Craig Venter's Synthetic Bacterium

Wow, it's been a while since I posted. I have been getting occasional prods to write something, and everything seems to have fit into place for it to happen now, so here we go.

Much has been said over the announcement last week of the creation of a "synthetic life form" by the J. Craig Venter Institute. Much of that has been woefully uninformed, which is probably the topic of another post. The news is impressive, to be sure, but it is not really that groundbreaking. The actual procedure is the bacterial equivalent to the procedure that produced Dolly the cloned sheep, technology that, while remarkable, is hardly news (although I would imagine that it might be more difficult to do with a bacterial cell than a mammalian one). The big advance in this project was the fact that the genome that was introduced into the cell was completely synthetic -- its sequence designed on a computer, and its chemistry produced in a laboratory. In fact these tasks are both routine in biology and biochemistry laboratories. The difference here is the application: specifically, the combining of the synthetic-DNA and cloning procedures. The fact that we have a functioning cell with a completely synthetic genome is a remarkable outcome, to be sure, but the principle has been an obvious one for a couple of decades now. If one were to compare this to a society-changing invention, it would be to Henry Ford's adoption of the assembly line to produce the same cars he had been making for several years, rather than the Wright Brothers' first powered flights.

Another aspect that gets sometimes mentioned but (I suspect) overlooked is the nature of this new organism's genome. True, it did not exist in any chemical state before its synthesis by human researchers, which is to say that it was not spliced together from fragments of preëxisting genomes taken from extant viable organisms. However, that is true only in the chemical sense. The actual sequences for the genes used for this genome were taken from extant viable organisms, and if one were to do a phylogenetic analysis of any of those genes, the new organism would be a sister lineage for the source of whichever gene was used, not a completely separate branch from any other life form. In fact, as far as I understand it, there is nothing to distinguish the actual organism from a hypothetical one made from spliced bits of the same source genomes -- in other words, a clone in the more traditional (Dolly-the-sheep) sense. This work, important though it unquestionably is, is not the creation of a completely new life-form, but a proof-of-concept that such a creation is possible.

There are one minor and two major hurdles that need to be overcome before we actually do have the sort of unprecedentedly novel life-form that many in the press and the public think this is. The minor one is that the new organism that Venter and his team have created is based mostly on genes from an obligate parasite with highly specific environmental requirements: it is not what we would unreservedly call "free-living". Parasites can be tricky to grow in the lab, and parasites potentially missing parts of various biochemical pathways (which this one is likely to be) can be a nightmare to keep alive, even if they start off growing vigorously. Venter's new organism has a synthetic genome, yes, but it has been injected into another cell whose genome had been removed, leaving all the rest of the life-giving biochemical machinery intact. While it is estimated that the new organism should replace all of that in about twenty generations, it is still possible that (for instance) some important and overlooked protein is also long-lived enough to keep the cell and much of its progeny alive for quite a while before finally giving out and causing the population to crash.

In fact this points to one of the most important applications of this research. In spite of all of the attention given of late to genomics, proteomics, transcriptomics, interactomics, and a number of other "omicses", we really have only an inkling of what is actually required to keep a cell functional. One obvious future direction of this research is to produce organisms with various subsets of the current genome, to determine exactly what the minimal set of genes is to keep something alive. I hasten to add that the subset that would eventually be arrived at would be specific to the starting set of genes in the genome; other starting points will almost certainly result in other final genomes. In other words, what might be the smallest number of genes needed to keep a Mycoplasma-derived organism alive might still be more than the smallest number of genes required for (say) a Rickettsia-derived organism, even if the original genome is larger. Nevertheless, given that the Mycoplasma genome is the smallest known, this is a good starting point.

So the minor hurdle that I mentioned earlier is that, while the genome is supposed to be functional from a minimal standpoint, there is no guarantee at this stage that it is in fact indefinitely viable; Venter may already have stripped the genome past its minimal complement of genes, and omitted some critical component to the genome without which the cell can eke by for several generations. Time will tell whether this is in fact the case, of course, and if it is, the remedy is obvious. Venter and his team have proven that they can generate a synthetic bacterium once; if this one fails, they need only do it again with a different genome, and repeat as necessary until they have something that works.

That leads to one of the major hurdles. This is a new genome, yes, but as I said already, it was taken from bits of other organisms' genomes. Probably the greatest milestone in synthetic biology will be when we are able to design completely new genes. This would amount to deciding what chemical reaction we want the gene's product to perform, how we want it regulated in the cell (specifically, what other genes and gene products it must interact with), and with that information alone coming up with a previously unknown string of A's, C's, G's and T's that can be inserted into a genome to do exactly what we ask of the new gene product. A fully synthetic life-form would have all of its genes so constructed, and none taken from already-extant organisms. This is precisely opposite to Venter's new organism, and its advent is probably decades away still, barring some major and sudden advance in our understanding of protein function and generation.

Meanwhile, the fact that this technique requires that the new genome be injected into a "recipient" cell -- a previously viable organism that has left all of its life-sustaining machinery for its new genome to use -- is itself the other major hurdle to making a completely novel organism. While a truly and completely synthetic organism would need entirely novel genes, it would also need to be made without using any pre-existing cellular materials. This, and this alone, would be the actual creation of new life, similar to what happened naturally in Earth's primordial oceans some four billion years ago. We can already make coacervates, lipid vesicles similar to cell membranes, in the laboratory -- in fact, it was an exercise in my high school biology class! Putting those vesicles into the proper context for a living cell is probably not so easy, but also not impossible. Generating life in this sense will also probably require a rather different biochemistry from what Venter's techniques require. It may not be possible (or if so, prohibitively difficult) to make it work with the DNA-and-protein biochemistry used by all currently extant life. It may instead be necessary to replicate the "RNA World" that is thought to have preceded it, and probably in a progenotic sense, meaning that while all functions necessary for life would be carried out by the complete population of protocells, no individual cells would carry the full complement of genes required for those functions.

What all this amounts to is that Venter's procedure is a top-down approach: taking pre-existing components and combining them to create a new combination. The further steps down this road amount to trying to figure out which components can be removed without causing the system to collapse, and which can be simplified. This is a laudable goal, and I congratulate Venter and his team for making the advances that they have. But the truly groundbreaking work, based on the bottom-up approach, generating new life from whole cloth, has yet to be accomplished, and will not come soon.

Heckling

Earlier in the week, on my way home from a long day, I passed a group of protesters outside one of the hospitals here. The professional-looking signs and banners that they were displaying said "Pray to End Abortion". My immediate and cynical reaction, as both a supporter of abortion rights and an atheist, was one of approval: these people are using as ineffective a means as possible to support a cause with which I disagree entirely. Two of them had big pieces of cardboard with handwritten signs as well. One said "Today? Abortion - Tomorrow? Godless Anarchy", and that almost made me stop. I am a big fan of civilisation (see my previous post for more thoughts on that) and, Ursula K. LeGuin notwithstanding, I suspect anarchy to be its antithesis. I do not see the connection between abortion and anarchy, but was not tempted to ask the protester for details. Rather, I was more than a little incenced at the use of the word "godless" as a negative modifier. "What's wrong with being godless?" I wanted to ask. The obvious connection that the religiously deluded seem not to get over is that it is impossible to be moral without a belief in God, and I feel that this should be challenged vigorously and often.

But I had had a long day, which began with swimming for the first time in six months and at a time far earlier than I am usually out of bed, a surprisingly busy and productive time in the lab, and just now a soccer game, and I just wanted to get home. I passed the protesters without comment, but I thought about the possible consequences of heckling on the way. Would it be possible for me to make a difference that way? I would not attempt to argue for abortion rights, or make any snide comments about the efficacy of prayer: just challenge the notion that "godless" is a bad thing. Perhaps I might make the person think a little. Perhaps I might at the very least make him aware that equating "godless" with "immoral" ranges from annoying to offensive for a substantial number of people. Keep the topic focussed and the discussion civil, and maybe some good would come of it. That would be worth the effort. But I figured that the effort would have to be spent another day.

A couple of days later, as I got on the bus to go home, I was heckled myself -- by the bus driver! It was late, and it was windy, and I was cold. For those of you who have not lived here, Halifax can get impressively windy. It would not actually have been unpleasant except for the wind-chill factor. The bus pulled up, and I stepped in, grateful to start warming up, and the fellow that was heading out pushed by me. I flashed my U-Pass and headed back, and the bus driver barked at me to come back and "take those things out of your ears" (meaning my earhones). I figured that maybe he needed a second look at my U-Pass, but no, he asked me, "Why did you charge in here without letting that guy off first?" I told him that it was cold outside, and I wanted to get out of it, and he went on that I was supposed to let people off the bus before I got on myself, and that "you can't just push people around like that." I have no idea what made him think that I got some sort of satisfaction from bullying people, but there were people behind me waiting to get on the bus as well, and I did not want to keep them out in the cold, so I tried to shrug it off. But the bus driver was not going to accept that. He kept at it, insisting that I change my attitude to those around me. The fellow that I had bumped into was long gone, and did not seem to have made any issue of the matter: why was the driver so offended? Eventually I expressed enough flustered apology for him and he let me go.

I would have fumed had I not recently contemplated heckling people myself. But I think there are definite differences between the two situations. The bus driver was acting on an event that took only a few seconds, and did not consider the possibility of extenuating circumstances. The protester was, after a fashion, asking for a response. I was not about to give the protester the response that he was expecting -- and in fact I had made up my mind when I fist saw the sign not to address the issue that he was protesting. In retrospect, "What's wrong with being godless?" is a rather confrontational approach, but there are worse ways of addressing the topic, especially if one maintains a calm demeanour while doing so. Perhaps I am deluding myself, but the more I think of the two events, the less similarity I see between them, aside from a spontaneous interaction between strangers. Still, it had me thinking, and that is always a good thing.

Health and Taxes

Civilisation is an agreement. It is an unspoken acknowledgement to behave in particular ways towards strangers, and an acceptance that others have many of the same needs and rights as ourselves. We agree not to kill, hurt, or steal from others, and they agree not to kill, hurt, or steal from us. Furthermore, we agree that there are limits to our individual capacities, and that a division of labour allows us to live beyond those limits. We agree that we cannot afford some things individually, such as protection from rogue elements within and hostile groups without our own. Thus, we willingly constrain our actions in such a way as not to impede the well-being of others, and we (often not as willingly) pay in part for those services that we cannot afford by ourselves. Enlightened civilisations have further recognised that we are better off individually if we are all well-educated, and if we are all healthy.

This, fundamentally, is the rationale behind universal healthcare. We live in a time when the US, long the only developed nation without it, is finally facing that reality, and considering correcting it. The more intelligent objections to this focus on the notion that it would require individuals to pay for a system for which they might not approve, and which might not function as well as what the better-off citizens have come to expect. But these arguments tend to focus upon the failings, perceived or real, of individual systems. There are legitimate observations here, but these are not reasons to abandon the principle. Rather, they are examples to us, datapoints to be analysed, challenges to overcome. They can be overcome. It is entirely possible that America will wind up with a respelling of the same expensive, exploitive, and unjust system that it has now. I hope that this does not happen. The principle is worth struggling for, to get it right. We gain nothing, and lose much, by allowing those in less fortunate circumstances to suffer. Civilisation has its price: most of us pay taxes to fund it, but we must also remember that it also requires compassion.

The Origin, Chapter Fourteen

This chapter comprises two very distinct sections. It is titled appropriately ("Recapitulation and Conclusion") although we might expect there to be less of a distinction between the two than Darwin gives us. Even then, the first part is not a proper recounting of the entire book, but a somewhat ricocheting run through most of its major concepts. Here more than before he emphasises the distinctions between common descent and special creation, finding for all cases the former to fit far better than the latter. He rightly identifies that the introduction of the supernatural into science has a tendency only to perpetuate ignorance: "But it deserves especial notice that the more important objections relate to questions on which we are confessedly ignorant; nor do we know how ignorant we are." Of the latter, he points out the identification of species as an example made far more contentious because of an assumption of independent creation. The Victorian view of diversity was that each species was separately created, while varieties (including subspecies) had arisen afterward, "by secondary causes", meaning by natural ones. Such arguments are meaningless if, as Darwin says, "species are only well-marked varieties"; indeed all controversies (and Darwin suggests that there were several) over the boundaries of extant species are meaningless.

Darwin spends most of his time here on his strengths, and especially on biogeography, but does not ignore his other evidence. The origin of modern diversity through adaptation of existing structures is evident throughout: "We can plainly see why nature is prodigal in variety, though niggard in innovation." His pioneering of ecology gets a brief mention, amounding to emphasis on the primary importance of the biotic environment to the success or failure of any species. He brings up again the "Red-Queen" nature of invasiveness: "As natural selection acts by competition, it adapts the inhabitants of each country only in relation to the degree of perfection of their associates; so that we need feel no surprise at the inhabitants of any one country, although on the ordinary view supposed to have been specially created and adapted for that country, being beaten and supplanted by the naturalised productions from another land." It is unsurprising that we should see in this concluding chapter Darwin's least ambiguous writing, but the assertions are nevertheless uncharacteristically forceful: "The real affinities of all organic beings are due to inheritance or community of descent. The natural system is a genealogical arrangement, in which we have to discover the lines of descent by the most permanent characters, however slight their vital importance may be." There is no room for doubt here.

The conclusion section is more of a meta-study of evolution, looking at the contemporary state as well as the history and probable future of biology. It starts with an assertion that Darwin and his theory will face opposition. Some few naturalists will be persuaded by his work, he speculates, and certainly, given that the idea of common descent was much discussed, many more would already have been looking for proof, and might have their minds made up. But the most important recruits to Darwin's cause, he expects, will be the next generation. Modern creationists would actually find a friend in Darwin, had they lived then, as he suggests that we should (in their words) "teach the controversy": "I look with confidence to the future, to young and rising naturalists, who will be able to view both sides of the question with impartiality." But in our modern persective, we must bear in mind that this controversy raged some 150 years ago! Science has settled on an answer, and has moved on. On the other hand, Darwin is not content to allow his opponents to continue unchallenged, and asks them to answer some of his own questions. How did the Creator go about creating? How many forms were originally created? Were they adults, or juveniles, or seeds or eggs? If they were adults, did mammals have signs of having been gestated (in other words, did they have navels)? This section is a startling contrast to Darwin's usual demeanour. He is almost mocking in his requests, but he does not ask them without full knowledge that they are, after all, questions about the natural world, which follow logically from the theory of special creation, and which are therefore not unfair.

He then moves onto questions of his own theory. How far, he asks, can common descent be taken? Owen's work on homology makes it clear to Darwin (indeed, to the modern reader as well) that all phyla (plant and animal) have had each their own common ancestor. Darwin speculates that this can be taken further, that all animals and all plants had each a single ancestor, and probably all life, although he doubts that this can go far beyond speculation in his own time. On the finer end of the scale, he comes very close to proposing his own species concept: "Hereafter we shall be compelled to acknowledge that the only distinction between species and well-marked varieties is, that the latter are known, or believed, to be connected at the present day by intermediate gradations, whereas species were formerly thus connected." This, consistent with most modern species concepts, covers many of the points of its competitors, but places each in a different light. Extant species, says Darwin, are discontinuous from other extant species, while genealogically intermingling groups are necessarily the same species. This combines aspects of the biological and phylogenetic species concepts; whatever its utility today, it must be recognised as one of the first attempts (if not the first) to define "species", and indeed an early (although implicit) assertion that such a need exists in the first place.

It is difficult to convey how exactly Darwin can retain his customary modesty while predicting that his theory will revolutionise biology, but somehow he manages it. He sees its subjects as being "ennobled" by common descent, and that in that light, "how far more interesting ... will the study of natural history become!" Geology will be influenced as well: "The noble science of Geology loses glory from the extreme imperfection of the [fossil] record. The crust of the earth with its embedded remains must not be looked at as a well-filled museum, but as a poor collection made at hazard and at rare intervals." In other words, what biologists knew all along to be a highly imperfect understanding of the world is not dissimilar to what geologists must come to grips with. The fossil record's scantiness nevertheless does not hide an emphasis on change over time, and although he only at most implies this, living things becomeall the more precious by their transiency: "Judging from the past, we may safely infer that not one living species will transmit its unaltered likeness to a distant futurity."

There is a great deal of eloquence in these final pages, which I will not reproduce here; it is readily enough looked up. This amplifying rhetoric almost hides the fact that Darwin recognises this work to be a turning point in the history of science, a change in its world-view, a paradigm shift. Very, very few people can do more than try to imagine what that realisation must have felt like. I have not pursued the matter far enough to read Darwin's notes on the subject, but by all accounts he knew what he was about to do when he wrote this book. He does so with admirable humility, presents his arguments as humbly as is possible, but does not back down from its implications. Not only in how the world works, but in how to present one's understanding of it, we all have a lot to learn from him.

The Origin, Chapter Thirteen

This chapter of the Origin, the last before its conclusion, is something of a grab-bag of miscellaneous points. As is typically the case for such chapters, its author is clearly wrapping things up, drawing them together for the big conclusion to come. At the same time, it presents some of Darwin's stronger points, albeit more in favour of the principle of common descent (what we now refer to as "the fact of evolution") than of that of his mechanism behind evolution (natural selection). This is not to say that the latter goes unsupported (indeed Darwin makes some cogent arguments for it); rather it is that it is simply not the point of this chapter to make the case for natural selection. Here, as in the last chapter, Darwin contrasts his view of the living world against that of what was then "the ordinary view of special creation", and finds the latter wanting. And here, as in the last chapter, I am somewhat surprised that he has chosen to make these arguments so late in his work. This is essentially opposite to how I (and, I like to think, most other modern biologists) would present their case: first show the data, and then explain how the theory fits it. The "data" here is the genealogical organisation and common ancestry of all life, which itself is not necessarily obvious, and in Darwin's time required some hefty arguments in order to be taken seriously, arguments which he has provided in these latter parts of his book. But he has not provided them in such a way that they require an understanding of his theory in order to make sense. He refers to his theory here, but any other theory involving common descent (Lamarck's being the one most often presented to beginning students in biology) would be as apt. Once again, I am somewhat perplexed at the organisation of this book, although I will not deny that it works as presented.

The first topic brought up in this chapter is of classification. Darwin's view on this head is entirely modern: Classification should be genealogical. Einstein once said that "the most incomprehensible thing about the world is that it is comprehensible." Darwin notes a similar point in biology: the hierarchical classification that we all take for granted (even those of us who are not biologists are familiar with it on an intuitive level) should be remarkable, if we were honestly to assume that every living thing was made independently of every other. That this is not the case is a compelling argument in favour of common descent; at the very least it should be a noteworthy puzzle. The universe, as far as biological classification is concerned, is eminently comprehensible. And yet, Darwin's lengthy discussion of the topic gives no imminent indication that this was regarded as particularly revelatory. The idea of evolution had been in the air for over half a century by the time that Darwin wrote publicly about it; it could well be said that, like Galileo's popularisation of the heliocentric model of the Solar System, the world was ready to hear about it when Darwin wrote about it, even if it required to be convinced.

This is not to say that there were not contemporary alternatives to the principle of genealogically based classification (which requires common descent). Darwin lists a couple: similarity of form in closely-related organisms either "gives some unknown plan of creation" or is "simply a scheme for enunciating general propositions and of placing together the forms most like each other". Neither of these is satisfactory; for either to be true would require a tremendous amount of coincidence that looks very much like common descent. In contrast, common descent does not provide any substantial difficulties that are eased by assuming either of these alternatives.

Darwin quotes Linnaeus a few times in this chapter: "The characters do not make the genus, but the genus gives the characters." Most of this chapter regards character evolution, so this is an apt point. There is still debate as to how best to define taxa, whether it should be by some suite of characters unique to the group in question or by some limits to its genealogical makeup. The latter is harder to overturn, assuming that the phylogeny used to define the group is accurate, but the former is more satisfying. The risk there is that, after the group is defined according to its shared ancestral character states, some critical character will be found to have been misinterpreted, or some member with an abnormal character state will be discovered or found to be basal, calling into question the basis for the group's identity. Certainly, when starting work on a new group, it can be easier and more intuitive to start with the assemblage of organisms and to try to figure out what they have in common, and with modern molecular phylogeny this is exactly what happens. However, a genuinely objective system would require a completely consistent set of diagnostic features which would definitively place an organism within or without a group, rather than requiring its genealogy to be known (which in any event is often difficult to determine). Personally, I prefer the character-based definition, but this requires frequent updating as our understanding of the evolutionary history of the group is improved. Ultimately, what we take for significant characters in a group is dictated by our understanding of the group's evolutionary history, which in turn is based on a number of sources. So ultimately, Linnaeus is right, but not in quite the way that we (or I, at least) first read him: rather than the genus indicating which character states are significant (here meaning that they are constant within the genus in question), the genus indicates which characters -- variable within the containing group, and constant within the genus under discussion -- are important to use as diagnostic markers.

Darwin elaborates: important characters are prone to vary. Things that are critical to an organism's way of life can easily converge, and so we have fish and dolphins superficially resembling one another when in fact they are very different animals. The phylogenetically important characters do not vary, and are not affected (at least, not within the more primitive members of the group in question) by natural selection. (Here, incidentally, is the one point in this chapter where an understanding of Darwin's theory is actually important to his arguments in favour of common descent. Even still, it could as well be brought up later in the book, had he chosen to present common descent first and natural selection later.) This is not to say that such characters never vary; indeed, characters that are highly conserved in one group (and so are reliable indicators of membership in that group) can be highly variable in another, related group; furthermore, these characters may have ample and even equal value to members of each group. On the face of it, things that unite a group may be of trifling importance, but consistent: Darwin gives the example of an inflection in the jaws of marsupials, which is indeed diagnostic, but probably not significant to the animals' physiology. Another example that Darwin gives, which betrays his lack of understanding of biochemistry, is the colour of algae: this is known (and has been for a long time) to be related to the biochemistry of the pigments used in collecting light, and of great physiological as well as phylogenetic significance. In any event, this is what Darwin means in his invocation of Linnaeus: we cannot guess what aspect of an organism's anatomy is significant to determining its classification without reference to other organisms, both similar and dissimilar. "Hence, as has often been remarked, a species may depart from its allies in several characters, both of high physiological importance and of almost universal prevalence, and yet leave us in no doubt where it should be ranked. Hence, also, it has been found, that a classification founded on any single character, however important that may be, has always failed; for no part of the organisation is universally constant."

Darwin returns to his prior point with remarkable pithiness: "all true classification is genealogical." He addresses this now from the other angle: the question of descent itself implies the existence of ancestors. We classify the descendents of a single genus in several, but those little changed from the common ancestor may be placed in the same genus as that ancestor. Does this make sense? To some extent, perhaps; and yet, all members of the lineage will have undergone some amount of adaptation. It would be true to say that they have all evolved for the same period of time, but this is not necessarily relevant. Did they all proceed through the same number of generations in that time? If not, the amount of evolutionary pressure that could be brought to bear on any one descendent lineage is not necessarily comparable to that of any other. Even if they have, the number of cell cycles undergone by one individual (each of which, on a smaller scale, presents its own opportunity for mutation and selection) may not be the same as another, and once again the lineages may not be comparable. So we may reasonably ask whether it is proper to put any living organisms in the same genera as their far-removed ancestors. But this is a question that is itself far removed from Darwin's discussion, and one which is still discussed today.

Returning to Darwin's observations, he notes that relatedness in character states follows certain patterns. Specifically, a member of one group resembling members of another will do so only in generalities; the first will not resemble any one member of the second group more than any other -- unless some members of that group are obviously less derived, in which case they will be the ones to which the member of the first group will bear a resemblance. This is a very important point, and one which requires us again to return to Linnaeus's dictum: what we regard as important in defining a group requires that we look around to related groups. Darwin concludes his discussion of classification with another nice quote: "We shall never, probably, disentangle the inextricable web of affinities between the members of any one class; but when we have a distinct object in view, and do not look to some unknown plan of creation, we may hope to make sure but slow progress."

The next section is ostensibly about Morphology, but is actually more about Homology. It should be mentioned here that Darwin uses the modern terminology in distinguishing actual homology (a term defined in its modern form some ten years earlier by Richard Owen) from analogy (a term not used in Owen's treatise) -- I do not know when the term first eneterd into use, but it is unlikely that Darwin introduced it here, as he does not define it. Much of Darwin's attention in this section focusses on serial homology, the phenomenon in which structures within the same organism can be seen to have developed from similar primordia. Thus our arms and legs have similar skeletal structures, and our vertebrae are all fundamentally similar, based on the same essential pattern. Owen went further, to suppose that the bones of the skull were themselves highly modified vertebrae, an idea that has since fallen from favour. (One of the hallmarks of any type of homology is that homologous structures arise through similar processes, but the plates of the skull have a very different embryonic origin from the components of the vertebrae, thus ruling out the possibility of homology.) Darwin also cites Owen's observation that more highly advanced forms (by which he means organisms more removed than their contemporaries from their common ancestor) have fewer similarities in their serially repeating body parts. Thus, to give a modern example, insects have only three pairs of functional legs, while their ancestors, the crustaceans, have several. Darwin cites Huxley as well, who says that serially homologous structures are not formed one from another, but all from some primitive precursor. Darwin corrects this view, though, pointing out that that precursor could well be, and usually is, present in even highly-derived modern forms.

From this discussion of the origins of serially homologous body parts, it is only natural that Darwin should turn to the subject of embryology in general. This is a topic that has recently exploded in evolutionary utility, the subject of evolutionary developmental biology, or "evo-devo". Here, Darwin's understanding of the topic is strikingly modern. Over and again he emphasises that "[t]he question is not, at what period of life any variation has been caused, but at what period it is fully displayed." Again: "at whatever age any variation first appears in the parent, it tends to reappear at a corresponding age in the offspring." In other words, not just an organism's form, but the regulation of development that produces that form, is heritable. We often think of there being "a gene for" a given trait, but in reality this is rarely the case: many, perhaps most, of our genes are for fairly standard things, like digestive enzymes or structural proteins. What varies amongst multicellular organisms like ourselves is more the patterns in which those genes are expressed than the genes themselves. For example, all of my genes for actin (a structural protein used, among other things, to make muscles contract) could be replaced by those from a chimpanzee, and nobody would be able to tell the difference unless they actually sequenced my genes. However, if the regulatory regions of my genome were to have been replaced with those of a chimpanzee's while I was growing up, I would have some distinctly chimpanzee-like characteristics, assuming that such replacements did not sabotage some essential bodily functions. To put it another way, the components are the same in most organisms; what changes is the way in which they are assembled.

Another point in which Darwin sounds strikingly modern is his view of the relationship of embryonic morphology to evolution. Haeckel famously said that "ontogeny recapitulates phylogeny" (a saying I find remarkable in its concentration of both syllables and jargon), meaning that an embryonic mammal was in fact a fish. Darwin, while not making a point of the matter, disagrees: rather, the embryo of a mammal resembles the embryo of a fish. Fishes may not develop much beyond that embryonic state in many ways (for instance, they retain the gill pouches that mammals lose) but in others they do depart from the common form (as in, for example, the development of fin rays). I am not well-read in Darwin's views of the matter, but in the first edition of the Origin he gives a very modern account of this relationship, even if he does not contrast it against Haeckel's view.

This is not to say that Darwin gets everything right here. He regards holometaboly in insects (the process in which individuals undergo a radical metamorphosis from larva through pupa to adult) as ancestral, and incomplete metamorphosis (a blanket term covering various alternatives now understood to be primitive amongst insects) to be derived. He gives no explanation for this, and supposes that incomplete metamorphosis arose from the juvenile insects being under the same ecological pressures as their adult counterparts. Certainly something like this has occurred in cephalopods, which lack the larval stages common to other mollusks, but in the case of insects we know this to be the wrong way around. Interestingly, this bears on a fundamental question in animal evolution, one of which Darwin either was unaware or chose to ignore: that of the point at which planktonic larvae arose. Darwin points out that he was amongst the first to have recognised barnacles as crustaceans, based on their obviously crustacean larval stage; obviously he regards crustacean larvae to have been ancestral, and the adult crustaceans to have adapted from that. But whether the larvae of other animals represent their ancestral state, from which the current adult form is a later development, or the adults were the original forms, and the larvae arose later to fill different ecological or life-history roles, is not a topic that Darwin broaches.

The remaining original section of this chapter is on vestigial organs. Darwin has already discussed this topic, and brings little new to it here. He is again impressively modern in his understanding of the matter, and I have little to add to his discussion. Likewise, his summary of the chapter is short and (almost) sweet, beginning with another impressively colossal Victorian sentence, enumerating his main points, and bringing little new by way of synthesis to the matter. This is not terribly surprising in a chapter devoted to the miscellaneous ideas that have not received discussion earlier, of course. All that remains now is his final summary, the capstone on the entire project.

The Origin, Chapter Twelve

This chapter is very clearly a continuation of the previous, and very much a climax of the ideas outlined therein. Darwin starts it by plunging right into the question of how freshwater species are distributed, and applies the same arguments as before to eggs and seeds. He then returns to oceanic islands, and reiterates his pivotal observation: they have a small number of species, but a high proportion of those species are found nowhere else in the world. Furthermore, these species are often easily outcompeted by invasive species brought in by humans. Here Darwin implies the Red Queen hypothesis again: living things need only be good enough to survive in their present circumstances. The more species present in a given environment, the more variables must be accounted for by each (a point that Darwin has made before and emphasises repeatedly in this chapter), and so the more likely it will be ready to conquer those species which have had to adapt to fewer such variables. In his discussion of island species, Darwin brings up what would become known as Wallace's Line, although he mentions it here as described by Windsor Earl but to be reported further on by Wallace. And finally, some four hundred pages into the book, we get to the Galápagos Islands! Darwin mentions his famed finches here but spends less time on them than one might expect; all the same, he makes his points clear.

Moreso than in the previous chapter, and in fact moreso than in most of the book so far, Darwin regards the findings of natural historians (what biologists were called in his time) in the context of his theory of evolution and of that of special creation. In all cases, the latter is found completely unsatisfying, while the former answers most questions and suggests useful avenues for addressing the remainder. It must be remembered that, while we today regard fossils as an important line of evidence for the theory of evolution, they were more of a puzzle to be explained in Darwin's time. Comparative anatomy was and remains a powerful source for evidence in favour of common descent as well, but this evidence was also interpreted -- somewhat unsatisfyingly, but nevertheless not unreasonably, and by very highly regarded authorities -- to support special creation. One of the most convincing lines of evidence, that of molecular and genetic data, was not even imagined in Darwin's time. Accordingly, it was biogeography, the subject of this and the previous chapter, that provided Darwin's strongest case for common descent -- what has been called elsewhere "the fact of evolution". Natural selection was a critical insight, providing the mechanism by which dissimilar things could have had a common ancestor, but convincing though the theory was, the Victorian audience needed as well to be convinced of the facts which that theory was meant to explain. That is the purpose of this and the previous chapter (although of course Darwin makes his case that natural selection is right at home in this context here as well as previously), and Darwin's descriptions and explanations are nothing if not sound.

Really, I find myself having little to critique here. This is perhaps not Darwin's finest work: it is not his most eloquent, nor his most revolutionary, but it fulfills a very necessary function, and it does so with a rigour not often seen elsewhere. Darwin is very careful not to insist that everything has been explained in his examples, but rather (and more importantly) that everything is explainable. It is somewhat odd that, after first explaining the theory so well, Darwin should then move on to describe the facts that the theory is meant to explain; certainly if I were writing this work I would have done so in the opposite order. But for all that, this chapter is satisfying: it addresses all manner of issues and shies away from none of them. Before the Origin, natural historians had ample argument against evolution; afterward, such arguments' days were numbered, and in no small part these chapters on biogeography were the pivotal development that changed that.

The Origin, Chapter Eleven

In this chapter Darwin returns to a favourite subject, that of biogeography. This is one of the topics that led him to start thinking about evolution in the first place, and it is here that we can expect to find some of his strongest arguments. Oddly, he is not very forceful; while he does argue here and there that special creation cannot account for the data that he describes, he does so almost in passing. Mostly he gives his by-now-familiar "long lists of facts", albeit tempered with some actual experimentation! -- and a thorough analysis of how these data concord with the principle of common descent.

He starts out with the fundamental observations of biogeography: regions similar in climate but remote from one another have very different organisms living therein, while regions different in climate but adjacent have similar organisms. This is an argument for common descent, the principle wherein related but distinct species diverged from a single ancestral species. Such observations have little to say about the mechanism by which related forms come to differ, and Darwin accordingly spills little ink on the topic here. What he does say is emphatic that natural selection is more important than other mechanisms: change, he says, is always adaptive! This is (at least to my recollection) at odds with what he has said earlier in the book. Then again, this is pretty much a footnote observation, and (as I have already said) largely irrelevant to the topic at hand.

Another point that Darwin emphasises is quite familiar by now: the organisms living in an environment are far more important than the physical conditions when determining what pressures will be faced by anything living there. Another, less familiar, point, more genetic than ecological, and made with admirable emphasis, is that the lineages that we trace through evolutionary history are not those of individuals, but of populations. Although Darwin did not imbue upon it as much import, this is nevertheless a very important point. Here as elsewhere he hints, prehaps unconsciously, at what would become productive avenues of research.

An interesting fact of this chapter is its complete neglect (at least by name) of the Galapagos Islands. We refer today to some of the birds living there as "Darwin's finches" and we know that observations of them were incendiary to Darwin's thoughts on evolution, and yet Darwin at best coyly alludes to them in this chapter, where he could easily be using them as a powerful example. I can only suppose that he mentioned this in his notes and correspondence, and that his reasons are more clear there; or perhaps he discusses them in the next chapter.

Returning to his main observations, Darwin notes that biogeography indicates the closeness of existing species across geographical barriers, and infers that such barriers had to have arisen before the species diverged. Such barriers can be greater than is obvious, as oceanic islands are often volcanic and therefore not geologically related to the closest land, which in turn indicates that they were not connected at any point in history recently enough to be populated by the species that now reside there. Dispersal therefore must be proven to have occurred through the water or the air, and to demonstrate that this is possible Darwin resorts (again!) to experimentation. In a modern work, the results would have been presented in a table, allowing for easy comparison and confirmation, but Darwin gives us a few lengthy paragraphs with more of his "long lists of facts". Happily, he interprets things for those of us whose eyes glaze over. One of his experiments involves feeding different species of bird prey that had previously ingested seeds, and looking for the seeds in their excrement. One might well wonder how he did this, given that the birds whose digestion he was tracking included "fishing-eagles, storks, and pelicans"! (Naturally, he concludes that birds are effective agents of dispersal.) Overall, the middle part of this chapter amounts to another of Darwin's set-up-and-take-down of his opponents, although much more drawn-out than previously: dispersal is not inconceivable, and over time inevitable. At the same time, at least for the time-scales involved with this chapter, actual naturalisation of species as they move through different regions is not discussed, and neither is the possibility of populations remaining in a region and adapting as the climate changes. In all likelihood, it is more probable that they would be outcompeted by invading organisms already adapted to the new climate, but the possibility remains that they might adapt quickly and well enough to fend the invaders off is not even addressed by Darwin.

The remainder of the chapter concerns the exchange of flora (Darwin here concentrates on plants) through the course of recent geological history -- namely, glaciation, and the immediately preceding epoch during which Darwin understands global temperatures to have been warmer than now. Darwin's arguments, at least at first, apply best to immutable species. He brings up natural selection and local adaptation every so often, but he recognises (without specifying) that he is discussing changes in the history of life on Earth on a timescale insufficient for much evolution to have occurred. Interestingly, he considers the intermingling of related forms resulting from mass emigration to be of great import, colouring the descendants in both regions after the climate changes and their accompanying emigrations have reversed themselves. This (unbeknownst to Darwin) mirrors the relative importance of mechanisms of change in eukaryotic reproduction: recombination is more likely to cause change in the short term than is mutation.

Darwin gives a great deal of attention to species that are remarkably similar in extremely disparate regions: plants in England that are obviously related moreso to those in New Zealand than to those in any intervening region. On the face of things, this would be a powerful objection against Darwin's models of dispersal. Here Darwin seems almost meek, in that he does not address this argument at all. Rather he slowly builds up examples and then explains how they provide a reasonable exception to his theory rather than a major challenge to it. On a less extreme scale, he notes the point made famous by Jared Diamond, that species in northern regions tend to expand their ranges southwards, but the converse is rare. Darwin draws the same conclusions, too, that the larger areas of the northern regions allow for a larger population, which will have had to have undergone more intraspecies pressure to survive (competition being, as Darwin supposes, fiercest between individuals of the same species), and therefore will be better competitors against species not so challenged.

Darwin's grasp of geology is occasionally frustrating. Continental drift is an extremely powerful theory, one which makes a lot of phenomena perplexing in Darwin's time transparently obvious. And yet, Darwin explicitly denies its possibility, for reasons not at all obvious (and in any event not given in this chapter). Certainly the amount of continental drift that occurred during the last few epochs has been insufficient to have impacted the emigrations with which Darwin concerns himself here, so the modern mind is not terribly assaulted by this plesiological notion. But another supposition does rankle: Darwin expects sea levels to have lowered as temperatures rose! I do not know whence this idea comes. More satisfactorily, Darwin extends his observations beyond islands, with the attractively terse observation that "A mountain is an island on the land;" and here, he leaves us, to discuss further details on the same topic in the next chapter.