By Matthew Cobb
On June 25, 2000, Bill Clinton, flanked by Francis Collins of the National Human Genome Research Institute and Craig Venter of Celera Genomics, with Tony Blair incongruously at the end of a satellite feed, stood at the White House. Clinton announced that “the international Human Genome Project and Celera Genomics Corporation have both completed an initial sequencing of the human genome – the genetic blueprint for human beings.” They claimed that the genome “promises to lead to a new era of molecular medicine, an era that will bring new ways to prevent, diagnose, treat and cure disease”.
In this week’s issue of Nature (which published the draft sequence in February 2001), there is the first of what will undoubtedly be a series of articles and books looking at what has happened over the last 10 years [these articles are open access].
Or maybe there won’t be any such flood of publications, for the simple reason that, despite all the hype, the contribution of the genome to human health has been pretty negligible. In other words, from a purely medical point of view, there isn’t much to celebrate.
Part of the reason for this slight sense of disappointment can be found in that first, triumphal declaration: a genome is not a “blueprint”, in the sense of a plan that can be read off to deduce a particular structure or behaviour. You cannot look at the chicken genome and deduce that a cockerel will go “cock-a-doodle-doo”. And there are no “cancer genes”.
The genome has turned out to be a much more complicated place than many suspected (I would argue that many of us who actually worked on how genes function in whole organisms predicted this). Genes regulate other genes and, above all, interact with the environment. Organisms are not simply the expression of the genome, they are constructed through myriad interactions between the environment and the genes.
And those interactions turn out to be incredibly complicated. Although computing power has also increased over the last 10 years, attempts to model what all these genes are doing have floundered, and people who work in these areas are in danger of drowning in a sea of data. Those who thought there were big bucks to be made have still to make their fortune; many have lost their shirts. My hunch is that it will be a long time before the promised health benefits turn up.
On the other hand, the prospect of lots of money – and health benefits – did mean that a massive amount of attention was paid to sequencing, and the result has been an unprecedented explosion of information about the evolution of life. Over 3,800 organisms (including around 200 humans) have had their entire genomes sequenced, while sequence information on more than 200,000 species has been obtained. This figure is growing all the time, as the price of sequencing plummets and the ease of obtaining entire genomes increases.
We are living through an astonishing revolution in science, and young biologists should be grabbing the opportunity to make some amazing discoveries about the evolution of life. For example, I am interested in the evolution of the sense of smell. These databases contain the sequences of genes that code for olfactory receptors; it is relatively straightforward to see how they evolved in different lineages, and above all, to gain insight into the role of this sense in the life of a given organism.
Up until 2004, it was argued that birds didn’t have much of a sense of smell (there was no real basis for this prejudice, but it was widely held). Then the chicken genome revealed that there were over 500 olfactory receptor genes (more than in a human). And this week, the genome of the zebra finch reveals that this songbird has about 215 functional olfactory receptor genes. This should be leading people to start finding out what exactly birds are doing with their sense of smell – finding food, navigating, finding mates?
For any young scientists reading this – not just biologists, but computer scientists, mathematicians, chemists – the current revolution in genomics should be seen as a new ocean to explore, a sea of unexploited knowledge that they can play in. It really is that amazing. As the poet William Wordsworth wrote with regard to a rather more bloody revolution – the French revolution of 1789:
“Bliss was it in that dawn to be alive,
But to be young was very heaven!”
Great post, Matthew. I learned something. Thanks.
On the picture caption, it looks like only the number of viruses sequenced has had exponential growth, and a slowing increasing slope at that. Bacteria comes close. The question is does adding together multiplicative growth always look exponential?
Given the vast difference in size between viral and eukaryotic genomes, it would be a better reflection of the explosion of genomic data to plot the total number of genomic bases deposited over time.
There are very few data points, so what appears linear may in fact be exponential – you’re just looking at a small part of the curve. 🙂 Of course you can turn that around and say that with so little data it is absurd to claim that there is an “exponential growth”. In this case it is reasonable to expect some exponential growth as laboratories go “me too!” and tool up to do similar work.
This graphic is very deceptive. The top of the trend pattern does indicate the # of deposits over time and that does appear to approximately double every 4 years. The individual color patterns, however, are easily misread as being similarly interpreted, which I don’t believe they should be. A cursory glance, for example, would seem to imply that the trend for eukaryotes exceeds that of virus or bacteriophage, which makes no sense in terms of their relative complexities. I believe that instead, one must interpret the height of each color within a year as the percentage of that category in that year. Virus deposits do appear exponential and bacteria may be as well, while eukaryote deposits have been very limited and are only now starting to increase relative to other organisms.
Would be interesting to see the number olfactory receptors in a very sensitive animal like a bloodhound. Do they possess better detection or better processing and is it related to the number of receptors in their genome?
Isn’t it more that simply a much larger number of receptors that can be packed into their long noses vs. an increased number of different receptors? A Nobel prize was shared for unraveling this system just a few years back.
Until looking here:
http://nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html
I wasn’t aware that 3% of our open reading frames are devoted to odorant detection! (I heard Linda Buck speak once, and I’m pretty sure that at the time she was talking about 100 different receptors, not 1000.)
Only a very tiny portion of our noses actually contains any oderant receptors. Space is not the limiting factor here.
If people weren’t forced to oversell the immediate benefits of the HGP, we wouldn’t be in this situation right now. But it all has to be about health and cures, so people who probably knew better were basically deliberately exaggerating so that the thing could have gotten funded.
Probably the biggest thing we have learned from the genome is how much we don’t know understand about it, and this is of enormous importance, but try explaining it to a public that demands cures against cancer here and now…
Well said. To constantly have to exaggerate the potential direct and immediate health benefits of basic research questions to keep the grants funded get tiresome.
What I’ve seen over the past 20 years or so is people overhyping claims so they can get funding. The vague “nanotechnology” domain is one which really irritates me. Suddenly people were branding what they had been doing for over 30 years as “nanotech” (though admittedly some people were doing excellent work but feared losing out on funding if they didn’t have “nano” in their name). I knew someone who was very successful at attracting funding for “nanotech” and I said to a colleague once “he sure has a gift for finding every sucker born”. For any honest scientist in the field, his claims were nonsense – and yet he could talk non-chemists into handing over money for empty promises. Another colleague nicknamed the guy “Golden Bollocks”. I was pretty much banned from sitting in on discussions of that group because I often made the comment that students appeared to be working blindly and suggesting they will develop a sensor of some sort without the slightest clue as to why what they are proposing might work. I said it was “a recipe for failure” – sure enough, 15 years later the group has not produced anything significant at all.
No wonder you are now ‘mad’. 🙂
And then there is Henry Markram’s claiming that the Blue Brain Project will produce a fully functional simulation of a human brain within the next ten (!) years. (His public dust-up with Dharmendra Mhoda seems to have been about whether it’s beyond the pale for a scientist to lie about what he has already done rather than simply make impossibly grandiose promises about what he is going to do.) Markram’s real-life accomplisments are beyond reproach of course, and I have to think he has his tongue planted firmly in his cheek when he says this, espaecially when he follows up by blandly stating that the most obvious use for such a veritably world-shattering technology would be better testing protocols for psychiatric drugs.
Actually, this passage is in the very long poem (two complete versions even), “The Prelude” by William Wordsworth.
That is OK. I like anybody who quotes good poetry in aid of an idea. And this was a fine selection for the occasion.
The passage under discussion is, of course,
“Bliss was it in that dawn to be alive,
But to be young was very heaven!”
So, failing in memory, I decide to look the subject lines, and find, as feared, that the passage is not from the Prelude, but from a short piece called “The Friend”.
Folks might find interest in how the poem ends:
Now was it that both found, the meek and lofty
Did both find, helpers to their heart’s desire,
And stuff at hand, plastic as they could wish;
Were called upon to exercise their skill,
Not in Utopia, subterranean fields,
Or some secreted island, Heaven knows where!
But in the very world, which is the world
Of all of us,–the place where in the end
We find our happiness, or not at all!
“That is OK. I like anybody who quotes good poetry in aid of an idea. And this was a fine selection for the occasion”
I found Dr Weinbergs’ final paragraph (Point: hypothesis first) a sharp summary of a potentially devastating situation (if not already) for many people working in perfectly great ‘small” schools and perfecly great “small science programs”:
“The stakes here are high. The repercussions of major agencies shifting their funding allocations will be felt for a generation. Running laboratories focused on small-scale, hypothesis-driven research has become unattractive for many young people because of the enormous difficulty of procuring enough money to launch and expand such a research programme. The long-term effects will be an increasing inability of many biological disciplines to attract the brightest young people — and they are, after all, the engines of scientific progress. Without them, we are lost”.
I would emphasize this is not an exclusive consequence of HGP mode of funding, one can find it in the LHC “program{s]”, the space ‘program’, (NASA “programs”), the gargantuan homo origins “programs” and many more. Technologies sold first on behalf, seemingly, of knowledge. I find rather curious his ‘hypothesis driven research”(sic) remark. Certainly many in big progams have their own hypotheses, maybe.
The development of a few techniques and isolation of sequence-specific lyases made it possible to automate the sequencing. Humans didn’t even have to make sense of the data (well, just a little of the data at the start); the computers could sort out the sequence of all the fragments. All the humans had to do was prepare samples and keep feeding the machines. All that information was generated in a fairly short amount of time and no one was really studying any of it (only doing quality control work and interacting where the machines informed them that some problems could not be worked out by the machine). As I said way back then, now the hard work starts – people have got to figure out which bits are associated with what. Since there are no mathematical models to help, we’re pretty much stuck with laborious laboratory experiments. Patenting the fragments did not help at all. We’ll have at least another 7 years (possibly more since it can take a few years for a patent to be reviewed and approved) before the patents lapse and people can use the information freely. But even then – that’s some mess of information you’ve got to wade through. Now if someone would only work out how these things regulate the assembly and folding of proteins …
“Up until 2004, it was argued that birds didn’t have much of a sense of smell (there was no real basis for this prejudice, but it was widely held). Then the chicken genome revealed that there were over 500 olfactory receptor genes (more than in a human).”
Well, birds do have reduced olfactory lobes compared to their ancestors. So it’s not like it’s completely baseless to posit a reduced sense of smell on average. And saying they have more such genes than a human isn’t that impressive, since we have a worse sense of smell than most other mammals.
Cobb: “And there are no ‘cancer genes’.”
with the exception of oncogenes.
and the tumor suppressor genes.
and the cancer specific translocation fusion genes.
Apart from that there are no cancer genes.
Well, apart from the endogenous oncogenes, the tumor suppressor genes, the cancer specific translocation fusion genes and the viral oncogenes.
And the oncogenic and tumor suppressive microRNAs.
Apart from that there are no cancer genes.
The good news is that since there aren’t any cancer genes, I won’t have to do any more mircoarrays!
What, no slime molds?