Pushing boundaries

I have a soft spot for men who are willing to throw themselves out of balloons (I professed my undying love for Joseph Kittinger in my Day at the Science Museum post). There were a couple of things that impressed me most about the recent Baumgartner records:

1. He found himself in an out-of-control spin and pulled himself out of it. What amazing presence of mind and calmness under pressure.

2. He broke the sound barrier and highest freefall records. Definitely cool.

3. He didn't hit a bird. At least none that we know of.

4. He captured the imagination of the entire world. Eight million people watched his stream on youtube.

We can't help it, we all love people who push boundaries. Have you looked at the X prizes lately? They're super cool. The X prizes are a series of multi-million dollar competitions designed to push boundaries. They have prizes for putting robots on the moon (governments need not apply), sequencing genomes with incredible speed and accuracy, and cleaning up disatrous oil spills in oceans and seas. They try to identify "Grand Challenges" and design prizes to spur innovation and development in these areas. Go on, take a look. Maybe you should enter!

The Old Man and the G (G to A transistion, that is)

When I was a kid, my dad used to make the same joke every time my mom's birthday came around. "Twenty-nine again, eh?" he'd say. We'd laugh a bit at my mom's expense, but at that age I didn't really understand why adults, particularly women, cared so much about their age. Women dye their hair and buy "rejuvenating" creams. Female models over 30 are relegated to Dove ads. Men, on the other hand, compare themselves to fine wines. The Bernie Ecclestones of the world outnumber the Duchesses of Alba.

Much of this underscores the importance of maternal age on fetal health. Pregnant women over the age of 35 are routinely screened for chromosomal abnormalities in their fetuses. Meiosis, the process through which oocytes (eggs) and sperm are generated, is very different in men and women. Men produce sperm on-the-go from germ cells with a virtually unlimited production capacity. Those germ cells spring into action whenever they're needed, and men can produce viable sperm from puberty 'til death. Women's germ cells are already half-way to being oocytes (eggs) by the time they're born. Women don't have an unlimited capacity to produce oocytes because their germ cells don't self-renew. Biology can be a bit quirky, and oogenesis is a particularly odd example. The partially mature oocytes in a newborn baby girl are stuck half-way through a cell division, with their chromosomes aligned in the centre of the cell. One of the problems with this is that large chromosomal abnormalities, such as those seen in Down syndrome, can occur more easily when the DNA is coiled and lined up side-by-side for a long time. The only place I can think of where this happens is in oocytes. The longer the cells remain with their DNA lined up ready for division, the greater the chance that things will go wrong when meiosis resumes. Hence the routine screening for women over 35. When things go wrong they go really wrong, with big chunks of one chromosome getting stuck on another chromosome. You don't need to look very closely at the DNA to see the abnormalities. You need a microscope, but not a DNA sequencer.

So women have all their oocytes with them when they're born and they don't produce any more. But sperm production is ongoing, and it relies on continued cell division in the adult. Each cell division carries its own risks. DNA must be reliably copied, checked for mutations, packaged and sent off to make a new cell. Since most mutations occur during DNA replication, every cell division presents an opportunity for mutations to arise. Sperm are no exception. Recent work on Icelandic parent-offspring trios (mom, dad, baby) shows that the number of new mutations in a baby is strongly correlated with the age of the father at the time of conception. The age of the mother has no detectable impact. The child of a 20-year-old father has an average of 25 mutations, while the child of a 40-year-old father has about 65. That translates to about 2 additional mutations for each year of paternal age. The number of mutations doubles every 16.5 years, and is surprisingly linear. Many mutations have no obvious consequences, but others can give rise to diseases ranging from autism to cancer predisposition syndromes. Many diseases, particularly those associated with impaired brain function such as autism, schizophrenia, dyslexia and reduced intelligence are caused by multiple mutations working together and are associated with paternal age. Increased paternal age increases the probability of having enough mutations to make a difference in a child's overall health.

A French teacher of mine had an amusing way to remember the gender of disaster words. Un probleme, c'est masculine. To really make a mess you need the feminine: une catastrophe. The same idea seems to apply to DNA. Massive damage to the DNA comes from ageing mothers, while ageing fathers provide multiple smaller problems. Catastrophic DNA damage rarely makes it into viable babies; they don't usually make it past the first few weeks of a pregnancy. A fetus with a collection of DNA "problems" is much more likely to make it through gestation. So next time your charming partner makes a crack about your age, you can do what my mom used to do and tell him to put a cork in it. Even fine wine ages poorly without one. And you might need to double your order of hair dye.

The rise of scientific activism

A couple of weeks ago I heard Mark Henderson speak about his new book, the Geek Manifesto. He has recently been appointed Head of Communications at the Wellcome Trust, but was previously the science editor for the Times. Henderson's central thesis is that science should play a bigger role in politics, and that those of us who are scientifically-minded should become more political to ensure this. We should be writing to our MPs to push the scientific agenda. Scientific process should be used to determine policy. The scientific consensus should be presented as "expert evidence", and ill-informed and incorrect science should not. He proposes the establishment of an Office for Scientific Responsibility, an independent body which would hold MPs to account for their assurances of scientific evidence in the House of Commons.

I've never written a letter to an MP. Even after hearing Mark speak I don't plan to. I think there are better ways to push a scientific agenda, many of which have been growing in the last decade. Henderson complains that  only 1 in 650 MPs has a scientific background. But what he doesn't mention is that the House of Lords is a different story. Of the 825 peers, about 700 are there because of their achievements outside the House. This includes accomplished medics and scientists along with the expected collection of lawyers, politicians and business-people. Many Lords are crossbenchers, and therefore do not expressly support any political party. The Lords, like the House of Commons, has a Science and Technology Committee. Unlike the House of Commons committee the Lords committee contains distinguished lecturers and scientific minds, including John Krebs (a zoologist), Alec Broers (an engineer), Narendra Patel (an obstetrician), and Martin John Rees (president of the Royal Society). I'm against Lords reform for precisely this reason. I want people like this to look at every bill and decide if it passes muster before being passed into law. MPs are often chest-thumping, highly politicized line-toers, but the Lords are not. They are the measured voice of reason. The Lords is full of smart people who have genuine political power. Let's keep it that way.

The government also gets scientific advice from independent science advisers. Last week Radio 4 had an interview with Robert May, the Chief Scientific Adviser to the UK government from 1995-2000. He's exactly the kind of person we, as scientists, want to have an influence on politics. I've written about some of his work in a previous post, but his contributions to the fields of ecology, mathematics, and theoretical physics are outstanding. His job as Chief Scientific Adviser was, in his own words, to "speak truth to power". He advised the government through the first death from variant CJD, the human disease caused by the prions found in cows with BSE. He then advised the government through the public uprising against genetically modified foods. Since the GM debate took off shortly after the first CJD death, I don't think GM ever had much of a chance in the UK. People were just too worried that their food was going to kill them. But during his time there he set up a protocol for giving scientific advice to the government. When something important comes along, the government should seek the best scientists in that field to give advice. They should deliberately include dissenting voices. They should do it in the open, and they should emphasize the uncertainties. That protocol was excellent advice from an outstanding scientist. By the way, he's also a Lord.

Perhaps due to issues such as BSE and GM crops, scientific activism and public engagement in science is on the rise. The "lay summary" required by virtually all granting bodies is becoming more and more important. In the last month, scientists protested against the "death of British science" in a rather over-the-top and uncharacteristically childish march to Downing Street. I don't think it was particularly productive and I don't support these types of protests, but I do think it's a sign that scientists are getting more political. More importantly, anti-science protesters who were trying to dig up an important GM research site at Rothamsted were stopped by a bunch of pro-science protectors. The Rothamsted site is purely a research site, not a commercial site. It has been measuring the effects of agriculture since 1843, and is therefore one of the longest running agricultural and environmental experiments in existence. The scientists' appeal to the protesters on youtube has over 30,000 hits. Organizations like Sense about Science, which provides scientific advice to anyone who's looking for it, are one of our best tools in the pro-scientific movement. They are independent and respected, and look for ways to expand public understanding through targeted campaigns as well as by answering individual questions. Scientists should support them. They provide a means for us to promote libel reform, engage with protesters in a productive way, and ensure our voices get heard. Organizations with strong public support such as the Royal Society, the Medical Research Council, and the Wellcome Trust should follow their example.  And we should all get behind them.

The mind-robot connection

I admit it, I cry sometimes when I watch movies. But this is the first time a movie in the supplemental figures of a paper has brought tears to my eyes. This video shows a tetraplegic woman using a robotic arm controlled by an implant in her brain to lift her coffee and take a sip for the first time in 15 years. The smile on her face at the end is amazing.

It's an outstanding medical achievement, too. The researchers implanted microelectrodes in the motor cortex of two patients rendered tetraplegic and anarthric (could not speak) as a result of a brainstem stroke. They then asked the patients to imagine moving objects, and looked to see which motor cortex cells were activated. This information was used in the next trial, where the patients controlled a robotic arm with their minds and used it to grasp balls in 3-dimensional space. That was an immense achievement, and is the focus of the paper. But what really got me was the idea of giving this woman, who has been unable to physically control her environment for 15 years, a touch of independence. What an accomplishment for the researchers and their subject alike.

http://www.nature.com/nature/journal/v485/n7398/extref/nature11076-s5.mov

For those of you without Nature subscriptions, you can watch a shortened version of it here:

http://www.nature.com/news/mind-controlled-robot-arms-show-promise-1.10652

How we hear

More stories for Cosmos- how turning your head can cause you to lose "streams" of sounds (like conversations). http://www.cosmosmagazine.com/news/5527/hearing-readjusts-after-head-movements

Let them eat mud

The hygiene hypothesis has always appealed to me. I like dirt. I like playing in dirt. I’ll believe just about anything that gives me a good reason to do something that feels a bit naughty. I love the concept of “good fat”. I’m sure ice cream is full of it (although I make a point of never checking).

The hygiene hypothesis states that children need exposure to infectious agents early in life to ensure the normal development of their immune systems, and that without this exposure they will become atopic. Atopy refers to the inappropriate activation of the immune system that can cause allergies, eczema, and asthma. The hygiene hypothesis was originally proposed to explain why children from larger families have fewer allergies. The theory is that children from large families are exposed to more infectious agents through their siblings, and these good and necessary immune stimulations prevent the bad and unneccesary immune stimulations later in life known as allergies. It’s as though the immune system gets bored if it has nothing to do and starts attacking anything it can get its dirty little hands on. Get a few more colds as a kid and you won’t have allergies. Let your kids play in the dirt. Sounds like a good idea. Given my partner’s family history of allergies and my daughter’s infantile eczema and milk sensitivities, I particularly liked the idea of pro-actively preventing future allergies in my children. I’ve never actually looked into the science of it, and it’s about time.

The immune system is fascinating and dynamic. It is comprised of T cells, B cells, macrophages and a few others. The B cells produce antibodies. The macrophages eat things like parasites, bacteria and viruses. The T cells just help. They recognize the infection and can either help the macrophages (in what’s known as a Th1 response) or the B cells (Th2 response). Allergies are all Th2 since they involve the production of IgE from B cells, which then causes histamine release from mast cells (mast cells fall into my broad category of “other” immune cells).

Evidence for the hygiene hypothesis comes from 2 sources: epidemiology and mouse experiments. There are a number of interesting mouse models of atopic diseases. A few weeks ago, a paper in Science argued that mice raised in a germ-free environment were more prone to allergic asthma. Exposure to germs as a newborn could reverse this, while exposure during adulthood did little. The mouse evidence is quite nice, and definitely supports the hygiene hypothesis.

Epidemiology doesn’t establish causes, but it’s about the only way to find correlations in human populations. Epidemiology showed us the correlation between smoking and lung cancer. It can produce powerful information. The epidemiological data supporting the hygiene hypothesis are as follows:

1. Children from large families are less likely to have hay fever and eczema

2. Allergies and asthma have been increasing dramatically in developed countries in recent decades, where hygiene standards have also been improving

There are a couple of glaring issues with the epidemiological data. Asthma can have a variety of underlying pathologies and is more like a bunch of different diseases which all look the same. Some types of asthma are immune-related, some are not. It’s about a 50:50 split. Changes in the incidence of asthma are therefore inaccurate indicators of atopy. Furthermore, the incidence of asthma in the developed world is now on the decline (with the notable exception of inner-city African Americans). Despite the popularity of the hygiene hypothesis, I don’t think we’re any dirtier than we were 10 years ago. Given the number of handbag-sized hand sanitizers on offer at my local drugstore, it might be the opposite. A recent world-wide WHO study showed a U-shaped relationship between GDP and asthma, further undermining the hygiene hypothesis as an explanation for increasing asthma in developed countries. The poorest and the richest countries tend to have more asthma and wheezing than those in the middle. Even if we take asthma out of the picture altogether, the evidence for increasing atopy of any kind in the developed world is unclear. Some countries are experiencing declines, others are not. The epidemiological evidence for the hygiene hypothesis is sketchy at best, even though the hypothesis originated there.

In its original form the hygiene hypothesis argued that Th1 responses early in life (the macrophage-stimulating ones) could prevent subsequent inappropriate Th2 responses (the antibody-producing ones). But there’s a bit of an adaptation of that original hypothesis that seems to hold more weight. It’s not as much about exposure to infectious agents as it is about repeated, low-dose exposure to the allergens themselves. It’s more about inducing tolerance than it is about immune-skewing. Epidemiology can help here, too. Farming and early exposure to pets are associated with lower incidences of allergies and asthma, and that data is relatively robust. Recent allergy-prevention strategies involve low-dose shots of allergen in an attempt to induce immune tolerance. They don’t cause disease and they don’t induce immune responses.

Perhaps the hygiene hypothesis should be renamed. I’m not convinced that my kids need to come into contact with every infectious agent that causes the outpouring of fluids from noses, mouths and bums, but I’m glad to see that there is some evidence that letting them play in the mud and pet strange dogs might help them avoid future allergies. And if current allergy-prevention strategies are a good indicator, perhaps low-dose exposures even as an adult can induce tolerance. Yay for dirt.

Will the Y chromosome disappear completely? Take a look at my recent article for Cosmos magazine: http://www.cosmosmagazine.com/news/5328/extinction-men-put-hold

Go on, take a shot

A mathematical model suggests NBA players should be shooting earlier

Depending on which side of the Atlantic you call home, basketball is either riveting or coma-inducing. Basketball players are both athletes and actors. For sports enthusiasts, much of the excitement comes from waiting for the right scoring opportunity to arise. But a recent study suggests that NBA players may be waiting too long before shooting, and that shooting earlier could add about 4.5 points per game.

For mathematicians, the high scores and frequent shots found on basketball scoresheets give robust data sets. With only 5 players per team and a limited playbook, the interactions between players can be examined using classic models such as game theory. Most sports require quick decisions, and the results of those choices determine the score at the end of the game.

Shot-selection in basketball falls under the broad category of “optimal stopping problems”, the most famous of which is the so-called secretary problem. In the secretary problem, an administrator wishes to hire the best secretary out of n applicants. The applicants are interviewed one-by-one, in random order, and the outcome of the interview is determined immediately. Each applicant can therefore only be ranked relative to those already interviewed. How can the administrator maximize the probability of selecting the best candidate? The secretary problem has a surprisingly simple solution. The best strategy is to interview about 1/3 of the candidates (n/e, to be more precise), reject all of them and then offer the job to the first applicant after that who is better than the unlucky 1/3.

Deciding when to shoot the basketball presents a similar problem, but the solution is more complicated. By shooting early, a team forfeits any shots that would have arisen later in that possession. On the other hand, teams waiting too long pass up opportunities and instead take low-percentage shots in the dying seconds. Brian Skinner of the University of Minnesota constructed a model of the “shoot or pass up the shot” decision. In his model, the optimum time to shoot depends on three factors: the probability that a shot will go in, the distribution of shot quality that the offense will generate in the future, and the time remaining (the NBA allows each team 24 seconds before they have to either take a shot or surrender the ball). The resulting model states, unsurprisingly, that only high-quality shots should be taken early, and that the cut-off for shot quality decreases as the clock ticks down. But NBA players seem to take this too far; with 15 seconds left on the clock, the optimal model predicts about 3 times more shots than are actually taken. NBA players prefer to shoot in the dying seconds.

The model makes a number of assumptions, the most controversial of which is that shot opportunities arise randomly in time. It takes time for a team to set up its offence. Break-away plays may not use the same decision-making process, so shots from the first 7 seconds of ball possession were discounted. After 7 seconds, a team’s offence should be in place. In support of the assumption, there was little correlation in the NBA data between average shot time and the probability that a shot would score.

Under-shooting could be a sign of over-confidence. Players may be unwilling to take moderate-quality shots early in their possession, believing they’ll generate better scoring opportunities in the near future. They may also be underestimating the probability of a turnover and therefore overestimating the time remaining. This model advises ‘ballers to do less acting and more shooting. After all, smug grins are best worn by winning teams.