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For Life On Earth

presents a summary of

Current Understanding of Evolutionary Biology

as illustrated by Animal Models in Light of Evolution (2009), Drs Ray Greek MD and Niall

Shanks PhD, together with additional data from other experts. All the following quotations in

italics (with chapter and page numbers) are from the same author’s FAQs about the Use of

Animals in Science: a Handbook for the Scientifically Perplexed (2009).

Modern Genetics and Molecular Biology Because the Theory of Evolution is the single organizing principle of

modern biology, it enables us to put the facts of biology in their

proper places and gives us the overarching theoretical framework for

understanding the how’s and why’s of the remarkable similarities—

and at the same time the profound differences—of all living things on

earth. (Chapter 3, p 35)

When Darwin put forward his theory of evolution, he observed that the

characteristics of organisms might change during the process of being

passed on to offspring. However, because the principles of genetics

were not yet known, he could not explain how or why these changes

occurred. More recently, the advent of modern genetics and molecular

biology has informed our understanding of how evolution operates at

the molecular level. (Chapter 3, p 37)

The Theory of Evolution provides us a theoretical framework while

advancements in genetic and molecular biology provide the empirical

data as to why animals cannot adequately predict human drug and

disease response. Mice are unique and interesting creatures in their

own right, they are not simply men writ small! (Chapter 4, p 49)

At the subcellular and genetic level, where the vast

majority of research is now taking place organizational

differences between animals and humans outweigh the

similarities in ways that are relevant to a discussion about

prediction. (Chapter 4, p 49)

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What defines prediction? In science,

guessing correctly or finding correlations are

not the same as predicting the answer. A

fundamental part of any theory or practice

claiming predictability is its ability to predict

the result of an experiment that has not yet

been done. This concept separates the

scientific use of the word predict from the lay

use of the word, which more closely

resembles words such as guess and

conjecture. (Chapter 4, p 51)

Sean Carroll Endless Forms Most Beautiful:

The whole tool kit of an animal contains several hundred or so

different DNA-binding proteins, most with different signature

preferences. There are an astronomical number of potential

combinations of signature sequences in switches. If we assume

a tool kit of 500 DNA-binding proteins in an animal, there are

500 x 500 = 250,000 different pairs of combinations of

sequences and tool kit proteins. There are [25,000]00 x 500 =

12,500,000 different three-way combinations and over 6 billion

different four-way combinations. These calculations illustrate

the power of combinatorial logic of the tool kit and genetic

switches…

This simple example illustrates well why different individuals even of the same species respond

differently to the same stimuli, say a medicine. You may metabolize a medicine rapidly while another

person metabolizes it slowly; therefore, the safe and/or effective dose will be different for each of

you. You may be allergic to penicillin, even though your mother is not. You may be susceptible to AIDS

or lung cancer while your cousin is not. Even monozygotic (formerly called identical) twins suffer from

different diseases. (Chapter 3, p 44)

Differently organised intact systems: Humans and the animals used to model them exhibit causally relevant organizational differences. Mice and men may be intact systems, but they are differently organized intact systems. The line leading to modern mice diverged from the line leading to modern humans about 70 million years ago – for 140 million years of independent evolution and adaptation to diverse challenges posed by nature. From the standpoint of evolutionary biology, it is frankly bizarre to suppose that having pursued such divergent evolutionary trajectories, mice are men writ small. (See Animal Models in Light of Evolution for a more detailed discussion of these matters). (Chapter 4, p 60)

Dr Charlotte Uhlenbroek with orang-utan in Borneo

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Science thrives on open discussion and debate

In September 2000, BBC Radio 3’s The Today

Programme broadcast an historic live interview

with one of the authors of Animal Models in

Light of Evolution, Dr Ray Greek, together with

Professor Colin Blakemore, a leading

proponent of animal experiments. Professor

Blakemore had been requesting for some

months that “the opposition abandon

uninformed argument and engage in open,

solid and transparent dialogue”. The interview, presented by acclaimed broadcaster Sue McGregor,

centred around an invitation by Dr Greek extended to Professor Blakemore, requesting that he take

part in a series of five to seven live radio debates covering all areas of human illness, to enable the

public to hear that there is scientific opposition to the use of animals as predictive models for human

response. Professor Blakemore refused to take part in this debate; instead he invited Dr Greek to a

closed group at Oxford University - The Boyd Group – which would not have allowed the British

public to hear, or actively participate in, this event.

Those who claim that animal models are predictive must demonstrate that this claim is correct. The

evidential burden of proof resides with those who make the claims. (Chapter 4, p 51)

There are many ways in which animals can be used

in science that are scientifically valid.

However, this does not include animal models being predictive for

human response to chemicals, medicines and diseases. The following

is a précis of the list on page 1, chapter 1 of the FAQs book.

Scientifically valid uses include the use of animals as “spare parts”,

such as when a person receives an aortic valve from a pig. Animals can

be used as bioreactors or factories, such as for the production of

insulin or monoclonal antibodies, or to maintain the supply of a virus.

Animals and animal tissue can also be used to study basic physiological

principles and are used in education to educate and train medical students and to teach basic

principles of anatomy in high school biology classes. Animals can be used as a modality for ideas or

as a heuristic device, which is a component of basic science research and can be used in research

designed to benefit other animals of the same species or breed. Animals can also be used in research

in order to gain knowledge for knowledge sake. (Chapter 1, p 1)

From animals we can learn that cells are common building blocks of tissues, the way blood circulates,

that life consists primarily of carbon, oxygen, hydrogen, and nitrogen, what an immune system is,

and so forth. As long as the questions concern basic heritable properties, we can and have learned

things from using animals. (Chapter 3, p 46) Science has learned much about the way the body plan

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goes together by studying fruit flies. But as your examination becomes finer, for example seeking the

mechanism by which HIV enters the cell, then the differences begin to outweigh the similarities.

Today, the questions we’re asking are not so simple. In fact, they’re incredibly complex. Advances in

technology enable us to study human disease at the genetic level. And that is precisely where species

differentiation is most pronounced. Rather than studying what makes us similar, we’re studying what

makes us different. (Chapter 3, p 47)

SUPPORTING EXPERT RECOGNITION

David F. Horrobin wrote in Nature Reviews Drug Discovery (2003):

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…there is

little rationale for using animal models which frequently simply draw attention and funds away from

the careful investigation of the human condition.

January 12, 2006 (FDA), 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.

Kola and Landis wrote in Nature Reviews Drug Discovery (2004): The major causes of attrition in the

clinic in 2000 were lack of efficacy (accounting for approximately 30% of failures)…animal models of

efficacy are notoriously unpredictive.

Dr. Francis Collins, the director of the National Institutes of Health (NIH)…said about half of drugs

that work in animals may turn out to be toxic for people.(Reuters 2011)

Leaf also quotes Homer Pearce, ‘who once ran cancer research and clinical investigation at Eli Lilly

and is now research fellow at the drug company’, as saying “that mouse models are “woefully

inadequate” for determining whether a drug will work in humans. “If you look at the millions and

millions and millions of mice that have been cured, and you compare that to the relative success, or

lack thereof, that we’ve achieved in the treatment of metastatic disease clinically,” he says, “you

realize that there just has to be something wrong with those models.” (Leaf 2004)

Alan Oliff, former executive director for cancer research at Merck Research

Laboratories in West Point, Pennsylvania stated in 1997: “The fundamental

problem in drug discovery for cancer is that the [animal] model systems are

not predictive at all.” (Gura 1997)

Handbook of Laboratory Animal Science Volume II Animal Models: ‘It is

impossible to give reliable general rules for the validity of extrapolation from

one species to another. This…can often only be verified after the first trials in

the target species (humans)…Extrapolation from animal models…will always

remain a matter of hindsight’ (Salén 1994, p6).

Toxic Waste report, courtesy IPPL

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THE EXORBITANT FINANCIAL COST

Robert Weinberg, of Massachusetts Institute of Technology, was quoted by Leaf in Fortune

magazine (2004) as saying: “And it’s been well known for more than a decade, maybe two decades,

that many of these preclinical human cancer models have very little predictive power in terms of

how actual human beings—actual human tumors inside patients—will respond . . . preclinical

models of human cancer, in large part, stink . . . hundreds of millions of dollars are being wasted

every year by drug companies using these [animal] models.

In an editorial introduction to one article by Ellis and Fidler and another by Van Dyke (Van Dyke 2010), the editors of Nature Medicine stated: The complexity of human metastatic cancer is difficult to mimic in mouse models. As a consequence, seemingly successful studies in murine models do not translate into success in late phases of clinical trials, pouring money, time and people’s hope down the drain. (Ellis and Fidler 2010) April, 2010, issue of The Scientist: 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 (Zielinska 2010)

The Editors of Nature Reviews Drug Discovery wrote in 2011: “Unpredicted drug toxicities remain a leading cause of attrition in clinical trials and are a major complication of drug therapy.” (Editors 2011) “Fewer than 10% of new drugs entering clinical trials in the period from 1970 to 1990 achieved FDA approval for marketing, and animal models seemed unreliable in predicting clinical success” (Chabner and Roberts 2005)

Usha Sankar in The Scientist 2005: The typical compound entering a Phase I clinical trial has been

through roughly a decade of rigorous pre-clinical testing, but still only has an 8% chance of reaching

the market. Rats and humans are 90% identical at the genetic level, notes Howard Jacob, cofounder

of Wauwatosa, Wisconsin-based PhysioGenix. However, the majority of the drugs shown to be safe

in animals end up failing in clinical trials. "There is only 10% predictive power, since 90% of drugs fail

in the human trials" in the traditional toxicology tests involving rats, says Jacob. (Emphasis added).

Dr Andre Menache director of Antidote Europe and author of the Toxic Waste primate report:

“REACH deals with the Registration, Evaluation, Authorisation and Restriction of Chemical

substances. To study a single chemical using animals it will cost REACH in the region of 3 million

euros per compound. Using human biology-based toxicogenomics will cost about 100 times less”.

Drs Greek and Shanks FAQs p 13 and 15 This (1985) is an old table but is still the most recent record

of the amount of money spent by NIH on experiments involving animals. Since 1985 basic research

has if anything become more connected with animal-based research, which receives the lion’s share

of grants.... With roughly two-thirds of research dollars going to basic research and most basic

research using animals we can safely confirm the 1985 numbers of at least 50 percent of research

dollars going to animal-based studies. If we assume a $30 billion dollar NIH budget, one can estimate

tens of billions annually are spent on animal-based studies from NIH alone.

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OUR POSITION

FOR LIFE ON EARTH supports modern, human biology-based methods that can protect the

safety of humans by providing data relevant to precisely the species in question. We hold the

distinct position that animal models need to be abandoned without hesitation on the strength of

current factual evidence best illustrated by Animal Models In Light Of Evolution, together with

additional supporting expert recognition. FOR LIFE ON EARTH presents the crucial

significance evolutionary biology holds for medical research, as outlined by AFMA/EFMA

(Americans and Europeans for Medical Advancement) whose position is as follows:

AFMA/EFMA opposes animal models as a modality for predicting or seeking cures and treatments for

human disease based on overwhelming scientific evidence that animal models are not predictive for

humans while acknowledging that animals can be successfully used in science in other ways.

AFMA/EFMA is frequently accused by those who advocate animal-based studies as being an animal

rights group, and this accusation is used as an ad hominem attack. For example, in their book The

Animal Research War, Conn and Parker list AFMA under animal rights organizations. The reason for

this can only be that such people are trying to confuse people who are

not familiar with AFMA/EFMA. Our scientific arguments are sound and

our position on ethics-related issues is also well known; AFMA/EFMA

does not oppose the use of animals in science, but does oppose the

use of scientifically invalid methodologies be they animal-based or

otherwise. We take no position on issues relating to the ethics of

using animals. (Emphasis added)

Science is the opposite of dogmatic adherence to unfounded beliefs.

Whereas dogmatism demands that its constituency not question the

beliefs of the system, science welcomes and even initiates questioning.

Followers of dogma are taught not to study it, nor examine its

veracity, nor weigh whether alternative explanations better explain

the system governed by the dogma. They cannot debate the fundamentals upon which the system is

based. They are taught unquestioning belief, not to search for truth.

Science, on the other hand, withstands questioning from every

quarter. In any forum, all experts’ opinions bear consideration,

and that consideration will through consensus, determine the

present understanding of truth. German philosopher Jürgen

Habermas stressed “the importance of public debate and

rational consensus for preventing the domination of society by

one group of interests. Consensus suffers inaccuracy when

relevant opinions are suppressed.” (Chapter 10, p 138

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The Animals in Scientific Procedures Act

The Home Office’s position

as outlined on its website:

The development of drugs and medical

technologies that help to reduce suffering among

humans and animals depends on the carefully

regulated use of animals for research.

EFMA/AFMA:

If the claimant is saying that animals were necessary then he needs to support that claim with

evidence and argumentation…In fact, demonstrating that a medical science discovery could only

have been made by using animals—that animals were necessary (not merely useful or important as a

contingent, accidental fact of history)—is a very tricky proposition. Simply pointing to examples is not

enough. The claimant must show that the discovery in question could not have been made any other

way. This must be done for the claimant to say the discovery was necessarily dependent on animal

use. (Chapter 4, p 61)

Conclusion (Chapter 10, p 132)

All vertebrates are examples of evolved complex systems. Restricting our attention to mammals, this

means that humans and mice (say) have taken divergent evolutionary trajectories in which, in the

course of evolutionary time (70 million years since divergence of the respective lineages) causally

relevant differences have accumulated between the species to the extent that there is no reason to

suppose that the latter (mice) can serve as predictive models for the former (humans). We explore

this matter from the standpoint of both evidence and basic biological theory.

Living complex systems also manifest different responses to the same stimuli due to: (1) differences

with respect to genes present; (2) differences with respect to mutations in the same gene (where one

species has an ortholog of a gene found in

another); (3) differences with respect to

proteins and protein activity; (4) differences

with respect to gene regulation; (5)

differences in gene expression; (6)

differences in protein-protein interactions;

(7) differences in genetic networks; (8)

differences with respect to organismal

organization (humans and rats may be

intact systems, but may be differently

intact); (9) differences in environmental

exposures; and last but not least (10)

differences with respect to evolutionary

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histories. These are some of the important reasons why members of one species often respond

differently to drugs and toxins, and experience different diseases. These are the kinds of differences

that are relevant to an assessment of animals as predictive models.

Therefore, we now understand why even two very similar complex systems (e.g. a chimpanzee and a

human, or even monozygotic twins) may respond differently to drugs and experience different

diseases, and hence why one complex system/species cannot reliably predict responses for another.

Current biomedical research is studying disease and drug response at the level where the differences

between complex systems (be they two different species or two different humans) become highly

significant from a biological point of view, hence using animals (e.g. vertebrates) as predictive causal

analogical models for human disease and drug testing may eventually be replaced with methods that

are biomedically effective. Immense empirical evidence supports this position.

So-called less complex organisms (e.g. C. elegans, E. coli, Drosophila, and S. cerevisiae) are very

useful, however, for discovering, among other things, genes that produce the core processes of living

systems.

Animals such as vertebrates can be viably used as a modality for ideas, education, a source of spare

parts, incubators, factories and growth media, for the study of diseases affecting the same species,

to study basic biological principles, and axiomatically, to add knowledge to the world. (Chapter 10, p

132)

FOR LIFE ON EARTH (FLOE) presents evidence from current science that needs to

be examined closely by all of those responsible for administering The Animals in

Scientific Procedures Act (ASPA).

Science now shows us why the ASPA - in its present wording – does not protect human

health and lacks up-to-date understanding of the principles of evolutionary biology. It is

therefore the position of FLOE that the ASPA can no longer be justified in providing

guidance for the continued use of non-human laboratory animals as predictive models

for human response to chemicals, medicines and diseases.

FOR LIFE ON EARTH is an alliance presented by

advocates for human health, including patients and

their families, primatologist and television wildlife

presenter Dr Charlotte Uhlenbroek PhD and the

support of The Beagle Association.

Science illustrated by

Animal Models in Light Of Evolution

www.afma-curedisease.org

www.forlifeonearth.org