A Massachusetts biotechnology company, Advanced Cell Technology, provoked
a storm of outrage last month by reporting that it was trying to create
human embryos by cloning. But the company faces another difficult challenge:
its goal, the use of such therapeutic cloning to produce useful treatments,
may simply be impractical.
That is because the approach, if it works, will involve cloning patients
individually in order to develop treatments tailored to them.
"It's too laborious and costly to employ as a routine therapeutic
procedure," said Dr. Alan Colman, research director at PPL Therapeutics,
the Scottish company that helped cloned Dolly the sheep.
Other leading stem cell companies apparently agree.
For one thing, unless success rates improve drastically, the therapeutic
cloning will require a large number of eggs — and women willing
to donate them — to make clones for the thousands or even millions
of potential patients.
"They're never going to have enough women's eggs available
to do it," said Dr. Alan Trounson, director of the Monash Institute
of Reproduction and Development in Australia and an adviser to ES
Cell International, a company based in Singapore and Australia.
Companies in the stem cell field have to be conscious of business
issues because many prospective investors are skeptical about the
field. The investors believe the payoff may not come for many years.
Even then, many believe, cell transplants will not be as profitable
a business as mass producing drugs.
The companies' lack of interest in therapeutic cloning raises questions
about how vigorously business leaders, scientists and patient groups
will fight to prevent a ban on the practice.
The goal of therapeutic cloning is not to create babies, but rather
embryos from which embryonic stem cells can be harvested. The stem
cells can theoretically be turned into other types of tissues, like
nerve, heart and liver cells, that have the potential to repair organs
and cure diseases.
One potential problem is that stem cells are now created from embryos
left over in fertility clinics, and tissues transplanted from those
embryos may be rejected by a patient's immune system as foreign. With
therapeutic cloning, scientists would make an embryo clone of the
patient, remove its stem cells and use them to grow needed tissue,
which presumably would not be rejected.
But executives of stem cell companies say making such customized
tissue will be extremely expensive. "That's a product of one,
so the costs are going to be enormous," said Dr. Allan Robins,
chief scientific officer of BresaGen Ltd., an Australian stem cell
company. He estimated the costs at hundreds of thousands of dollars
per patient.
Dr. Michael J. Ross, chief executive of San Diego-based CyThera
Inc., said getting such individualized therapy approved by regulators
might be hard because of problems verifying the safety of each tissue
batch. "The amount of testing you can do for an individual patient
is significantly less than if you're doing a drug for a million people,"
he said.
These executives say there are other ways to overcome rejection
that will allow standardized embryonic stem cell lines to be used
instead of having to create a customized cell line for each patient.
New drugs are being developed to supplement existing anti-rejection
drugs, which can have severe side effects. Dr. Robins said 200 different
stem cell lines could be made so that virtually every patient could
find a close match, to minimize rejection.
Dr. Thomas B. Okarma, chief executive of Geron Corporation of Menlo
Park, Calif., said his company was trying to genetically engineer
stem cells so they would not be recognized as foreign by immune systems.
Another idea would be to make bone marrow cells out of the stem
cells and put them into the patient's bone marrow — where the
cells of the immune system are generated — to try to create a
mixed immune system, something that has happened with some bone marrow
transplants. Then, the tissue could be transplanted and would not
be seen by the immune system as foreign.
But Dr. Robert P. Lanza, vice president for medical and scientific
development at Advanced Cell Technology, said all those approaches
had been worked on for decades, so far without success.
For now, he insisted, therapeutic cloning remains the best option.
"None of us would be doing it if there was another way of doing
it," said Dr. Lanza, who is an expert on transplant immunology.
Dr. Lanza would not estimate how much treatment using therapeutic
cloning would cost, but he said it would be worth it for life-threatening
diseases. And he said friends or relatives would donate eggs to make
the clones of the patients, just as people now donate kidneys to loved
ones. Donating eggs is far easier than donating organs, he pointed
out.
In therapeutic cloning, a cell, perhaps a skin cell, would be taken
from the patient. The cell's nucleus, containing its DNA, would be
put into an egg that had had its own nucleus removed. The egg would
be tricked, in effect, into believing it had been fertilized and would
turn into an embryo. In about five days the embryo would grow into
what is a called a blastocyst, from which stem cells could be extracted.
The stem cells would then be cultured to grow into self-sustaining
colonies and treated with various chemicals to turn into different
types of tissue like nerves or heart cells.
But now the process is inefficient, and it may require 30 to 100
eggs for each patient. In one experiment with mice reported in April,
scientists at Rockefeller University started with 1,016 eggs that
had already had their own nuclei removed and each had the donor nucleus
or cell put in. They ended up with 35 embryonic cell lines, a success
rate of about one cell line for every 29 eggs.
Researchers at Monash University, also working with mice, got one
stem cell line after starting with 926 eggs. Only 39 percent of the
eggs even survived the first step — taking out the egg's DNA
and putting in the donor DNA.
It is not clear whether the numbers will be the same for humans.
The Jones Institute for Reproductive Medicine in Norfolk, Va., using
in vitro fertilization rather than cloning, started with 162 women's
eggs and got three stem cell lines. Advanced Cell Technology, in the
first cloning of human embryos, started with 71 eggs and got no stem
cells because no embryos developed into proper blastocysts. The company
tried both cloning and another technique aimed at creating embryos
out of unfertilized eggs.
Women who undergo in vitro fertilization typically produce 10 to
15 eggs after days of hormone injections. So if 30 to 100 eggs were
needed per patient, more than one egg donor might be needed. Patients
needing stem cells might end up competing with couples seeking egg
donors.
Dr. Alan DeCherney, a professor at the University of California
at Los Angeles and editor of the journal Fertility and Sterility,
said a large source of eggs might be the roughly 20 percent of eggs
collected at fertility clinics that failed to be fertilized.
But those eggs may fail to be fertilized because they are defective,
so it is unclear if they are usable for cloning, he and others said.
There may also be ethical problems with using them. And while it appears
that fertility clinics get tens of thousands of unfertilized eggs
each year, that would be enough for only a few thousand therapeutic
cloning treatments.
"We really have to find a way of dispensing with eggs we collect
from women," said Dr. Peter Mombaerts, assistant professor at
Rockefeller University and a scientific adviser to Advanced Cell Technology.
One way, he said, may be to use animal eggs, something the company
has tried. Another approach may be to make eggs out of stem cells,
since stem cells can theoretically be used to make any kind of cell.
But therapeutic cloning is years from being tried on patients in
any case, and by then the efficiency may have improved, reducing both
the number of eggs required and the cost of the procedure. Even executives
who said they did not think therapeutic cloning would be practical
also said the practice should not be banned. At this early stage,
so little is known about which technology is best that all options
should be kept open, they said.
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