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THE TRANSFORMATION OF HUMAN CONSCIOUSNESS
BY GENOME KNOWLEDGE
Dr JIM VADOLAS* and PROFESSOR PANOS IOANNOU
In memory of Professor Panayiotis A. Ioannou who died in April 2005.
Professor Panos Ioannou
Professor Panos Ioannou died after a battle with cancer in April
2005. We very much appreciated the contribution from Panos to our
earlier events and look forward to continuing to support his quest
for a cure to the blood disorder of thalassaemia.
Panos led the Cell & Gene Therapy Unit at the Murdoch Children's Research Institute. He was
an Associate Professor in the Department of Paediatrics at the University of Melbourne
Introduction
Over the last 50 years we have witnessed an exponential increase in our
understanding of genes and the human genome. In 1953, Watson and Crick reported
the DNA structure in the journal Nature. In the late 1970’s we saw the development of
gene cloning techniques, and in 2001 the sequencing of the human genome.
The sequencing of the human genome heralds a new age in medicine, with enormous
benefits to mankind. For the first time we are able to read our genome as an
instruction booklet or medical textbook. With increased understanding of the genome it
may ultimately be possible to eradicate common inherited diseases, but at the same
time we need to be cautious about possible misuses of our genetic information.
Today we have several thousand gene sequences entered into international databases
every day with genetic information catalogued and maintained in different forms. We
can not afford to ignore this inevitable and rapidly increasing progress in understanding
our fundamental make up.
As scientists, we all want to know the truth and once found we cannot permanently
ignore it, we cannot go back.
But we are at a point where we are able to decide how radically we want this
technology to change the way we live. In this report, I would like to illustrate how this
technology is being used to help us understand the genetic basis of disease and allow
us to develop better therapeutic strategies with fewer side effects.
Human Genome Project
In 1988 the Human Genome Project (HGP) was initiated by founding the Human
Genome Organisation (HUGO) in the USA. The two main forces behind this project in
the United States were the National Human Genome Research Institute (NHGRI) at the
National Institute of Health (NIH) and the Office of Biological and Environmental
Research at the Department of Energy (DOE).
The project originally was planned to last 15 years, but rapid technological advances
accelerated the completion date to 2001. It was an international collaboration to
understand the hereditary instructions that make each of us unique.
The aim of this international organisation was to:
1) Identify all of the approximately 30,000 genes in human DNA,
2) Determine the sequences of the 3 billion chemical base pairs that make up human
DNA,
3) Store this information in databases,
4) Improve tools for data analysis,
5) Transfer related technologies to the private sector, and
6) Address the ethical, legal, and social issues (ELSI) that may arise from the project.
In February 2001, two competing research groups announced the near completion of
the primary goal of the HGP: the DNA sequence of 3 billion or so DNA base pairs that
make up the 22 somatic chromosomes, and the X and Y chromosomes. Issues of the
scientific journal Science and Nature contained the first analyses of the working draft of
the human genome sequence.
The Human Genome Project (HGP) was viewed as a race between a publicly-funded
consortium (Headed by Francis Collins at the National Human Genome Research
Institute), committed to free access to its data, and a private company, (Headed by
Craig Venter at Celera), which restricted access to its data, selling access to industry at
very high prices.
There are several very good online documents describing the techniques used in the
HGP. These documents can be viewed or downloaded from the Oak Ridge National
Lab website1.
Since its inception, leaders of the project have used such metaphors as the “book of
life,” the “holy grail” and the “blueprint of life” to describe the importance of the human
genome sequence. Clearly, the availability of a reference human genomic DNA
sequence is a milestone towards understanding how humans have evolved, because it
opens the door to large scale comparative studies.
With the availability of the human genome sequence a new era in molecular medicine
begins, with enormous benefits to mankind. The technology and resources to arise
from the HPG are beginning to have a profound impact on biomedical research and
promises to revolutionise biological research and clinical medicine.
(www.ornl.gov/sci/techresources/Human_Genome/project/benefits.shtml).
For example, the detailed genomic maps have helped scientists identify genes
associated with dozens of genetic conditions, including myotonic dystrophy, fragile X
syndrome, neurofibromatosis types 1 and 2, inherited colon cancer, Alzheimer's
disease, and familial breast cancer.
Moreover, scientists will be able to identify all the genes contributing to a particular
disease, thus leading to a more accurate diagnosis and classification of disease
severity. In addition, healthy patients can now determine which diseases they could be
predisposed to, therefore giving them the opportunity to seek preventative medical
intervention or make some lifestyle changes in order to protect their health.
Medical researchers will also be able to devise novel therapeutic regimens based on
new classes of drugs, immunotherapy techniques, avoidance of environmental
conditions that may trigger disease, and possible augmentation or even replacement of
defective genes through gene therapy.
Human Genome Unplugged
i) Gene Chip Expression Profiling
The HGP has provided access to the thousands of genes and their products (i.e., RNA
and proteins) which function in a complicated and orchestrated manner that creates the
mystery of life. Trying to understand this network has usually been a time-consuming
process relying on traditional methods in molecular biology which generally work on a
"one gene in one experiment" basis.
This process is very limited and the "whole picture" of gene function is hard to obtain.
In the past several years, a new technology, called DNA microarrays has evolved,
extending the biologist’s capacity to investigate in the areas of gene discovery, disease
diagnosis, and drug discovery.
DNA microarrays consist of small DNA fragments, chemically synthesised at precise
locations on a coated quartz surface. Hundreds of thousand of small DNA fragments
can be contained on one array no bigger than your thumbnail.
By extracting, amplifying, and labelling nucleic acids from experimental samples, and
then hybridising those samples to the array, the amount of label can be monitored at
each target, enabling the precise identification of hundreds of thousands of target
sequences yielding a gene expression signature.
This procedure allows simultaneous relative quantitation of tens of thousands of
different RNA transcripts. Genes that are over expressed can usually be identified as
red while genes which are under expressed are shown as green.
There are two major application forms for the DNA microarray technology:
1) Identification of sequence (gene / or genetic mutation); and,
2) Determination of expression level (abundance) of genes.
For example using this technology it is now possible to determine genome-wide
expression profiling of particular diseases like breast cancer, leukemia, and prostate
cancer. Such genome-wide screenings have revealed that similar tumour types have
distinctly different molecular differences. This observation has helped to explain why
clinicians have been baffled for years when, for instance, two breast tumours looked
identical, but patient’s response to treatment and the outcomes were radically different.
In reality, the patients had different diseases, requiring different treatments.
Cancers are currently being grouped according to this type of phenotype analysis.
Gene expression signatures can now be determined for any type of cancer, thus
allowing physicians to determine the best form of treatment. This will lead to
individualised regimens with more effective and appropriate treatment based on the
gene chip results2 (For further details in this technology please visit
www.affymetrix.com).
ii) Human Genome and Bacterial Artificial Chromosomes
One of the most valuable resources to come out of the human genome project is the
availability of large genomic fragments available as bacterial artificial chromosome
(BAC) clones. The large-scale physical mapping and BAC end sequencing projects by
the public sector have provided large overlapping contigs of BAC clones with known
sequence end points across the entire genome. The BAC clones have been arrayed
into microtitre plates and high-density replica filters for screening of the human
genome, creating a complete physical library of the human genome. It is now possible
to use publicly available databases to rapidly search for BAC clones whose ends are
located at defined positions across almost any region in the human genome, and to
subdivide a large area of interest into several intervals defined by the positions of BAC
ends.
With the increasing interest in genomic approaches to biological research, the demand
for BAC libraries has increased rapidly. The human genome BAC library has now been
distributed throughout the world in an array format thus allowing sharing of resources in
the public domain (The MCRI possesses the human BAC library RPCI-11).
One of the main obstacles when working with BACs has been the size of the clones
(100-250kb) which prohibited the use of conventional molecular biology manipulation
procedures. With the recent development of targeted modification techniques for
BACs, based on homologous recombination and site-specific BAC mutagenesis, the
main obstacles have largely been overcome thus making BACs more attractive
substrates for transgenic constructs.
We have used the targeted modification approach to introduce several types of
modifications, including the insertion of the green fluorescent reporter gene as well as
disease-causing mutations into genes of interest.
This has allowed us to create cellular-based tools and strategies needed to identify and
evaluate potential pharmacological therapies.
A particularly promising example of this approach is the use of libraries of small
molecules such as natural compounds, or the products of combinatorial chemistry in a
high-throughput screening to identify compounds that act as positive or negative
regulators of individual gene products, pathways or cellular phenotypes.
Although the pharmaceutical industry applies this approach widely as the first step in
drug development, few academic investigators have access to this methodology.
Moreover, the genomic approach has also allowed us to create ‘humanised’ transgenic
mouse models, which accurately depict human diseases. Such in vitro and in vivo
models are hoped to facilitate the identification and evaluation of potential therapies for
a number of inherited or acquired conditions.
iii) Political, Ethical and Social Issues
The applications of human genetic research have great potential to improve medical
treatments and prevent disease. Despite the potential benefits, many ethical, legal and
social concerns exist. To ensure that genomic research benefits all, it will be important
to investigate the application of genome-based information in the health care system.
This investigation will be critical in countries where societies are segmented based on,
indigenous or ethnic populations, rural and inner city areas, and rich and poor
communities.
Early in the development of the publicly funded HGP, approximately 5% of the budget
was set aside to fund the ELSI program (Ethical, Legal and Social Implications of
human genome project). We now address research that focuses on society itself, more
than on biology or health. Such efforts should enable the research community to:
1) Analyse the impact of genomic information based on race, ethnicity, individuality
and group identity, health, disease and behavioural traits.
2) Define policy options, and their potential consequences, for the use of genomic
information and for the ethical boundaries around genomics research.
The use of genomic information is not limited to the biological and medical arenas. The
public is also deeply concerned about the concept that personal genetic information
might potentially be misused. One of the main concerns is the potential for
discrimination in health insurance and employment.
A significant amount of research in this area has been performed, and several policy
options have been published, forcing governments to pass on legislation to protect the
people from genetic discrimination. The difficulty will be for policy-makers to find a
balance between the promotion of genetic research and the use of genetic information
without infringing on human rights.
The Genomic Contributions to Human Traits and Behaviours
Genes influence not only health and disease, but also human traits and behaviours.
Scientists are only beginning to unravel the complex pathways that contribute to
various characteristics such as handedness, addiction, and cognition.
Genetic information has begun to be catalogued from certain groups in order to identify
the genetic contribution to a particular trait. Certain alleles have been associated with
what some people perceive as 'negative' physiological or behavioural traits, which may
or may not require medical intervention in order to reduce natural or social inequalities.
But what happens when certain alleles are identified for ‘positive attributes’ such as
improved ability to excel in sport?
Recently, Kathy North, a neurogeneticist in Sydney, at the Institute for Neuromuscular
Research, while looking for a gene responsible for muscular dystrophy she identified
the ACTN3 gene instead, which is associated with human elite athletic performance.
This gene normally produces the protein actinin-3, which helps to produce the fast
twitch muscle used in sprint and power sports.
Another performance enhancing genes, angiotensin-converting enzyme (ACE) has
also been identified and it appears to be more prevalent in endurance runners. It is
associated with less muscle, less fluid retention, and more relaxed blood vessels,
which would enhance oxygen uptake. These genes do not necessarily guarantee a
person’s ability to be an elite athlete but could potentially multiply the predictive athletic
capacity.
The identified ACTN3 allele has now opened the door to genetic testing at an early age
to identify promising potential athletes.
For the first time we can now obtain a cheap and non-invasive genetic test which will
tell us whether we are likely to be good at sports. For AUS$110, the Australian
company Genetic Technologies will test a cheek swab for the variant of the ACTN3
gene. This test measures just one gene that affects the performance of fast-twitch
muscle fibre3.
It will take the identification of probably tens or hundreds or even more alleles to
influence athletic performance before genetic testing will be able to predict the
individuals athletic potential. Too often, research in behavioural/trait genetics has been
designed in such a way that the findings have been communicated in a manner that
oversimplifies and overstates the role of genetic factors.
It is also particularly important to gather sufficient scientifically valid information about
genetic and environmental factors to provide a sound understanding of the
contributions and interactions between genes and environment in these complex
phenotypes.
With many people aware of the publication of the human gene map, clinicians are
frequently asked about DNA testing.
• Which genes could we test for?
• Where could it be done?
• How much would it cost?
• How accurate are the results?
It is already possible to screen those at risk of having a child with a serious disease.
Genetic testing laboratories offer tests for more than 500 genetic disorders. Persons
being tested rely on prenatal screening, or use a more recently developed procedure
called pre-implantation genetic diagnosis, or PGD.
PDG embryos are created by IVF and then screened for the genetic configuration in
question. Only not affected embryos are transferred to the woman’s uterus. Of course
genetic tests can be misused. What will happen in such societies if they start to
combine PDG with the knowledge of ACTN3 and ACE genes?
The Genomic Contributions in Society
Some people may argue that there is no difference in selecting a child by PGD without
a negative trait vs a child with a positive trait. Of course this raises certain issues,
which concern genetic enhancement. Genetic enhancement could exaggerate existing
social inequalities, especially if only the prosperous can afford them.
Even if this technology could be applied safely and without using immoral means, the
concern is that naturally born children would not be able to compete with those who are
genetically enhanced. Overlay this upon a society obsessed by youth, health and
success and a society in which many of its members lack sufficient income, education,
and health care, and are thereby already are excluded from opportunities for
advancement.
Social justice would mandate improving the well-being of those who are on the margins
of society rather than further segregating the poor by enhancing a few far above the
norm.
Let us take China as an example. They have taken one of the more extreme measures
in an attempt to control population growth and to accelerate their climb out of poverty
by introducing the One-Child Policy.
Since the implementation of the One-Child Policy, society’s preference for boys has
skewed the male-female ratio to averages as high as 100 females to 131 males,
compared to a world standard of approximately 100 females to every 105 males born.
This world ratio includes the two most populous countries in the world: China and India
where pre-natal gender selective abortions and infanticide are common. This largely
stems from the preference for sons over daughters. One of the primary reasons is
economic.
Moreover, this situation has been exacerbated by the availability of ultrasound
machines to the wider community, thereby significantly influencing the gender make up
of the traditional societies.
Chinese people lack knowledge of western eugenic history. Chinese culture plus
current family planning policies make eugenic ideas more acceptable. This raises a
whole series of questions:
• What happens if they start to combine PDG with the positive trait selection such as
the ACTN3 and ACE genes?
• If you were to be restricted with one child, would you not want that child to succeed
in society?
• As a parent, would you not want your child to be fit, intelligent, and of course to be
able to look after you when old?
• Perhaps, a fit and strong child may also equate a long and healthy life?
One can aIso wonder what the "superpowers" of the world today would have to say
about such social changes, especially taking place in a country already with a
population of some 1.3 billion people. What if China encouraged this enhancement
technology while the West bans it? Within a few generations the Chinese economy
and perhaps military capability would be an even greater force. Would this not be seen
as a possible threat?
Of course this is all a scenario thinking process which allows us to explore uncertainty
and ambiguity. This process serves to create scenarios, which may initially be
uncomfortable, but may turn out to be the most effective way of embracing the
unknown.
Today our great scenario thinkers are the bioethicists. Their role is to allow for a more
balanced view of both the risks and opportunities to come from the genomic revolution.
They display a willingness to explore uncharted territory and to provoke the
imagination. They enable a more complete view of the risks and opportunities of the
future, which is based on rigorous fact-finding exercises.
They create multiple futures, rather than just one, and allowing for a more complete
exploration of the future. Importantly, this type of exploration provides the ground for
decision-makers such as the health ministers and governments who cannot accurately
predict the future, to apply appropriate legislation.
Some applications of information derived from genomic research to humans are viewed
by some members of the public as controversial, thus questioning scientific exploration.
Although freedom of scientific inquiries has been a fundamental feature of human
progress, it is not unbounded. It is important for society to define the appropriate and
inappropriate uses of genomics.
Conversations between diverse parties based on an accurate and detailed
understanding of the relevant science and ethical, legal and social factors will promote
the formulation and implementation of effective policies and thereby promote the use of
genomic information for the benefit of mankind.
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