Our last posting (1) reviewed key facts about mumps and rubella; the other two viruses targeted by the trivalent MMR vaccine. The current posting tells how, in 1941, Australian ophthalmologist, Norman McAlister Gregg (1892-1966), discovered a link between rubella infection of a woman during pregnancy and her baby suffering from severe birth defects. Gregg’s finding was astonishing at the time because rubella, which is characterized by a rash and swollen glands, was regarded as nothing more than a mild childhood illness; a mere nuisance.
Rubella is also known as German measles, since it was initially recognized in Germany (in 1814), and since it was at first thought to be a variant of measles. It was suspected of having a viral etiology as early as 1914, but rubella virus per se was not isolated until 1961. Norman Gregg’s story and his remarkable 1941 discovery are as follows.
Gregg received his medical degree in Australia in 1915. World War I was underway at the time, and Gregg immediately joined the British Expeditionary Force, which was then fighting in France. While Gregg was serving in France, as a captain in the Royal Army Medical Corps, he was wounded and was awarded the British Military Cross for gallantry in the field.
Gregg’s Military Cross citation read: “For conspicuous gallantry and devotion to duty during a raid. He untiringly attended to the wounded under heavy enemy fire until the last man was cleared, and showed great coolness and devotion to duty. He worked persistently throughout the raid in the open, and searched for any wounded that might have been overlooked. He behaved splendidly.” [See Aside 1]
[Aside 1: For more on the wartime experiences and heroism of several other important individuals in the history of virology see references 2, 3, and 4.]
Incidentally, Gregg was an outstanding athlete, who excelled at several sports. And, if it were not for the occurrence of World War I, he likely would have played on the Australian Davis Cup team. Note that Australian tennis players dominated international tennis tournaments until the 1960s.
When World War I ended, Gregg returned to Australia, where he served as a resident at the Royal Prince Alfred Hospital in Sydney. He then went to England in 1922 for further training in ophthalmology, and returned to Australia the following year to practice ophthalmic surgery. By 1941, Gregg established himself as senior ophthalmic surgeon at both the Royal Prince Alfred Hospital and the Royal Alexandra Hospital for Children. That very same year he published his landmark paper linking rubella infection during pregnancy to congenital birth defects.
The story of Gregg’s discovery began in 1940, during the Second World War. Australia was then in the midst of a severe rubella epidemic that began in 1939 under the crowded conditions in Australia’s wartime army camps. The illness was spread to the general population by infected soldiers, and it is very likely that some of these young soldiers transmitted the virus to their young wives; some of whom were likely pregnant. There had not been a rubella epidemic in Australia for many years prior to the 1939 outbreak.
In 1940, Gregg, in his role as an ophthalmologist in Sydney, noticed an unusually high incidence of infants born with cataracts. Gregg’s concern over the frequency of these infant cataract cases led him to write to other doctors in Australia to inquire into whether they might likewise have noticed an unusually high incidence of newborns with cataracts. After Gregg’s colleagues reported back, he knew of a total of 78 infant cataract cases, 44 of whom also had heart defects.
Several aspects of these of fetal cataract cases led the perceptive Gregg to suspect that they might be caused by an infectious agent, rather than by a solely developmental or genetic abnormality. First, from his perspective as an ophthalmologist, Gregg noted that the cataracts were atypical in that only the innermost layers of the lens, which form early in development, were affected. Second, many of the children also had heart defects and stunted development, suggesting to Gregg that a more systemic factor caused the syndrome . And, third, there was the uncommonly high frequency and widespread distribution of cases.
To determine whether these cases of congenital birth defects indeed might have a common thread, Gregg carried out a retrospective study (also called a case-control study), in which one tries to identify possibly relevant factors or conditions that existed before the outbreak of the disease. Gregg interviewed the mothers of the 78 affected infants. Remarkably, from these interrogations he learned that 68 of these mothers had contracted rubella early in their pregnancies. [Note that rubella can be so mild that some mothers, who did not report having been infected, may unknowingly have been infected.]
To inquire further into whether there might be a causal relationship between maternal rubella infection and congenital fetal deformities, Gregg next carried out a prospective study (also called a cohort study), in which one tracks a sample of the population that was exposed to the putative etiologic agent before the onset of disease. Thus, Gregg identified a cohort of pregnant women, who had experienced a rash-like illness during their current pregnancies, and then monitored those women to see if their babies displayed congenital defects. A comparison of this group of babies, with those born of mothers who had not experienced a rash-like illness, corroborated the relationship between congenital defects and maternal exposure to rubella virus.
Gregg was bold to assert that rubella during pregnancy could cause congenital malformations. First, the prevailing view at the time was that the placenta provides an impenetrable barrier to infections in utero. Second, the established belief among medical doctors was that all congenital abnormalities are inherited. Third, doctors found it difficult to accept that rubella, which was thought of as a mild disease of childhood, could be connected to severe birth defects. Fourth, there was not yet a laboratory test for rubella. Thus, Gregg’s proposition was based entirely on clinical assessments. For these reasons, Gregg’s work was initially met with skepticism by the medical community.
Nonetheless, Gregg’s findings aroused enough interest that the Australian National Health and Research Council sponsored a follow-up study by medical researcher, Charles Swan, which, when published in 1943, completely substantiated Gregg’s findings. Incidentally, it was Swan who added deafness to the symptoms of congenital rubella syndrome. Mental retardation was noted later by others.
Despite Swan’s corroborating findings, several more years would pass before Gregg’s determinations were widely accepted. [Curiously, the British medical journal The Lancet, which later published Andrew Wakefield’s discredited paper claiming a link between autism and the measles vaccine (5), stated in 1944 that Gregg had failed to prove his case.] The key that led to Gregg’s findings being finally accepted was the analysis by Oliver Lancaster, a statistician and epidemiologist at the University of Sydney, who concluded that Gregg’s data, which related severe birth defects to rubella infection during pregnancy, was statistically significant. Once accepted, Gregg’s pioneering study would greatly stimulate further research into birth defects and their causes. See Aside 2.
[Aside 2: The history of science contains many examples of correct hypotheses that were initially viewed as too radical to be accepted by the scientific community. Howard Temin’s provirus hypothesis is a particularly apt case in point (6).]
Gregg received numerous prestigious awards for his discovery from the governments and scientific societies of Australia, Canada, Great Britain, and New South Wales. But despite his many honors, Gregg is said to have remained an exceptionally humble, friendly, and caring man, who was “held in great respect and affection by all.” When he was notified that there was interest in nominating him for the 1958 Nobel Prize in physiology or medicine, he modestly stated: “I must confess that it comes as a great surprise and rather a shock that my name should even be considered . . . I feel it only fair to you to inform you that I have really no serious publications except those on Rubella as I have found very little time or inclination for writing during a very busy life.”
As noted above, rubella virus was isolated in 1961, and a live attenuated rubella vaccine was developed by 1969. The vaccine, usually given as a component of the trivalent MMR (measles, mumps, and rubella) vaccine, has vastly decreased the incidence of congenital rubella syndrome in regions where it has been used (1).
References:
(1) Andrew Wakefield and the MMR Vaccine Controversy: What about Mumps and Rubella?, Posted on the blog February 18, 2015.
(2) Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis, Posted on the blog October 30, 2014.
(3) Renato Dulbecco and the Beginnings of Quantitative Animal Virology, Posted on the blog November 19, 2014.
(4) Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob, Posted on the blog January 28, 2015.
(5) Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.
(6) Howard Temin: “In from the Cold”, Posted on the blog November 25, 2014.
Leonard Norkin Virology Site 