Xenotransplantation and Prion Diseases

[George78]

My friends,
Concerning the Diacrin clinical trial and soon the one of Alexion, I have a question. As those two procedures are involving pigs cells, how can we be sure the transplanted material is not carrying any prion diseases ?...
http://www-micro.msb.le.ac.uk/335/Prions.html
George

[Wise Young]

George,

The dangers of xenotransplantation have been extensively discussed. Almost every horror, from prions to a form of pig AIDS has been brought up as a argument against xenotransplants. Most of the discussions have been highly theoretical and biased. People who write about the subject generally begin with the premise that it is dangerous. Here are some examples of anti-transplantation articles:

http://www.theecologist.org/1man.html
http://www.uib.no/People/mblpp/bioet...lantation.html

Here are some examples of more balanced articles:
http://www.nature.com/nm//web_specials/xeno/
http://www.xeno.cpha.ca/english/index_e.htm
http://www.cdc.gov/ncidod/EID/vol2no1/michler.htm

I strongly recommend a series of television shows on this subject:
http://www.pbs.org/wgbh/pages/frontl...ows/organfarm/

In answer to your question, George, the possibility that pigs may pass some form of slow degenerative disease related to prions is unlikely for several reasons:
1. Prion disease develops in older animals. It is not a disease of young or fetal animals.
2. There is no evidence of this disease in the transgenic pigs that are the sources of the cells.
3. There is no evidence of prion disease being transmitted from pig to human
4. Pig organs have been transplanted to humans for nearly a decade and no case of prion disease has been reported.

The above of course does not mean that it cannot happen but simply that the risk of prion disease transmission from porcine transplants is relatively low.

Please note that the same possibility or perhaps a higher risk occurs with the transplantation of fetal human tissues. Many fetuses that are aborted are infected with HIV, hepatitis, or other pathogens.

Many important and promising avenues of research are being shut down because of fears of theoretical dangers. For example, the possibility of therapeutic cloning is being shut down because many people are convinced that cloning will be abused. There is no evidence at all that cloning can and will be abused and yet the fear of that potential abuse has led to the passage of legislation that may close down human cloning as a possible research and therapeutic avenue.

I think that the community must clearly understand these issues and not be swept up by the misinformation that is being purveyed by politically motivated groups. In the case of xenotransplantation, animal rights have played a major role. In the case of cloning, anti-abortion politics have played a major role.

Wise.

[George78]

Three month ago, I could meet Professor Brotchi, the neurosurgeon at the head of the service of neurosurgery at the Hopital Erasme. He previously has done a lot of human fetal cells grafts for Parkinson. Besides, a Proneuron Cellular Center has been lately inaugurated in his service.
When I first met Dr. Brotchi a few month ago, the question was for us to organize a useful clinical trial. Our association doesn't have a lot of money and the trial must be a working one and quickly available for chronicals. We obviously could discuss of xenotransplantation and Prof. Brotchi told me he was just returning from a meeting concerning transmission of prion diseases to human. Because of that, he told me he prefer to drop the subject of xenotransplantation.
Anyway, Wise, if you tell me that we have same chances to transmit such diseases in eating a Big Mac from the Mac Do or other veal's brains with bearnaise sauce, I will believe you and I will go for xenotransplantation.
Besides, I perfectly understand your fears about misinformation purveyed by lobbying groups. The implied purpose of my question was to know why we must do complicate if we can do simple.
Why do we have to spend $ millions to build genetically modified porcine fetal spinal cord cells like Diacrin has done it ?.... It certainly will represent a saving in money and time to use human cells, it will be riskless, and the sci community will certainly be more inclined to be involved in clinical trial with human material.
George

[Wise Young]

Very good points. There is rampant fear amongst the scientific and the "lay" community about xenotransplants. In my evaluation of the published literature on the subject, I don't think that the fear is justified by the data. There has not been, to my knowledge, a single reported case of prion disease, AIDS, foot-mouth disease, or animal disease that has passed to people as a result of a cell transplant. Thus, the fear is largely theoretical. As I pointed out, this does not mean that there is no risk, only that the risk appears to be relatively small and appropriate precautions can minimize that risk.

In the case of the pig cells, the area that is of greatest concerns is the possibility of hidden viruses present in the genome of the pig cells. As you know, viruses incorporate their genes into the cells of the host. In the genetically modified pigs that are being used by Diacrin to produce the cells for transplants, viral sequences have been discovered in the genome of the pig cells. None of these viral sequences have been expressed in the form of an overt infection but the viral sequences are nonetheless present in the genome of the pig cells. Experiments have shown that when pig cells are co-cultured with human cells, there is passage of the pig viral sequences to human cells, particularly germ cells (i.e. testicular or ovarian cells). This was discovered in 1997 and Novartis (the company that was funding the development of the Diacrin pigs) had rushed to test every patient who received the pig cells to see if there is any expression of proteins that contain the pig viral sequences. None of the patients showed any protein that showed the viral sequence. This was sufficient to reassure the FDA that the risk is low enough to approve the clinical trials. However, the Diacrin trial requires people to sign papers indicating that they will not have children and that they will remain on an FDA registry for life.

Regarding your question of simple vs. complex, we should not assume that human cells will be any simpler or less risky than xenotransplants for the following reasons. First, except in the case of cloned embryonic stem cells, cells that come from unrelated embryos may be rejected without immunosuppression. Immunosuppression does pose a substantial risk of infection, as well as increased cancer incidence in people. If I were to compare the risk of immunosuppression to the risk of some disease passage from xenotransplants, I think that the former poses much more risk. Second, human cells, particularly from aborted fetuses, are very likely to carry human pathogens. Third, like pigs, human cells contain viral sequences that may represent dormant viruses. The risk of these pathogen expressing themselves, particularly in immunosuppressed individuals, is high.

There is one other potential advantage of pig cell transplants. Even though the Diacrin cells come from genetically modified pigs that are less immunogenic, these cells contain many pig proteins that allow the cells to be identified and also allow the individual's immune system to control the cells should they grow into a cancer. In contrast, a human stem cell transplant (whether adult or embryonic) may well lead to a teratoma or other cancer that cannot be as easily eliminated. My guess is that future human stem cell transplants will probably be genetically modified so that they contain a suicide gene that can be activated by a drug, so that they can be eliminated if they start growing out of control.

I consider pig cells a viable and important source of cells for human. If it works, it will be cheap and potentially less risky than human cells. It is also available now... which is more than can be said for human embryonic stem cells. With the recent passage of laws in the United States and EU forbidding the cloning of human embryos, even for the purposes of creating stem cells, I don't see the potential of cloned stem cells becoming available in the near future.

Wise.