8-Humans: Genetically modified humans: For what and for whom?
- To: GENETfirstname.lastname@example.org
- Subject: 8-Humans: Genetically modified humans: For what and for whom?
- From: GENET <email@example.com>
- Date: Wed, 10 Jul 2002 16:38:11 +0200
- Content-Transfer-Encoding: 8bit
- Content-Type: text/plain; charset="us-ascii"
- Reply-To: firstname.lastname@example.org
- Sender: email@example.com
genet-news mailing list
-------------------------------- GENET-news --------------------------------
TITLE: Genetically Modified Humans: For What and for Whom?
SOURCE: ISIS, UK, Feature Article
DATE: July 2002
------------------ archive: http://www.gene.ch/genet.html ------------------
Genetically Modified Humans: For What and for Whom?
'Gene therapy' has been aggressively pursued for more than twelve years
with little success. The death of a healthy teenager in a clinical trial in
1999 alerted the public to the hazards involved. Although regulations are
tightened up, the technical and scientific problems remain unsolved.
Diseases are not understood; animal models are misleading; vectors for
delivering genes are ineffective and unsafe; and the effects of genes
delivered cannot be predicted.
The most damning criticism of gene therapy, is that it is a simplistic,
reductionist solution to complex diseases that must be understood in terms
of the human being as a whole in his or her social, ecological environment.
An in-depth analysis from Dr. Mae-Wan Ho and Prof. Joe Cummins
If you wish to see the complete document with references, please consider
becoming a member or friend of ISIS. Full details here
Promises and perils
Gene therapy involves introducing genes into human cells in order to cure
diseases. Billions have been invested, and hundreds of clinical trials
carried out since 1990, mostly in the United States, but there has not been
a single documented case of the miracle cure that was promised.
It took the death of a healthy teenager Gelsinger in an early phase
clinical trial in September 1999 to alert the public to the hazards of gene
therapy. The US Food and Drug Administration (FDA) and the National
Institutes of Health (NIH) responded to widespread concern. Clinical trials
were suspended. A public enquiry turned up 652 cases of serious adverse
events that went unreported, along with seven other deaths. David
Baltimore, Nobel laureate and president of the biotech company Caltech with
interests in gene therapy, declared, " I disagree we've had any benefit
from gene therapy trials so far, many of us are now asking, what the hell
are we doing putting these things into people?"
Administrative changes were put in place amid calls for more research, and
clinical trials resumed with further promises. Although more stringent
regulation can tighten up the protocols and ensure quality control, the
inherent technical and scientific problems remain unsolved. Some of the
necessary research that should have been done long ago is only now being
carried out, revealing findings that confirm our worst fears.
These problems are not new. The NIH's 1995 report documents a plethora of
scientific and clinical risks associated with gene therapy research, many
highlighted independently in an ISIS report.
The NIH expert panel found that all gene transfer vectors were ineffective
and little is understood on how they interact with the host. Basic studies
on disease pathology and physiology have not been done. It was not possible
to extrapolate from animal experiments. In cystic fibrosis, cancer and
AIDS, animal models do not have the major manifestation of the human
disease. Gene transfer frequency is extremely low. There were no controls,
and biochemical or disease endpoints were not defined.
The panel concludes, "only a minority of clinical studies... have been
designed to yield useful basic information". It expressed "concern at the
overselling of results of laboratory and clinical studies by investigators
and their sponsors, either academic, federal, or industrial, leading to the
widespread perception that gene therapy is further developed and more
successful than it actually is".
Gene therapy, genetic determinism and eugenics
Gene therapy is currently directed towards changing the genetic makeup of
the cells in the body of an individual only (somatic gene therapy). Most
countries outlaw gene therapy on germ cells (germline gene therapy) - which
would change the genetic makeup of the next generation – on account of the
its obvious eugenics implications. But there have nevertheless been calls
for gene therapy on the unborn and on human embryos, all on the back of the
publicity generated by the human genome project.
Among the promises of the human genome project and genomics research are
the possibilities of replacing 'bad' genes in gene therapy, including
germline gene therapy, of 'genetic enhancement'and 'designer babies'
to create superior human beings.
In reality, the only concrete offering from the human genome sequence is
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. At the same time, healthy subjects who testing 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 fuelling 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 advocating human
genetic engineering, not just in 'gene therapy' for genetic disease, but
in positively enhancing and improving the genetic makeup of children
whose parents can pay for the privilege, and have no qualms about human
reproductive cloning either (see "Why clone humans?", this series).
The United States Food and Drugs Administration suspended an experiment in
gene therapy because of concerns that it might alter the germ line, a
possibility many have pointed out previously. The recombinant DNA Advisory
Committee (RAC) of the National Institutes of Health met to consider the
implications, regarded the risks to be 'extremely low' and germ-line
modification acceptable as one of the 'side-effects'.
Meanwhile, researchers isolated male germ-line stem cells from the testis
of mice and genetically modified them in vitro. The modified stem cells
were then injected into the testes of genetically infertile mice, which the
cells successfully colonised, and matured into sperms.
This is so easily done that it may become the method of choice for all
genetic engineered animals in future, including human beings. The testis of
genetically infertile mice is so readily colonised by the male germ-line
stem cells that it is an open door to corporate control of male
reproduction. It has already been suggested that human males undergoing
irradiation and chemotherapy treatments for cancer that destroy stem cells
could have their male germ-line stem cells removed and frozen, to be re-
transplanted after the cancer is eradicated. This is a short step from
genetic manipulation of the male stem cells in vitro.
In vitro fertilisation, human nuclear transfer cloning, surrogate
motherhood, have all passed with relatively little comment from the
establishment, as these were all aimed at manipulating reproduction in
women. Adding male reproduction certainly increases the possible routes for
germ-line gene therapy (see Box 1). Germ-line gene therapy has enormous
impacts on the social fabric of human societies, and should not be allowed
in the name of 'scientific progress', particularly as it is based on a
discredited, outmoded paradigm that has largely ignored both physical risks
and ethical implications.
Routes for Germline Gene Therapy
-- Via female germ cells and embryos
---- Injecting naked DNA into egg or embryo
---- Transducing eggs by retroviral vector
---- Transducing embryonic stem cells by retroviral vector and injecting
transgenic stem cells into blastocyst embryos
---- Transducing adult stem cells and injecting transgenic stem cells into
---- Transducing adult cells by retroviral vector and transferring
transgenic nuclei into ‘empty’ eggs
-- Via male germ cells
---- Transducing sperms by retroviral vector and fertilizing eggs in vitro
---- Transducing male germline stem cells with retroviral vector and
injecting transgenic stem cells into testis to develop into sperms
Gene therapy, how and for what?
In gene therapy, an artificial construct – consisting in the minimum, of a
promoter driving the expression of a gene, and the gene itself - is
delivered, either by viral vectors, or as naked DNA into cells. There are
two main ways to carry out gene therapy, ex vivo and in vivo. In the ex
vivo procedure, the constructs are transfected (or transduced) into cells
outside the body, and the resulting transgenic cells are reintroduced into
the body. In the in vivo procedure, the constructs are introduced into the
body by numerous routes depending on the locating of target cells,
emphasizing the ease with which cells take up foreign DNA. These include
rubbing on the skin, applying in drops to the eyes, inhalation, swallowing,
injection or perfusion into the bloodstream or directly into the tissues
such muscle or solid tumours.
The only limited success stories so far have been associated with the ex
vivo procedure, which avoids most, if not all the risks of in vivo
procedures. In April 2002, a team in London's Great Ormond Street Hospital
in Britain used gene therapy to cure a child with X-linked severe combined
immunodeficiency disease (SCID). They followed the approach taken earlier
by the team at the Hospital Necker-Enfants Malades in Paris, which involved
ex vivo manipulation of bone marrow stem cells.
The identification and successful isolation of stem cells (both adult and
embryonic) may make ex vivo gene therapy the preferred procedure for some
Four main types of disease are targeted for gene therapy: rare single-gene
inherited disorders such as cystic fibrosis and sickle-cell anaemia, multi-
factorial disorders such as cardiovascular disease and diabetes, cancers
and infectious diseases.
Among the first candidates for gene therapy was cystic fibrosis, a mutation
in the gene, cystic fibrosis transmembrane conductance regulator (CFTR).
But 12 years on, there has been no success. It is difficult to deliver the
vector to the cells, there's lack of persistent gene expression, while
immune responses developed to viral gene products, transgenes, or the cells
targeted by the vectors. Furthermore, mice with deletion of the CFTR gene
or the common human CFTR mutations do not develop lung diseases like people.
Multi-factorial disorders, like coronary heart disease or diabetes, involve
many genes and are strongly influenced by environmental factors. Studies
from Finland, US to China have all documented the overwhelming influence of
diet and exercise in reducing type 2 diabetes as well as heart disease.
In 2000, the American Heart Association (AHA) expert panel on clinical
trials of gene therapy in coronary angiogenesis found gene therapy
unsatisfactory, especially in comparison to conventional treatments, and
expressed serious concerns over safety.
Hazards of gene therapy
One of the major technical hurdles for delivering foreign genes is the form
in which the constructs are delivered. Although naked DNA is widely used
for modifying germ cells, this does not work as well for somatic cells
therapy, for which viral vectors are routinely used.
The ideal vector would possess the characteristics listed in Box 2.
Unfortunately, such an ideal vector has not yet been developed. Plasmid
vectors are easy to produce and manipulate and capable of stably
transducing cells. But they are inefficient in delivering transgenes to non-
proliferating cells - which constitute most of the cells in the body - and
can cause immune responses directed against CpG repeat sequences that are
plentiful in plasmids of bacterial origin. All the problems of gene
delivery are the same as those involved in creating other GMOs (see "GMOs
25 years on", this series).
The Ideal Vector
-- Is easily produced in pure forms at high titres (yields)
-- Targets genes to specific site in the genome
-- Tranduces non-proliferating cells in vivo efficiently and stably
-- Enables long term expression of transgenes without toxic effects,
inflammation or immune responses
-- Capable of tissue-specific targeting and transgene expression
-- Allows regulated transgene expression
There are several kinds of viral vectors, all of which carry risks of
generating new viruses by recombination, or by activating endogenous
viruses. As they insert into the genome at random, they can cause genetic
disturbances (position effects) including cancer. In addition, some are
immunogenic, and can trigger acute fatal reactions. The main vectors used
are as follows.
Retroviral vectors such as murine leukaemia virus-derived vectors, were
among the first used, but are no longer regarded as first choice because of
several drawbacks. Low titres, inability of virus to infect non-dividing
cells, lack of stable expression and recombination within cells are feared
to cause activation of pre-existing, dormant retroviruses.
Adenoviral vectors were used for epithelial cells specifically, and was the
first choice for cystic fibrosis. They can infect non-dividing cells, but
not stem cells, so treatment has to be repeated at intervals. The vector is
immunogenic and even the first application can cause inflammatory events.
After repeated applications, the cells will no longer become infected. The
teenager Gelsinger died from a high dose of adenovirus, leading to liver
failure followed by multi-organ failure. Post-mortem revealed that many
organs were infected with high concentrations of adenovirus, contrary to
the anticipated cell-specificity of adenovirus infection. As with
retroviral vectors, gene delivered with adenoviral vectors are frequently
Adeno-associated viral vectors (AAV) are not pathogenic, and are thought to
integrate at a defined position in chromosome 19. However, this site-
specific integration is linked to the viral rep gene involved in viral
replication. Immune responses occur also against AAVs. Moreover, a helper
virus (usually herpes simplex or adenovirus) is required for AAV
production, with danger of contamination as well as recombination to
generate infectious viruses.
Recently, researchers in the Department of Medicine, University of
Washington Seattle, reported that the AAV does not integrate at specific
sites. The AAV integrated into at least six different chromosomes. Although
it was most frequently found in chromosome 19, the insertion was not at the
specific intended site. Furthermore, insertions were "associated with
chromosomal deletions and other rearrangements", or genome scrambling.
In another experiment, newborn transgenic mice with the mucopolysaccharide
storage disease MPSVII were treated with recombinant AAVs carrying the
enzyme that breaks down the mucopolysaccharide. A high proportion of the
mice were found to develop liver and other cancers. The cancers were found
to be specific to rAAV, as they were absent in mice with bone marrow
transplant and in transgenic mice carrying the same enzyme cassette but
without the rAAV.
Lentiviral vectors, a subgroup of retroviruses, are capable of infecting
non-dividing, but not truly quiescent cells. The AIDS associated virus HIV-
1 is currently the candidate, after disarming the genes that cause disease.
However, cell lines used for packaging may contain the disarmed genes, and
give them back to the vector to generate pathogenic viruses. Like other
retroviruses, these might activate endogenous retroviruses within recipient
Apart from these main classes of viral vectors, others have been developed,
including herpes simplex virus and baculovirus, an insect virus that's
being modified to control insect pests in agriculture, and has been found
to infect all kinds of mammalian cells.
Even bacterial pathogens that can gain access into mammalian cells are
being exploited as vectors, including Agrobacterium, widely used in genetic
modification of plants, that was also found to transfer genes into
mammalian cells. There is no limit to the dangerous agents that are being
developed for gene therapy.
Researchers in Heinrich-Pette-Institute, Hamburg, and Hannover Medical
School, and their colleagues found that a retroviral vector carrying a
marker gene, thought to be 'biologically inactive', actually induced
leukemia in all the mice. The disease appeared to have resulted from a
combination of the vector inserting in a position that activates a cancer
gene and the transgene product interfering with cancer suppression.
Although cancer itself is a risk of gene therapy, it is also the major
target for gene therapy, for economic, if not good medical reasons.
Gene therapy for cancer
Cancer gene therapy has indeed taken over as the more active research area.
A recent review states, "Although no cures can consistently be expected
from today's cancer gene therapy, the rapid progress may imply that such
cures are a few short years away."
Cancer gene therapy targets cancer cells, cancer blood supply, the immune
system and the bone marrow.
One of the main candidate genes is the tumour suppressor gene p53, which
induces cell death if DNA damage is extensive. Viral-mediated p53 gene
therapy is in clinical trials with certain lung cancer and head and neck
Another candidate is the 'suicide gene'. This gene kills cells as it
codes for an enzyme that converts a precursor drug to a toxic compound.
The suicide gene is delivered to the target cells in a viral vector by
injection before the precursor is given. The Herpes Simplex Virus (HSV)
thymidine kinase is an example, it adds a phosphate group to the drug
ganciclovir, 1000 times more efficiently than the mammalian enzyme. This
blocks DNA synthesis, leading to cell death. Clinical trials are already
Anti-angiogenic gene therapy uses inhibitors of blood vessel formation in
tumours. Another approach is through genetic enhancement of anti-tumour
immune responses by modifying immune cells.
Cytokine-based therapy aims also to enhance the immune response to tumours.
The genes used include those encoding the interleukins, IL –1b, IL-2, IL-4,
IL-12, as well as GM-CSF and IFN-g. In clinical trials, a partial clinical
response has been recorded in some of the patients.
Simplistic approaches to complex reality
The profusion of cancer gene therapy reflects the desperate attempts of the
simplistic gene-centred science to cope with the complex reality of the
organism. Decades of cancer research focusing on molecular genetics have
brought us no closer to understanding the causes of cancer while many
cancers have been increasing at alarming rates.
The stepwise development of human cancer is clinically well-recognised:
initiation, promotion and progression, but trying to establish causal links
between genetic alterations to different disease manifestations is
One of the hallmarks of cancer cells is genetic instability, both at the
level of single nucleotides and the chromosomes. Thousands of point
mutations and small deletions are typically present in cancer cells, as
well as large-scale chromosomal disturbances.
A cancerous cell does not stop dividing. Cell division is a complex
process, involving not just precise copying of the genes but also their
exact distribution to the two daughter cells so that each has two copies of
every chromosome. Anything that disturbs this process can result in genomic
imbalance. Damage to the genes that monitor the intricate copy and delivery
process, the so-called guardians of the genome, can result in an altered
chromosome balance in the daughter cells. Mutations in those key genes can
initiate chromosome imbalance, so there may be a role for gene mutation in
However, many other disturbances can start the process going wrong, such as
chemicals from the environment, radiation or any form of stress, or indeed,
stray foreign DNA jumping into the genome, as in gene therapy. It doesn't
have to be a gene mutation.
Once genomic imbalance starts, it will tend to get worse: further
disturbances to cell division will result from a positive feedback effect.
However, this is counteracted by the reduced survival of disturbed cells
and the body will tend to get rid of them, until some eventually escape the
immune system and grow out of control. There does seem to be a positive
correlation between the number of chromosomal alterations within a tumour
and the malignant potential of the cancer.
As every cancer is genetically different, it will be very difficult to
target cancer cells with specific drugs, let alone specific genes. So the
key is prevention.
Recognition of the diverse factors that can disturb cell division means
that the multitude of chemicals that pollute our environment must be
screened for their capacity to induce chromosomal imbalance. Most of these
don't cause mutation, but may well disturb chromosome separation.
Finally, the phenomenon of cancer remission needs to be much more
thoroughly investigated. Remissions can occur after various types of
stimulus to the whole body, such as change of diet or life-style, and many
other non-specific influences. Cancer is primarily a systemic disease of
the whole organism, and only secondarily a disease of particular cells or
of genes in those cells.
The same kind of simplistic approach characterises other forms of gene
therapy. The expression of the introduced gene is not the only, nor the
main problem, its regulated expression within the body is the key to normal
functioning. Unfortunately, most foreign genes are introduced with
aggressive viral promoters that simply make them over-express in an
unregulated way. The underlying assumption is that the single gene product
is necessary and sufficient to provide a cure. But this does not even work
for so-called single gene disorders.
Helge Grosshans of Heidelberg University, Germany, has said it well: "Gene
therapy follows a simple principle: causal therapy instead of symptomatic
treatment. Accordingly, expectations were high....By now, however, it has
become evident that particularly in those cases where the idea of "causal
therapy" appears most appropriate, i.e., monogenic diseases, success is
minimal. This is due, among other factors, to the cell being a very complex
and dynamic system. A change in the genetic make-up that causes a cellular
defect also brings about a number of compensating mechanisms. Mere addition
of the "health" gene does not automatically re-create the original
situation, because the compensatory mechanisms will not necessarily be
turned off again."
Also, "A newly synthesised normal protein will appear abnormal to an immune
system that has never been exposed to it".
In other words, the cell, and ultimately the entire organism functions as a
whole, so practically every part of it will have changed when even a single
gene is mutated. Consequently, restoring that gene is unlikely to put
things right, and may even result in the gene product being targeted by the
body's immune defence.
Most of all, the procedure of gene therapy is itself hazardous: "The
additional steps of gene therapy, such as integration and expression, would
present additional problems and safety risks. A therapeutic chemical can be
broken down and will be eliminated from the body within a certain period of
time. Foreign DNA, on the other hand might stay in the body until death and
even be transferred into additional cells or passed on to future
The simplistic gene-centred approach has failed because it is fundamentally
at odds with the complex reality of the organic whole. By contrast, many
indigenous cultures all over the world never lost touch with the organic
reality that encompasses an entire way of life. Contemporary western
science is beginning to rediscover this sense of the whole across the
disciplines. It is a challenge for western and indigenous scientists to
work in equal partnership towards restoring sustainable, healthy ways of
life to all.
| GENET |
| European NGO Network on Genetic Engineering |
| Hartmut MEYER (Mr) |
| Kleine Wiese 6 |
| D - 38116 Braunschweig |
| Germany |
| phone: +49-531-5168746 |
| fax: +49-531-5168747 |
| mobile: +49-162-1054755 |
| email: firstname.lastname@example.org |