Stripping Down Science (12 page)

All in the mind, mind over matter, push through the pain, high pain threshold, no pain no gain.
Ask a muscle man, marathon runner or even a woman in labour what pain is all about and they'll often answer ‘willpower'. But now a family of feted firewalkers, impalers and stunt daredevils – who can't feel pain at all – have revealed to researchers that pain is as much down to DNA as it is to mental fortitude.

Cambridge-based scientist Geoff Woods
³⁷
was in Pakistan when he first heard about several families who appeared to be able to weather pain with impunity. To entertain their friends, for instance, affected children would go as far as to jump off roofs or even plunge their hands into boiling liquids, often sustaining horrible injuries in the process, but without apparent concern. The reason? Despite being neurologically otherwise normal, these individuals could not tell when something should be painful. They could tell hot from cold and smooth from rough, they were ticklish and they enjoyed curry, although in the
latter case it didn't burn them in the same way that it would a normal person.

Attractive as a pain-free existence sounds, it's actually bad news because, as the affected individuals sadly showed, not being able to experience pain means you can't always tell when you're doing real harm to yourself, inadvertently or otherwise. More unfortunate still, some might argue, the affect does not extend to numbing the excruciating sound of James Blunt.

However, there is a plus side, at least genetically speaking, because the bizarre all-over anaesthesic affect manifest amongst the members of these Pakistani families was found to be passing directly from parents to offspring. This sent a molecular-biological shiver down Woods' spine, because he realised that it meant it could be down to a single dodgy gene. Finding this gene might therefore unlock some of the secrets of ‘nociception', including new ways to hit pain harder where it hurts.

Using DNA samples collected from six of the Pakistani family members, and comparing affected with unaffected individuals, Woods and a team of researchers performed the genetic equivalent of combing through a genome-sized
haystack to find a very small needle. Their endeavours were rewarded when they successfully homed in on a region of chromosome number two that contained the genetic cause of the Pakistani families' insensitivity to agony. The gene they uncovered is called SCN9A. Normally it codes for a channel, resembling a tiny pore, which allows sodium to enter and excite pain-signalling nerve cells in response to painful experiences. Among members of the affected families, however, the gene contained a mutation that prevented it from functioning correctly. As a result, their nerve cells were effectively deaf to the screams of painful events going on around them.

The story doesn't end there, because then the team began to wonder whether other forms of the gene might exist, accounting for why some people are more stoical than others. And, thanks to a bunch of people with backache, the answer, it appears, is yes! The researchers discovered this
³⁸
by comparing the pain scores reported by 578 arthritis patients with the severity of their disease as it appeared in X-rays of their joints. Some patients, the team found, were reporting much more pain than others, despite having
arthritis of a similar severity. To find out why, they matched up the patients' pain scores with the DNA sequences of their SCN9A genes. This led the team to identify two variants of the gene in the patients, a rarer A form and a more common G form. On average, they found patients carrying the A variant tended to report more severe pain than patients carrying the G form of the gene.

To confirm the findings, the researchers repeated the study on 179 patients with lumbar back pain, with similar results. They also subjected a group of female volunteers to a range of painful stimuli, again demonstrating that individuals carrying the A form of the gene were more pain-sensitive. To find out why this genetic variation was having this effect, they then expressed the SCN9A gene in cultured HEK293 cells, which have nerve-like properties. In these cells the A and G forms of the gene had subtly different electrical effects, sufficient to explain the increased sensitivity of carriers of the A form to painful stimuli.

So it seems that sensitivity to pain, and an individual's threshold for recourse to the pill packet, is as much under genetic influence as it is an exercise in tough-mindedness! More seriously, as
and his colleagues point out, understanding how to modify the functions of genes like SCN9A will lead to better analgesics with fewer side effects, as well as the identification of those who have more specific painkilling requirements.

FACT BOX

Other ways genes can provoke a deleterious lifestyle

As well as determining physical fortitude and pain-sensitivity, the genes we carry are also instrumental in controlling behaviour, because they dictate how the brain develops and wires itself together. This means that now, thanks to the human genome project, scientists can begin to discover how different combinations of genes, and variations within individual genes themselves, can affect the kinds of lives we lead and to what diseases we're likely to succumb.

One area that is attracting a lot of interest is nicotine addiction. Apart from caffeine and alcohol, tobacco is one of the world's most popular
legal drugs, but it's also directly responsible, according to the World Health Organisation (WHO), for causing the premature deaths of up to five million people every year. Most of these deaths are from heart disease, as well as lung cancers, chronic bronchitis and emphysema.

Amongst the smoking population, some people appear to be far more genetically vulnerable to developing one or more of these disorders than others, and there are also individuals who are genetically more prone to become hooked on tobacco in the first place. But can we tell who these people are, so that we can warn them?

According to research being carried out at the University of Auckland by chest specialist Dr Rob Young and his colleagues,
³⁹
the answer is ‘yes, definitely'. To reach this verdict, they've been comparing the genetic make-up of large numbers of individuals who have smoked for many years yet have not developed any chest diseases, with a second group of patients with similar histories of tobacco exposure but who have developed chest problems. This
has enabled the researchers to home in on 19 different genes that together can be used to predict an individual's risk of developing a smoking-related disorder. This means that those at high risk could now be warned ahead of time – while their lungs are still healthy – to stop smoking before it's too late.

The evidence is that more than three-quarters of smokers want to kick the habit, but only about 5–10% are successful in any given year. Young hopes that removing some of the uncertainty from the situation and highlighting the risks might help to motivate quitters to be more successful. ‘We think that there are people out there who, given the information, might be prompted to be more proactive and engage in quitting activities with greater vigour and greater success, and there is data to support this.'

But what about getting hooked in the first place? Well, that's down to genes too. Jacqueline Vink, from VU University in Amsterdam,
⁴⁰
screened the DNA of 3500
people, including smokers, past-smokers and nonsmokers, to look for genetic sequences that cropped up more often amongst the smokers or previous smokers than nonsmokers.

A number of DNA hotspots emerged from the analysis, which she then checked in a further three groups of people containing about 400, 6000 and 1600 participants respectively. The result was the identification of a clutch of genes that had never previously been linked to smoking, which included receptors for the excitatory nerve transmitter chemical glutamate, genes that control the transport of chemicals into nerve cells and genes encoding adhesion molecules to help cells to link together. The motivation for carrying out the study was straightforward: ‘Identification of genes underlying the vulnerability to smoking might help identify more effective prevention strategies and thus diminish smoking-related morbidity.'

That said, according to Mark Twain, ‘To stop smoking is the easiest thing I ever did. I ought to know; I've done it a thousand times.'

An urban legend, often bandied about, is that blood changes to a blue colour when oxygen is removed from it, so veins, which carry deoxygenated blood back to the heart, look blue beneath the skin.

The myth owes its origins to the Spanish upper classes who championed ‘
sangre azul
' (blue blood) as a sign of pure breeding. Their thinking worked along the lines that blue veins were only visible beneath the pale skin of someone with a bloodline untainted by the darker-skinned Moors, who had controlled large parts of the country in years gone by. Unfortunately, the expression has since led to some serious scientific disinformation.

Blood is a rich red colour because it contains haemoglobin, a protein which carries oxygen from the lungs to the tissues. Haemoglobin is actually four proteins stuck together, known as a tetramer, comprising two alpha-haemoglobin and two beta-haemoglobin molecules, each with an iron atom at the centre. It is this iron which
gives haemoglobin its colour. Each molecule of haemoglobin can bind four molecules of oxygen, and when the oxygen unites with the haemoglobin it changes its shape and its light absorbency so that it reflects relatively more red light. So oxygen-rich blood in arteries, on its way to our tissues, looks much redder than venous blood.

In hospital, doctors sometimes collect arterial blood samples to see how much oxygen is present and hence how well the lungs are working. In a well-oxygenated person the blood is a bright brick red. If the person is very short of oxygen, or if you miss the artery and instead collect the sample from an adjacent vein, the blood appears much darker and is a red-black maroon colour … but still, not blue. So while it seems reasonable to assume that the colour of veins is partly down to the colour of blood they contain, that's not the whole story. The give away is that superficial veins (those just below the skin surface) don't look blue at all. Anyone with ‘thread veins' on their legs or face knows only too well that they are red. So what's going on?

Some light was shed on this problem in recent years by Alwin Kienle at the Institut fur Lasertechnologien in der Medizin, in Ulm,
Germany.
⁴¹
He set up a model vein comprising a blood-filled tube suspended in a milky solution designed to mimic the optical properties of the skin. By moving the blood vessel up and down in the solution, to simulate deeper or more superficial veins, it was possible to measure the different wavelengths of light being reflected and hence work out why deeper vessels look blue. Sure enough, when he immersed his surrogate vessel at greater depths, it ceased to appear red and instead took on a blue hue without actually changing colour at all.

The reason for this colourful conundrum, Kienle found, is due to a combination of the way the brain decodes colours, together with the fact that different tissues absorb some wavelengths (colours) of light more than others. In general, blue light penetrates into the skin much less well than red light. So if a vein is near the surface of the skin, as in a thread vein, almost all of the blue light hitting the tissue is going to be absorbed. This means that relatively more red light will be reflected back, making the vein look red overall.

So far so good. But what about a deeper-situated
vessel? This, Alwin Kienle found, is where the way that the brain processes colour comes in. Even though red light penetrates further through skin than blue light, for veins sited more deeply within the skin the amount of red light reaching them begins to dwindle. At the same time, the deoxygenated blood they contain soaks up some more of the incoming red light, which is why venous blood is a darker red. This means that light coming back from the vein is slightly less red – in fact, it's a bit more purple – than light reflected back from the tissues adjacent to the vein. Because the brain processes colours in a relative way, if something purple is viewed next to something red, it ends up looking blue, hence the illusion and the myth.

Despite blue blood being a myth for humans, for some animals, including lobsters, crabs, shrimps and other crustacea, it's a reality. The reason for the colour change is that these creatures use copper, instead of iron, in their equivalent of haemoglobin, which is a protein called haemocyanin. For them, blood is blue when it is oxygenated and gradually loses its colour as the oxygen is removed. But the real hippies of the haemoglobin world are definitely
the brachiopods, sipunculids, priapulids and magelona (a type of worm). These animals have a blood pigment called hemerythrin, which is a bright violet pink when it's charged up with oxygen.