Tag Archives: Ray Greek

Animal Testing and Greek Mythology

Ray Greek has been held up by the animal rights community as a standard bearer for the “animal research doesn’t work” movement. While his arguments appear credible at first glance, they quickly fail under scientific scrutiny. In this post we take a broad look at the arguments made in his key work, Animal Models in the Light of Evolution.

Those willing to play dirty in the service of animal rights activism have employed many tactics over the years, from breathless but groundless “reports” describing the ‘barbarism’ of the animal lab to threats of physical violence and beyond.

However, the modern era has been marked by the rise of pseudoscience which argues from a perspective that animal research is ineffective, rather than immoral. It is often underpinned with an assertion that there are “modern alternatives” that should be used instead, if only scientists would take off their blinkers!

The response of the scientific community thus far has largely been to refute such claims via sending papers to what are (to the public) obscure scientific journals, or maybe a stiff letter to Scientific American. For instance Adrian R. Morrison, writing in Perspectives in Biology and Medicine, Volume 45, Number 4, Autumn 2002 illustrates how animal rights pseudoscientists misuse references, often quoting passages out of context so they contradict the wider conclusions of a paper.

Dr. Ray Greek

Dr. Ray Greek

However, we must do more to argue openly and publicly against these scientific distortions, and it might be helpful to first consider what elements go into a misleading proposition.

Perhaps a good place to start is by looking at some of the work of Ray Greek, who will be familiar to readers of this site, but has just started manifesting in the UK with his work used as the basis of a Parliamentary Motion and as the “scientific” rationale behind pseudoscience organisations like For Life on Earth.

There are two aspects here. Firstly, Greek is careful to qualify his work as being limited in its scope, although even he must admit that some of his sources aren’t used honestly.  Secondly, the narrow focus of Greek’s work is often extrapolated across all animal research by protesters, so although he argues, along with Niall Shanks, in Animal Models in the Light of Evolution (AMLE) that:

“We are primarily concerned with the practise of using animals as predictive models of human and biomedical phenomena. […] [However], there can be no doubt that studies of animals have contributed greatly to our scientific understanding of life, and there is little doubt that these studies will continue to illuminate these matters in the future” (page 30)

Their intended audience has clearly misunderstood their claims and extrapolated their narrow evidence base to all animal research. So, it’s arguable that their harmless (if lucrative) enterprise is becoming dangerous in the same way that the novel of Frankenstein is harmless until it inspires an angry mob to burn down a lab, or, more likely, an undereducated politician influenced into making a silly decision.

Greek and Shanks – Animal Models in the Light of Evolution (2009)

Of course, animal models in most cases aren’t being used to “predict” anything. They are being used to test a hypothesis (in which sense there is no such thing as a failed experiment – only an incorrect hypothesis) or to discover or understand a process. Such descriptions cover much basic research, as well as many other areas. Greek acknowledges that there are valid uses of animals and instead focuses on animals as models of human biology, particularly drug development and safety testing.

Where animals are used in drug testing it is to suggest that an effect observed in animals may also be observed in humans. When an effect is observed across multiple mammalian species, the probability of it also having that effect in humans can be sufficiently high to allow the compound to proceed to human trials. It should be noted that the system is primarily screening for acute undesirable effects (such as severe vomiting or seizure) which would prevent a drug candidate from proceeding to human trials. The tests cannot possibly predict all adverse drug reactions, and many will only be known about when a compound is administered across a large number of human patients across the globe. Nor are they intended to – they are intended to prevent the illness or death of phase 1 clinical trial volunteers – something animal tests achieve remarkably well.

Prediction in this context is about probability. An analogy might be if I told you that if you walk into the road right now you have a 9 in 10 chance of getting run over. Note I am not saying you will be run over, but there’s a good chance you might be. This is how ‘prediction’ is understood in this context, not as a form of precognition or the outcome of a complex model where all variables are known.

Initially, then, the enterprise has been to frame the concept of prediction in a particular way which will of course make it unachievable. What comes next is mathematically correct but largely irrelevant – a tactic that crops up again in his discussions of complexity[i].  This is in turn complemented by cherry-picked references that seem to support the argument, in many cases from papers describing out-of-date and far less effective toxicology than we have today.

Animal models in light of evolutionIn one case in AMLE a 1983 paper from D Salsburg is cited, giving us our famous “We’d have been better off tossing a coin” quote beloved by many animal rights activists. What isn’t mentioned however is that the study, 30 years old last year, was an examination of the validity of a lifetime feeding study as a potential assay. He concluded this particular assay wasn’t much use for that one particular purpose, not that all animal experiments give the same poor results, so this quote is not being used in a way its author would recognise.

Elsewhere, AMLE’S companion “FAQs about the use of animals in science” (FAQ) quotes heavily from “Animal Toxicity Studies: their relevance for man”, an out-of-print book of essays from 1990 in which a selection of toxicologists consider how toxicology models could be improved. Greek gleefully cherry-picks from their examples, which are necessarily focused upon examples where the models of the day weren’t working well. Nonetheless he regularly ignores the overriding points that they make – that animal research remains important and that the animal models need improving not removing. Greek is happy to support his case with quotes such as:

“In one small series in which the toxicity in clinical trials led to the termination of drug development it was found that in 16/24 cases toxicity was not predicted in animals [49] “

[49] Lumley C: Clinical toxicity: could it have been predicted? Premarketing experience. In Animal Toxicity Studies: Their Relevance for Man. Edited by Lumley C, Walker, S: Quay; 1990: 49-56.

This appears on Page 53 of his FAQ (and his marketing excerpt of the book), but curiously does not appear in either the chapter of the book quoted, nor anywhere else in Lumley’s (et al.) book. On the other hand the chapter of Lumley’s book that Greek points to does include:

“Dayan, stated that the rarity of predictive toxicity in man demonstrates the success of the animal toxicity procedure at preventing toxic compounds from reaching the clinic. The pilot study confirms earlier findings that only a very small proportion of compounds evaluated in volunteers and/or patients are terminated due to clinical toxicity.”

So there are a few red flags here: old or irrelevant references, suspect definitions, cherry-picked data, a certain amount of “blinding them with science”. These effects are compounded since neither his Animals Models in Light of Evolution, nor FAQs about the use of animals in science are peer reviewed (since they are books not journal submissions).

Arguing that animal models are not predictive because life is complex, when there hasn’t been a single death during a phase 1 clinical trial in the UK in over 30 years (and only one serious incident, due to human error), is a bit like arguing that airplanes can’t fly whilst being seated on an airplane at 30,000 feet.

As far as I can see, features of Greek’s pseudoscience include:

  • Narrowly defining the terms (probability = strict definition of prediction, now).
  • Limiting the data set – Greek is not alone here, animal rights activists like Victoria Martindale have created myths entirely out of limiting the dataset.
  • Quoting out of context – Discombobulated quotes from old papers are common, especially when the paper is making recommendations on how to improve the quality of animal research (similar tactics used by Akhtar when quoting Macleod)
  • Demonstrating how the limited data set doesn’t satisfy the narrow definition.

What is most troubling is it’s hard to tell if such writers have got a point, or could contribute usefully to refining experiments or reducing animal use, because their arguments are wrapped up with poor evidence, geometry, vague or invalid sources of information, faulty statistical methodology and easily-disproved claims. I have written elsewhere about one of the citations used by Greek being based on a “very rough estimate” of the predictive value of toxicity testing of 45 random drugs in 1978. It’s time to stop the mischief, stick to appropriate methodology and, when the science still supports animal research, attempt to criticise animal experiments from an “ethical” perspective (although it’s a slim ethical argument at best).

There is no great conspiracy on the part of pharma companies and regulators to use animals unnecessarily, and this patronising notion that scientists are so thoughtless, institutionalised or psychotic that they use animals when there are easily-accessed alternatives shows the highest arrogance. If animals are poor models for humans, then let it be proven properly and scientifically, hand in hand with regulators and industry, neither of which have an interest in animal research continuing unnecessarily. Regulators are using well-established statistical models as diagnostic tools, and if they’re wrong then it should be possible to prove it to them without statistical trickery. Otherwise the intellectually honest thing to do is abandon the claim.

Chris Magee

[i] To make the point about complexity, Greek takes us on a meander through complexity theory, arguing that, because living things are complex, they cannot be similar enough to truly cross-predict physiological effects. However, the science aside, drug development is also about what works, regardless of whether we understand the mechanism in all its glorious complexity. For example, we knew that insulin worked long before we understood the action of the Glut-4 transporter, or how it may differ in animals.
Reintroducing the science, another place we encounter the misapplication of complexity is in Greek’s reversing of the normal manner in which biologists would use mathematical models i.e. constructing a mathematical model, then (hopefully) confirming its predictions with live observations, leading to ever more refined models. Greek flips this around and sketches out, at length, the difficulty of modelling complex systems. However, one could ask, “Does a basketball player understand the complex physics behind how the ball moves through the air? No. Are they going to get the ball toward the hoop? Probably.” Greek’s argument seems to be that the basketball player needs to know the physics if they’re to score a goal.
Greek takes this as far as showing how hard it is to bring dynamical field theory to a complex biological system (Page 86-103), something that I would argue is indeed impossible given our current understanding of biology, not least because a dynamical system is a mathematical concept where a fixed rule describes the time dependence of a point in a geometrical space and we don’t know enough about the starting physical state of animal biology, or indeed how it functions at a molecular level, to use it to make predictions. But nobody but Greek is suggesting this is how it should be done.
Due to this reversal of the norm, the reader has to deal with some heavy mathematics, quite unnecessarily.  Quite why Dr Greek would try to push the argument beyond the scientific or statistical grasp of the typical reader is anyone’s guess. One hates to caluminate or imply tenebrous intent, but could it be because it’s easier to assume false authority or conceal an anaemic proposition by obfuscation via sesquipedalian vernacular?

You can fool some of the MPs all of the time…

The British Parliament, for all its efficacy at passing thousands of pieces of legislation each year and civilising debate, nevertheless still contains one strange confection – the Early Day Motion (EDM).

The name makes it sound as if these statements, which Members of Parliament can put their names to in support, lie at the foothills of some sort of legislative process, sparking debates and justifying Parliamentary scrutiny. In fact, the process begins and ends with MPs sending a letter to the Vote Office, where their name will be added to a list. They are essentially meaningless.

They are beloved, however, by lobbyists who can claim to their clients that they have gained enormous influence over the policymaking process and journalists who can report that a “Parliamentary Motion” has been put forward, garnished by quotes for and against whatever it is the EDM is promoting.

EDMs, then, are naturally attractive to animal rights activists, who also like to look busy. Like politicians, they can claim that they are doing something and, as lobbyists, can claim to be influencing Parliament. They can even give the journalist their quote.

EDMs are naturally attractive to animal rights activists,

EDMs are naturally attractive to animal rights activists,

Animal rights activists also have a rich heritage of making spurious claims and peddling pseudoscience. So what do we get when EDMs meet pseudoscience? One splendid recent example is EDM 263, which asserts:

“That this House notes the new campaign For Life On Earth which is critical of avoidable experiments on animals; is alarmed that all studies measuring the claimed ability of animals to predict human responses expose a low success rate in the region of 31 per cent; further notes that a success rate in the region of 90 per cent is required by medical practice; further notes that the National Cancer Institute has said that cures for cancer have been lost because studies in rodents have been believed; and calls for properly moderated scientific public debates on the misleading results and bad science of animal experiments.”

Regular readers will be familiar with For Life On Earth (FLOE), which draws heavily on the work of Ray Greek and Niall Shanks, from an earlier SR investigation into its activities. So what on Earth have these 22 MPs put their names to?

I suppose the first thing to note is that the UK legislative environment is entirely different to that in the US but, putting that aside, every aspect of the EDM is a fraud. The reference to the National Cancer Institute is a case in point. Far from criticising animal models, the NCI have a website devoted to demonstrating why animals are essential to researching cancer. The source of the EDM’s claim comes from a 1997 news article in Science:

“But not only have very few of the drugs that showed anticancer activity in xenografts made it into the clinic, a recent study conducted at the National Cancer Institute (NCI) also suggests that the xenograft models miss effective drugs. The animals apparently do not handle the drugs exactly the way the human body does. And attempts to use human cells in culture don’t seem to be faring any better, partly because cell culture provides no information about whether a drug will make it to the tumor sites.”

So the article, referring only to xenografts, discussed why there was a lack of new cancer drugs (in 1997), partly due to no methods – animal or non-animal – being effective enough at identifying working drugs. Certain animal methods had missed cancer treatments, but so had, for example, tissue cultures and clonogenic assays. The article does discuss the promise of the then new hollow fibre models, which rely on the use of mice, and have shown positive results in recent years. The cherry picking of quotes from the news section of scientific journals gives a misleading impression regarding the efficacy of animal experiments.  Since then other improved mouse cancer models of cancer have been widely adopted, including genetically modified mice and “tumourgrafts”, leading to the development of new therapies.

Elsewhere, we encounter the assertion that “a success rate in the region of 90 per cent is required by medical practice” which, apart from being not supported by its references, is complete nonsense, particularly in a country where homeopathy is available on the NHS (I know!). It is also inapplicable to some 90% of research, and rather neglects to mention that animal research does not claim to achieve prediction rates of 90% – that’s why there are three stages of human trials before drugs are used in a clinical setting. Likewise with the reference to “avoidable” experiments – what is an “avoidable” experiment, particularly since it is the case that each UK experiment must specifically be licensed as unavoidable by the Home Office?

The idea of a debate is interesting, and indeed many of us do participate in such debates already – on campuses, in the press, on television and online. However, it is a rotten way to make policy, and the opposite of the scientific method. Protesters who are confident in their speaking ability love a debate – the science is too complex to get across to a lay audience, but narratives can be adequately developed and the “Gish Gallop” rhetorical trick can be employed as it has been in the text of the EDM. If they were as confident in their science they would be using their time to write papers for scientific journals, since the probable truth is established via scientific method, scepticism and challenge, not a bun fight in a church hall followed by a show of hands.

However it is the claim of the ‘low success rate of 31%’ that really showcases pseudoscience at its most insidious.

Putting aside the odd “success rate” term, the reference given by FLOE appears in numerous papers by Ray Greek, which is presumably where FLOE found it. It references an out-of-print book from 1990 called Animal Toxicity Studies: Their Relevance for Man, published by Quay. I managed to find a second-hand copy in Maryland and had it shipped to the UK.

In it, Heywood makes a claim that the correlation (not prediction) of toxicology effects seen between humans and rats is “about 30%”. Other studies from 1990 pegged it at closer to 70% given their understanding at the time. Heywood’s claim is not substantiated in the book, but the reader is referred to one of his own papers from 1981: Target organ toxicity in Toxicology Letters, 8 : 349 – 358. Reference 2 of this paper accompanies this passage:

“Fletcher [2] reported on drug safety tests and subsequent clinical experience with 45 major new drugs. Some effects were seen only in animals, while others were observed only in man. The survey established that 25% of toxic effects observed in animals might be expected to occur as adverse reactions in man.”

Once again, we have no evidence, but we do have a further reference: A.P. Fletcher. Drug safety tests and subsequent clinical experience, J. R. Sot. Med., 71 (1978) 693-696.

Journeying further into the rabbit-hole, we discover that it’s a paper in the Journal of the Royal Society of Medicine, Volume 71, September 1978, called ‘Drug safety tests and subsequent clinical experience’ by one A P Fletcher MB PhD of the former Department of Health and Social Security. Hardly “all studies”.

AP Fletcher had been looking at “45 major new drugs that have been considered by the Committee on Safety of Medicines during the past eight or nine months.”

And on the basis of this small sample size and 1970s toxicology science concluded that:

“It can be said with certainty that correlations between animal toxicity and adverse side effects in man do exist and that they are considerably more frequent than discrepancies. As a very approximate estimate, for any individual drug, up to 25% of the toxic effects observed in animal studies might be expected to occur as adverse reactions in man.”

Why would only 25% of the toxic effects seen in preclinical animal studies be observed as adverse reactions in humans? One frequent reason was dosage; many of the adverse effects were seen at high doses – including acute toxicity tests- in animals, doses that were a lot higher than those used in subsequent human trials. It’s hardly surprising that many adverse effects are not seen in the clinical trials. it’s what you would expect to see if there is concordance between the animal and human studies.  The animal studies also included tests of reproductive toxicity that were not assessed in humans, since pregnant women were excluded from clinical trials.

Our ‘region of 31%’, then, is based on a “very approximate estimate” of one small aspect of animal research, by a Department of Health doctor in 1978 based on 45 drugs that happened to have been licenced in the last year. Not only does the paper conclude that animal experiments correlate to human reactions, in terms of prediction it was a generation ago, it was a different regulatory environment, it was based on a 35-year old understanding of toxicology, it had a sample size of 45 and it was a rough analysis. The claim that this paper shows that animal studies have a “low success rate of 31%’” is simply pseudoscience.

As well-intentioned as I’m sure FLOE is, this jolly but dishonest organisation has misconstrued toxicology experiments as all “animal experiments”, using a cherry-picked quote and a guessed percentage based on an incorrect interpretation  of a paper from 35 years ago wrongly extrapolated not just to all animal experiments, but all efficacy metastudies, to support an EDM that has fooled 22 of the UK’s lawmakers. The further risk is that the MPs will be taken in again, perhaps repeating similar myths in a debate, or legislating on the basis of bunkum to the detriment of man, animals and the environment.
It is at times like this that we feel furthest away from a sensible dialogue on the purpose and ethics of animal research. Researchers want to use the most predictive models, and if the debate was about how to refine statistical and biological models, as is it within the scientific community, we would all be happy. However, when gullible MPs are being tricked into flinging mud at medical, veterinary and scientific researchers on the basis of a paper-thin claim about the utility of that research, it seems clear that we still have a long way to go.


For Life on Earth – The Birth of Another Pseudoscience Organisation

Who are FLOE?

There is a new British animal rights group on the scene called “For Life on Earth” or FLOE for short. Founded by Louise Owen, who has worked with both Medical Research Modernisation Committee and Seriously Ill Against Vivisection (both now defunct), the website seems almost an advertising tool for the various writings of Ray Greek and Niall Shanks (There are no shortage of Amazon links on the site and recommendations that you “buy it now”), with typical pseudoscience about how animal research is no longer necessary.

A professionally finished video on the front page (above) informs us that since we don’t take ourselves down the vet, or our pets to a hospital, that “common sense” would suggest research cannot cross species lines. It is worth noting that veterinarians deal with a variety of different species (so much for not crossing species lines), furthermore, the One Health Initiative DOES aim to get greater collaboration between veterinary and human medicine due to their overwhelming similarity. The Zoobiquity website discusses many aspects of the similarity between human and animal treatments.

The video goes on to suggest that personalised medicine offers opportunities for “treatments [that] are tailor made for you and you alone, for your unique genetic makeup”. Again, they negate to note the huge influence  and growing role of animals in personalized medicine (such as the creation of mouse avatars which are injected with a person’s tumour cells so as to find the specific treatments that will work for that person). I also recommend reading our earlier post “When Personalised Medicine and Animal Research Meet”.

The video finishes with the curious phrase:

“We at For Life on Earth present science illustrated by “Animal models in light of evolution””

This makes me wonder if the whole website is not simply a straight marketing tool by Greek and Shanks’ publishers.

Much of the website revolves around Ray Greek’s regular writings (often on “Opposing Views”) that assert that animal models are not predictive. In reply, you should read a great post by Dario Ringach, an excerpt of which can be found below:

Researchers create models of disease in animals by trying to replicate what they believe are the essential components at play. These animal models can then be used to generate predictions for therapeutic interventions, which can then be tested in human clinical trials. If a prediction is falsified, so is that specific animal model of the disease.

When this happens, scientists seek to understand how the data depart from the prediction, what factors were ignored that might play a role, and use prior knowledge and intuition to develop a better, improved model. In the course of developing and refining such a model, scientists will go through many such cycles. A model is expected to be valid if and only if it captures all the key ingredients of the human condition.

The fact that one can postulate inaccurate animal models of human disease does not invalidate the whole methodology of animal research, it merely shows the work is difficult. But animal models can in fact be successful.

So what are the aims of FLOE?

For Life on Earth (FLOE) - Animal Research Science

“For Life on Earth is committed to making this level of science debate happen. Our objective is to ensure that such debates are broadcast live on television, via a platform such as BBC’s Newsnight or Question Time, both being suitable for the seriousness of such an important topic, and able to incorporate audience participation.“

It is a common claim among animal rights groups that there is no debate. In Britain, over the last 11 years, there have been four independent enquiries about animal research: House of Lords Select Committee (2002), Animal Procedures Committee (2003), Nuffield Council on Bioethics (2005) and the Weatherall Report (2006). On television there has been one Newsnight debate (below) on the scientific merits of animal research between Michelle Thew (BUAV) and Professor Tipu Aziz. Perhaps Ray Greek is simply frustrated that his fellow anti-viv organisation chose not to put up a scientist, but rather their own CEO. Question Time would not fit For Life on Earth’s vision of a scientific debate; as it is a current issues discussion programme dominated by the 3 partisan political panellists (of 5 total) that rarely discusses scientific issues. An animal research debate would be held in short sound bites, with political panellists trying to get the biggest applause. In terms of other opportunities for debate, Dr Greek himself has debated against scientists like Dr Michael Conn on CNN (contrary to the website’s assertion that such debates have never happened).

“For Life on Earth will focus on the most efficient routes by which to advertise the fact that veterinary principles must not be applied to ill, or critically ill humans. An effective pressure campaign, coordinated with the help of the international community, can then help to ensure that legislative decisions made by governments implement current scientific knowledge.”

This straw man argument suggests that current biomedical methods are based on veterinary principles. While there are some similarities between veterinary and clinical medicine (they both try to make ‘animals’ better), there are also clear differences. Given the overwhelming majority of scientists are in support of animal-based research, perhaps FLOE should not be so confident about explaining what “current scientific knowledge” entails. Modern animal research remains at the cutting edge of scientific discovery.

Wait, who are For Life on Earth again?

Well this is where things get interesting. FLOE is registered to a virtual London address through the company British Monomarks. This is not remarkable in itself, until you discover the host of other animal rights organisations that also use this same company for a virtual mailing address.

WC1N 3XX FLOEFLOE are in the company of the Animal Liberation Front Press Office and Supporters Group (offering support to jailed animal rights extremists). They also share their address with the Gateway to Hell campaigns and SHAC – who have a long history of animal rights extremists in their ranks. One wonders what individual connections draw these same organisations to use the same virtual address company.

Overall, For Life on Earth shows all the signs of being another antivivisection, pseudoscientific organisation. I guess it’s another excuse to get out the Animal Rights Bingo.

Speaking of Research

Addenum 13th May 2013

FLOE have removed the address from their website since this article was posted. Click the image below to see a cached version of the website for evidence.

For Life on Earth Address

The Golden Goose Awards

Politicians sometimes deride research based on the what they perceive as being “silly” titles of federal funded grants.  If they spot a title that deals with “games”, for example, they may assume it deals with some sort of amusement of little value to society, instead of a deep, powerful branch of mathematics that describes the behavior of competing rational agents with much relevance to voting, economics, cooperation, and so on.  Animal rights activists also enjoy the hobby.  The latest example is IDA’s list of “ridiculous research” ,whose claims were sadly repeated by far too many news journalists who were clearly too lazy check if they were accurate.  There were some honorable exceptions, notably an excellent editorial entitled “When the facts ruin a good spin” in the Times Union, which discusses a project on the role of music as a conditioning stimulus for drug use ends with a statement with which we heartily agree:

What’s “ridiculous,” to borrow the press release’s language, is that we fall for it, over and over, egged on by politicians eager to score easy points. And what’s “wasteful” is the time and energy that could be so much better spent on something other than a cheap shot.”

Back in 1976 the House Committee on Appropriations asked the National Science Foundation “Why does the Foundation persist in supporting research whose results have no apparent value to the American people?”  The NSF responded in part that:

Basic research seeks an understanding  of the laws of nature  without  initial  regard  for specific  utilitarian  value. Ultimately, however, it  is of the  most important  practical significance, because in a broad sense it is the foundation upon  which rests  all technological development.  Applied research builds on the results of basic research, seeking detailed  information  about  a specific situation  whose general laws have  been  discovered by  basic  research.  The  final step  toward  utilization  of research-development is  the systematic  application  of knowledge to  the  design  of  end products. [...]

As we  increase  our  knowledge  of nature  and  mankind,  in order  to adjust  nature  to our survival, safety,  comfort and convenience, we must  depend  upon  scientific research  to clarify the  relationships  of many, many things.  Thus,  we study  atoms,  even  though  they  will never  be seen  by an  unaided  human  eye.  We study  stars  too  faint  to  be  seen without  a  telescope  and  with  wavelengths  which  can  only be  detected  with  radio  receivers  or  photographic  plates. To  understand  geology, we must  look  at  geologic formations  and processes in many  parts  of the world where different  conditions have existed.  To understand  more about the  phenomena  of life, we must  study  the  behavior  of viruses,  single  cells,  plants,  and  animals  of  many  species.

A book was compiled covering various areas of research with Isaac Asimov writing an essay defending the value of basic research.

Thus, it was with some surprise and delight that we read in the news about Rep. Jim Cooper (D-Tenn) understanding the value of basic research.  The Washington Post reports that:

On Wednesday afternoon, Cooper rose to the defense of taxpayer-funded research into dog urine, guinea pig eardrums and, yes, the reproductive habits of the parasitic flies known as screwworms–all federally supported studies that have inspired major scientific breakthroughs.

Together with two colleagues he created the Annual Golden Goose Awards to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”

Studying dog urine, among other stuff deem crazy by animal rights cranks, led to major medical discoveries

The article goes on to describe how research on dog urine led to an understanding of the effects of hormones on the human kidney, how studies in the guinea pig led to a treatment for hearing loss in infants, and how studies on the screwworm led to the effective control of the a deadly parasite that targets cattle.  All these provide additional examples refuting the notion that learning about life processes from animals cannot yield knowledge applicable to human health.

The Golden Goose Award has the backing of the American Association for the Advancement of ScienceAssociation of American Universities (who in 2011 published a series of “Scientific Inquirer” articles skewering dubious politically-motivated attacks on basic science) and the Progressive Policy Institute, who are to be congratulated for this excellent initiative to highlight the importance of basic research.

At the press conference to launch the award Rep. Robert Dold told reporters that “When we invest in science, we also invest in jobs. Research and development is a key part to any healthy economy,” while  Rep. Charlie Dent (R-Penn.) added “It’s critical, and the federal government has an important role to play,” who went on to describe how injecting horses with snake venom might “seem peculiar” but led to the discovery of the first anti-venom.

Taking us, once again, to the concluding words of Asimov’s essay:

Unless we continue with science and gather knowledge, whether or not it seems useful on the spot, we will be buried under our problems and find no way out.  Today’s science is tomorrow’s solution — and tomorrow’s problems , too — and, most of all, it is mankind’s greatest adventure, now and forever.

Predictions and Animal Models of Human Disease

Some animal activists argue human disease cannot be modeled in animals.  They think physiological differences between species imply that treatments developed by means of animal research will not translate to humans.

Prediction through the development of models is no doubt a goal of scientific work.  Predictions are the fruits of theories that can be tested experimentally. If a prediction is false so is the theory, and a new one must be generated based on prior knowledge and the specific way in which the data falsified the theory.

Unfortunately, those that claim animal models are not predictive of human response take some literary license in restating the above along the following lines:

Predictions, generated from hypotheses, are not always correct. But if a modality or test or method is said to be predictive then it should get the right answer a very high percentage of the time […]

If a modality consistently fails to make accurate predictions then the modality cannot be said to be predictive simply because it occasionally forecasts a correct answer. The above separates the scientific use of the word predict from the layperson’s use of the word, which moreclosely resembles the words forecast, guess, conjecture, project and so forth. […]

Many philosophers of science think a theory (and we add, a modality) could be confirmed or denied by testing the predictions it made.

This language delicately nudges one to equate different concepts, namely theory, hypothesis, modality and method. In this deceptively innocuous equation, resulting from either an honest misunderstanding or mischievous intent, lies the foundation to a seriously flawed argument.

Consider the domain of physics. Here, physicists put forward mathematical theories of some natural phenomenon which, in turn, generate testable predictions. If a prediction is falsified, so is the theory. When this occurs, scientists seek to understand how the data depart from the prediction and use prior knowledge and intuition to develop a new working hypothesis, which is embedded in a new theory.

Mathematics is the language of physics — its methodology. Obviously, by using mathematics one can create many different theories. The overwhelming majority of them will be false. Science is difficult because most of the time our ideas turn out to be wrong.

But one’s ability to conjure up large numbers of incorrect theories does not invalidate mathematics as a method in the physical sciences. Mathematics can in fact be used to arrive at accurate descriptions of how matter behaves. It makes no sense to describe this state of affairs by stating that mathematics (the modality) gets it right occasionally.

A similar situation arises in the domain of biomedical research. Researchers create models of disease in animals by trying to replicate what they believe are the essential components at play. These animal models can then be used to generate predictions for therapeutic interventions, which can then be tested in human clinical trials. If a prediction is falsified, so is that specific animal model of the disease.

When this happens, scientists seek to understand how the data depart from the prediction, what factors were ignored that might play a role, and use prior knowledge and intuition to develop a better, improved model. In the course of developing and refining such a model, scientists will go through many such cycles. A model is expected to be valid if and only if it captures all the key ingredients of the human condition.

The fact that one can postulate inaccurate animal models of human disease does not invalidate the whole methodology of animal research, it merely shows the work is difficult. But animal models can in fact be successful.

knockout mice, animal research, animal rights

A laboratory mouse in which a gene affecting hair growth has been knocked out (left), is shown next to a normal lab mouse. (Courtesy NIH)

One of the proponents of the idea that animal research cannot be used to predict human response to disease is Dr. Ray Greek who was recently interviewed by Steven Novella for the Skeptics Guide to the Universe (as it turns out, Dr. Greek won a bid to appear in the podcast).

There is an interesting part of the exchange where Dr. Novella attempts to explain hat some models have indeed been extremely predictive of human response.  Starting at 15:45min into the program he gives Dr. Greek the example of a how SOD1 mutant mice have helped in the treatment of ALS.  The model “is a home run for humans with SOD1 mutation”, he said.

Dr. Greek’s reply was simply “Well, let’s face it.  If you study 10,000 genetically modified mice there is bound to be one that you are going to hit a home run with.”

In the eyes of Dr. Greek and the animal rights activists that adhere to his views, the type hard scientific work that leads to the development of a predictive model of human disease boils down to a mere chance discovery.

Dr. Novella tries insists that such a characterization of animal research as not predictive is meaningless — it is as if one were to ask “Does surgery work?”.  The answer, he says, is “of course, some surgeries work and some don’t, and you have to ask which ones work and for what [...] You [Dr. Greek] want to make a final pronouncement for surgery as a medical intervention.”

But there is little hope of getting the message across.

Dr. Greek retreats to discussing toxicology testing and declares disease research to be, well… “more complicated.”

Dr. Novella appears to politely give up in frustration and rapidly moves on with the rest of his show.

We sympathize.

Indeed, genetically modified mice have been and continue to be a very useful tool to dissect the roots of human disease and develop new treatments.  This includes the study of type II diabetes using mice with mutations in the glucokinase gene, the shaker1 mouse as a model of human genetic deafness, the role of genes in inherited psychiatric disorders, in cancer research in general and for the development of successful new therapeutics for breast cancer in particular, in the advance of new treatments for lupus, and Duchenne muscular dystrophy, and so on.

The Nuffield Council on Bioethics has a full chapter dedicated to how genetically modified animals are used in the study of human disease.

It is absurd for anyone to claim such advances are the product of chance.  They are the product of the hard work of dedicated individuals who spend countless hours in laboratories around the world with the goal of advancing the well-being of those affected by disease.  They are the product of those that go to bed thinking about how a protein may work, why muscles may weaken, how a tumor spreads, or why memory fails, in the hope of waking up the next day with some new ideas. They are the product of those that are determined to solve some of the most complex puzzles of biology that afflict human kind.  They are the product of talented students, staff and scientists that together work to rid the world of disease.  They are the product of science.

Herceptin: When personalized medicine and animal research meet.

Personalized medicine is very popular among medical researchers these days, and it’s not hard to see why. By tailoring treatment to fit an individual patient, for example by using information about their genetic makeup, scientists hope to make treatments more effective while at the same time avoiding or minimizing adverse effects.

Anti-vivisectionist Dr. Greek writes about personalized medicine as if one could do this work without relying on animal research at all.

For example, he writes:

When will personalized medicine become a reality?

We are already seeing it, with breast cancer being a prime example. Breast cancer treatment is now determined in part based on a patient’s genetic makeup. About 25-30 percent of breast cancer patients overexpress the HER2 oncogene, which is a gene involved in the development of cancer. The overexpression results in an increase in the replication of the cancer cells. Physicians are now able to identify which breast cancer patients overexpress HER2 and give them Herceptin, a monoclonal antibody that inhibits HER2

This is true…  but where did Herceptin come from?   Does he know?

Herceptin, a humanized mouse monoclonal antibody. Image courtesy of Andrey Ryzhkov.

The basic research that led to the development of Herceptin (Trastuzumab) goes back to work by Milstein and Kohler who discovered the potential for using antibodies to fight disease.    They developed the first methods to produce monoclonal antibodies using mice.   Both Milstein and Kohler went on to win the Nobel Prize partly for this work.

Harold Varmus (now back as Director of the National Cancer Institute) showed that disturbances in some gene families could turn the cells cancerous.  He also went on to win the Nobel Prize for this work.  Robert Weinberg subsequently discovered in rats that a mutant gene (named “neu”) encoding a tyrosine kinase promoted cancer features in cells, contributing to the development of neuroglioblastoma tumors.

Later, Axel Ullrich and collaborators at Genentech cloned the human HER2/neu gene.  Work at UCLA Dennis Slamon and colleagues showed HER2 over-expression in 25% of patients with aggressive breast cancer.

Through screening studies on monoclonal antibody candidates in vivo in mice implanted with HER-2 positive human tumors the group at Genentech then developed the mouse 4D5 (parent of Herceptin) and showed that 4D5 could suppress the growth of HER2 tumor cells as well as enhance the ability of the host immune system to kill them.   A collaboration between UCLA and Genentech then demonstrated that radio-labeled 4D5 localized to HER2-expressing tumors in both mice and human patients.

With the information obtained from animal experiments, Genentech created Herceptin by humanizing the 4D5 mouse antibody directed at HER2.   The ability of Herceptin to prevent tumor growth was then assessed in mice implanted with HER-2 positive human tumor xenografts, and the concentration of Herceptin required in the blood to achieve anti-tumor activity was determined before starting human clinical trials.

So, you see…  Herceptin was derived from a mouse antibody.

Let me repeat: a mouse antibody!

Clinical trials in humans subsequently showed the effectiveness of Herceptin to treat HER2 positive breast cancer.

Perhaps, Dr. Greek and other animal rights activists should carefully listen to the experts that were actually involved in the process of developing Herceptin (a drug he appears to thinks highly of) which, indeed, benefits so many women battling breast cancer.   A drug derived from mice, and developed in mice.

Here is what Robert Weinberg had to say about Dr. Greek’s views on research:

Dr. Greek says the silliest things, [...] implying that people are not studying human tumors, and implying that the kinds of experiments that one can do in mice can be done as well in humans — truly mindless!

I couldn’t have said it better.

Dario Ringach

Laying the foundations of medical research

For the past couple of weeks a debate has been raging on the Opposing Views website between Speaking of Research’s Dario Ringach and the anti-vivisectionist Ray Greek. It has been a debate shaped by Dr. Greek’s attempts to persuade readers to agree with his very narrow concept of what prediction means in biology and his frankly impoverished view on the role of basic research in advancing medical science, and to oblige those debating them to accept a playing field rigged to set them at a disadvantage.  Judging by Dario’s most recent opinion piece and an article written a couple of days ago on the role of basic research Dr. Greek failed in this attempt.

British biochemist Sir Tim Hunt, who won the Nobel Prize for medicine in 2001.

Among all the discussion was one comment that directed readers to an excellent example of the value of basic research and the how study of animal models made many key discoveries possible. Earlier this week the BBC aired a program in their Beautiful Minds series featuring Sir Tim Hunt, who was awarded the Nobel Prize in 2001 for his research on how the cell cycle – through which cells grow and divide – is controlled.  Sir Tim’s work focused on the role of a family of proteins known as cyclins and as the Beautiful Minds program explains the initial breakthrough came from studies of the fluctuations in the pattern of protein expression during the cell cycle in sea urchin eggs.  This discovery was followed swiftly by the demonstration that cyclins were also present in yeast, clams and frogs, allowing Sir Tim and his colleagues to predict that they would have a role in regulating the cell cycle in many species,  including humans, a prediction that was soon confirmed to be true (1).

This program is a reminder that while discussion of animal research tends to focus on animals such as mice, rats and monkeys a lot is being learned about the fundamentals of our physiology through research on more humble model organisms, a diverse collection that includes not just sea urchins and clams but also nematode worms and flies .  These animals, along with other model organisms such as yeast and bacteria, enable us to study how living things work at a very fundamental level, laying the theoretical foundations for future applied and translational research that yields innovative treatments for disease and injury. At the same time, researchers studying other aspects of physiology often require higher mammals. The study of complex brain functions, including vision, hearing, memory, attention and motor planning, as well as how these functions fail in diseases of the central nervous system, is a prime example of this.

If you haven’t watched the Beautiful Minds series yet I strongly urge you to do so, the programs provide a fascinating (if not always flattering) insight into how science works.  And don’t delay: they are only available to view on the BBC iPlayer for another 7 days!

Paul Browne

1)      Pines J.  and Hunter T. “Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2.” Cell Volume 58(5), Pages 833-846 (1989)  PubMed: 2570636