Basic Science and Prediction

I thank LifeScientist for continuing our discussion.

I do not think I implied that “basic research rests on immediate returns in the form of technological advances or new treatments.” I thought I stated very plainly “Basic research, by definition, must stand on the premise of knowledge for knowledge sake.” I also said, that basic research using animals is something society is not comfortable with unless it leads to treatments and cures. So I am perplexed as to how LifeScientist can suggest I implied otherwise. Let me state again, basic research is valuable and should be funded. However, it should not be funded because of promises it makes regarding cures and treatments. Nor is society comfortable using sentient animals in basic research and as Nature said, animal based research must revolved around “a concensus of what people find acceptable and unacceptable (1).” There is no contradiction here. Basic research can easily continue without using animals and without claims of curing human disease.

Once again, I agree that the division of research into basic and applied can be problematic but the division between using animals as predictive models and using them in other circumstances is easy. To maintain that any research on animals or in vitro research might someday lead to a cure is not helpful. Funding is limited and if a project is going to be funded on the basis of someday maybe something will happen then all grants are equal. There is a difference between good basic science research and not so good. But that difference is not going to revolve around which animal-model project is predictive for humans. Neither are researchers going to distinguish themselves by appealing to society that their particular basic research project using animals will predict human response to drugs or disease and therefore society should not be uncomfortable with it. Promising or implying cures in an NIH grant application based on using animals as predictive models is fraud.

As I have stated many times, Dr Shanks and my issue with using animal models focuses on using them as predictive models for human disease and drug response. LifeScientist states animal models are predictive and that most scientists agree with him that animal use is necessary. Consider the following:

January 12, 2006, then U.S. Secretary of Health and Human Services Mike Leavitt:

Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies. (2)


Dixit uses a variation on a famous real estate phrase to explain what scientists are looking for: "Prediction, prediction, prediction is everybody's call, everybody's desire. We all want to predict safety and efficacy early so that we have fewer and fewer drugs failing so we can reduce the cost of drug development. It's not the cost of developing a successful drug; it's the cost of having unsuccessful drugs." (3)

Hurko in Drug Discovery World Spring 2000:

We have become very efficient in finding compounds that are safe and effective in laboratory animals, however, for novel targets, we still are not very efficient in identifying drugs that work in people. Most do not. (4)

 In the April 1, 2010 issue of The Scientist

Mouse models that use transplants of human cancer have not had a great track record of predicting human responses to treatment in the clinic. It’s been estimated that cancer drugs that enter clinical testing have a 95 percent rate of failing to make it to market, in comparison to the 89 percent failure rate for all therapies . . . Indeed, “we had loads of models that were not predictive, that were [in fact] seriously misleading,” says NCI’s Marks, also head of the Mouse Models of Human Cancers Consortium . . .

Nature Biotechnology 2010:

The low predictive value of mouse cancer models for human disease is a major challenge for cancer research. Whereas human tumors develop from individual cells in the context of normal tissue, cancer research mostly relies on models employing xenografts or carrying oncogenic mutations throughout the whole animal or tissue. (5)

Dr. Richard Klausner, then-director of the National Cancer Institute:

The history of cancer research has been a history of curing cancer in the mouse . . . We have cured mice of cancer for decades—and it simply didn't work in humans. (6)

David F. Horrobin wrote in Nature Reviews Drug Discovery:

Does the use of animal models of disease take us any closer to understanding human disease? With rare exceptions, the answer to this question is likely to be negative. The reasoning is simple. An animal model of disease can be said to be congruent with the human disease only when three conditions have been met: we fully understand the animal model, we fully understand the human disease and we have examined the two cases and found them to be substantially congruent in all important respects . . . All the other animal models — including those of inflammation, vascular disease, nervous system diseases and so on — represent nothing more than an extraordinary, and in most cases irrational, leap of faith. We have a human disease, and we have an animal model which in some vague and almost certainly superficial way reflects the human disease. We operate on the unjustified assumption that the two are congruent, and then we spend vast amounts of money trying to investigate the animal model, often without bothering to test our assumptions by constantly referring back to the original disease in humans.

These unexplored assumptions are the fundamental flaws in any animal model scenario. The animal rights campaigners are justified in pointing out that there is little rationale for using animal models which frequently simply draw attention and funds away from the careful investigation of the human condition. The Castalian establishment is wrong in not drawing attention to the unjustified assumption of congruence in most cases of animal experimentation on disease models . . . What can be done to reduce the risk of isolated self-consistency? First, there must be a recognition that in the last analysis the human disease itself must be studied in human subjects. It is at least arguable that if we devoted as much effort to the human disease as we do to unvalidated models, then we might be much further forward in understanding. If we are to have any confidence our models are valid, then we must know at least as much about the diseases we investigate as the models we use. (7)

 In a Newsweek piece on primate experimentation Animal-based research advocate Michael Conn is quoted:

"There is a degree of truth to the argument that animals are not a good model for humans," says Conn, who is not affiliated with OSU. "But it's also true that adults are not the best model for children and men are not the best model for women. The only perfect model for you is you, but obviously we can't test every substance on every individual. (8)

Kola and Landis wrote in Nature Reviews Drug Discovery:

The major causes of attrition in the clinic in 2000 were lack of efficacy (accounting for approximately 30% of failures) and safety (toxicology and clinical safety accounting for a further approximately 30%). The lack of efficacy might be contributing more significantly to therapeutic areas in which animal models of efficacy are notoriously unpredictive (9)

Referring to the results when using human cells, Palfreyman, Charles and Blander state: “They are clearly superior to those obtained from animals.” (10

Much of LifeScientist’s two essays responding to my April 19 post revolve around what prediction means. To a degree in my blogs on Opposing Views and much more thoroughly in Animal Models in Light of Evolution, I have explained what prediction means and the difference between the lay use, where astrology can claim to be predictive and the scientific use, which involves mathematical formulas. In biomedical science when a scientist claims a modality (like animal models) is predictive for humans, proof is required. Animal models have been tested for their predictive ability for human response to drugs and disease and they have failed. (See Animal Models in Light of Evolution and the following articles (11-38) for more on prediction. I apologize for the number of references in this blog, but as long as LifeScientist and others challenge the notion that animal models cannot predict human response to drugs and disease, I will by necessity need to use the references to prove my point. It will be mush easier for the interested reader to just read Animal Models in Light of Evolution.)

Finally, as I have said numerous times, I do not see the prediction issue being settled (or even much more light being shed) in these blogs. I suggest that Dr Ringach and or LifeScientist debate me on this issue at UCLA and that the debate involve unbiased scientists who can moderate, judge, and weigh in on this issue. I participated in their panel discussion based on promises that a debate would happen. It is not happening.



1.            Editorial, Nature 462, 699 (2009).

2.            FDA. (FDA, 2006), vol. 2010, pp. FDA News Release.

3.            P. McGee, Drug Discovery & Development, 18 (2006).

4.            O. Hurko, Drug Discovery World, 63 (2000).

5.            M.E., Nature Biotechnology 28, vii (2010).

6.            M. Cimons, J. Getlin, T. H. Maugh_II, “Cancer Drugs Face Long Road From Mice to Men,” LA Times,  1998.

7.            D. F. Horrobin, Nat Rev Drug Discov 2, 151 (Feb, 2003).

8.            J. Interlandi. (Newsweek, 2009), vol. 2009.

9.            I. Kola, J. Landis, Nat Rev Drug Discov 3, 711 (Aug, 2004).

10.            M. G. Palfreyman, V. Charles, J. Blander, Drug Discovery World Fall, 33 (2002).

11.            E. J. Calabrese, Drug Metab Rev 15, 505 (1984).

12.            E. J. Calabrese, Principles of Animal Extrapolation.  (CRC Press, 1991).

13.            J. M. Collins, Chem Biol Interact 134, 237 (May 16, 2001).

14.            A. P. Fletcher, J R Soc Med 71, 693 (Sep, 1978).

15.            S. Garattini, Crit Rev Toxicol 16, 1 (1985).

16.            D. G. Hackam, BMJ 334, 163 (Jan 27, 2007).

17.            D. G. Hackam, D. A. Redelmeier, JAMA 296, 1731 (Oct 11, 2006).

18.            R. Heywood, Toxicol Lett 18, 83 (Aug, 1983).

19.            R. Heywood, in Animal Toxicity Studies: Their Relevance for Man, CE Lumley, S. Walker, Eds. (Quay, Lancaster, 1990),  pp. 57-67.

20.            T. Igarashi, in CMR Workshop: The Timing of Toxicological Studies to Support Clinical Trials, N. M. C Parkinson, C Lumley, SR Walker, Ed. (Kluwer, Boston/UK, 1994),  pp. 67-74.

21.            T. Igarashi, S. Nakane, T. Kitagawa, J Toxicol Sci 20, 77 (May, 1995).

22.            T. Igarashi, T. Yabe, K. Noda, J Toxicol Sci 21, 497 (Dec, 1996).

23.            Y. Igarashi, “Report from the Japanese Pharmaceutical Manufacturers Association 1994 Seiyakukyo data.”.

24.            J. I. Johnson et al., Br J Cancer 84, 1424 (May 18, 2001).

25.            A. Knight, Altern Lab Anim 35, 641 (Dec, 2007).

26.            A. Knight, J. Bailey, J. Balcombe, Altern Lab Anim 34, 19 (Feb, 2006).

27.            T. Koppanyi, M. A. Avery, Clin Pharmacol Ther 7, 250 (Mar-Apr, 1966).

28.            T. Lindl, M. Voelkel, R. Kolar, ALTEX 22, 143 (2005).

29.            T. Lindl, M. Völkel, R. Kolar, ALTEX 23, 111 (2006).

30.            J. T. Litchfield, Jr., Clin Pharmacol Ther 3, 665 (Sep-Oct, 1962).

31.            C. Lumley, in Animal Toxicity Studies: Their Relevance for Man, C. Lumley, S. Walker, Eds. (Quay, 1990),  pp. 49-56.

32.            P. Perel et al., BMJ 334, 197 (Jan 27, 2007).

33.            D. Salsburg, Fundam Appl Toxicol 3, 63 (Jan-Feb, 1983).

34.            N. Shanks, R. Greek, Animal Models in Light of Evolution.  (Brown Walker, 2009).

35.            N. Shanks, R. Greek, J. Greek, Philos Ethics Humanit Med 4, 2 (Jan 15, 2009).

36.            N. Shanks, R. A. Pyles, Philos Ethics Humanit Med 2, 4 (2007).

37.            C. Spriet-Pourra, M. Auriche, (Eds), SCRIP Reports.  (PJB, 1994).

38.            R. J. Wall, M. Shani, Theriogenology 69, 2 (Jan 1, 2008).

Dr. Greek- What I don't understand is, what are the alternatives? If you think that animals are such terrible predictors, what are the options?

As I understand it, most treatments, diseases etc, are studied in vitro, then in animals and then in humans. I don't think anyone who cured cancer or found a vaccine for HIV in mice would think their job was done. Of course there are differences between humans and animals but without animals, where is the starting point? How do you identify good treatment candidates ? How do you know what is likely to do more harm than good? How do you elucidate the molecular pathways of developing disease? How do you determine which neural pathways are being targeted by an anesthetic so that we can develop improved anesthetics? How do you know which genes are faulty or missing or working when someone is sick? How do you develop in vitro models without knowing how something works in a living organism? Even if that organism is a mouse instead of a human isn't that a step closer?

I'm sure that researchers will continue to develop in vitro models and alternatives, but until then, what are the options?

I realize you are not a scientist. Your assumption is based on faulty logic. First of all, it's incorrect to imply or believe that animal research is a viable science . I believe I had read somewhere in Ray Greek's articles that it's like asking for an alternative to " driving a truck to the moon ." To begin with, you can't drive a truck to the moon.

You didn't answer my question. What is the rocket ship?

A rocket ship is not a truck. A truck is not a rocket ship. And you still can't drive a truck to the moon .

Go read Greek's latest post. %E2%80%99t-experiment-on- animals

Well it's good to see that Dr Greek is finally getting the point that there is no firm dividing line between basic and applied research , even if examples at either end of the spectrum can be found .

"To maintain that any research on animals or in vitro research might someday lead to a cure is not helpful. Funding is limited and if a project is going to be funded on the basis of someday maybe something will happen then all grants are equal. "

But all grants are not equal, most funding organizations divide their funding between blue-skies basic research, applied/clinically-relevant research, translational research and clinical research and have at least a rough idea (in some cases such as the MRC policies) about how much funding they will put into each area even before any grant applications arrive. Grants are not awarded simply based on what somebody claims the benefits might be in the grant but after detailed evaluation - usually involving peer review - of the proposed project by people who know the field of research in question.

"Basic research can easily continue without using animals and without claims of curing human disease."

Well basic research could continue without animals, but it's value to medical science would be severely diminished, and to avoid all claims that the research could lead to cures for human disease would itself be highly dishonest.

And now torrent of quotes out of context. For example I noted a long quote from a paper by David Horrobin (Nat Rev Drug Discov 2, 151, 2003) but other portions of his paper put Horrobins views in a somewhat different light.

'Second, although we know little aboutthe congruence between particular animalmodels and particular human diseases, we
do know that with respect to many aspects of their function there is indeed substantialcongruence between animal physiology and biochemistry and human physiology andbiochemistry.When critically examined,much of the strongest evidence for the importance of animal experiments to human disease comes from efforts to understand normal animal physiology and biochemistry (that would be basic research, LS). The insulin story, the importance of cardiovascular function for cardiac surgery and renal function for the management of kidney failure are examples in which the main value of the animal models lay in the understanding they generated about normal human physiology and its responses to stressors. There we
can indeed be reasonably confident that animal and human studies will be substantially congruent.

It is therefore arguable that the biggest failure of modern medical and pharmaceutical research lies in its near abandonment of
attempts to learn more about normal function in intact normal animals.Whole-animal studies teach two lessons that many medical researchers have forgotten. First,whole organisms are extremely complex. Although the apparent clarity provided by simpler systems can often be useful, it almost inevitably also
introduces distortions. The simpler systems must always be subject to reality checks by constant referrals back to the way the whole organism works.

The second major lesson that comes from whole-animal studies is that kinetic understanding is crucial. In order to understand
diabetes , it is not necessary merely to understand the anatomical layout of the biochemical pathways but also how they interact kinetically. Without that functional kinetic knowledge, which in the end can come only from in vivo animal studies, then no sense at all can be made of the information from, for example, cell culture studies or applied to
human physiology. '

His comments on the limitations of in vitro work are also of interest, especially the conclusion that:

'The Castalians are perhaps concerned that in vitro studies which form a very large part of their work are open to criticism. However, their unwillingness to discuss the paucity of evidence that in vitro studies can mimic either the complexities or realities of the in vivo world has the effect of acting in favour of the anti- animal research lobby. The Castalians are not as clearly spoken as they should be when the anti-animal research lobby advocates switching from animal to in vitro studies. The idea that in vitro systems—or even computer models—might be able to reflect acurately and reliably the complex in vivo systems of an
intact human being involves a leap of faith. Such a leap, without critical and sustained discussion of congruence, should have no
place in rational science.'

Personally I think Horrobin is being far too negative, but he may have a point where some areas of research are concerned, for example the reliance of a small and probably unrepresentative set of cell lines for most in vitro and mouse xenograft cancer studies, the subject of the report in The Scientist to which you refer /

Thank you to LifeScientist for continuing the discussion!
Shanks and I explained in Animal Models in Light of Evolution and I previously stated in these blogs that basic and applied research is a spectrum. My above blog was not something new in that regard. LifeScientist’s claim that basic research could continue without animals but that “it's value to medical science would be severely diminished” is just that, a claim. Attempts at proving this have been problematic (1-4). As that is the topic we are debating it is also circular to make such a claim. Claims are not proof.
As to quoting DR Horrobin’s paper out of context, I should point out that we included his entire paper in Animal Models in Light of Evolution. That is very inconsistent with trying to pretend Horrobin stated a position that he in fact did not. As I might have said once or twice, if someone really wants to understand our position then reading Animal Models in Light of Evolution is preferable to blogs. I encourage the reader to read Animal Models in Light of Evolution and the Horrobin article (contained therein) and decide for yourself on the out of context issue.
One more thought on out of context. I have said many times that the strength of some of the quotes we use is that they come from people whose livelihoods and egos are tied up very tightly to using animals in research. Any negative commentary on the topic from people in that category demands more consideration that similar comments from nonscientist animal rightists. I have said many times that many of the people we quote support the use of animals in research; although this disclaimer does not seem to make it into assertions from the opposition. Hardly making their quotes out of context, it merely shows that even they have concerns about the modality. However, even if the most violent and irrational animal rightist said 2 + 2 = 4, he would be correct. In science, the facts matter, not the person saying them. We do not and did not quote anyone out of context but if supporters of using animals in research cannot challenge our position on prediction I expect them to continue to argue out of context.
I appreciate LifeScientist continuing this discussion! Now, if I could just get Dr Ringach to live up to his promise of having a debate on prediction at UCLA, like he promised.


1. J. Grant, S. Hanney, M. Buxton, BMJ 328, 48; discussion 49 (Jan 3, 2004).
2. J. Grant, L. Green, B. Mason, Research Evaluation 12, 217 (December, 2003).
3. J. Grant, R. Cottrell, F. Cluzeau, G. Fawcett, BMJ 320, 1107 (Apr 22, 2000).
4. J. Grant, L. Green, B. Mason, “From Bedside to Bench: Comroe and Dripps Revisited” (Health Economics Research Group. Brunel University, Uxbridge, Middlesex UB8 3PH, UK, 2003).

The Grant et a study has numerous weaknesses even acknowledged by the authors themselves: - “the-scientific-basis-for-the- support -of-biomedical- science ”/

WOW! A study that is not perfect! What a shock. Not perfect does not mean not valid. Or am I quoting out of context? Maybe Dr Ringach could explain all this in the debate he promised to do.

In this case not perfect certainly does mean not valid, since the imperfections in the study by Grant et al almost certainly led them to underestimate the contribution of basic research by at least 3 fold. I find it amusing that your obsession with accurate prediction suddenly vanishishes when the result of a flawed study suits your purpose.

That's not to say that the method used by Grant et al was all bad, it's a very interesting approach to answering a difficult question, and I believe that with some adjustments it may well be able to provide a reasonably accurate picture of the contribution of basic science to medical progress.

I'd also dispute the claim that the public expects animal research to produce an immediate dividend in the form of specific treatments. I believe that most members of the public who have an interest in science given consideration to this subject do appreciate that pure or directed basic research is important to future progress in medicine even if at the outset a specific application of the knowledge gained is unknown or uncertain.

Of course basic research does also include "pure/blue skies" work where the practical applications not apparent at the outset, but where the subject being studied is so fundamental that practical implications are almost inevitable.

An excellent example is the discovery of the role of the protein cyclin by Tim Hunt, the story of which was told in an excellent documentary on BBC4 last night as part of the "Beautiful Minds" series.

It's an excellent insight into science , and especially basic research works, and how knowledge gained from the study of one species - sea urchins in this case- can allow us insight into the fundamental biology of many species.

Tim Hunt won the Nobel prize for his efforts

And to think that Ray Greek would have banned his work!

Politicians also appear to appreciate the value of fundamental research as indicated by the EU parliament's vote , after much debate and deliberation, to allow non-human primates to be used in basic research (the original proposal had limited their use to applied research).

"And to think Ray Greek would have banned his work ." Where did I suggest banning? And once again I am not opposed to basic research . You can spin this all day and those facts will not change .