Basic research in paediatrics: Does it exist?

The present article will attempt to answer the question of whether there is such a thing as ‘basic paediatric research’. While largely based on my experience at The Hospital for Sick Children, I believe that the points raised can be generalized to the Canadian and international academic community.

To me, basic research includes any investigation into fundamental scientific questions. In this respect, basic research is not limited to laboratory work. Attempts to develop methodologies for clinical trials with small subject numbers, for example, is one type of nonlaboratory basic research. However, because the use of the term ‘basic research’ is usually equated with laboratory-based research, I will use this latter definition.

Given the nature of basic (fundamental) research, is there research of this type that one could consider ‘paediatric’? One could, for example, take the position that ‘paediatric’ research is by definition applied, because it is already focused on a specific set of questions, ie, those that impact children. While strictly speaking, this is the case, for the purposes of the present article, I take the position that basic research on children does exist. In particular, I suggest that there are areas of investigation where children are the inherent subject matter; that without having children to study, the research would not get done. From this perspective, there are three areas of basic (fundamental) ‘paediatric’ research where children must be the subject matter: genetics, developmental biology and integrative biology.

Canadian science has been justly noted for its impact in the area of human genetics, reflecting the long-standing interest and activity in this field on the part of Canadian institutions. Paediatric hospitals have been leaders because as infections and nutrition have ceased to be the cause of infant mortality, genetic determinants have become a significant factor in admissions to paediatric hospitals. Thus, it has been relatively easy for these tertiary care institutions to gather information on significant numbers of patients with defined genetic aetiologies. These patient populations have been key to further research. Because many of these etiologies are due to defects in single genes, the development of molecular genetic methodologies has allowed the identification (cloning) of these defective genes through analyses of patient and family samples. While many such discoveries have been made in Canada, perhaps the most notable one was the identification of the cystic fibrosis conductance regulator gene as the gene defective in cystic fibrosis (1). Without having children properly classified as having cystic fibrosis, the discovery could not have been made. Recent examples of this type of discovery are the identification of the genes defective in Lafora disease (2) and Schwachman-Diamond syndrome (3).

The study of biological development, as it applies to humans, is another important area of ‘paediatric’ basic research. Again, the development of molecular genetics has allowed us to better understand the interactions among a plethora of genes that guide mammalian development. Much of this work has been done in model organisms, ranging from worms, to fruit flies, to fish and mice. Notwithstanding the advantages of these organisms as experimental models, understanding human development must inevitably require the study of humans throughout their developmental period. Again, human developmental disorders provide key signposts to important genetic determinants. The knowledge gained from these defects in development complement that obtained from the artificial mutations produced in the model organisms. More specifically, given that disorders of cognitive and neural development are seen as highly relevant to our modern societies, our understanding (and, hopefully, treatment) of these conditions will require that, ultimately, humans be the subject matter, because model organisms will only provide limited help. One recent example of this type of research is the identification of the gene defect in Williams syndrome, a developmental disorder (4). Further, unlike cancers in adults, where significant environmental determinants occlude the definition of their etiology, much of paediatric cancer is the result of abnormal genetically controlled developmental processes. For example, the gene defects leading to medulloblastoma (5) and acute megakaryoblastic leukemia (6) have recently been identified.

Finally, we come to an area of research that has been, to date, somewhat neglected. This is the study of the functioning of the whole organism. I have termed this broad area of research integrative biology and it can be viewed as the sum of a variety of sciences that study whole organisms: physiology, pharmacology and pathology. While for the past 20 years these sciences have taken a back seat to molecular science, the success of the latter has made evident the need for the former. More specifically, the study of the integrative biology of children will require the development and use of methodologies that can be used on organisms at various stages of development. This is evident, for example, in the need for equipment and procedures to test respiratory function in children of various ages, some who can be active participants in the measurements and some who cannot.

Because integrative biology is inherently developmental and development is inherently genetic, all three areas of research are closely intertwined.

I have alluded to some results from Canadian institutions, in particular, my own, because the Canadian health care and health research systems provide us with considerable advantages. Our integrated single payer health care system promotes the capture of relatively rare patient populations on which investigations can be based. As well, the fact that our system is universal means that there are no biases of ascertainment due to economic or social status. In this aspect, our health care system resembles those of Europe and Australasia more than the American system. On the other hand, our health research system is based on an entrepreneurial model like the American system, where initiative resides in the principal investigator. This has allowed many young investigators to carve out their own programs to take advantage of the more structured health care system. I believe that this combination of a national health care system with an entrepreneurial health research model provides us with significant competitive advantages to the rest of the world.

Finally, I would like to comment on the role that basic research has on health care itself. There is, of course, the obvious connection, somewhat long term in some cases, between the results obtained at the bench and improved practice (clearly evident in the genetic tests that follow directly from the cloning of disease genes). Equally important is the connection between basic research and the training and employment of highly skilled clinical staff. At present, this applies largely to physicians and surgeons, especially those working in academic health science centres, who are attracted to such institutions because of the opportunity to perform basic research. However, in the future, this will apply to other health professions as they develop a cadre of highly trained practitioners who want the advantages of participation in a modern academic setting. The development of the first Canadian Child Health Clinician Scientist Program (7), transdisciplinary in nature and co-sponsored by the Canadian Institutes of Health Research and a variety of Canadian academic health science centres, is evidence that demand for research training, and subsequent employment, is a reality today.

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