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8-Humans: Genetically modified humans: For what and for whom?



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TITLE:  Genetically Modified Humans: For What and for Whom?
SOURCE: ISIS, UK, Feature Article
        http://www.i-sis.org.uk/GMhumans.php
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.

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
                                   Box 1
--------------------------------------------------------------------------
                      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 
     blastocyst embryos
---- 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 
diseases.

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).

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
                                   Box 2
--------------------------------------------------------------------------
                              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 
shut down.

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 
cells.

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 
cancers.

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 
taking place.

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 
something else.

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 
cancer.

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 
generations."

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.



--


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