The year 2009 marks the bicentennial of the birth of Charles Darwin and the 150th anniversary of the publication of his master work, “The Origin of the Species.” In universities and museums across the United Kingdom, events and exhibitions have been convened to celebrate this anniversary. Indeed, it has been possible to see everything from an academic wearing a false beard and a stovepipe hat doing a passable imitation of Charles Darwin while giving a slide show presentation on his visit to the Galapagos Islands (University Museum Oxford, February 2009) to exhibits that offer an insight into this remarkable man, such as the page of the final draft manuscript of “The Origin” containing some decipherable pencil arithmetic—the homework of his grandchildren undertaken on what was for the family a piece of scrap paper! (Talbot Rice Gallery, Edinburgh, Fall 2009)
Here in Edinburgh, we claim Darwin as one of our own. This is because he spent the first 2 years of his higher education studying medicine in Edinburgh.1 In common with other students of that age, Darwin did not choose his subject of study himself; the decision was made for him. Medicine ran in Darwin's family; his father was a successful physician and his grandfather Erasmus Darwin, a notable physician in the cathedral city of Lichfield,2 had also been a key figure in the English enlightenment that was centered in the Midlands and Potteries in the preceding century. But Charles Darwin was not destined to become a doctor and indeed did not enjoy his medical studies. He was apparently averse to surgery (pre-anesthesia, of course) and found the didactic lectures tedious. (I might add, for any parents of prospective medical students, that our curriculum has changed significantly since 1826, and our reputation for taught components is excellent!). As a result, Darwin filled his time collecting insects and observing natural history and marine life. Ultimately he dropped out of medicine, and, under the guidance of his father, enrolled as an undergraduate in Cambridge University to study to become a clergyman….and the rest, as they say, is history.
In modern terms, Darwin's time as a medical student would be considered a failure, but his time was not spent aimlessly; he learned taxidermy and joined the Plinian Natural History Society, presenting a paper there on the marine biology of the Firth of Forth.1 He also came into contact with Robert Grant, who, using sea sponges as a model, observed and published evidence for a “transmutation of species.”1 Edinburgh in the early 19th century was also one of the major settings of the European enlightenment and was undoubtedly an exciting place to be a student. Moreover, Darwin came from a strong tradition of free-thinking intellectuals who advocated empiricism, observation, and analysis to define and make sense of the natural world. His great grandfather had discovered a plesiosaur fossil in a field adjacent to the family home. He thought this was a fossilized crocodile, but like several of that age was struck by the parallels in anatomy and developmental process that characterized not only the flora and fauna around him but that was also present in fossils.2 Indeed, Erasmus Darwin had speculated that all life may have evolved (my term, not his) from a common putative ancestor in his work “Zoonomia,” itself an influence on Robert Grant.2 Charles Darwin's masterwork of course provided, through natural selection, a mechanism by which evolution could work. I sometimes worry that the relentless increase in pressure of the curriculum within our universities, particularly in vocational subjects such as medicine, risks stifling creative and innovative thinking demonstrated so perfectly by Darwin's early career.
It is of course as a direct result of the works of Darwin and others that we now know so much about the evolution and development of the process underpinning metabolism. Much is now known about the genomes and fundamental metabolic functions in organisms as diverse as bacteria and yeasts to the nematode, fruit fly, and xenopus, in addition to birds and mammals. This knowledge has created a platform from which nonvertebrate and lower vertebrate models can be deployed to investigate basic developmental and pathological processes. The increased use of simpler metazoans with smaller genomes has, in recent years, played an increasingly important role in defining and dissecting a number of processes and key players of particular importance to biology. Already these are impacting on our understanding of liver development and disease. The opportunities presented by the study of simpler organisms to dissect function and pathology are now growing.
The use of nonvertebrate and lower vertebrate models provides researchers with a number of key advantages. These include defined and relatively limited genomes, a short lifespan, ease of genetic manipulation, in some examples direct visualization of an organ or tissue, and of course homologous biological systems with higher vertebrates. Additionally, for these lower organisms, antisense or knockout strategies are easily deployed to dissect out multiple components of pathways of interest for pathological processes. Effectively, libraries of knockout or knockdown organisms can be created for the research community.
For example, in the last few years, critical observations relating to liver biology and development have been driven by the zebrafish model. This includes the identification of the Wnt2b gene as critical for normal fish liver specification and development.3 Looking to the future, however, fish offer multicellular/multiorgan models for screening. Because the zebrafish embryo is transparent and has relatively close homology with other higher vertebrates, it renders itself as an extraordinary yet simple multiorgan in vivo model in which to screen drugs.4, 5 Fish can be created that incorporate reporter systems expressing fluorescent protein when a target gene is transcribed. Multiwell plates in which each well contains a single transparent fish embryo can be exposed to novel therapies, and compounds regulating transcription in particular pathways may be rapidly identified. This opens the door to, for example, screening existing licensed drugs for novel indications. Additionally, because the array can take place in a 96-well plate format, literally thousands of compounds can be screened in a whole vertebrate organism in vivo assay.
It is easy to see how organisms such as zebrafish, which possess a defined liver, might be used as models for hepatological research. It is less clear, though, for Drosophila (the fruit fly), which lacks a discrete organ homolog for the liver. Traditionally, the fat body, the major glycogen store in the fly, oriented in a segmental fashion during larval development, has been seen as being the equivalent of the liver for the fruit fly. However, current evidence suggests that Drosophila does not have a discrete organ ortholog to the liver, but rather that specific metabolic functions associated with the mammalian liver have evolved to be delivered by different tissues. Arguably, a fruit fly larva inching along and ingesting anything it comes across might have greater need of a systemic detoxification mechanism than a higher mammal, which can at least express some preference for what it puts into its gastrointestinal tract. However, in the absence of a “liver,” that function may be subserved by cell systems. For example, cytochrome p450 expression is detected in several larval tissues. These include the fat body, but also critically, the malpighian tubules and mid gut.6, 7 The roles of these topographically distinct cytochromes have been the subject of significant research, because they are major determinants of resistance to insecticides. Interestingly, when the relative roles of cytochromes within individual drosophila tissues have been analyzed, those in the malpighian tubules (rather than in the gut and gut-related tissue) seem to be the most important to determining survival when the organism is challenged with DDT (dichlorodiphenyltrichloroethane).6 With the identification of a further cell cluster, the oenocytes, which appear to be critical to fat metabolism and other metabolic pathways, the picture of the Drosophila hepatocyte ortholog has become even more complex. Although the fat body acts as a major lipid store, the Gould group has recently demonstrated that the oenocyte accumulates lipids during starvation.8 Moreover, there appears to be bidirectional regulation of lipid metabolism in which the oenocytes are required for depleting stored lipid from the fat body during fasting. Additionally, the oenocytes express lipid-metabolizing proteins including Cyp4g1 and appear to share some of the lipid processing functions of the mammalian liver.8 As more is learned about the interplay between the broader functional repertoire of the oenocytes and the oenocyte–fat body interplay, the Drosophila system may well prove to be a model that can be deployed to study aspects of fat metabolism and hepatic function that is orthologous to higher mammals. Indeed, the topographic separation of tissues delivering specific hepatic functions within Drosophila means it may prove a valuable and unique model to study specific metabolic phenotypes. The evolution of the fruit fly provides a curious insight into the manner in which co-evolution of processes vital to life that have been grouped within a single, though multilineage, cellular system in the mammal, are topographically distributed across organ and tissue systems in the fly.
So much for normal evolution and development, but what of the evolution of the response to disease? Here, intellectually simulating though the subject is, we can only conjecture. Unfortunately, we do not have the luxury of being able to conduct a controlled trial running for thousands, if not millions, of years. However, the evolution of certain hepatotropic viruses (hepatitis B and C viruses), the host immune response, and viral escape strategies provide fascinating models of host–pathogen coevolution that merits at least a whole journal issue of discursive review. What of the other hepatic responses such as fibrosis? I am often asked at conferences why, given that the liver responds to damage with scarring, should we have evolved such an apparently adverse response to injury? I think the answer is straightforward; the genes regulating the scarring process in the liver are identical of course to the whole of the rest of the body, including the skin. I suspect that the evolutionary pressure on the process of scarring has been dominated by the requirement to have a rapid and avid fibrotic response to repair traumatic damage to the skin, gut, and lungs and that scarring is the price we pay to be protected from our environment. Additionally, the scarring response may not have been entirely disadvantageous for hepatic function when humans or lower mammals were living in more adverse circumstances. Indeed, a rapid scarring process is a highly energy-efficient means of dealing with parasites. Because the time frame over which this or other insidious fibrogenic stimuli such as chronic viral infections impact is measured in years, when the age of reproduction lies between one and two decades, the fibrotic response of internal organs such as the liver may never have had a significant influence on natural selection.
Perhaps the liver's response to injury is actually highly tuned and entirely fit for purpose; our problem is rather that hepatic insults resulting from a 21st-century lifestyle now challenge this highly evolved response.
I wonder what view Darwin would take?