The human genome: we’re just getting started

When the human genome was sequenced over a decade ago, it was a momentous scientific breakthrough. The human genome is enormous. The genome is about 3 billion DNA bases lined up one after the other along chromosomes (which are conveniently broken up into 23 parts). It contains all our genes as well as all the information about when those genes should be switched on and off. Many diseases are caused by genetic changes, so by comparing your or my genome to the average we should be able to see what diseases await us. It was as though a crystal ball had been dropped into our laps. All we had to do was look into it and see everything from our next colds to our eventual deaths. Really, by now there should be an iPhone App for it. So what happened?

As with many scientific discoveries, the sequencing of the human genome was over-hyped. It was a scientific breakthrough, but not a medical one. It takes a long time for scientific discoveries to become medicines that affect the lives of patients. A decade or more usually passes from the time a treatment is thought up to the time the first patient is treated, and most drugs don’t work and therefore never make it into patients at all. One of the most important things that scientists have used the genome data for is genome-wide association studies. In these studies the genomes of healthy people are compared with the genomes of people with diseases like heart disease, diabetes, cancer and autoimmunity. Scientists have found a number of mutations in people with those diseases, but knowing that a mutation is there is only the first step. The next steps are to see what that mutation does, try to develop drugs to fix the problem, and then see if those drugs are safe. These discoveries will take time. But without the genome data there in the first place, we wouldn’t even have a starting point. There are over 500 genetic diseases from cystic fibrosis to hemophilia. We can test for most of these. Now we need to develop ways to treat them.  

Another important change has occurred over the last ten years. DNA sequencing has become cheaper and faster. Since most genomes differ by 1-3%, we need to have a better idea of what “normal” is. The only way to do this is to collect a bunch of normal samples and see how they differ from one another. The Human Genome Project, the publicly-funded effort to sequence the human genome, cost about £1.5 billion and took 11 years to complete. Sequencing the genome now would cost closer to £15,000 and take a couple of months. The X-prize Foundation currently has a $10 million prize for anyone who can sequence 100 human genomes in 10 days for less than $10,000 per genome. We’re not there yet, but we’re not far off. The competitive spirit has been part of sequencers’ ethos since the very beginning. The race to publish the genome itself was nail-biting, including a photofinish between the Human Genome Project and a splinter biotech company founded by a maverick scientist out to show us all how it should be done. Who says scientists are boring?
 
Anyone with internet access and a penchant for staring at repetitive things can look at the human genome for themselves ( http://genome.ucsc.edu/ has a good browser for this). The Human Genome Project and the scientific journals have been instrumental in ensuring that all the data is publically available. Before the human genome it was difficult to convince another scientist to show you his data unless you showed her yours. Anyone with little to show was left in the dark. Having easy access to data means that scientific discoveries happen faster. Genomes are being sequenced faster and faster, and that data is available to anyone who wants it. DIY biologists are starting up companies in their garages. Making DNA is becoming faster and cheaper. Bacteria with synthetic genomes have been created. Biology is accelerating.
 
As Isaac Newton once said, “If I have seen further it is only by standing on the shoulders of giants”. The sequencing of the first human genome was a gigantic accomplishment. It will take some time before we can use this information to improve our health, but as discoveries start happening faster and faster it’s only a matter of time before the era of genetic medicine is upon us. These are exciting times, and they will yield exciting results. One day we will be able to sequence a person’s genome, know what diseases they’re likely to get, and then prevent those diseases from happening. It will, however, take time. Patience, patients.

Higgs vs Jupiter: a modern-day David vs Goliath

Physics is about extremes. Even by Newton's time we had figured out the rules governing most things we can see with our eyes, so physicists for the last 200 or so years have been left with the task of investigating things that are either too small, too far away, or too hard to detect with our meagre five senses. The first half of the 20th century was devoted to small things. Thomson discovered electrons, Rutherford discovered atoms, Marie Curie discovered radioactivity, nuclear bombs were made. Bohr's and Schrodinger's atomic models remain largely unchanged today. Nuclear physics was born, space exploration was still a fantasy. It was all about the small guys.

Tides turned when the Cold War started. The space race captured the imagination of big and little kids everywhere. Astronauts became the coolest people on the planet. Men went into space and walked on the moon. Space stations orbited the earth. When we were little, my dad made a set of bookshelves for my brother where the endpieces were shaped like rocketships launching into space. Go figure, my brother grew up to be a space physicist and spends his time launching things into space (although not bookshelves). NASA and its counterparts in Japan (JAXA) and Europe (ESA) have successfully sent probes to every planet, some of their moons, and a handful of meteors, meteorites and dwarf planets. There's still a lot more to be learned about these bodies, but the tides have turned once again.

On July 21, NASA's space shuttle program came to a controlled stop at the end of the Kennedy Space Center's runway. As the Atlantis landed for the last time, the reins of human space flight were turned over to the likes of Richard Branson and friends until the International Space Centre de-orbits in 2020 and humans come back to earth. Since its first manned flight in 1958, NASA has spent $470 billion, at an average of 1.2% of the US annual budget. That's a serious commitment to looking at big, far-away things. The knock-on effects of NASA spending were huge and impossible to quantify, but it unquestionably inspired two generations of scientists, engineers and other dreamers in the US and beyond. NASA really did boldly go where no man had gone before. NASA's most recent mission, the Juno probe's trip to Jupiter, successfully launched last Friday. The Juno probe will take a polar orbit to look at the biggest planet in our solar system, a huge gas planet that resembles the sun except for the obvious lack of fire. An interesting mission, but we are entering the post-astronaut era. The "wow" factor has waned. Although they strapped a couple of smiling Lego people to the probe in an attempt to attract a younger audience, Lego people are simply too big. Our imaginations have moved on.

On the other end of the size spectrum, the Higgs boson and other particles currently being sought by the large Hadron collider (LHC) have attracted an astounding amount of media attention since the accelerator was turned on in September 2008. Even on the subatomic front there has been considerable rivalry between the big guys and the small guys. There’s more than one way to look for subatomic particles. Colliders such as the LHC make atoms move really really fast and then crash them into each other, hoping that not only does the hubcap pop off, but that the seat leather comes off too. These theoretical, subatomic particles should also exist in space, and probes outside the earth’s atmosphere can look at waves from distant objects that would be destroyed by the time they reach the earth. So we should also be able to detect Higgs in space, as Miss Piggy has known from the start. NASA’s FERMI satellite is currently doing just that. The race is on. Even people who traditionally focus on big things are investigating subatomic structure. The coming decades will push the limits of our understanding of all things small. I’d better start building some atomic structure bookshelves.

The problem with science careers is sample size

Science is an attractive career for many reasons. On the surface, academics have no real boss, flexible working hours, and job-for-life stability. They spend their time poking around, collecting tidbits of data on whatever catches their eye, and self-aggrandizing to passers-by in the hallways. Sounds like a pretty enjoyable career. An undergraduate science student looking to extend her jean-wearing, coffee-guzzling days into retirement could be easily fooled into thinking this was for her (that’s right, over half the undergraduate science students at most universities are female).

As you might guess from the title of this blog, the reality is very different. In fact, the statistics are rather appalling. One in ten biologists has a professor/assistant professor position 10 years after completing her PhD. Admittedly, some of those have left science of their own volition, but many more have been driven out by a lack of opportunity. Theoretically, if everyone wants a to become an academic, a 10% success rate should mean that the best 10% of scientists get positions while the rest do something else, which isn't that different from a lot of other careers. Surely we want the best scientists to lead their own research programs. That’s the problem. I’ve seen people in that top 10% get academic jobs, and I’ve seen people in that top 10% leave science altogether. Same for the other 90%. It all comes down to a problem of iterations.

Let’s say a person can get an academic job if she publishes in one Holy Trinity journal (Cell, Science, Nature- make sure to cross yourself as you say these) during her PhD/post-doc. If a young scientist publishes a total of 4 first author papers during this time, she’s done well. The papers that make it into the Holy Trinity are there because they’re interesting. And they’re interesting because they’ve asked timely questions and gotten useful and sometimes unexpected results. Some of this comes down to outstanding experimental design and skillful execution, but in equal measures it comes down to luck. Even outstanding scientists don’t publish exclusively in the Holy Trinity. Some great ideas simply don’t pan out, or the answer to a key question was “no” rather than “yes”. Biology can’t be bent to the experimenter’s desires. The answer doesn’t change the quality of the work, but it changes the interest factor and therefore the impact factor of the resulting paper. That “yes” or “no” answer often comes at the end of a body of work, when the scientist has already invested 2-3 years in the project, is running out of time and money and needs to publish or perish. Out of 10 great ideas, perhaps 1 or 2 will result in a Holy Trinity paper. Ensuring that 1 in 4 early-career papers gets into a Holy Trinity journal is as much luck as it is skill. In order to gauge scientific ability instead of luckiness scientists need to have more iterations before having their CVs scrutinized. If a paper took 6 months of full-time work, an early-stage scientist could put out at least 10 before applying for independent funding. Three-month projects would give her 20. Then there would be enough data points to assess the quality of the candidate. The more data points there are, factors such as luck will play a smaller and smaller role. As scientists and statisticians, we should know this better than anyone.

Unfortunately, I can’t imagine science moving in that direction. Today’s papers have much more information in them than papers from 10 years ago. A knock-out mouse model used to be a paper in itself; now it’s Figure 1a. The amount of time it takes to do the experiments, however, has remained unchanged. A PhD still produces 1-2 papers, same for a post-doc. Time seems to be constant.