Genes and environment in brain development

January 20, 2014

K. VijayRaghavan

The overlap between the behaviours of ‘genes’ and the ‘environment’ challenges the age-old debate of the apparent dichotomy between ‘nature’ and ‘nurture’

The age distribution of India’s population shows a young country, our so-called ‘demographic-dividend’. Yet, poor maternal and foetal nutrition, poor sanitation, open defecation, infections and diseases — such as diabetes in mothers — severely affect the development of India’s children.

The health of our young people is of great importance and will ensure their future as productive adults and healthy seniors. The long-term consequences of early ill health can be severe. Recent studies point to the high prevalence of stunted growth of children in India aged 0-5 years. The frequencies are comparable to those in sub-Saharan Africa.

Research is also challenging the conventional belief that the brain is the organ least affected by early developmental problems stemming from nutritional deficits or diseases. Importantly, the cognitive consequences of early developmental disorders can range from the mild to the severe. Many who do not show obvious impairment could be affected. The frequency of severe cognitive disability may only indicate the more widespread range of less obvious impairments. Some of these can be manifested as more serious deficits or loss of cognitive abilities in later life.Strategy for diagnosis and cure

Disorders of early brain development, therefore, represent a growing and major public health issue for India. The solutions to this complex problem will come from diverse interventions, many of which are ongoing. An immediately effective prevention could come from addressing maternal and foetal health and nutrition. Early diagnosis and identification of the most effective strategy for management is another important component.

Recent advances in neuroscience provide valuable understanding and tools for early diagnosis and management of brain developmental disorders and likely avenues for developing effective treatment. These brain disorders are a disparate group of currently untreatable conditions that include both autism spectrum disorders and intellectual disability (previously known as mental retardation). The precise causes of these neuro-developmental disorders are complex, involving both genetic (nature) and environmental (nurture) factors.

Using laboratory organisms, such as worms, flies, fish and mice, scientists have made major breakthroughs in understanding the way the human brain develops. Transfer of knowledge from the laboratory to the human context was made possible by some major advances. First, studies in brain development were aided immensely by the human genome project and projects on the genomes of all the above laboratory organisms. These genome projects and related biological studies in the laboratory suggested that the ways in which the brains of different animals, including humans, developed have shared mechanisms.

The human brain, which is much more complex, uses the same rules for its construction as a mouse does for its brain. This is analogous to a modestly sized computer sharing the same principles for its construction as a network of many such computers, each slightly modified from the other, to create a massive parallel computer. Similarly, studying how the brain of a laboratory animal, such as a fruit fly, a worm or a mouse, develops has taught us about the very complex human brain. Advances in brain-imaging technologies and pathology have also contributed significantly.Model organisms

In the laboratory, scientists can manipulate one gene at a time in the developing brain, keeping other tissues normal. These sophisticated studies are done in tissue culture or through the use of ‘model organisms’. The studies have revealed information on the importance of correct timing and location of the expression of genes during development for a brain to form and function normally. When these genes are defective the animal has an abnormal brain and consequent abnormal function and behaviour.

These fundamental studies have contributed much to the understanding of human brain disorders and evolving of treatment mechanisms. Recent scientific breakthroughs that targeted rare genetic forms of brain disorders have identified pivotal developmental processes that are necessary for normal brain development. Studies of the human genome, and the research that logically followed, have led to the recognition that the key biological processes identified from genetic causes may be shared across many kinds of brain disorders, indicating that discoveries in one group of disorders will inform the other and vice versa.

Just as defective genes (nature) affect brain development in specific ways, environmental and lifestyle factors (nurture) can do so too. Studies in the laboratory and in human populations demonstrate that ‘nurture’ — through diet, lifestyle and the impact of infection — works itself into ‘nature’ by affecting gene expression. Genes that are disrupted in neuro-developmental genetic disorders in humans show a remarkable overlap with those that underlie abnormal development of the brain that are driven environmentally. There are ‘critical’ periods in foetal brain development when environmental insults or gene defects, acting in similar ways, can cause lasting damage. This striking overlap between the ways ‘genes’ and ‘environment’ act challenges the age-old debate on the apparent dichotomy between ‘nature’ and ‘nurture’.

Genetics not only points to the causes but also provides insights for potential treatments of these disorders. This is perhaps best illustrated by research being done on Fragile-X and Rett Syndromes, where interventions have been shown to be effective in laboratory models of these disorders. Indeed these interventions are effective, irrespective of the age at which they are initiated. Thus, in mice at least, the disease can be treated even in the mature animal. These studies have led to the first rationally based therapeutic interventions that are now in large-scale human clinical trials elsewhere in the world. In each case, we will know how effective these interventions are only after such trials are completed.

India must embark on its own research and therapeutics as the environmental and genetic factors here are different from those of Caucasian populations amongst whom most studies have been conducted. We have a strong foundation in basic neurobiology and human genetics and excellent clinical neurologists and clinicians. We are therefore well placed to address, understand and eventually treat disorders of brain development in the Indian context that are caused by a wide range of inherited as well as environmental factors.

The best international interactions and collaborations are vital so that lessons learned here and elsewhere can be shared and progress is faster. There is also an urgent need to train the next generation of clinician-researchers to better understand and treat these disorders. Much will be required by way of resources and these must be garnered. However, more challenging than resources is the courage to embark on such a course that weds basic and clinical research and to take it forward, step by relentless step.

The size of India’s problems in these, and indeed all other health challenges, is huge and seemingly intractable. Yet, this is matched only by our potential to search for and find solutions. India can lead in research on neuro-developmental disorders in human populations and by doing so provide hope to people here and the world over.

(The writer is Secretary, Department of Biotechnology, Government of India)

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