Animal Rights

Animal-based Research and Core / Conserved Processes

| by Dr Ray Greek

I have wanted to write about conserved processes for some time but the subject is really not amenable to a blog. The following from Mehal, however, gives me an opportunity to at least broach the subject.

Mehal et al 2011:

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Studies of organ fibrosis have flourished over the last decade, identifying a growing number of molecules that regulate the development of fibrosis in experimental models. Fibrotic diseases account for up to 45% of deaths in the developed world, yet there are no approved antifibrotic therapies. Translating advances in experimental fibrosis to clinical management has been challenging, in part, because there are now many candidate antifibrotic targets, and most are tested in highly controlled experimental settings, usually only in a single organ type and species. The therapeutic implications of these animal studies are therefore only relevant to that specific rodent strain and within the constraints of the experimental design. Moreover, the field is driven by a bias toward publishing the most novel findings and away from confirmatory or relevant negative observations. . . .

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The concept of 'core' and 'regulatory' pathways in fibrosis may help tackle this conundrum. Whereas a core pathway is essential to convert an initial stimulus to the development of fibrosis, regulatory pathways are those that can influence the core pathway but do not directly convert the initial stimulus into the basic component of fibrosis. Therefore, cells and molecules along the core pathway are essential to fibrosis, and their targeting may be sufficient to limit progression. The regulatory pathways may have substantial effects on fibrosis but will also have greater variability between organs, species and individuals, challenging the value of these targets. For this core-versus-regulatory pathway approach to have utility in fibrosis, criteria should be established for identifying components of these pathways, and, unfortunately, the reductionist approach used in animal models rarely makes this distinction. (Mehal, Iredale, and Friedman 2011)

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There several point to be made about the above. In some ways, the above explains why animal-based research was successful in the early days of medical science—when scientists were examining the anatomy and physiology that mammals have in common—but not today, when the questions being asked are about a level of organization that is much higher / more complex. When the questions being asked have different answers depending on which human we are talking about, the level of organization being addressed is not likely to be amenable to study in monkeys. The response of humans to drugs and disease must be studied in the context of the whole—complexity—not in the context of the sum of the parts—reductionism. (NOTE. Reductionism works! It has worked very well for questions of the past and some of the questions being asked today are still very much amenable to study by reductionism. However, the fact that disease and drug response varies intra-species is the reason for fields like systems biology and personalized medicine. When I say that reactions to diseases and drugs be examined in the context of the whole, I am NOT talking about so-called “Holistic Medicine”. Search the site Science-Based Medicine for more on Holistic Medicine.)

Kirschner and Gerhart have written about core processes and conserved processes. (Gerhart and Kirschner 2007; Kirschner and Gerhart 2006). For example:

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A big surprise of modern biology has been conservation—that even distantly related organisms use similar processes for cellular function, development, and metabolism. Each process, comprised of many protein components working together, contributes to the phenotype. When a process is conserved, most of its protein components are conserved. Details of metabolism are the same in bacteria and humans; basic cell organization and function are similar between yeast and humans; and developmental strategies in fruit flies are strikingly similar to those in humans. The conservation of key processes in diverse organisms today implies, as we shall see, that we can deduce the basic physiological and developmental processes of organisms in the past. Even though these processes are not revealed by the fossil record, broad conservation  among living organisms puts us in an unambiguous position to extrapolate back to our ancestors. . . .

The surprisingly small number of genes for humans and other complex animal forms reflects the anatomical and physiological complexity that can be achieved by the reuse of gene products. The conserved processes are fundamentally cellular processes; they operate on many levels in the development and functioning of the organism. They are the core processes of the organism. . . .

The small number of genes in multicellular organisms—14,000 in Drosophila and 22,500 in humans—and their high degree of conservation raise two concerns for understanding biology. The first is how the staggering complexity of animals, reaching a kind of apotheosis in the human central nervous system, can be generated from such a small number of gene products. To put things into perspective, the number of neurons in the human brain is estimated to be a hundred billion, and the total number of synapses to be a million billion. They are arranged and function in complex spatial networks. A second concern is that many of the small number of genes are highly conserved; how can the relatively few differences support the extraordinary diversity of anatomy and physiology of organisms on this planet?

The answer to both concerns must come from the use of these genes in combinations. Combinations add up quickly; even 20 different factors deployed in all possible combinations add up to far more than a million billion. . . .

Most evolutionary change in the metazoa since the Cambrian has come not from changes of the core processes themselves or from new processes, but from regulatory changes affecting the deployment of the core processes. These regulatory changes alter the time, place, circumstance, and amount of gene expression, RNA available or protein synthesis of components of the core processes or alter the activity and interaction of proteins of the processes by modifying them or by changing their stability. Because of these regulatory changes, the core processes are used in new combinations and amounts at new times and places. Also because of the regulatory changes, different parts of the adaptive ranges of performance of the processes are used in new circumstances. [(Kirschner and Gerhart 2006)p34-5, 109-112, 156, 220-222]

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(I strongly recommend Kirschner and Gerhart’s book The Plausibility of Life. I do not know how anyone can seriously claim to understand/criticize animal models without understanding the material in that book.)

The reason older/less complex organisms are good models for pathway and gene analysis is that core processes are likely to be preserved down the evolutionary line. Mark Ptashne and Alexander Gann write in Genes & Signals:

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…it is generally believed that mammals—humans and mice, for example—contain to a large extent the same genes; it is the differences in how these genes are expressed that account for the distinctive features of the animals…changes in patterns of gene expression (rather than evolution of new genes) have had an important, perhaps even determinative, role in generating much of that diversity (that occurred during the Cambrian explosion)…a relatively small number of genes and signals have generated an astounding panoply of organisms. Thus, the regulatory machinery must be such that it readily throws up variations—new patterns of gene expression—for selection to work on. 

Most of what we have learned about gene regulation has come from the study of bacteria such as Escherichia coli and yeast such as Saccharomyces cerevisiae. Most genes are expressed by initiation of RNA polymerase. The first studies to reveal that RNA polymerase regulate genes were done on bacteria in the 1950s. Even in the 1950s, scientists suspected not all 3000 genes in E. coli. were expressed all the time. By studying E. coli, scientists determined that some genes were dormant until something turned them on. There are numerous ways of turning a gene on and the more recently evolved and more complex an organism is, the more ways there are. Bacteria evolved about three ways to control gene expression: regulated recruitment, polymerase activation, and promoter activation.

Yeast (with around 6000 genes) has evolved more than three ways to activate their genes. Yeast is more like humans than bacteria as we both have DNA wrapped around a protein and residing in a nucleus. Yeast and humans, and flies, worms, plants, and other organisms similarly organized, are thus categorized as eukaryotic. Yeast uses the same regulatory mechanisms as bacteria but has evolved add-ons that allow more complexity into the system. Nature did not throw away what worked in the bacteria; it merely made additions that allowed new functions and thus a more complex organism. (Ptashne and Gann 2002)

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The reason drugs and diseases affect people, and species, differently lies, in part, in the how the conserved and core processes are regulated. Studying core processes in yeast, for example, is not the same as studying drug reactions in dogs or mice. The level of complexity has increased both in the form of more modules interacting and the same processes / genes being regulated and expressed differently.

The information contained in Genes & Signals and The Plausibility of Life is vital for anyone who wants to really engage in a discssion about, or present arguments against, the use of animals in science.

References

Gerhart, John, and Marc Kirschner. 2007. The Theory of Facilitated Variation. In In the Light of Evolution: Volume 1. Adaptation and Complex Design, edited by J. C. Avise and F. J. Ayala. Washington DC: National Acdemy of Sciences.

Kirschner, Marc W, and John C Gerhart. 2006. The Plausibility of Life: Yale University Press.

Mehal, Wajahat Z., John Iredale, and Scott L. Friedman. 2011. Scraping fibrosis: Expressway to the core of fibrosis. Nat Med 17 (5):552-553.

Ptashne, M, and A Gann. 2002. Genes & Signals: Cold Springs Harbor Laboratory Press.