It would appear that I'm hosting the Molecular and Cell Biology Carnival on Sunday. This, I suppose, involves me finding some last minute creativity to put the thing together.

Anyway, due to the unreliability of the BlogCarnival.com system, you can submit items by leaving a comment here, or emailing me. I will be accepting the usual mix of reviews and commentary on research, but I'll also find room for short posts and "classics" -- items you're especially proud of, but which were written long before the carnival was created.

Update: my apologies -- due to the problems with BlogCarnival.com I do not yet have the items that have been submitted. 12/5/08

I've talked about Horizontal Gene Transfer (HGT) on the blog a few times before, particularly in the context of bacteria acquiring genes for things like antibiotic resistance, and in the context of operons (more of which in a week or two). Jeferson Gross, J�rg Meurer, and Debashish Bhattacharya have an interesting story to tell about HGT in last week's BMC Evolutionary Biology.

Firstly, the brief introduction to HGT for those unfamiliar. Genes like to make copies of themselves -- or rather, natural selection tends to favour those genes which are good at making copies of themselves. There are two principal categories of methods by which genes ensure their presence in increasing numbers of individuals. The obvious one is vertical transfer: when cells divide, the daughter cells each contain the same compliment of genes; and offspring inherit their genes "vertically" from their parents. The other category, horizontal transfer, makes things so much more complicated and fun. In horizontal transfer, a few genes (usually a fraction of the total possessed by the individual) are copied and given to another individual. That individual does not have to be closely related -- indeed, in extreme examples they can be as distantly related as a bacterium and an animal. HGT is common between bacteria, but rare in eukaryotes (animals, plants, etc).

HGT has some very interesting consequences for the process of evolution, and for the way we see the history of life on earth. The image of the "tree of life" begins to break down, especially in bacteria -- there is no longer a branching lineage which can be traced back to the universal common ancestor. Rather, there is a network of crisscrossing lineages, diverging and merging. Pairs of genes depart, while other pairs meet. The genomes of modern bacteria are chimeras made from bits and pieces of very different ancestors. This makes things difficult for those researchers trying to describe what life was like a few thousand million years ago, when the earth was young.

It is generally believed that ancient life experienced a great deal of HGT, and genes were flowing all over the place. This view may to some extent have arisen as a result of the common image of ancient life as being just-like modern bacteria -- simple, unsophisticated and dull. Trouble is, modern bacteria are not simple or dull, and they have particularly sophisticated devices to enable HGT. The process of "bacterial conjugation" involves the construction of molecular needles, the transmission and recognition of "mating signals", and the activity of a specialised enzyme complex. This is a complicated system which must have arisen at some point through evolution. There is therefore no reason to automatically believe that HGT has been rampant forever, and whether HGT was common in ancient organisms is an empirical question.

How do you go about answering a question like this? It can not be answered by any fossil, and the nature of HGT makes it very difficult to get an answer of any use by sequencing genomes and drawing trees. Fortunately, there is a window -- or rather, several windows -- on ancient life. There is a group of microorganisms which have become totally isolated such that they have been unable to participate in HGT. Though they have still been subject to other evolutionary process, these organisms provide a good estimate of their free-living ancestors of 1,500 million years ago (mya) -- they are living fossils, if you like. The organisms -- if they can still be called that -- are plastids. The plastid that you're most likely to be familiar with is the chloroplast -- responsible for photosynthesis in plants. Chloroplasts are the descendants of once free-living cyanobacteria. Around 1,500mya a cyanobacterium found itself stuck inside another, larger cell. The cyanobacterium found its new shelter comfortable, while the host cell found the cyanobacterium's photosynthetic nutrients useful; the rest is history.

So things are as simple as looking at the genes in the chloroplast genome and determining where they came from? Well, actually, evolution never makes things that simple. Over the millions of years that the chloroplast has been sponging off plants, bits of the chloroplast genome have migrated into the plants' nuclear genomes. Chance events got those fragments from the chloroplast to nucleus, I imagine. Selection perhaps favoured their new home -- for safety from mutagens, access to more sophisticated control of gene expression, or more advanced DNA repair mechanisms, perhaps. Whatever the reason, we now find bits of the plant genome that look uncannily like bits of the cyanobacterial genome.

So, now we get to Gross et al's contribution to this story. In their paper they look at the men family of genes. This family contains eight individual genes (A-H), the products of which are enzymes involved in a photosynthetic pathway. These genes are very similar to other metabolic genes found in bacteria, where they are clustered in operons. Gross et al found that in plants, seven of these genes are found in the nuclear genome, but we can be reasonably sure that they originate from bacteria (via chloroplasts) because they are also arranged in an operon-like structure in the plant genome (plants do not usually have operons). Additionally, a relic of the operon containing these seven genes can still be found in the chloroplast genome, albeit mutated and unused. Now, if you believe John Maynard Smith, the fact that these genes are arranged as an operon is itself evidence for HGT, as JMS' hypothesis is that operons evolved to aid HGT.

Of course, not everybody does believe JMS, and alternative hypotheses about the selective advantage of operons have been proposed -- for example, that operons are the simplest way to control and coordinate the expression of a team of genes. But Gross et al have additional pieces of evidence. Firstly, one of the eight genes, menA is not found in the cluster of genes, suggesting that in the ancient ancestor of plastids this gene had a separate origin to the seven genes in the operon. And secondly, having created phylogenetic trees of the men genes from plants, algae, and a variety of bacterial species, they find that several (but not all) of the nuclear encoded men genes from plants look uncannily like those from green sulphur bacteria -- even though they almost certainly found their way into the nuclear genome via the chloroplast.

There are lots more details and suggestions for the histories of these genes, but I needn't bore you with them. The important point is that the simplest explanation for this fossilised mosaic genome is that HGT was well established 1,500 mya, and we are therefore justified in making the assumption that HGT has been around for a significant fraction of life's history. Perhaps, even, early life really was just one big gene pool -- a river out of Eden, with genes mixing in the eddies and rapids.

Gross, J., Meurer, J., Bhattacharya, D. (2008). Evidence of a chimeric genome in the cyanobacterial ancestor of plastids. BMC Evolutionary Biology, 8, 118. DOI: doi:10.1186/1471-2148-8-117

With apologies to Mitchell and Webb, and further apologies if I invoke Godwin's Law along the way.

Pope: Very well. [puts phone down] They're coming. Now we'll see how these atheists deal with a crack vanity-published hack writer division.*

Cardinal: uh... papa?

Pope: Have courage my friend.

Cardinal: Yeah, ah... Papa, I've just noticed something.

Pope: These atheists are all amoral sinners.

Cardinal: Have you looked at our miters lately?

Pope: Our miters?

Cardinal: [nods] The badges on our miters. H.. have you looked at them?

Pope: What? No? A bit?

Cardinal: They've got Roman torture devices on them.

Pope: huh?

Cardinal: Have you noticed that our miters have actually got little pictures of devices that the Romans used for horrible painful murder on them?

Pope: I er.. I don't ...

Cardinal: Papa... are we the baddies?

* Yes, yes I did just make fun of vanity published writers on a blog. And?

Humphrey Lyttelton, 1921 - 2008

Humph tells me he has to leave us now as he's been invited to a club night by St Peter, and this is something of a climax for him. He'll drop everything to be taken to heaven by St Michael. He says he can't wait to see the kindly old keeper-of-the-keys' famous entrance and part his Pearly Gates, and I can just imagine St Peter's joy as Humph gets red in the face blowing on his trumpet all evening. There are rumours that God might come and play with his instrument too -- he has needed cheering up lately as the Archangel Gabriel keeps rubbing him up the wrong way, and he was last seen giving Gabriel a good mouthful.

St Michael won't be joining them as he's off to the pub with Mary. He likes nothing more after a long hard day than to rest his staff in the Queen's Head, and once Mary gets the pints out he'll be up all night, and finish off with a stiff one in the early hours. Mary, bless her, never learns to drink in moderation, and I know she'll be feeling a little dicky in the morning.

Samantha will be there, and she tells me she has been baking some of Humph's favourites, and bought the whiskey that he loves. I know that she's very much looking forward to having him try her muffins and liquor out in the Garden of Eden.

Humph, you touched us all, blew us away, and leave us all gushing this weekend. We raise a glass to the legendary Humphrey Lyttelton, and can only play another round of Mornington Crescent.

I'll open with Great Portland Street.

. . . imagine a puddle waking up one morning and thinking, "This is an interesting world I find myself in, an interesting hole I find myself in, fits me rather neatly, doesn't it? In fact, it fits me staggeringly well! Must have been made to have me in it!"

Douglas Adams

It took me a while to work out what was bugging me, but I think I've got there. We were at Skeptics in the Pub rambling about epistemology and other such nonsense, when for whatever reason, somebody felt the need to bring up the example of "chemical" versus "natural" -- something that I discussed here a few weeks ago. I did my quick piece on "flipping the Necker cube" and looking at the nasties in our environment in terms of our evolution: nothing is intrinsically healthy or harmful, it is only in the context of our evolved anatomy, physiology and biochemistry that it becomes so.

I was up against quicker witted and more articulate fellows than myself, and after a long day, a couple of hours of Bad Astronomy, and more than a couple of pints, I was not able to adequately put into words just why the response to this point was wrong. Since the point about flipping theNecker cube is one that I have also made on the blog, I thought I would discuss it again here, in-case anybody else has misunderstood the point that was being made.

First, a rough characature of that response: by talking about evolution and nasties I was elevating humankind to a position that we don't deserve. Man is a tiny part of life on earth, and we shouldn't flatter ourselves to believe that the universe is deliberately out to get us, any more than we should flatter ourselves by believing that the world was made to have us in it. God is famously fond of beetles and bacteria, after all.

Of course, the problem, so obvious now, is that the Necker cube has not been flipped at all. We're still trying to answer the question of why the nasties are nasties by looking at how they got to become nasties. The other side of the cube is to try to answer the question of why nasties are nasties by looking at how we evolved. This means recognising that we have been built, bit by bit, from scratch. Every system, organ, tissue, cell type, metabolic network and enzyme has a birthday, somewhere in the depths of time. They have been shaped by selection to perform a function with some minimum of efficiency, and to have a minimum of robustness in the face of countless environmental variables.

And it is only by having encountered particular values for those variables that evolution can have prepared us for them. Evolution has no foresight and goes no further than those minimum values. It picks the first successful candidate solution that it finds, and it's just luck if it solves more problems than were asked of it. If a population encounters a novel chemical, sourced from a plant for example, evolution will not have prepared the population for that chemical. That does not mean that we are elevating humankind by suggesting that the plant is producing the chemical with that specific population in mind.

Not convinced? It helps if only one of the parties is evolving, so we'll ignore plants, bacteria, and xeno-biochemicals altogether, and just watch how man performs against the elements. An enzyme that has never encountered a particular pH or temperature, for example, can reasonably be expected to perform poorly under such conditions. Break, even. We are not witnessing a conscious decision on the part of God or Mother Nature or the Universe to challenge us with extremes of pH; it is merely the outcome of an unconscious "decision" not to prepare for such events. Acidophilic archaea, organisms that have evolved in the context of extremes of pH, have enzymes that are similarly unprepared for the conditions in which we live.

When you look at it from this angle, it doesn't just seem obvious that species are adapted to that which they have experience of, and vulnerable to many things that are unfamiliar to them. It seems absurd to even bring up the issue of whether nature gives a damn about us. It is we who are giving the damn. And that is the point of Douglas Adams' puddle.

I intended to post this a couple of weeks ago, before Ham did his London lecture. Since nobody bothered going anyway, I ended up procrastinating instead.

I listened to a sermon^[1] by Ken Ham, creationist head of Answers in Genesis, the other day. I was erm ... researching a role? Anyway, it was great fun. My knowledge of church services is limited to the Anglican tradition, and it was very educational to hear how things are done evangelical style. I won't bother dissecting Ham's argument bit by bit -- though it's worth mentioning the occasional bursts of outright Lying For Jesus, such as the claim that textbooks state that there are higher and lower races of man, or the conflation of species (of cats) with breeds (of dogs). You know, things so absurdly wrong and depressingly easy to fact-check. Rather, what really interested me was the way he wove two very different classes of (equally fallacious) arguments together. On the one had were his creative truth-claims in favour of biblical literacy and against the findings of science. On the other were arguments about perceived consequences that acceptance of evolution has for morality. Ham flickered back and forth between the two, ignoring the distinction. It's an acceptable rhetorical technique, I suppose: mix claims about what is true with scare stories about what happens if you don't believe it. I'm sure many of the arguments for atheism could even be charged with using this technique at times, and it's a staple of politics and tabloid news. But I think that it says something very interesting about the motivation of creationists.

Ham's argument from consequences comes down to this: if the bible is literally true, God determines morality. If evolution is true, morality is based on man's fallible word. And you know what? He's right. The bible is wrong about an awful lot of things (sometimes it's just asking too much to believe that it was intended as allegory), and God does not determine morality. To paraphrase HectorAvalos : it is not sufficient to demonstrate that the bible gets one fact right in order to demonstrate that it is is useful, relevant, ethical, or the revealed word of God. But one inaccuracy is all that it takes to prove that it isfallible and questionable.^[2] Ham therefore believes that it is his duty to defend every word of the bible as the truth. Only that with "save their souls." The end goal of promoting creationism is not to have everybody believe in creation, but to fight the rise of the "pagans." (Lol.) Ham believes that if people are taught that it doesn't really matter how God made the world, they will question whether he made it at all. If people are taught that it doesn't really matter whether everything in the first book of the bible happened, they will question whether the events of the Gospels really happened. And you know what? I can't argue against that. Our only difference is that Ham believes that this is a bad thing.

The tactic of mixing truth with consequences is something that has been inherited by the intelligent design movement. Take the Wedge document, the DiscoveryInstitute's 1998 manifesto (leaked, and now subject to desperate attempts at distancing and damage control from the Disco Inst.). The document makes vague appeals to science here and promises research programmes there, but it is primarily concerned with the perceived effects of "scientific materialism". Socialism is the preferred bogeyman of the Disco Institute, though the link between evolution and socialism never seems far from confused. Or, of course, we have Ben Stein in theater(s) (for one week only) rather offensively lying for Jesus about racism and playing games with the holocaust.^[3] School shootings, abortion, homosexuality, and all the other traditional demons are these days the responsibility of "evolutionization".^[4]

Claims about the truth and claims about consequences are not the same thing, and I'd be rather offended if somebody gave a lecture or made a film mixing the two so thoroughly and expected me not to notice.

References

1. ^  Available here.
2. ^  From his Minnesota atheists lecture, if I recall correctly.
3. ^  In Expelled.
4. ^  Attributed to Tom DeLay, 1999. "U.S. Republican politician blames the Columbine shootings on "evolutionization".

One last thing about hybrid embryos. Yeah, yeah, I know. Old news and all that. It takes me a while to get from shouting at the radio to writing up a post, OK? Anyway, it's about something that struck me while listening to Radio 4's Leading Edge on theiPlayer while half awake the other day. Leading edge is a pop-science programme: it's aimed at the masses, but it's supposed to have higher standards than news bulletins when it comes to explaining reality in detail. This particular gem of absurdity hadn't occurred to me before; perhaps I've become somewhat immune to the crazy misunderstanding of science in the news, but I really notice it when it comes to science programmes.

The crime in question? Being so obsessed about DNA. The problem with hybrid embryos, apparently, is that you'll be mixing human nuclear DNA with a tiny (really tiny) amount of mitochondrial DNA (mtDNA) from other mammal species. On Leading Edge, the correspondent went on to allay our fears of such an unholy chemical congress by explaining that this has been done many times before with pairs of mammal species with a conspicuous lack of devastating explosions, zombie epidemics or eightlimbed monster mice. He went on to describe the mitochondrion for us (the "power pack", of course), the percentage of our DNA which it actually contains (point-twelvety), and the number of copies in which it found in the cell (17 1/2 billion, except on sundays or if you earn over 20% of your annual income from savings and investments).

What do you mean, I'm not taking this seriously? Oh, well, maybe I do think that perhaps the whole hybrid-embryo-in-the-media thing is just verging a little bit on the totallybatshit insane. Does anybody actually think that the religiously motivated opponents of science are worried about mtDNA ? Will explaining mitochondrial copy number make them feel better? OK, no, but what about all the non-partisan chaps who have heard these militant bishops on the radio telling us that hybrid embryos will be the worse thing that humanity has ever done, you ask? They will surely have concluded that there must be some genuine controversy involved, you add? Well, maybe.

But if that is the case, how is a discussion of DNA going to help anyone understand that the "controversy" is not scientific. What, indeed, does DNA have to do with anything? I could give you a vague introduction to what DNA has to do with hybrid embryos, and indeed what DNA does not have to do with hybrid embryos. But can the journalists who are covering this story? No. It would appear that they have all be on How To Talk About DNA In The Media 101. DNA is, you'll be interested to learn, the blueprint for the body; and by the sounds of it, DNA is pretty much the only thing in the cell that does anything at all. Oh, except for the mitochondria, obviously. But then, they contain their own DNA,init?

Confused accounts of biology aside, you can not solve a religiously motivated controversy by talking about science -- not in a week, anyway. The barking bishops have made it quite clear that they couldn't give a damn about the science. Facts mean nothing when the truth is divinely revealed. So you can discuss the hybrid embryo controversy or you can discuss the hybrid embryo science. Combining the two convinces nobody, but gives the impression that the controversy has some sort of scientific legitimacy. It doesn't.

Somebody in the Nature Podcast editorial team is clearly not a fan of "new atheists". The "guest rant" spot, or whatever it is they call it -- podium, I think -- has been given to a succession of lectures on the "new atheists" and the compatibility of science and religion. Take John Durant, director of the MIT museum and self-contained pun, who took the spot on February 21 (yes, I know, I've been a little slow in getting 'round to publishing this one). Durant tells the story of atheist Darwin and Asa Gray, American Christian botanist^[1] and populariser of evolution. Darwin and Gray were, shockingly, good friends and correspondents, despite their overwhelming incompatibilities. Not like these days, when we "Darwinists parade [our] science under the banner of militant atheism." Oh yes. He played that "militant atheism" card with style.

Indeed, can you imagine screechy Richard Dawkins being friends with, say, his local Anglican bishop? And what on earth could drive Dawkins to such shrillness anyway? Why can't he be more like those polite politicians in the Commons, who never raise their voices and argue? I mean, just look through any newspaper. All of those columnists being calm and keeping their opinions to themselves. Why do these atheists think that they alone have the right to start a public discussion?

Whatever. You get the point. It has been argued to death already, and if Durant is too unimaginative to spot the absurdity of his argument, and too lazy to actually look at the responses that the "militant atheists" have already made to the argument, there's not really much point in me wasting your time going over old ground. But the real reason that I couldn't let his rant pass is his conclusion:

If there were more Darwins and Grays in the world of science today, discussions about evolution and creation could continue within science, instead of being relegated to the lunatic fringes of the so-called culture wars.

WHOA! Hang on a moment! Discussions of creation have a place within science? Now you've really lost me, and I think you may perhaps have lost some of your fellows in the "militant atheists are too screechy" camp, too. And it's not like I can be accused of misinterpreting "creation" in this instance. Durant is not talking about discussions of abiogenesis or the anthropic principle. He is talking about the sort of "creation" that is currently on the "lunatic fringes". Like seeing the signature of the Almighty creator in mitochondrial proteins, or asserting that the universe was created on a pleasant September afternoon in 4004 BC?

We do have modern Darwins and Grays. None of them think that polite discussions of creationism belong in science.

Footnotes

1. ^  A botanist who happened to be Christian, that is. I don't mean "Christian Botany" like "Creation Science".

Regular readers may have noticed that I get rather annoyed by the casual use of the word "chemical" to mean "synthetic chemical", and the use of the naturalistic fallacy (natural good, chemical bad) that is associated with this phenomenon. It is really quite inexcusable. I've known plenty of intelligent and educated people who are aware of why they are mistakes, and yet continue to make them. Such usage is particularly associated with concerns about cancer, so I thought it may be time for a basic (or intermediate?) concepts post on chemical carcinogenesis.

In healthy cells, the processes of cell growth, division, and death -- the cell cycle -- are carefully regulated. Carcinogenesis is the loss of that regulation, and carcinogens are the agents which cause that loss. Such a loss transforms the cell into a cancer cell, which is then able to proliferate unchecked. Though the terms "carcinogenesis" and "carcinogen" most commonly refer to the events and agents which cause that initial transformation, they are sometimes also used to refer to those events and agents which promote tumour growth later in the disease. In reality, those two categories heavily overlap, and in fact, it takes several of these events before a cell line can really be called "cancer". Physical and biological agents can be carcinogens, but we'll ignore their mechanisms for now (after all, it's just too easy to point out that the sun and viruses are "natural"), and concentrate on the chemicals.

Some chemical carcinogens are able to directly influence the cell cycle. For example, Bisphenol A (which I mentioned a few weeks ago) worries some people because it is able to mimic the effect that estrogen has on regulating the cell cycle -- it binds to and activates estrogen receptors, whose job it is to promote cell division. And then there's tobacco (not to be confused with tobacco smoke, which is a cocktail of chemicals), which has all sorts of effects on cell signaling, which in turn feed back on gene expression and the cell cycle.

Most carcinogens, however, are mutagens: they damage the DNA. They punch holes in useful genes, switch on genes that should not be switched on, and subtly change what genes do. In this respect, cancer is a genetic disease. The mutations are, of course, acting largely at random, though it is easy to forget this (and a similar problem of overlooking the random nature of mutation exists in popular views of evolutionary biology). Billions of mutations have occurred within you, but the overwhelming majority will have had no effect whatsoever. They may have hit part of the 80+% of the genome which is junk, or had a neutral or insignificant effect on the gene that they landed in. Of those that actually hit something important, most will be dealt with by the cell's DNA repair mechanisms, or will trigger cell suicide. Finally, to contribute to cancer, the mutagens must happen upon certain types of genes: those involved in regulating the cell cycle (you may remember the terms "oncogene" and "tumour suppressor gene" from previous posts), cell death, or the DNA repair mechanisms themselves.

Mutagens are typically divided into direct-acting carcinogens, and procarcinogens -- the latter requiring modification before they become harmful. That modification comes in the form of your own metabolism. It's not the job of your metabolism to turn procarcinogens into full (or "ultimate") carcinogens. Rather, we have sets of enzymes which break down classes of complex molecules into less complex molecules, and one of the complex molecules in its class might just happen to be a procarcinogen. Such procarcinogens are found in everything from wood smoke to the fungus that grows on the out-of-date food in your fridge.

Pick any topic in biology and you will be able to discuss it in terms of evolution. I have discussed cancer in terms of mutation and selection events occurring within the tumour before (here, for example), but the chemical carcinogenesis story can also tell us about the evolution of our inherent defences against cancer, and about a couple of important evolutionary principles. At the same time, we can learn about whether artificial really does mean "bad". First we have to flip the necker cube and look at carcinogens -- and other chemicals -- from a different angle. Rather than talking about those chemicals which are, in some way, poisonous to us, and those which are safe, we can recognise that no chemical is inherently good or bad, and call the categories "chemicals to which we are vulnerable" and "chemicals to which we are resistant". It is only in the context of our evolved bodies that chemicals take on such properties as "carcinogenic".

Evolution has equipped us with a number of strategies to cope with harmful chemicals. One is to find a physiological or biochemical context in which they are not harmful: if the harmful chemical is interfering with your vital molecular machine (i.e. enzymes), change the shape of the vital molecular machine. Or you could develop kidneys that are capable of filtering the chemical out, or an enzyme capable of breaking the chemical down. Another strategy is a change in behaviour: a fear or brightly coloured bugs, or a distaste for bitter plants. A third strategy is to make you have children, and then stop caring.

Humans have all of these defences and more. Alongside our DNA repair mechanisms, we have strong, stable and specific enzymes; we have a digestive system, liver and kidneys, which do their best to keep the bad guys out; and most importantly, we preciously guard a small set of genes to pass on to the next generation. The defence mechanisms that evolution has given us work wonders, but have failed to make any individuals immortal. Evolution cares little for those who have passed reproductive age: selfish genes have little to gain from maintaining a dead end. Our DNA repair mechanisms are therefore tuned to keep our bodies from cracking and crumbling just long enough to bring a new set of gene vehicles into the world.

The second evolutionary principle that the chemical carcinogenesis story highlights is that evolution has no foresight. Evolution works by trial and error, life and death, and if you put a product of evolution in a novel situation, it may find itself in trouble. Our throat and lung cells were therefore wholly unprepared for the chemicals in cigarette smoke (fortunately, evolution has equipped us with one last defence -- a brain -- and it looks like we won't have to adapt to cigarette smoke the hard way). Similarly, enzymes don't "know" not to break down procarcinogens into carcinogens, because our ancestors did not consume any of them in significant volumes. In this respect, we can consider the hypothesis that "natural" things are less likely to cause cancer: we've probably had longer to adapt to them.

The trouble arises when one tries to turn all of this into a set of simple rules. Carcinogenesis is not simple, and chemistry is not simple. When it comes to the safety of chemicals, the empirical approach is the best we've got. And that's something that I ought to leave for another post.

I've been following CBC's How To Think About Science series, and caught the Evelyn Fox Keller episode the other day. It was interesting, but there were a couple of issues that I just can't let pass. Keller talks about the hype of genomics ten years ago -- during the human (and other) genome projects, when huge amounts of a new kind of raw data were piling up, and everyone was speculating about the interesting things we could do with it. Leaving aside the fact that many of the claims about genomics have and are coming true (albeit, over a longer time-frame than mainstream media imagined it would), I have a problem with Keller's own bit of hype.

It's epigenetics, of course -- reversible and heritable changes (both between generations of cells and generations of individuals) in gene expression patterns which do not alter the DNA sequence itself. Epigenetics is where all the hype is in biology at the moment. Don't get me wrong: I think the field is interesting and exciting. But as the hottest newest branch of biology, everybody knows the name, and few know the details. It's cited as the mechanism of faith healing, mind reading, and homeopathy. In Keller's case, epigenetics is cited as a problem for theneo-Darwinian view of evolution. By "neo-Darwinism", Keller particularly means the gene-centered view of evolution. The name "Dawkins" may have arisen once or twice. The problem that Keller thinks that epigenetics has for mainstream modern evolutionary biology is that organisms may be able to control their mutation rates in response to changes in environmental conditions, and thus alter the rate of evolution.

Keller is referring, I suppose, to the checkpoints and DNA repair mechanisms that spot and fix errors in DNA replication during gametogenesis (the production of sperm and eggs). It's difficult to make a copy of three billion base pairs without making a few mistakes, and too many mistakes in too many important genes add up to a miscarriage. So there are some molecular machines which follow the copiers around, checking that they got it right. The machines do their best to fix the typos, and in extreme circumstances, will kill the cell if the mistakes are too big. Where epigenetics comes in is in the regulation of those molecular machines. Epigenetics hires and fires the copyeditors. Specifically, there are epigenetic mechanisms which pack away genes -- wrap them around proteins called histones, to form structures called chromatin. Locked away in these packages, the genes can not be switched on, and no new copyediting machines can be produced.

The hypothesis that mutation rates may be under control by some mechanism which recognises changes in the environmental conditions and responds by altering the expression levels of the copyeditors is, I'm sure you'll agree, a fascinating one. But a problem for the neo-Darwinian picture of evolution? I'm not sure I see the connection, there. Here is how I imagine such a mechanism working: in the cells producing sperm and eggs, a set of receptors monitor environmental conditions; when environmental conditions change, those receptors pass the message on to the nucleus, where a set of machines make the appropriate changes to gene expression. Why do I propose such a mechanism? Because just such mechanisms coordinate development, transmit the messages of hormones, detect pain smell light taste, determine the activity of drugs, and do a-hundred-and-one other things in the cell. They are the default way of getting a cellular response to an external stimulus. And it has already been empirically determined that such a mechanism exists in the case of DNAcopyeditors. The DNA copyeditors are not switched on 24/7 -- after all, they are needed primarily during cell division. The mechanism which switches them on was discovered by researchers interested in cancers, who found that this mechanism is often damaged in tumours, leaving thecopyeditors in a permanent 'off' state.

Perhaps it doesn't work this way. Whatever. My point is that it is very easy to imagine a mechanism by which environmental changes lead to heritable changes in mutation rates -- a mechanism which can be created by the simple modification of another very similar mechanism. That modification? Orthodox neo-Darwinian evolution. The receptors and signals, the gene expression machinery and the chromatin re-modellers are all the product of orthodox neo-Darwinian evolution. And the system no doubt remains at the whim of natural selection. The idea that evolution itself evolves is fascinating, but it does not appear problematic or revolutionary to me.

--

I said I had a second issue with the programme, didn't I? Ah, yes, still on the topic of Dawkins and the idea of the selfish gene. Keller suggests that the ideas expressed by Dawkins have been surpassed and overturned by the modern developments of molecular biologists. Developments such as the fact that genes have complicated networks of interactions with each other. Gosh. It's almost as though Keller hasn't read The Selfish Gene. InTSG (Or was it The Extended Phenotype?), Dawkins is very careful to point out the fact that the "genes" of population geneticists -- Mendelian particles of inheritance, and the "genes" for which the word "gene" was coined a century ago -- are not quite the same thing as the "genes" of molecular and developmental biologists. Dawkins' selfish genes need not be defined by start and stop codons, upstream promoters, or discreet messenger RNA products. Which makes Keller's criticism largely irrelevant.

Whatever. Who cares? Somebody slightly mischaracterised an obscure academic problem, buried in an obscure podcast. Well, the main reason I care is that Keller is herself telling us that we should be more precise when talking about genes. When first used, the term "gene" was just a placeholder for a phenomenon we understood little about, she reminds us. Over time, we've filled in the details. The problem is, the population geneticists and evolutionary biologists have filled in different details to the molecular geneticists and developmental biologists. They've all continued to use the term "gene", but they're now using it to mean different things to each other. Oh, wait, haven't I heard this somewhere before?

I guess it's just that Richard Dawkins is so shrill and screechy that it's impossible to read him carefully.

Continue reading under the fold...

So, Jerald J. Block thinks that internet addiction should be an oficially recognised psychiactric disorder. Here are the warning signs:

1) excessive use, often associated with a loss of sense of time or a neglect of basic drives, 2) withdrawal, including feelings of anger, tension, and/or depression when the computer is inaccessible, 3) tolerance, including the need for better computer equipment, more software, or more hours of use, and 4) negative repercussions, including arguments, lying, poor achievement, social isolation, and fatigue

Well, you may have noticed that I haven't been writing so much here these past couple of months. This is because I have a terrible addiction. I made a mistake. I thought I'd go out and get a life -- just a little, what harm could it do? The trouble is, it's so addictive. I looked up the symptoms, and the news isn't good:

1) excessive interaction with other people, often associated with a loss of sense of time or a neglect of basic drives,

I went for an after work drink last Thursday. Suddenly it was two in the morning. It was only when I woke up that I realised I had not eaten since the previous lunch time.

2) withdrawal, including feelings of anger, tension, and/or depression when friends are inaccessible,

I spent a few months living in the middle of nowhere in Dorset while unemployed. Everyone I knew was doing fun things in far away cities, while I sat around wondering what the point was.

3) tolerance, including the need for railcards, event organisation, or more hours of use,

I added the Nature Network London pub meet, London Skeptics Lectures, and the flickr midsummer allnighter to my Google Calendar this weekend. Never been to any of those before.

4) negative repercussions, including arguments, lying, poor achievement, social isolation, and fatigue

I upset somebody by not replying to a message from them in time, I lied about writing at least two pieces for the blog per week, I've been failing to keep up with a long running debate on a forum, neglected to contact my American friends on MSN or Skype for weeks. I've spent so much time reading books on buses that I have trouble keeping up with the new items in my Google Reader.

I am seeking help, and hope to be able to spend a more healthy amount of time online soon.

Wow, a slow news day, eh? The BBC, shunning predictable Chinese military aggression, another turn of the tides in Iraq, and yet more boring news about the economy, lead with "Brown criticised over embryo bill". Somebody at BBC News is clearly a fan of Cardinal Keith O'Brien. 'Keith who?' I hear you ask. What do you mean you've never heard of the leader of the Roman Catholic church in Scotland? The big news is that O'Brien is making a fuss over the Human Fertilisation and Embryology Bill. The bill, currently in parliament, will, amongst other things, make it easier for researchers to develop methods of growing tissues and organs that are genetically identical to those who require transplants or grafts, and is likely to help solve the problem of transplant rejection and the need for immunosuppressive drugs after transplants. Then there's cancer, Alzheimer's, HIV, blah, blah. This is, I'm sure you'll agree, a terrible thing. I couldn't put it better than O'Brien himself:

"This Bill represents a monstrous attack on human rights, human dignity and human life."

The reason, of course, is that this bill enables the use of hybrid embryos. Putting little bits of reprogrammed adult human DNA into animal zygote cells. This presents all sorts of obvious problems for the Roman Catholic Church. It suggests the clearly impossible: that humans are animals, evolved like all other animals, and following the same developmental rules as our neighbours. The Cardinal is, I am sure, confident that hybrid embryos will never work, because of the obvious fact that cows, pigs and mice are not created in God's image. That's elementary stuff. Comes right at the beginning, in Genesis 1:27. It's almost embarrassing that these biologists don't know that.

Then there is the problem that this bill mentions embryology. The Roman Catholic church has, for the past few decades, tried to convince the world that it knows all about embryology. And don't they just. Is it not the case that human embryos are human beings? Is it not so that fertilised eggs can think and feel, recite their twelve times tables, and lead missions into pagan lands? O'Brien is privileged with an intimate knowledge of God's colossal mind, and he knows that God loves zygotes. So of course the Roman Catholic church must oppose a bill that makes such absurd claims as development being mind bogglingly complicated, life having fuzzy boundaries, or that you are infinitely more valuable and important than the half dozen skin cells that have fallen off your right index finger during your current browsing session.

Of course, it's not just the mind of God that O'Brien knows intimately. God knows what you and I think, and he has spilled the beans to O'Brien:

"I can say that the government has no mandate for these changes: they were not in any election manifesto, nor do they enjoy widespread public support."

Yes of course. Who is better placed to judge the beliefs, feelings and fears of the public on this matter than Cardinal Keith O'Brien? And he's the perfect candidate to head this "single permanent national bioethics commission" that he proposes, too, what with his deep knowledge of developmental biology and reproductive medicine, and his profound understanding of the national mood. Not to mention that direct line to God. You couldn't find a more representative candidate in the land.

Indeed, people were talking of nothing but the Human Fertilisation and Embryology bill on the crowded train home yesterday, and I can tell you, they're not too happy about the army of monsters that are coming our way. "Haven't these scientists ever heard of zombies," one of them asked? Another was concerned that the convergence of reprogrammed human nuclear DNA with bovine mitochondrial DNA within the same cell membrane could just be the final straw that breaks the camel's back and leads God to break his promise never again to commit genocide by flooding the earth. One gabbling mouthbreather even pointed out that such an untested and unprecedented confluence of incompatible nucleotide sequences could, for all he knew, flip the earth's magnetic poles and precipitate the fiery conclusion of the universe.

Oh wait, have I got that right? Now I think about it, perhaps Britain is not the reactionary backwater that O'Brien thinks it is. Perhaps the senile and simple individuals who pray for the souls of cells do not make more than an entertaining but tiny minority of people in this country. Perhaps, just maybe, O'Brien's series of non-sequiturs have led him to a confused and offensively hyperbolic fantasy about morality that he is pretending is representative of a universal hallucination of the British public. Sure, this bill does not have widespread popular support. But that is because parliamentary bills get only widespread popular obliviousness and apathy. The cardinal is dreaming if he believes that there is widespread popular opposition to it.

How about a front page science story that doesn't give 99% of the coverage to absurd ideas?

I was watching the TANK vodcast the other day. They had a short feature: "what is skepticism?" It had a series of vox pops shot in Sydney. People told us what they think skepticism is. It's all about being stubborn, close minded and refusing to believe the things that everybody else believes, apparently. The programme makers didn't answer the question themselves -- after all, "you and I know what it is". Well, I do know what skepticism is, but how would I explain it to those who don't? Skepbitch has managed to get in with an answer before me, but I'd like to add my own way of describing what it means to be a skeptic.

Skepticism is the opposite of naivety. Being a skeptic means being aware of all of the ways you can be deceived. It means knowing the methods that other people use to deceive you -- the propaganda and rhetoric techniques, and the fallacies in their own thinking. It means knowing the limitations of your senses, and designing ways to get around those limitations. And it means knowing the appropriate volume of evidence to demand for claims about the world. A skeptic does not have a closed mind, but their mind is not a free-for-all. Skepticism is the doorman who checks for fraudsters.

When I was very young, ghosts were fashionable in the UK. I loved the ghost stories on television -- Fortean TV on Channel 4, and an ITV programme whose name I forget, hosted by a man with large dusty book and a candle. Though the stories were transparent fiction, the ten year-old me believed them. He was naive. He got fooled, and one can chuckle at his expense. If more people realised that the antonym of "skeptical" is "naive", they might be a little less inclined to use it as a derogatory term. There is nothing to celebrate about being gullible and exploitable.

If you have ever worked in a molecular or medical biology research laboratory, chances are one of the first things you learnt was tissue culture (or the microbiology equivalents). Even if you know nothing about biology, you've probably heard mentions of "cell culture" on the news, or at the very least heard about the results of studies in tissue culture. If you hear about "cell lines", you've got culture. If you hear about a "laboratory study" showing that your favourite chemical is carcinogenic, you've probably got culture. If you hear about new trials on a miracle cancer cure that has been shown to be effective in "preliminary laboratory tests", you've probably got culture. Everything from zombie epidemics to �10,000 animal-free beef is cell culture. Knowing a little bit about what tissue culture is, and what its uses and limitations are, is therefore important when answering such questions as "is my baby's bottle poisonous?", "is stem-cell research ethical?" and "is vitamin C an effective cure for colds/cancer/HIV?"

So. What is tissue culture (TC)? It's when you take specific cells from a multi-cellular animal and grow them in a dish full of nutrients (a mimic of your blood serum). The point of doing this is to create a system on which to experiment which does not require growing and killing lots of individuals -- something that is, for some reason, considered unethical. Especially when it's humans you propose using. Typically, human or other mammalian tissues are used -- especially "model organisms" such as mice. You can use healthy or diseased cell lines from all sorts of different organs. Once you've grown up a nice batch of cells in your dish, you can see how they respond to your cancer drug, environmental contaminant, or new junk food ingredient. You can see exactly how the behaviour of your cells changes over the minutes, hours and days of exposure; how they recover after the chemical has been flushed away; how your cancer drug works in dozens of different tumours; how your junk food ingredient works in the old and young, male and female, fit and fat; and how your environmental contaminant interacts with other environmental contaminants. It's great. If you work hard enough, you can know everything you want to know about your chemical within a week. Wipe out cancer and save the world by next Monday. At least, that's what the animal-rights movement would have you believe. And the tabloid press fall for it daily.

Trouble is, it's very easy to get superficially interesting answers using TC. Which makes it very easy to convince a journalist that you have important results, but very difficult to convince a scientist. That's not to say that TC is not important. But everything that we measure in TC is an estimate of what happens in real life situations. It's a model that uses surrogate measures from which we can develop hypotheses about what happens in reality. A bad analogy is in order, I think. Suppose you are building a car. You want to protect your future drivers from side-on impacts. Very early on in the design process, you have an engineer conduct strength tests on different materials and designs for doors. From this, you can narrow down the field of designs, and make hypotheses about which designs will perform best on the road. But you can not be sure that the strongest material will provide the best protection against injury and death. You would want play with the crash test dummies, before putting the car on the road. And once the car is on the market, you would analyse incidents. Because when the door is attached to the car and put on the road, a huge number of other variables comes into play. And so it is with, er... what was the topic again? Tissue culture.

Cells did not evolve for growth in a dish. They evolved in the context of cooperation with a vast number of other specialist cells in a body. They are not fine tuned for survival in the absence of skin, an immune system, a digestive system, liver and kidneys. They are not supposed to live like barnacles on plastic. But if you've worked with research quality cell lines, you'll know that it's surprisingly easy to make them grow in a dish. Feed them every couple of days, and they'll happily live for many months. Well go and say that to the post-docs and technicians who made it that way. They were up until midnight processing disgusting lumps of freshly excised tumour. They spent months trying out different combinations of nutrients and fungicides in an attempt to make the cells survive longer than a week. They may be easy to grow now, but don't think there wasn't any effort involved. Under these circumstances, you can hardly expect the cells not have evolved a little. You are introducing them to a vast number of novel mutagens by taking them away from the protection of skin. And putting anything into a new environment is going to mean new selection pressures. When you finally manage to immortalise your cell line, is it because you've perfectly adapted the conditions to the cells, or because the cells have adapted to the conditions?

So. There are all sorts of reasons why TC can not be anything more than an approximation of what is happening in real life. A useful approximation, but unreliable in the absence confirmatory evidence from in vivo and population studies. But these are only the intrinsic limitations of TC. When judging the merits of TC based research, you must also take into the account the fact that TC is easily misused and misrepresented, and that charlatans are doing it all the time. TC is a favourite of cargo-cult healers and nutritionists -- those who like to keep up a superficial appearance of having a scientific basis for their quackery. Take, for example, the shamen who pedal vitamin C as an HIV/AIDS drug (Patrick Holford, for example) or as a cancer therapy. They will tell you that in TC, vitamin C has been shown to kill tumour cells, or those cells that are infected with HIV. Therefore, the reasoning goes, we should abandon proven therapies, in favour of taking some vitamin supplements. Trouble is, you can chuck a big lump of any chemical in a dish of cells and the cells will die. I could pour a bag of vitamin C into a dish of healthy cells. They will die. Conclusion: those vitamin supplements are deadly poisonous. Except that your cells will never be exposed to a bag of vitamin C, because you have skin, a digestive system, and kidneys. And because people just don't go around pouring bags of vitamin C down their throats. I could spit in a dish of cells and tell you that spit is a killer. It's not.

But it's not just charlatans that abuse TC. Many legitimate scientists bend the rules a little. They may not even be aware that they are doing it. Take the case of Bisphenol A (BPA), something I did a little work on a couple of years ago. BPA is a component of some plastics, notably bottles. It is known to very slowly leach out of the bottles and into your drink. There is a little bit of evidence (mostly from rats) to show that consuming BPA may be harmful. And there are a lot of TC experiments on the chemical. BPA is a xenoestrogen, meaning that it mimics the activity of estrogens. Estrogen, of course, regulates prolactin release, and cell division (particularly in the breasts). We know that BPA mimics estrogens because when we put some in our dish of tumour cells, we see that within seconds the estrogen receptors have been activated, and all the other effects of estrogen follow. There are loads of results to confirm this because there are a lot of experiments into the effect of estrogen (there's plenty of money in breast cancer research). If you're doing the experiment anyway, it's hardly any more effort to look at BPA. And you can pretend that your research has another potential medical application. Since it's not the primary aim of your research, the journal's reviewers won't notice that you're using it at a thousand times the concentration that you would find it in the body. So even if enough BPA does leach out of your bottle, and even if BPA does do interesting things in the body, a large proportion of the TC studies will be irrelevant to understanding how it does those things, because they look at inappropriately large concentrations and inappropriately small timescales.

So, next time you are flicking through the health pages of the Daily Mail -- which I know all of you like to do -- engage healthy skepticism when they update the list of miracle cures and carcinogens. Like statistics, tissue culture is incredibly useful -- whether you're searching for the truth, or a convincing lie.

Go on. If you haven't already. Have you got an old account lying around, that you'd forgotten about? It's really very easy:

1. Log in
2. Click "home" (top left)
3. Click "account settings" (top right)
4. Click "cancel account"
5. In the box put "Your persecution of atheists disgusts me, and your aesthetic values offend me."
6. Check your inbox.

While you're waiting for the email to arrive, you can watch this short moving picture presentation from Messers Fry and Laurie:

This post is part six in a series. The series so far can be found here.

Cogito, ergo sum.

Ren� Descartes, 1637.

I've given five posts and several thousand words over to introductions to principles in development, evolution and molecular biology. I won't be dropping those topics altogether, but it's time to explore new territories in the Sunday syndrome, including the philosophical and political. Things should be a little more digestible from here on. Chromosomal aberrations -- that is, large scale mutations in which so much genetic material is deleted or duplicated that a difference is visible under the light microscope -- have serious effects on development. We have discussed a few examples of syndromes which arise in individuals which carry these aberrations, but the individuals we see are the exceptions. In each case, I have given the frequency of the disease in terms of live births, but the frequencies are much higher in conceptions. The deletions that we see in live births are a relatively small proportion of the genome, and we rarely see live births in which both of the two copies of the genome are affected. More extreme deletions do occur, but the individuals carrying them never make it to birth. The rule is miscarriage.

Perhaps the most extreme syndrome that we see surviving to term is anencephaly. And yet, paradoxically, anencephaly has the smallest number of symptoms and directly affected organs of any of the syndromes that I have so far discussed. In most cases, physical development is largely normal, with the exception of one particular system: the nervous system. Anencephaly is classified as a neural tube defect, alongside spina bifida, and is caused by an error during the developmental process of neurulation.

Neurulation starts on day 18 of development, and is complete by day 30. The cells along the centre of the back fold in to form a grove, which then closes over to form the neural tube, the precursor of the central nervous system. With a frequency above one in every 500 births, closure of the neutral tube fails to complete. If this occurs towards the posterior,spina bifida arises, and the individual is physically disabled. When this occurs at the head, the skull does not form properly, and the amniotic fluid destroys the developing brain. Those individuals which survive to term are born without a brain. All will die within hours of birth. The reason anencephaly is the most extreme of our syndromes is because it affects those parts of us that are most uniquely human, and raises important questions about medical ethics, and the fuzzy boundaries of humanity.

This is one of the great social functions of science: to free people from superstition.

Steven Weinberg

Last year, a court case was brought in Ireland to determine whether a woman whose foetus had been diagnosed with anencephaly could travel to the UK for abortion. A French website exists solely to oppose the abortion of anencephalics . It is murder. Despite the fact that these individuals will never have a life. Never have a thought or feeling, either of pain or joy. Never know that they exist or will cease to exist. Never, no matter what the anti-abortionists may tell you, "know God". There is no they.

I am not willing to believe that the anti-abortion movement is solely about the control of women -- though that is undoubtedly a motivation for cynically manipulative church elders. Rather, it is about simple rules. When faced with difficult moral decisions some people are just too cowardly