The Argument in a Nut-Shelltraflite.gif (995 bytes)
Excellence Adjudicated
The Two Competitions
Shuffling Deckchairs

The cure of cancer by 1976 (Irvine Page, 1971)

Research Grants (Szent-Gyorgyi, 1974)

In Praise of Smallness (Erwin Chargaff, 1980)

Malice's Wonderland (Daniel Osmond, 1983)

Bicameral Review (Five Papers by Forsdyke: 1989, 1991, 1993a, 1993b, 1994)

CARRF.traflit2.gif (224 bytes)
Some Quotations
Case Histories in Innovative Science

W. D. Hamilton
Harmon Craig
Adolfo J. de Bold

The Thrasybulus Anecdote
Scullduggery - L'affaire Olivieri
Election 2000 - Just Ice
Demographic Shift
Genome 2001
Study Groups and Spiritualism
Brzustowski's Epiphany 
Result worse than coin tossing
Matching Funds
Brush with Big Pharma 2009
Less Bang for More Bucks. The Law of Diminishing Returns in Health Research
Mission-Orientated Agencies: Good Intentions not Enough


Book: "Tomorrow's Cures Today? How to Reform the Health Research System"traflit3.gif (995 bytes)

Reviews of the book
Further Reading
What is a Grant Application Like?

Other Internet Sites on Peer Review


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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. That current processes of peer review were tolerated for so long will be a source of amazement to future generations. To prevent further deterioration we must act now. It is here proposed that conventional peer review be replaced by a new form of peer review - "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 (Click Here). 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 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, a giraffe its neck, or an elephant its trunk!

   Also there is the communication gap that develops between the real leaders in a field and their peers. In my 2001 evolution book I showed how Romanes and Gulick lost touch with their fellow Darwinians: "Romanes and Gulick had been separately climbing towards the peak of a high mountain, their heads much of the time lost in the clouds. But every so often the clouds would clear and they would be privileged to views, lonely views, which they could partially communicate to each other, but not to their contemporaries [the peer reviewers] on the slopes below."  

    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, decreasing the quality of "expert" advice so necessary in a democratic society, and impairing 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.


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.

   The issue of "Why Experts Get the Future Wrong" is discussed by Kathryn Schulz (New York Times, 25 Mar. 2011) when reviewing Dan Gardner's Future Babble: Why Expert Predictions are Next to Worthless (Dutton 2011). Here there is reference to the  study of Philip Tetlock who found the forecasts of 284 academics, pundits and the like, were generally wrong: "Not only were they worse than the statistical models, they could barely eke out a tie with the proverbial dart-throwing chimps."

"The most generous conclusion Tetlock could draw was that some experts were less awful than others. Isaiah Berlin once quoted the Greek poet Archilochus to distinguish between two types of thinkers: "The fox knows many things, but the hedgehog knows one big thing." Berlin admired both ways of thinking, but Tetlock borrowed the metaphor to account for why some experts fared better. The least accurate forecasters, he found, were hedgehogs: "thinkers who know one big thing, and aggressively extend the explanatory reach of that one big thing into new domains" and "display bristly impatience with those who 'do not get it,' " he wrote. Better experts "look like foxes: thinkers who know many small things, and are skeptical of grand schemes" and are "diffident about their own forecasting prowess."

   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 and military dictatorships. Yet, in vain, we await the fall 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 it would seem that we could save ourselves a lot of trouble by just tossing a coin. 

  • 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 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.

    Samuel Butler's work, light years ahead of the Darwinians on heredity in informational terms, was self-funded, yet he gained little recognition in his lifetime (see these web-pages).

    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 a Nobel Prize (the awarding of which is itself an error-prone human enterprise). 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, legal 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 to profoundly change 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 that 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 cure cancer by 1976 (Click Here if you want to skip the papers).

The cure of cancer by 1976 (Irvine Page, 1971)

Research Grants (Szent-Gyorgyi, 1974)

In Praise of Smallness (Erwin Chargaff, 1980)

Malice's Wonderland (Daniel Osmond, 1983)

Bicameral Review (Four Papers by Forsdyke: 1989, 1993a, 1993b, 1994)

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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)

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Some Quotations Worth Remembering

"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


"What a shock must the discovery of the rotation of the earth have given to the moral sense of the age in which it was made. How it contradicted all human experience. How it must have outraged common sense. How it must have encouraged scepticism even about the most obvious truths of morality. No question could henceforth be considered settled; everything seemed to require reopening; for if man had once been deceived by Nature so entirely, if he had been so utterly led astray and deluded by the plausibility of her pretence that the earth was immovably fixed, what else, that seemed no less incontrovertible, might not prove less false? It is probable that the opposition to Galileo on the part of the Roman church was as much due to some such feelings as these, as to theological objections; the discovery was felt to unsettle not only the foundations of the earth, but those of every branch of human knowledge and polity, and hence to be an outrage upon morality itself.

    A man has no right to be very much in advance of other people; he is as a sheep, which may lead the mob, but must not stray forward a quarter of a mile in front of it; if he does this, he must be rounded up again, no matter how right may have been his direction. He has no right to be right, unless he can get a certain following to keep him company; the shock to morality and the encouragement to lawlessness do more harm than his discovery can atone for. Let him hold himself back till he can get one or two more to come with him."

    Samuel Butler (1873) The Fair Haven, London. A tongue-in-the-cheek ironical defence of Christian orthodoxy.

All originality is estrangement!

"The laws of intellectual progress are to be read in History, not in the individual experience. We breath the social air: since what we think, greatly depends upon what others have thought. The paradox of today becomes the commonplace of tomorrow. The truths which required many generations to discover and establish, are now declared to be innate. Even discovery has its law, and is only an individual product inasmuch as the individual voice articulates what has been more-or-less articulate in the general thought. The great thinker is the secretary of his age. If his quick-glancing mind outrun the swiftest of his contemporaries, he will not be listened to: the prophet must find disciples. If he outrun the majority of his contemporaries, he will have but a small circle of influence, for all originality is estrangement."

George Henry Lewes [partner of George Eliot] (1874. Problems of Life and Mind, First Series, Trubner, London)


"To be original is not so much to say or do things that have no origin except in a man's own self, as to get as near as may be to the origin of those ideas which one may be trying to express, to understand the sources from which they spring, and thus to be able to present them more clearly and concisely before those for whose use they are intended."

Samuel Butler (9th October 1885) Proficiency and originality. in Collected Essays, volume 1, Cape, London (1923), p. 230.


"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) 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).


"The great field for discoveries" said a scientific friend to me the other day, "is always the Unclassified Residuum." Round about the accredited and orderly facts of every science there ever floats a sort of dust-cloud of exceptional observations, or occurrences minute and irregular, and seldom met with, which it always proves less easy to attend to than to ignore. The ideal of every science is that of a closed and completed system of truth. The charm of most sciences to their more passive disciples consists in their appearing, in fact, to wear just this ideal form. Each one of our various ologies seems to offer a definite head of classification for every possible phenomenon of the sort which it professes to cover; and, so far from free is most men's fancy, that when a consistent and organized scheme of this sort has once been comprehended and assimilated, a different scheme is unimaginable. No alternative, whether to whole or parts, can any longer be conceived as possible.

Phenomena unclassifiable within the system are therefore paradoxical absurdities, and must be held untrue. When, moreover, as so often happens, the reports of them are vague and indirect, when they come as mere marvels and oddities rather than as things of serious moment, one neglects or denies them with the best of scientific consciences. Only the born geniuses let themselves be worried and fascinated by these outstanding exceptions, and get no peace till they are brought within the fold. Your Galileos, Galvanis, Fresnels, Purkinjes, and Darwins are always getting confounded and troubled by insignificant things. Anyone will renovate his science who will steadily look after the irregular phenomena. And when the science is renewed, its new formulas often have more of the voice of the exceptions in them than of what were supposed to be the rules.

William James Scribner's Magazine (March 1890; 7(3) 361-374).


[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).


"If you know the facts and are strong enough to look them in the face, you must admit that unless we are replaced by a more highly evolved animal ... the world must remain a den of dangerous animals among whom our few accidental supermen, our Shakespears, Goethes, Shelleys, and their like, must live as precariously as lion tamers do, taking the humour of their situation, and the dignity of their superiority, as a set-off to the horror of the one and the loneliness of the other."

George Bernard Shaw (1903) Man and Superman - The Revolutionist's Handbook


"Inspector MacDonald of Scotland Yard was ushered into the room. Those were the early days at the end of the '80's, when Alec MacDonald was far from having attained the national fame which he has now achieved. He was a young but trusted member of the detective force, who had distinguished himself in several cases which had been intrusted to him. ...Twice already in his career had Holmes helped him to attain success ... . For this reason the affection and respect of the Scotchman ... were profound, and he showed them by the frankness with which he consulted Holmes in every difficulty. Mediocrity knows nothing higher than itself; but talent instantly recognizes genius, and MacDonald had talent enough for his profession to enable him to perceive that there was no humiliation in seeking the assistance of one who already stood alone in Europe, both in his gifts and in his experience. Holmes was not prone to friendship, but he was tolerant of the big Scotchman, and smiled at the sight of him."

Arthur Conan Doyle. The Valley of Fear (1914) Strand Magazine, London.


"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


"Experience has pretty well convinced the working physicist that ... to be an effective scientist, he must be naive, and even deliberately naive, in making assumptions that he is dealing with an honest God, and [he] must ask his questions of the world as an honest man. Thus the naivite of a scientist, while it is a professional adaptation, is not a professional defect. A man who approaches science from the point of view of an officer of detective police would spend most of his time frustrating tricks that are never going to be played on him ... . I have not the slightest doubt that the present detective mindedness of the lords of scientific administration is one of the chief reasons for the barrenness of so much present scientific work."

Norbert Wiener (1950) The Human Use of Human Beings. Cybernetics and Society.


"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. Jane S. Smith in Patenting the Sun. Polio and the Salk Vaccine (1990) dissects this remark in more detail.


It is in the making of weapons of absolute destruction that you see my central theme at its sharpest and most dramatic, or most meladramatic if you like. But the same reflections would apply to the whole assembly of decisions which are not designed to do harm. For example, some of the most important choices about a nation's physical health are made, or not made, by a handful of men, in secret, and ... by men who normally are not able to comprehend the arguments in depth. ...

The paper [of Lindemann (Lord Cherwell who had the ear of Churchill)] went to Tizard. He studied the statistics. He came to the conclusion, quite impregnably, that Lindemann's estimate of the number of houses that could possibly be destroyed was five times too high. ... Everyone agreed that, if the amount of possible destruction was as low as that calculated by Tizard ... the bombing offensive was not worth concentrating on. We should have to find a different strategy. ... The bombing survey after the war revealed that [Lindemann's estimate] had been ten times too high.

C. P. Snow. 1960. Godkin Lectures. Science and Government


If you are going to have a scientist in a position of isolated power, the only scientist among non-scientists, it is dangerous whoever he is. This was the lesson which burnt itself in upon many during the controversies of 1939-1945: whoever he is, whether he is the wisest scientist in the world, we must never tolerate a scientific overlord again.

C. P. Snow. 1961. Postscript to Science and Government


"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.


"I am sure, as is often the case in scientific endeavour, that much of the successful recognition and isolation of this virus lay in perseverance, newness to the field, and failure to be bound by preconceived ideas that caused others in the laboratory to miss this new effect."

Thomas Peebles (1967) whose isolation of the virus led to the measles vaccine


"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.


"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 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.


On Wisdom

"The fool doth think he is wise, but the wise man knows himself to be a fool.�

William Shakespeare (circa 1600) In As You Like It Act V, scene 1.

"Never underestimate a person's wisdom; never overestimate his/her importance"

[Often true in underdeveloped countries where there are insufficient openings for talent.]

"Never overestimate a person's wisdom; never underestimate his/her importance"

[Often true in developed countries where there are sufficient openings, but those with less talent too often win out.]

Modified from a Cambridge anaesthesiologist (circa 1963).

"Repetition is necessary to teach the fools the rules, the wise the lies."

Donald Forsdyke (2001) In The Origin of Species, Revisited p. 34.



 "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



If the study of history does nothing more than teach us humility, skepticism and awareness of ourselves, then it has done something useful.

Margaret Macmillan, 2009


 "We should welcome with open arms everything that modern technology has to offer us, but we must learn to use it in new ways. Biology urgently needs a theoretical base to unify it, and it is only theory that will allow us to convert data to knowledge. Sequencing the human genome was once likened to sending a man to the moon. The comparison turns out to be literally correct because sending a man to the moon is easy; its getting him back that is difficult and expensive.

      Today the human genome sequence is, so to speak, stranded on a metaphorical moon and it is our task to bring it back to Earth and give it the life it deserves. Everybody understood that getting the sequence would be really easy, only a question of 3M Science - enough Money, Machines and Management. Interpreting the sequence to discover the functions of its coding and regulatory elements and understanding how these are integrated in to the complex physiology of a human being was always seen as a difficult task, but since it is easier to go on collecting data, the challenge has not really been seriously taken up."

Sydney Brenner (2010) Sequences and consequences. Philosophical Transactions of the Royal Society B 365, 207-212.


It may not be possible for those in power to master the arguments themselves, but they must be surrounded by those with a good enough scientific background to follow the reasoning processes ... The way to achieve this is to include science alongside art and literature, at the heart of the education received by everyone. ... Fifty years on, Snow's ominous prophesy of a governing class lacking the competence to make informed policy choices where science and technology are concerned continues to reverberate. In recent debates about GM crops, nuclear energy and climate change, the public at large - and I include governments and senior administrators - have shown themselves liable to be swayed by the most pursuasive of the advisors or interest groups, because they are unable to judge for themselves either the soundness of the scientific arguments or the data that support them.

                                                                  Lisa Jardine. C. P. Snow's Two Cultures Revisited (2009). C.P. Snow Lecture, Christ's College, Cambridge.


 "What does seem clear is that the cancer genome project and the cancer atlas are examples of the inefficiency that is the consequence of funding large projects without accompanying large ideas. To be fair, given the impetus of the new technology [the technological imperative], it was probably impossible not to set these machines on to the available tumors in the expectation of finding druggable targets. However, the suggestion ... that 'the ultimate solution will probably involve ... massive amounts of whole genome sequencing' amounts to a dogged adherence to a failed strategy - similar to the massive attacks on the trenches by the Generals of World War I. In a period in which funding of new ideas by untried investigators is at particular risk, it might be helpful to ponder their lesson."

Bernard Strauss (2013) "Mutation and Cancer: A View from Retirement" DNA Repair 12, 875   


 "A Fred Sanger [twice winner of Nobel prize] would not survive today's world of science. With continuous reporting and appraisals, some committee would note that he published little of import between insulin in 1952, and his first paper on RNA sequencing in 1967, with another long gap until DNA sequencing in 1977. He would be labelled as unproductive, and his modest personal support would be denied. We no longer have a culture that allows individuals to embark on long-term - and what would considered today extremely risky - projects."

Sydney Brenner (2014) Frederick Sanger (1918-2013). Science 343, 262.


"Serving on grant review committees, I have observed senior researchers who are fair and well-intentioned, but also those who slam proposals from creative investigators, then steal their ideas. Similar fratricide occurs with submitted manuscripts, with reviewers denigrating competing research so it is not published. There is an ugly side to the scientific hierarchy that comes from unchecked lust for success and fame."

"Imagine Sacks sitting for our cascade of standardized tests that culminates in the SAT. Such educational assessments narrow students' thinking into a binary mode, allowing scant opportunity for an expansive mind that thrives on nuance."

Jerome Groopman (2015) Review of autobiographical book by Oliver Sacks. New York Review of Books 62 (9) 4.



"Increasingly, we become so secure in our bubbles that we accept only information, whether true or not, that fits our opinions, instead of basing our opinions on the evidence that's out there."

During his January 2017 farewell speech in Chicago, President Barack Obama

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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.

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 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.'"

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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."


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 ANF99-126.

    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."

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The Thrasybulus Anecdote

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)

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  Scullduggery - L'affaire Olivieri  (Click Here)

colorb02.gif (1462 bytes)   Election 2000 - Just Ice Click Here

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Demographic Shift in the Research Community             

From 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). Those in the education "industry" spend much time figuring how to paper over the cracks with new teaching approaches rather than recognizing that an excellent teacher is an excellent teacher whatever the approach he/she employs.

    The Pages, Szent-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 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


In research, like motor car racing and the rise of career professionals in Wall Street investment houses, the prizes go to the practitioners of brinkmanship. In motor car racing the brink is tested by going faster than is safe. The all-or-none rewards system spurs greater risk taking. In investing, the brink is tested by various types of leveraged buying on credit. If you do not do it, your competitor will, so you had better move quickly. In both these cases the end comes rapidly with a crash or burst bubble. In research, however, the gullibility brink seems never to be reached. Here the crash or bursting bubble is barely visible. The patients who might have been cured, but will not because of inappropriate research funding priorities, just fade away. So overpromise (Irving Page's word) reaps few penalties, and the crash, if ever, comes when one's career path is well established. See the quest for an AIDS vaccine elsewhere on these pages Click Here.

Donald Forsdyke, 9th December 2008

Responding to the $50 billion Madoff scandal in an article entitled "The End of the Financial World as We Know It" (New York Times), Michael Lewis and David Einhorn today point to the pleadings of Harry Markopolos, a former investment officer "who, for nine years, tried to explain to the Securities and Exchange Commission that Bernard L. Madoff could not be anything other than a fraud. Mr. Madoff's investment performance ... was not merely improbable but mathematically impossible. And so, Mr. Markopolos reasoned, Bernard Madoff must be doing something other than what he said he was doing." When a new appointment, Jonathan Sokobin, was made at the S.E.C., Markopolos hoped that the new face would mean a new ear:

'Attached is a submission I have made to the S.E.C. three times in Boston. ... Each time Boston sent this to New York. Meagan Cheung, branch chief, in New York actually investigated this, but with no result that I am aware of. In my conversations with her, I did not believe that she had the derivatives or mathematical background to understand the violations.'

One can imagine how, within the S.E.C., with the facts staring them in the face, Markopolos was dismissed as someone trying to settle some old score with Madoff, or as having a personal "axe to grind," or "chip on his shoulder."

Donald Forsdyke, 4rd January 2009

Commenting on the US government response to the 2008 financial meltdown, Paul Krugman writes (NYRB June 6 2013):

'It's a terrible story, mainly because of the immense suffering that has resulted from these policy errors. It is also deeply worrying for those who like to believe that knowledge can make a positive difference in the world. To the extent that policymakers and the elite opinion in general have made use of economic analysis at all, they have, as the saying goes, done so the way a drunkard uses a lamppost: for support, not illumination.

    Papers and economists who told the elite what it wanted to hear were celebrated, despite plenty of evidence that they were wrong: critics were ignored, no matter how often they got it right. The Reinhart-Rogoff debacle has raised some hopes among the critics that logic and evidence are finally beginning to matter. ... For now, the broader message of the past few years remains just how little good comes from understanding.'

Donald Forsdyke, 3rd June 2013

Yet, ironically, the capitalist system, despite its imperfections, is the finest example of what we should be aiming to achieve in our academic peer-review processes. The 'alpha' capitalists, are less constrained by the potentially peer-reviewing 'beta' capitalists, to the extent that they are free to buy, sell, etc., and progressively expand their fortunes. In the same circumstances, the 'betas' would have fallen by the way-side, unless propped up by their 'beta' buddies. The 'alphas' are free to 'beat the system,' and are less constrained by PR considerations. Thus, to paraphase Krugman, the broader message should be just how much good can come from real understanding, an understanding of which the 'alphas' (the Irvine Pages, Szent-Gyorgyis, and Erwin Chargaffs) are more capable than the 'betas.'

Donald Forsdyke, 23rd August 2013

An Ebola Virus epidemic is currently expanding in west Africa. A US health care worker contracted the disease and was returned to the USA where he was treated with a new, untested, anti-viral medication. He emerged smiling from the hospital, cured. But his physician carefully spelled out that his speedy recovery from this usually lethal disease might be unrelated to this medication. Since untested, we may assume either that it helped, that it made no difference, or even that it had delayed recovery. Such frankness was not apparent at the birth of the peer-review system as it has operated since circa 1940s. Since untested, we may assume either that it has advanced our understanding of diseases, that it has made no difference, or even that it has delayed progress in understanding diseases. While, with proper controlled testing, we should soon know into which category the new Ebola therapy will fit, several decades later the value of peer-review as currently operated remains a mystery. Among others, historians of science wait in the wings for proper funding so that they can begin this task.

Donald Forsdyke 25th August 2014


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Genome 2001: C'est magnifique mais ... (Click Here)

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Study Groups and Spiritualism (Click Here)

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Brzustowski's Epiphany (Click Here)

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Matching Funds (Click Here)

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Mission-Orientated Agencies: Good Intentions not Enough (Click Here)

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Toxic Professor Syndrome: Neglect of Biohistory (Click Here)

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Further acknowledgements. The delightful giraffe pictures were from the Birmingham Zoo(Click here), and from Planet Pet(Click here), which had copied them from the  "National Geographic: Book of   Mammals". National Geographic Society, Washington DC, USA. The fine Alice pictures are Tenniel's, scanned by Cathy Dean (Click here).

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Book. This web-page supplements:

Tomorrow's Cures Today?

How to Reform the Health Research System

By Donald R. Forsdyke


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

Published by Harwood Academic for Gordon & Breach (Spring 2000; ISBN 90-5702-603-1), now part of the Taylor & Francis Group. 

For further information Click Here

Reviews of the book: Click Here.

"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."

The Journal of the American Medical Association (2001; Vol. 285, 655-656) Click Here

"This review is about Forsdyke's observations and recommendations relative to how granting agencies fund research. To present and critique the author's thoughts, I adopt the imaginary interview format he effectively uses."

HMS Beagle for BioMedNet (2001: Vol. 100) Click Here. [or Click Here].

"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."

CAUT Bulletin (2001, 48, no.6, a9-a10) Click Here

"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."

The British Medical Journal (2001: 322, 1550) Click Here

"Which areas of research is the "quick fix" mentality driving, and which researchers are deemed worthy of funding support? Are scientists forced to engage in unethical practices to ensure continuity of funding? Does the race for funds risk alienating young and talented scientists from the research enterprise? These are some of the questions that biochemist Donald Forsdyke seeks to address."

Canadian Public Policy (2000: 26, 271-272) (Click Here)

"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."

Further Reading

Citation aspects of peer-review by Eugene Garfield (1986 onwards) Click Here

Research on the peer review of grant proposals and suggestions for improvement.

Does Scientific Progress Come from Projects or People? by Joshua Lederberg (1989) Click Here

Lederberg answers "people." 

Peer Review in the Health Sciences Edited by Fiona Godlee and Tom Jefferson. BMJ Books (1999). 

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

Trust Us, We're Experts. How Industry Manipulates Science and Gambles with Your Future. by Sheldon Rampton and John Stauber.  Tarcher/Putnam, NY ( 2001)  

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

Science, Money, and Politics Political Triumph and Ethical Erosion, by Daniel S. Greenberg, University of Chicago Press (2001).

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."

The Truth about the Drug Companies: How They Deceive Us and What to Do About It, by Marcia Angell, Random House, New York (2004).

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."

The Great Betrayal: Fraud in Science, by Horace F. Judson,  Harcourt, New York (2004).

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

The Wrong Way to Fund University Research by David J. Currie in

University Affairs (Jan 2010; pp. 26-27) and Nature (2009; 461, 1198)

Using data from Canadian sources, Currie showed that The Law of Diminishing Returns applies to our health research system just as it applies to many aspects of our economic system: 

"Productivity per dollar decreases as total funding increases. Bang for the research buck is better in [the lesser funded] small institutions. ... To concentrate funding in a few universities would likely improve their research productivity and their bragging rights when global rankings are considered. However, my analysis suggests that the research productivity and impact of the Canadian university system as a whole would decrease as a result."

 See also: "In Praise of Smallness" by Erwin Chargaff  Click Here

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Other Internet Sites on Peer Review

Peer review and the 'selective' funding system. By Alexander Berezin, 1996 (Click here).

"Canadian research councils need fundamental reform". By Alexander Berezin, Geoffrey Hunter, Joseph Pear, and Chary Rangacharyulu. 1998 (Click here).

Juan Miguel Campanario on the regular rejection of Nobel-class discoveries (Click here)

Stephan Harnad on Journal peer review (Click here)

David Healy, Academic Freedom and Pharmaceutical Industry Pressures (Click here)

John Hewitt on Peers who cheat (Click Here)

David Horrobin on peer review (Click here)

Ronald Kostoff on peer review (Click here)

Gilbert Ling on the frustration of the original thinker (Click here)

Brian Martin, Peer review, and the Origin of AIDS  (Click Here)

Walter Stewart on Peers who cheat (Click Here)

Integrity in Science Database (Click Here)

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DISCUSSION FORA - The Scholarly Kitchen and Rescuing Biomedical Research  

The internet newsgroup Bionet.journals.note, which I founded in the 1990s with the support (non-financial) of some publishing houses, provided a forum for discussing peer review as it affects publication in journals, and the transition from paper to electronic forms of publication (see Stephan Harnad's contributions). It was hoped that the newgroup would also provide a forum for discussing peer review as it affects research grant applications. However, there was no one to monitor input and that forum is now archived. However, the new incarnation, The Scholarly Kitchen, has been set up from within the publishing industry and, with close monitoring, is continuing to provoke lively discussions (see:

The sad state of Canadian research funding that struck decades ago, is now catching up in the USA with NIH grant success rates down to 10%. A self-styled "gang of four" members of the US research establishment, including Shirley Tilghman, have initiated a discussion forum: Rescuing US Biomedical Research (see: ).

Finally it should be noted that PubMed Commons has now come into its own, allowing retrospective commentary on papers sometimes within hours of their online publication (see: ).

Donald Forsdyke July 2015

Sadly, spoke too soon. While the Scholarly Kitchen is thriving, US Biomedical Research is far from being rescued. Furthermore, PubMed Commons founded in 2013 fooled us all. It turned out to be "an experiment," and those who contributed their time and energies were mere guineapigs. It was an experiment that was deemed to have failed, so it stopped taking comments on papers in the scientific literature in March 2018. Even worse, the links from 5 years worth of comments were disconnected from the PubMed abstracts that referred to the papers that were commented upon. One cannot help wondering whether any of those whose papers had been the subject of criticism had a hand in the demise of PubMed Commons. For more see bottom of my laboratory page: Click Here

Donald Forsdyke April 2018




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This web-page was established in 1998 and last edited 28 November 2018 by Donald Forsdyke

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