Malnutrition: Classic experiments from the 1970s—and what happened next

John Waterlow at 93 (from Millward, see below)

I was reading the recently-published biographical memoir of John Waterlow CMG FRS (1916-2010) written by Joe Millward, when I realised I needed to look something up—the outcome of a conversation I had with John over lunch at his club, the Savile, a couple of years before he died.

He was one of the authors of a paper in an important series from the 1970s written by members of his department at the London School of Hygiene and Tropical Medicine. Most of his work had centred on the nature, treatment and consequences of infant malnutrition, notably in Jamaica from 1954 until 1970 when he returned to London.

During the 1990s I became interested in maternal effects, and especially those where some change in the mother affected not just her offspring but those of one or more subsequent generations, that is, intergenerational effects. The field, then largely ignored, is now the huge band-wagon of epigenetics (using the term epigenetics in its wide sense and not the narrow definition employed by some molecular geneticists who restrict its use—and thereby cause confusion—to the switching of genes on and off by methylation).

Some non-genomic effects are now known to be transmitted from the father as well as from the mother. Thus, parental effects can be defined as arising when the parent makes a contribution to the phenotype of its progeny over and above that which results from the genes it contributes to the zygote. Thus in subsequent generations, if the effect persists we have grand-parental effects and so on. The essence of such an effect is that it involves no difference in the genome—the basis of genetic inheritance.

Unfortunately, while Lamarckian in character, there are those who overstate the importance of epigenetics in terms of evolutionary mechanisms, arguing that the generally accepted neo-Darwinian orthodoxy should be changed. But intergenerational effects are usually restricted to a few generations and there is still on evidence that changes in phenotype during a lifetime can affect the DNA of the germ line. I regard parental effects simply as part of the genetically controlled and therefore subject-to-natural-selection suite of options available to a parent to maximise the chances of survival and reproductive success of its offspring.

There is now considerable evidence for important parental effects of considerable importance in such fields as human health and welfare, conservation biology, farm animal health and welfare and in plant sciences. But back to London and John Waterlow’s department in London.

To explore the effects seen in malnourished human populations, the group in London kept rats on a low-protein diet for 10-12 generations. There was a rapid change in size and shape of the animals which stabilised after two or three generations. Males were 40% lighter than well-fed controls; females 30%. There were changes in the weights of various organs except the eyes. Changes also occurred in the endocrine system, in the reaction of the rats to noise and in their ability to learn.

These findings were interesting and important in mimicking the effects in children born in malnourished communities but the effects of rehabilitation to a normal diet were even more so. Mothers previously malnourished were given a normal diet from about two-thirds the way through pregnancy or pups born to malnourished mothers were fostered from birth by well-fed mothers. Physical recovery was fairly rapid but still took 2-3 generations to be complete. However—and this was the point stressed to me by John Waterlow—complex behavioural deficiencies were still evident. In fact he said, as far as he could remember the behavioural effects were not followed up further because the animals had been passed on to somebody in the U.S.A. to explore the long-term effects further—but he could not remember who. Remember he was around 90 at the time of our chat.

It is what happened to that colony of rats that Joe Millward’s memoir prompted me to find out.

Janina Galler in 2016 (Wikipedia)
Photograph: MaynardClark

The work was continued by Janina Galler at Harvard. She described in a chapter of a book published in 2001 the background:

Approximately 30 years ago, I first began working with an important colony of rats that originated with R.J.C. Stewart at the London School of Tropical Hygiene. When Reg Stewart was forced to retire at age 65, I inherited the colony. The rats were then in their thirteenth generation of malnutrition, and I had the privilege of bringing the colony from England to the United States. This animal model was particularly relevant to human populations where malnutrition is usually not a one-time event, but rather a chronic, insidious process present throughout the life span and across generations.

I will not describe the test procedures for behavioural differences suffice it to say that with simple tasks there appeared no difference between well-fed and previously malnourished rats. Complex tasks were a different matter, with a clear deficiency in the previously malnourished animals. The differences in behaviour and ability to cope with the world were not confined to the pups. Mothers paid more attention to previously malnourished foster pups; they seemed to compensate for the inability of the young pups to find their way back to the nest (a standard test).

Janina Galler then compared the findings in rats with those in the long-term studies she was doing on the human population of Barbados in relation to the alleviation, treatment and long-term effects of malnutrition. Her study began in 1973 using data on every child born between 1967 and 1972 who had suffered malnutrition. At that time the incidence of malnutrition increased when the price of sugar decreased. While the physical effects were relatively quickly reversed, differences in behaviour (attention deficit and poor performance in the 11+ exam) were not and indeed persisted, just as in the rat, into, at least, the next generation.

Thanks to that work alongside and in collaboration with Sir Frank Ramsey (1926-2009) on the public health side, malnutrition has been eliminated from Barbados. But clearly the effects persist with the question being: for how long?

Those rats in the studies started in London by Reginald J.C. Stewart have certainly played an invaluable part in demonstrating the immediate and intergenerational—and sometimes cryptic effects—of malnutrition.

Galler, J. 2001. The early experience. In, The Origins of Creativity, edited by K.H. Pfenninger and V.R. Shubik, pp101-116. Oxford University Press.

Millward DJ. 2018. John Conrad Waterlow. 13 June 1916-19 October 2010. Biographical Memoirs of Fellows of the Royal Society 69, 429-448.

Stewart RJC, Sheppard H, Preece R, Waterlow JC. 1980. The effect of rehabilitation at Merent stages of development of rats marginally malnourished for ten to twelve generations. British Journal of Nutrition 43, 403-412.