The ultimate guinea pig, or “What’s in 168 genes?”

This is about humans. And animals. And experiments. It’s not about “animal experiments” as such; that’s a whole separate kettle of party that we’ll save for another fish. It’s about remembering the uniqueness of the human organism – as compared to, say, mice. Or fish. Or kettles. It is inspired by a talk that I heard last week, given by the pugnacious, mischievous and frequently hilarious Pasko Rakic. The man is something of a rockstar in the world of brain evolution and he argued with great conviction that the human brain, in particular, is irrefutably unique and deserves specific, careful scientific attention. I’ll try to give a snapshot of his evidence and a smattering of my own thoughts.

Humans are special.

The big grandaddy of modern biology Charles Darwin said in The Descent of Man that ‘there is no fundamental difference in man and the higher mammals in their mental functions’. He explored all sorts of ways that animals interact and communicate their emotions, and compared them favourably to human behaviours. (Famously, he drew a great deal of inspiration from watching his own children play and develop.) The dominance of this idea, together with the reliance of modern biology on animal models, has led to what Rakic poses as a ‘fascination with similarity’ and ‘neglect of difference’ between us and our  fellow mammals. Remember the kerfuffle when the human genome sequencers revealed our rather humble entry in the “most genes on earth” competition? Furthermore, only 168 of those paltry 30,000-ish genes are uniquely ours (‘It was published in Science,’ quips Rakic, ‘so it must be true.’) Thus, to proclaim the uniqueness of humans has become anti-Darwinian – a veritable scientific heresy. I share some of Rakic’s sentiment here; Darwin had a blindingly sharp mind and a truly wonderful way with words (please, please read the last paragraph of Origin if you never have!) but the way he is sometimes deified by my fellow scientists can be unsettling. I am a total fanboy too – don’t get me wrong – but we shouldn’t let our own scientific thinking be clouded by our reverence for the man and his massive contribution to how we understand the world.

In particular, the human brain has some pretty damn singular characteristics. In just a few million years, which is really evolution at full throttle, it has more than tripled in size and crumpled inside its container to form what T.H. Huxley called ‘a perfect labyrinth of tortuous foldings’. It also has some pretty distinctive thinking-and-talking capabilities that we could think and talk about for hours. There are even some unusual types of brain cell that are only found in us man-apes; Rakic himself described one of them thirty years ago and he laments that nobody else picked up on it until just this year – this, he says, is a symptom of the humans-are-just-mammals malaise.

What a mess. This was flat, before evolution screwed it up...

According to Rakic, studying the uniqueness of humans should be ‘no more controversial than the special properties of ants’. Sounds perfectly natural, doesn’t it? Perhaps he is overstating the scale of the pro-Darwinian dogma. But then Professor Rakic has watched scientific trends come and go during his long career, and he tells an interesting story from 2002. His lab submitted a paper to Nature about how inhibitory neurons are generated during the early development of the human cortex. They received a reply along the lines of ‘We like the findings but we don’t publish human work.’ (Those are my italics. Italics of incredulity.) When Rakic complained, the editors said they would send the paper out for re-review. Rakic: ‘But the only reason you rejected it was my choice of species!’  Nature: ‘Oh, well, OK then.’ Voilá – Nature paper. Well, I’m paraphrasing. But you get the point.

Nevertheless, even if the prejudice against human studies has been as strong as Rakic suggests, I think he undersells the importance of animal models. Although both post mortem and embryonic human brain tissue are available, with varying levels of complication, there is a big gap in the middle. And there are some things you just can’t find out using human subjects – even the cash-starved undergraduates who dominate the subject pool of so many experiments! The well-known story of Barry Marshall drinking helicobacter to confirm that it caused stomach ulcers is inspiring and brilliant, but when you’re a neuroscientist self-experimentation is somewhat less feasible. (And before you ask, swallowing a drug cabinet full of ketamine doesn’t count.) Furthermore, there are at least two categories of animal experiment that I really see no way around; firstly, novel therapies, from deep brain stimulation to the pill, simply have to be tried on something that’s not a patient before they can be whisked into the clinic. The second category is those experiments that look at the fine detail of biological functions – eg. brain circuits – and which require the sort of access that you really can’t expect from human subjects. Nearly everything we know (which is an awful lot but also almost nothing) about how brain cells alter their connections to form memories, comes from experiments that use garden-fresh slices of rat or mouse brain, in which the cells are still alive and can be manipulated and recorded from. No matter how much you pay an undergraduate research subject, you can’t really pack him or her off to afternoon lectures with one cerebral hemisphere left behind in slivers.

Rakic, of course, is not arguing that animal experiments are pointless. But there are certainly limitations to these methods, and he is right to emphasise the difference rather than the similarity between, say, mice and men. The thrust of scientific thought in the era of molecular biology, together with the preoccupations of the big journals, has too often swung the other way. It is certainly food for thought for scientists like me, who out of necessity study ‘smaller, cuter humans’ (a quote from a yeast geneticist, Rakic says with glee, to whom ‘all mammals are the same’). Those 168 genes – along with, of course, all the epigenetic frippery and non-coding shenanigans that I haven’t even touched on here – have done themselves proud. Humans are a piece of work, and no mistake.

[The talk I’ve drawn from above was part of a Royal Society meeting on ‘Computation, Cognition and Consicousness’ which I hitch-hiked along to with fellow alert-nerd Joe. Stay tuned for his post about Henry Markram’s blue brain business - coming soon to the Weekly Wrangle!]

by jonathan