Animal Rights

Worms and Flies and Basic Research

| by Dr Ray Greek

Bruce Alberts, Editor-in-Chief of Science, stated in his editorial for the December 24, 2010, edition:

In this issue of Science, we highlight the impressive efforts to describe and analyze the genomes of the two organisms—the fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans—that serve as the best models for understanding the biology of all animals, including humans.

I think the last part is hyperbole; the claim for the importance of Drosophila and C. elegans can stand on its own without further ado that they are the best models for all animals. However, there is some truth in the statement, which I will examine momentarily along with the part that is misleading and that is also relevant to my usual blog topic.

Alberts is referring to two studies: Gersteinet al., Science 330, 1775 (2010) and modENCODE Consortium et al., Science 330, 1787 (2010). A “Perspective” by Blaxter in the same issue summarizes the studies:

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The modENCODE (model organism Encyclopedia of DNA Elements) strand of the project is using the power of model organism genomics to reveal genome-wide patterns of regulatory interactions (1, 2) . . . Fruit fly and nematode modENCODE projects have performed hundreds of experiments and produced billions of data points to permit the building of new models of gene expression regulation. These can be used to describe the idiosyncratic development and biology of each animal, but the excitement lies in the commonalities in the overall structures of the regulatory landscape they reveal  . . .  The Large Hadron Collider is the preeminent, long-term cooperative enterprise in the physical sciences, dedicated to gathering data to fully parameterize the basic physical constants of the universe and understand dark matter. In the same way, the modENCODE and ENCODE deep genomics programs will, in time, deliver the power to model and predict organism function from multidimensional data, shine light on the dark genome, and hopefully allow a better understanding of the healthy human and how to treat human disease. (Emphasis added.)

Very briefly, the above says that all animals are built on a similar blueprint and use similar “parts.” There are both gross and specific similarities among the blueprints and parts. By studying less complex organisms, like worms and flies, scientists can discover the very basic “parts” and what they do. These “parts” are probably conserved throughout the animal kingdom, hence Alberts is correct when he states that these less complex organisms serve as the best models for all animals. Scientists could not achieve these discoveries by studying more complex organisms as, for one thing, there are more interactions and “noise” hence it would be more or less impossible to separate out all the genes and regulatory components and assign functions and so forth. So studying flies and worms works for this sort of thing whereas studying monkeys and mice would not.

(This is not an insignificant point for the animal activist. If I were campaigning to get animals out of labs, I would stress the important research being done with worms and flies; research that could not be done using primates and dogs. The questions being asked today are best answered by studying humans and or less complex organisms like worms and flies.)

These papers are valuable additions to the body of scientific knowledge. So far so good.

Alberts continues:

Strange as it may seem, this research, aimed at reaching a deep molecular understanding of how the bodies of a fly and a worm are formed and maintained, will be critical for improving human health.

In so saying, Alberts is mimicking Blaxter (or vice-versa) who said

In the same way, the modENCODE and ENCODE deep genomics programs will, in time, deliver the power to model and predict organism function from multidimensional data, shine light on the dark genome, and hopefully allow a better understanding of the healthy human and how to treat human disease.

These are not as clear-cut as the previous statements, but I agree that eventually the knowledge gained from these projects will, in all likelihood, benefit humans. The problem with such statements is that Alberts and Blaxter are now on a slippery slope. Alberts:

Despite the many advances in our understanding of cells and tissues produced by this [type of basic] research, many diseases remain incurable. The disparity between the enormous amount now known about the chemistry and molecular biology of cells and our ability to intervene in human disease may seem incongruous to the public, but it is not at all surprising to the scientists involved. (Emphasis added.)

Actually it is. For example, Carmichael and Begley 2010:

From 1996 to 1999, the U.S. food and Drug Administration approved 157 new drugs. In the comparable period a decade later—that is, from 2006 to 2009—the agency approved 74. Not among them were any cures, or even meaningfully effective treatments, for Alzheimer’s disease, lung or pancreatic cancer, Parkinson’s disease, Huntington’s disease, or a host of other afflictions that destroy lives . . . From 1998 to 2003, the budget of the NIH—which supports such research at universities and medical centers as well as within its own labs in Bethesda, Md.— doubled, to $27 billion, and is now $31 billion. There is very little downside, for a president or Congress, in appeasing patient-advocacy groups as well as voters by supporting biomedical research. But judging by the only criterion that matters to patients and taxpayers—not how many interesting discoveries about cells or genes or synapses have been made, but how many treatments for diseases the money has bought—the return on investment to the American taxpayer has been approximately as satisfying as the AIG bailout. “Basic research is healthy in America,” says John Adler, a Stanford University professor who invented the CyberKnife, a robotic device that treats cancer with precise, high doses of radiation. “But patients aren’t benefiting. Our understanding of diseases is greater than ever. But academics think, ‘We had three papers in Science or Nature, so that must have been [NIH] money well spent.’?” . . . The barriers to exploiting fundamental discoveries begin with science labs themselves. In academia and the NIH, the system of honors, grants, and tenure rewards basic discoveries (a gene for Parkinson’s! a molecule that halts metastasis!), not the grunt work that turns such breakthroughs into drugs. Colleagues tell me they’re very successful getting NIH grants because their experiments are elegant and likely to yield fundamental discoveries, even if they have no prospect of producing something that helps human diseases,” says cancer biologist Raymond Hohl of the University of Iowa. (Carmichael and Begley 2010) (Emphasis added.)

Crowley:

The article by Contopoulos-Ioannidis et al. (Contopoulos-Ioannidis, Ntzani, and Ioannidis 2003) in this issue of the journal addresses a much-discussed but rarely quantified issue: the frequency with which basic research findings translate into clinical utility. The authors performed an algorithmic computer search of all articles published in six leading basic science journals (Nature, Cell, Science, the Journal of Biological Chemistry, the Journal of Clinical Investigation, the Journal Experimental Medicine) from 1979 to 1983. Of the 25,000 articles searched, about 500 (2%) contained some potential claim to future applicability in humans, about 100 (0.4%) resulted in a clinical trial, and, according to the authors, only 1 (0.004%) led to the development of a clinically useful class of drugs (angiotensin-converting enzyme inhibitors) in the 30 years following their publication of the basic science finding. They also found that the presence of industrial support increased the likelihood of translating a basic finding into a clinical trial by eightfold. Still, regardless of the study's limitations, and even if the authors were to underestimate the frequency of successful translation into clinical use by 10-fold, their findings strongly suggest that, as most observers suspected, the transfer rate of basic research into clinical use is very low. (Crowley 2003)

Butler in Nature:

 “NIH stands for the National Institutes of Health, not the National Institutes of Biomedical Research, or the National Institutes of Basic Biomedical Research.” This jab, by molecular biologist Alan Schechter at the NIH, is a pointed one. The organization was formally established in the United States more than half a century ago to serve the nation's public health, and its mission now is to pursue fundamental knowledge and apply it “to reduce the burdens of illness and disability”. So when employees at the agency have to check their name tag, some soul searching must be taking place.

There is no question that the NIH excels in basic research. What researchers such as Schechter are asking is whether it has neglected the mandate to apply that knowledge. Outside the agency too there is a growing perception that the enormous resources being put into biomedical research, and the huge strides made in understanding disease mechanisms, are not resulting in commensurate gains in new treatments, diagnostics and prevention. “We are not seeing the breakthrough therapies that people can rightly expect,” says Schechter, head of molecular biology and genetics at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.

Medical-research agencies worldwide are experiencing a similar awakening. Over the past 30 or so years, the ecosystems of basic and clinical research have diverged. The pharmaceutical industry, which for many years was expected to carry discoveries across the divide, is now hard pushed to do so. The abyss left behind is sometimes labelled the 'valley of death' — and neither basic researchers, busy with discoveries, nor physicians, busy with patients, are keen to venture there. “The clinical and basic scientists don't really communicate,” says Barbara Alving, director of the NIH's National Center for Research Resources in Bethesda . . . The basic biomedical research enterprise has now evolved its own dynamic, with promotions and grants based largely on the papers scientists have published in top journals, not on how much they have advanced medicine. And many clinicians who treat patients — and earn fees for doing so — have little time or inclination to keep up with an increasingly complex basic literature, let alone do research. This has diminished the movement of knowledge and hypotheses back and forth between bedside and bench. At the same time, genomics, proteomics and all its cousins are generating such a volume of potential drug targets and other discoveries that the pharmaceutical industry is having trouble digesting them. With pharma spending more on research but delivering fewer products (see graph), it is no longer in a position to take forward most academic discoveries. “There is a real crisis in the industry,” says Garrett Fitzgerald, head of the CTSC based at the University of Pennsylvania in Philadelphia. (Butler 2008)

An editorial in Nature:

The readers of Nature should be an optimistic bunch. Every week we publish encouraging dispatches from the continuing war against disease and ill health. Genetic pathways are unravelled, promising drug targets are identified and sickly animal models are brought back to rude health. Yet the number of human diseases that can be efficiently treated remains low — a concerning impotency given the looming health burden of the developed world's ageing population. The uncomfortable truth is that scientists and clinicians have been unable to convert basic biology advances into therapies or resolve why these conversion attempts so often don't succeed. Together, these failures are hampering clinical research at a time when it should be expanding. (Editorial 2010)

Rothwell stated in the Lancet in 2006:

Indeed, most major therapeutic developments over the past few decades have been due to simple clinical innovation coupled with advances in physics and engineering rather than to laboratory-based medical research. The clinical benefits of advances in surgery, for example, such as joint replacement, cataract removal, endoscopic treatment of gastrointestinal or urological disease, endovascular interventions (eg, coronary and peripheral angioplasty/stenting or coiling of cerebral aneurysms), minimally invasive surgery, and stereotactic neurosurgery, to name but a few, have been incalculable. Yet only a fraction of non-industry research funding has been targeted at such clinical innovation. How much more might otherwise have been achieved? (Rothwell 2006)

(For more on basic research that relies on sentient animals, see Is the use of sentient animals in basic research justifiable?)

There are two points to be made regarding the Science article and editorial.

1. Basic research in general does not automatically translate into treatments or cures. Research that uses complex models like mammals to predict human response to drugs and disease has been demonstrated time after time to fail. So making promises of future treatments based on basic research in general is suspect and making such claims about mammal-based basic research is even more suspect because of the complexity problem. (See Animal Models in Light of Evolution for more.) Yet, when vivisection activists seek support, this is exactly what they claim.

2. What does translate with a high degree of success is finding fundamental processes in less complex organisms like fruit flies and worms and tracing those processes through evolutionary time. The Hox genes are one example. However, as I have said many times in this blog, scientific advances are not synonymous with medical advances. I think discoveries of basic processes in flies and worms will, some day, aid in advancing medicine. But, like the Rothwell quote above states, even research on flies and worms must be weighed against human- and technology-based research that does inform clinical practice today.

I think the fly and worm research can be justified on its own merit without appealing to future cures. Research using worms and flies is not exactly fueling the flames of controversy and violence in the animal rights community. (It is difficult to say if these critters are even sentient. Maybe they are, but the jury is still out on them, as opposed to vertebrates, where the scientific evidence is overwhelming to anyone that does not have a vested interest in using animals.) Further, such research is breaking new ground. Seems like a win-win scenario for everyone.

The problem occurs when Alberts slides down the slippery slope and commits the argumentum ad misericordiam fallacy and links the basic research on flies and worms to future cures for Alzheimer’s disease (AD). Yes, we all want to see cures for AD, cancer and other diseases, but it not clear that basic research using flies and worms will provide this. Alberts is using the same appeal to fund worm research that he and others use when asking for money for mammal-based research. We have heard such appeals to pity many times. Especially after society has funded basic research using animals for many decades yet it has failed to yield treatments. Vivisection activists then continue the mantra saying that if society just keeps funding basic research using sentient animals a little while longer they will receive cures for their most dreaded diseases. But, again, these cures simply have not materialized. Reminds me of Wimpy saying: “I will gladly pay you Tuesday for a hamburger today.”

It is a shame that Alberts uses the same argumentum ad misericordiam for worm and fly research that is used in an attempt to justify research on mammals. While I agree that worm and fly research will in all likelihood lead to scientific breakthroughs in humans and that some of those breakthroughs will someday aid in treating disease, there is no evidence that a cure for AD or cancer or paralysis will come from this research. Selling such research based on fallacies damages science, especially when the same sales pitch has been used and refuted for other research practices.

I hope worm and fly research does cure AIDS and Parkinson’s. However, when all is said and done, I bet those cures will come from human-based research and breakthroughs in technology.

References

Butler, D. 2008. Translational research: crossing the valley of death. Nature 453 (7197):840-2.

Carmichael, Mary, and Sharon Begley. 2010. Despeately Seeking Cures. Newweek 2010 [cited May 31 2010]. Available from http://www.newsweek.com/id/238078?obref=obinsite.

Contopoulos-Ioannidis, D. G., E. Ntzani, and J. P. Ioannidis. 2003. Translation of highly promising basic science research into clinical applications. Am J Med 114 (6):477-84.

Crowley, W. F., Jr. 2003. Translation of basic research into useful treatments: how often does it occur? Am J Med 114 (6):503-5.

Editorial. 2010. Hope in translation. Nature 467 (7315):499.

Rothwell, P. M. 2006. Funding for practice-oriented clinical research. Lancet 368 (9532):262-6.