Senior Physiologists' News
Letters to G. Edgar Folk, Jr.

Albert Hyman writes: “How kind of you to remember me and my 80th birthday! It was exciting to hear from you!
   “I’m officially retired! Albeit, I still see cardiac consultations at the hospital four mornings a week and work on research projects related to the pulmonary circulation every afternoon with my ‘younger’ colleague, Phil Kadawitz. We’re still turning out good MD-PhDs and PhDs in pharmacology—a work that keeps quite ‘an courrant’ and excited. The email of NIH grant applications is always upon us.
   “The cardiology section at Tulane where my primary appointment remains, erected a surprise wall poster for my birthday and it displayed much of the cardiac catheterization work I’d done since 1947(!). When I saw it, quite by accident, as I collected my mail and the announcements, I was truly overwhelmed. Then just before the usual Friday noon pharmacology seminars, the Chairman, Krishna Agawald, and Phil, surprised me with a birthday party and dedicated the seminar to me.
   “Incidentally, several years ago, Gabby Navar honored me with giving the annual Hyman Mayerson Memorial Lecture. I talked about some of the work on stem cell transfer to the lung for pulmonary hypertensive states.”

Leonard B. Kirschner writes: “Thanks for the letter with birthday greetings. Your ‘Welcome to the ranks of more senior citizens’ is late, but it’s okay, because I received the welcome 10 years ago on my 70th. It might even have come from you.
   “I’m well. The core (cardiovascular, respiratory, renal, etc.) functions as well as it did 40 or more years ago. Of course, all the peripherals either need a boost (i.e., vision, hearing, etc.) or have quite functioning altogether. But at 80, I can’t complain, and in fact, am enjoying life. The only ‘downer’ is that I lost all three of my professional icons the past year or so; Ladd Prosser, who started me out; Hans Using, my postdoc mentor and Herb Eastlick, the chairman who hired me 50 years ago. All lived into their 90s, and Prosser and Ussing were sentient to the end, so I guess complaints are not in order on that score, either.
   “What am I doing? About what I’ve been doing for nearly 60 years. I was able to retain a lab and office, and so I still do research, although with no students or technicians, it goes pretty slowly. I gave up the grant business more than a decade ago. I had 34 years of generous support from NIH and NSF and hated every minute of it. I now support the lab out of pocket, and if this doesn’t make me one of the dean’s favorites, it’s more relaxing and just as satisfying. I still work on epithelial ion transport in aquatic animals and was able to publish a paper in 2002 and one in 2003. A review has just been accepted by the Journal of Experimental Biology.
   “Thanks to you and the APS for remembering me, even though it might be kinder not to remind one that he’s 80 (sounds as old as dirt!)”

Letter to Michael Barany

Akira Arimura writes, “When I graduated from the medical school in Nagoya, Japan, in 1951, I did not intend to become a physiologist. I wanted to be a clinician in Internal Medicine, hopefully a research oriented physician. Due to my poor health during my young age, I chose to specialize in Neurology which I could learn with less rigorous training than other subspecialties. Fortunately, the director of the Neurology Section was a very competent and farsighted mentor, and he advised me to study to establish a method for diagnosis of hypothalamic dysfunctions. Accordingly, I handled many patients with various neuroendocrine disorders, including diabetes insipidus. This seemed to have decided the direction of my life. I was immediately caught with fascination of the intricate regulatory mechanisms of the hypothalamic control of the human body through the endocrine and the neural systems. A couple years before, du Vigneaud first isolated and identified oxytocin and then vasopressin, and the concept of neurosecretion had been firmly established. Before that period of time, the hypothalamic function in patients was judged only by the physical manifestation seen in various types of disorders caused by tumor or injury or other lesions in the hypothalamic region. The discovery of oxytocin and vasopressin opened a new page in modern neuroendocrinology. Humoral control of the anterior pituitary function by the hypothalamus through the hypophysial portal vessels was advocated by Jeffrey Harris, and several laboratories started to prove the existence of such chemical substances in the hypothalamus which regulate the secretion of the anterior pituitary hormones. With the permission of my mentor in the Department of Medicine, I started my graduate study in Physiology under Professor Yas Kuno, who established the systemic foundation of physiology of human perspiration, and under Dr. Shini Itoh, who was studying the effect of vasopressin in perspiration. I joined Itoh’s laboratory to study the antidiuretic mechanism of vasopressin which was related to the treatment of my patients with diabetes insipidus. Then I learned that vasopressin also stimulates the anterior pituitary glands by altering ACTH secretion.
   “My University in Nagoya, Japan, was completely destroyed by bombardments during World War II and we had to conduct research in temporarily built barracks. For the bioassay for ACTH, we had to hypophysectomize rats by ourselves. In the 1930’s, Dr. Koyama established a simple method for hypophysectomy through the external auditory canal using a syringe with an 18-gauge needle. Since I heard that this method had been improved by Dr. Tanaka at the Shionogi Pharmaceutical Co’s laboratory and routinely used for assaying ACTH there, I went to the company in Osaka to learn the technique. I was fascinated by seeing that a team of young female technicians removed the hypophysis so easily and quickly through the ear, about one per minute. Although I could not do it as skillfully as these young female technicians, I did barely master this technique for hypophysectomy.
   “In 1956, I completed my PhD study in Physiology. Through the advice of my mentor Itoh, who was then in the United States, I applied for postdoctoral positions at Harvard and Yale. I also wrote a letter explaining my work on the effect of vasopressin on ACTH secretion to the potential mentors, Dr. George Thorn, a famous endocrinologist at Harvard, and Dr. C. N. H. Long, a leading endocrine physiologist at Yale. Fortunately, I was offered a marvelous scholarship from Yale. In addition, with the generous aid of a travel grant from the Fulbright Commission, I could join the Department of Physiology at Yale as a postdoctoral fellow. The life of the United States in the 1950’s was indeed like heaven compared to the still devastated Japan. My first article with Itoh submitted to Nature from Japan was accepted, but we, as well as our University in Nagoya, could not afford to subscribe to the journal or even order the reprints. I saw my published article in Nature for the first time at the library at Yale. The atmosphere of the Department of Physiology at Yale at that time looked rather like a British University. Many faculty members and fellows, including my predecessor, as well as the animal care taker, were British. Professor Fulton still taught Medical History. Many scientists visited Yale to meet with Dr. Long and he showed them around the laboratories. One day, he brought Dr. Jeffrey Harris from Oxford University to my laboratory and asked me to show him the technique for hypophysectomy through the external auditory canal. Although I did not have much confidence in my technique, I barely managed to show the technique to Harris. He wanted to try the hypophysectomy by himself. I gave him the instrument. To my surprise, he removed the pituitary gland successfully in the first trial. It was marvelous. He commented his view on this technique very precisely, including its advantages and disadvantages. The second scientist whom Long brought to my laboratory was a young physiologist, Dr. Roger Guillemin. After I showed him the technique, he also wanted to try the method by himself. He tried, tried and tried, but never succeeded with it. He finally gave up. The third visitor was a famous Swedish endocrinologist at Karolinska Institute, Dr. Rolf Luft. After I demonstrated the technique, he quietly asked me if the technique could be applied to humans. I said, ‘no.’ He nodded, and said, ‘thank you.’ And he left.
   “After completing my postdoctoral study at Yale for two years, I joined Tulane University to be trained at the Endocrine Section of Department of Medicine, under a new mentor, Dr. Joseph Dingman, introduced by Dr. George Thorn. He was a former associate of Thorn and studied the regulation of vasopressin secretion in patients. After training under Dingman for three years, I returned to Japan to work in the Physiology Department of Hokkaido University with Itoh, who was then the Chairman of the Department. I returned to Tulane again in 1965, to work with Dr. Andrew V. Schally to isolate and identify the hypothalamic hormones as the chief physiologist. The primary target of our work was to isolate and identify gonadotropin releasing hormone (GnRH or LHRH). There was a hectic race between laboratories for the isolation of LHRH and other hypothalamic hormones. The discovery of TRH was first reported by Schally’s group in 1969 just one week before the report by Guillemin’s group appeared. In 1971, we won the race of LHRH. Then somatostatin was found by Guillemin’s group. Then GHRH was isolated from the ectopic tumors by Vale and Guillemin’s groups. CRH was then discovered by Vale’s group. In 1977, Schally shared the Novel Prize with Guillemin for the isolation and identification of the hypothalamic hormones. The humoral regulation of the pituitary gland by the chemical substances elaborated by the hypothalamus, the theory first proposed by Jeffrey Harris, was now firmly established. The chairman of the Nobel committee at that time was Dr. Rolf Luft. It was quite intriguing that I showed the transauditory hypophysectomy technique to Drs. Harris, Guillemin and Luft, at Yale, and helped Schally with the isolation of LHRH. This may be called EN in Japanese.
   “As a physiologist, I could not be satisfied with the notion that the regulation of the anterior pituitary function could be wholly explained by these ‘classical’ releasing and inhibiting hormones. Based on the fact that all classical releasing hormones activate adenylate cyclase in the pituitary cells, regardless of whether the signaling cascade is directly coupled to the secretion of the corresponding hormone, I proposed to screen for novel hypothalamic hormones based on their ability to stimulate adenylate cyclase in the pituitary cell cultures. I applied for a NIH grant and the application was turned down. They said that such a non-specific method would not reveal any novel peptide with a specific activity. I wondered if the Study Section knew that I worked with Schally as his chief physiologist for establishing the screening methods for various releasing hormones and screened various releasing activities for many years along with his purification work. Fortunately, due to the generous support from a Japanese pharmaceutical company, we could initiate the study and isolate the novel hypothalamic peptides based on their ability to stimulate adenylate cyclase. We named the first novel peptide Pituitary Adenylate Cyclase Activating Polypeptide (PACAP). It is a pleiotropic peptide. The peptide began to attract the interest of many investigators; now publications on this topic have exceeded 1,700. It was found to be an extremely potent neuroprotectant as tested in vitro and in vivo . We have just found an entirely novel function and the mode of action of this peptide in the testicular germ cells, and are about to ask all scientists who have an interest in this neuropeptide for the validity of the new concept about the neuropeptide physiology in germ cells. When we open a door, we always see fascinating scenes and also another door behind which more fascinations may wait for the curious scientists. Research is indeed a lot of fun.”
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