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Biological excitement: the international and Australian revolution in genetic science

By John Shine - posted Thursday, 2 September 2004


Last year was the 50th anniversary of the famous discovery of the structure of DNA by Watson and Crick in Cambridge. Since that seminal finding, progress has been exponential in understanding our fundamental genetic makeup, how our genetic code underlies our development from a fertilised egg cell to a complex human being, and what goes wrong in disorders as diverse as cancer, mental illness and obesity.

We can't afford to ignore this inevitable and rapidly increasing progress in understanding our fundamental makeup and the corresponding social and economic opportunities and challenges. We can't go back in time.

And certainly when it comes to our health, let's not harbour any distorted views of “the good old days”. Life expectancy, even for the well off in England in 1750 was only 36, up to 45 in 1850.

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Over the past 100 years (1900–2000), the average life expectancy in Australia has increased from 55 to 77 for males and 58 to 82 for females, and is still increasing. Does anyone want to return to the misery of the plagues of infectious disease, polio, early heart disease and septicaemia?

What has been happening in the biological sciences in the past few years?

Human Genome Project

Your genome, or your DNA, is your genetic blueprint, the information you inherited from your parents. It is composed of four simple chemicals – guanosine, adenosine, thymidine and cytosine - abbreviated G, A, T and C, arranged like beads on a string. Each of us has approximately 3 billion of these G's, A's, T's and C's linked together in extremely long strings. The order of these beads on a string is your DNA sequence.

As a single gene is only a few thousand G, A, T, C's long, you can imagine that finding that single gene out of the 3 billion G, A, T, C's has been more difficult than finding the proverbial needle in a haystack.

It was therefore no surprise that when President Clinton and Prime Minister Blair announced the first draft of the complete human genome sequence in 2000, with great fanfare on both sides of the Atlantic, it was hailed as the pinnacle of 50 years of scientific endeavour.

Over those 50 years we have witnessed an exponential increase in our understanding of genes and the human genome. From 1953 and the structure of DNA, through the late 1970s and development of gene cloning techniques, to 2001 and the complete human genome sequence, to today where several thousand gene sequences are entering the international databases every day. The Genome Consortium churns out over 1,000 G, A, T, C's of sequence every second.

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What can we do with this previously undreamt of database?

For scientists the benefits are immediate – new insights into every field of biology. But the benefits will extend far beyond the research community to impact virtually every aspect of our life, but especially medicine and health care.

Most of the major diseases that challenge our community - such as heart disease, arthritis, diabetes, cancer, mental illness - all involve several genes, and environmental factors as well. We already know much about many of these environmental factors, such as smoking in cancer and heart disease and exercise and diet in diabetes and obesity. But the genetic factors underlying these complex, so called multifactorial diseases, have been hard to find.

How will the human genome sequence help?

For a start, it has changed the way we do science. Previously, rigorous research was hypothesis-based. For example, if there was evidence that a certain growth factor stimulated the growth of breast cells, I might hypothesise that a mutation causing overproduction of this factor might cause breast cancer and I would carry out experiments to prove or disprove the hypothesis. With the availability of the human genome database, it is now possible to spot gene sequences from each of the approximately 50,000 human genes onto a small silicon chip the size of my thumbnail.

I can then take a sample of breast cancer tissue and a sample of normal breast tissue, incubate them with the gene chips and see which genes have altered activity in the breast cancer sample, compared to the normal sample. I therefore make no prior assumptions about which gene or genes have gone wrong in development of this cancer and I can also identify new cancer causing genes which were previously unknown. This so-called discovery approach is therefore not limited by previous research.

In addition to identifying all the human genes, a major research effort is being undertaken to catalogue gene variations between different individuals and to correlate these changes with susceptibility to different disorders. Although we are all at least 99.9 per cent identical in our DNA sequence, the other 0.1 per cent still represents about 3 million differences. Some have no known effect; some influence our appearance, our behaviour, our metabolism, our susceptibility to different diseases and our response to medications.

Not only will this individualisation lead to early detection and better treatment of disease but, most importantly, to prevention. Furthermore, knowledge of genetic variation between individuals also promises to explain why some people respond better to certain drugs while others experience side effects. This will lead to cheaper, more effective clinical trials for new medications, better use of existing therapies, more specific targeted pharmaceuticals and the rational use of some so-called “alternative” or “complementary” medicines.

For example, at the Garvan Institute, we have recently signed a formal agreement with the Shanghai Institutes of Biological Sciences to undertake an extensive collaborative program. This program will look to combine Eastern and Western expertise to identify and develop the active ingredients in traditional Chinese medicines for the treatment of obesity and diabetes and to link such research to an understanding of the genes responsible for an effective response to such treatments.

The availability of this amazing database, the Human Genome Sequence, free to researchers around the world, is thus changing forever the way we think about health care. As new targets for specific pharmaceutical development are being identified from gene chip experiments and disease susceptibility and response to treatment being measured at the level of the individual, the focus of future health care will be prevention and personalisation.

From very early in life, we will be able to develop a matrix of our genetic risk for various diseases and act, both through lifestyle and targeted personalised pharmaceuticals, to counter this risk.

This of course is already happening, albeit in a fairly simple form. For example, many thousands at risk of heart disease take cholesterol-lowering drugs; in the US, anti-oestrogen drugs are approved for the prevention of breast cancer in women at high risk of developing the disease. We all justify an extra glass of wine on the basis that the antioxidants help prevent cancer and heart disease.

The technologies central to success in the human genome project, that is, the ability to rapidly determine the G A T C sequence of any DNA molecule, have also revolutionised research in infectious disease. Viruses and bacteria have much simpler, smaller genomes than a human. Their genetic makeup can therefore now be analysed very rapidly. The war against infectious disease will never be won totally, but each battle now should be more decisive and brief.

In the case of SARS, within a couple of months of isolating the virus responsible, researchers had determined the complete sequence of its genetic code, made diagnostic kits to detect an infection, and now have several vaccines in trials.

Stem cells

We have known for some time that every cell contains the complete set of genes, a complete genome. However, it was generally believed that once a cell became specialised during the development of a whole animal or human - that is, it became a blood cell, a nerve cell, a muscle cell - then its programming was locked and it could not change back to an embryonic type of cell capable of giving rise to many types of new cells. Unlike more primitive organisms, it was therefore considered that 'cloning' of higher animals was not possible. Then along came Dolly the sheep, followed by Molly the mouse, rats, pigs, cows, the whole farm.

Certainly, few issues in recent science have generated as much excitement and controversy as the potential use of stem cells to treat disease. The hope of course is that, one day, it will be possible to grow some of your own skin or blood cells in culture, reprogram them to become new nerve or muscle cells, then re-implant them to replace cells lost to Parkinson's or Alzheimer's disease or heart failure or stroke or spinal cord injury. The hope though is still very much a dream.

While few would argue that realisation of this dream is a noble goal, many in our society are deeply concerned about the use of stem cells isolated from embryos. While I believe we would all accept that fertilisation (the coupling of sperm and egg) is a key moment (for some, THE moment) in the creation of a unique individual, Dolly changed forever our view that only by combining genes from two parents can a new individual be formed. Dolly demonstrated that any cell in the body, under certain circumstances, could give rise to a new individual.

As we realise the dream to grow and reprogram our own stem cells in culture, removing concerns about using embryonic stem cells, we will be faced with a new challenge. Our normal cells, which we discard in millions during the course of a normal day under certain special circumstances, if implanted into a womb, these cells will have the potential to develop into another individual.

Such cells however are critical to development of new treatments for a range of devastating disorders and we will need strong international agreements to stop these cells being placed into the womb with all the ethical and medical risks that would entail.

Although, as a biologist, I might find it hard to admit that some of the more physical sciences are also making great advances, the combination of biology and physics in this area is one of enormous potential. Developments in materials science and biocompatible alloys are suggesting that true repair and even improvement of the human machine is becoming feasible. Already, we have very effective and virtually routine artificial hips, knees, heart valves and cochlear implants.

What has been happening in Australia?

Australia has a particularly proud record in health and medical research including amongst others Howard Florey and penicillin and John Cade and lithium. In more recent times, Barry Marshall revolutionised the treatment of ulcers and a vaccine for cervical cancer is being developed from research in Brisbane.

Another example, closer to home for me - at the Garvan Institute, we have discovered that a specific brain chemical controls not only appetite (particularly important given the current epidemic of obesity in our society) but the same neuropeptide also regulates the density and increases the strength of our bones. This is important, not just for the prevention and treatment of the crippling effects of osteoporosis, but imagine what it might mean for the Wallabies and our potential dominance of the Rugby World Cup.

Today, the practical advances we see in medicine are the results of research undertaken a decade or so ago. But also today, we see the continuing exponential advances in research outcomes that must similarly translate into health outcomes in the not too distant future.

Australia is also among the international leaders in stem cell research - leading in not only the science, but also in recognising the importance of balancing realisation of the potential of stem cells with recognition of genuine community concerns. Progress will only occur if the community can see that appropriate consultation and consistent ethical standards are an integral part of the scientific endeavour.

What of the future?

One could argue that our modern technology revolution is limited by our ancient biology. However, our biology database is now being updated to an extent that we are beginning to witness a corresponding biology revolution – initially directed at major diseases and improvements in quality of life but then at improving life itself.

Understanding what goes wrong in the loss of control of cell division in cancer also means that we unlock the secrets of how to control cell growth and aging; understanding the chemical signalling abnormalities that cause mental illness also means that we gain insight into the brain chemistry underlying behaviour; understanding and preventing the loss of neurons in Alzheimer's disease also means opportunities to enhance memory formation.

Why are we afraid of reworking our own biology?

As we begin to understand the complex and coordinated interactions between genes and between the myriad of chemicals and molecules that they encode, we inevitably begin to modify and adjust them.

From the very beginnings of the human race, we have always used technology to transform the world around us. Now it is inevitable that we will change our biology and our internal environment, as in the past we have changed our external environment. It is this perception that humanity is at the threshold of reworking its own biology – controlling its own evolution – that troubles so many people. But what are we really concerned about?

As with any new rapidly developing technology, there are immediate and real concerns:
Concerns about:

  • fairness in use of genetic information
  • privacy and confidentiality
  • psychological impact/stigmatisation
  • reproductive decisions (embryo selection)
  • uncertainties of genetic tests for complex conditions
  • safety and environmental issues
  • human responsibility vs genetic determinism

These are all important issues brought into sharp focus by developments in gene technology and biological research, but many are not new. For example, our family medical history can today be an issue with insurance and social isolation. Issues around patents and achieving a balance between commercial incentives and public good are not restricted to genetic discoveries.

So, our real concerns are much broader and revolve not so much around whether or not someone might be hurt or disadvantaged by a rapidly and not yet well understood technology, but rather by the fact that, as our genome is the blueprint of the human machine, it is at the very core of who we are.

We are concerned at the philosophical implications. It may change the sense of who we are. We will need to make difficult choices that we are very uncomfortable with, but the biggest fear is that of losing control over humanity's future. The long term consequences of being able to play a direct role in our own evolution are not things we can plan, because it involves the shape of technologies that we cannot yet see and the values of future humans we cannot yet understand.

The real danger is to succumb to these fears and to unduly delay these advances. They cannot be stopped. Think of the untold suffering that would have occurred if the development of antibiotics or of a polio vaccine had been delayed for a decade.

Fear of the unknown is nothing new; it is an important element of human nature. It is therefore more critical today than ever that scientists work in partnership with the broader Australian community to share the vision of what a thriving science base and associated industries can create for our county. At the same time we need to acknowledge, respect and address the very real concerns that many people have, not just about human genetics and stem cells, but also GM foods and biotechnology in general.

Australia

There are many compelling reasons why Australia should be in the vanguard of these changes.

We have a strong research base, our health system costs are under enormous pressure (on recent trends they will rise from $45 billion to over $90 billion in the next 20 years), our population is ageing, with quality of life issues of paramount importance, and there is an opportunity for biotechnology to deliver enormous social and economic benefits to our community.

These developments will dramatically change the economics of health care and provide a myriad of commercial, as well as social, opportunities for the next generation. It is therefore crucial that the next generation more actively embraces science as it sits at the centre of our future prosperity and well being.

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Article edited by Jenny Ostini.
If you'd like to be a volunteer editor too, click here.

This is an edited extract of an address to the National Press Club on July 21, 2004.



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About the Author

Professor John Shine is the Vice President, Australian Academy of Science, Executive Director, Garvan Institute of Medical Research and Chair, National Health and Medical Research Council.

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