by George Poste
Health Technology Networks
United States
Genetics offers unprecedented
opportunities to advance human
health and quality of life and to
resolve perplexing inequalities
in healthcare around the world.

Decoding of the three billion chemical letters in the human genetic code, just completed, has been a prodigious technological feat. Yet it marks just the beginning of the more challenging task: to use this knowledge to create better medicines, vaccines and diagnostic tests.

Genetic technologies will also be central to addressing the unacceptable toll imposed by infections, parasitic diseases and malnutrition in developing countries.

The analysis of the structure and function of genes (genomics) and their protein products (proteomics) in health and disease is creating a rapid expansion of knowledge about the causes of disease at the molecular level. These insights are driving dramatic innovations by pharmaceutical and biotechnology companies in the discovery of new molecular targets for drug action and novel diagnostic methods. Similar research on the genetics of microorganisms is yielding a bountiful reward in the search for the design of novel antibiotics, antivirals and vaccines.

Imaging cell chemistry
Profiling of the molecular changes in diseases will also expand the scope of body imaging. In the last three decades body imaging has been transformed from reliance on black and white, two-dimensional X-ray pictures to the now routine use of colour-enhanced, three-dimensional images generated by CT, MRI, PET and SPECT that reveal body structure with exquisite clarity.

These non-invasive methods have spared millions from the pain of exploratory surgery, and have accelerated new surgical advances such as keyhole surgery, remote-virtual surgery and stereotaxic robotic surgery.

But current imaging approaches are still confined largely to documenting the shape and structure of major body organs. The next generation of imaging technologies will monitor the chemical functions of the cells within these organs to produce realtime images of genes and proteins at work within cells. These will deliver sophisticated fingerprints of disease processes and better assessment of the effectiveness of treatments.

These impressive gains in understanding body function in health and disease have depended heavily on progress in the development of new analytical tools and instruments for gene sequencing. They are allowing us to define the genetic variation (polymorphisms) between different individuals, to resolve protein structure and to show how genes and proteins are regulated. Future progress will continue to rely heavily on sustained innovation in instrumentation and computational methods for handling and interpreting the explosive growth of information in molecular biology and medicine.

Understanding the molecular basis of disease will alter irrevocably the way medicine is practised and how future doctors will be taught. In addition to the promise of new medicines and vaccines, molecular medicine will also radically alter the way disease is diagnosed. New molecular diagnostic tests will become increasingly influential in the selection of patient treatments.

Genetics is revealing that patients presenting with similar symptoms who would previously have been viewed as suffering from the same disease, and given the same treatment(s), in fact have assorted subtypes of disease, each with its own distinct molecular pathology.

Most important, the same medicine may not act as effectively on the various subtypes. As these molecular diagnostic classifications become increasingly commonplace, new diagnostic tests will ensure that we use ‘the right medicine for the right disease’. Molecular subtyping of major diseases into distinct categories, each with its own different treatment requirements, is already becoming standard practice in cancer and neurology and will eventually permeate all branches of medicine.

Photograph by Charlie Fawell – a thumb
print acts as an analogy for each human
being's unique genetic make-up. He has
then superimposed it on a pregnant
woman to portray the inherited source
of that very life code.

Genetically profiling people
The second axis of how genetics will make the use of medicines more rational will come from understanding how the unique genetic profile of every individual affects how they respond to medicines. Subtle chemical differences in the genes of individuals called single nucleotide polymorphisms (SNPs – phonetically referred to as ‘SNIPs’) exert a significant effect on whether medicines will work. They also determine who is at risk of suffering an adverse reaction to a particular medicine.

The influence of our individual genetic uniqueness in affecting how we respond to medicines, and also to various chemicals in the environment, is known as pharmacogenetics. An intense research effort is now under way to link specific SNPs with lack of responsiveness to different medicines, and to identify patients at risk of suffering dangerous side-effects. Success will bring a second forceful dimension to ensuring that medicines are used in a more rational fashion by dictating that treatment not only involves the right medicine for the right disease, but also uses the right medicine for the right patient.

Predisposition
The third aspect of research into the genetics of disease, and by far the most profound in its implications for the health service and for society, involves understanding how specific genes, or mutations and SNPs within these genes, may predispose each of us to particular diseases.

Knowledge of genetic predisposition(s) to major disease(s) heralds the prospect of shifting medical practice from its current emphasis on the diagnosis and treatment of existing disease, usually only after symptoms have appeared. The objective would be to act proactively to predict and prevent disease, either through prophylactic treatment, changes in lifestyle, or mitigation of known environmental risk factors.

Despite the enormous social and economic benefits that disease prediction and prevention can bestow, the research needed to make this a reality will be technically complex, lengthy and costly. With the exception of infections, most of the common diseases that afflict us – cardiovascular disease, stroke, mental illness, neurodegeneration, cancer, diabetes and osteoporosis – involve not just one, but multiple, genes.

Characterisation of how many genes are responsible for any particular disease, together with how different SNPs in each gene predispose to disease developing at a later date, will be a formidable technological challenge for the coming decade. It will require genetic profiling (genotyping) of large populations to map the genetic differences between those who succumb to a disease versus those who do not, as well as ensuring that the influence of environmental factors such as smoking, diet, or work environment in modifying genetic risk are understood fully. Even when these complex interrelationship are defined precisely, the probability of developing disease will still be a relative risk and not absolute. Doctors will need to acquire sophisticated new skills to interpret genetic profiling tests to know how best to counsel their patients.

New risks
As in every epoch of substantive technological change, beneficial uses of new technology are accompanied by new risks, uncertainties and the opportunity for abuse. Genetics offers unprecedented opportunities to advance human health and quality of life and to resolve perplexing inequalities in healthcare around the world. But it will also present society with ethical, legal and social questions of vexing complexity, for which the current political and regulatory apparatus of public policy is ill equipped. Discriminatory practices based on genetic profiling, procreative freedoms, prenatal diagnostics and abortion, behavioural genetics, eugenics and the proper uses of gene therapy will feature prominently in this debate and will probably evoke highly polarised opinions. Reconciliation of extremist positions, as in other elements of contemporary debate about technology such as GM food, animal experimentation and embryonic stem cells, may never be possible.

What is essential, however, is that academia and industrial enterprises engaged in advancing medicine be in the vanguard of the debate in a responsible and fully transparent manner. The unequalled promise of molecular medicine could all too easily be jeopardised by reluctance to engage in the debate.