A breakthrough for HIV prevention?

This week a breakthrough for HIV prevention was announced in Science. AIDS researchers in South Africa just completed a long-term study of Tenofovir Gel, and found that the gel, inserted into the vagina before sex, results in a 40% HIV protection rate for women. With 900 women being followed up for 30 months, the results look very solid, and potentially even better than the headline figure of 39% protection. As with all such studies, the protection rate given is with average usage, not ideal usage. The average study participant only actually used the gel for ~75% of sexual intercourse occasions. For the "high adherers", the group using the vaginal gel for >80% of sexual intercourse occasions, the protection rate was 54%. How important is this breakthrough? In a way, it is both bigger and smaller than the headlines would suggest.

A new tool to fight HIV spread

In the age of vaccines with efficacy rates of >99%, a ~40% protection rate sounds rather poor. Furthermore, this is currently a form of protection only against heterosexual transmission of HIV to women, with no data yet on any protection granted to males having sex with a HIV+ woman or as an anal gel for male homosexual transmission. HIV acquisition by non-sexual routes, such as intravenous drug use, will of course be unaffected by the gel. This is a very poor efficacy rate when compared to condom use. A Cochrane meta-analysis has determined that consistent use of condoms results in an 85% protection rate against HIV, which can go as high as 95% with correct usage. The protective effect is only on par with that of male circumcision, which multiple randomized trials have found protects males from heterosexual HIV transmission at a rate of around 60%.

Is the new gel then completely redundant? A downgrade from the condom? No, not for a key population group - the women of southern Africa. The ten countries of southern Africa together constitute 35% of global HIV cases, with HIV reaching a hyper-endemic situation with 10-30% of adults infected with HIV. In this region, heterosexual spread is the dominant form of HIV transmission, and indeed the risk factor of greatest magnitude at the population level goes to married women. Condom usage in Africa is generally very poor, with an average of only 4.6 condoms available per man per year, due to low demand. Only 7% of women in southern Africa reported using a condom the last time they had sexual intercourse with a regular partner. In particular, women who are food insecure are 70% less likely to use a condom when having sex, with less personal control over sexual relationships. Other women may not use a condom during sex for more personal reference - such as trying to conceive. A vaginal gel therefore provides (partial) HIV protection for the first time to any women who would not otherwise use a condom during sex, either because of personal choice, lack of sexual control, or through a desire to become pregnant.

The other important consideration is that any protection results in a greater number of cases being prevented than the effectiveness of the protection to the individual. This is because each case stopped also prevents the flow-on cases which would have spread from the infected individual. It has been estimated that a weakly protective vaccine, with only a 50% protection rate and only given to 30% of the population, would reduce new HIV infections by more than half, over 15 years. These figures are comparable to the results for Tenofovir Gel, so if the maximal potential is realized, this breakthrough has the ability to halve new African HIV cases.

A tool that will sit idle?

The problem, of course, is that the potential of this gel will not be realized. In many ways, the HIV epidemic is not a problem waiting for a medical solution, but rather a problem waiting for a social and political solution. Consider mother-to-child HIV prevention. Current medical treatment of HIV+ women during pregnancy and after birth reduces the transmission rate to the child by more than 99%. Even in developing countries, the treatment program has over 98% efficacy. And yet these cases, almost entirely preventable under current treatment, make up 15% of global HIV cases and 40% of HIV cases in southern Africa, since only 33% of pregnant HIV+ women in Africa get any form of anti-HIV treatment, let alone the recommended treatment program.

Other strategies, which are already proven to work, could make similar impacts if broadly implemented. Widespread male circumcision would reduce HIV rates by 60% in males and, by reducing prevalence, 30% in females. Comprehensive sexual education focused on preventing new infections can be highly successful. An aggressive campaign of university HIV testing and near universal antiretroviral treatment would be capable of reducing new HIV infections by 95% within 5 years. Just the simple treatment of individuals with genital herpes with current antiherpatic drugs could be expected to reduce transmission of HIV in southern Africa by 50%.

No, a new tool to fight HIV is not going to stop the virus. Realistically, the current tools available could cut new HIV cases by 99% within the decade, if only they were implemented. The true scourge of HIV is that it attacks the marginalised in society, hitting regions of great poverty, infecting those on the receiving side of racial and sexual discrimination. The people that, quite frankly, too many people feel deserve to be sick. Being interwoven with issues of sexuality, drugs, race and poverty, people in power have not only been slow to move - they have often moved in the wrong direction, such as the $15 billion pledged in aid by George W. Bush, with its focus on replacing effective condom use with ineffective "abstinence only" programs.

A major part of the problem is certainly lack of resources, both funding and public health infrastructure. The response to HIV has been delayed, fragmented, inconsistent and grossly under-resourced. Lesotho launched a national voluntary counselling and testing campaign aiming at universal testing, which fell through due to a lack of resources. In South Africa only 28% of HIV+ people have access to antiretrovirals. In Zimbabwe only 4.4% of HIV+ pregnant women are receiving antiretroviral treatment to prevent mother to child transmission. In Nigeria 10% of all HIV transmission events are due to lack of funds for hospitals to screen transfused blood, a situation which requires only funding to remedy. However, funding is not the only impediment to an efficient HIV prevention campaign. Policy makers have repeatedly failed to spend limiting resources on HIV prevention, concentrating on medical treatment without adequate care and support. This is despite the cost of most HIV prevention techniques being well under the $4770 per infection prevented that it would take to create a cost savings compared to simple treatment. What is needed to end the HIV crisis is, in fact, simple in health terms and is difficult only in political implementation – a coordinated and adequately funded approach to integrate evidence-based HIV prevention strategies, in concert with major social and economic development efforts to eliminate gender disparities, race- and sexuality-based discrimination and extreme poverty.

European Research Council funding

A major investment of my time last year and this year was in putting together an application for a European Research Council Start grant. The process was quite an ordeal, with both a substantial written grant and a challenging oral defense, probably consuming over 100 hours of my time. Fortunately, with excellent independent researchers in the laboratory, great research continued to be done in the laboratory while I was locked away with the computer.

Being open to researchers across Europe, in any discipline, the competition is fierce, however there are some large advantages to the ERC Start grant process: 1) the committee looks favourably upon large ideas, rather than safe ideas; 2) the competition is segregated according to career stage, so that I was only competing with other researchers less than five years out from their PhD; 3) the funding is sufficient in scale and duration to really put forward a grand plan. Just recently I found out that the application was approved, and the VIB put out the following press release:

VIB receives high score from European Research Council (ERC)
Two young top researchers awarded €1.5 million research grants!

Leuven - VIB landed two research grants worth 1.5 million euros each. The prestigious grants are courtesy of the European Research Council (ERC) and are aimed at giving talented young scientists the opportunity to develop their own research team. The honor fell to Adrian Liston and Patrik Verstreken, both recently transferred to VIB-K.U.Leuven from abroad.

The European Research Council
ERC was created to encourage excellent research in Europe. ERC starting grants give young talented researchers the opportunity to develop a research group. At present, there are still too few opportunities in Europe for young scientists to initiate and lead their own research, which is extremely unfortunate as it results in top researchers leaving the region to develop their careers elsewhere.

Adrian Liston studies autoimmune diseases.
The immune system is our body's defense system and allows it to fight off foreign substances and micro-organisms. In people with an autoimmune disease, the immune system has gone awry: it can no longer distinguish between the body's own and foreign substances and ends up attacking vital tissues and organs. Adrian Liston studies immune system cells (T cells) that are responsible for this malfunction. With his ERC research grant, he plans to bridge the gap between his research on mice models and humans. This may be a first step in the development of new therapies for autoimmune diseases.

Patrik Verstreken explores the communication between brain cells.
Brain disorders take a major toll on society. Many brain diseases are caused by the disruption of communication between brain cells. Finding a solution depends on understanding this communication in the smallest detail. Patrik Verstreken uses the fruit fly as his model organism for studying genes involved in the communication between brain cells. The ERC research grant gives him the opportunity to expand his research to more complex neural communication networks that control behavior. This step is crucial if we are to understand neurological disorders such as Parkinson's disease.

One year as a junior faculty member

One year in numbers:

62: the number of grants I have reviewed for various foundations
19: the number of articles I have reviewed for different journals

25: the number of grants I have submitted
7: grants accepted
4: grants declined
14: grants pending
1,029,685: euros given in grants
830,493: euros spent in research

10: invited talks
3: conferences
3: lectures

13: article submissions
9: articles published or in press

5: PhD projects started
11: number of permanent staff in the lab
8: number of full-time permanent researchers in the lab

0: number of days I've spent doing experiments

Negotiating a start-up package

After my previous posts on science careers I was asked about negotiating a start-up package. Unfortunately here I have little input - for a new faculty member there is very little negotiation that can take place. The faculty will have a budget set aside for recruitment and this is not going to change in any substantial way. There are a few minor points to consider:

1. The edges can be flexible. The net value of the start-up package is unlikely to change, but a one-size-fits-all package may be adopted to your circumstance. Will it be possible to have no teaching commitments in the first year? A discount on departmental services? Perhaps make your start-up fund open-ended rather than time-limited. Look carefully at the package being offered and find any conditions that could be an issue to you - and only ask about changes that will make a real difference to your research. Often the hardest part is working out what would be important to you, since you will not be familiar with the inner workings of the department in advance.

2. Negotiate for the research, not for yourself. If you talk about changes in terms of things you would like, the faculty will weigh this up against how much they want you. Instead phrase the changes in terms of how they can add to your research. Why will this change make your research output substantially better? The faculty will be much more willing to make changes if they can see the value to your research output - after all they want you to succeed.

3. Don't grandstand. These are your colleagues and your requests will typically come at a cost to them, either in terms of faculty subsidies or extra workload. Do not make a little issue into a big issue. Also, don't bluff. In my negotiations with one faculty I did have one "make or break" issue. There were a few things that would have been nice but I could live without - these I let go when they were turned down. But when I discussed one particular clause I explained exactly why this would make my particular research program untenable, and when they couldn't change that one clause I walked away. Don't make an issue "make or break" unless it is literally a deal-breaker.

4. Get it in writing. Okay, this is not exactly in line with #3 about being considerate in negotiations, but a contract should be in writing. If a faculty is happy to agree to a condition there is absolutely no reason why it shouldn't be written down in your contract. Things change over five years. Departmental heads leave and get replaced by new heads. Memories on exactly what was agreed become hazy over time.

Applying for faculty positions

I've had some occasion recently to contemplate the strategies for applying for faculty positions. In 2008 I interviewed at eight different universities for a faculty position, and two of those experiences in particular were very illuminating - the IRIC (Institute for Research in Immunology and Cancer) and VIB (Flemish Institute of Biotechnology) held open applications where all the applicants were interviewed together. This gave me a fascinating insight into the faux pas made and the important criteria for being offered a faculty position.

These are the three criteria I recommend post-docs to consider:

3. Publications. Yes, telling people they need Nature papers is useless advice - everyone knows the importance of publications. Actually, I have put publications at #3 because I think it is much less important than the other two criteria. I interviewed back-to-back against post-docs with outstanding publication records that I couldn't match, multiple major Cell papers that redefined a field and opened up new technologies. Yet I've seen these same people fail at criteria #1 and #2 and miss out to people with less outstanding publication lists. I see publications almost as a threshold effect. For a post-doc to be competitive at a high-level institute they will need to have multiple papers at JEM or higher journals. But in a way it is more important to have a diverse portfolio of publications. Primary papers in multiple laboratories demonstrate an ability to research in different environments. Middle author publications demonstrate willingness to collaborate. Review papers show a grasp over the field. The risk for an applicant with a few good first author Nature papers is that the credit will go to the last author. Having a broader repertoire with senior authorships and multiple laboratories tells the selection panel that you have carved out your own research niche and that you were more than a PhD student put on a lucky project.

2. Experience outside benchwork. The enormous importance that is placed on publications tends to drive post-docs to make a fundamental mistake - you cannot learn to be a PI from the bench. Once you have a faculty position the amount of research time you have available will drop precipitously. Skills are needed in setting up a lab, writing grants, working on a budget, mentoring students, teaching undergrads, faculty business, etc etc. The selection panel is well aware of this, they are not looking for a post-doc to work in their lab, but someone who can run a successful operation, someone who can translate their previous first-author success into future last-author success. One applicant I interviewed with had an outstanding publication record but didn't get a job offer because it was clear that they were an outstanding post-doc but would be a terrible PI. When asked about supervision experience this candidate said "Oh, my PI gave me a technician, and I've trained her to sit behind me and pass me solutions and pipettes reset to the right volumes. It is great, I can now do research twice as fast as before". Perhaps - but how would he fair when he was tied to a computer writing grants and relying on his technician to produce data? It is important for post-docs to show that they have the skill set to run a lab - a different skill set to being a post-doc. Mentor students, write fellowships or grants, train technicians, teach classes - show the selection panel that you have already been running a sub-lab within a larger lab, and you are now ready to expand your operation.

1. Emotional intelligence. We work in science, the bar is pretty low - but still I have seen the stunned look on faces as applicants show zero emotional intelligence. I'm going to put this one at number 1, because an applicant who is above average but not genius on publications and management experience can shoot to the top of a list if they have emotional intelligence. This stuff should be simple but it obviously isn't. I remember standing around at a coffee break during the interview day and listening to a selection panel member ask an applicant how they were finding the experience. The reply? "Actually, to be honest it is terrifying, there are so many good people here that I feel like a fraud". Okay, this is not uncommon, a study by the American Astronomical Association found that more than 50% of graduate students admit to being afraid their peers will find out how little they know. Only 5% strongly disagreed. But don't confide in the selection panel. Every interaction with the selection panel or any faculty member, regardless of how informal, is part of your assessment. An applicant needs to work out what each person is after, and show them that you can deliver - both in body language and your response. Be calm, authoritative and deliberative without being aggressive, flighty or nervous. Consider that every panel member is looking for something different. A good selection panel wants the best person for the department and also the best person for their laboratory in particular. They are picking a long-term colleague, show them that you have skills they can use, knowledge they can draw on, that you are willing to collaborate, that you have an ability to "value-add" to the department. The right applicant in the right place will not only bring in their own research value, but will also increase the research value of other laboratories in the faculty. An applicant should research the faculty and the faculty members, think about collaborative potential and engage each individual they interview with on their own terms.

Now the corollary to this advice - don't fake it too much. If writing grants and mentoring students feels like an annoying distraction from benchwork, think again about whether you want to be a PI. If you are not genuinely excited about the collaborative prospects in a department, don't send in an application there. The interview is not just about the selection panel interviewing you, it is about you subtly working out whether the department will be good for you, so if you have to make promises you don't want to keep you are looking in the wrong place.

Sex determination

If yeast sex is simple, how complicated is sex in multicellular organisms? Actually, the act of sexual reproduction in plants and animals (including humans) is essentially identical to that of yeast, fungi, plants and animals, including humans. Multicellular organisms have two different copies of the genome in every cell. Like yeast, to undergo sex we need meiosis to occur. Specialised sexual cells duplicate the two genomes, cut and paste them into four unique genomes, and then divide into four daughter cells. These cells are either large cells containing a single genome and lots of energy (the female egg) or small cells containing nothing more than just a single genome (the male sperm). When they combine the new cell has two genomes, one from the female parent and one from the male parent. Importantly, just like yeast, the offspring that results has a unique genetic composition. The two genomes that the offspring possesses are each novel, created by the combination of the two unique genomes in each parent.

While sex for multicellular organisms is identical to yeast at the cellular level, at the sex determination level things get very complicated. There are many different ways for determining whether an individual is male or female. As a measure of the broad diversity of ways in which species have solved the sex determination problem we can look at a few different examples: clownfish, crocodiles, humans, whiptail lizards and komodo dragons. And this is not including some of the really complicated systems that exist, such as in earthworms, bees and platypi.

Clownfish and crocodiles

Clownfish and crocodiles both have non-genetic sex-determination systems. Males and females have the same genetic make-up and every genome has potential to encode either a male or female individual. The physical manifestations of sex occur due to environmental influences on which set of genetic controls to activate. In clownfish the important environmental influence is the social interaction of other clownfish. All clownfish start out as males. When the sole female in the group dies, the largest male undergoes a rapid sex change and becomes a female. Interestingly, this sex change is reversible – a female moved into a new group where she is no longer the largest will revert back to a male. This plasticity ensures that there is always a breeding female in every group, and that the female comes from the most successful individual in the group.

Like clownfish, crocodiles have no genetic difference between males and females. Unlike clownfish, however, there is no sex plasticity. A male hatches as a male and stays a male for life, a female hatches as a female and stays a female for life. The important environmental influence in this case is the temperature of the egg. If the temperature of the egg is between 31.7°C and 34.5°C the embryo is set as a male, if the temperature of the egg is outside this range the embryo is set as a female. There are several important restraints that this sex determination system has had on crocodile evolution. Firstly, the crocodilian mother has become very active in nest maintenance, as a temperate far from the threshold will result in hatchlings of a single sex. Secondly, this sex determination system has forced crocodiles to maintain a link to land. Other aquatic species, such as dolphins and sea snakes, have been able to become entirely aquatic by giving live birth in the water. These species all have genetic sex determination systems (below). By contrast, crocodiles and turtles need to return to land to lay eggs because a temperature-dependent sex determination system is incompatible with live birth – internal body temperatures are too stable to give the diversity in temperatures required.

Humans and whiptail lizards

Humans and whiptail lizards both use the XX/XY sex determination system. In this system, sex is determined by the combination of sex chromosomes inherited from the parents. XX results in females and XY results in males. As females can only pass on an X chromosome while males can pass on either an X (50% chance) or Y (50% chance) chromosome, this system results in roughly equal numbers of females and males being born. It is very important to note that differences between the sexes are largely not due to genetic differences. Both males and females have the X chromosome, and while females have two copies one of these copies is “inactivated”, making them equivalent to males. The only substantial genetic difference between males and females is the presence of the Y chromosome in males. This Y chromosome is tiny (only 2% of the human genome) and is mostly made of up junk. The only essential gene on the Y chromosome is the SRY gene.

All human embryos, whether XX or XY, spend the first six weeks as females. At this point embryos with the XY genome express the SRY gene in the genital tissue, starting the development of testes. The testes then express testosterone and the embryo detects this testosterone production through the androgen receptor. The effect of this production is a complete remodelling of the genitalia from female into male between 7 and 12 weeks gestation. Many different genes are used to initiate the “male” program instead of the “female” program, but only the SRY gene is on the Y chromosome. In other words, females have all the genes required to develop the physical attributes of a male, and males have all the genes required to develop the physical attributes of a female, and only a single gene decides which program is used. When thinking about physical differences between males and females it is not helpful to think about genetic variation, such as exists between different populations of humans. Instead the best comparison is to think about your heart and your liver. Both cells have the same genome, the same genetic code, but the two cells have initiated different programs from the same code so that the cells can perform different functions.

Most whiptail lizards use the same XX/XY system as humans, with XX lizards being female and XY lizards being male. However 15 species of whiptail lizards have reverted to an asexual system of reproduction. These species consist only of XX females. The females still undergo sexual meiosis to create an egg with a single X chromosome, however in the absence of sperm these eggs spontaneously duplicate their genome to become XX females, in a sexual system called parthenogenesis. It is unclear as to why these whiptail lizards have evolved to abandon the advantages to sexual reproduction, however a clue may be the environment they live in – the dry deserts of North America. It is likely that with the low population densities of lizards living in a desert finding a mate becomes very difficult. By breeding through parthenogenesis females can still reproduce even if they fail to find another lizard, and furthermore every individual offspring is capable of bearing young, allowing more efficient use of resources during dry times, and faster population growth during wet ones.

Komodo dragons

The ZW/ZZ sex determination system used by Komodo dragons is essentially the opposite of the XX/XY system. Here, ZW results in a female while ZZ results in a male. As with the Y chromosome, the W chromosome is a minor chromosome with few functions beyond sex determination. When breeding, a female Komodo dragon can pass on either a Z or W chromosome while a male Komodo dragon can only pass on a Z chromosome. This results in 50%:50% females to males. Interestingly, the Komodo dragon has also developed parthenogenesis, like the whiptail lizard. A female Komodo dragon kept alone will have spontaneous genome duplication of an egg. The outcome, however, is the opposite of that occurring in the whiptail lizard. The whiptail lizard female, using the XY sex determination system, can only pass on an X chromosome, so duplication results in an XX female. The female Komodo dragon, however, uses the ZW sex determination system, so the egg could either have a Z chromosome and duplication to be a ZZ male, or it could have a W chromosome and duplication to become an unviable WW embryo. In practise, therefore, this means that female Komodo dragons that revert to parthenogenesis will always generate ZZ males. This means that a lone female washed up on a new island will generate male offspring by parthenogenesis, allowing later sexual reproduction. What is the advantage of this system of parthenogenesis? There are two likely possibilities. The first is that it avoids the spiral into an inbred population that occurs in whiptail lizards, with only a single necessary parthenogenic generation interrupting sexual reproduction. This may be a more appropriate adaption to the “rich uninhabited island” scenario, with the XX parthenogenic strategy more suitable for the “low population desert” context. Alternatively, and equally plausible, the ZW parthogenesis strategy is less efficient than XX parthenogenesis in both contexts (or vice versa). Since evolution always works from the current genetic situation in incremental steps, non-ideal compromises are common.

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.

The things they don't teach you about being a scientist

One of the frustrating issues in a science career is the limited extent to which each career stage prepares you for the next. An undergraduate degree in science will typically focus on teaching established science theories and testing them via examination. The research proportion is limited and shrinking due to budget constraints.

Then you finish undergraduate studies and start a PhD, and the ability to learn established theories and sit an exam is completely useless. Instead you need to completely reorientate yourself to research skills, both practical (in terms of benchwork) and theoretical (in terms of experimental design and analysis). Exactly where your PhD mentor expects you to pick up these new skills is a mystery, as there are no lectures or classes to teach it. Throughout your PhD and postdoc you know that you are going to be judged solely on your research output. Do experiments and publish, do experiments and publish, anything else is irrelevant.

So you finish your postdoc with a lot of research experience and a handful of publications and manage to land a faculty position. You are now an independent principle investigator and all the skills you have learned to date are redundant. No time for benchwork anymore, you need to master a new set of skills within a year or fail miserably and end with a whimper. Having only written one or two short fellowship applications at the end of your PhD, you now need to master the major project grant. A detailed and elaborate research proposal which needs to be tailored towards the language and politics of the particular granting body (information which is never given on the website of course), your grant has to compete with successful investigators who have been operating in the field for decades.

While you wait for a year for the grant results to come back, your startup grant seems to disappear - quick, learn the skills of an accountant! So far you've only spent money in the lab, now you need to know the complete salary costs (including taxation status, social security contributions and yearly increments), equipment depreciation costs, which items should go on which budget (international staff on the VIB budget can gain expat taxation status, but international students on the KUL budget are exempt from social security), the cost threshold for requiring multiple quotes, how to negotiate with reps for good prices, and so much more. When you have mastered this you realise that you wasted far too much money on furniture when the university has a hidden basement full of free cast-offs and that expensive piece of equipment you bought already exists unused in a laboratory two floors down.

Of course, while you are becoming a grant writer / accountant, research needs to occur, so you'll need staff. You are a complete unknown, so no high power post-docs coming with their own fellowship. You didn't teach undergraduate classes last year, so good luck in snapping up a student able to attract a scholarship. You place a few adds in Nature and for the next six months you get ten applications a day from India and China. How to judge them? Hiring decisions are a science in themselves, then labour contract law is a mine-field. Nevertheless, with a few bumps along the road you somehow manage to put together a surprisingly talented and hardworking team. You already knew from personal experience that a lab can be an emotional boiler-room, now you need to manage that or manage the consequences. You need to understand every staff member as an individual, what makes them tick, how to keep them happy and productive, the best way to redirect them when they go off-course. Skills that can take a lifelime to learn about your partner you need to pickup within a few months about six strangers from six different cultures. Plus you'll need to leave your computer enough to spot trouble brewing in the early stages. The small things matter, the person irritated about someone else casually borrowing pipettes and not returning them happens to have a habit of writing directly on glass bottles. And let's face it, scientists are not exactly trained in emotional intelligence.

Think that you can do research now? Equipment, check. Reagents, check. Grant money, check. Staff, check. Stir the pot and research comes out? Hah! You would be breaking a surprising number of regional, national and international laws. You'll need a liquor license for that ethanol to clean benches, a permit to use sedatives on mice, ethics clearance of course but also an animal use license. Biosafety permits, equipment certification, occupational health and safety monitoring, a fire-warden. The most frustrating part is that there is no check-list to work down, you only find out about a requirement when you think you are there and you hit a brick-wall.

Then there are the unpredictables, that sap away your time until you are ready to scream. Your immunology department is the only one in the world without a flow cytometry core unit. The research assistant you hired to look after the mouse colony turns out to be afraid of mice. Your contract unexpectedly stipulates that you become fluent in Flemish within three years. That assay you used to do in your sleep simply doesn't work in Belgium. Your post-doc falls in a legal loophole that makes them ineligible for fellowships designed for both locals and foreigners. The SPF mouse house didn't tell staff to set up breeders inside a hood and all your imported mouse strains are contaminated. Your weeks of slaving over an FWO grant are wasted because you didn't know that the FWO does not have anonymous peer review and requires you to submit your own reviewers. You find out that your start-up grant also has to cover your own salary and you over-hired in the first year. You have a hundred meetings, departmental politics, collaborations to foster and suddenly a year has gone by and you didn't even manage to finish off that project that was nearly ready for publication at the end of your post-doc.

Of course, I could be externalising. Perhaps I just missed the training session.

The inefficient consequences of evolution

Vertebrates are unique in developing an immune system capable of anticipating pathogens that are yet to evolve. Birds and mammals have taken this "adaptive" immune system to the pinnacle, with T cells and B cells using a randomised form of genomic engineering. The advantage of a system based on randomised generation is striking - by making every T cell and B cell unique it becomes exceptionally difficult for pathogens to "out-evolve" their hosts. Regardless of how a pathogen will change, pre-existing T cells and B cells will be capable of recognising the new modified pathogen. The importance of the adaptive immune system to humans is evident in the fatal consequences of its absence, such as patients with end-stage AIDS or primary immunodeficiencies caused by genetic mutations. These benefits greatly outweigh the cost of the adaptive immune system in resources used and the threat of autoimmune disease.

But does the adaptive immune system make vertebrates more healthy? There is no obvious evidence that it does. In a key essay on the topic, Hedrick argues that vertebrates do not appear to have a lower pathogen-induced mortality rate than invertebrates. Instead, he argues that the development of the adaptive immune system provided only a short-term benefit, with pathogens rapidly being specialised to vertebrate hosts. The result is an immunological arms race, with each side incrementally ratcheting up the armaments. Vertebrates are essentially impervious to non-specialised pathogens unless rendered immunodeficient, but the additional mortality from specialised pathogens is probably equivalent to the invertebrate state.

This still-controversial hypothesis high-lights an important aspect of evolution by natural selection. It has highly inefficient consequences. Natural selection takes place at the level of the individual and evolution takes place at the level of the species. Most importantly, natural selection only occurs in the present. An individual who has an advantage for even a single generation will be over-represented in the next generation. A species that has an advantage for a single generation will be able to exploit more resources for reproduction. The long-term consequences - that each species will waste more resources in an ever more expensive battle - is irrelevant.

The evolutionary arms-race between host and pathogen is one incredibly important example. A more illustrative example of the patent futility of this arms-race comes from Sir David Attenborough, one of the leading science communicators of all time. In Life in the Undergrowth, he films two species of harvest ants living in the desert. Each population needs to collect seeds to survive, however the number of seeds produced in the desert is so low that there is fierce inter-species competition. One species of ant is diurnal, the other nocturnal, and each is capable of collecting the entire daily seed dispersal. In order to survive, every second night the nocturnal ants spend an evening carrying rocks to cover the entry hole of the diurnal ants. The diurnal ants can't collect seeds the next day as they need to spend a day clearing the rocks from the entrance. This gives the nocturnal ants a night to harvest the uncollected seeds. The following day the diurnal ants are able to collect every seed and that night the nocturnal ants spend carrying rocks. Two species end up literally carrying rocks backwards and forwards every second day.

The elegance of evolution is the beauty of such specialised behaviour, but the consequences are gross inefficiency in resource use. If each species simply spent alternative cycles conserving resources both species could survive with a higher population density than currently exists. But neither species can be the first to stop the wasteful use of resources, as that would give a fatal advantage to the other, and so they are trapped together in a cycle of carrying stones. The battles of night ants vs day ants and of hosts vs pathogens illustrate the bizarre, elaborate and ofttimes perverse consequences of evolution by natural selection

Science is not a family-friendly career

There is a brief article in this week's Nature entitled "Tenure or family?"

Marriage and childbirth are what stop most female US graduate students from becoming tenured researchers, according to a report by Washington DC think tank the Center for American Progress (CAP) and the University of California, Berkeley, School of Law. Staying Competitive: Patching America's Leaky Pipeline in the Sciences found that married mothers with a PhD are 35% less likely to enter a tenure-track position in the sciences than married fathers with PhDs, according to a National Science Foundation survey. And they are 27% less likely than their male counterparts to get tenure after securing a tenure-track post. The report advises universities and funding agencies to create family-friendly policies, including six weeks of paid maternity leave and a week of paid parental leave.

Obviously there is an enormous problem in career progression for women in science. A 35% reduction at the tenure-track stage and a 27% further reduction at the tenure stage - women get whittled out of the academic career pathway. This article kind of misses the point though. Marriage and children are not what stops women progressing in science. Extra maternity leave is not going to help if it puts women further behind the publication scramble. To put it bluntly, in my opinion this is the real problem:

1. A career in science is horribly unfriendly to a balanced life. There is no security or safety, every step of the way 90% of people are going to jump or be pushed. Everyone is smart at the top, that isn't enough, you also have to be lucky and obsessively determined. Most tenure-track professors don't even take weekends or holidays - they can't afford to be left behind.

2. Society still has structural sexism built in. Yes, women are now free to pursue any career they want, in addition to their previous workload. If it was purely child-rearing that was a problem the blockade would be in all scientists who have children. Instead the burden falls disproportionally on women scientists who have children, because on average they still end up doing more of the work than men. Consider the recommendations of the report: six weeks of paid maternity leave and a week of paid parental leave. Even if the recommendation is passed, women will be expected to do six times more child-rearing work than men.

These problems are much harder than simply paid parental leave, although obviously that would be a positive contribution. Instead we need to tackle the two fundamental issues. The science career needs to be made more family friendly, or at least not a horrific all-consuming ordeal. We can't continue with the same massive bottle-necks in careers or with a system where every person works themselves to death to stay in the game one more round. Competitive peer review has grown into a destructive monster that chews people up and spits them out. Secondly men need to pull their own weight rather than expecting women to sacrifice their time to make up for a thoughtless spouse.