Thursday, 20 May 2010

From synthetic genome to synthetic life: prospects as well as perils of gene technology exponentially multiplied

In today's issue of Science it is announced that (in)famous private genetics research wizard Craig Venter's team has succeeded in cooking a working genome out of non-living constituents. The popular summary describes the crucial breakthrough as being (1) not only making DNA-strands, but making them properly packed in the form of chromosomes, (2) inserting the synthetic chromosome into bacteria as replacement for its "natural" chromosome, (3) ending up with a living organism (the bacteria) that continued to replicate and produce proteins. Since the technique involves the use of "natural" bacteria as hosts for the synthetic DNA, this is not a case of the creation of synthetic life. Therefore, the suggestion by, e.g., Art Caplan that Venter and colleagues' achievement means that "What does it mean to be alive? /.../ What seemed to be an intractable riddle -- and one with significant religious overtones -- has been solved" is a clear overstatement (and, arguably, partial evidence that bioethics needs to be combined with careful attention to scientific detail). This misreading of what has actually happened is repeated in many newsreports, also in my own country. It still remains to be seen if human engineering is capable of creating a wholly synthetic living organism.

Nevertheless, the news clearly means that Venter and colleagues  race to the top of Nobel Prize candidates for the coming decade. The achievement is truly stunning – both as a piece of genetic engineering, and as a source for understanding scientifically what is involved in organic reproduction and many other processes involving the genome. During the last 15 plus years that I have worked as a researcher and a commissioned expert on the ethics of genetics, I have had reason to touch on the possibility of gene technology breaking lose from the bonds of using as building blocks only pieces of DNA already to be found in nature a few times. My message has been, first, that this possibility seems rather remote and, second, that when it is realised, the ethical issues surrounding gene technology will not only multiply, but exponentially so. On the first point I was wrong, wrong, wrong. The second one, however, holds firmer than ever.

The new area of synthetic genomics opened up by Venter's and colleagues' result is of relevance primarily for two areas of genetic research and development: (1) basic science (that gets a new tool to play around with for the attainment of new knowledge), (2) genetic modification and design. However, as far as I can understand, it will not have any significant impact on what is so far the most potent application of gene technology to human beings: genetic testing and analysis. Synthetically made genetic variants never before present in nature will not improve our abilities to detect the genes of cells, humans or other organisms. In that case, the prospects offered by nanotechnological methods for studying the content of cells without destroying them has a greater potential for changing the prerequisites of present-day ethics discussion about genetic testing, prenatal diagnosis and, in particular, preimplantation and preconception genetic diagnosis (the latter being detection of the genome of gametes that allows these to be subsequently used for reproduction).

With regard to genetic modification and design, the last two decades have seen many applications to non-human organisms, primarily crops and animals used for food, pharmaceutical production or medical research. Although the modifications done so far have not been very far-reaching (mostly changes of one or a few features of organisms), the effects are rather unsettling. Biologists and Ecologists warned early on for systemic effects within the DNA, the ability of the modified DNA to spread into the rest of nature and for the modified variant's capability of taking over habitats and thereby eradicate other species and variants through ordinary processes of natural selection. In sum, due to our lack of understanding of the subtleties of the DNA and its adventures in larger biotic complexes, this side of genomics can be likened to a lottery with all our basic living conditions in the pot in order to gain a few bucks here and there. All of these scenarios have proved real enough, albeit commercial interests have so far been powerful enough not to have policy makers react as they should have to begin with. The possibility of beefing up this virtual wild west of in situ technological experimentation with synthetic genomics is hardly appealing.

Moving over to genetic modification applied to human beings, this has been a wet dream of medical researchers for many decades and work on achieving the curing of some of what are doubtlessly the worst diseases we may imagine has been committed. However, what has been achieved so far is two results: prohibition and failure. All around the world, so-called germ-line genetic modification of human beings is legally banned in some way or other (if nothing else through bans on so-called reproductive cloning). The reason for the banned is either mystical ideas about such modification violating religious commands, incomprehensible ideas about the procedure threatening human autonomy, dignity or identity, or the much more sensible claim that such a procedure is much too uncertain to be responsible (i.e. the argument that applies with even greater force to non-human genetic modification). It does not appear overly speculative to suggest that the addition of the possibility of synthetic germ-line genetic modification would mainly change this argumentative and legislative picture to the disadvantage of genetic modification supporters.

Regarding somatic genetic modification, medical science has indeed seen some daring attempts, but alas with rather depressing outcomes. It seems that, apparently, the theoretically much less complex undertaking of modifying the genome of adult cells in the body, is proved by experience to suffer from uncertainties making it not very controversial to suggest that also such applications are very hard to justify before our understanding of the mechanisms involved have multiplied and deepened considerably. Again, adding synthetic genomics to that calculus seems mostly to worsen the prospects of ethically responsible gene therapy.

None of this will, of course, intimidate those people whose megalomaniac lack of consideration for the collateral damage of their attempts to have their names written into the book of history have already produced a number of scandals and tasteless applications within, e.g., preimplantation genetic diagnosis, reproductive medicine, stem cell science and reproductive cloning. Such people are presumably already drooling over the prospect of cooking some of their own DNA and chromosomes and then lure some desperate people into playing guinea pigs. Similarly, regarding the non-human applications, the large companies presently cashing in handsomely on the risking of all our livelihood can be expected to apply the same wild west mentality to the new possibilities delivered by Venter & Co.

For this reason, the urgent call of Art Caplan for oversight and regulation is well placed to say the least, and the challenge that he highlights of implementing a system for identifying synthetic genomic products is indeed important to take on. However, Caplan seems to me overly optimistic about what sort of applications will in fact see the light of day, and actually naïve regarding the risks involved. His dream about synthetically engineered bacteria that solve our economic, environmental and human problems is, to my mind, just as unrealistic as the dreams of the geneticists of the 1980's that DNA technology would end world hunger. What we got was Roundup Ready. There's simply no big money in that sort of thing, it creates no sustainable markets; for that, what's needed are small improvement opportunities that at the same time sustains the underlying problem (e.g. poverty and dependence). Rather, my reaction is that governments all over the world now have a golden opportunity to put a halt to any further development of the institutionalised irresponsibility that is the business of non-human genetic modification. In the human case, the safeguards are already in place. Let's apply the same common sense reasoning to the non-human case, and thereby create an opportunity for responsible technological progress – at least from this synthetic point and onwards.

Postscript: having finished this piece, a number of my colleagues around the world have made their initial comments. A nice collection is provided by the BBC.


  1. Thanks! Possibly more coming on this in a few weeks.

  2. It seems what Venter et al. has done is that they have made a synthetic copy of a natural occurring genome, and put it into a bacterium which has had its genome removed. This is of course a great feat in the advance in laboratory technolgy, but not so much more than that, whatever some people may wish to think.

    Firstly, as you point out it is not an example of creating artificial life, which even if it had been, would not have revolutionized biological thinking since it is already assumed that the cell is a mechanism, and so it should in principle be possible to assemble it artificially.

    Secondly, this has no relevance for what I an sure is a much more difficult problem in artificial genomics, namely creating properties in living organisms from scratch, through design of DNA with a certain purpose in mind, where there is no naturally occurring DNA that can be borrowed. This would among other things involve designing a new protein or a cascade of new proteins that would fulfill the purpose. There are steps in this process that are very complex indeed. For this reason I think genetic engineering will rely on copying nature for a very long time to come.

    In this light Venter's achievement seems more or less irrelevant, apart from showing laboratory prowess. After all what is the difference between using DNA that already exists in nature and using artificially synthesized copies of naturally occurring dna other than a much higher cost of production?

  3. Absolutely with you on this, Johan, except on one point. If one ever would want to truly design life containing functions not hitherto found in nature, one would need to know in detail the mechanism from the micro- to the macro-level. In bacteria that doesn't involve so many steps, but as you point out, at least what proteins, enzymes etc. would result in various environments.

    However, Venter's technology seems crucial for attaining that knowledge. If you are unable to actually construct a synthetic genome and have it functioning within an organism, you are unable to research the phenotypical functions of synthetic genomes.

  4. Yes, so it is a necessary step on the way to being able to synthetically construct properties.

    I guess this would be especially suitable in bacteria where you have a fast generational turnaround and a simple genetic structure. You could think of using the principles of natural selection coupled with artificilly induced controlled mutation, possibly using methods from Venter, using some kind of guided randomness, to get new and functional genes coding for new properties.

    I can see this coming, but the practical (not to mention the ethical) problems surrounding this type of experimentation with humans seem rather daunting in comparison.

  5. Due to the regulations already in place worldwide, we will see no such experimentation for ages except if some nutter scientist turns rogue. That's why the issue of having a way to identify cells with synthetic genomes is so important (without that, we can never identify the bad guys). My guess is also that Venter & Co. will run into some serious technical problems already when moving up from mycoplasma to slightly more advanced creatures. Both because these have much more complex genomes and because their morphology is more challenging (such as having a cell wall). It will take a while before we hear about synthetic genomes working in, e.g., insects, and even longer before it's mammal time.

    In the meantime, the non-human applications seem to me to be the most worrying. Not least since Venter has so far only talked wildly about various dream-scenarios and not stressed the risk side. This worry increases by knowing his backers are purely commercial actors with shareholders keen on receiving a return in their investment....

  6. Yes and we know how much responsibility such commercial backers usually take when it comes to externalities not directly affecting their bottom line. It is scary.

    Even more scary because as soon as there is money to make from it, legislative action that facilitates it will in all probability follow, at least in the US given the level of conflict of interest that many times seems to exists in the political sphere there.