It was that Augustinian monk, Gregor
Mendel experimenting with his smooth and wrinkled garden peas in
the 1860s who led us to an understanding of genetic
inheritance. Then in 1953 it was Francis Crick’s and James
Watson’s Nobel prize-wining work on the structure of
deoxyribonucleic acid (DNA) that showed it to be the ‘messenger’
of the genetic code. Then for the last 20 years recombinant
DNA technology, or so-called genetic engineering, has been the
much hyped technique. Now there is gene therapy. Ten
years ago this sort of therapy was mere speculation, today it is
reality. What it is? Is it good, bad or
indifferent? How is it done? What has it done?
What about its future?
Every cell of your body (except the
germ cells, namely, sperm or ova) contains 46 chromosomes and each
of these contains your genes packed in coils of DNA. These
genes contain the codes for a myriad of proteins that constitute
and regulate our bodies (that’s not a reductionist statement
because we are more than just our physical being). We should
marvel at this complexity – every human cell contains over 3
billion codes in its DNA and every human adult carries about
120,000 million miles of DNA strands in his or her body.
It is all mightily complicated, so perhaps it is not surprising
that the system sometimes goes wrong. Indeed, we are all
carriers of defective genes, but diseases are not necessarily
expressed in us or in our offspring because some, like breast
cancer, are the result of the interaction of several faulty genes
and we do not carry all of them, or because though you may be a
carrier of say, cystic fibrosis, your spouse is not, or because
other factors, like diet and environment also play a part in the
onset of such diseases.
Recently advances have been made in screening for genetic
diseases. Carriers of cystic fibrosis can now be detected by
analysing cells scraped from the inside of the mouth. A
benefit of such screening might be a personalised life plan; if
you were predisposed to a heart disease, then you could be
advised, ‘do this, don’t do that.’ Predisposition is the
buzz-word. And it is now being applied to diseases like
schizophrenia, depression and Alzheimer’s. But screening can
have a downside. Employers will want us screened, so will
insurance companies; who we marry may be a problem; with whom and
how (probably by IVF and then embryo selection) we have our
children may be controlled to lessen the incidence of genetic
diseases. In the 1970s a sickle cell anaemia screening
programme in the US went awfully wrong; there was discrimination
and job dismissals of healthy people because the tests were
inaccurate.
In a similar way, although we can now state, ‘Yes, you are, or no,
you are not a carrier of cystic fibrosis, there is still a 15%
uncertainty factor and this is appallingly unnerving for such
people. Or what about the woman who is told there is a 1 in
5 chance that her child will suffer from schizophrenia? What
about her anxieties? Could she cope? Screening is only
sensible if a proper cure is available. Can gene therapy
help?
What is gene therapy?
Basically, it is inserting a healthy
gene into body cells carrying a defective gene. There are
three types of potential gene therapy. First, germline
therapy, that is inserting genes into gametes (ova or sperm) or
the gamete-producing cells. Second, zygote gene therapy
performed on a fertilised ovum (a zygote) in conjunction with
IVF. This may be effective for diseases like cystic fibrosis
because all affected tissues would be changed. These two
therapies would be heritable, that is, they are a form of
eugenics. Third, somatic gene therapy, that is inserting
genes into cells, such as bone marrow cells to cure a disease like
thalassemia, which is a sometimes lethal form of anaemia.
This treatment does not cause inheritable changes and is more
similar to current medical procedures such as bone marrow
transplants.
At the moment only somatic gene therapy is being used and the most
promising candidates for treatment are disorders caused by the
impairment of a single gene – as opposed to those caused by
multiple genes, or even whole chromosomes, like Down’s
syndrome. A disease that fits this criterion is a rather
rare condition known as severe combined immunodeficiency (SCID),
where because of their limited resistance to infection, patients
have to live inside those sterile bubbles. SCID is cause by
a faulty gene that should produce the enzyme, adenosine deaminase
(ADA); SCID patients thus have an ADA deficiency.
How
is gene therapy done?
The most successful strategy so far
used involves viruses and their ability to enter a cell bringing
their own DNA with them. Some viruses can be engineered to
contain particular DNA sequences of the correct, healthy gene, but
there are huge technical problems concerned with packaging enough
of the right sort of DNA, and in addition, most viruses do not
readily splice their genetic material into the genes of the cells
they infect.
What has been done so far?
The first US-approved clinical trial
of a gene therapy started in September 1990 with a four-year-old
girl, Ashanti DeSilva, suffering from ADA deficiency. She
had been on enzyme replacement therapy for two years., but the
efficacy of this was decreasing as shown by increased
infections. So once a month, some of her blood cells, called
T-lymphocytes, which mastermind the workings of the immune system,
were sampled, grown in the laboratory, incubated with a viral
vector (which carried the normal ADA gene), then these cells were
infused back into her. Over the next 10.5 months she had
seven more infusions. Her clinical condition improved and
the treatment periods were lengthened to 3-5 month
intervals. Another girl, aged nine, has begun a similar
regime. Both have shown improvement; they are now attending
school regularly and have had no more than an average number of
infections, also no significant side effects have been
noted. This approach requires repeated treatment because the
effect lasts only as long as the life of the corrected T-cells, so
it is not a cure, but it marks a watershed in gene therapy.
Another hereditary disease, hypercholesterolaemia which leads to
premature death from heart attacks, has been treated by a similar
method since early 1992. The cause is a faulty gene in the
liver that produces a defective version of a protein called low
density lipoprotein (LDL) receptor, which controls the cholesterol
levels in the body. The patients have about 15% of their
livers removed, these samples are homogenised and the liver cells
isolated. The cells are then exposed to a virus that has
been genetically engineered to contain the correct DNA sequence
for the LDL receptor. The treated cells are injected back
into the patient’s liver via a vein. Once there, the idea is
that they will implant, grow and produce the required protein.
Such trials are now starting regularly. In China, a therapy
for haemophilia B has just begun; results are not yet
available. During June 1992 two firsts in gene therapy were
achieved. A corrected gene was injected directly into the
tumour of a 67-year-old US woman with a malignant melanoma – it
was the first time that such a gene had been put directly into a
human patient. Also it was the first time a non-viral vector
had been used to deliver the modified gene – in this case the
vector was liposomal cells. The principal investigator at
the University of Michigan, Gary Nable said, ‘We have begun to use
DNA as a drug.’
Is gene therapy safe?
Such treatments are certainly
experimental and medical science is invariably inexact.
Nevertheless, a recent report from a leading scientist in the
field summarised 106 monkey-years and 23 patient-years’ work with
viral-mediated gene transfers. No side effects, pathology or
malignancy have been reported. Nevertheless, the danger
always exists of producing a germline mutagenic event during gene
insertion.
Is gene therapy ethical?
Some fairly profound questions are
now being asked. Do infants have the right to inherit
unmanipulated genes? What about informed consent for
patients who do not yet exist? At what point do we cross the
line of ‘playing God’? What about ‘enhancement’ experiments,
inserting genes to improve desired physical or mental
characteristics? When does ‘enhancement’ become ‘treatment’
and vice versa? But such pertinent questions have a
habit of being swept away by the momentum of scientific
achievement.
Currently, there is a broad consensus that somatic cell gene
therapy for the treatment of a serious disease is an ethical
option. And while there is still considerable opposition to
germline therapy, this should not be misconstrued as a permanent
moratorium. As Sir Walter Bodmer, president of the Human
Genome Mapping Organisation has said, ‘Most of us believe this
(germ cell therapy) is something we shouldn’t do because we don’t
know enough about it.’ Even Baroness Warnock tends to agree,
but she does not rule out germ cell therapy for all time.
However, W. French Anderson, a leading US molecular scientist, is
perhaps more realistic when he states that, ‘The feeling (my
italics) of many observers is that germline gene therapy should
not be considered until much more is learned …’ It would be
naive of us to think that germline therapy will not be started
sometime, somewhere, by someone.
What
of the future?
As already mentioned, one of the
current major problems is controlling the vector, or delivery
system, of the corrected gene. Viruses, which can invade
cells and control the genetic mechanisms, are considered the best
available at present. But there are still many
questions. How safe are they? How specifically can
they insert the right information into the right tissue? How
long will they continue to function? When satisfactory
vectors are available, gene therapy may have more impact upon
medical science. Or will it? Certainly, today’s
procedures, whereby cells are removed from a patient, the desired
gene inserted and the gene-corrected cells returned, are too
specialised, too expensive and too labour intensive. Gene
therapy will have a major impact only when vectors are developed
that can safely be injected into patient, like insulin is
now. A wider range of diseases may be treatable in the next
few years, but (like IVF) it will be for the thousands rather than
the millions of patients. We should also remember that as
radical as gene therapy is, it cannot cure all human
diseases. Most illnesses are not genetic, most are caused by
agents such as microorganisms and malnutrition.
Unlike Baroness Warnock, I do believe in the ‘slippery slope’ of
medical ethics. She maintains that we are in safe hands –
medical practice will be regulated by society, so nothing terrible
will happen. I maintain something terrible is about to
happen – some genetic experimenters are already tiptoeing on the
edge and looking longingly down that slope! And a brief look
at the recent history of medical ethics will bring no comfort to
the morally sensitive. The 1967 Abortion Act was designed to
help with a few problem pregnancies – now, 25 years later, more
than 600 abortions are performed each day in England Wales.
As Schaeffer and Koop warned us years ago, ‘Practices once
labelled unthinkable are now considered acceptable.’
So far, we have not begun any gene therapy in the UK, but it will
come. Be warned, be ready and beware!