FULL TEXT OF PAPERS WITH COMMENTARY
The Argument in a Nut-Shell
The Two Competitions
The cure of cancer by 1976
(Irvine Page, 1971)
Research Grants (Szent-Gyorgyi,
In Praise of Smallness
(Erwin Chargaff, 1980)
Malice's Wonderland (Daniel
Bicameral Review (Four Papers by Forsdyke: 1989, 1993a, 1993b, 1994)
Case Histories in
W. D. Hamilton
Adolfo J. de Bold
The Thrasybulus Anecdote
Scullduggery - L'affaire
Election 2000 - Just
Study Groups and Spiritualism
Brush with Big Pharma 2009
Bang for More Bucks. The Law of Diminishing Returns in Health Research
Book: "Tomorrow's Cures Today? How to
Reform the Health Research System"
Reviews of the book
What is a Grant Application Like?
Other Internet Sites on Peer
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.
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").
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
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
The Argument in a Nut-Shell
lip-service to the contrary, the grant agencies assess projects, not people
In the final analysis they hold it is better that a less able researcher
carry out an approved project, than that a more able researcher carry out an
unapproved project. Indeed, they hope with the funding carrot to coerce 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
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."
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
- 2. Hedge your bets
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:
impossibility not accepted.
It is very difficult for those in Western
culture systems to accept that some things are virtually
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 its a terrible system, but its the best we have".
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".
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?
compete needs big bucks.
To keep up with top laboratories in other
countries the "best" must be
funded. This argument has much weight if
could really predict the
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
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
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
"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
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
it cannot be evaluated, then it would seem that we
could save ourselves a lot of trouble by just tossing a coin.
it can be evaluated with precision then we should just fine-tune the
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").
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
Gregor Mendel's work,
funded from monastery coffers, provided
the basis for the modern revolution in biotechnology, but was not
appreciated for 35 years.
Darwin's work was self-funded and initially was much opposed by the religious
establishment and by many in the scientific establishment.
Butler work, light years ahead of the Darwinians in thinking about
heredity in informational terms, was self-funded,
yet he gained little recognition in his lifetime (see these
Romanes' work was self-funded and opposed by the scientific
establishment (see these
Bateson's work was largely self-funded and opposed by the scientific
establishment (see these
Einstein's special theory of relativity was funded by working for the
local patent office.
discover of the bacterium causing syphilis was greeted with scorn (see
& Crick discovered DNA structure "on the side", while
being funded for other work. ...
Mitchell's studies of novel ideas on energy formation in mitochondria
were largely self-funded.
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,
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 ....
agency administrators point with pride to the power of "DNA
evidence" in judicial settings. Too often for comfort,
decisions which appeared clear cut at the time, have since been
overthrown. Yes, a triumph for our medical research system in exposing
defects in our legal system. However, in some
cases it was too late. The accused had been found guilty and a death
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!
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.
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?
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
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
to make a
discovery, is the real competition. This is the competition which the
current peer-review system destroys, but which bicameral review
Modern political campaigns are expensive.
Successful politicians are usually those who are most successful at campaign fund-raising.
Indeed, quite often it is success at fund-raising, rather than ability in skills which
make for wise governance, which decides whether a politician will be elected.
So, in the hope of future favours, special
interests move in. Thus, public pressures mount for the reform of campaign financing. In
Canada we had Bill C2 (Feb. 2000), and there
were similar calls for legislation in
the USA and elsewhere. However, despite much lip-service, such reforms never seem to be
who have most to lose from the reforms are those who decide whether the reforms will be
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
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
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.
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
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.
CIHR (MRC) juggernaut, a few lone voices
speak out. They call themselves CARRF, the
Canadian Association for Responsible Research Funding. Some examples of their
attempts to get government support for the reforms which the CIHR (MRC) itself is unwilling to
implement are documented in these pages. First, some background papers by people who have
thought long and hard about peer review are provided. We begin with President Nixon's plan
to achieve a cure of cancer by 1976 (Click Here
if you want to skip
The cure of cancer by
1976 (Irvine Page, 1971)
Research Grants (Szent-Gyorgyi,
In Praise of Smallness
(Erwin Chargaff, 1980)
(Daniel Osmond, 1983)
Bicameral Review (Four Papers by Forsdyke: 1989, 1993a, 1993b, 1994)
Canada an organization of researchers called Canadians Association for Responsible Research Funding (CARRF) has been seeking reform of the research system
for many years. For the CARRF response when, after a period of devastating
cut-backs, the Canadian Government promised to increase total research funding: (Click Here)
"On the other hand,
I will say you deserve this and worse, for you have been disarming by steps those who have
control of the sciences, and they have nothing left but to run back to holy ground"
Archbishop Piccolomini to Galileo 1633 concerning the outcry over the Dialogue
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
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
Butler (1872) On the Colleges of Unreason in Erewhon
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.
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,
A tongue-in-the-cheek ironical defence of
All originality is estrangement!
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."
Henry Lewes [partner of George Eliot] (1874.
of Life and Mind, First Series,
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."
(9th October 1885) Proficiency and originality. in
Collected Essays, volume 1,
Cape, London (1923), p. 230.
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
(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).
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.]
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."
Einstein (on his controversy with Drude 1901. Collected Papers).
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."
Bernard Shaw (1903) Man and Superman - The Revolutionist's
"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.
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
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
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
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
"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
...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
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.
story has a simple moral,
With which the wise
will hardly quarrel;
Remember, Prof, it
Pays to be too bloody
J. Maynard Smith et al. (1952). An ode entitled "The
Folly of Being Too Clever" to J. B. S. Haldane on his 60th
Murrow to Jonas Salk (April 12th 1955):
"Who owns the patent on
"Well, the people, I
would say. There is no patent. Could you patent the
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
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
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.'
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
Richard Goldschmidt (1960) In and Out of
the Ivory Tower. University of Washington Press, p. 60.
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.
"The cure for boredom
There is no cure for curiosity."
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.
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.
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
|"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."
B. S. HALDANE,
in Science and Life (1969)
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
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."
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
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.
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.
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.
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,
is necessary to teach the fools the rules, the wise the lies."
Donald Forsdyke (2001) In
The Origin of Species, Revisited
"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
[Often true in underdeveloped countries where there are
insufficient openings for talent.]
"Never overestimate a person's wisdom; never underestimate his/her
[Often true in well
developed countries where there are sufficient openings, but those with
less talent too often win out.]
Modified from a Cambridge anaesthesiologist (circa 1963).
"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)
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."
Letter to a young student
FEBS Letters (2004) 558,1-2
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
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,
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.
C. P. Snow's Two Cultures
Revisited (2009). C.P. Snow Lecture, Christ's
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
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 -
Sydney Brenner (2014) Frederick Sanger
(1918-2013). Science 343,
Case Histories in Innovative
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
Obituary by Alan Grafen
Thursday March 9, 2000
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
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.
|Geochemistry pioneer. In 1998 he was
awarded the Balzan Prize... considered the equivalent of the Nobel Prize in the fields of
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
- middle game
(enlarging a subject), and
- end game
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,''
'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
Adolfo J. de Bold
of Atrial Natriuretic Factor
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."
L. Zeidel (2001)
J. de Bold
Journal of the American Society
Volume 12 February 2001
[With the permission of A. J. de Bold]
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
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
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
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 
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
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 
. 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  .
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.
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 . 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 . 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 . All of these properties were confirmed later by biochemical means
following the isolation of ANF.
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.
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.
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
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 .
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  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 ). 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.
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.
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.
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
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
. 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.
article in Life Sciences 
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.
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.
laboratory also was the first to isolate, purify, and sequence ANF 
 . 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.
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.
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 . The Japanese workers produced the human sequence the following year.
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."
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
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
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
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,
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
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
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
Bold AJ: Morphometric assessment of
granulation in rat atrial cardiocytes: Effect of age. J Mol Cell Cardiol
10: 717-724, 1978
Bold AJ: Heart atria granularity effects of
changes in water-electrolyte balance, Proc Soc Exp Biol Med 161:
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,
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
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"
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
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
In 1994 a Ciba Foundation award
was given to Adolfo J. De Bold
"for his discovery of atrial natriuretic factor."
Periander sent a messenger to Thrasybulus to ask for advice on
ruling Corinth. Thrasybulus did not answer, but took the messenger out for a walk in the
corn field. As they strolled along, Thrasybulus idly swatted the corn with his stick, so
cutting back the stems that stuck out above the rest. The messenger returned and told
Periander what had happened. Periander deduced that Thrasybulus's advice was to kill the
most outstanding citizens. Any student of modern tyranny knows that Thrasybulus's advice
is followed to this day. The most outstanding citizens are likely to be the prime
challengers of the tyrant's power.
For more of the significance of this
is the present context (Click Here)
Scullduggery - L'affaire
Olivieri (Click Here)
2000 - Just Ice Click Here
Demographic Shift in the Research Community
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
When your child goes to university, the chances are he/she
will receive instruction on this one style from this one type.
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
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
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.
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.
will prevail as long as:
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
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
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):
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
- 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.
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
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
Donald Forsdyke, 28th
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
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
Donald Forsdyke, 9th December 2008
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:
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
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
Donald Forsdyke, 4rd January 2009
Commenting on the US government response to
the 2008 financial meltdown, Paul Krugman writes (NYRB June 6 2013):
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.'
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