MRC National Institute for Medical Research, London
Science for Health
2012 meeting - Fetal afflictions and the most important days of our lives
The idea that the womb is a tranquil nursery untroubled by worldly pressures is charming but wrong: the fetus reacts to its unique environment, with profound consequences for later life. Our speakers bring to this topic insights that originate in work that might seem remote from human biology. Alex Gould describes the discovery of a key system for protecting the developing brain from malnutrition that originated in genetic studies of fruit flies. Malcolm Logan discusses the thalidomide tragedy in the context of his lab’s work on development of mammalian limbs.
You are what your mother ate - Dr Alex Gould
The developing human brain consumes almost half the energy intake of a fetus and newborn and is potentially very vulnerable to malnutrition in the mothers diet. However, physiological systems exist to protect the energy supply and to maintain the developing brain’s neural networks during pregnancy. This is achieved at the expense of the viscera (liver, pancreas and other organs), so that human babies affected by maternal malnutrition are often undersized with relatively large heads. Such individuals reach adulthood successfully but they may be predisposed to premature age–related diseases such as type-two diabetes or cardiovascular disease.
Alex Gould’s lab studies the mechanism that drives this brain-sparing process in the fruit fly. Growth ceases when larvae of these flies are deprived of nutrients, but the stem cells that make the brain continue to function. The key gene that facilitates this brain-sparing activity is a close relative of a human gene that is well known for its involvement in various cancers (Anaplastic Lymphoma Kinase, or Alk). Alex Gould’s work shows that Alk has a key function in promoting the growth of the nervous system under adverse nutritional conditions. It also demonstrates the importance of fruit flies in biomedical research. With a generation time of ten days, these tiny insects provide extraordinary opportunities for discovering the function of previously unknown genes; indeed more than two thirds of human disease genes have a counterpart in fruit flies.
Limb formation and perils from inadequately tested drugs - Dr Malcolm Logan
One of the many miracles of mammalian development is that limbs form in exactly the right place and at the right time, very early in the life of the embryo. Forelimbs and hindlimbs look identical when they first appear as tiny limb-buds but they quickly take their definitive shape. Malcolm Logan’s lab studies the mechanisms that drive this process in several types of vertebrate embryo. The strategy has been to identify the molecules involved and to find ways of interfering with their function. From this has emerged an understanding of the processes that determine whether a limb bud will become a fore- or a hind-limb.
It has been possible to construct a hierarchy of genetically-controlled steps that explain this process and which tell us how the tissue elements involved (bones, muscles etc) establish their complicated anatomical arrangements. This has provided important insight into a genetic disease (Holt-Oram syndrome) that affects limb formation, and also into the effects of thalidomide, a drug that was used as a therapy for morning sickness fifty years ago. Now that we know the master-genes that initiate limb development we can ask where in “The Tree of Life” these genes first appeared. It seems a homologue of one these genes exists in Amphioxus, a limbless creature that is a link between invertebrates and vertebrates but which lacks the regulatory sequences to make a limb.
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