Prepared By Dace Shugg
Professor Bob Williamson AO, FRS
Professor of Medical Genetics at the University of Melbourne, Australia
Bob Williamson recently addressed scientists, doctors,
research students, parents and PWCF about this topic at four meetings
in Tasmania. This is a brief summary or “conference report”
of some of the things he had to say to a group of 42 enthralled parents,
grandparents and PWCF, which I would like to share with readers of CFW
newsletter.
Each of us, in our way, can feel frustrated with the systems within
which we work. This is true for doctors and scientists, who start working
on a new experimental idea with great enthusiasm (such as gene therapy,
or stem cells), but end up feeling really ground down as a result of
years of dealing with restrictions imposed by lawyers, ethics committees
and hospital and health department systems. Bob recommended that all
those living with or doing research on CF should read an article published
in the New Yorker to give us an idea of what we should aim at for our
CF children and adults.
http://www.newyorker.com/fact/content/?041206fa_fact
Carrier Testing
There are an estimated one million carriers of mutations
that cause CF in Australia (population 20,000,000 people). Tasmania,
the smallest State of Australia has a high incidence of CF, probably
because many of the settlers came from Ireland and Scotland. In a place
the size of Tasmania, with a population of only half a million people,
it would be feasible to test the entire population for CF carrier status
at a laboratory cost of around a dollar per head. It should certainly
be offered to the extended families of known cases and carriers. The
real cost is the time it would take for doctors, nurses and counsellors
to discuss the meaning of the results with the great majority of those
identified, who previously had no idea they might be carriers.
Healthy Carriers
Why are there so many carriers in Australia and why is
CF so common? The reason seems to be that CF carriers are actually healthier
than non-carriers because they are resistant to diarrhoea in childhood.
This is because common germs causing diarrhoea, Salmonella and E coli,
may attack the body by binding to CFTR in the gut. Since carriers only
have half as many proteins on the surface of these cells as non-carriers,
they are less likely to pick up a bug! This was news to all in the room,
I am sure!
Prenatal testing
Parents who have a CF child, and wish to have another
child but do not think they could cope with a second infant with CF,
can now be tested at 10-11 weeks pregnancy, rather than 18-20 weeks
as used to be the case in the past. Some parents choose to have IVF,
in which case the 8-cell embryo can be tested before implantation to
ensure that a child without CF will be born.
No cure yet
In our frustration that no optimum treatment and no cure
is yet available for CF, we tend to forget that 25 years ago the outlook
for CF children was very bleak, and few children reached adulthood.
In Australia, 98% of cases of CF are diagnosed in the first few weeks
of life as a result of antenatal screening tests, and babies are started
on appropriate therapies within hours of diagnosis. In Australia, almost
half of those living with cystic fibrosis are over 18 years and soon
it will be over 50%. We have a new situation: better antibiotics, better
mucolytics and better enzymes are now available for treatment, and for
those who need a transplant, better anti-rejection drugs.
Small steps matter
In the USA $170 million dollars is raised for CF research
every year from charitable donations. The Cystic Fibrosis Foundation
(CFF) funds a very active and innovative drug discovery program, which
coordinates the testing of dozens of new and old drugs and compounds
which can improve therapy for PWCF. If every year a drug is found which
helps to make a difference and extends the life of PWCF by 6-12 months,
it adds up. But as far as those who are committed to much better CF
care, such as Professor Williamson, are concerned, this is not fast
enough.
He went on to describe what advances have been made using
gene therapy and stem cells, and whether these could be a permanent
fix for those living with cystic fibrosis.
Gene Therapy
When the CF gene was discovered and isolated scientists
thought that it would be a simple matter to get a healthy copy of the
gene, insert it into the cells that line the lungs, and restore normal
salt transport function. Right? Unfortunately, not right.
The healthy copy of the gene was easy to get, from anyone who does not
have cystic fibrosis. Lots of copies can be grown in the laboratory,
using a fermenter that is similar to the ones used to make beer! However,
doctors and scientists vastly underestimated the difficulty of getting
the genes into cells in the lungs. The human body has powerful defences
against taking up foreign DNA. Bob’s group tried (in 1994) to
insert the healthy genes by wrapping them in fat and spraying the mixture
into the airways of twelve CF adult volunteers. The scientists obtained
a 50% correction for a few hours. This was wonderful news scientifically,
because it is a starting point for more research, but it did not bring
any direct benefit for the 12 CF patients.
Cancer and cold viruses
Viruses have been used to transport healthy genes into
cells. They are very effective but unfortunately there have been serious
side effects in some cases. For instance, when cancer viruses were used
to treat patients with “immunodeficiency” (the children
who have to live in bubble tents because they have no resistance to
infection), four out of twelve developed leukaemia following this treatment.
There are worries that viruses would also have side effects if used
for CF. Although gene therapy is a great idea, it has proven to be very
difficult to get the results we want.
Stem cells
Bob believes that stem cells could provide part of the
answer. What are they, what can they do for PWCF and why has stem cell
research created such controversy? A stem cell is a cell, which is pluripotent,
which means it can give rise to lots of copies of many kinds of cell
when triggered in certain ways. Both embryos and adult tissues can give
stem cells.
We used to think that an egg and a sperm are needed to
make an embryo, but the creation of Dolly the sheep proved that it could
be done without sperm. Removing the nucleus out of an ovum and inserting
the nucleus of a cell from an adult tissue, such as skin, can produce
stem cells, which can then give every kind of cell. In the case of Dolly
the sheep it was the nucleus of a cell from Dolly’s mother’s
udder. In the laboratory, after 300 unsuccessful attempts, this transplanted
artificial embryo gave a real embryo and eventually a cloned sheep.
Scientists have now proved that it is possible to take
cells from a nuclear transfer in the lab and grow cells that are pluripotent
in a Petri dish. These can be kicked into growing as respiratory cells
by using biochemical factors to trigger this procedure. The question
now is, can we put a healthy copy of the CF gene into these cells, and
then put the cells into the patient. Will the body accept or reject
these cells? Clearly, if the starting nucleus is from a person with
CF, it will be seen as “their cell”, and not be rejected,
but this means finding a way to correct the CF mutation in the lab.
Surplus Embryos from IVF
The easiest way to get stem cells is to use spare
embryos left over after IVF procedures. If the couple agrees,
spare embryos can be used for research rather than being flushed down
the sink. However, some people believe very strongly that using embryos
in this way devalues human life, even though the embryos would be destroyed
in any case. This is why any proposals to use spare embryos have to be approved by Research Ethics Committees.
If IVF has been used to allow a couple to have a baby
without CF, then the CF-affected embryos that are not implanted, are
especially valuable for CF researchers. If they can correct the fault
in cells from the embryo affected by CF, it will be a great model system
to show that CF patients could be treated with their own corrected cells,
without any problem of cell rejection.
Cord Blood
Cord blood from the placenta of a newborn baby is very
rich in stem cells. If cord blood is saved from the non-CF brother or
sister of someone with CF, then the cells would have a one in four chance
of having an identical immune pattern to the cells in the child with
CF. Cord blood cells might be grown into respiratory cells and used
to treat the CF sibling, if the HLA match is good.
Adult Stem Cells
Bob reported that it seems as if most adult tissues also
have some stem cells, though they are often hard to grow. This work
is attracting a lot of funding not just to fix CF but because it has
exciting implications for diseases such as Alzheimer disease, Parkinson’s,
spinal injury and cancer. Christopher Reeve, who campaigned for this
research, was able to show very small improvements in movements before
he died. This was only a small step, perhaps only a 5% improvement,
but one that gives hope to other quadriplegics who long to regain some
independence.
The Law
Legislation in the area of what is allowed and what is
not in Australia does not seem to be based on common sense or logic.
Surplus healthy embryos from IVF can be used for research subject to
Ethics Committee approval, but a couple cannot donate egg and sperm
to make a CF embryo to treat their own CF child. It is forbidden to
transfer a nucleus from one cell to another even if it stays in the
laboratory and goes nowhere near a womb. In some respects Australian
laws are very liberal, but in other ways (such as nuclear transfer)
they are much more restrictive than those in other countries such as
the United States and Europe. The Australian laws are currently under
review and hopefully the outcome will be beneficial to the CF community
and enable Australian scientists to stay in Australia and continue work
to find a cure.
Why do research in Australia?
Some people question, is it important to have CF research
in Australia? Why not wait for developments from other countries like
the USA and UK? Why keep raising money for research in Australia? What
difference if we stop funding CF research in Australia? Bob said that
at first, for a few years, the difference will not be noticeable, but
after five or ten years the critical mass of first rate doctors and
scientists will have moved on to other countries. This means that Australian
PWCF would have to wait in line to benefit. Every country needs to try
to keep some excellent research going, to remain a player in the international
world of cystic fibrosis research.
