Governments in the industrialized countries have handed over the human
genome to private ownership together with the most triumphant hyperboles
to boot, notwithstanding that it was mapped and sequenced at great public
expense. A multi-billion bio-informatics goldrush is on, as
private companies scramble to mine the public database for genes to patent
and to assemble their own proprietary databases which are sold at
exorbitant fees to subscribers. Beneath the hype, bio-informatics is a
desperate attempt to turn the exponentially increasing amount of
information into knowledge. The human genome programme has dominated the
scientific scene for the past ten years, raising hopes and fears in equal
measure. Is it likely to deliver? No, especially if it continues to be
misguided by a discredited genetic determinist paradigm that serves to
divert attention and resources away from the real causes of ill-health and
to stigmatize the victims. We are already witnessing the resurgence of
genetic discrimination and eugenics that have blighted the history of much
of the last century.
Bio-informatics suffers from the reductionist fallacy that knowledge
will automatically arise once information is exhaustively listed.
Molecular biology is suffocating from information overload. What we need
is a quantum leap to a new paradigm for understanding the organism as a
coherent whole. Otherwise, human genome research will remain a scientific
and financial black hole that swallows up all public and private resources
without any return either to investors or to improving the health of
"To-day, we are learning the language that allowed God to create
life." That was how Clinton greeted the announcement of the human
genome map on June 26 (1). The Human Genome Project, (HGP) an
international public consortium of research laboratories led by the United
States, and Celera, a private American company, made the announcement
jointly, ending months of competition to complete the first sequence of
the human genome. Craig Venter, Director of Celera, referred to this "historical
day in the 100,000 years of human history" when, for the first time, "the
human species can read the letters of its own text." Not to be
outdone, Francis Collins, head of the public project, called it "the
revelation of the book of life".
Craig Venter claimed his discoveries could definitively cure cancer,
thus securing Celeras place in the private investment market, while
Francis Collins stressed that "the real work is starting",
thereby justifying the next round of major public finance.
French Research Minister, Roger-Gérard Schwartzenberg, hailed the
event as " the victory of those who wanted knowledge to remain free"
(2). In reality, it is the biggest sellout in human history dressed up
with the most far-flung hyperboles.
The human genome has been sequenced separately and independently with
major public finance, from the United States and the European Community.
The US Government alone had earmarked $3 billion for the initiative. But
that has not prevented the human genome from being owned and exploited by
private companies. Earlier in March, Clinton and Blair released an
ambiguous statement calling for open access to the human genome data. It
sent biotech stocks on a downward slide, with some dropping 20% at the end
of the day. In the weeks following, officials in the Clinton
administration clarified that they still favor patents on "new
gene-based health care products."
Celeras genetic maps would eventually be available on the
Internet, and the company will claim royalties from any commercial
pharmaceutical application of its discoveries. In contrast, the gene
sequences and gene maps produced by the public consortium have been
deposited regularly within 24 hours of completion in GenBank, a public
database set up in the early 1980s when DNA sequencing began, access to
which is totally free. Celera kept its own human genome data secret while
benefiting from free access to the public database throughout the period
that the company was busy sequencing, thereby significantly reducing the
time and effort needed to complete the task.
Celera is not the only company stealing from HGPs Genbank (3).
Others such as Incyte has mined the public data to help build its
catalogue of genes and patents. At least 500 gene patents have already
been awarded, while another 7000 have been applied for. Human Genome
Sciences has won more than 100 gene patents and filed for roughly another
7000. There are some 20 000 patents on gene sequences pending at the US
patent office (4).
The US and European Governments, in line with the private companies, are
downplaying the free access to the public human genome database on grounds
that raw genome sequence is useless. During the quarterly meeting of
Research Ministers of the G8 in Bordeaux at the end of June, to which
Mexico, Brazil, China and India were invited, all agreed that DNA
sequences - the fundamental data - must not be patented, in recognition
that they are discoveries and not inventions (5). This seems like a
definite improvement over the previous situation in the United States
where over 4 million patents on human genome sequences have already been
granted (6), the majority of which are on short fragments of DNA with no
The US Patent and Trademark Office (USPTO) had tightened up the criteria
for gene patents by issuing two new directives under section 101 "utility",
and section 112 "written description requirements" last December
(7). Under the new utility guidelines, the USPTO is looking for "specific
utility" and "substantial utility". So, DNA fragments
or express sequence tags (EST) will require a written description of their
specific utility in order to be patented (though millions have been
awarded patents already). Similarly, according to the current EU Directive
on biotechnological inventions, genes and gene-sequences can still be
patented if an "industrial application" is specified.
However, an "industrial application" may amount to no more
than speculation based on similarity to gene sequences in the existing
database. A notorious case involves the CCR5 gene patent awarded to Human
Genome Sciences in the US this February. The company isolated the gene
using automated computers to sequence it and software to determine that it
belonged to a class of cell membrane receptors that pick up chemical
signals in the body (8). A few months later, scientists at the Aaron
Diamond AIDS Research Center in New York discovered that the AIDs virus
requires the receptor to enter cells. A drug that can block the receptor
would thus be a new weapon against AIDS.
Another industrial application for which many patents have been awarded
is "association with condition X", where X is anything from
cancer to criminality. There are already 740 patented gene tests on the
market, among them BRCA1 and BRCA2, genes linked to breast cancer in
women. Years after the tests were launched, scientists still do not know
to what degree those genes contribute to a woman's cancer risk (3). But it
is precisely this ignorance that is fueling the human genome goldrush in bioinformatics.
The bioinformatics gold rush
The public GenBank holds sequence data on more than seven billion units
of DNA, while Celera Genomics claims to have 50 terabytes of data in
store, equivalent to 80 000 compact discs. The raw sequence data consist
of monotonous strings of four letters - A, T, C and G -that make up the 3
billion or so bases in the human genome. It is impossible to access the
data or to make any sense of the sequences without special software. Some
software are developed and made freely available in the public domain, but
the databases of private companies are provided to paid-up subscribers
only. Incyte launched an e-commerce genomics program in March that allows
researchers to order sequence data or physical copies of more than 100 000
genes on-line. Subscribers to the companys genomics database include
drug giants such as Pfizer, Bayer and Eli Lilly. Celera's gene notes,
similarly, will cost commercial subscribers an estimated $5 to $15
million, and academics, $2000 to $15000 a year.
This first wave of the human genome goldrush , bioinformatics,
is a fusion of information technology with biology (9) that promises to
turn the raw genomic base-sequence data into knowledge for making even
more lucrative new drugs. Bioinformatics is already a $300 million
industry expected to grow to $2 billion within 5 years.
One of the most basic operations in bio-informatics is searching for
similarity or homology between a new sequence and one in the database,
which allows researchers to predict the type of protein encoded and its
function, thus enabling the sequence to be patented. However, sequence
homology is no guarantee of homology in function, as we have seen.
With the understanding of protein structure, it is possible to conduct
searches for specific inhibitors and activators before carrying out actual
biochemical experiments in the laboratory. Only 1% of proteins so far has
had their structures determined (by X-ray crystallography).
Some bioinformatics companies cater to large users, aiming their
products and services at genomics, biotechnology and pharmaceutical
companies by creating custom software and offering consulting services.
Lion Bioscience, in Heidelberg Germany, has a $100-million contract with
Bayer to build and manage a bioinformatics capability across all of Bayers
divisions. Other firms target small or academic users. Web businesses such
as Oakland, Californiabased Double Twist, and e-Bioinformatics in
Pleasanton, California, offer one-stop internet shopping. These on-line
companies allow users to access various types of databases and use
software to manipulate the data. Large pharmaceutical companies have
established entire departments to integrate and service computer software
and facilitate database access across departments.
Close on the heels of bio-informatics, and possibly part of
bio-informatics, is proteomics. Its focus is on when and where
genes are active and on the properties of the proteins the genes encode.
It attempts to make sense of the complex relationships between gene and
protein and between different proteins (10), and has so far also attracted
hundreds of millions in venture capital.
According to Mark J. Levin, CEO of Millennium Pharmaceuticals in
Cambridge, Mass., large pharmaceutical companies need to identify between
3 and 5 new drug candidates a year in order to grow 10 to 20 percent
the minimum increase shareholders will tolerate. Right now, they are only
delivering a half to one and a half a year. Millennium has a relationship
with Bayer to deliver 225 pretested "druggable" targets within a
few years. Celera is in negotiations with GeneBio, a commercial adjunct of
Swiss Institute for Bioinformatics in Geneva to launch a company dedicated
to deducing the entire human proteome. As the number of human genes could
be as high as 100 000, it is estimated that the number of proteins could
well be in the region of 1 million. Up to the mid 1970s, scientists had
assumed, wrongly, that one gene codes for one protein. Instead, the
relationship between genes and proteins are complicated by many layers of
processing and editing starting before the genes are even transcribed
Proteomics has spawned a number of technical innovations, among which is
the Gene Chip, developed by Affy-metrix in Santa Clara, California. It
consists of glass microarrays coated with cDNAs (complementary DNA) to
identify which mRNA species are made (and hence which genes are
expressed). One microarray allows researchers to identify more than 60 000
different human mRNAs. The US National Cancer Institute has been examining
the mRNAs produced by various types of cancer cells in a Human Tumor Gene
Index project involving government and academic laboratories as well as a
group of drug companies including Bristol-Myers Squibb, Genetech, Glaxo
Wellcome and Merck. So far, more than 50 000 genes have been identified
that are active in one or more cancers.
The reality test
The sequencing of the human genome is undeniably a technical feat
comparable perhaps to landing on the moon. And it is difficult not to be
caught up in a frenzy of speculation on what can be achieved as genomics
joins forces with the latest in information and nanotechnology.
According to John Bell at Oxford , within the next decade, predictive
gene testing will be widely used both in healthy people and for diagnosis
and management of patients. Francis Collins, Director of the National
Human Genome Research Institute in the US, has stated that the benefits of
human genome mapping would include "a new understanding of genetic
contributions to human disease" and "the development of rational
strategies for minimizing or preventing disease phenotypes altogether."
Will predictive gene tests kill the insurance industry? That was one
worrying aspect considered (13). Apparently, during an industry conference
held in Boston, senior executives from several of the world's leading
genomics concerns agreed that genomics, with its promise of being able to
show who will be predisposed to what disease, would eventually give rise
to universal healthcare in the United States. "This could happen
especially if the defects in our genomes make us all uninsurable,"
said panelist Craig Venter.
"The good news about genomics is that we could soon be able to
catch deadly diseases in their earliest stages, when many are still
treatable and even curable. And genomics also holds the promise of being
able to deliver a bold new generation of drugs that will work more
effectively with our individual genetic quirks. The bad news is that
everyone will learn they are a walking time bomb, in one way, shape or
form.". But how reliable are gene tests in predicting what will
happen to the individual?
Two medical geneticist writing in the New England Journal of
Medicine (12), warned that the genetic mantle currently
put onto all diseases "may prove to be like the emperor's new
As has been pointed out by many scientists, most diseases are complex,
and correlations between genes and disease are therefore weak.
Associations between a disease and a genetic marker (of
unknown function) can occur by chance and some have proved to be spurious.
Although many disease-related genes have been mapped to regions of
specific chromosomes, no clear markers for asthma, hypertension,
schizophrenia, bipolar disorder, and other disorders have been found
despite intensive efforts.
Searches for susceptibility genes in breast cancer, colon cancer, rare
early-onset forms of type II diabetes, and Alzheimer's disease have been
more successful, but in each case these account for less than 3 percent of
all cases. That is because the risk of disease depends not only on other
genes but also on environmental factors. The problem of identifying
susceptibility genes is compounded when different combinations of genes
are implicated in a disease, for it means that finding enough patients to
serve as research subjects in a study will be extremely difficult.
Holzman and Marteau conclude, "In our rush to fit medicine with the
genetic mantle, we are losing sight of other possibilities for improving
the public health. Differences in social structure, lifestyle, and
environment account for much larger proportions of disease Those who
make medical and science policies in the next decade would do well to see
beyond the hype."
Let us take stock of some of what is on offer. The human genome
sequence, we are told, will enable geneticists to
understand more about diseases and thereby to design better drugs
design customized cures based on our individual genetic makeup
prescribe an individuals lifestyle based on genetic makeup.
More contentious are the claims to
diagnose all the bad genes that cause diseases
identify all the good genes responsible for desirable qualities such
as longevity, intelligence, being slim and beautiful, good at sports,
and so on
replace bad genes in gene therapy, including germline
create genetic enhancement by introducing good
create designer babies and superior human beings.
In reality, the only concrete offering from mapping the human genome are
the hundreds of patented gene tests. The high costs of the tests have
prevented them from being used in cases where it might benefit patients in
providing diagnosis (14). At the same time, those healthy subjects who
have tested positive are likely to suffer from genetic discrimination and
risk losing employment and health insurance. The value of diagnosis for
conditions for which there is no cure is highly questionable. The claim to
identify putative bad and good genes is also
fueling the return of eugenics, which has blighted the history of much of
the 20th century. This is exacerbated by the dominant genetic determinist
mindset that makes even the most pernicious applications of gene
technology seem compelling.
A prominent band of scientists and bioethicists are actively
advocating human genetic engineering, not just in gene therapy
for genetic disease, but in positively enhancing and improving the genetic
makeup of children of parents who can pay for the privilege, and have no
qualms regarding human reproductive cloning either (15). In many ways,
this is the most subtle form of hype for business to prosper. It is no
accident, therefore, that the Novartis Foundation has invited
arch-eugenicist Arthur Jensen, to speak at a scientific meeting on
intelligence (16). Jensen is best known for his insistence that black
people are genetically inferior in intelligence to white people, and hence
all efforts at enhancing the education of disadvantaged black children are
bound to fail.
It is clear that the promises as well as the threats remain largely in
the realm of future potential if not outright fantasy. We were promised no
less than "the blueprint for making a human being" by no less
than Nobel laureate James Watson when the Human Genome Project was first
touted, along with miracle cures for cancer and other diseases, and even
immortality. Now, ten years and dozens of sequenced genomes later, it is
all too obvious that geneticists havent got a clue of how to make
even the smallest bacterium, or the simplest worm, let alone a human
being. Nor has anyone been cured of a single disease on the basis of genes
or genetic information.
Despite the proliferation of genetic tests, many of them are
uninformative because the association between the genes and the diseases
is tenuous in the first place. And even the most informative tests
those associated with so-called single gene conditions cannot
predict the age of onset or the severity of the disease, as pointed out by
Wendy R. Uhlmann, president of the National Society of Genetic Counselors
(3). Indeed, an air of realism, if not disillusionment, pervades the
scientific community in the public sector.
"For a long time, there was a big misconception that when the DNA
sequence was done, wed have total enlightenment about who we are,
why we get sick and why we get old Well, total enlightenment is
decades away." This remark is attributed to geneticist Richard K
Wilson of Washington University, one partner in the public consortium
(17). He should have said that the misconception has been perpetrated by
the proponents of the HGP themselves. Still, he is promising "total
enlightenment" in a matter of decades. But will the human genome
project really deliver?
Rather than address the contentious claims of the human genome project,
I want to concentrate on those offerings that are largely seen to be
beneficial and uncontroversial; for if it cannot deliver on those, it can
certainly not deliver on the rest.
Will it deliver?
The growth in bioinformatics and proteomics is
an admission of the vast realms of ignorance that separate the 100 000
genes in the human genome from the living human being. It is also an
acknowledgement that the genetic determinist paradigm, which has done so
much to promote the human genome project, has failed miserably. There is
no simple, linear causal chain connecting a gene to a trait, good or bad.
Behind the hype is a desperate attempt to turn the exponentially
increasing amount of information into knowledge that can pay off the heavy
investments already sunk into the project.
Private ownership of the human genome is obviously not ever going to
benefit those who cannot afford to pay. Proponents of human genetic
engineering, indeed, see the creation of a genetic underclass
to be inevitable, as those who can afford to pay for genetic enhancement
will become gene rich relative to those who cannot afford to
pay (15). But can knowledge of the human genome really deliver the goods?
The fallacy of genetic determinism is widely recognized (18). Genuine
genetic diseases that can be attributed to single genes constitute less
than 2% of all diseases. And more and more geneticists are coming around
to the view that even those are subject to so many other genetic and
environmental influences that there is simply no such thing as a
single-gene condition. For the rest, the association between the condition
and the specific genes or genetic markers reduces to tenuous predispositions
or susceptibility (see above).
Predipositions to cancer for example, conceals the fact that
important environmental factors are left out of consideration. These
include the hundreds of acknowledged industrial carcinogens polluting our
environment. It is well-known that the incidence of cancer increases with
industrialization and with the use of pesticides. Women in
non-industrialized Asian countries have a much lower incidence of breast
cancer than the women living in the industrialized west. However, when
Asian women emigrate to Europe and the United States, their incidence of
cancer jumps to that of the white European women within a single
generation. Similarly, when DDT and other pesticides were phased out in
Israel, breast cancer mortality in pre-menopausal women dropped by 30%.
The overwhelming causes of ill-health are environmental and social. That
is the conclusion of a growing body of research findings. Environmental
influences swamp even large genetic differences.
The genetic determinist approach of the human genome programme is
pernicious because it diverts attention and resources away from addressing
the real causes of ill-health, while at the same time stigmatizing the
victims and fueling eugenic tendencies in society. The health of nations
will be infinitely better served by devoting resources to preventing
environmental pollution and to phasing out agrochemicals, rather than by
identifying all the genes that predispose people to
ill-health. The UK Royal Society produced a report in July, calling for
national and international coordination to deal with the dangers posed to
humans and wildlife by endocrine-disrupting chemicals, substances thought
to mimic or block natural hormones in amounts too minute to trigger a
conventional toxic response (19).
But it is the inherent complexity of the human organism and the lack of
a concept of the organism as a coherent whole that will continue to
frustrate all attempts at understanding health and disease within the
dominant, reductionist framework.
Despite the almost weekly hype on cancer cures, there is none, or none
that has resulted from information on genes and gene sequences. As
mentioned earlier, some 50 000 genes have been identified that are active
in one or more cancers using the Gene Chip, which is half of the maximum
number of gene predicted in the human genome!
In principle, knowing the genes that are over-expressed or inactive in
individual cancers can allow specific genes to be targeted. But this is no
different from interventions that have previously been available to
single-gene defects such as sickle cell anaemia or cystic fibrosis, none
of which has been cured as a result; which is why gene therapy has been
attempted, equally to no avail so far. One obstacle to effective cure is
that it is impossible to avoid unintended side-effects in a
system where proteins interact with one another and with the genes. But
the main problem is the failure to recognize that just as health is a
property of the organism as whole, so too is disease.
To try to understand disease in terms of genes and protein interactions
is worse than trying to understand how a machine works in terms of its
nuts and bolts, simply because the parts of the organism, unlike those of
a machine, are inseparably tangled up with one another. Mechanistic
understanding in terms of interacting parts is extremely unlikely to lead
to the design of better drugs. For that, we require knowledge of the
design of the human organism. And no amount of information on genes and
protein interactions will ever add up to the complex, entangled whole that
is the organism.
The promise of customized medicine and prescribed lifestyle based on an
individuals genetic makeup is a pipe-dream. The effect of each gene
depends not only on external environmental factors, but on the genetic
back-ground of all other genes in the genome. Individuals differ on
average by one base per thousand in their DNA. This amounts to three
million bases over the entire genome. As each gene is at least a thousand
bases in length, it means that every gene will most probably be different.
Assuming that only two variants exist in each gene, the number of
different genotypes is already 3(100 000). In fact, hundreds of variants
are typically found for each gene. Consequently, every individual is
genetically unique, except for identical twins at the beginning of
development, before different genetic mutations can accumulate in each of
the pair. That is why it is generally impossible to give accurate
prognosis of even single gene diseases unless the genetic background is
homogenous, as in an inbred laboratory strain of mice. And even then, the
mice have to be raised in a uniform environment.
The population in Iceland is thought to approach genetic homogeneity,
which is why the company deCode Genetics has acquired the genetic database
of Icelands 270 000 inhabitants, linked, anonymously to medical
records. The hope is to enable all the genes linked to a variety of
diseases to be identified. Unfortunately, the results will be valid
for the Icelandic population only, and will not be transferable to other
populations. Thus, mutations in the gene giving rise to cystic
fibrosis among Northern Europeans is associated with quite another
condition among the Yemans; while conditions diagnosed as bonafide cystic fibrosis in the latter population is associated with
mutations in another gene altogether (18). Some geneticists, indeed, are
beginning to think that better data for linkage to diseases might be found
in genetically heterogeneous populations, such as those in Manhattan and
London, rather than in homogeneous populations, such as those in Iceland
and Finland (20).
In classical genetic analysis, the net effects of a gene are determined
over all environments as well as over all genetic backgrounds (21), in
recognition that both environmental and genetic interactions have to be
taken into account. So, the most reliable data are those obtained in large
populations which are as heterogeneous as possible genetically as well as
environmentally. But the predictive power of such genetic data is always
limited to populationaverages. It is impossible, in
principle, to predict anything based on any individual genome. Those
who claim otherwise are ignorant of the most basic principles of
In case you still think that the blueprint for making a human being is
written in our genome, just take note that up to 95% of the human genome
may be junk DNA, so called because no one knows what its
function is. The same is true of all genomes of higher organisms. The
rough draft of the human gene map announced in June is only 85% complete
for the coding (functional) regions only.
It is difficult to see any definite strategy within either
bioinformatics or proteomics that can pay off, either in terms of basic
understanding the human organism as a whole, or in terms of miracle cures
and wonder drugs. There is nothing beyond the proliferation of more and
more detailed information on genes and proteins that have been spilling
out of the pages of scientific journals for the past decade. The one
million proteins encoded by the 100 000 genes interact with one another,
with the genes themselves, and small molecular weight cofactors
and messengers. Those interactions vary in different cells and
tissues at different times, subject to feedback from the environment.
Feedback from the environment can alter the genes themselves, and hence
the entire cascades of interactions involved. All that is the reality of
the fluid and adaptable genome (11), which the moguls of genomics and
bioinformatics have yet to come to grips with. The prospect of
understanding the human being by a detailed description of its molecular
parts is essentially nil. This reductionist fallacy has been exposed in
different forms, starting with the physicist Walter Elsasser (22).
Elsasser pointed out that there is no unique correspondence between the
states of the molecules within the system and the macroscopic condition of
the organism, say, whether it is ill or well, simply because there are
infinitely more molecular states than macroscopic states. Hence, a
detailed description of all of the molecules, even if it were possible,
will not enable one to determine the condition of the system as a whole.
If we were to define the state of the human organism in terms of its 100
000 genes simply as to whether each gene is active or not in each of its
70 trillion cells, the total number of possible states for each cell
is 2 (100 000). And that does not include the proteins, nor the
interactions among genes, proteins and cofactors. We need a computer large
enough to represent the states of all the molecules and their interactions
in each cell, and fast enough to give a description of how they change in
real time as the entire organism goes about its business of living. But
even then, we would still be left with no understanding of what is being
described. Current computation is unable to handle the dynamics of one
single protein folding, even given all the information on the amino-acid
sequence and the final shape of the folded protein. It takes the computer
four hours to find a solution that is at best 70% accurate; whereas the
protein itself folds to perfection within a fraction of a second (23).
What we need is a quantum leap to a new paradigm for understanding the
organism as a coherent whole (24). Without that, human genome research
will remain a scientific and financial black hole that swallows up all
public and private resources without any return either to investors or to
improving the health of nations.
"The Genome Triumphs in World Vision" Francois Sergent, New
York Times, 27 June 2000.