Overselling Science, Halting Progress, Killing Opportunities: Gene Therapy, Cloning, Stem Cell Medicine & Synthetic Biology

Here's a note, slightly provoked by a pretty ridiculous piece posted at the webpage of the Institute for Ethics and Emerging Technologies. In this piece, a self-proclaimed, so-called "positive futurist" named Dick Pelletier delivers a sales-pitch for the program of synthetic biology much as envisioned by Craig Venter when holding his regular presentations aimed at potential funders, investors and customers in order to raise the value of his services, products and patents. Right off the bat, I want to underscore that what I mean to be saying here is not against Venter's scientific aims or, for that matter, his visions of what his science might eventually be good for. Not at all. What I want to point to, however, is the sort of overselling of scientific areas which are, frankly, in rather early stages of development that is going on in Pelletier's piece and that Venter himself is a bit guilty of as well, but that does not in any way limit itself to this particular field. Rather, I will here use similar patterns from the areas of human genome and associated gene therapy research, research on cloning and stem cell medicine to illustrate what this sort of overselling actually achieves, and why people and organisations (such as the IEET) seriously committed to using science and technology for the good should be wary of of this type of rhetoric.

So, what is it that Pelletier says? Well, a lot of unsubstantiated stuff, mostly, besides a lot about what synthetic biology "might" or "may" lead to, such as all of that which Craig Venter said when presenting his institute's breakthrough a while back. Very nice. I can see why Venter wants to attract investors and raise the share price of the company holding his patents, as well as the prices of the latter, and I suppose that Pelletier has some personal reasons, unknown to me, to help him doing that. What boggles my mind, however is the lack of complications, risks and the pretty optimistic (or is it infantile?) time-scale applied:

...they will produce a complete cellular system by 2015. Once this happens [...] Darwinian evolution will take over. This knowledge will help scientists understand how humans evolved in the past, and provide guidance towards a future human evolution driven, not by nature, but by tomorrow’s synthetic life technologies. We will see tiny self-reproducing factories, disease-killing machines, and exotic creations performing many useful functions.

 Nice. Getting help from something that certifiably works to understand nature better with the help of some technological innovation. Sound scientific strategy, right? But, who would have thought that....

....by 2020, synthetic life creations could eliminate, or make manageable, nearly all human sicknesses, including most of today’s dreaded age-related diseases.
 

Hmmm? And that is not the end, for in fact....

...by 2030 or before, human-made life forms could provide everyone with an affordable, ageless and forever healthy body fashioned from newly-created ‘designer genes.’

Right. Fantastic. Here's my life savings, then - no questions asked.

Not a word about risk, failure, misuse, limitations or the wicked ways of the world that most likely will see to it that this, just as any other piece of technology, no matter how well it works, will certainly not provide "everyone" with anything worth having. In particular if guys like Pelletier (as well as Venter) continues to cry wolf long, long before there is anything even close to worth having in those areas where imminent delivery is ambitiously promised. Perhaps this is what it means to be a positive futurist? Well, in that case we don't really need them do we? We already have them, just they are known under other names (take your pick) when calling us up at the least suitable hours, or filling our email inboxes, with one senseless business scam after another.

Ok, ok, so calm down. So far, this is just another of these naïve grown-up school boys and useful idiots letting some steam off. Admittedly, there is also a wider organisation with academic ambitions that for some reason is publishing the rant, which is perhaps a bit more of a reason to get worked up. But, hey, that's nothing new, is it? So what is the problem? To get to that, I need to widen the lens a bit, in order to describe how this is just one of many examples of how – indeed! – exciting and promising scientific and technology areas are ridiculously oversold, to the possible financial gain of a few of the involved experts, but to the detriment of those people that could in fact have reaped substantial benefits from the field, had it not been for the fact that once that stage is near, everyone with a buck to spare to make it happen has lost interest and, frankly, faith. So here's my cases:

1. Gene therapy. This baby has in fact been pitched as being right around the corner since the 1950's (and through the 60's and 70's), believe it or not (just pick up some of the scientific articles in the field and look for the little motivator sentence at the end). It is a wonder that James Watson was able to reuse it to attract funding for the HUGO project (although he had to switch to the wider concept of genomics half-way, when the prospect revealed itself to be much less practical than what had been thought at the outset). However, now when at last some of the first really promising clinical applications are indeed surfacing, investors have lost interest and so would I, had I been in their midst. The example of a fully developed, initially tested and very promising gene therapy for cancer sitting in the freezer due to lack of funding to do the larger sort of trials needed to have good evidence for safety and effectiveness is telling. I mean, who would believe anyone claiming to have a "promising" gene therapy that just needs some testing when that song and dance has been performed a million times before with the same depressing aftermath?

2. Cloning. Well, this story is in fact a part of that of gene therapy, as well as the next one of stem cell medicine. Here, the overselling has been mainly in the form apparent mavericks claiming to be planing very shortly or to actually have done human cloning, as well as to claim human cloning to be a help for a large number of problems that may engage people. I won't supply any link here, since this is fraud and tinfoil-hat territory, but if you're curious, just google "human cloning" and surf away. In any case, human cloning comes in two basic varieties. One is what is also known as "therapeutic cloning" or, better, somatic cell nuclear transfer, as used in a process to produce pluripotent embryonic stem cells. Another one is what is sometimes referred to as "reproductive cloning", meaning that SCNT is used to produce a human embryo, which is then transferred into a woman's uterus and allowed to be carried to term. This latter technique is interesting mostly as the most realistic prospect for having a gene therapy procedure that could in fact work for some of the major and most serious genetic diseases. However, the prospect of having anyone allow that to happen, even less to provide funding for it has been substantially crippled by the actions of the mentioned mavericks. In effect, while gene therapy for mitochondrial genetic disease might slip through the net raised in response to the proof of the apparently obvious irresponsibility of scientists provided by said mavericks, the dream of of this sort of powerful gene therapy has otherwise been effectively bumped off.  

 3. Stem cell medicine. This is a very much alive area, and in recent years there has been a stream of news about fraudulent or highly questionable operations (other examples are here and here, and these are just a few, among the ones popping up through a simple search). Hurrying to promise this or that on the basis of a scientific basis that is still pretty frail and full of gaps, and clinical experience is effectively nil. All of these operations, of course, grossly oversell the potential of whatever stem-cell based service they are offering and, of course, they do that to attract paying customers and investors. A step away from that regarding fraudulent behaviour, but still related when it comes to vested interests playing a part, we have the recent European case of the failed attempt to have embryonic stem cell lines patented. While the reasoning of the court may be discussed, it is clear to me that the case for a patent at this early stage will have to contain pretty obvious misleading parts, lest the condition of usefulness present in all patent laws would be difficult to meet. Furthermore, said sort of overselling would have had to continue when making use of the patent. Stem cell scientists and supporters enraged over the ruling were all pretty open about that the idea of the patent was to sell it to big pharma in order to have them fund clinical development, research, large trials, and so on. Well, that's fine, but would at this early stage seem to imply promising said corporate actors enough to have them open the purse. So, one may justifiably wonder what was indeed happening in the case of professor Brüstle, who was denied a patent by the European Court of Justice – was it just a loss of clinical prospect or was it his personal financial exit strategy that disappeared in a cloud of mist, or was it a bit of both? Probably the last, so we may be certain that he would have just as good a reason to oversell as in the other cases I have mentioned, had he instead been allowed his patent. And I'm pretty sure that this would have backfired, just as the other examples I have been given above, all while the rights of the patents would have blocked the scientific progress that might one day have made the sales-pitch honest and fair. Or, it that would have proven to be overly pessimistic, to discourage any potential funder or investor, just as in the case of gene therapy.

And backfire it will also in the synthetic biology case if people like Pelletier continue to rant and do Craig Venter's marketting work for him, albeit the latter – I'm sure – will laugh all the way to the bank.

Will the Synthetic Genome Breakthrough Be Any Good? - Reasons for Doubt

Just a short while after private genetic research entrepreneur Craig Venter announced the successful creation of a functioning synthetic genome, and thus opening the door to the feasibility of creating life-forms functionally governed by DNA never before present in nature, debate is heating up over what the consequences will be of this scientific breakthrough. On May 25, John Sulston – genetics professor at the University of Manchester – went public at a speech to the Royal Society in London with worries about Venter's and associates' ambitions to screen off public access to the new technology through patents and other legal commercial protection mechanisms. The comment from the Venter side so far is merely that they are not alone in doing their best to squeeze some dough out of this branch of science. However, this can hardly be seen as a valid defense if Sulston's main point is correct; rather, it would just make things worse.

In my initial comment on Venter's and colleagues' breakthrough, I devoted some space to demonstrate that the sort of utility applications boasted about  by Venter and some of the initial commentators (e.g. pollution eating or biofuel-producing bacteria) are in fact very, very far from what is achievable today or even in the foreseeable future. Even more so if we add the sensible conditions that such applications need to be introduced in an ethically responsible way. However, as I emphasised, this reason for playing down the expectations leaves one area of application that is of particular importance: that of using Venter's new technology (or some of the procedures involved) as a tool in basic science. However, if Sulston is right, also this prospect of the new discovery to have a practical impact fades in front of the eyes of a careful investigator.

In his speech, Sulston reminded about the fights around the Human Genome Project, where Venter's commercially funded side-show initially wanted to have the basic genetic blueprint of humanity as much as possible hidden behind the shields of commercial secrecy and application protection. As it turned out, the side (to which Sulston belonged) that advocated the submission of all acquired information to the public domain won that battle. Had they not, chances are that the genomics research that is now gradually producing actual knowledge and applications of use to people suffering from disease or impairment, would have been stalled considerably. For instance, we would presumably have seen much more of the sort of tricks that some US genetics companies have tried to pull on the basis of a temporary situation in the application of US patent legislation, that is now hopefully being disbanded thanks to a recent legal ruling. That is, the holders of patents and other legal commercial protection mechanisms would have demanded of researchers working for the public good that they pay for the mere use of the knowledge about the basic structure of the human genome and the connected technological processes.

Such prospects are bad news for science, since science works best when tools and information are shared as freely as can be. Patents and other commercial legal protection mechanisms become desirable only when science is ready and done, and the stage of developing actual commercial products is entered. One should not let oneself be fooled by the fact that in this particular case, a commercial research institution succeeded, since it did so by acting within the public domain context of science, thus profiting from the publicised results of all other researchers that have been working in synthetic biology according to these basic scientific principles. The move towards patents by Venter & Co. is, in this light, a disturbing case of parasitical piggybacking, where the Venter research team effectively says to the scientific community: we played you for suckers! now that, thanks to all our combined efforts, we have reaped our harvest, we'll not only bake our own bread, but we'll refuse you to use our recipe - unless, of course, you pay up.

Now, Venter himself may of course claim that he has nothing like that in mind. But how much say in such matters will Venter have in the end? Being an entrepreneur, Venter is caught in the claws of his financial backers, and his scientific empire is in all practical respects run no different from any commercial company. There are shareholders who expect a swift return on their investment, there are company boards and managements who have to comply with the standard legal requirements of setting the economic interests of the company and the shareholders before anything else. In that light, Sulston's worries are highly realistic; what initially looked as a fantastic scientific breakthrough is highly likely to turn into a serious inhibitor of basic scientific research in synthetic as well as general biology.

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.