Mae-Wan Ho
Director, Institute of Science in Society
A Time & A Place for Gene Transfer
Mae-Wan Ho spiced up her talk with some sex – showing a slide of butterflies engaging in rampant gene transfer of the natural kind. She reiterated that there is a proper place and time for gene transfer, and only between soul mates, not just with anyone.
Gene transfer has to be thought of in terms of evolution. Life on earth began 3.8 billion years ago when the earth’s atmosphere was a mix of noxious gases, and the only organisms that could have survived were bacteria that could transform chemicals to obtain energy. She gave a quick lesson in evolution, spanning from the oldest fossils – stromatolites – dating to 3.5 billion years ago, which were blue-green bacteria, through to the Eukaryotes (organisms with genetic material enclosed in a nucleus, appearing 1.6 billion years ago), to multicellular, soft-bodied animals thought to have originated a billion years ago, to animals with shells, and so on, until the present time.
At every stage the conditions on earth became right for the emergence of major groups of animals, and all the species didn’t evolve all at once or all in the same place. She stressed that there is thus a time and place for species to come together on the evolutionary stage to exchange genes.
Ho explained that before the three major domains of Archaea, Bacteria and Eukaryotes became distinct there was a certain amount of horizontal gene transfer. But by and large the rule is that different species don’t exchange genes, although there were exceptions especially among bacteria. She stressed, however, that organisms, including bacteria, have many ways to prevent foreign DNA getting into their genomes, so we don’t have to worry when we eat normal food.
Since the mid-1970s, geneticists have made the discovery that there is no holding the genome still. Francis Crick and James Watson may be largely right about DNA structure, but they are woefully wrong on how genes are supposed to determine the characteristics of organisms in linear, one-way causal chains. If the Central Dogma of molecular biology – that genetic information flows strictly one way, from DNA to RNA to protein – is right, then genetic engineering would work.
Instead, by the 1980s geneticists had already coined the term ‘the fluid genome’, as genes and genomes actually function in a flexible, non-linear way, and the structure of the genetic material is subject to turnover and modification in the course of development and evolution. Ho quoted Gabriel Dover and Dick Flavell, two geneticists who were key in defining the new genetics: “The application of new molecular techniques reveals that, beneath the level of the chromosome, the genome is a continuously changing population of sequences. Mobility, amplification, deletion, inversion, exchange and conversion of sequences create this unexpected fluidity on both an evolutionary and developmental timescale.” James Shapiro has referred to these processes as ‘natural genetic engineering’, which the organism has to do to survive. The fluidity of the genome reflects the constant intercommunication between all parts of the organism.
Ho emphasised that genetic engineering is breaking all the rules of evolution. Genetically modified organisms (GMOs) are unnatural, not just because they have been produced in the laboratory, but because many of them can only be made in the laboratory, and have never existed in the billions of years of evolution. Genes from bacteria, viruses etc., are incorporated into crops and food crops, which we have never eaten before nor have they been part of our food chain. It involves recombining DNA from different sources, which would not have opportunity to meet in nature, and deliberately inserting the artificial constructs into the genomes of organisms.
She gave a quick lesson in genetic engineering, explaining how a foreign gene is never transferred alone; it needs a promoter to say to the cell “copy the following message for making a protein” and a terminator to say, “stop here”. All three parts are often from different sources. The gene itself could be a composite of different DNA from different sources. The artificial constructs are cobbled together and tend to have weak joints, which causes instability. There is no legitimate evolutionary history that would have stabilised them.
The artificial constructs are further spliced into gene carriers or vectors and introduced into cells by invasive methods. The genetic engineer has no control over where and in what form the foreign DNA ends up in the genome, giving rise to unpredictable, random effects. In other words, there is no possibility for quality control. This makes a mockery of risk assessment. There is also a vast literature that shows transgenic instability.
In contrast, the ‘natural genetic engineering’ that the organism itself carries out is quite precise, and in coordination with the rest of the organism. It’s as if the whole of the organism is singing and dancing and making music together.
Ho warned that genetic engineering is inherently dangerous. For example, in January 2001, researchers in Australia ‘accidentally’ created a deadly mouse virus that killed all its victims in the course of manipulating a harmless virus. That and the current SARS epidemic remind us that horizontal gene transfer and recombination create new viruses and bacteria that cause disease epidemics. And this is what genetic engineering greatly enhances, in both scope and frequency.
Genetic engineering short circuits the entire evolutionary process, and allows the rampant recombination of genetic material from diverse sources that would otherwise have very little opportunity to mix and recombine in nature. Newer techniques like ‘DNA shuffling’ can create in the matter of minutes millions of new recombinants in the laboratory that have never existed in billions of years of evolution. How can we test these millions of recombinants to see which are deadly pathogens? Furthermore, the basic materials and tools of genetic engineering are DNA from viruses and bacteria that cause diseases, just as for making bioweapons. Ho asked, with genetic engineers like these, who needs bioterrorists?
She stressed that this is no longer a theoretical discussion, as despite the paucity of research dedicated to horizontal transfer of transgenic DNA, there is already evidence of horizontal gene transfer of transgenic DNA from plants to bacteria in soil and bacteria in the gut of human beings. She said that the Newcastle feeding study was designed to underestimate horizontal gene transfer, probably in the hope of not finding it. Unfortunately they did find horizontal gene transfer to human gut bacteria, but the risks were played down.
Already, in the mid-1990s, a research group found that transgenic DNA fed to mice can pass through the gut and placenta, ending up in white blood cells, cells in the spleen and liver, and in the foetus and newborn. In a paper published in 1998, the researchers said that the consequences of foreign DNA uptake for mutagenesis (generating mutations) and oncogenesis (causing cancer) have not been investigated.
The relevance of this remark is striking with regard to the two cancer cases recently identified among the recipients of gene therapy. It makes the point that exposures to transgenic DNA carry the same risks, regardless of whether it is from gene therapy or from GM foods. Ho emphasised that gene therapy is just the genetic modification of human beings, and uses constructs very similar to those for the genetic modification of plants and animals.
She raised the worrying spectre of the cauliflower mosaic virus (CaMV) 35S promoter, used widely in GM crops, which has a recombination hotspot, i.e., it is prone to break and join up. This means it can transfer horizontally and recombine much more readily. Ewen and Pusztai had suggested that the damage done to young rats fed GM potatoes could be due to the transformation process itself or the transgenic construct, which contained the CaMV 35S promoter.
Critics say that people have been eating the cauliflower mosaic virus in infected cabbages and cauliflower for years without harm. But Ho stressed that we have not been eating the CaMV promoter, which has been cut out of its evolutionary and genetic context, and put in combination with strange genes and put into strange genomes. The growth factor effect referred to by Ewen may be connected to the hazard created by transgenic DNA jumping into genomes.
Ho concluded by sketching an analogy of the fluidity of the genome, one of all the genes intercommunicating and playing music and musical chairs together in the genome. Into this harmony, a rouge piece of DNA is inserted, with the CaMV promoter. The CaMV promoter is like an amplifier forcing the cell to express the gene that follows. Integrating the CaMV promoter into a genome is like putting in a rogue who does nothing but play the same phrase of heavy metal music over and over again through the loudest amplifier. This is clearly discordant with life’s exquisite music and musical chairs in the genome, more akin to Mozart.
During the Question and Answer session, Ho was asked what makes transgenes more prone to horizontal gene transfer. She explained that transgenes are designed to overcome species barriers and invade genomes, they are unstable and tend to fragment, and many have the CaMV promoter that has a recombinant hotspot. She mentioned an experiment that was conducted to see if transgenic crops are different. They found clear differences – transgenes from the transgenic line were 30 times more likely to spread than the same gene obtained by mutagenesis. (Bergelson J, Purrington CB, Wichmann G. Promiscuity in transgenic plants. Nature 1998, 395, 25.)
Commenting on so-called ‘pharm crops’ used to produce pharmaceuticals and industrial crops, Ho said that these are the most dangerous applications. For example, some of the pharmaceuticals are immune suppressants, and some contain the spike protein of the corona virus. Some pharm crops have a gene from the AIDS virus, and the gene undermines the immune system and recombines with opportunistic, infective viruses to generate new recombinants.
Ho also explained that the Independent Science Panel (ISP) is a follow on from a discussion paper Towards a Convention on Knowledge (available at www.i-sis.org.uk). She said that it is dangerous to discuss ethics in the absence of knowledge, as we can’t have science-free ethics. Science is too important and scientists have the obligation to communicate both risks and benefits. She noted that the ISP report discusses the benefits of sustainable agriculture. When risks and benefits are placed side by side, the rational choice is clearly to forgo GM crops and shift to sustainable agriculture.