PES Trivia, at Your Fingertips
These tidbits were originally published in our 2017 President’s newsletters.
December 2017 – submitted by Walter Miller
DNA Sequencing
The development of rapid, accurate DNA sequencing did for genetics what invention of the microscope did for cell biology. Maxam & Gilbert (PNAS 74:560-564,1977) and Sanger (PNAS 74:5463-5467,1977) devised the first viable DNA sequencing tactics. Insulin (Science 196:1313-1319,1977) and GH (Nature 270:486-494,1977) were among the first genes sequenced, and advances in the Sanger technology led to sequencing the human genome (Nature 409:860-921,2001; Nature 431:931-945,2004). Next-generation, massively parallel sequencing has delivered genome sequences of hundreds of living and extinct species, making sequencing a routine tool in biology, anthropology and medicine. Third generation, hand-held technologies will soon permit genome sequencing in the field or at the bedside. This 40-year history of DNA sequencing is celebrated in a 19 October review (Nature 550:345-353,2017).
November 2017 – submitted by Alan Rogol
Growth and the pituitary
The pituitary’s role in growth was established in 1886 by the association of acromegaly with pituitary tumor [P Marie, Rev Med (Paris) 6:297]. S Crowe, et al. associated the cessation of growth with hypophysectomy in puppies [Bull Johns Hopkins Hosp 21:127, 1910]. Evans and Long [Anat Red 21:62, 1921] and noted increased growth in rats following injection of an extract of anterior lobes. PE Smith showed that normal growth required the anterior pituitary [Am J Anat 45:205, 1930 (renamed Developmental Dynamics in 1992)]. Daily anterior pituitary homeotransplants restored normal growth in hypophysectomized rats; but intraperitoneal injections of aqueous pituitary extracts had no effect on the atrophied reproductive organs. Growth hormone is water-soluble, but gonadotropins are not.
October 2017 – submitted by Alan Rogol
The Ascheim-Zondek (A-Z) test for pregnancy
In 1927 Selmer Ascheim and Bernhard Zondek established the first bioassay to detect early human pregnancy by injecting a woman’s urine into an immature female mouse. The test was positive (pregnancy) if the mouse went into “heat”. Later modifications used rabbits and then frogs, but all relied on the biological activity of hCG, whose identity was not established until the 1960’s, even though its specific biological activity was known in the 1930’s. The first few thousand tests were deemed more than 98 % accurate with just a few false positives or negatives, a remarkable success rate! These bioassays have been supplanted by immunoassays, which quantitate hCG and can detect pregnancy at about 3 days post-implantation.
September 2017 – submitted by Walter Miller
Non-Classic Congenital Adrenal Hyperplasia (NCCAH) – A Common Disorder with Many Parents
Classical congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency has a worldwide incidence of 1 in 15-20,000, but NCCAH, the mild attenuated form, is seen in up to 1 in 1000 in some populations (Am J Hum Genet 37:650, 1985). NCCAH was first described by Decourt et al. (Ann Endocrinol 18:416, 1957), but that paper was published in French, and was not widely read. Describing NCCAH is typically credited to Maria New (13th PES President, 1985-86) (JCEM 48:356, 1979) and to Zev Rosenwaks & Claude Migeon (first PES President 1972-73) (JCEM 49:335, 1979), but Rosenwaks and Migeon cited nine previous reports from 1958-77! About half of mutant CYP21A2 alleles in NCCAH carry V281L (NEJM 319:19, 1988; Clin Endocrinol 82:543, 2015).
August 2017 – submitted by Alan Rogol
The Ascheim-Zondek (A-Z) test for pregnancy
In 1927 Selmer Ascheim and Bernhard Zondek established the first bioassay to detect early human pregnancy by injecting a woman’s urine into an immature female mouse. The test was positive (pregnancy) if the mouse went into “heat”. Later modifications used rabbits and then frogs, but all relied on the biological activity of hCG, whose identity was not established until the 1960’s, even though its specific biological activity was known in the 1930’s. The first few thousand tests were deemed more than 98 % accurate with just a few false positives or negatives, a remarkable success rate! These bioassays have been supplanted by immunoassays, which quantitate hCG and can detect pregnancy at about 3 days post-implantation.
July 2017 – submitted by Walter Miller
Growth hormone (GH): the first triumph of recombinant DNA technology
Bovine GH was isolated in 1944 (Li & Evans, Science 99:183), and incomplete amino acid sequences were obtained for bovine, rat and human GH by 1975, but it was slow work, and results were not always accurate. Recombinant DNA technology changed everything. Rat (Seeburg et al., Nature 270:486, 1977), human (Martial et al., Science 205:602, 1979) and bovine (Miller et al, JBC 255:7521,1980) GH were cloned; recombinant human and bovine GH were produced industrially. The discovery that clinically-used human cadaveric GH carried a substantial risk of Creutzfeld-Jacob disease (Koch et al., NEJM 313:731, 1985) overrode hysterical, non-scientific claims of the risks of biosynthetic proteins. Recombinant human GH was approved in 1985 and bovine GH (which promotes milk production) in 1995.
June 2017 – submitted by Walter Miller
Sulfation factor, Somatomedin-c, NSILA, and IGF-I
Administering GH to hypophysectomized rats restored growth and incorporation of 35S into chondroitin sulfate (“sulfation factor’ activity), but adding GH to cultured cartilage in vitro did not. Serum from normal animals stimulated 35S incorporation, serum from hypophysectomized animals did not, but serum from hypophysectomized animals treated with GH did, suggesting the ‘somatomedin’ hypothesis (Salmon & Daughaday, J Lab Clin Med 49:825, 1957). A non-suppressible insulin-like activity (NSILA) remained in plasma treated with anti-insulin antibodies (Froesch et al., JCI 42:1816, 1963). Rinderknecht & Humbel isolated a 7.5 kDa NSILA/insulin-like growth factor (IGF-I) with sequence similarity to pro-insulin (JBC 253:2769, 1978). Judson VanWyk (5th president of the LWPES, 1976-77) showed that IGF-I and somatomedin-c had identical amino acid sequences (Endocrinology 112:2215, 1983).
May 2017 – submitted by Arlan Rosenbloom
Abnormal hemoglobin in the red cells of diabetics was initially described in 1968 (S Rahbar, Clin Chem Acta 22:296-298), but it remained uncertain whether this was a marker for diabetes or a secondary phenomenon (LA Trivelli et al., NEJM 284:353-357, 1971; EP Paulsen, Metabolism 22; 269-271:1973). Measurements of HbA1c and the development of self-monitoring of blood glucose (Clements et al. Diabetes Care 4; 392-395, 1981) provided the means for monitoring intensified therapy, resulting in the landmark diabetes control and complications trial (DCCT) (NEJM 329:977-986, 1993; RD Lasker NEJM 329:1035-1036, 1993). The DCCT Research Group included about 700 investigators at 35 centers, including many prominent members of the Lawson Wilkins Pediatric Endocrine Society.
April 2017 – submitted by Alan Rogol and Walter Miller
Robert Blizzard and the National Pituitary Agency (NPA)
Bovine growth hormone (GH) was isolated in 1944 (Science 99:183), but growth-promoting effects were species-specific (Endocrinology 60:166, 1957), and only human GH could stimulate growth in GH-deficient children (Science 125:884, 1957; JCEM 18:901, 1958). To stimulate clinical and basic research, and pre-empt premature commercialization, a centralized mechanism was needed to collect pituitaries and extract the hGH. In 1960, Robert Blizzard (third President of the PES, 1974-75), the NIH, The College of American Pathologists, and others organized the NPA. From 1963 to 1985, when it became apparent that cadaveric hGH was a potential cause of Creutzfeld-Jacob disease, virtually all hGH in the USA was provided by the NPA. The history of hGH was reviewed by Frazier (J Pediatr 131:S1, 1997).
March 2017 – submitted by Walter Miller
Contemporary pediatric endocrinologists will quickly suspect adrenocortical carcinoma (ACC) in a 3-6 year old girl with severe Cushingoid features, growth arrest and virilism. The first known published case of apparent ACC was that describing Hannah Taylor (1682-1688), a 6-year old whose autopsy was reported by Henry Sampson (Philosophical Transactions 19:80-82, 1697); this fascinating paper was reproduced and its historical context discussed recently (J Steroid Biochem Mol Biol 165:109-113, 2017). Fuller Albright’s mid-20th century perspective on ACC is seen in NEJM 241:874-877, 1949. Most pediatric ACC is caused by mutations in the p53 tumor-suppressor gene, usually in association with Li-Fraumeni syndrome (Endocr Rev 35: 282–326, 2014). Early diagnosis can permit surgical cure, but prognosis in metastatic disease remains poor.
February 2017 – submitted by Alan Rogol
Sir Charles Robert Harington was a classical organic chemist, who with George Barger completed the chemical structure of thyroxine (Biochem J 20:109, 1927). They devised an organic synthesis from tyrosine and proved its structure by comparing the composition of degradation fragments (some synthesized) with the compositions of the expected products. The mixed melting point of combined entities was the same as either individually for a number of these degradation products. They ended with: “Insofar, then, as the matter is susceptible of decision by chemical methods the identity of the synthetic product with natural thyroxine may be regarded as established”. Additionally, it raised the basal metabolic rate from about -40 % to around 0% (normal) in two profoundly myxedematous women.
January 2017 – submitted by Walter Miller
Hans Selye, who first described the hormonal stress response (Nature 138:32, 1936) and coined the terms ‘glucocorticoid’ and ‘mineralocorticoid’, observed that progesterone was a potent anesthetic agent that permitted abdominal surgery on rats (Proc Soc Exp Med Biol 46:116, 1941; Endocrinology 30:437, 1942). Research into the clinical use of steroidal anesthesia ended with the development of halothane (1956). Progesterone membrane receptors (Front Neurosci 7, Article 159, 2013) may mediate the anesthetic actions of progesterone. Allopregnanolone (3,5-tetrahydroprogesterone) is an endogenously produced neurosteroid progesterone metabolite with potent anesthetic, anxiolytic and anticonvulsant actions that acts via GABAa (and possibly other) receptors (similarly to barbituates and benzodiazepines). Allopregnanolone may play a role in stress disorders and has potential therapeutic uses, but is under-investigated.