Here Be Dragons

One of the more common misnomers flying around the pop-sci publications is this idea of “Junk DNA”. Now to be fair, this label originated with the scientific community. Even Francis Crick was dismissive of its utility, but that was thirty years ago. As it turns out, junk DNA (more accurately called non-coding DNA) contains both a variety of sequences with biological utility and large portions of our genomic history. It is the later that I wanted to bring up today.

One of the major forms of transcriptional control involves histone deacetylase. You can think of histones as essentially spools of DNA. If DNA is wrapped tightly around histones it is unavailable to be transcribed to RNA and then translated to protein. Modification of histones determines the precise manner in which the DNA interacts with them, and acetylation of histones loosens the wrapping of the DNA, making it available. So your cells employ histone deacetylase to make sure that regions of the genome stay nice and silent. Which is good, cause there is some scary stuff hiding in the sea of non-coding DNA.

Recently there has been a push to use histone deacetylace inhibitors to cause expression of genes of interest (e.g. it is suggested they could be used to flush latent virus out of memory T-Cells to destroy latent reservoirs of HIV). Now, these ideas seem really sound on the surface. If we could destroy that reservoir of latency, we could see long-term drug free remission in HIV infection. But what else might you wake up? As far as I know there is no reliable method (if there is indeed a method at all) to target histone deacetylase inhibitors to specific regions of the genome, so this would be a general approach inhibiting all of a cells histone deacetylase, which I can’t but think would lead to A) steps towards tumor transformation as cell cycle controls  were disabled, and B) the activation of unfriendly endogenous elements in the genome. Fishing out integrated HIV provirus is an excellent idea, but what else might we pull in with it?

Mitochondria are Weird

Let’s get one thing straight: I like my mitochondria. They are a necessity for eukaryotic life (although there have been some theories about alternate high yield ATP production pathways or schemata of power management). But for all that…dang are they weird.

The situation is basically a symbiosis event. At some point the ancestor of eukaryotic cells engulfed a prokaryote (most likely Rickettsiales). However, instead of being broken down into constituent molecules, this prokaryote persisted, reproduced, and evolved within the cell. One of the most fascinating things about this arrangement is that, as time went by, the mitochondria actually began to outsource their genome to their host. This is debatably the point at which they completely lost their independence and became organelles as opposed to organisms.

The human mitochondrial genome is 16,568 bases and contains no introns. It codes for about 37 genes, a fraction of what the organelle actually requires. The rest of the proteins are made from your nuclear DNA and imported through an annoyingly complex transport system. As we look across species, we can see that the mitochondria in different organisms have retained more or less of their original genome (e.g. plasmodium have 5 genes in their mtDNA and reclinomonas have 98 genes), but no organism retains completely independent mitochondria. And there are a lot of extra tricks that the genome picks up across species: sometimes linear, sometimes circular, sometimes with introns, sometimes not, multiple copies of the genome per mitochondria, etc. As an added bonus you can wind up with multiple mitochondria per cell with multiple different genomes in that mitochondrial population.

The practical side of this is that inheritance of mitochondrial disorders is emphatically not Mendelian, and tracking such disorders can be all sorts of a headache. A headache we are going to have to work through if we want to effectively study and prevent these diseases.

Sources & Further Reading

• I highly encourage anyone with a background in genetics and some time to kill to go take a look at MitoMap. It’s the human mitochondrial genome database and includes some great references.
• One of my commenters has recommended Nic Lane’s Power, Sex, Suicide: Mitochondria and the Meaning of Life, although I personally can’t speak as to whether it is good or not. Am looking for a copy but even if I find one it will have to wait its turn in a long line of reading material.
• And because spec-fic is fun I find myself compelled to recommend Parasite Eve both the novel by Hideaki Sena and the PS1 game put out by Square. Nothing approaching scientific accuracy, just plenty of “What if mitochondria were an evil hive mind?” lovelyness and body horror. There is also a movie, but I hear that it wasn’t that great.

Sex & the Myth of Gender

So recently the lovely ladies over at Fishnet Bluestockings added me to their blogroll, and I have reciprocated in kind. If you are at all interested in a rational slant of feminism, especially as it concerns the entertainment industry, I highly encourage you to go check them out (and I am not just saying that because one of their writers is a dear friend). This post is inspired by something I started saying in their comment sections, and as it concerns something that influences my view on humanity in general, I thought it would be best to expound on it here.

Sex is a defined, binary, biological distinction. It is a genetic designation based on the possession of a particular genotype. In humans this is the presence or absence of the Y chromosome and even more specifically the gene SRY (Sex-determining Region Y).

There's the little bastard now (courtesy of the NLM).

In other animals it can get a little more complicated and fun, but that’s beyond the scope of this post. So, the presence or absence of this one thing is the difference between male and female. It’s a pretty tiny piece of genetic material, but then you know what those people with penises say… And (in this case) they are not too far off the mark. The cascade effects of having this are huge and make for a great deal of phenotype variation between males and females (for a good example of this, just check out my article on Estrogen, Leptin, and Obesity). Males and females are biologically and genetically geared towards different things: e.g. males store fat in different areas of their body, males create sperm instead of ova, males tend to have an easier time developing muscle, etc. There is also a great deal of structural change, bone shape, brain shape, there have even been recent studies showing a difference right down to the cytology of certain cell types, etc.

But what does all this mean? It means that biology is damn awesome, and it means that males and females have a number of legitimate differences that need to be taken into account if for no other reason than their medical significance. As a for instance, hip replacement therapy needs to be different for males and females since we have different bone structures in our reproductive regions (ironically there is currently only a single ‘sexless’ hip on the market because doctors have been accused of being evil and sexist for saying that their male and female patients need different prostheses). What this most emphatically does not mean is that one sex is somehow better than the other. This latter idea is part of the myth of gender, and is one that should be expunged.

Gender is a fuzzy, poorly-defined, spectrum with a basis in sociology and psychology. The important thing to take away here: GENDER IS NOT SEX. This would be a lot more clear if our society could stop marginalizing transgender individuals (and stop conflating the larger transgender community with strict transsexualism or any kind of display of sexuality). Now, gender would like to be sex, and for quite a while the enforcement of a narrow gender role based on biological sex has been the status quo (in recent years this has become less true for the concept of ‘woman’ thanks in large part to the feminist movement). The idea of gender is deeply ingrained and wants to survive and so it will often pretend to have a ‘natural’ basis. In recent years this has adopted the language of science and the lie that gender has a biological basis, or that indeed gender and sex are one. Both of these are easily shown to be false due to varied gender roles across culture and race, and especially by the presence of both eclectic third gender individuals (like your humble author and many American transgendered people) and organized third gender groups (like the Hijra). None of us have a fundamentally different biology than any of the normative folk walking around. None of us are not, at a genetic level, male or female. But we are most emphatically not men or women. And given how that false dichotomy has been repeatedly abused as the subject of a patriarchal power play, why would we want to be?

You might just be disingenuous if…

Okay, so I know several other bloggers have hit this before (I personally found out about it from erv), but given my interests I couldn’t help but toss in my two cents. And I am going to at least try to focus on a slightly different aspect of the issue.

This all begins in the (web)pages of Nature: Transgenic bacterium sparks row in French schools. It seems that the Committee for Research & Independent Information on Genetic Engineering, is all in a tizzy because French schools want to teach basic E. Coli transformation to 15 and 16 year olds. A great deal has been made over what motivates these people, and I am not going to go into that at any length. I think it is clear that their motives are anything but pure: they are an alarmist, anti-GMO political advocacy group. It will be more interesting to instead look at what they are saying and realise that, regardless of their motivation, it’s completely idiotic. Let’s say that you feel that genetically modified organisms are going to bring about the apocalypse, fine (I for one welcome our new cat-lizard overlords, and will argue that with you another day), you still need to see that these guys are nutjobs.

Gilles-Eric Séralini, president of the organization’s scientific committee, says that CRIIGEN is in favour of genetic engineering, as long as it is properly controlled. But the necessary restrictions are not currently in place, he says.

CRIIGEN “will urge the education ministry to impose a moratorium until a full debate on the question is organized”, says Séralini. “We believe such material should not be manipulated by students before they reach university.”

He warns against trivialization of a sensitive subject, contamination risks and possible violation of European directives on the manipulation of genetically modified organisms in confined spaces. “I am also concerned that practical classes erode the time spent imparting knowledge of biology,” he adds.

Let’s break that down:

(1) trivialization of a sensitive subject. This is a meaningless statement. I do not see a case that can be made that education trivialises anything (either that or European schools are much more different than I have been led to believe). And as for sensitive subjects…please. CRIIGEN claims to be a scientific organisation. We do not have sensitive subjects. It’s one of those weasely, soft words that is meaningless in discussions of facts.

(2) possible violation of European directives on the manipulation of genetically modified organisms in confined spaces. This is odd…I am pretty sure that European directives allow a process that has been going on for over half a century in labs across Europe. Doubly odd in that CRIIGEN themselves think that these directives should not inhibit university students. I am going to be very surprised if anyone can turn up a European directive setting an age limit on performing science experiments.

(3) “I am also concerned that practical classes erode the time spent imparting knowledge of biology.” And here is the big one. Science is an admixture of theory and practice. To teach one without the other is…not teaching science. It’s rather definitional. Séralini is both a university professor and researcher. He cannot be ignorant of this. This last statement is an outright lie. Or perhaps not, I have no doubt that he is concerned by this, but I do doubt his concern is for the students’ benefit.

So in short: non-sense, non-sense, and non-sense.

Look, if you have decided to say that your organisation is for “Research & Independent Information”, shouldn’t you be advocating…I dunno, maybe research and information? The message presented here is that ‘There is a terrible danger from the sensitive subject of GMO and we do not want people to learn about it.’ If you believe that GMO presents a threat, how are you protecting people by deliberately trying to keep them from understanding it? This is not the sign of an honest and well intentioned organisation. The ‘personal experience and independent verification of our claims is bad, you should really just listen to us’ camp is neither a reasonable nor proper position for any organisation that claims “To carry out research and provide information on genetic engineering and its impact in the fields of biology, the environment, agriculture, food, medicine and public health,” or “To make every effort towards the removal of the status of secrecy prevailing in genetic engineering experiments” (both of which appear in Article 3 of their Articles of Association). In fact, it seems to me to be the very antithesis of both of those claims and of the scientific attitude in general.

Regardless of what you believe about the GMO issue, does anyone really think that the proper course of action is to withhold education and information? If you want to convince anyone that GMOs are bad, then you need to use data and transparency. The only reason to fight against education and understanding is to protect the spread of falsehood, which is exactly what CRIIGEN is doing.

The Nobel Laureate That Wasn’t

As much as I take notice of the Nobel prizes from time to time, they are far from any kind of perfect system for delineating and recognising the most important research and researchers in the sciences. This is nowhere more apparent than in the case of Oswald Avery. There were many great contributions to biology over the course of the 1900s, but arguably none more important than the Avery, et al. 1944 paper “Studies on the chemical nature of the substance inducing transformation of pneumococcal types.” Now, the last one hundred years have seen some amazing biological feats, and the Nobel foundation has caught a lot of them: double-helix nature of DNA, PCR, etc. However, without this one 1944 paper those discoveries wouldn’t have been possible, because we wouldn’t have been looking.

As with most things, this needs a little  history to understand. Oswald Avery was born in Canada in 1877. His family moved to America while Avery was still young, and as a youth he displayed a great talent for oratory, music, and art. But he didn’t pursue any of these paths. Instead, he went into biology and medicine. Avery did not have a natural talent for this, at least so it seemed. His career was almost entirely unremarkable, that is until he was picked up by the Rockefeller Institute (and even there his first several publications were complete flops). This trend would continue until the eve of America’s involvement in WWI.

The Rockefeller Institute had essentially become the medical R&D arm of the government as Woodrow Wilson slowly forged America into a (really quite horrifying) war machine. The camps where soldiers lived during training (overcrowded in complete disregard for military hygiene rules) were really the most perfect breeding ground that disease could ask for. And it struck hard. Even before the infamous 1918 flu, the American training camps were hit by an epidemic of measles. Now, measles itself doesn’t kill you, but it does leave you open to secondary infections, most notably pneumococcus and it fell to Oswald Avery, now a private in the US Army (the entire institute had been inducted into the military practically overnight), to deal with the problem. And he did. Avery went after pneumococcus with a passion, studying it, cataloguing it, and working tirelessly to find some kind of vaccine.

It is difficult for me to believe that Avery did not first come across the transforming principle in his work, since we do know that he tried mixing live pneumococcus and heat-killed pneumococcus in his attempts to create a vaccine. But perhaps not. Or perhaps in the midst of war he failed to realise the significance of what he had done. But almost around ten years later, Frederick Griffith didn’t. Frederick Griffith was a British researcher trying to solve the same problem Avery had been: How to inoculate people against pneumoccocus. Once again he tried mixing live strains and dead strains of the bacteria. But something strange happened when he did that, and he took note. If he took a non-lethal strain and injected a rat with it, the rat was fine. If he took a heat-killed lethal strain and injected a rat with it, the rat was fine. However, if he took a non-lethal strain and a heat-killed lethal strain and injected a rat with both at the same time, the rat would die. Moreover live, lethal strain pneumoccocus could be isolated from the corpse. He happened upon the idea that the non-lethal strain could somehow be made into the lethal strain merely by being put in close contact. Something passed between them. This became known as “the transforming principle”.

No one really knew what to make of this. Although of course, the main theory was that it was due to genetic material being taken up by the living bacteria. Y’know, genetic material a.k.a. nuclear proteins. Because, after all, proteins are large and dynamic. That nucleic acid junk floating around in there was obviously just extraneous trash. Everyone believed this. Probably even Avery. When he returned to research on pneumococcus in the 1930s in an attempt to isolate the transforming principle, he most likely thought he was going in search of a protein. But bias has never been a friend to bleeding edge research, and fortunately Avery was able to look past that. He, Colin MacLeod, and Maclyn McCarty performed a series of experiment spanning more than a decade and published their findings in 1944: DNA was the transforming principle. Therefore, DNA was the most likely candidate for the genetic material.

This was it. This was the big one. We lost a century of scientific progress to phlogiston theory, how much time would molecular biology have remained stymied without Avery? Indeed, the understanding that DNA is the hereditary material laid the foundation for every advance that came afterwards. This is the lynchpin of modern biology, and every one of us who work in the field are personally indebted to him and his fellows. However, the initial reaction to Avery’s publication was very negative. Many scientists had a lot invested in this whole nuclear protein theory and some of Avery’s fellows at the Rockefeller Institute took the opportunity to slander him and his research at every turn. This included to the Nobel Foundation. Of course, once it became generally recognised (around 1950) that Avery was correct, the Nobel Foundation couldn’t just swallow its pride and admit error. So they staunchly continued denying Avery the award until his death in 1955 at which point he became ineligible.

Fortunately, by all accounts Avery really didn’t care about recognition (or really much besides his work), so we can hope he didn’t take offence. Of course, given the recent behaviour of some Nobel recipients perhaps we should be glad.

Further Reading

• “Studies on the chemical nature of the substance inducing transformation of pneumococcal types.” Avery, et al.
• The Transforming Principle: Discovering That Genes Are Made of DNA by Maclyn McCarty

The failed promise of genomics

Ironically, in certain circumstances, praise can do more damage than insult. One of my favourite television shows, Dylan Moran’s Black Books, has an episode in which the protagonist, Bernard Black, has a date ruined by one of his friends. However, instead of telling his date what a miserable bastard Bernard actually is, she does so by playing him up as impossibly brilliant (saying that he paints, and speaks seven languages, etc). Later, after things have begun to fall apart, he wheels on his friend and shouts: “You! What did you say to Kate? She thinks I’m the Renaissance!” I bring this up because an analogous relationship exists between Science, the Media, and the Public.

Perhaps in no place is this relationship so clear (in recent years at least) as it is with the subject of genetics & genomics. I often talk about “the failed promise of genomics”, and let me explain what I mean by that. If you ask a scientist: genomics is a fascinating field with a great many applications. It has been a vital step in understanding life and its tools will remain valuable in facing the challenges biology presents. It is the blueprint on which we will build many further endeavours. If you ask a journalist or (ugh) soft sci-fi author, genes are magic. Okay, maybe it isn’t that bad. But it’s close. And it becomes a problem when we look at scientific literacy and have to ask: who is the public getting their information from? Because it sure as hell doesn’t seem to be the scientist.

The Human Genome Project started in 1990. Even if there was a little bit of awareness before that, the HGP turned it into an obsession. Such is the vanity of H. sapiens. Suddenly genetics and genomics were catapulted from the scientists toolbox to the public eye. By the time the drafts were released in 2000 and 2003, we had genomania.

Genetic engineering and gene therapy had entered popular entertainment with films like Jurassic Park and Gattaca and games such as Metal Gear Solid and Bioshock. Our fiction portrayed genetics as mystically resurrecting dead species, fuelling dystopias, and granting abilities on par with magical powers. And the journalism on the subject hasn’t been much better. Over the past two decades we have been presented with everything from ‘obesity genes’ to ‘gay genes’ to a gene for every disease under the sun. Genes were suddenly the cause of and solution to everything.

But why does this happen?

Here we come upon one of the general principles involved in the distortion of science. Science is hard. It is a complicated field of study with a staggering amount of depth (biology with its irregularities and great breadth doubly so). Journalists have neither the training nor the time to accurately report on research. Genetics however has a simple, even elegant explanation. To the novice, a system of cause and effect presents itself. You can almost convince yourself there is a perfect little Mendelian world running with as much surety and clockwork as Newtonian physics. But once you reach the level of genomics (and  especially if you look into the newer studies of epigenetics and proteomics) this elegance breaks down. Such a breakdown isn’t pleasant. There is a parsimony and sense of ‘rightness’ to the “if I have gene A then I have trait A” paradigm. I have been in classes with students who have had total meltdowns over finding out that that is simply not true.

A full discussion of why that isn’t true is beyond the scope of this blog, but let me just throw out some examples: gene A might have multiple different alleles leading to multiple different products, each of those alleles might go through different processing, transcripts of gene A might be degraded by the protein product of gene B, the protein product of gene A might be degraded by the cell unless you also posses just the right amount of the protein product of gene C (or hell, maybe gene A doesn’t even get transcribed without gene C’s product promoting it!), maybe the protein product of gene D dimerizes with the protein product of gene A rendering it inactive (or maybe that is the only way to render it active), etc. And reasons like these just scratch the tip of the iceberg. The number of possible snafus in the pathway from genome to phenotype are so numerous that there is no such thing as a classic Mendelian single phenotype genetic disorder (something I will discuss in greater length if I ever get around to doing a write up on one of my favourite journal articles: Loscalzo, et al. 2007)

So what we have here, is an incredibly complex system with an enticing misconception just waiting to be picked up and ran with. It is a misconception that makes sense, it is a misconception that makes people happy, and it is a misconception that promises power over and easy solutions to all of the ills that surround us. The problem is that it doesn’t exist. And the scary part comes when you realise that it is kind of like crying wolf. How long until the public says: “Oh, geneticists, bah, they promised to cure my cancer and let me grow wings and have a dog-opus and make me not fat. I didn’t get none of that. And now scientists are asking for more money? Screw em.”

The human genome gives us a blueprint. Nothing more and nothing less. And don’t get me wrong. That is huge. But it is not the finished product. You can’t sit down and fly a jet, just because you have the blueprints. Hell, you can’t even necessarily build a jet just because you have the blueprints. But it is a vital step, and a really solid start. The problem is that “the failed promise of genomics” is really a misnomer. Because genomics never made these promises (well…perhaps we should say that it never made these promises outside of over-enthusiastic grant proposals). The media made promises for it, and the public becomes disappointed and disillusioned with the field when scientists can’t deliver on promises they never made in the first place. And without the support and funding of the public, science is going to fall flat.