Animal Rights

Sialic Acid

| by Dr Ray Greek

From ScienceDaily:

Researchers at the University of California, San Diego School of Medicine have discovered that a kind of sugar molecule common to chimpanzees, gorillas and other mammals but not found in humans provokes a strong immune response in some people, likely worsening conditions in which chronic inflammation is a major issue.

I normally do not address the issue of using animal parts in drugs meant for human consumption or of using animal tissues for nonpharmaceutical human use. These are more or less animal welfare issues and I try to avoid the whole ethical argument. But this brings up a scientific aspect of using animal parts so I decided to address it.

First I need to say that animal use in science can be classified under nine headings. We have pointed this out in pretty much every book or article we have ever written. The two areas that we find scientifically untenable are using animals to predict human responses to drugs and diseases. The other seven ways animals are used include as bioreactors, for example monkeys were used as reservoirs for poliovirus during the early and mid 20th century. Animals can be used for spare parts, for example the aortic valve from a pig can be placed into a human suffering from disease of the aortic valve. The others ways are listed in my blog The 9 Ways Animals Are Used in Science. What these seven ways have in common is that they work. The animal or animal part can be successfully used in the way it is claimed to be used. Shanks and I cover this in more detail in FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed.

But as the above research points out there can be problems with using animal parts for human consumption, namely reactions. ScienceDaily:

This non-human sialic acid sugar is an ingredient in some biotechnology drugs, and may be limiting or undermining their therapeutic effectiveness in some patients, the scientists report in a letter published in the advance online July 25 edition of the journal Nature Biotechnology.

This is a recurring theme when using animal tissues. From FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed.

Just because there are scientifically viable uses for animals in science, as you say there are, does that mean using animals is always the best way?

Not necessarily. As we discussed earlier, the original research on mAbs [monoclonal antibodies] was performed on mice, and mice were initially used to produce the mAbs given to humans. However, this approach was not without its problems. The mouse mAbs did not work well in humans because they did not trigger the appropriate response. Additionally, the mouse mAbs had a very short half-life in humans.

Today mAbs that are almost 100 percent human-derived are available that circumvent all these problems. Loisel et al. in 2007:

Animal models are not suitable for predicting the immunogenicity of therapeutic mAbs in humans, and transposition of the immunogenic potential of therapeutic antibodies in animals to the human situation has no scientific rationale, even in primates . . . In conclusion, complement activation by therapeutic antibodies in animal models is strongly influenced by a variety of parameters and does not necessarily reflect the human situation (Loisel et al. 2007) . . . .

What are the risks in using animal-derived ingredients in in vitro tests?

First, understand that a great deal of in vitro research involves animal-derived products like blood from cows and cells from other animals in the growth medium. Consider fetal bovine serum (FBS), which is used in many cell cultures. There are problems with using FBS:

  1. There is batch-to-batch variability, which is not a good thing in a culture medium that by definition needs to be consistent.
  2. The amount and type of growth factors and growth inhibition factors varies from batch to batch.
  3. The FBS may vary, depending on the sex of the fetus, species, and developmental stage.
  4. FBS “can interfere with genotypic and phenotypic cell stability and can influence experimental outcomes.”
  5. FBS can “suppress cell spreading, cell attachment, and embryonic tissue differentiation.”
  6. FBS “can be contaminated with viruses, bacteria, mycoplasma, yeasts, fungi, immunoglobulins, endotoxins, and possibly, prions.”
  7. Many substances in FBS have not been identified, and the effect of these substances on cultured cells is unclear (Jochems et al. 2002).

Historically, we have seen the risks of contamination in the development of vaccines:  Monkey kidney cells that were used in the production of the original Salk and Sabin polio vaccines were contaminated with Simian virus 40 (SV40), a virus that infects several species of monkeys.  

Sialic acid has also been implemented in important differences between humans and nonhuman primates (Hopkin 1999). Jon Cohen in Science 2006:

A new study that compares the immune responses of chimps and humans offers yet more compelling evidence that subtle differences in gene activity can result in big distinctions between the two species. The researchers, led by hematologist Ajit Varki of the University of California, San Diego (UCSD), suggest that their findings may explain why chimps and other great apes do not typically develop AIDS when infected with HIV, cirrhosis after infection with hepatitis B or C viruses, or any of several other diseases common in humans….

As they report in the 1 May [2006] Proceedings of the National Academy of Sciences, Varki and co-workers studied proteins called Siglecs that his lab co-discovered in the 1990s. Many immune cells express Siglecs (which stands for sialic acid--recognizing Ig-superfamily lectins), and some of them appear to calm the immune response by preventing a process of immune cell expansion known as activation. Humans and apes share the same Siglec genes, but Varki's group explored whether they were turned on to the same degree in T lymphocytes taken from humans, chimps, gorillas, and bonobos.

Using monoclonal antibodies to various Siglecs, the researchers found that although the T cells of people from many different geographic and ethnic backgrounds sported low levels of the Siglecs or none at all, the ape T cells produced clearly detectable amounts of the molecules. When they genetically engineered the human cells to express high levels of one key Siglec, they found that, as predicted, T cell activation was inhibited. Conversely, they cranked up activation of chimp cells by using an antibody to block that same Siglec on them. "I think what's happening is that Siglecs are providing a brake in ape T cells," says Varki. "Human T cells seem to have lost these brakes." Varki and his co-authors speculate that early humans faced novel pathogens as they migrated into new areas, which may have created pressure for hyperactivated T cells to evolve.

Varki's team notes that AIDS, chronic hepatitis B and C, rheumatoid arthritis, bronchial asthma, and type 1 diabetes are all T cell--mediated diseases that are linked to overactivation of the immune cells--and none appear to afflict apes. Varki says it may ultimately be possible to develop a therapy that turns up expression of Siglecs in humans with these diseases, dampening activation and preventing symptoms. But he emphasizes that this study only hints at that possibility. "At the moment it's all in vitro," stresses Varki. "But it is all internally consistent with what we know about the biology."

The new insights on Siglecs may also help avoid tragedies like the one that recently occurred in a U.K. drug trial (Science, 24 March, p. 1688). The study involved a monoclonal antibody that stimulates T cell activation and proved safe in monkeys. But when given at much lower doses to six humans, it quickly caused serious illness. "When it comes to the immune system, be careful about predicting whether a primate model will predict human responses, especially for T cells," cautions Varki, noting that an in vitro comparison of rhesus and human cells similar to his study might have revealed the stark differences between the species. (Cohen 2006)

That is the point of Animal Models in Light of Evolution: very small differences between species can manifest as large differences in drug and disease response.

 

References

Cohen, J. 2006. Immunology. Differences in immune cell "brakes" may explain chimp-human split on AIDS. Science 312 (5774):672-3.

Hopkin, Karen. 1999. The Greatest Apes. New Scientist (2186):26-30.

Jochems, C. E., J. B. van der Valk, F. R. Stafleu, and V. Baumans. 2002. The use of fetal bovine serum: ethical or scientific problem? Altern Lab Anim 30 (2):219-27.

Loisel, S., M. Ohresser, M. Pallardy, D. Dayde, C. Berthou, G. Cartron, and H. Watier. 2007. Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit Rev Oncol Hematol 62 (1):34-42.