From Hyperkeratosis to Apoptosis: Lessons Learned from 65 Years of Research

Abstract

In 1950, shortly after completing my Ph.D. degree requirements and joining the faculty of the Animal Science Department at Cornell University, I heard about X-disease, or, more accurately, bovine hyperkeratosis, from Dr. Kenneth McEntee, a pathologist in the Veterinary College at Cornell. Affected animals developed thick skins, resembling armor plate. This was a consequence of their inability to convert carotene to vitamin A [1]; they lacrimated profusely so that their faces were constantly wet and they lost weight and eventually died. The disease, at first thought to be caused by a virus, was increasing rapidly in the United States and Europe, especially in Germany, prompting the U.S. Department of Agriculture to establish a special research program for the disease. Dr. McEntee and I, along with Dr. Peter Olafson, chairman of the Pathology Department, set out to find the cause of this disease. Luckily, we found some bread crumbs collected from beneath the slicer in a bakery in Burlington, VT, that had been fed to calves that later developed the disease. We extracted the active compound with ether and subjected the extract to column chromatography, testing each fraction for potency by monitoring plasma levels of vitamin A in test calves. Finally, we were able to crystallize the active compound(s) and identify them by spectrophotometry as highly chlorinated naphthalenes [2]. These compounds had been added to heat-resistant lubricants and fire-retardant paints and were also found in a wood preservative made in Germany. When these discoveries were published, and the napthalenes were removed, the disease rapidly disappeared, and few scientists today have ever heard of it. In retrospect, this early research achievement was a great morale booster, at a critical time in my career. My major research project—the measurement of steroids and gonadotropins in blood and tissues of cattle—was floundering. Plasma levels of steroids, particularly estrogens, proved to be lower than found in other species, and the methods we were using (differential extractions followed by column chromatography and measurement by spectrophotometry) were not adequate. The first comprehensive data correlating plasma luteinizing hormone (LH), estrogen, and progesterone levels during the bovine estrous cycle were not published until 1972 [3]. The Lesson Learned