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NATIONAL PRESS CLUB ADDRESS

Humanity's heritage: The human genome and stem cells
21 July 2004

Professor John Shine
Secretary, Biological Sciences, Australian Academy of Science
Executive Director of the Garvan Institute of Medical Research, Sydney

It is an honour and a pleasure to deliver the 4th Academy of Science Address to the Press Club, in what is a very important year for the Academy – its 50th anniversary. Over the 50 years since it was founded, the Australian Academy of Science has witnessed remarkable advances in science and has seen, despite our relatively small population, many pioneering contributions from Australian scientists and Australian institutions.

Last year was also the 50th anniversary of the famous discovery of the structure of DNA, our genetic material, 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.

This progress is not restricted to ethereal academic/intellectual discussions between researchers removed from everyday realities. These exciting developments in the biological sciences (often called the biological revolution) will have an enormous impact on virtually every aspect of our life – our health, our wealth, our environment, our food, our economy, our view of ourselves. They have already produced advances in agriculture and industrial processes and are revolutionising the practice of medicine.

The simple message today is that 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 – we all know that truth and knowledge, once found, cannot be permanently ignored.

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.

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 still going. Does anyone want to return to the misery of the plagues of infectious disease, polio, early heart disease, septicaemia? Not only did you die young, you also didn’t leave a very good-looking corpse.

I would like today to touch on just two of the major recent developments in biological research – the Human Genome Project and stem cells – and to try and briefly explore some of the issues and concerns they raise for our future, as well as the enormous potential they promise.

At the outset, I stress that much of this is in the future, and who can accurately predict what tomorrow brings? However, in science and in the pursuit of knowledge, history teaches us that predictions, which at the time were considered extreme, with the benefit of hindsight, have usually been shown to be very conservative.

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

Human Genome Project

Your genome, your DNA, is your genetic blueprint, the information that 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 – together about 2 metres in length. The order of these beads on a string is your DNA sequence. As each of the 75 trillion cells in your body contains the same 3 billion long string of beads, if you donated your body to science and your DNA was extracted and stretched out as a single molecule, it would reach to the moon and back approximately 8000 times.

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 Bill Clinton and Prime Minister Tony 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 a thousand G,A,T,C's of sequence every second.

• The human genome sequence is truly an amazing database – If your 3 billion G, A, T and C's were typed out in the font size of a telephone directory, it would fill five hundred, 200-page directories.

• It has often been referred to as the book of life – it’s actually many books.

• It’s a history textbook and contains a rich tapestry of human evolution and migration around the planet.

• It’s a detailed parts and construction manual with all the information needed to construct a complex human being from a single fertilised egg.

• It’s a sophisticated medical textbook describing the makeup of a healthy body and what goes wrong in disease.

• It’s also a Who’s Who’s in the World, listing both the overall similarities of the human race but also our unique individual differences.

• It provides a special appreciation of what we share and the richness of our diversity.

Let me give you two quotes, which I believe very accurately summarise the significance of this development.

The first is from the United Nations – Universal Declaration on the Human Genome and Human Rights:

'The human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity.

In a symbolic sense, it is the heritage of humanity.'

The second is from the Editorial, Nature, 15 February 2001 on the occasion of the publication of the human genome sequence:

Humans are much more than simply the product of a genome, but in a sense we are, both collectively and individually, defined within the genome. The mapping, sequencing and analysis of the human genome is therefore a fundamental advance in self knowledge; it will strike a personal chord with many people. And application of this knowledge will, in time, materially benefit almost everyone in the world.

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, but environmental factors as well. We already know much about many of these environmental factors – smoking in cancer and heart disease, 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, that is, a researcher would develop an hypothesis based on available evidence, and then test it experimentally. 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 and 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.

In the latter case, for example, we know that there is a long history of effective use of traditional Chinese medicines in Asia, but we also know that their use is limited in our society by the fact that there is often only anecdotal evidence that they work and some work for some people but not for others. Modern developments based on the human genome sequence and related technologies now provide the opportunity to bring the clear evidence-based approaches that Western medicine understands to the analysis of these complex extracts.

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-estrogen 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.

Imagine if SARS had evolved just a decade earlier, before we had the tools to analyse the detailed nature of the virus. In this case, 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 a SARS infection, and now have several vaccines in trials.

New infectious agents will always evolve to challenge us. However, we now have the tools to rapidly elucidate their molecular structure, decipher the changes that make them dangerous and devise new approaches to their identification, prevention and treatment. The war against infectious disease will never be won totally, but each battle now should be more decisive and brief.

Stem cells

As I mentioned earlier, 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 it’s 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 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. Although enormous technical barriers need to be overcome to realise this dream, it seems much more real now than it did only a decade ago.

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, (brushing our teeth, washing our hands, combing our hair) 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 the 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.

Australia is leading the way in developing appropriate forums for debate about these important issues and I would like to quote Bob Williamson, a Fellow of the Academy, and a founder of the Independent Stem Cell Ethics Advisory Committee.

Bob sums up the views of any responsible scientist when in a recent Newsletter he points out that 'A cell from you or me in a lab dish is just that, and should pose no ethical dilemma as long as it stays there.'

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, cochlear implants.

In the future it seems that, with a combination of stem cell therapies and biocompatible scaffolding to build organs and tissues, we are looking at not just a grease and oil change, but a complete engine rebore, computer-reprogramming, panel beating and painting.

What has been happening in Australia?

Australia has a particularly proud record in health and medical research: Howard Florey and penicillin, John Cade and lithium and a long list of pioneering achievements. In more recent times, Barry Marshall revolutionised the treatment of ulcers; 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.

Around the country, we hear and read regularly of many, many exciting 'breakthroughs' in cancer, heart disease, mental health, asthma, arthritis and the list goes on. In reality, of course, it still takes 7–10 years to translate a basic research discovery that gets scientists excited into a real treatment and benefit for patients.

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 as I mentioned earlier 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 (mobile phones, the internet, GPS, digital everything) 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 ageing; 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.

Two revolutions are underway today – one based on silicon: telecommunications and computers – I noticed the following statement in a US journal last year 'we have begun to breathe into inert sand, silicon, a level of complexity rivalling life itself.'

On the other hand, I don’t believe that the machines will take over just yet – a carbon revolution is also beginning, as molecular biology begins to move evolution into fast forward.

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 – it is an integral part of human nature – now it is inevitable that we will change our biology, 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 – if we’re in trouble, we often like to blame our parents, our upbringing; but how do we deal with someone charged with a crime whose appeal is that 'it’s not my fault, I was born with a G-A mutation in my Neuropeptide Y1 receptor gene'?
• commercialisation (patents, ownership of DNA).

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 (we’ll muddle through that), 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

I hope that I have convinced you of the unprecedented excitement and opportunity in health and medical research worldwide, that the landscape is changing rapidly and that 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 because it sits at the centre of our future prosperity and well-being.

Conclusion

Let me finish with another couple of quotes.

The first is from a US President, Thomas Jefferson, and I’m sure that similar views were expressed by Confucius, Plato, Socrates and Aristotle, and undoubtedly also held by the Prime Minister and Mr Latham:

'The important truths are that knowledge is power, knowledge is safety, knowledge is happiness.'

What is also just as important, but only implicit in this quote, is that:

'Ignorance is vulnerability, ignorance is dangerous, ignorance is misery.'

My final quote, and I’m not sure where it came from, is:

'Imagination, based on knowledge, is the key to discovery.'

Humanity is rich in imagination, now we have a dramatically increasing knowledge base; we therefore are truly entering an exciting age of discovery.

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