling act of collective self-censorship. ... The participants say that, given the dramatic shift in priorities since Sept. 11, they have neither the staff nor the space to pursue a stale-dated story.

Come again? The issue is who would have won the U.S. election if the choices of 180,000 voters had been respected; the story has major implications for American Democracy and the U.S. Supreme Court's intervention in the vote. Even with a war to cover, that's a tale that needs to be told.

It is hard not to see this as a further subordination of news judgement to the desire not to rock the government's boat at a perilous time. Once again, journalistic independence is the loser."

From all this it is hard not to suspect that, just as the real experts who might have given advice on bioterrorism were sent "off fishin" because of the way our health research peer-review system works, so (?)President Al Gore (and his probable Secretary of State, Richard Holbrooke) were sent "off fishin" because of the way the US electorial system works.

At times which demand the very best of the very best, we should know if our world is in the hands of Governor George Bush or President George Bush? He states that, while being cautious, US citizens should get on with their lives and show the terrorists that they cannot succeed. However, "business as usual" requires that the press be unshacked.

Donald Forsdyke, 14th October 2001

On 12th November, the press were unshackled. Yes, if all the Florida votes had been counted Gore would have won by from 42 to 171 votes. However, the headlines did not reveal this and one had to dig deep to find the truth. Gore's requests for limited recounts had been rejected, so it showed good judgment that he had requested, but not pressed for, a state-wide recount. If the limited recount proposal were rejected than it is certain that the state-wide recount would also have been rejected.

It turned out that, if only the limited recounts had been performed, then Bush would have maintained a slight lead. But that detracted from the real issue. Governor Bush was now in charge, for better or for worse. The most valid question was, who got the most votes in Florida? The result, albeit through a "photo-finish", was President Gore. There was much mumbling about the result being statistically insignificant. Well, so is the result of a photo-finish in the 100 metres dash. Yet, to the winner we accord the gold. Political contests are won by those who get a nose ahead. Statistics are irrelevant.

Donald Forsdyke 12th November 2001

From all the above, you should be getting an increasingly clear idea of the role of politics, and particularly drug politics, in the decline in the health research system.

The drug companies' campaign contributions support the politicians, who, in turn, do the drug companies bidding.
The drug companies provide the politicians with political cover by blanketing the media with advertisements declaring how benevolently the companies work for the good of humankind.
The politicians pressure the research funding agencies which, in turn, pressure the health researchers and their institutions.
Those researchers with the ability to perceive which way the wind is blowing, and the "will" to act on those beliefs, leap to do the agencies bidding, namely to align their research with that of the drug companies.

The result has been a demographic shift, over several decades, in the academic composition of our universities and research institutes. While there should be a place for all types of researchers and all styles of research in these institutions, now one type and style prevails.

When your child goes to university, the chances are he/she will receive instruction on this one style from this one type.
When your loved ones are stricken by a life-threatening illness, the latest treatment will derive from the studies in the style of this one type.
When politicians turn to academics for advice on AIDS, mad-cow disease, the safety of new biotechnologies, and biomedical warfare, again the advice is from this one type.

Would Charles Darwin have survived in the modern research environment? Well, he was independently wealthy and did not have that problem. But wouldn't it be nice to have Darwin around today to advise on AIDS!

The days of the wealthy "gentleman scientist" are long past. Most researchers are obliged to enter the funding marketplace, which then coerces the direction their research takes.

Researchers are rather like the drunk who, when asked why he was searching for his lost latch-key beneath a street-lamp, explained that "It's too dark where I dropped it." Researchers are pressed to work in the funding light even if that light does not illuminate where they feel the solution to the research problem lies.

This situation will prevail as long as:

the agencies believe that it is better to fund a less able researcher to do approved work than to fund an able researcher to do unapproved work.
the drug companies are "on top" rather than "on tap."

The pervasive influence of "the dollar" is everywhere. Just as it is ability at campaign fund-raising, rather than ability to govern that decides our political leaders (see above), so Boards of Trustees elect University Principals or Presidents based on their fund-raising potential, rather than on their potential for wise governance. When a University Department or Research Institute considers the Curriculum Vitae of a possible recruit the major question asked is "Is he/she fundable?" not "How able and innovative is this person?" The likes of Irvine Page, Szent Gyorgyi and Erwin Chargaff have disappeared from view.

When your son or daughter expresses disappointment about his/her university experience, think not that the fault lies with the complainant. That he/she is inclined to drop-out, may reflect the fact that the chances of finding teachers of caliber are now greatly reduced (although thankfully not entirely eliminated).

The Pages, Gyorgyis and Chargaffs can no more survive in the modern research climate than rabbits can swim, or elephants can fly. The gate is open to those who market, market, market. And marketing is much of what they teach. Lessons are concerned not with how to find "truth," but how to tune to the perceptions of those likely to be able to influence one's future. To this end, these days a routine exercise is the writing of a mock grant application: Find out what the gate-keepers think, and propose research which supports and marginally extends those thoughts. Do this, and the keys of academic heaven are yours.

For how this is playing out tragically in the case of AIDS in South Africa Click Here.

However, the implications of this go far beyond the management of natural diseases. Currently, the greatest threat to humankind seems to be overt or terrorist warfare conducted not with nuclear weapons, but with biological weapons. A nation which uses the peer-review process, as it currently (2002) operates, to select those who give it advice on biomedical matters, may not fare well in confrontation with a nation which has adapted the peer-review process to identify those (e.g. Irvine Page, Szent-Gyorgyi, Erwin Chargaff) who can see beyond their noses. For more: Click Here

When the author of these web-pages presented some of the above views to the Canadian Standing Parliamentary Committee on Industry, Science and Technology (29th Nov. 2001;(Click Here)), one of the nation's elected representatives suggested he was engaging in hyperbole! How many more scandals at The Hospital for Sick Children, how many more Fabricant shootings, must there be, before it is appreciated that the peer-review emperor might be less than fully clad?

The rigidity of the system parallels only that of the financial empires which rule our private enterprise system. In an article entitled "The Betrayal of Capitalism" Ambassador Felix Rohatyn pointed to the failure of peer-review when yet another scandal (Enron) rocked the USA (New York Review of Books 49, #3; Feb. 2002):

"At present, five accounting firms ['granting agencies'] have a virtual monopoly on the audits of most of the US companies listed on the stock markets, a highly unusual level of concentration for any industry. These firms had enough political power to prevent former SEC chairman Arthur Levitt from adopting rules that would prohibit the conflicts of interest inherent in the present system, in which accounting firms often audit the accounts of a company while also acting as its paid financial consultant. For the accounting industry to rely on a system of 'peer review,' by which the major accounting firms are responsible for reviewing one another's work, is evidently unsatisfactory.... Enron's failure was a failure of particular people and institutions but it was above all, part of a general failure to maintain the ethical standards that are, in my view, fundamental to the American economic system."

One by one, the idols fall and public disillusion increases.

The lack of confidence in the integrity of the stock market was held to be an important factor in the dramatic decline in the stock market in 2002.
Priests long held in high regard, turned out to be a pedophiles.
Hormone replacement therapy, touted for a decade as an elixir for post-menopausal females, turned out to have more risks than benefits.
Homeland security was revealed a myth on September 11th 2001.

Furthermore, for reasons set out on these pages, we could no longer trust in the agencies funding health research. Yet, while action was taken under all the above headings (stock market integrity, the catholic church, HRT, homeland security), not a finger was lifted to reform the peer-review system. The media were of little help. When a subject was deemed political, the "experts" were interviewed with full consideration of opposing viewpoints. But matters concerning science and health were usually held as in a different ball-park. The "expert" was interviewed with great deference and ex-cathedra pronouncements went unopposed.

Donald Forsdyke 28th December 2002

Tomorrow's Cures Today?

How to Reform the Health Research System

By Donald R. Forsdyke

CHAPTERS

1. The Credulity of Kings. How Research is Marketed.	1
2. The Slaughter of the Innocents. Diphtheria	9
3. On Giraffes and Peer Review. How We Got into this Mess	17
4. The Origins of the Clonal Selection Theory. A Case Study for Evaluation in Science	25
5. Huxley and the Philosopher's Wife. Another Case Study for Evaluation in Science	35
6. Alas, We are No Longer at School! Teacher Review and Peer Review are Different	55
7. Damage-Limitation or Superelitism? The Case for a Sliding Scale of Funding	65
8. Promise or Performance as the Basis for Distribution of Research Funds	71
9. A Systems Analyst with AIDS asks about the Research Funding System	83
10. How a Systems Analyst with AIDS would Reform the Research Funding System	91
11. Not Cricket	99
12. Pavlovian Effects	111
13. Partnership with the Drug Industry?	123
14. Prospects for Reform?	131

"Dr. Forsdyke has provided the kind of level-headed critique that is long overdue. He has done so with more grace and and more careful analysis than many can muster after they have endured the grievous traumas of grossly unfair reviews.... Forsdyke's book should be compulsory reading for all who are involved in research and research funding in any way."

"This review is about Forsdyke's observations and recommendationsrelative to how granting agencies fund research. To presentand critique the author's thoughts, I adopt the imaginary interviewformat he effectively uses."

"These reforms are interesting, radical, and certainly worthy of consideration. The critique of the current system will hit home for those involved in research.... this small book raises big issues and attempts to improve the system. It is not just scientists who should care about it."

"Forsdyke raises critically important issues that go to the heart of peer review. ... I agree with much of his critique of the existing system but we part ways in his recommended solution....While I do not support the bicameral system proposed in this book, the concerns raised are real and require redress."

This multiauthor work deals with both editorial peer review and grant agency peer review.

Compare with Chapter 2 of Forsdyke's book, which considers the role of "experts" in the diphtheria immunization fiasco.

A reviewer writes: "Although funding for scientific research has been readily available since the end of World War II, Greenberg maintains research bureaucrats have transformed the enterprise into 'a clever, well-financed claimant for money' and the successful quest for that funding into a condition of employment and advancement. Given that climate, Greenberg suggests, basic research has suffered, so that many diseases go unconquered, while more politically glamorous investigations are rewarded."

Concerning the drug companies Angell writes: "Instead of being an engine of innovation, it is a vast marketing machine. Instead of being a free-market success story, it lives off government-funded research and monopoly rights."

A reviewer writes: Judson thinks that fraud is common because it is the inevitable product of the current culture of science. Fraud, he says, is intrinsic in institutional cultures that are "characterized by secrecy, privilege, lack of accountability". Scientists have won exactly such a privileged place in society by presenting themselves as altruistic seekers of truth whose method will invariably ferret out not only truth, but also fraud. "The grandees of the scientific establishment", writes Judson, "regularly proclaim that scientific fraud is vanishingly rare and that perpetrators are isolated individuals who act out of a twisted psychopathology"... .

Most worrisome of all, most of the fraud Judson describes was done by individuals seeking acceptance and advancement in the world of science. Increasingly, a great deal of research is in fact product development; researchers often have more than their egos and grants on the line � a fortune can rest on their results. Judson paints a dark picture of science today, but we may see far darker days ahead as proof and profit become inextricably mixed.

The Lancet 6 Nov. 2004