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On Being a Scientist: A Personal View

by John C. Polanyi*
1986 Nobel Laureate in Chemistry

 

Doing Science

Science never gives up searching for truth, since it never claims to have achieved it. It is civilizing because it puts truth ahead of all else, including personal interests. These are grand claims, but so is the enterprise in which scientists share.
How do we encourage the civilizing effects of science? First, we have to understand science.

Scientia is knowledge. It is only in the popular mind that it is equated with facts. That is of course flattering, since facts are incontrovertible. But it is also demeaning, since facts are meaningless. They contain no narrative.

Science, by contrast, is story-telling. This is evident in the way we use our primary scientific instrument, the eye. The eye searches for shapes. It searches for a beginning, a middle, and an end.

What we see is as a consequence, culturally conditioned. This is open to misunderstanding. It might be construed to mean that our conclusions are simply a matter of taste, which they are not. Though we explore in a culturally-conditioned way, the reality we sketch is universal. It is this, at its most basic, that makes science a humane pursuit; it acknowledges the commonality of people's experience.

This in turn, implies a commonality of human worth. If we treasure our own experience and regard it as real, we must also treasure other people’s experience. Reality is no less precious if it presents itself to someone else. All are discoverers, and if we disenfranchise any, all suffer.

It is important that we reflect upon our craft, since our understanding of science will inform public policy towards it – ‘science policy’ as it is called. For example, if seeing is a skill, then we should rely on those who have that skill to determine what science we do.

In Canada, we routinely offend against this principle. We have, for example, numerous ‘Centres of Excellence’ because we recognize that the skill on which discovery depends is possessed by a few. But then we proceed in evaluating such centres, to give only a legislated twenty percent weight to ‘excellence’. A preposterous eighty percent is reserved for considerations having to do with ‘socio-economic worth’.

Our assessment of socio-economic worth is largely a sham. We scientists should not lend ourselves to it - though we routinely do. We should, instead, insist on applying the criterion of quality. That this criterion is real, is evidenced by the awesome success of science - peer-reviewed science - in this century.

Have we failed, as scientists, to explain science? Seemingly. Have we, too often, kept silent because we thought it expedient? Undoubtedly.


Being a Citizen

Though neglectful of their responsibility to protect science, scientists are increasingly aware of their responsibility to society. But what is this responsibility?

Some dreamers demand that scientists only discover things that can be used for good. That is impossible. Science gives us a powerful vocabulary, and it is impossible to produce a vocabulary with which one can only say nice things.

Others think it the responsibility of scientists to coerce the rest of society, because they have the power that derives from special knowledge. But scientists, like any other group, are not permitted to seize the levers of power. Nor should they be blamed for failing to do so. They must work through democratic channels. Anything else would be incredible arrogance.

What responsibilities remain? Plenty. Scientists are only beginning to come to terms with them.

In the time that I have been a scientist, I have seen huge changes in our perception of these responsibilities. Let me give some examples.

In the late 1950s a major topic under discussion was whether Canada should acquire nuclear weapons. The United States was trying to get Canada to do the decent thing, and arm itself with nukes. The weapons were, after all, for the defense of North America.

Individual scientists like myself - and many more conspicuous - pointed to the dangers of radioactive fallout over Canada if we were to launch nuclear weapons to intercept incoming bombers. On the face of it, this was technical advice. But more truthfully it was a philosophical position. We chose to make our calculations concerning fall-out because we were opposed to the acquisition of nuclear weapons; not the reverse.

I do not mean to discount the technical element. I merely want to stress (as I did in the context of discovery) that what the scientist sees is influenced by what he believes.

Much the same applied to the next public debate, which had to do with nuclear fall-out shelters. Technical arguments were once more advanced (by myself, among others) to illustrate the absurdity of sheltering a nation from a determined nuclear attack. At a deeper level, however, we were objecting to an outlook according to which security was to be found in the life of a troglodyte.

We were appalled by the abandonment of attempts at coexistence in favour of the life of a mole. Better to die in the pursuit of civilized values, we believed, than in a flight underground. We were offering a value system couched in the language of science.

Around 1970 my scientist friends in the U.S. indoctrinated me in a fresh question of policy. In the war in Vietnam, the United States was using herbicides (Agent Orange) and a tear gas (CS2). This could well be construed as being in contravention of the Geneva Protocol, which for almost half a century had banned the use of chemical weapons. It was, at that date, one of the few instruments of international law regulating the use of weapons, and was correspondingly precious.

I went off to see our Ministers of Defence and of Foreign Affairs, as well as the Prime Minister. God knows how I got into their offices, but I did. They gave me a hard time - as was proper - protesting, "these things are used for killing weeds and for riot control; how can you say they are weapons of war?" The answer was that when employed to prosecute a war, they had become weapons of war. They were being used to expose the enemy, so as to kill him.

One does not need to be a chemist to make that point. But it helps to come from a community with a commitment to objectivity, and a degree of independence from special interests. Under this scientific and moral pressure, the Canadian government conceded publicly that the use of these weapons in Vietnam was, in their view, a contravention of
the Geneva Protocol. The government of the United States was not pleased.

What we in the scientific community were seeking, in our idealism, was a world ruled by law. The moral force that we brought to this debate derived from our membership in an international community ruled by law - albeit unwritten law. For without the acceptance and enforcement of standards of probity, there would be no functioning scientific community.

And without steps being taken to widen this realm of rule-based co-operation, beyond the narrow bounds of science and similar professions, there will be anarchy leading ultimately to all-out war. But technology had made such war intolerable. The solution is to be found not in more technology, but in less war.

When in March 1983 President Reagan announced the Strategic Defense Initiative (SDI), popularly known as Star Wars, this issue was clearly joined. President Reagan was
offering a technical fix to the threat of nuclear war. The SDI, he made it clear, was to be the scientist's antidote to the nuclear poison. However, in the process of distributing this illusory antidote, we were to abandon the only genuine defence against nuclear missiles, which lay as it still lies, in institutionalised restraint.

The SDI was an invitation to a new arms race; one in nuclear-shields which would proceed in parallel to the continuing arms race in swords. With missile-defences back in the news today, this is a lesson to remember.

In the course of these political struggles, scientists became increasingly aware of themselves as an international non-governmental organization. This NGO bases itself, I claim, not primarily on its technical expertise but on its moral tenets. In science, we have a group of individuals supporting one another, world-wide, in an endeavour whose success depends upon placing the truth ahead of personal advantage.

Not all succeed in doing this, but all are agreed in its necessity. In science, truth must take precedence not only over individual advantage, but also over 'group advantage' - sectional interests such as nationality, creed or ethnicity.

This assertion of higher purpose has made scientists (and all scholars) supporters of human rights. Our championing of human rights puts to rest the notion that what we are offering is primarily technical expertise. Technical expertise has nothing directly to do with human rights. It is once more the moral force of science - evident in such individuals as Einstein, Russell, Pauling, and Sakharov - that makes it effective.

Our community's voyage of self-discovery is not over. I believe that it will lead us to a more active support of democracy, wherever it is threatened.

That notion would have seemed preposterous when I began my life as a scientist. But no longer. Today, Academies of Science use their influence around the world in support of human rights. They should do the same for democracy, for the death of democracy is the death of free enquiry. The bell tolls for us.


*This article was published previously in The Globe and Mail (Canada), April 29, 2000 issue.
http://www.nobel.se/chemistry/articles/polanyi/index.html

Schack August Steenberg Krogh - A Versatile Genius

by Jan Lindsten*

 

"The Physiologist's Physiologist"

In 1997, at the Sixteenth Nordic Congress of Medical History in Stockholm, Dr. Ole Munck - consultant at the Museum of Medical History in Copenhagen, concluded his presentation about August Krogh with the following comment: "We are facing a versatile genius: from bicycle to cyclotron, from diffusion of air components to active sodium transport, from physiology at the high school level to insulin production.

August Krogh in 1920 with his Nobel diploma on the table at the left.
Photo provided by Agnes Krogh Lindberg, photographer unknown.

Independently of what he dealt with, something came out of it.... Krogh has described Niels Stensen, who lived 300 years ago, as Denmark's greatest biologist. Maybe Krogh has taken over this standing." This statement is in no way an expression of Danish patriotism, which is clear among other things from the symposium held in Copenhagen in 1969 to celebrate the 50th anniversary of August Krogh's first works about capillary physiology. His former student and colleague Eugene Landis quoted the following from Man's Unconquerable Mind by Gilbert Highet: "There are men who express the age and the milieu in which they are educated but who, by the intensity of their imagination, the sweep of their knowledge and their astounding versatility, rise above their era and their neighbors so that they inhabit both time and eternity at once. When we analyze their minds, we can identify nearly all the component elements tracing this to family and that to school and the other to social climate and yet the compound is far more than the sum of all these elements; richer, intenser, different in quality as a diamond is different from carbon." Then Landis added: "For Professor Krogh, however, I enjoy the thought that even this metaphor can be extended."

The same spirit is found in a 1967 editorial in the Journal of the American Medical Association (JAMA) with the impressive heading "August Krogh (1874-1949). The physiologist's physiologist".

 Caricature of August Krogh produced by Carl Benedickt in 1944.
Photo from the collections of the Royal Swedish Academy of Sciences.

In the following, I shall try to elucidate what may be behind statements of such an admiring nature, in light of Ole Munck's comment: "The exciting thing about geniuses is the areas where they cross borders, which others only can reach the nearness of. Where is it that Krogh did the great leap in his line of thinking? How did he arrive at it?"

Brief Background

August Krogh was born in Grenĺ on Denmark's Jutland peninsula in 1874. His father was a shipbuilder, but since the age of wooden ships was in decline, he instead switched to operating a small brewery. As a child, August Krogh found learning extremely easy and had an unusually inventive and inquiring mind. By the age of 12, for example, he had already studied two extensive reference works very thoroughly, The Book of Discoveries (seven volumes, 4,288 pages, 2,115 figures) and The Forces of Nature (three volumes, 1,508 pages, 868 figures). Not only this, but using simple means he also repeated many of the chemistry and physics experiments described in these books.

His great interest was animals, especially insects, which he collected and whose behavior he studied with great insight. This deep interest was strongly encouraged by a close friend of the family, William Sřrensen, a passionate but slightly eccentric zoologist who eventually managed to earn his doctorate but never received any permanent academic post - he was too controversial a person for that.

August Krogh earned his upper secondary school diploma at the Cathedral School of Ĺrhus in 1893 with great self-confidence but also with top marks. By then he had already decided to become a researcher. Aside from zoology, his great interests were mathematics and physics. He was initially hesitant as to which of these subjects he should specialize in, but he finally chose zoology. His choice seems to have been partly influenced by William Sřrensen. Out of respect for his father, he never dared to explain and persuade him in person of the wisdom of this choice, but instead did so by letter. This letter contained an exhaustive analysis of his own interests and character traits as well as the future prospects in various professions. It ended as follows: "When I say that I can not live without zoology, it is an exaggeration, and when I say that I do not want to live without zoology, you can look upon it as a fancy and, when I persist in doing so, as restiveness, and yet both aspects are in principle true."

In 1895, he chose to specialize in zoophysiology after listening for the first time to a lecture by the prominent human physiologist Christian Bohr (father of Niels Bohr, 1922 Nobel Laureate in Physics). Otherwise Krogh believed, characteristically, that he could learn far more from practical work than from lectures and studies (probably because he had already mastered the topics of the lectures and was a born experimenter).

Krogh applied to Bohr's department and was accepted as an assistant in the autumn of 1897. Although he had performed numerous and rather advanced home experiments (for example on the ability of Corethra larvae to regulate their capacity to rise and sink in water aided by closed air bladders), this year marked the beginning of his actual scientific career.

A Monumental Contribution to Research in Integrative Physiology

To begin with, Krogh continued his studies of Corethra larvae. He constructed a device that could analyze the composition of the air in their bladders (0.03 mm3). He used it to show that the air bladders did not contain oxygen but almost exclusively nitrogen and to explain how their pressure regulation system worked. The air pressure in the bladders rose when water was absorbed into them and air was diffused out. Analogously, air diffused into the bladders when water was reabsorbed out of them.

Bohr soon became aware that Krogh had a natural aptitude for laboratory work. Krogh set up his experiments in a simple way and constructed the necessary equipment with extraordinary skill. This equipment was often so ingenious that only Krogh himself could operate it. So Bohr gave him a free hand in furnishing the laboratory, despite his youth.

Together with Bohr, in 1904 Krogh published a work demonstrating that carbon dioxide reduces the capacity of hemoglobin to bind oxygen. All at once, they had managed to explain how the blood transports and releases oxygen to tissues. The discovery became known as the Bohr effect but was based entirely on equipment that Krogh had designed, which made it possible to measure the oxygen-binding capacity of blood.

Meanwhile, Krogh had traveled to Greenland in 1902. In conjunction with this trip, he had developed an improved device (tonometer) that made it possible to measure the carbon dioxide content of seawater. Works that he published in 1902 discussed the role of seawater in buffering the carbon dioxide content of the atmosphere (Krogh - and before him in 1896 Svante Arrhenius, 1903 Nobel Laureate in Chemistry - thus dealt with the question of the greenhouse effect, which of course remains equally relevant today).

The collaboration between Bohr and Krogh thus began well, but it ended in disaster. Earlier, Bohr had performed measurements showing that the oxygen content of arterial blood was higher than that of the alveoli in the lungs. He therefore assumed, as did all the other main authorities in this field at the time, that oxygen was actively transported from the alveoli of the lungs into the blood. Krogh did not believe this (in his 1903 dissertation, he had studied gas exchange via the skin of frogs - an important part of their breathing - and found that it was a matter of passive diffusion). In 1904 he constructed his famous microtonometer, which made it possible to determine the gas content of blood with great precision.

Microtonometer constructed by August Krogh for determining the oxygen and carbon dioxide content of blood.
Skan. Arch. Physiol. vol. 20, pp. 279-288, 1908
©Acta Physiologica Scandinavica

The gas content was measured in a small air bubble, no larger than 3-4 microliters, before and after absorption of gases. In other words, unlike his predecessors, his trick was to use a very small volume of gas instead of a large volume. This was because it quickly achieved equilibrium with the gas content of blood, for example. As early as 1906, Krogh found that there was no difference between the oxygen content of blood and the alveoli, thus leading him to believe that the passage of oxygen into the blood is a passive diffusion process. On April 22, 1907 he demonstrated his device and his measurement results to Christian Bohr. The demonstration was successful, but from that day onward, Bohr never spoke to Krogh again. His own student had shattered his authority.

Only in 1910 did Krogh publish his findings in a series of seven works ("the seven little devils"). Krogh lectured his former mentor, explaining why it had been difficult to arrive at the correct conclusion with the techniques that were used previously. But his conclusion was mercilessly, crystal clear: "The absorption of oxygen and the elimination of carbon dioxide in the lungs take place by diffusion and by diffusion alone. There is no trustworthy evidence of any regulation of this process on the part of the organism".

In March 1999, I interviewed August Krogh's then 81-year-old daughter (Bodil Schmidt-Nielsen). I asked why he had delayed publication of these findings, and why he had formulated them in the way he did. She explained that her father had agonized a great deal before publication. First, he absolutely wanted to avoid harming Bohr, a man he revered and to whom he owed a great debt of gratitude. Second, he wanted to be sure that publication of his findings would not destroy his own future as a researcher. But the truth needed to come out, so all other considerations had to be put aside (Christian Bohr died in 1911).

While establishing that the movement of gases between the alveoli and the blood occurs through passive diffusion did put an end to a lengthy debate, the solution of this problem was not what won August Krogh the Nobel Prize in Physiology or Medicine. "Settling a question in dispute, whose relations and implications are known in advance, should hardly be considered a discovery," said J. E. Johansson in his presentation speech about Krogh at the 1920 Prize Award Ceremony. Krogh won the prize for dealing with a completely different problem and making what one can speak of as a genuinely new discovery. Or to quote Professor Johansson's presentation speech: "Several scientists saw the capillaries change in response to various stimuli. But none of them thought of investigating whether these phenomena could be related to a new mechanism."

When the body performs work, this greatly increases its need for oxygen, especially in the muscles, but the question was where this increased oxygen supply came from. The capillaries had been known for 250 years. The conventional view was that they all stood open. It was assumed that the speed of blood flow increased during work. Krogh's mathematical calculations indicated that this could not be true. Faster blood flow through the capillaries hardly increased the potential for more oxygen supply, because the time for diffusion meanwhile decreased. Instead, Krogh elegantly and clearly demonstrated (by measurements of the oxygen content in capillaries and muscle fibers, direct observations and histological sections) that a relatively small number of capillaries are open during rest. In fact, capillaries are opening and closing all the time. During work, however, more capillaries are open. He also found that capillaries can vary in diameter and are thus independently contractile. Although the speed of blood flow through the capillaries is the same during rest and work, the oxygen supply increases because so many capillaries are open and each capillary can hold more blood.

Schematic drawing of a piece of muscle with a small artery and capillaries (above, left). Open and closed capillaries in a cross-section of a muscle (above, right).
Cross-section (above, left) of vital injection preparations of muscles at rest (top) and after hard work (bottom) from a guinea pig. Capillaries (above, right) in the tongue of a frog before (above) and after (below) mechanical irritation.
Figures from Krogh's Nobel Lecture, Les Prix Nobel 1919-1920.


Krogh carried out his investigations of capillaries in the form of a long series of animal experiments. His first findings were published in a Danish journal in 1918 and in English-language journals in 1919. Because Krogh received the Nobel Prize in 1920, the faculty of Karolinska Institutet lived up to the wording of Alfred Nobel's will that the discovery awarded the prize is to have been made during the preceding year. This has not always been the case.

In 1922, Krogh summarized his own work on capillaries and that of others in a monograph (now published in several editions) about which Eugene Landis says, "Very few books yielded as prompt and as widespread stimulation of research as this monograph did when it was read by histologists, physiologists, pathologists and clinicians." It is also worth recalling that August Krogh was a natural scientist, not a medical doctor.

The Nobel Prize improved Krogh's working conditions from many standpoints, but it did not influence his scientific activity in any way. He concluded his Nobel lecture with the words "I will do everything within my power to appear worthy of the confidence that Karolinska Institutet has bestowed upon me". And he genuinely lived up to this, because he continued to work assiduously as a researcher until his death in 1949.

Both before (from the time he got his own laboratory in 1910) and after receiving the Nobel Prize, Krogh worked in the field of exercise physiology. Together with his colleague, the exercise physiologist Johannes Lindhard, he started this whole field of research in Scandinavia during the years 1910-1915. As part of this work, he developed his famous automatically controlled bicycle ergometer (1910-11).

 Automatically controlled bicycle ergometer from 1913, designed by August Krogh.
Photo provided by Dr. Ole Munck, Museum of Medical History, Copenhagen.

This was not actually an original discovery, but an improvement of an earlier model. But it was not just any improvement. The accuracy with which this device could study the effect of exercise was amazing, and the ergometer is thus still being used today (in 1997 in Copenhagen alone, five were in use). A special ergometer that was suspended (including the person being tested) from a balanced system in the ceiling was used to measure weight changes during exercise.

Healthy experimental subject (above, left) working out on a suspended bicycle to allow measurement of small weight losses caused, for example, by perspiratio insensibilis. The change in body weight is read manually on the curve recorded on the drum (above, right).
Photo provided by Professor Bodil Johannsen.

The equipment was designed by August Krogh and his colleagues around 1936 and is still in use today. It was so accurate that it could record a loss of one gram in 20 seconds. This device, too, is still in use, like so many other devices that Krogh designed.

Among all of Krogh's other scientific works, there is reason to mention that he demonstrated that the muscles burn fat during exercise, which had previously been denied by the authorities in the field, for example the French physiologist Auguste Chauveau. This may not seem so sensational, but considering that this is the background for understanding the role of exercise in health, this discovery assumes a larger dimension.

Krogh's scientific work during the final years of his life dealt with the energy metabolism of insects in flight. Once again, he designed ingenious methods to study this problem, among them his spectacular grasshopper carousel (grasshoppers were suspended in a carousel, located in a closed chamber with circulating air that stimulated the grasshoppers to fly, after which their energy and oxygen consumption could be determined).

August Krogh and his grasshopper carousel.
©Berlingske Tidende

Practical Applications of Research Findings

To August Krogh, it was important that research findings with the potential for practical applications were also used in society. He personally introduced physiology as a subject of instruction in the upper secondary schools and wrote a textbook especially adapted for this.

He was also interested in the residential environment. He designed a climate chamber (with about the same diameter as a large coin, but somewhat thicker) that people could carry on their body to record humidity and temperature continuously for a 24-hour period.

 Climate chamber for continuous recording of temperature and humidity under a person's clothing for 24 hours, designed by August Krogh in 1938-39. (Boligopvarmningsudvalgets meddelelse nr. 5, Copenhagen, 1948)
Photo kindly provided by Dr. Ole Munck.

Together with Niels Bohr (1922 Nobel Laureate in Physics) and George de Hevesy (1943 Nobel Laureate in Chemistry) - who worked in Copenhagen for a few years in the 1930s - Krogh also introduced the use of radioactive isotopes in biological research. A cyclotron had been installed in Copenhagen as early as 1938 with funding from the Rockefeller Foundation.


 August Krogh (center) together with Hans von Euler-Chelpin (left) and Georg de Hevesy (right) - 1929 and 1943 Nobel Laureates in Chemistry, respectively - during a 1945 visit to Stockholm.
Photo provided by the Niels Bohr Archive in Copenhagen.

Without Krogh, it is likely that biologists would not have realized the importance of isotopes for their research at such an early stage.

Perhaps his most important contribution in this context, however, concerns the manufacture of insulin. August Krogh's wife Marie Krogh, a physician and his research colleague, had become ill with diabetes (the diagnosis was probably made in 1921). She was treated with a special diet by the young physician Hans Christian (H.C.) Hagedorn. The Nobel Prize had made August Krogh internationally famous, and in 1922 he and his wife traveled to the United States. Sitting beside well-known diabetologist Eliot P. Joslin at a dinner, Marie Krogh learned from him that a research group in Toronto had succeeded in isolating insulin. Marie persuaded her husband to extend their visit to Toronto. On November 23-25 they were guests in the home of John Macleod (1923 Nobel Laureate in Physiology or Medicine together with Frederick Banting). When the Kroghs returned to Copenhagen on December 12, they carried with them a license to manufacture insulin. As early as December 21, the first laboratory experiments were made and on March 13, 1923 the first patient was treated. Together with H.C. Hagedorn, August Krogh established the Nordic Insulin Laboratory, which was the starting point of a Danish pharmaceutical company that remains highly successful today. However, August Krogh soon withdrew from the business and returned to his research. His wife Marie was treated with insulin and lived until 1943, when she died of breast cancer (until then, their children knew nothing about her diabetes).

Driving Forces

On October 28, 1920, during the birthday celebration of the University of Copenhagen, journalists began pouring into the room where the event was taking place. They asked, among others, the members of the faculty of medicine where they could find Professor Krogh, who had just won the Nobel Prize. The reply was: "It must be a mistake, there is no Professor Krogh here." By the time the matter was finally sorted out, and a speech of congratulations was held, August Krogh had already disappeared from the room.

Who was this August Krogh that no one knew?

He was a genuine biologist, with an extreme curiosity. He devoted his whole life to trying to understand biological, and especially physiological, phenomena - day and night (he even conducted experiments on his wedding day). His daughter, Bodil Schmidt-Nielsen, told me that her father was always working but that he was never pressed by his work. Of all the Krogh family photographs in existence, one motif reappears time after time: August Krogh sitting and discussing scientific work with his wife Marie. She was thus highly important to him in that context as well.

 August and Marie Krogh in 1935.
Photo provided by their daughter, Agnes Krogh Lindberg, who also took the photograph.

He appreciated problems and was stimulated by challenges, but he was never satisfied with stating that there was a problem. Instead he wanted to find an explanation for the phenomena he had observed. Because the truth had to be revealed, his problem-solving had to be based on exact measurements and mathematical calculations. This explained his great interest in the construction of equipment. In such situations, his sound knowledge of physics and mathematics served him well. Danish writer Piet Hein's Gruk, originally written in English,

"Problems worthy of attack,
Show their worth by fighting back"

sums up Krogh's attitude toward problem-solving rather well. Krogh said that he had always learned more from practical work than from lectures. Reading too much increased the risk of being influenced by authority and could therefore have a restraining effect. "Be always prepared to reject or modify a hypothesis, if an experiment shows something unexpected." The following statement from Professor Hans Ussing, a former student of August Krogh, represents the attitude toward flexibility that Krogh supplied to his students: "If Krogh can make a mistake, then we can too..."

In addition, Krogh had an unfailing intuition in choosing the right problem (that is, problems of fundamental importance), the right solution and the right experimental organism ("For many problems there is an animal in which it can be most conveniently studied" - the August Krogh principle) as well as an unusually good, almost pedantic talent for planning and an irrepressible drive. His establishment of insulin production in Denmark demonstrates this especially well. The current head of the August Krogh Institute, Professor Erik Hviid Larsen, says that Krogh knew how to proportion questions and their solutions and had an enormous talent for evaluation.

Add his need for scientific honesty and firm principles, and it is understandable that Krogh had many admirers, but not only friends. He was something of an "either-or person" and sometimes broke with people, yet he was able to separate the issue from the individual.

As mentioned, Krogh was rather introverted, shy and modest. He declined positions of honor, because they took away too much time from his research, and he steered clear of attention and publicity. But not always. He was capable of taking advantage of his position to generate publicity, for example when he resigned from the Royal Danish Academy of Sciences and Letters in 1949. He did so because he felt that the Academy was far too conservative and, among other things, unwilling to implement the reform proposals he had introduced, for example when it came to investing more in young researchers.

What about prestige, status and personal finances? Bodil Schmidt-Nielsen told me with a smile that Krogh did not need to seek prestige and status - he had them. As for finances, his demands were relatively modest. He wanted to live close to his institute, and the institute should not be too large. The funds that flowed in from various inventions, the sale of equipment and the production of insulin should be used entirely for research.

Working Methods

As mentioned, Krogh was stimulated by biological problems. He wanted to find solutions to them, and these should always be based on accurate measurements. And he accomplished this in a very special way, which he called visual thinking. He described it as follows: "A considerable part of my work was done in bed during the night when I would try to visualize the processes studied and the experiments to be carried out. I found that I could visualize fairly complicated apparatuses and all details of their working. The constructive ideas would come, apparently, out of nowhere, but the visionary examination of them was a conscious and rational affair. I never made, and even now never make, drawings, not even rough sketches, until the construction of an apparatus was complete, because I found that a drawing would hamper the free flow of ideas and bind me down to that particular solution of the problem."

Besides having knowledge of mathematics and physics that was useful in this context, Krogh also had a very practical bent. His devices were ingeniously designed for specific purposes, and it was very much a matter of precision technology. To enable him to develop these instruments, he had access to a large workshop employing a number of people with whom he had a very close working relationship, yet he often built devices himself. After all, he had already worked them out and tested-operated them in his own mind.

H.C. Hagedorn has described Krogh's working method as follows: "He often utilized rather simple experimental arrangements, making use of glassware which he had blown himself and which were fixed with modeling clay or something similar in a very primitive way. When he had to change or correct something in these simple devices, his slender hands approached them with remarkably few and slow movements, which resulted in the effect wanted with amazing skill. Sometimes the arrangements were such that hardly anyone except himself had the ability to use them. In contrast, apparatuses for permanent use were thoroughly gone through."

Krogh very much appreciated the atmosphere and working methods he had experienced during his happy years with Christian Bohr. As a result, he always wanted his home to be right next to his laboratory, so that he could go there at any time - when thoughts popped up - or talk to his colleagues. He did not want his institute to be too big, because he always had at least one project in common with each of his colleagues. Aside from visiting them occasionally outside of working hours, he dropped in on each of them every morning to talk and find out how things were going. He was pleased when they were going well, but usually even more pleased if complex problems had arisen. It is easy to understand why he was enormously well-liked by his colleagues and his many guests researchers over the years.

August Krogh created an institute that is still very much alive and that has produced many prominent researchers. Integrative physiology was his life interest. This is why all types of physiology, including human physiology, are still being pursued at the August Krogh Institute in Copenhagen.

Epilogue

August Krogh died of cancer on September 13, 1949. Among the books he read toward the end of his life was 100 Dikter (100 Poems) by the Swedish poet Hjalmar Gullberg (late during World War II, Krogh had spent some time in exile in Sweden). One day, he showed his daughter, Bodil Schmidt-Nielsen, the poem he was reading, "Efterlyses" (Wanted) in which the author searched for his lost childhood faith and promised a reward to anyone who could find it.

Acknowledgements

The author gratefully thanks August Krogh's daughters Bodil Schmidt-Nielsen and Agnes Krogh Lindberg for a very interesting and informative interview and for the photographs used in some of the figures, respectively; Dr. Ole Munck of the Museum of the History of Medicine in Copenhagen for stimulating discussions and for the photographs used in several of the figures; Professors Bodil Johannesen and Bengt Saltin at the August Krogh Institute in Copenhagen for providing photographs of the suspended bicycle; The Niels Bohr Archive in Copenhagen for allowing me to use the photograph of Krogh, von Euler-Chelpin and Georg de Hevesy; Acta Physiologica Scandinavica for permission to reproduce drawings of the microtonometer; the Center for History of Science at the Royal Swedish Academy of Sciences for permission to publish the caricature of August Krogh drawn by the late Professor Carl Benedickt; and the Nobel Assembly at Karolinska Institutet for letting me study the archive material concerning August Krogh.

Bibliography

"August Krogh (1874-1949), the physiologist's physiologist" (editorial). JAMA, 1967, 199, 156-157.

Deckert, T.: Dr. med. H. C. Hagedorn og det danske insulin-eventyr (Dr. H.C. Hagedorn and the Danish Insulin Adventure), Poul Kristensens Forlag, Copenhagen, 1998.

Landis, E.M.: Professor August Krogh: An Appreciation, Alfred Benzon Symposium II, 1970.

Les Prix Nobel en 1919-1920, P.A.Norstedt & Söner, Stockholm, 1922.

Munck, O.: "August Krogh - Nobelpristagare i fysiologi eller medicin 1920" (August Krogh - 1920 Nobel Laureate in Physiology or Medicine), Svensk Medicinhistorisk Tidskrift, 1997, 1, 85-90.

Schmidt-Nielsen, B: August and Marie Krogh. Lives in Science, Oxford University Press, New York, 1995.

 

***



*August Krogh was awarded the Nobel Prize in Physiology or Medicine in 1920 "for his discovery of the capillary motor regulating mechanism." During the 1939-40 Winter War between the Soviet Union and Finland, when the Danes began collecting money in support of Finland, August Krogh was urged to donate his Nobel medal, which was made of solid gold, for this purpose. He did so, but first he had his daughter Bodil Schmidt-Nielsen make a copy of the medal in silver, which was then gold-plated.

***

Every effort has been made by the publisher to credit organizations and individuals with regard to the supply of photographs and illustrations. The publishers apologize for any omissions which will be corrected in future editions.

http://www.nobel.se/medicine/articles/krogh/index.html

Roger Wolcott Sperry

by Norman H. Horowitz

 

Roger Wolcott Sperry (1913-1994) was born in Hartford, Connecticut and grew up on a farm outside Hartford. He attended Hartford public schools. At West Hartford High School he was a star athlete in several sports, but he also did well enough academically to win a scholarship to Oberlin College, in Ohio. He graduated from Oberlin in 1935 with a degree in English. At college, Sperry's main passion, aside from 17th century English poetry, seems to have been athletics, as in high school. He was captain of the basketball team, and he also took part in varsity baseball, football, and track.

Sperry stayed at Oberlin after graduating and took a Master's degree in psychology. He then went to the University of Chicago, where he worked for his Ph.D. in zoology under Paul Weiss, one of the most influential biologists of the time. Following his Ph.D., he spent some years at Harvard and the Yerkes Laboratory for Primate Biology in Florida before returning to Chicago as a faculty member.

In 1951, Sperry was invited to present his work at the California Institute of Technology (Caltech), which was seeking to fill the newly endowed Hixon Professorship of Psychobiology. His lectures on neurospecificity (summarized below) were brilliant, and he was offered the position. He joined the Caltech faculty in 1954 and remained there for the rest of his life.

Sperry's first major scientific work--one which occupied him for over a decade--was to disprove a widely accepted theory that had been advanced by his professor at the University of Chicago, Paul Weiss. According to this theory, the vast neural network that connects the sense organs and muscles to the brain originates as an undifferentiated and unspecified mesh of randomly connected nerve fibers which is later transformed, under the influence of experience and learning, into the highly coordinated, purposeful system that is actually seen in animals. Plasticity and interchangeability of function were the key ideas. This theory did not come out of the blue, of course, but was based on careful experimental work that Weiss had performed, but misinterpreted.

In a series of experiments that have become famous, Sperry showed that the actual state of affairs is precisely the opposite of that imagined in Weiss' theory. Instead of being composed of interchangeable parts, the circuits of the brain are largely hardwired, in the sense that each nerve cell is tagged with its own chemical individuality early in embryonic development; once this happens, the function of the cell is fixed and is not modifiable thereafter.

 

Roger Sperry at his desk.
Photo by W. W. Girdner © Copyright California Institute of Technology. All rights reserved. Commercial use or modification of this material is prohibited.

 

The experiments that led to this radical conclusion involved surgical procedures on a variety of animals from fish and salamanders to monkeys. Sperry showed that if nerve connections were rearranged--for example, by redirecting to the other side of the animal the sensory nerves that innervate the left foot of a rat--inappropriate responses resulted that could not be unlearned. In this case, stimulation of the right foot caused the rat to move its left foot, and no amount of experience or retraining could change this response.

In experiments with fish, frogs, and salamanders (chosen because they have great powers of regeneration), Sperry demonstrated that individual nerve fibers (which are actually different cells) behave as if each is chemically different from every other, and these chemical differences are matched in the brain. The result is that in an animal whose optic nerves are severed and then allowed to regenerate, the thousands of individual fibers that make up each optic nerve grow back into the brain and there make the same connections they had before. The animal is then able to see as if the nerves had never been severed. Proof that no adaptive reorganization of the neural circuits is involved in regeneration consisted of showing that if an eye whose optic nerve is severed is also rotated in its socket, the world seen by the eye after regeneration is still upside down and backwards. Furthermore, as in the case of the rat with the crossed nerves, no amount of retraining makes it see correctly: the animal invariably strikes to the left when it sees a worm on its right.

The conclusion that the circuitry of the brain is fixed in early development is supported by much more evidence than I can summarize here. It has given rise to a field of research focused on "axonal guidance". Sperry's result concerning the chemical individuality of each nerve fiber has been confirmed by modern molecular methods. It is a result that is loaded with meanings at many levels--from immediate consequences for neurosurgery to large and still not fully explored implications for evolution and development, and even for social-political questions. It raises other fascinating and still unsolved questions. For example, the capacity to learn obviously implies some neural plasticity. But given the basic determinism of the brain that Sperry uncovered, what does learning actually consist of at the cellular and chemical level? These and other questions posed by his findings are now being studied, and no doubt they will continue to be worked on for a long time in the future.

Important as his work on neurospecificity was, it was not this for which he was awarded the Nobel Prize in 1981, but his discoveries on split brains. Essentially, Sperry and his students showed that if the two hemispheres of the brain are separated by severing the corpus callosum (the large band of fibers that connects them), the transfer of information between the hemispheres ceases, and the coexistence in the same individual of two functionally different brains can be demonstrated. The findings contradicted the generally held view--again based on misinterpretation of evidence--that sectioning of the corpus callosum produced no definite behavioral effects. The probable explanation is that the two hemispheres, although separated from one another, are usually in agreement, so that no obvious conflict results. By means of ingenious tests, however, Sperry and his group showed that definite behavioral phenomena can be demonstrated following the brain-splitting operation.

Sperry started this investigation with cats and monkeys, but later extended it to human beings when patients became available whose hemispheres had been surgically separated in order to control intractable epilepsy. It was with these patients that he was able to show that a conscious mind exists in each hemisphere. The left hemisphere is the one with speech, as had been known, and it is dominant in all activities involving language, arithmetic, and analysis. The right hemisphere, although mute and capable only of simple addition (up to about 20) is superior to the left hemisphere in, among other things, spatial comprehension--in understanding maps, for example, or recognizing faces. Until these patients were studied, it had been doubted whether the right hemisphere was even conscious. By devising ways of communicating with the right hemisphere, Sperry could show that this hemisphere is, to quote him: "indeed a conscious system in its own right, perceiving, thinking, remembering, reasoning, willing, and emoting, all at a characteristically human level, and . . . both the left and the right hemisphere may be conscious simultaneously in different, even in mutually conflicting, mental experiences that run along in parallel."

As with his earlier work, the discovery of the duality of consciousness revealed in the split-brain experiments opened whole new fields of brain research, and these are now being worked by a new generation of biologists, and, of course, philosophers.

http://www.nobel.se/medicine/articles/sperry/index.html

Controversial Psychosurgery Resulted in a Nobel Prize

by Bengt Jansson

 

Summary

In 1936, the Portuguese neurologist Egas Moniz introduced a surgical operation, prefrontal leukotomy, which after an initial period came to be used particularly in the treatment of schizophrenia. The operation, later called lobotomy, consisted in incisions that destroyed connections between the prefrontal region and other parts of the brain.

At that time there did not exist any effective treatment whatsoever for schizophrenia, and the leukotomy managed at least to make life more endurable for the patients and their surroundings. The treatment became rather popular in many countries all over the world and Moniz received the Nobel Prize in 1949.

However, by this time the treatment had had its most successful period and in 1952 the first drug with a definite effect on schizophrenia was introduced, chlorpromazine, our first neuroleptic drug. Since about 1960 lobotomy, with a strongly modified technique (more discrete incisions), has been used only when there are very special indications such as in severe anxiety, and compulsive syndromes which have proved to be resistant to other forms of therapy. Perhaps about five operations a year are now being performed in Sweden.

However, I see no reason for indignation at what was done in the 1940s as at that time there were no other alternatives!

Chains, straitjacket, cell belt and covered bath tub (72 x 150 x 69 cm) for restraining raving patients, Burghölzli Hospital, Zurich.
Courtesy of The Museum of the History of Medicine of the University of Zurich.

Therapeutic Alternatives for Psychotic Patients Before the 1930s

As a rule therapeutic methods developed considerably later in psychiatry than in other medical fields. Violent patients, dangerous to their surroundings, sometimes had to be restrained or immersed in baths for long periods. Another alternative was heavy sedation with opiate derivatives or barbiturates. However, none of these treatments had long-term effects on psychotic patients.

It was not until the 1930s that Manfred Sakel in Vienna introduced hypoglycaemic coma, produced by injections of insulin, as a treatment for schizophrenia. At the same time the Hungarian Ladislav von Meduna started seizure therapy by intravenous injection of cardiazol (in depressive states), a therapy that was abandoned when in 1938 the Italians Cerletti and Bini introduced electric convulsive therapy, E.C.T., for severe mental states. This treatment was first used in schizophrenia, but severe depressive states very soon proved to be the main indication. Tranquilizers with more than a very short-lived sedative effect did not exist until 1952 when the Frenchmen Delay and Deniker introduced our first neuroleptic drug, the phenothiazine derivative chlorpromazine.

Introduction of Prefrontal Leukotomy

Cerebral surgery had been tried in a few psychiatric cases as early as 1891 and 1910, particularly patients with manic-depressive psychosis. These trials did not attract much attention, but at a neurology conference in London in 1935, at which the Portuguese neurologist Egas Moniz participated, Jacobsen & Fulton presented data from operations on two chimpanzees which, after a leukotomy, managed to make mistakes without becoming aggressive, something which they had not managed to do before. Many people have considered this information to have instigated Moniz's "bold step" in November 1935. In 1936 Moniz published his first report on prefrontal leukotomy.

One reason why Moniz's operations gained better acceptance than the earlier trials mentioned above was evidently the fact that he was internationally respected for having developed cerebral angiography. Moniz's first twenty cases all survived and did not develop any serious morbidity. The leukotomy soon achieved a good reputation in, among other countries, Brazil, Italy and the United States. Moniz strongly believed that the potential benefits of surgical lesions in the frontal lobes, even allowing for some behavioral and personality deterioration, outweighed the debilitating effects of severe psychiatric illness.

Leucotome

Refined Surgical Techniques

Moniz, working together with the neurosurgeon Almeida Lima, first injected alcohol as a sclerosing agent into the white matter of the frontal lobes. Moniz soon refined his technique by designing a "leucotome," an instrument with a retractable wire loop and later replaced with a steel band, which he used to cut six cores in the white matter of each hemisphere. For twenty patients in a first series, and eighteen in a second, the results were considered rather acceptable by Moniz in 1937, although he concluded that deteriorated patients did not benefit much from the operation. Of the 18 patients in the second group (all schizophrenic), three were characterized as almost cured and another two also had become much better. Moniz's conclusion was this: "Prefrontal leukotomy is a simple operation, always safe, which may prove to be an effective surgical treatment in certain cases of mental disorder."

Blue spots indicate the areas operated on

Among those who followed Moniz's lead, none was more prominent than the neurologist and neurosurgeon team of Walter Freeman and James Watts in the United States. Freeman and Watts first used Moniz's leucotome technique, but they soon developed a procedure designed to more completely ablate the white matter tracts to and from the prefrontal lobes. Freeman and Watts performed about 600 operations with this "closed procedure," which became known as the standard prefrontal lobotomy of Freeman and Watts. The first "open operation" was performed by Lyerly in 1937 who, using a superior approach to each frontal lobe with the aid of a specially lit speculum, attempted to separate the white fibers under direct vision. This method became the standard procedure in the United States as the open method was considered to reduce the main complication of psychosurgery, haemorrhage of the anterior cerebral artery.

Side Effects on Personality

Negative effects on personality were observed as early as the end of the 1930s. In 1948, Swedish professor of forensic psychiatry Gösta Rylander, reported a mother as saying: "She is my daughter but yet a different person. She is with me in body but her soul is in some way lost." Hoffman (1949) writes: "these patients are not only no longer distressed by their mental conflicts but also seem to have little capacity for any emotional experiences - pleasurable or otherwise. They are described by the nurses and the doctors, over and over, as dull, apathetic, listless, without drive or initiative, flat, lethargic, placid and unconcerned, childlike, docile, needing pushing, passive, lacking in spontaneity, without aim or purpose, preoccupied and dependent."

Who Were Operated On?

Initially operations were performed on a majority of patients with affective disorders, i.e. various types of depression, such as involutional depression, agitated depression and so on. Very few psychiatrists remember this because E.C.T. (electric convulsive therapy) had already been introduced in 1938 and quickly proved to be a very effective treatment for depressive states. Other groups of patients were those with severe obsessive-compulsive and hypochondriac states. As a rule, severity was a more important factor than diagnosis, i.e. consideration was taken to suicidality and dangerousness, among other things.

A few patients suffering from schizophrenia were operated on at the end of the 1930s, but neither Moniz's original seven patients nor any of those 12 schizophrenic patients from Freeman & Watts´ first 80 cases showed any marked improvement. Freeman based his opinion quite early on that if schizophrenic patients are to be operated, it should be done early before they have become apathetic or have deteriorated, because such patients "behaved the same with or without their frontal lobes" (Swayze 1995). This opinion became more and more dominant (Kalinowsky & Scarff, 1948). In other words the first year of illness should be used to try all the other somatic therapies. At a conference in 1953, it was shown that mortality varied between 0.8% and 2.5%. At the same time, approximately 10% of operated patients were known to have some problems with epilepsy.

Why Was Psychosurgery so Popular in the 1940s?

Swayze (1995), whose paper is strongly recommended for reading (see reference), mentions some important contributory factors. First, there were no alternative therapies available for chronically institutionalized patients. Second, during and following World War II there was an alarming increase in the number of admissions to psychiatric institutions in the United States. For example, there were 100,000 new admissions to mental institutions and only 67,000 discharges in 1943, and in 1946 nearly one-half of the public hospital beds were devoted to the mentally ill (Menninger 1948). Third, prior to 1930, patients continuously hospitalized for 15 years with a diagnosis of manic-depression had a 18% mortality rate due to tuberculosis and other infectious diseases. Thus, the importance of discharging patients from the state institutions was apparent. Another factor, according to many doctors, was that a long stay in a mental institution in itself contributed to the fact that many patients became apathetic.

Were the Patients Cured?

A survey of all patients who underwent leukotomy in England and Wales from 1942 to 1954 (Tooth et al 1961) documented 10,365 single leukotomy operations. An additional 762 patients underwent more than one operation. A follow-up study covering 9,284 of the above mentioned patients showed that 41% had recovered or were greatly improved while 28% were minimally improved, 25% showed no change, 2% had become worse and 4% had died. Not surprisingly, patients with an affective disorder showed the best prognosis with 63% recovered compared to 30% among schizophrenic patients.

In the United States approximately 10,000 operations had been performed by August 1949. After 1954 the number of operations steadily decreased. As there were no alternative therapies for severe mental disorders, psychoses in the 1930s, it is not surprising that lobotomy was quickly accepted as a therapy for chronic schizophrenic psychoses, even if it seems a bit strange that lobotomy initially was tried with affective disorders. Lobotomy is an ethically dubious treatment if carried out against the patient´s wishes, but this is always a difficult question in severely psychotic patients who totally lack insight about their illness - what is it exactly that such a patient wants? Historically, it is easy to understand that psychosurgery was considered as a therapeutic advance. Today, it is easy to hold a negative opinion about the use of lobotomy and consider it very strange that Moniz was awarded the Nobel Prize. However, I agree with Swayze (1995) who has written: "If we learn nothing else from that era, it should be recognized that more rigorous, prospective long-term studies of psychiatric outcome are essential to assess the long-term outcomes of our treatment methods."

Development of Alternative Methods

The development of neuroleptics, which started with chlorpromazine in 1952, very soon made lobotomy uninteresting in the treatment of schizophrenia, and the number of lobotomies in schizophrenia dropped dramatically after about 1960. During the 1970s a refined computed tomography-based stereotactic technique was developed making it possible to make selective lesions of specific fiber systems. The main target area is the limbic system which is closely related to emotions. The most important procedure is bilateral anterior capsulotomy (in the United States also cingulotomy), and the indications have changed to chronic anxiety - and obsessive compulsive syndromes which have shown themselves resistant to other treatments. Anxiety disappears first, but the obsessive symptoms gradually also diminish when they are not maintained by anxiety. In Sweden we perform about 5 such operations a year.

Chlorpromazine

Did Moniz Deserve the Nobel Prize?

Moniz, who was born in 1874, was shot in the leg by a patient and had to spend the rest of his life in a wheel chair (he died in 1955). Moniz had problems with his hand and did not very often hold the knife himself. However, there is no doubt that it really was Moniz who initiated and managed to inspire enthusiasm for the importance of prefrontal leukotomy in the treatment of certain psychoses. The more sophisticated surgical methods, however, were developed by other people, primarily by Freeman and Watts but also by Lyerly-Poppen, Strecker and others. Moniz's main interests were evidently encephalography, and cerebral arteriography. Already in the 1920s Moniz succeeded in making cerebral arteriographies possible by injections of a contrast agent containing iodine, an invention which made it possible to diagnose tumors and vascular deformities. Actually, I think there is no doubt that Moniz deserved the Nobel Prize.

X-ray examination of brain vessels using the method - cerebral angiography - introduced by Moniz. A radio-opaque contrast medium has been injected into one of four neck vessels (carotid artery) supplying the brain. Normal case (left). A case of vascular malformation situated in the parietal (mid superior) part of the brain and fed by an enlarged artery (right).

 

Moniz's life history contains a few surprising details. He grew up and was educated in Coimbra, but after having been professor there and also professor of neurology in Lisbon in 1911-14, he devoted some years to business and politics. Moniz became ambassador to Madrid in 1918 and in 1918-19 was minister for foreign affairs before returning to the Institute of Neurology in Lisbon.

 

Glossary

Affective disorders - all states where the patient’s mood is higher (manic or hypomanic states) or lower than normal, that is, various kinds of depression, for instance, involutional depression in old people with signs of ageing. (Manic-depressive psychosis is an older term for the same kind of disorders).

Cerebral angiography - an X-ray investigation of the blood vessels of the brain. The blood vessels are made visible by injecting a dye that is opaque to X-rays.

Cingulotomy and bilateral anterior capsulotomy - are methods used to destroy connections between cortical areas and basal ganglia, areas which have shown signs of hypermetabolism in tomographies. The operations may be accomplished by thermic coagulation with high frequency electric current or gamma radiation. In the former method electrodes are conveyed through two bore-holes, and the latter method is totally unbloody.

Electric convulsive therapy (E.C.T.) - is the most efficient treatment of severe depressions. A short electric stimulation results in seizures which last for about 30 seconds. Repeated five to eight times, 3 times a week, this will as a rule make the patient healthy again without any side effects, except for minor memory disturbances which disappear within 3-4 weeks.

Encephalography - any of various methods for recording the structure of the brain or the activity of the brain cells.

Hypoglycemic - a state in which blood glucose level is below normal.

Leukotomy/Lobotomy - leukotomy is the surgical operation of interrupting the pathways of white nerve fibers within the brain. Lobotomy was the name given to a prefrontal leukotomy in which the nerve fibers connecting the frontal lobe with other parts of the brain were cut.

Limbic system - situated in the temporal lobe of the brain, is a center of vegetative functions, emotional experience, behavior and consolidation of memories.

Neuroleptics - which were introduced with chlorpromazine in 1952, are the most effective drugs in the treatment of psychotic symptoms (hallucinations, delusions, so-called "positive" symptoms) in schizophrenia. Many of them, but not all, also have sedative properties.

Obsessive-compulsive states - are conditions in which the patient sometimes may be very incapacitated by intensive thoughts he can not get rid of (obsessions), or ridiculous, meaningless things he feels compelled to do over and over again in order to hinder his anxiety level from increasing to an intolerable level (compulsions).

Prefrontal (lobe) - the area of the brain at the very front of each cerebral hemisphere. This area is concerned with emotion, memory, learning, and social behaviour.

Psychoses - are the most severe mental disorders, that is, schizophrenia, affective psychoses and also severe mental states often with confusional symptoms produced by toxic agents.

Schizophrenia - a psychotic condition, is the most severe psychiatric disorder. There are various subtypes, but symptoms like hallucinations, paranoid reactions and a reduced emotional capacity (and ability to relate to other people) and, sometimes, even isolation in an autistic state are characteristic. Until the introduction of neuroleptics in 1952, a majority of beds in our mental hospitals were used by schizophrenics, many of them from the age of 20-30 until death. Thanks to neuroleptics, most schizophrenic patients can take care of themselves outside hospitals, but very few become totally healthy. Most of them have residual symptoms which often make it difficult for them to work full-time, at least in qualified professions.

Stereotactic - a stereotactic surgical procedure is one in which a deep-seated area of the brain is operated upon after its position has been established with great accuracy by three-dimensional measurements.

Tomography - the scanning of a particular part of the body using X-rays or ultrasound. Computerized tomography (CT) scan is an X-ray procedure in which a computer draws a map from the measured densities of the brain. This method produces a three-dimensional representation of the brain.

Tranquillizers - are drugs with a sedative effect enabling an anxious patient to relax. Some of these drugs are neuroleptics, whereas others only have a relaxation effect of a rather short duration, for instance, benzodiazepines.


 


 

References

Hoffman, JL: Clinical observations concerning schizophrenic patients treated by prefrontal leukotomy. N. Engl. J. Med. 1949, 241:233-236.

Kalinowsky, LB and Scarff, JE: The selection of psychiatric cases for prefrontal lobotomy. Am. J. Psychiatry 1948, 105:81-85.

Menninger, WC: Facts and statistics of significance for psychiatry. Bull. Menninger Clin. 1948, 12:1-25.

Swayze II, VW: Frontal leukotomy and related psychosurgical procedures in the era before antipsychotics (1935-1954): A historical overview. Am. J. Psychiatry 1995, 152 (4):505-515.

Tooth GC, and Newton, MP: Leukotomy in England and Wales 1942-1954. London, Her Majesty's Stationary Office, 1961.

http://www.nobel.se/medicine/articles/moniz/index.html

Life and Discoveries of Santiago Ramón y Cajal

by Marina Bentivoglio

 

Biographical Sketch

Santiago Ramón y Cajal was born in May 1852 in the village of Petilla, in the region of Aragon in northeast Spain. His father was at that time the village surgeon (later on, in 1870, his father was appointed as Professor of Dissection at the University of Zaragoza). Cajal was a rebellious teenager, and his father apprenticed him for a while to a shoemaker and to a barber. Cajal, however, had decided to become an artist. His passion for drawing, his sensitivity to visual esthetics and his talent in converting visual images into drawings remained the hallmarks of his future scientific activity. Finally enrolled in the medical school at Zaragoza, as a young student, Cajal, seized by a "graphic mania," was very fond of philosophy and gymnastics, restless, energetic, shy and solitary. He graduated in medicine at the University of Zaragoza in 1873. Shortly after his degree he was drafted into the army and dispatched to Cuba, at that time under Spanish rule, as a medical officer. Cajal returned to Spain very sick (he had contracted malaria in Cuba, and then tuberculosis), and at the end of 1875 he started his academic career as "Auxiliary Professor" of Anatomy at the University of Zaragoza.

 Portrait of Cajal with his wife in their first years in Madrid.

In 1879 he married Silvería Fańanás García, a non-educated young woman, who stood at his side for the rest of their lives (she died in 1930). They had seven children (two of them died in their childhood).

 Self-portrait of Cajal with his children (from left to right: Fe, Jorge, Pula and Santiago) in Barcelona.

In Zaragoza, Cajal purchased in 1877 with his own funds ("using every peseta saved from the service in Cuba"), an old-fashioned microscope and started his scientific activity. His first studies were devoted to inflammation and to the structure of muscle fibers. In 1883, Cajal was appointed to the chair of Anatomy in Valencia. In 1885, during his tenure as Professor at the University of Valencia, the Provincial Government of Zaragoza, in recognition of his labor during a cholera epidemic, awarded him with a modern Zeiss microscope. At the end of 1887 Cajal moved to Barcelona, where he accepted the chair of Normal and Pathological Histology, and in 1892 he was appointed Professor of Histology and Pathological Anatomy at the University of Madrid. Cajal continued to work productively in Madrid until his death in 1934.

Self-portrait of Cajal in his laboratory in Valencia.

A Flash of Lightning

The key event for Cajal's scientific career and for the development of modern neuroscience took place in Madrid in 1887, when Cajal was 35 years old. In this year, Luis Simarro Lacabra, a brilliant psychiatrist interested in histological research, showed to Cajal, who had traveled from Valencia to get an update on technological advances, material impregnated with the Golgi staining. Dr. Simarro had just returned from Paris, and had brought specimens stained by the new technique of silver impregnation (the reazione nera), that had been discovered 14 years earlier by Camillo Golgi but still had a very limited diffusion. Cajal wrote in his autobiography "it was there, in the house of Dr. Simarro...that for the first time I had an opportunity to admire...those famous sections of the brain impregnated by the silver method of the Savant of Pavia."


Microscope slides with Cajal's histological preparations; the letter 'b' (bueno, good) indicates the quality of the sections.

At the time, Cajal had only been studying the nervous system for one year, mainly to collect suitable illustrations for a book of histological techniques, and he had realized how inadequate the ordinary methods were to study the nervous tissue. The observation of preparations impregnated by the Golgi stain was a flash of lightning: "a look was enough" and Cajal was enraptured. Nerve cells appeared "coloured brownish black even to their finest branchlets, standing out with unsurpassable clarity upon a transparent yellow background. All was sharp as a sketch with Chinese ink," Cajal wrote in his autobiography. In a feverish burst of activity ("...as new facts appeared in my preparations, ideas boiled up and jostled each other in my mind. A fever for publication devoured me"), Cajal worked on the retina, the cerebellum and the spinal cord, applying to the tissue the Golgi stain, of which he worked out some modifications.

Photomicrographs from Cajal's preparations (housed in the Museo Cajal at the Cajal Institute, Madrid, Spain) of the cerebral cortex of a newborn infant, showing neurons impregnated by the Golgi stain. The material was kindly provided by Dr. Javier DeFelipe; reproduced with the permission of Dr. Ricardo Martínez-Murillo, Director of the Cajal Institute, CSIC, Madrid. These two photos have also been published in DeFelipe and Jones "Cajal on the Cerebral Cortex." Oxford University Press, New York, 1988.

 

An Indefatigable and Creative Scholar

In October 1889, Cajal who had never traveled outside Spain except for his service in Cuba, went to Berlin, to the Congress of the German Anatomical Society, to show his slides to the leading authorities in the field, in order to convince them of the importance of his observations. On this occasion, he obtained the recognition of several qualified professors, including the eminent Swiss histologist Rudolf Albert von Kölliker (1817-1905), who from there on became a supporter of Cajal and of the "neuron doctrine," which would be officially enunciated by Wilhelm Waldeyer (1836-1921) in 1891.

Cajal was fiercely opposed to the idea that the nervous system was made up a network of continuous elements, as it had been stated by Joseph von Gerlach (1820-1896) and supported by Golgi himself. Camillo Golgi had believed to have found in his own preparations the demonstration that the nervous system was made of a widespread network of filaments in continuity one with the other (the rete nervosa diffusa, 'diffuse neural network'). On the contrary, since the first observations and in his subsequent studies, Cajal's imagination was fired by the idea that the nervous system is made up of billions of separate nerve cells. Cajal's work led to the conclusion that the basic units of the nervous system were represented by individual cellular elements (which Waldeyer christened as "neurons" in 1891). This conclusion is the modern basic principle of the organization of the nervous system.

Cajal’s opus "Textura del Sistema Nervioso del Hombre y los Vertebrados" (1894-1904), was made available to the international scientific community in its French translation, "Histologie du Systčme Nerveux de l’Homme et des Vertébrés", (translated by L. Azoulay, published in 1911 by Maloine, Paris; the English translation, by N. and L.W. Swanson, was published in 1994 by Oxford University Press). Cajal’s opus provided the foundation of modern neuroanatomy, with a detailed description of nerve cell organization in the central and peripheral nervous system of many different animal species, and was illustrated by Cajal’s renowned drawings, which for decades (and even nowadays) have been reproduced in neuroscience textbooks.

Cajal's drawing of the cerebellar cortex (from a preparation based on Golgi impregnation of a kitten cerebellum). The letter A marks the Purkinje cells with their characteristic dendritic ramifications.

Cajal's drawing of the cerebellar cortex (from a preparation of the cat cerebellum stained with methylene blue) showing the axons of Purkinje cells which exit from the cortex directed downwards.

Preparation through the optic tectum (from a sparrow) impregnated with the Golgi technique. Note the variety of neurons drawn by Cajal.

Superficial layers of the human frontal cortex drawn by Cajal on the basis of Golgi impregnation. The main cell types of the cerebral cortex i.e. small and large pyramidal neurons (A, B, C, D, E) and non pyramidal (F, K) cells (interneurons in the modern nomenclature) are superbly outlined.

In addition, Cajal defined "the law of dynamic polarization," stating that the nerve cells are polarized, receiving information on their cell bodies and dendrites, and conducting information to distant locations through axons, which turned out to be a basic principle of the functioning of neural connections. Cajal also made fundamental observations on the development of the nervous system and its reaction to injuries (his volume "Degeneration and Regeneration of the Nervous System" translated and edited by R. M. May, London, Oxford University Press, 1928, has been re-edited by J. DeFelipe and E.G. Jones, Oxford University Press, 1991).

Golgi and Cajal, who shared the Nobel Prize in 1906 for their studies on the nervous system, met only in Stockholm, to receive the award. Golgi gave his Nobel lecture first, in which he tied to his belief in "reticular" neural networks, which was entirely contradicted by Cajal's Nobel lecture. Cajal, a strenuous supporter of the contiguity (and not the continuity) of individual cells representing the basic units of the nervous system, fought for his ideas until his death.


Self-portrait of Cajal at the microscope in 1920

Golgi and Cajal certainly shared the same passion for science and dedication to science but their personalities were very different. Cajal, impetuous, burning with enthusiasm, dedicated his life to the study of the organization of the nervous system, on which he made fundamental discoveries with his peculiar talent and intuition. Golgi, a "cooler" academic, discovered the tool used by Cajal in his studies and provided outstanding contributions in many fields of cell biology and of pathology, and important contributions also on the structure of the nervous system (such, for example, the description of branches given off by the axon, of different types of neurons, of glial cells). However, Golgi misinterpreted the overall view of the structural organization of the nervous system, which instead has been worked out by Cajal.

Extremely productive, Cajal was also an accomplished photographer (his photographs of Spain, villages, friends, faces, are kept at the Cajal Museum in Madrid), and he wrote several books destined to a not strictly scientific wide audience, including his autobiography "Recollections of My Life" (Recuerdos de mi vida, translated by E.H. Craigie with the assistance of J. Cano, MIT Press, Cambridge, Mass., 1989), a small volume of aphorisms ("thoughts, anecdotes and confidences," as stated in the subtitle) entitled "Coffee Chatters" (Charlas de Café), "The world seen at 80 years" ("El mundo visto a los ochenta ańos," with the ironic subtitle of "Impresiones de un Arteriosclerótico").

 

Credits

Cajal's four drawings from "Histologie du Systčme Nerveux de l’Homme et des Vertébrés" were reproduced by the permission of Dr. Ricardo Martínez-Murillo, Director of the Cajal Institute, CSIC, Madrid. The portrait and self-portraits of Cajal were taken from the book "Santiago Ramón y Cajal o la Pasión de Espańa" by Agustín Albarracín, published by Editorial Labor, S.A. (1982)

http://www.nobel.se/medicine/articles/cajal/index.html

 






KNOWLEDGE FOR EVERYTHING