Image Source: Wikimedia Commons, Waksman Laboratory
As part of the RSPCA Scientific Seminar 2014, Dr Thomas Hartung is on a lecture tour in Australia. Dr Hartung is Chair for Evidence-based Toxicology, Johns Hopkins Bloomberg School of Public Health, Center for Alternatives to Animal Testing, Baltimore, USA. He is NOT an animal advocate or linked to an animal welfare or animal rights group.
Last night, I attended his lecture in Melbourne. I found it very interesting, engaging, and I learned a lot. The focus was on cosmetics and drug testing.
Cosmetic testing
The EU has phased out animal testing for cosmetics: The testing ban on finished cosmetic products applies since 11 September 2004; the testing ban on ingredients or combination of ingredients applies since 11 March 2009. The marketing ban applies since 11 March 2009 for all human health effects with the exception of repeated-dose toxicity, reproductive toxicity and toxicokinetics. For these specific health effects the marketing ban applies since 11 March 2013, irrespective of the availability of alternative non-animal tests. In short, since March 2013 animal testing for cosmetics or ingredients in cosmetics is not allowed in EU countries. And the EU still produces around 5,000 new cosmetic products per year. This shows that it is possible to achieve this without animal testing.
There is no testing of cosmetics involving animals conducted in Australia. However, cosmetic products sold here may include ingredients that in the past have been tested on animals.
Drug testing
The development of new drugs is expensive. Very expensive. Forbes estimates that it costs $5 billion to invent, develop and bring a new drug to market.
New, promising drugs are usually first tested on animals before clinical trials with humans start. In regard to animal-based testing of drugs, it came as no surprise when Dr Hartung noted “Humans are not 70 kg rats”. He went on to list the facts of animal-based toxicology: animal studies are often statistically underpowered, too many endpoints without statistical correction for multiple testing, lack of reproducibility, and so on. Mice predict rats at about 60%. How predictive do we expect them to be of humans?
Dr Hartung reported that the latest figures indicate 95% of drugs fail in clinical trials. They do not predict toxicity or are not effective in humans. Two further reasons for this massive failure include false positive results and cell line contamination.
In vivo (experimentation using a whole, living organism) and in vitro (using components of an organism, or “test tube” experiments) testing have a high chance of false positives. A false positive is a test result that is incorrect because the test indicated a condition or finding that does not exist. It reports a result where there is none. Hartung suggested “When hazards are rare, false-positive results are getting more and more problematic … Most hazards are rare…”. (for further explanation of this phenomenon see Dr Hartung’s slides* 30-35).
The contamination of cell lines used in research is another problem.
In 1951, a scientist at Johns Hopkins Hospital in Baltimore, Maryland, created the first immortal human cell line with a tissue sample taken from Henrietta Lacks, a young black woman with cervical cancer. Those cells, called HeLa cells, became widely used in medical research. For example, they were essential to developing the polio vaccine, and they went up in the first space missions to see what would happen to cells in zero gravity.
While HeLa cells have been very useful in advancing medical discoveries in the last 60 years, these fast-growing cervical cancer cells have infected labs and cell lines around the world. Since 1967, scientists have known about cell line contamination. It is estimated that 10-20% of cell lines are contaminated with HeLa cells, and 18-36% are mislabelled (slide 57). For example, scientists might think they are working with human breast cancer cells when in fact they are dealing with mouse kidney cells.
So why has this problem, about which scientists have known for more than four and a half decades, not been rectified?
In 2009, researchers from the University of California, San Francisco (UCSF) published a study showing that a range of cell lines was contaminated and misidentified. The lead researcher, Osamu Tetsu, a salivary gland researcher at UCSF, reported that these contaminated cell lines were widely used, and publishing this fact had not stopped their use:
After publication of this paper, my colleagues recognized the problem, but they are [still] reluctant to check authentication of their own cell lines,” says Tetsu. “They overwhelmingly say they cannot do so because they are afraid of losing their data, and the chance of publication as a result of cell contamination.” … “I think the main issue is the ‘publish or perish’ climate endemic in science today. For researchers who have established a body of work based on a particular cell type, for that cell line to be revealed as non-authentic would be disastrous. I think this has led to a head-in-the-sand mentality.
Can we expect researcher to admit to working with contaminated cell lines? They might lose their reputation, many years of research, and jeopardise future funding. On the other hand, one in 100 patients in hospital dies from adverse drug reactions. Since 1990, 40 drugs have been withdrawn from the market. And yet, outdated methods for drug testing continue to be used.
In Australia, nearly seven million animals were used in 2011 with numbers increasing. In the UK, the number of animals used increased by 12% from 2011 to 2012. In the EU, the total number of animals used for research – 12 million – has been relatively stable between 2005 and 2011. The pharmaceutical industry, however, has reduced its use of animals. Animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. This must mean that researchers in academia are using more animals.
Alternatives
Hartung spoke briefly about available alternatives, though he said he doesn’t like the term “alternatives”. He voiced a preference for a “revolutionary” (as opposed to evolutionary) approach, to construct an entirely new system for testing. He likened the current system to this cartoon:
Source: slide 45
Hartung said we need new torches and spotlights, new tools for the 21st Century. He spoke briefly about these new approaches (I direct you again to his slides for more detail).
I asked Dr Hartung whether industry is more open, more proactive than academia in searching and using alternatives to animal research. In short, the answer was “yes”.
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I commend the RSPCA for bringing this series of lectures to Australia, and the University of Melbourne for making a venue available. A big thank you!
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The above words are by no means a summary of Dr Hartung’s presentation. I covered some points that I find of particular interest, and I used additional sources of information.
If you’ve read this blog post until here, I encourage you to listen to the NHMRC webcast, peruse Dr Hartung’s slides, and/or read his article “Look back in anger – what clinical studies tell us about preclinical work”. I’m sure you’ll find them interesting.
* The PowerPoint presentation available at http://cl.ly/1Z3G3F3a2Q3s is not the same presentation that Dr Hartung used for his Melbourne lecture, but he used some slides from this presentation.