Pioneers of Animal Cloning and the Medical Benefits of Their Work

pig pills

THE flock of sheep grazing in a field on a farm outside Edinburgh in Scotland
looks and behaves just like any other flock of sheep. But these animals are
highly unusual. They belong to PPL Therapeutics, a fledgling biotechnology
company, and they have been genetically engineered to secrete in their milk a
protein called alpha-1-antitrypsin, which helps to treat cystic fibrosis.

The idea of animals being manipulated to produce substances useful to humans
conjures up images of hi-tech efficiency. Yet in reality it is a pretty hit – and – miss affair. PPL’s flock of sheep contains both high and low yielders of the precious product, and for each transgenic sheep created there are numerous expensive failures. Unfortunately for PPL’s shareholders, these limitations mean that the flock can only ever supply a fraction of the £250-million world market for alpha-1-antitrypsin.

High hopes for cloning

But if future generations of these walking pharmaceuticals factories were
cloned from the current herd’s top producer using the technique that recently
created Dolly the sheep, the company’s share of the market would skyrocket.

In the furore which followed the announcement that Ian Wilmut, Keith Campbell
and others at the Roslin Institute and PPL Therapeutics had cloned a sheep
from an adult cell, the scientists tried to defuse public concerns that their
technique could be used to clone humans by listing the benefits that cloned
livestock could offer to medicine. They talked of a future in which herds
of identical cows supplied lavish amounts of medically important proteins, of
sheep with cystic fibrosis and other diseases which would help doctors find new
cures, and of cloned transgenic pigs that could help to meet the desperate
shortfall in human organs for transplant.

However, now that the dust has settled, many are beginning to ask whether
such a future would be as rosy as Wilmut and his colleagues would have us
believe. Now that cloning has the potential to turn a rare experimental
procedure—the creation of transgenic animals—into a profitable,
industrial process, ethicists, geneticists, agriculturists and animal welfare
activists are warning that the new technology could encourage serious abuses of
animal welfare. They point out that although the first transgenic farm animal
was created in 1985, issues such as how to minimise suffering and how to police
the production of engineered animals remain unresolved. It would be dangerous,
they say, to allow the cloning of transgenic animals without first tightening up
animal welfare regulations.

“Where transgenics and clones are concerned, it is legal and ethical free
fall,” says Andrew Kimbrell, a lawyer with the International Center for
Technical Assessment in Washington DC, which monitors the use of new
technologies. Bob Combes, a geneticist and toxicologist at the University of
Nottingham Medical School in Britain, who also works with the Fund for the
Replacement of Animals in Medical Experiments (FRAME), is calling for an
international committee to be set up to look at the welfare issues surrounding
transgenic animals. He would like to see regulations which prevent companies
from developing herds of transgenic animals until the long-term effects of each
foreign gene on the animals’ health have been fully assessed.

“There are insufficient controls,” says Combes. “People argue that these
animals are so fantastically important and the benefits so profound that they
should not have to go through the cost-benefit analysis and weigh animal
suffering and other ethical concerns in the equation. It’s the technology taking
over, and this is wrong.” Caren Broadhead, scientific officer for FRAME, says
that genetic engineers “have no idea how [transgenic] sheep could suffer”.

Current laws on transgenic animals are remarkably nonspecific. In the US,
once an animal has been engineered to produce a protein that is to be tested as
a medicine, its welfare is largely regulated by the Food and Drug Administration
(FDA) under the same laws that would govern a vat of cells. “If an animal is
used as a `bioreactor’, the animal is the source of manufacture, and the FDA
would regulate,” says biotechnologist Frank Tang of the Department of
Agriculture Animal and Plant Health Inspection Service in Riverdale,

In addition, there are no safeguards in the US to prevent a company from
creating large numbers of transgenic animals before it is certain that the
foreign gene will not harm the animal or its offspring. The regulations in the
European Union are just as vague.

Using transgenic animals to manufacture useful proteins still remains
inefficient. Out of 10,000 eggs injected with foreign DNA, only about three make
it to adulthood and produce the desired protein in sufficiently high quantities.
The techniques used to create Dolly offer two potential shortcuts. The
pharmaceuticals companies could create just one good transgenic animal by
conventional techniques and then clone it ad infinitum to create flocks with a
human disease such as cystic fibrosis for drug testing. Or, because Dolly’s
genetic material came from cultured cells from adult sheep, the genetic
manipulation could be done in these cells. This could allow geneticists to be
more precise about the changes they are making, enabling them to introduce and
remove genes at will.

Wilmut and his colleagues readily acknowledge that they have a few more
hurdles to clear before the two technologies — cloning and transgenics — can be combined. The technique that created Dolly must be repeated and made more efficient, they say. Campbell points out that just one out of 277 egg cells successfully took up the adult DNA. And no one has yet used the adult cloning technique in a species other than sheep.

But most agree that the financial rewards will be sufficient incentive to
overcome these barriers. “The whole reason [for] cloning is to make it a whole
lot easier to create transgenic [animals] that produce valuable
pharmaceuticals,” says physiologist and cattle rancher George Seidel of Colorado
State University in Fort Collins, who studies the possibilities for cloning
livestock. And there are plenty of successful transgenic animals that would make
suitable candidates for cloning, say scientists. According to Carl Gordon, a
biotechnology analyst for financial consultants Mehta and Isaly in New York,
genetic engineers have created no fewer than 45 transgenic goats, cows, pigs and
other livestock that secrete everything from human antithrombin III, a protein
that helps to stop blood from clotting, to human prolactin, which boosts the
immune system.

Although most welfare concerns are over the creation of transgenic animals
rather than the cloning of those animals, the new technology has itself thrown
up important issues. For instance, cloning by embryo division has a tendency to
create sheep and cows that are born up to twice the normal size. This strange
phenomenon has already led to the downfall of one cow cloning company, Granada
Genetics of Houston, Texas, because the mother cows could not deliver their

Transgenic mistakes can be unpleasant for the animal. One example is the
infamous “Beltsville pig”, which was engineered by researchers at the US
Department of Agriculture in Beltsville, Maryland, to produce human growth
hormone in an effort to stimulate growth and reduce fat on the animal. The
hormone succeeded in making the pig grow faster without extra food, but it
suffered terribly from side effects including severe bone and joint

Protected by investment

Some scientists dismiss concerns over the threat to animal welfare posed by
cloning. Robert Foote, professor emeritus of animal science at Cornell
University in Ithaca, New York, insists that cloning transgenic farm animals
would be a good thing. Producing medicinal products in milk is “an excellent
use” of animals, he says. He argues that the large amounts of money invested in
the development of transgenic animals gives them a measure of protection, as do
laws designed to ensure the humane treatment of farm animals and animals used in
experiments, such as the US Animal Welfare Act and the British Animal Scientific
Procedures Act.

But others insist that these laws are not comprehensive enough to prevent the
welfare of animals produced by genetic engineering and cloning from being
abused. Charles McCarthy, senior research fellow at the Kennedy Institute,
Georgetown University, suggests that the only way to ensure abuses are avoided
may be to have transgenic animals monitored constantly “by someone knowledgeable
about the species who will recognise signs of neurological disorders and
behavioral changes that may indicate suffering”.

Article Credit: New Scientist