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Entries in genetics (7)


If birds are baby dinosaurs and humans are baby apes...

A recent publication in Nature suggests that in many ways, birds are baby dinosaurs. The finding is less unusual than it might seem, afterall it is well established that humans have many traits of baby apes and dogs are in some ways baby wolves. The process is known as paedomorphosis or neoteny - the retention of juvenile traits in the adult form. This can take the form of enlarged eyes (birds), larger brains (humans) or retention of juvenile behaviour (dogs).

The reason why paedomorphosis works is that the basic body plan has much deeper evolutionary roots than the species-specific add-ons. Think of it this way, all mammals pretty much have the genetic program to make a nose, but only the elephant has evolved an additional genetic plan to turn that nose into a trunk. Deep in the genetic code of the elephant there is still the "standard nose" code (and indeed, the foetus has a relatively normal nose), it just has added lines of code that upgrade the standard nose into a trunk. This means that in theory, the elephant could evolve away from the trunk by just ditching the upgrade code, letting it default into the standard nose code. This is true for most of development - new code is never optimally created for the organ, rather it is always adding a bit of extra code to change the outcome. For a software engineer it would be the hight of laziness, creating bloated useless code, with every problem solved by kludge

Despite being inefficient and inelegant, the system of "generic code" plus "species specific" is very useful for evolution. This is because species evolve to be adapted to a specific environment. The flamingo beak is fantastic for a filter-feeder, but it has lost the generic functions that a sparrow could use its beak for.

Imagine an island with brine lakes that is populated only by flamingoes. If those brine lakes dried up, the flamingoes would go extinct. But what if new niches opened up? The ordinary "forward" process of evolving a generalist beak is quite slow, because you need to generate new code, but the "backwards" process of paedomorphosis could be quite fast, because it is just the process of deleting the species-specific code, defaulting back to the generic beak (as in anything else, destruction is faster and easier than generation). It is not difficult to imagine a relatively small set of genetic deletions that would mean the adult flamingo retained the juvenile generic beak, and then these "de-evolved" generalist birds could take advantage of the new habitat, and indeed start to evolve specific changes to specialise towards that new habitat.

As a general rule, following a large change in the environment, the generalised (juvenile) body plan is probably going to be more successful than the specialised (adult) body plan. Paedomorphosis in effect provides a default option to revert to in case of catastrophic change, allowing a species to shed its specialised features and start again. One possibility that interests me is that an open niche may drive paedomorphosis by selecting for rapid population growth. Consider the drying up of Africa that occured 5 million years ago. All of the apes that were specialised to live in rainforest would have seen dramatic contraction of their habitat, leaving just a few thousand gorillas left today. But the drying also created a new niche, the savanna, which could be exploited by any ape that was able to adapt. Paedomorphosis probably played a role in human evolution, by shedding the arboreal features required to swing in trees, allowing the pre-humans to venture onto the savana. Now consider the first pre-humans that were suitable for the savana - they has a continent to spread across, with the only limitation being the reproduction rate. We already know that a truly open niche creates an evolutionary pressure to fill it - such as the natural selection of cane toads in Australia with longer legs simply because they can move faster into virgin territory. What if this put selection on humans to reproduce at a younger age? Any variants that became fertile younger (and thus, while still carrying juvenile features) would outcompete the others, creating a population shift. In effect, there would be selection for paedomorphosis simply to increase the reproduction rate, with the retention of other juvenile traits (such as a larger brain) being a side-effect. 

If this model it correct, it would mean that open niches would drive paedomorphosis via two mechanisms - by selecting for the retention of juvenile traits to give a more generalist body plan, and by selecting for sexual maturity at a younger age to give more rapid reproduction. This dual selection force would drive much more rapid evolution, and may be responsible for some of the most remarkable evolutionary shifts, including the evolution of humans. 


New Year's Resolution Myth: Being Fat is not about having low Will Power

It is New Years Day, and around the world millions of over-weight people are making the resolution to lose weight. Popular culture harasses us with the myth that our weight is caused by our weak will power, if only we would eat less and exercise more then we would be skinny and beautiful like the good people.

The good news to the overweight is that you are not fat because you have weak will power. Your will power is no different from that of anyone else. The despicable treatment you receive from society is scientifically and statistically not your fault. The bad news to you dieters is that the science is pretty clear: you have very little chance of having any long-term weight loss. About the best that a typical overweight person can hope to achieve is to work harder than everyone else to stop becoming more overweight.

So why is there this myth that being fat comes from having low will power? It comes from the discredited idea of the human body as a consistent machine, where food going in and output by exercise has the same effect on everyone. This is not true. Each person has a different response to food and a different response to exercise, and these responses dictate their "set-point" weight.

It is in your genes

Geneticists are able to directly measure the component of any trait that is genetic through comparing the shared variability in genetically identical twins versus "normal" (genetically different) twins. The advantage of this approach is that it is able to take into account the shared environmental influence from conception, and so measures the pure genetic component of any trait. A disease such as Multiple Sclerosis has a genetic component of around 25%, and is considered to be a genetic disease even through largely unknown environmental factors dictate ~75% of the risk. For weight, the genetic component is ~60%. So the difference between you and that super-model is 60% due to the genes you inherited.

If you are among the most obese, or have been obese from a very young age (under 10), then the genetic component of your obesity is often 100%. At these extremes many people have simple inheritable defects which will cause severe obesity, guaranteed. The best known examples of this are mutations in the leptin and leptin receptor genes. Leptin is a hormone that is secreted by fat cells after you eat and travels to the brain where it suppresses your appetite. People with mutations in leptin or the leptin receptor simply never feel "full" after eating, regardless of how much they eat they feel like they are starving. Resisting over-eating for an hour is heroic, for a day it is impossible. We can mutate the same genes in mice and see the 100% heritability of obesity. 

It is from your early childhood

So 60% of your weigh is programmed in your genes. Well, you can still control the other 40%, right? Wrong. Another 25% is the variability is set from the early childhood experience. That is 85% of the variability locked in by the time you can make your own food choices. To put that in context, the genetic component of height is 80%.

And when scientists say early childhood, they mean early. One of the most powerful influences over weight is maternal imprinting during foetal development. Obesity rates in the Netherlands are quite low, except among the cohort of people conceived during the Dutch Famine of 1944. In these people, the uterine environment reprogrammed their genes for famine mode, in a process known as epigenetics. This "epigenetic" modification does not change the sequence of the gene, but changes the function for the life-time of the individual, while being (mostly) reset in the next generation. The effect of the epigenetic change is that the person's metabolism is wired for famine for the rest of their life, always hording calories as fat. When a person conceived in famine then goes on to live in famine this is an advantage, but when there is a mismatch between the food availability of the mother and the food availability of the offspring, the epigenetic imprinting results in obesity. Experiments in rats show that this is not just a famine-related phenomenon - simply giving rats a normal diet during pregnancy predisposes the young to obesity if they have a high-fat diet after weaning. 

It is in your intestines

Another way your childhood environment programs your future weight is through changing the bacterial colonies that live in your gut. It has been shown that obese people and mice both have a higher proportion of Firmicute species bacteria compared to Bacteroidetes species bacteria in their gut. Firmicutes are much better at breaking down roughage into digestible food, so having more Firmicutes means you get more calories from the same amount of food. Experimentally, you can make a skinny mouse overweight simply by transferring gut bacteria into it from an obese mouse - nothing has changed about the diet or the genetics, but the mouse starts to put on weight. 

That last 15%...

Well, I can still control 15% of my weight, right? No. What the data says is that 15% of the variation in weight is controlled by adult environmental factors. So 15% of the difference between your weight and the average weight is affected by everything some from your diet, exercise, stress, smoking, infections and every other non-genetic influence you can think of. 

Despite this, overweight people can lose weight. Semi-starvation diets, strict exercise programs and surgical intervention can have an effect, and even quite dramatic changes in weight can occur. We should be clear though, this is not just a matter of adopting the lifestyle of a skinny person. For an obese person to lose weight they need to exercise much more than a skinny person and eat much less, and the whole time an obese person will feel hungrier and tireder, in fact demonstrating much more "will power" than a "naturally" skinny person. Again, this is scientific observation, based on measuring hormones levels rather than just asking people how hungry they are - obese people produce lower levels of leptin from the same meal, so chemically they feel the effects of starvation on a diet that naturally skinny people enjoy.

So weight loss can happen. But then something quite unexpected takes place - the weight starts to go back on, a kilo here and a kilo there until you are back to your own weight. This will happen despite having an identical lifestyle to a naturally skinny person. The reasons for this are complex, but it appears that being overweight leaves a permanent alteration on your body. If you do lose weight your body desperately attempts to put it back on. Hormonal changes mean you crave more food than someone naturally at your weight, by contrast your body becomes more efficient at scavenging calories so you need to eat 10% less than someone naturally at your same weight. How long does this effect last? Well, we don't really know, since the studies haven't gone out long enough. We do know that the effects last at least 6 years after you lose weight, and they may be permanent. A series of studies done on those rare few who manage to keep their weight down long-term show common characteristics: obsessive OCD-levels of calorie counting, constant feelings of hunger and permanent semi-starvation diets.

Your body has a natural weight 

The final verdict is that your body has a natural weight. The skinny person next to you has no right to look down their nose at you, your will-power is the equal to theirs, it is your body that is different. That is not to say you should just give up. If your body is prone to weight gain, just maintaining your current weight over the years is a major challenge, and losing 1-2 kg over the span of a year is a major achievement (and may be easier to maintain than large weight drops). These achievements will result in real health benefits so they are worth striving for, the problem is that they are psychologically unsatisfactory. To be fat, work hard all year to lose 1-2 kg that no one notices and still be seen as fat by your colleagues and friends is devastating. Overweight people need to spend more effort on their body than the naturally skinny, and still get derided for it. Unfortunately, we just need to suck it up, be mentally stronger than the skinny people who never had to fight their body, and battle to keep our weight down one kilo at a time. 

The light at the end of the tunnel

For those who are overweight today, we know there will be a life-long battle with no silver bullet. There is, however, a light at the end of the tunnel for future generations. The more we know about obesity the better we can limit it. People think that "genetic" means unchangeable, bar genetic engineering. This is not so. Any figure for genetic contribution is limited to the particular environment that the measurements were done in. So today 85% of our weight may be programmed through genes and early environment, but by changing the environment the genetic effect could be reduced or even eliminated. Particular additives that trigger cravings in people genetically prone to weight gain can be banned from common foods, removing the genetic effect. Early intervention programs could prevent the epigenetic reprogramming that leads to later weight gain. Think of it this way, a genetic susceptibility to alcoholism has a huge effect when alcohol is everywhere, but no effect if alcohol is absent. The same is true for our genetic programming to be overweight. Careful research and well-designed public health policies altering food regulation and activity levels could dramatically reduce the obesity levels in future generations. I, for one, sincerely hope that our children will not have to suffer through year after year of broken New Year's Resolutions.


Freemarketeers are not honest about what they oppose

I was listening today to a talk by Arthur Brooks, President of the right-wing think-tank the American Enterprise Institute, on his thesis that free enterprise brings happiness. His logic went something like this:


1) Above a threshold amount, where increased money brings happiness, additional money does not bring additional happiness

2) For people above this basic threshold, they may think that more money will bring them more happiness, but in reality it is other things that will bring happiness, such as career satisfaction

3) ?

4) Therefore, we need to lower taxes and stop regulating businesses


Point #1 and point #2 have actual research backing them up, but of course they do not lead to #4. How did Brooks managed to make this leap of faith? Well, he said that most Americans believe free enterprise is essential for a strong economy, and therefore it must be so (ignoring point #2, which explicity states that a vast majority of people can be wrong about a very simple thing). A strong economy, in turn, provides a chance for people to get career satisfaction (because nothing screams career satisfaction like a job at McDonalds), therefore - happiness. I will get to the happiness argument later, but as a start the economic argument is flawed. Both public and private spending stimulate the economy. The relative multiplier of public and private spending is greatly debating, largely because there is no clear advantage - some types of public and private spending have a large multiplier while other types have a small multiplier. Brooks assumes that the private multiplier is always greater than the public multiplier, this is just not true, and certainly is not true when it involves taxing at the very high income rates for people working in the financial section and then spending in areas such as construction, education and health. Brooks also assumes that jobs in the private sector have greater career satisfaction than jobs in the public sector, again with no evidence - just ask a Walmart greeter and a university professor how much career satisfaction they have. Yes, jobs are important to happiness, but Brooks does not make a convincing case that an unfettered and unregulated economy creates more high quality jobs than a regulated and protected economy.


Little fish should be happy with what they haveThen on the happiness front. Why does Brooks think government is so bad? Well, because it takes away a small amount of money from the rich (but Arthur, I thought we agreed that excess money does not drive happiness?), and then gives it to the poor - who won't get any enjoyment from it (ah! so taking money away from the rich makes them unhappy, but giving it to the poor does not make them happy). In other words, he makes the mistake that so many free marketeers make (often on purpose) - he thinks that income redistribution is just giving cash to the poor, and therefore worries that it won't create happiness.


That is not the point nor the policy of progressive income redistribution. Good progressive policy does not just tax the rich and then give a cash grant to the poor. Yes, there is an element of cash transfer, such as through unemployment benefits. For anyone who cares to look at these things, the threshold at which extra money stops making you happier is around $75,000. As direct welfare checks are far far less than $75,000, there is every reason to believe that the cash transfer is creating a significant increase in happiness. If welfare checks were higher than $75,000, well, then Brooks might have a point, but they are not. More importantly, income redistribution is far more than a cash payment. Progressive income redistribution focuses more on supplying universal services (which disproportionally aid the poor, who would not otherwise have access). These universal services are things like funding civic societies, education, health care, libraries, public infrastructure and so forth. Progressive policy is also about providing minimum standards of living, both in work (minimum vacation days, protection against unfair dismissal, etc) and at home (minimum quality of air and water, etc). These are the exact parameters that are known to increase happiness - quality and quantity of leisure time, quality of the environment, health, reduced stress at work! Brooks ignores all of these factors, known to be linked to happiness, where progressive policy uses indirect income redistribution. If Brooks actually cared about total social happiness, he would support reducing the wealth of the rich (which does not decrease their personal happiness) and using it for social projects which increase the happiness of all.

Fine, Brooks gets paid to advertise right-wing economics, but this error is not unique to Brooks. The vast majority of freemarketeers that I read or listen to simplify progressive policy as simply a cash transfer, rather than the reality - progressive policy turns cash into services. Progressive policy takes in excess wealth (which does not create happiness) and uses it to fund the provision of services like health care, education and public transport (which do create happiness).


It was a waste of time to listen to Brooks, better by far to read The Spirit Level: Why Equality is Better for Everyone.


PS. Arthur Brooks, please never ever discuss genetics again, a "genetic component" does not mean what you think it does. The separated identical twin studies may have suggested that there is a genetic component to happiness, but they did not have the power to say that this component is 50%. And even if they did, one thing that every person who discusses genetics needs to remember is that the figure that comes out of these studies is only relevant to the particular population the study is done on, and the particular environment the study is done in. So even if you take the 50% figure uncritically, if it was collected in Minnesota in the 1970s it is only applicable in Minnesota in the 1970s. For example, imagine a powerful gene that is present in 10% of people and makes them socially quirky. If you had an environment where any deviation from the norm was socially punished, this gene would have an enormous effect over happiness of the 10%, such that the genetic component of happiness in the society is close to 100%. If, however, you then changed the society so that quirky was socially acceptable, this gene would stop having any impact over happiness, and the genetic component of happiness would drop to 0% - without any change in gene frequency or biology. "Genetic" does not mean "unchangable", it only means "unchangable in a set environment".


Juvenile Diabetes Research Foundation

Good news in funding appears to come in pairs. The Juvenile Diabetes Research Foundation is supporting the Autoimmune Genetics Laboratory through a Career Development Award. This is a grant that I am particularly happy to receive, not just for the science that will come out of it, but because I have been a long-time admirer of the JDRF, who tirelessly raise money for research on type 1 diabetes. They are not only the leading sponsor of type 1 diabetes research (spending over $1.4 billion on research since 1970), but also take an active role in coordinating researchers and integrating patient into trials to ensure that the best results come from the money spent. As a PhD student with Chris Goodnow, I always joined in the Walk for the Cure fundraiser, and JDRF sponsored my conference travel to the International Immunology Congress in 2004.

Now the JDRF is supporting our research project on the contribution of non-hematopoietic defects to autoimmune diabetes:

The Non-obese diabetic (NOD) mouse is one of the best studied models of common autoimmune disease in humans, with the spontaneous development of autoimmune diabetes. Similar to the way multiple autoimmune diseases run in families of diabetic patients, the NOD mouse strain is also susceptible to multiple autoimmune diseases, with specific disease development depending on slight alterations in the environment and genetics. These results demonstrate the complexity of autoimmune genetics – in both human families and inbred mouse strains there appear to be a subset of genetic loci that skew the immune system towards dysfunction and an additional subset of genetic loci that result in this immune damage affecting a particular target organ. In the case of NOD mice and type 1 diabetic patients these additional genetic factors result in damage to the beta islets of the pancreas. While the previous emphasis on type 1 diabetes was strictly on the immune system, this model suggests the important role the pancreas may play in the disease process. If certain individuals harbour genetic loci that increase the vulnerability of pancreatic islets to immune-mediated damage, the combination of immune and pancreatic loci could provoke a pathology not caused by either set of genes alone.

Current approaches to genetic mapping in both mice and humans are confounded by the large number of small gene associations and are not able to discriminate between these functional subsets of genetic loci. However, we have developed an alternative strategy for functional genetic mapping. Instead of mapping diabetes as the sole end-point, with small genetic contributions by multiple genes, we map discrete functional processes of diabetes development. This has three key advantages. Firstly, as simpler sub-traits there are fewer genes contributing, each with larger effects, making mapping to particular genes more feasible. Secondly, by mapping a functional process within diabetes we start out with functional information for every gene association we find. Thirdly, by mapping a series of functional processes and then building up this genetic information into diabetes as an overall result we gain a more comprehensive view of diabetes, as a network of genetic and environmental influences that cause disease by influencing multiple systems and processes.

In this project we propose to use the functional genetic mapping approach to probe the role of the pancreatic beta islets in the development of diabetes in the NOD mice. We have developed a transgenic model of islet-specific cellular stress which demonstrates that NOD mice have a genetic predisposition of increased vulnerability of the pancreatic islets to dying and hence the development of diabetes. This is a unique model to analyse the genetic, cellular and biochemical pathways that can be altered in the pancreas of diabetes-susceptible individuals, shedding light on the role the beta islets play in the development of disease.


The role of sex in evolution

Sex is a powerful force for evolution. On the face of it, sex seems like an absurdly complicated way to reproduce. Prokaryotic organisms, bacteria and archea, have a much faster a simpler system, where the cell simply duplicates its DNA and splits in half into two identical daughter cells. The entire process, called mitosis, only takes 20 minutes. This means that under ideal circumstances a single bacterium can divide to produce 8 offspring in the first hour. In the second hour that single precursor cell could form 64 offspring, after 6 hours a single cell could form over 200,000 daughter cells. This asexual reproduction is so efficient that it only operates at capacity for very short durations, as exponential growth of a single cell could use up the resources of an entire planet within days. Typically a bacterium ticks over slowly by scavenging what resources are available, only to explode into exponential asexual growth when new resources become available and a race to exploit them occurs.

Compare this to the elaborate, time-consuming and often bizarre process of eukaryotic sex, which multicellular organisms from plants to fungi to animals use to reproduce. Sex (and the accompanying mate selection) is one of the most difficult and dangerous parts of an individual’s life, and even passionate advocates of the activity find it difficult to explain. Yet through an evolutionary lens, sex provides very concrete advantages. The best illustration of the advantages of sex come from yeast mating, as these simple organisms are capable of both asexual and sexual reproduction.

Simple sex

Yeast can be thought of as being halfway between simple bacteria and complex multicellular organisms like humans. In terms of lifestyle and behaviour, yeast operate like bacteria – single celled organisms capable of an independent existence through the use of resources in their direct environment. Inside the cell, however, yeast are clearly eukaryotic organisms, with the same basic machinery for cell division, metabolism and survival as plants and animals. It is therefore convenient to think of yeast as essentially human-like cells, trapped in an early bacterial-like lifestyle. This is an oversimplification of course: bacteria, yeast and humans are all highly evolved organisms and none have remained static in evolutionary time, but it is a useful oversimplification.

So how do yeast reproduce? Asexually, like the bacteria they share a lifestyle with? Or sexually, like the multicellular organisms they are genetically closest to? The answer is both. When yeast are in a rich nutrient environment they reproduce asexually like bacteria. A single cell undergoes mitosis, duplicating its DNA and then splitting into two daughter cells, each identical to the parental cell. This gives the yeast all the advantages of bacterial reproduction – very simple rapid reproduction to win the race for abundant resources. The parental cell was successful in the environment, so the identical daughter cells should be equally successful and proliferate likewise.

However as noted above, exponential growth can never continue unabated, sooner rather than later resources become limiting or some other factor stresses the survival of the yeast. At this point yeast have a trick available that bacteria do not – sex. Instead of undergoing dormancy, the yeast mate.

In the best understood system, that of Saccharomyces cerevisiae, there are two sexes of yeast, a and a, controlled by a single gene. Mating is very simple, the a cells release a chemical called ‘a factor’ and produce a receptor that causes them to migrate towards the chemical ‘a factor’. By contrast, the a cells release a chemical called ‘a factor’ and produce a receptor that causes them to migrate towards the chemical ‘a factor’. The two yeast cells, one a and one a, attract each other and fuse into a single cell. This cell now has two different copies of the yeast genome, one from each parent.

The a-a fused yeast cell can now undergo a complicated cellular division process called meiosis. Unlike mitosis, where the cell duplicates its genome and divides in two, meiosis involves duplicating the genome and dividing in four. This is possible because the a-a fused yeast cell has two copies of the genome to start with, so duplication gives four copies, one for each of the four daughter cells that result.

The important difference between mitosis and meiosis is the splicing of two different genomes to form unique combinations. Mitosis just duplicates the existing genome. Meiosis starts with two different genomes, and during the duplication processes these genomes are jumbled up together, creating new combinations of old characteristics. This means that all four daughter cells at the end are unique and different from the original parental cells.

The advantage conferred by sex is very straight forward – the parental cells were not dealing well with the environment they were in, since yeast mating occurs only under stress. Therefore why reproduce more cells that cannot cope with the environment? Instead the yeast takes a life-or-death gamble that a combination of genetic information from another cell will produce offspring better able to deal with the environment. In a simple scenario there would be two yeast strains, one able to deal with acidity and one able to digest complex carbohydrates. A change in environment to a high acidity environment where the only resources available are complex carbohydrates will stress both parental strains. However, by sex there is a chance that one of the daughter cells will inherit the acid resistance of one parent and the ability to digest complex carbohydrates from the other parent. Other daughter cells will not be so lucky and will die, but that one daughter cell with the chance combination of two necessary characteristics will be able to divide asexually and rapidly reap the rewards of a new resource.

In one final complication, yeast can change sex. A single gene makes yeast either a or a, so after mating and meiosis the four daughter cells include two a cells and two a cells. If a single a cell is successful in the new environment, asexual reproduction creates exact copies, so all progeny will be a cells. This would create an obvious problem if a new environmental stress requires another round of mating, so yeast carry spare “silent” copies of a and a genes and use these backup copies to flip from one sex to another, to make sure a population is always a mixture of a and a yeast.


Infectious cancer

It has long been known that the several causes of cancer are infectious. Typically a virus contains a number of oncogenes to enhance its own proliferation, and in an infection gone wrong (for both virus and host) a viral oncogene is incorporated into the host DNA, creating an uncontrollable tumour cell. One of the best examples of this is human papillomavirus (HPV), a virus which infects most sexually active adults and is responsible for nearly every case of cervical cancer worldwide (which is why all girls should be vaccinated before they become sexually active).

However these cases are not "infectious cancers", they are infectious diseases which are capable of causing cancer. True infectious cancers, where a cancer cell from one individual takes up residency in a second individual and grows into a new cancer, were unknown until recently. With the publication of a new study in PNAS we now have three examples of truly infectious cancers.

1. In the most recent study, researchers in Japan documented the tragic case of a 28 year old Japanese woman who gave birth to a healthy baby but within two months had been diagnosed with acute lymphoblastic leukemia and died. At 11 months of age the child also become ill and was diagnosed with acute lymphoblastic leukemia. Genetic analysis of the tumour cells in the baby demonstrated that the tumour cells were not from the child herself, but rather maternal leukemia cells that had crossed the placenta during pregnancy or childbirth and had taken up residency in their new host. With this information, retrospective analysis indicates that this is probably not a one-off event, and at least 17 other cases of mother-to-child transmission of cancer have probably occurred.

2. In addition to mother-to-child transmission of cancer, cancer can spread from one identical twin to another. Identical (mono-zygotic) twins have identical immune systems, preventing rejection of "transplanted" cells, unlike non-identical (di-zygotic) twins. Thus a tumour which develops before birth in one identical twin can be transferred in utero to the other identical twin, where it can grow without being rejected. In one improbable but highly informative case, a set of triplets were born where two babies were identical and the third was non-identical. A tumour had arisen in one of the identical twins in utero and had passed to both other foetuses, but had been rejected by the non-identical foetus and accepted by the identical foetus. Of course, with the advent of medical transplantation, transmission of infectious cancers is now no longer limited to the uterus. Transplantation of an organ containing a cancer into a new host can allow the original cancer to grow and spread, as transplantation patients are immunosuppressed to prevent rejection. There is also a single case of a cancer being transmitted from a surgeon who cut his hand during surgery to a patient who was not immunosuppressed.

3. In a medical mystery well known to Australians, the population of Tasmanian Devils has been crashing as a fatal facial tumour has been spreading across the population. The way the fatal tumours have spread steadily across Tasmania and sparing Devils on smaller islands first suggested a new infectious disease that causes cancer, similar to HPV in humans. However a suprising study demonstrated that the cancer was directly spreading from one Devil to the next after having spontaneously developed in a single individual. These scrappy little monsters attack each other on first sight, biting each other's faces. The cancer resides in the salivary glands and gets transmitted by facial bites to the new Devil. Unfortunately for Tasmanian Devils, a genetic bottleneck left all Devils so genetically similar that they are, for immunological purposes, all identical twins. This means that the cancer cells transmitted from one Devil to another through biting are able to grow and kill Devil after Devil. The cancer from a single individual has already killed 50% of all Devils, and it is possible that we will have to wait until the cancer burns out by killing all potential hosts before reintroducing the Devil from the protected island populations. As unlikely as this seems, another similar spread occurs in dogs, where a cancer that arose in a single individual wolf is being spread through sexual transmission from dog to dog around the world. This example also illustrates the point made about cancers being "immortal" - the original cancer event may have occured up to 2500 years ago, with the tumour moving from host to host for thousands of years without dying out.


Recreating the thymus

I am writing today from the European Congress for Immunology in Berlin. A talk by Thomas Boehm was the highlight of the first day for me.

The Boehm laboratory has been looking at the genetic evolution of thymus development. The thymus is the nursery for T cells, the coordinator of the adaptive immune response. The Boehm laboratory analysed the genetic phylogeny of sample species spanning the 500 million years of thymus evolution and found several key genes that have been conserved through this process. The master coordinator of thymus development, Foxn1, had already been known, but how this master coordinator worked was a mystery, so the Boehm laboratory used the evolutionary analysis to try to recapitulate thymic development in zebrafish and mice.

In zebrafish, Weyn and colleages were able to use live imaging to analyse the genes that the thymus needs to express in order to recruit progenitor cells. This was done by using genetic expression of coloured dyes, making the primordial thymus glow red and the progenitor cells glow green. They found that just two conserved genes, Ccl25a and Cxcl12a, were synergistically acting to draw in all the precursor cells.

In mice, Bajoghli and colleages tried to use the knowledge gleaned from evolutionary analysis to completely bypass Foxn1. The rationale is that if we know exactly what Foxn1 does to drive thymic development then we should be able to recapitulate thymic development in the absence of Foxn1 by simply expressing the downstream genes. So the Boehm team took the four key genes that were conserved over 500 million years of thymic development, Ccl25, Cxcl12, KitL and Dll4, and expressed them in isolation or in combination in thymic cells that were genetically deficient in Foxn1. Normally, these deficient thymic cells cannot attract T cell precursors. However, Bajoghli and colleages found that just as in zebrafish, two genes in mice were able to essentially restore the capacity to recruit precursors, Ccl25 and Cxcl12. A third gene, KitL, allowed these cells to proliferate and increase in number. What these three genes could not do, however, was turn the precursors into T cells. That job required the fourth gene, Dll4, which had no role in recruitment or proliferation but which was essential for the differentiation of recruited precursors into T cells. Through evolutionary genetics the gene network of an entire organ is being unravelled.

Some of this research is current unpublished, other aspects just came out in the journal Cell.