It is almost an intrinsic part of our concept of science that we never know enough. At all times one could almost say: We can explain it all, but understand only very little.
Erwin Chargaff, "Preface to a Grammar of Biology," 1971

Not Another Breakthrough?

A brilliant idea for an experiment is one that works out successfully; a silly idea is the one that doesn't work out. Both may sound equally nonsensical when first proposed, A Sunday morning experiment is one that the investigator is ashamed to try out except on Sunday morning when everybody else is absent from the laboratory and can't make fun of him. There is no scientific basis for making a decision.
Harold L. Stewart, "The Cancer Investigator," in Cancer Research, 1959

Whenever I see that a new discovery has been made in cancer, either in the scientific literature or in the popular press, I withhold my judgment about its validity until the discovery has been confirmed by other scientists, because much of the stuff that is published is probably wrong. That skepticism applies not only to works of the new investigator, but to the work of many of the established scientists.

Every time that I am tempted to readily accept something that someone else has published, I remember Spiroptera neoplastica. That was the name of the parasitic worm in rats that won Johannes Fibiger of Denmark the Nobel Prize in Medicine and Physiology in 1926. He won it for showing that stomach cancer in rats was caused by this roundworm. The work could not be repeated by the many scientists who tried. The Nobel Committee has been cautious ever since, and the next Nobel Prizes for cancer studies were awarded forty years later in 1966 to Charles B. Huggins and Francis Peyton Rous. Both of these men did their significant work at least thirty years before the awarding of the Prize. Rous showed that a transmissible virus can cause cancer in birds, fifty-five years before being awarded the Nobel. Huggins, in 1936. successfully treated cancer of the prostate gland with castration and sex hormones. I don't mean to snicker at Fibiger's work. He was an honest and brilliant scientist. Charles Oberling refers to his experiments as "among the most brilliant in all the domain of cancer research." Fibiger found one cage of rats with stomach cancer, and found worms inside the tumors, He painstakingly followed one clue after another, and was eventually able to reproduce the condition in rats using these worms. Unfortunately, the phenomenon that he reported was not a consistent one, and other people were subsequently unable to obtain the same kinds of results that Fibiger did. Apparently the conditions in his laboratory were just right; the animals were on the proper diet, and so on. The worms might well have been carrying a specific virus; an explanation proposed by A. Borrell at the time of Fibiger's discovery. Borrel's proposals were ignored. At the present time there is no evidence for a virus, nor any other explanation for Fibiger's observation. It is an excellent example of a scientist coming to the wrong conclusions from the correct data. This is not an infrequent occurrence in the scientific world, but it is rare for most of the scientific community to go along with it. The converse of this mistake, drawing the correct conclusions from the wrong data, also occurs. The classic example of this is the work of Charles Edouard Brown-Sequard, who practiced his art in the late nineteenth century. He is sometimes called the "Father of Endocrinology." He had a genius for drawing the correct conclusions from the wrong data. He concluded that the adrenal glands were necessary for life because dogs died when he removed them. They also died when he removed only one of the pair of adrenal glands; something that should not have occurred if his surgery had been better. An animal can live just as well with one adrenal gland as it can with two. He also fed water extracts of testicle to animals and to himself and concluded that they possessed masculinizing activity. He was, of course, quite right; the adrenals are necessary to life, and the testis has masculinizing activity; except that the hormones that produced this masculinizing effect don't dissolve in water; and what's more can not be absorbed through the intestine in any great degree. His extracts were, in fact, worthless.

A scientist's acceptance of new scientific discovery has to be tentative. He must always be prepared to change what he accepts and does not accept as new evidence is brought forth. I hope that the scientific part of this book will have some value beyond one or two years. I have, therefore, placed very little emphasis on the "brand new" breakthroughs, but have tried to restrict myself to things that I consider to be reasonably well established. The "breakthroughs" that made the headlines in the last year or so may be very important or may be entirely trivial. There is no way of knowing until they have been tested and confirmed under a wide variety of conditions. I have, therefore, avoided discussing many of the "discoveries" that make headlines. They will keep.

We read periodically that some scientist has found "the cause of cancer." If it were true, and there were a single cause of cancer, then prevention might be a simple matter. Unfortunately, there are many causes; and we understand very little about any of them. Let us consider the possibilities.

1. We know that most cells are capable of division, and that, as a consequence, tissues are capable of growth. It is therefore possible for the regulatory mechanisms of the animal to push the button that says "go." If a small pellet of stilbeterol (a synthetic female sex hormone) is placed under the skin of certain strains of guinea pig, the animal crops up with what appears to be cancer of the connective tissue (fibrosarcoma). If the pellet is removed, the tumors go away. Another case is that of the breast of the rat: When a pellet of female sex hormone is placed under the skin of some strains of rats, they develop what appears to be typical breast cancer. If the hormone is removed, the cancer goes away. There are some people who feel that these are not "true cancers." It would be impossible to tell the difference, in people, between tumors produced in this way and tumors that occur as a consequence of some change in the "genetic information" of the cell. We can sometimes tell the difference in experimental animals by transplanting the tumors. If the tumor grows in the new host, then the cancerous change has been in the cell itself, rather than in the whole animal. It may be that this phenomenon, of tumors produced by hormonal changes, that may be responsible for some of the so-called spontaneous or miraculous cures. There are well documented cases of patients having cancers of various sorts which disappeared without any treatment whatsoever.

2. Tumors can be produced by changing the information in the cell. This can be done by affecting the information already there by means of an agent which changes it (mutation), or it can be done by adding new information. These mutational changes might possibly be brought about by radiation, or selection of variants, or chemicals, while the addition of information would be the consequence of the entrance of a virus.

Much of the work in cancer research is devoted to trying to understand these "informational" phenomena: and it is a very fruitful avenue of research at this time because of the explosion of our knowledge in the field of chemical genetics and our increased understanding of the way that the gene works.

It has been discovered that the information that enables a gene to make a human being is contained in a very simple code. There are four basic substances (adenine, thymine, guanine, and cytosine), the combinations of which provide all of the information that the gene has to have. How this code works is now the principal occupation of many scientists in the world. Molecular biologists are beginning to understand how abnormal genes are constructed and how they affect the individual bearing them. It is all very new and very exciting. It is also very intricate and its discussion should be left to someone who knows something about it.

3. Another way in which tumors can be formed is by a slight disorder in whatever regulatory mechanism keeps tissues and organs at a constant size. As we discussed in an earlier chapter, there is an equilibrium established between birth and death of cells, and anything which disturbs that equilibrium in favor of an increased number of cells can result in a tumor. This is a very exciting area of investigation because, at the present time, virtually nothing is known about it. It has largely been the province of the experimental embryologist, and while much has been discovered, the great advances in this field are in the future.

4. It is generally a good policy when one breaks down a problem into various segments to leave one blank space and say that there may be other possibilities that we are not aware of. Category number four is this blank space.

So, whenever you read about someone finding "the cause of cancer," you can attribute it to the scientist's excess enthusiasm or the tendency of the news media to exaggerate or oversimplify.

There are molecular biologists who believe that unraveling the genetic code and being able to manipulate the gene is "the key" to life. Since the gene is the fundamental regulator of many of the things that happen, this statement is fundamentally true. But to believe that just because we understand gene action we will be able to understand life in general (including cancer) is not true. Understanding the fundamental processes is an excellent start in trying to understand everything that is happening; but it is only a start. It is only a start because we have to deal with problems of different kinds at different levels. Let me explain: A simple analogy using the automobile might help. We have to understand the structure of steel in order to produce the kind and quality of steel that is required to build an automobile engine. We have to understand things about traffic flow, automobile speeds, areas of congestion, people's driving habits, and so forth in order to built safe highways. These are all interrelated --yet knowing the structure of steel or the physics of the internal combustion engine is not likely to help us much in the design of a national highway system. There are levels of study and levels of understanding. In biology these levels are often related to the physical size of the object being studied. A surgeon who has to remove a diseased gall bladder finds the structure of DNA to be useless to him in this endeavor. What he needs is a detailed knowledge of the anatomy of the area of the gallbladder.

About twenty years ago, I heard the mathematical biophysicist Nicholas Rashevski illustrate this point. As I remember it, he stated, "We know that everything in the world is the result of the action and interaction of atoms and molecules. It is therefore possible to reconstruct the boot shape of the Italian peninsula in terms of the action and interaction of molecules. Anyone who tried to do it is crazy."

There are many "worlds" and each has to be handled in its own peculiar way. There is the world of atoms (the province of nuclear physics), molecules (chemistry), genes (molecular genetics), the interior of the cell (cell biology), the cell, populations of cells, tissues, organs, organ systems (histology and physiology), the whole individual (medicine), populations of individuals (communities, nations, the world), the solar system, etc. While there is a considerable amount of interaction between people in adjacent fields, most scientists have little more than a Reader's Digest (Scientific American, if you wish) understanding of fields remote from their own. There is nothing wrong with either the Reader's Digest or the Scientific American, but it falls far short of the depth of knowledge that an expert needs. A molecular biologist has no reliable way of evaluating the truth of what a cancer pathologists writes in Scientific American any more than the cancer pathologist has any real yardstick for evaluating the discoveries of the molecular biologist. There is a limit to how much understanding a human being can acquire in a lifetime. We go by instinct; instinct which tells us that someone's writing is fundamentally honest; but there aren't many of us who have not been misled. Just as Napoleon led an army to its destruction, there is no guarantee that the pronouncements of a Nobel laureate are true.

It is human nature for a scientist to believe that what he is doing is more important than what anybody else is doing. I suppose that it's all right to humor him, but we shouldn't take these chauvinistic pronouncements too seriously; nor should they be so frequently quoted in the press.

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