Letter to the Editor

Were They “Wild Guesses” or “Educated Guesses”?

To the Editor:

Dr. Benjamin has presented an interesting and amusing tale of research in the cornea and contact lens field (“ ‘Wild Guesses’ and Scientific Serendipity,” ICLC, 1992; 19:93-94), but I believe that he misses the point. As co- author of two of the four papers Dr. Benjamin describes, I believe I am entitled to the space needed for an alternative view.

My coauthor on the 1968 paper “The Steady State Dis- tribution of Oxygen and Carbon Dioxide in the In Vivo Cornea” (E@ Eye Res 1968;7:103) was Mrs. Marie Theresa Bieber, a graduate student in engineering. Together with several other graduate students and a colleague, she was working on a mathematical description of oxygen diffusion in blood and vascular tissues. We had a grant from what was then the National Heart and Lung Institute to support this work. After several years of study and a half-dozen papers, we had reached the limits of our ability to apply mathematics to the very complicated problem of oxygen diffusion in blood and from the blood vessels to vascular tissue. We decided to backtrack to the avascular tissues where we could practice our mathematical skills on the simpler problem of oxygen diffusion without the complica- tion of an imbedded network of blood vessels. I was already working with Richard Hill and I had a close personal rela- tionship with David Maurice, so it was natural to choose the cornea as the avascular tissue in which to study oxygen diffusion. To find the distribution of oxygen in the cornea of the closed eye, we needed the oxygen tension in the capillary bed of the palpebral conjunctiva. But oxygen ten- sion in a capillary bed was a topic in which we were already experts. We, just like all physiologists, knew that arterial blood entered the capillary bed at an oxygen tension of about 125 mmHg and venous blood left at a tension of 40 mmHg. A straight averaging to give 83 mmHg is not proper because of the nonlinear nature of hemoglobin’s oxygen saturation versus oxygen tension relationship, but, never-

theless, we knew oxygen tension in the capillary bed must be in the 60-80 mmHg range. The epithelial cells of the palpebral conjunctiva use some oxygen, so we knew that the oxygen tension at the interface between cornea1 epi- thelium and conjunctival epithelium must be a few mmHg below the 60-80 mmHg range. When in our single exper- iment we arrived at a measured tension of 55 + 5 mmHg, we were entirely satisfied. For our purposes, there was no need for a large mass of data. Our knowledge of physiology and a reasonable model of diffusion in the palpebral con- junctiva had led us to predict a tension of about 55 mmHg. When we found this value, we saw that our hypothesis, model, and observation all fitted together. We could then move on to other elements of our research on oxygen dif- fusion in the cornea.

The second paper offered by Dr. Benjamin as an example of the validity of a “wild guess” is the Mandell-Fatt report on overnight cornea1 swelling and thinning upon awaken- ing. This report, “Thinning of the Human Cornea on Awakening” (Nature 1965;208:5007), did not report a wild guess. Dr. Benjamin tells of our observation of 3.6% cor- neal swelling overnight, but he fails to mention the parallel observation, namely, that the cornea returned to normal thickness after about 45 minutes. This observation of deswelling dynamics was an important clue that we were not far from the truth in this single observation. The Man- dell-Fatt paper reported a thinning of 0.02 mm in 45 min- utes. From what little we knew in 1965 of water flow in cornea1 tissue, this was about what we would expect.

The cause for overnight swelling is still a subject for debate. Several changes in the cornea1 environment take place simultaneously when the lids are closed. Temperature goes up, but only about one-half degree Celsius. Oxygen tension goes down from 155 to 55 mmHg, while carbon dioxide tension rises from zero to about 40 mmHg, Most researchers, other than Holden’s group, believe that 55 mmHg oxygen tension is above the critical tension needed to maintain normal cornea1 thickness. Finally, the osmo-

188 ICLC, Vol. 19, July/August 1992 0 1992 Butterworth-Heinemann

Letter to the Editor

tions without blood vessels or how the contact lenses he was fitting interfered with cornea1 function.

I would like to close with a story of true scientific ser- endipity. In 1946, the Los Angeles optometrist Dr. Edward Goodlaw postulated that contact lens performance (only scleral lenses were fitted then) could be improved if the contact lens transmitted oxygen and carbon dioxide. He apparently understood that the cornea needed oxygen from the air and must unload its produced carbon dioxide to the air. Why was Goodlaw’s postulate ignored for 20 years? Probably because it appeared in an obscure optometric weekly magazine, not read or referred to by the breed of researchers who entered the contact lens field in the 1960s and 197Os, and also because Goodlaw was not on the con- ference circuit, equipped with videotapes and two carrou- sels full of slides. There is a parallel with Gregor Mendel’s report on his discovery of the laws of inheritance. His re- port laid buried and unread for 20 years because it appeared in an obscure journal. The serendipitous discovery is often ignored because the discoverer does not push it forward in the scientific community. Even if colleagues take note, the discovery may not be accepted because by its very nature a serendipitous discovery presents a radical or unconven- tional idea.

The cornea and contact lens field must welcome seren- dipitous discoveries but it cannot sit back and wait for them to arrive. The mass of scientific knowledge that we already have must be used to construct models and hypotheses that can be tested in the laboratory and clinic. To make a sci- entific career a satisfying experience, there must be a rea- sonable rate of progress. Serendipity is too slow.

larity of the tears is reduced from 1% (equivalent sodium chloride percent) to 0.9%. Even in 1965, we knew enough about the influence of these factors to expect only a modest increase in cornea1 thickness upon closing the lids. The observed 4% increase in thickness during sleep did not violate any of the physical principles we believed applicable to cornea1 physiology.

I believe that the most serious weakness of cornea and contact lens research today is that the investigator goes into the laboratory or clinic without a hypothesis or a model. The philosophy is too often-let’s try the experiment and see what happens. Under these conditions, thousands of data points and complicated statistical analysis are neces sary but the underlying physiological process is rarely uncovered. One wonders how many wood and lead balls Galileo took up the Tower of Pisa to study his hypothesis on the working of gravity. He may have been familiar with the concept of an average, but I doubt that variances and standard deviations appeared in his notebook. Cer- tainly, he was spared the pitfalls and snares of ANOVA analysis.

Failure to interpret correctly an obvious physiological process was the downfall of the European ophthalmologist Dr. Josef Dallos. Just before he died in 1979, Dr. Dallas, considered by some to be a leader in the development of the contact lens, presented a paper to the BCLA entitled “The Myth of Gas Permeability.” Dr. Dallos in 1979 did not believe the cornea needed an oxygen supply at its anterior surface. As support for his belief, he offered the observation that the cornea maintained its health during sleep when it was covered by the lids. I do not know if he ever everted a lid. If he did, he failed to recognize the purpose of the easily visible capillary bed in the palpebral conjunctiva. Without a model of the cornea as a multilayer tissue containing metabolizing cells but no vasculature, Dr. Dallos could not develop in his own mind a picture of how the cornea func-

Irving Fatt, PhD School of Optometry

University of California Berkeley, California

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