Florianne Koechlin, Frankfurt, 1.12.2005
A personal remark in the beginning: I know you think CH is an obscure little country, full of chocolate, banks and biotech companies, and not even in the EU. Yet look at this map: We had a vote on the question: Do you want a 5 years moratorium on commercial releases of GMOs – Yes or No.
Map: Blue = Yes. All 26 states – without any exception – are blue – people voted FOR the moratorium. Even though government, Parliament, industry, main stream science and all right wing parties – which build a majority in CH – were strongly against. Now a 5 years moratorium is part of the Swiss constitution. As we kept saying: A 5 years pause to rethink risk assessment and also to look for innovative solutions without GMOs.
Rethink risk assessment is our agenda today too. For this conference Greenpeace issues a brochure which also contains 9 interviews with scientists – most of them you’ll hear today at this conference. I was in charge of these interviews – a most interesting order and I want to present you some of the results.
I’ll talk about:
1. Epigenetics,
2. Transgenic plants,
3. Risk assessment.
One of my interview partners was Professor Martin Heisenberg from the University Würzburg. I asked him if he could describe me the function of a gene. His answer was: “That is without doubt one of the most open questions there is. A gene can have a lot of different functions; the number of its functions has no upper limit. A gene can also acquire new functions. This applies to all genes, those of humans, flies or plants.
When I learn Chinese, genes which play a role in my language centre will have new functions. If I then ask what functions these genes have, I have to ask if this is before or after I learnt Chinese. My learning Chinese will have bestowed particular genes in my language centre with new functions.
I asked: So the function of a gene goes far beyond coding particular proteins. Genes influence various regulating mechanisms and communicate with one another ...
He answered: It goes a lot further. Take this language gene for Chinese. The gene was already there naturally, before human languages were developed, but it is used in a quite specific new way in Chinese language. But this was of course only a hypothetical example.
A closer look at the molecular level shows that genes are indeed highly context dependent, that they are ambiguous and that they can have many different functions.
Marcello Buiatti from the University of Florence, explained: “The human genome has approximately 30,000 so called “coding genes” and these can code for more than 500,000 different proteins. Therefore, gene “ambiguity” – more proteins coded by a single gene – is very high, and is present at the level of transcription, between transcription and translation and also after translation due to post-translational modifications of proteins. Ambiguity, leading to plasticity of responses is made possible by the presence of many sophisticated mechanisms fixed throughout evolution – that’s part of epigenetics.”
Epigenetics is one of Marcello's keywords. “Epi” means above. Epigenetics is concerned with regulation- and control systems above the level of the genome. One example is the methylation of genes , as mentioned by Marcello – genes can be silenced by adding methylmarkers. You find a thorough description of epigenetics and what is known about epigenetics of plants in the study made by Katja Moch from the Institute for Applied Ecology in Freiburg.
Richard Strohman, retired professor at Berkeley University, USA, explained in his interview the links between genes, epigenetics and cells. He said: "DNA has been called the Book of Life by Human Genome Project scientists, but many other biologists consider DNA to be simply a random collection of words from which a meaningful story of life may be assembled. In order to assemble that meaningful story, a living cell uses a second informational system. It is “dynamic” because it regulates changes in products over time, and it is “epigenetic” because it is above genetics in level of organization. And some of these changed products feed back to DNA to regulate gene expression. The key concept here is that these dynamic-epigenetic networks have a life of their own – they follow network rules not specified by DNA. And we do not fully understand these rules.” (1)
Perhaps one of the most intriguing new discoveries was that epigenetic systems build a bridge between the genome and the environment . Environmental changes can have direct influence gene-expression patterns, through epigenetic systems.
A recent example: Pregnant mice were given special food supplements in early pregnancy. This affected the genes of the embryos. The new born mice had a different fur-colour, they were leaner and less prone to cancer. As if their genes “remembered” the food their mother ate during pregnancy. The scientists believe that epiegentic systems mediated these changes. In the meantime more examples of such direct environmental influences on the genes are known, also in plants.
Jean Baptiste Lamarck might have looked pleased at these new findings – it contradicts the old believe, that only genes are responsible for heredity.
These findings, of course, conflict seriously with the old paradigm – the old Central dogma of the Gene as developed by Francis Crick in 19XX. A dogma which is still very much present nowadays.
In an official Swiss document I found this definition some years ago: “A gene is a section of the DNA, which contains the information for one protein (...). By the way of these proteins genes determine the structure as well as all metabolic processes of an organism.“ This is the old dogma. It basically means: Genes are context-independent entities, always encoding the same protein. It’s a onetrack street from gene to protein to everything else; the program of life is in its genes. It's a seductive paradigm, and its beauty is its simplicity.
But it is flawed. Epigenetics, as mentioned, turns the picture upside down and leads to a complete reversion of hierarchy: Genes are not the ones controlling life processes, but rather suppliers of biochemical substances which the cell needs in its respective development state or functional state. Genes are molecules like others too, and the cell signals what is needed and where. Genes do not determine the program.
It’s like you always looked at a box from above on the outside and suddenly you look at it from below in the inside. It is a completely new way to look at life. It’s not that the central dogma of the Gene is wrong – it’s only wrong in overseeing the limits of its validity, by referring to the genome as the ‘book of life’ or the blueprint of life.
Where does this leave us in agro-biotechnology?
With the Central dogma gene-transfers were said to be precise and predictable – we know the gene and we know the new organism and the sum of both cannot be more risky than each one of them.
This might sound naiv today, but in the last few weeks and months we heard this mantra in Switzerland again and again, during the campaign around the moratorium: Genetransfers are precise, they said, while conventional breeding is governed by chance and chaos. We have a gene for blight resistence , they said, and we soon will have blight resistent potatoes. We have the gene for draught resistence, they said – you all know these stories. An isolated technical one-factor solution for every problem. A gene for every problem.
Whereas – I will not go into this deeply – we all know that gene transfers are neither precise nor predictable. As Cesare Gessler from the ETH Swiss Federal Institute of Technology, Zurich) puts it: "Genetic engineering has not been fully developed. The products of genetic engineering today are still at the level of a dinosaur technology. We use genes which are foreign to a species, not knowing where they are inserted or what else will change in the whole chain from gene to protein. We don't know which regulatory relationships we're intervening in”.
Cesare Gessler – who by the way supported the Swiss initiative with great engagement – is doing research with apples. So he says:
“Personally, I can't easily accept a fish gene in an apple. Nor would I like a 35S promoter, which comes from a virus, in my apple. And I don't find antibiotic resistance genes entirely acceptable either as this can produce problems with horizontal gene transfer for example. I don't necessarily believe there could be really big problems, but I simply don't feel comfortable with the idea.” In a future time, he adds, with more sophisticated approaches, transgenic plants might be a valuable perspective.
In summary: While we have mounting data for epigenetics the outdated Central dogma of the gene still exists – mainly in the field of agro-biotechnology and commercial applications. We seem to hang in a state of suspense. The stubborn perseverance with which some still cling to the old dogma might have to do with commercial pressures and with patents. It’s easier to patent genes than to patent complex epigenetic networks.
Before turning to implications for risk assessment – my third point – let me look at 2 phenomena which strike me as curious:
The first is that there are relatively few studies on negative effects of epigenetics on transgenic plants.
But this does not surprise Gilles-Eric Seralini (Caen University). "When you study the role and regulation of genes," he told me, "you undertake a lot of trials and you only select the GMOs that do not have these kind of problems. That means that 98% of all the GMOs that you produce do not function just because the gene might be methylated or it might be present but is not used normally by the organism which received it. All the organisms that are modified but do not express the gene are put in the garbage. So you find very few studies on these issues. There are some papers about insertional mutagenesis or transgenisis in plants showing that artificial gene constructs may be more unstable than others. This has led to the discovery of antisense RNA or RNAi. So I think that we should bear in mind that the study of the composition and the analysis and the substantial equivalence are far below the level of sufficiency to be able to predict any toxicity or any unintended effect of a plant.“
The second point is: Almost 100 percent of all transgenic plants cultivated throughout the world are either herbicide-tolerant or insect resistant, Bt plants. Only 2 traits, 2 traits which were developed in the eighties – you could say an amazing lack of innovation from industry.
As some of my interview partners confirmed, this poor performance could have another deeper cause. The reason for the success of these two properties could be that their metabolic pathways are relatively isolated and do not interact with other ones. This is not the case with most other traits- there you will have interferences on the level of genetics, epigenetics as well as on the level of metabolism – hence the many failures in producing transgenic plants with other properties.
What are the impacts for risk assessment procedures?
The philosophy underlying the laws and reglementations for risk assessment still depends on the Central Dogma. A thorough reevaluation of previous assumptions never took place.
In the last few years there were attempts: impacts of so called “unintended effects” were cautiously acknowledged and introduced, be it in Codex Alimentarius, OECD-reglementations, the Biosafety Protocoll or the EU Directive 2001/18 on releases or the ‘food and feed’ regulation 1829/2003.
But if the whole body of risk assessment theory is based on flawed assumptions – on a crumbling pillar – it is also flawed. When the pillar crumbles, it will also crumble – slightly exaggerated. I hope we will discuss this issue today.
I’ll point at some problematic areas – some broad cracks in todays theorie of risk assessment.
First crack: Today a company has to test a GMO for its impacts on beneficial insects or ecological effects – in just one place. So Monsanto tests its new Bt-maize in Missouri and claims validity of the results in Sweden or Kenya. Beatrix Trappeser from the Federal Agency for Nature Conservation BfN requires in her interview that every application for commercial release should include data from diverse climatic and ecological conditions and from several years. New findings in epigenetics point strongly to the need of such a request.
Second crack: Gilles Eric Seralini proposes that GMOs should, like pesticides, be tested for toxicity using long-term feeding trials. The EU pesticide directive requires a much more thorough assessment. When you assess a new pesticide, you need 3 feeding trials for 3 months, one for 1 year and one for 2 years. Gilles Eric Seralini said: “There is absolutely no scientific reason to avoid these kind of experiments for actual GMOs.“ Today mandatory toxicity tests are not prescribed for GMOs. “I think it is stupid to give GMOs to people for an entire life time," he says, "when at the same time there is no requirement to undertake toxicity tests even for three months. So we should force industry to publish their results and we should enforce such long term tests.“
Manuela Malatesta will tell you today some results of long-term feeding experiments she did with GMO fed mice.
But then there is the problem that I feel ambiguous about long term animal experiments to test GMOs not having much benefits – but this is another discussion.
Another crack: Richard Firn from the University York says that enzymes of the secondary metabolism present a n additional layer of uncertainty, hardly looked at up to now. The general believe is that an enzyme is substrate specific, eg produces one specific product. That is what I learned at the University. But this theory is only correct for enzymes of the primary metabolism.
In contrast, enzymes of secondary metabolism can be multifunctional, much like genes. One enzyme can produce many different products.
So a gene transfer affecting the secundary metabolism can have highly unpredictable consequences.
His conclusion is:“ "It would be nice," he says, "if there was a greater humility and more experts would admit the limits of their knowledge.” This reminds me of the functions of the hypothetical gene with plays a role in Chinese learning from the interview of Martin Heisenberg. And another celebrity once said:
"Risk assessments," notes Firn, "are all about using knowledge and understanding to predict outcomes. The growing understanding of the mechanisms underlying epigenetic effects reveals a complexity that must inevitably mean that risk assessments being made of GM plants will carry greater uncertainty than one might have liked.” With regard to releases, there is not just one answer except that the simple views of the last two decades have, to some extent, to be be revised.
And another point: today we know a lot of genes which for the moment have no function. We know, for example, whole clusters of resistance genes. For the time being they have no function; they have been shut down. But when a pathogen alters its identifying proteins, it can happen that the plant, thanks to a resistance gene which until then has not been functional, nonetheless recognises the pathogen. This gene then has a function even if it hadn't been active for a long time.“ Cesare was one of the scientists supporting openly the moratorium in Switzerland – for the sake of research and of a better science.
Matthias Fladung, a proponent of GMOs, agreed that more reearch on epigenetics was necessary, but that the Bt-maize was the best examined plant and any epigenetic effects should habve been detected by now. He turned the argument around: There is so much reshuffling in the plant genome due to epigenetics or sexual reproduction, that the introduction of transgenes seems to be a minor event. All other interviewpartners had strong scruples about commercial releases of GMOs and recommended a carefull reevaluation of risk assessment procedures.
And he continues:”Additional ambiguity sources at the cell and organism level are somatic mutation, methylation, amplification processes and RNA interference all occurring in specific regions of the genome and affecting gene regulation. Some of these processes may be transmitted to cell progenies. When they occur in germinal cell lines, they can be transferred to subsequent generations.”
Note: (1) He didn’t say this, the interviewer repeated what he was reported to have said before.