ISIS Report 29/11/04
Fluid Genome & Beyond
Invited lecture presented at The Precautionary Principle in Science
and Politics, Federation of German Scientist Conference, 22-23 October
2004, Marie-Elisabeth-Luders Haus & Magnus Haus, Berlin
References for this lecture are posted on
members website. Details here.
Mae-Wan Ho Institute of Science
in Society, PO Box 32097, London NW1 0XR, UK,
A time and a place for gene transfer
These two butterflies, poised so delicately on a flower, are engaged in
rampant gene transfer of the natural kind. And they stay like that for hours,
quite remarkable considering their short lifespan.
Those butterflies know that there is a proper time and place for gene
transfer, and they only do it with soul mates.
Life began some 3.8 billion years ago. The geological epochs are marked
by origins of major groups, big transitions, radiations and extinctions. There
is a time and place for every group and every species to come on the
evolutionary stage. The species did not all evolve at once, or all in the same
place, so gene transfer was naturally limited by space and time; except at the
dawn of life, when the ancestors of the three major life-domains - Archaea,
Bacteria and Eukaryotes were not yet distinct. As a rule, organisms,
including bacteria, have many ways to prevent foreign DNA getting into their
In contrast, genetic modification involves recombining or joining
together new combinations of DNA from widely different sources, and
deliberately inserting the artificial constructs into the genomes of organisms
Genetic modification is breaking all the rules of evolution. Genetically
modified organisms are unnatural, not just because they have been produced in
the laboratory, but because many of them can only be made in the
laboratory, quite unlike what nature has produced in the course of billions of
years of evolution. It is short-circuiting the evolutionary process.
Thus, it is possible to introduce new genes and gene products, from
bacteria, viruses and other species, or genes made entirely in the laboratory,
into crops, including food crops, that we have never eaten; that have never
even been part of our food chain.
Thats important, particularly in view of discoveries that
geneticists have been making since the mid 1970s, which tell us there is really
no holding the genome still. Francis Crick and James Watson were largely right
about the structure of DNA, but they are woefully wrong on how genes are
supposed to determine the characteristics of organisms.
Francis Cricks Central Dogma of molecular biology decrees that
genetic information flows strictly one way, from DNA to RNA to protein, and by
implication, to the characteristic determined by that protein. That must have
been the inspiration for genetic modification. And if it were really that
simple, genetic modification would work just fine.
The scientific myth that launched and sank a thousand companies
But even as biotech companies were set up, genetic engineering as a
research tool was making momentous discoveries that would overturn every single
assumption of genetic determinism and eventually sink the industry, as
explained in detail in my book . A more representative picture is what
geneticists in the early 1980s were already calling, "the fluid genome",
although it is only within the past two years that it has become respectable to
question the Central Dogma :
"It will take years, perhaps decades, to construct a detailed theory
that explains how DNA, RNA and the epigenetic machinery all fit into an
interlocking, self-regulatory system. But there is no longer any doubt that a
new theory is needed to replace the central dogma that has been the foundation
of molecular genetics and biotechnology since the 1950s."
Gabriel Dover and Dick Flavell, two geneticists who played key roles in
defining the new genetics, put it succinctly in 1982 :
"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."
The fluid genome is in constant conversation with the
environment, which changes not only the patterns of gene expression in each and
every cell, but also the structure of the genome and the genes. You can read
more about the latest developments in successive issues of our magazine,
Natural versus artificial genetic engineering
James Shapiro , whose specialty is in jumping genes, referred to the
processes of the fluid genome as the "natural genetic engineering" that the
organism has to do to survive. This natural genetic engineering has all the
appearance of being quite precise, and to be regulated by the organism as a
whole. It is part of the dance of life in which every part of the
organism down to individual molecules - is intercommunicating and hence
working together in a perfectly coordinated way. In contrast, artificial
genetic engineering is crude and uncontrollable, basically because the human
genetic engineer does not know how to intercommunicate with the whole organism,
and can only gain force-entry into the genome, using aggressive means to make
the organism express the foreign genes (see below).
A typical unit-construct for artificial genetic engineering consists of
a promoter, a gene-switch that says to the cell, "copy the following message
(the gene or coding sequence) for making a protein", and another signal, the
terminator, to say, "stop here, end of message". All three parts are
often from different sources. The gene itself could also be a composite of
different DNA, made artificially in the laboratory, and with substantial
changes in the coding sequence as well .
So far, the only way to get foreign genes expressed reliably in the
organism is to use very aggressive promoters belonging to viruses. The
cauliflower mosaic virus (CaMV) 35S promoter is the most widely used.
The artificial constructs are further spliced into gene carriers or
vectors, and introduced into cells by invasive methods that result in random
integration into the genome, giving rise to unpredictable effects, including
gross abnormalities in animals and unexpected toxins and allergens in food
crops. One recent publication characterises the GM insert as follows :
scrambling of transgene sequences through recombination of both
large and small non-contiguous fragments of the delivered DNA, frequent
incorporation of genomic DNA sequences into the transgene loci and
rearrangement in the genome DNA flanking the transgene locus."
A transgenic line is essentially regenerated from a single cell in
which specific events of transgenic DNA integration occurred. Each event will
give rise to a different line. In other words, there is no possibility for
quality control. This problem is compounded by the overwhelming instability of
transgenic lines, because the artificial constructs cobbled together from DNA
of different sources tend to have weak joints.
I have referred to the instability of transgenic lines as the "best
kept open secret", because everybody has known about it for years, but agree to
say nothing, while regulators turned a blind eye. I have been pressing for
"event specific" molecular characterisation of the structure of the insert(s)
and their position(s) in the genome in successive generations, as proof that
the transgenic line is stable . This requirement was finally written into
the 2001 European Directive (2001/18/EC) for deliberate release.
But it was not until last year that French government scientists
checked the transgenic inserts of five transgenic lines: Monsantos MON810
maize, Roundup Ready soya, GA21 Maize, Bayers T15 maize and
Syngentas Bt 176 maize; and in every case, the transgenic insert(s) had
rearranged, not just from the construct used, but since characterised by the
company [9, 10]. Moreover, many breakpoints involved the CaMV 35S promoter,
there is scrambling of host genome at the site of insertion, and the inserts
appear to show a preference for retrotransposons, which is bad news, because
that means they could easily transfer again, and spread.
The French scientists reported their results in a poster at a
conference in Barcelona in June 2003 with the title, "Characterization of
commercial GMO inserts: a source of useful material to study genome fluidity"
. It is indeed genomic fluidity that makes genetic modification both futile
and dangerous .
Belgian scientists confirmed the instability of the transgenic lines
analysed by the French [11,12]. But there were small and large discrepancies
between the two studies, which suggest that the transgenic lines were also
non-uniform. Either one of those aspects would make the transgenic lines
illegal for Europe under the current deliberate release directive. I
communicated the findings to the European authorities and other governments.
Genetic instability is a serious safety issue, as the GM varieties are
now different from earlier generations that were assessed and licensed as safe
for cropping or for food and feed.
Major uncertainties over safety
Indeed, there are major uncertainties over the safety of GM food and
feed that have yet to be addressed. I give a list below.
- The European Food Safety Authority (EFSA) gave Monsantos GM
maize Mon863, containing the biopesticide Cry3Bb1 a positive assessment,
despite "very disturbing" results of feeding trials showing kidney
malformations and increased white blood cells in male rats and high blood sugar
and reduced immature red blood cells in female rats .
- Last year, up to 100 villagers in the south of the Philippines living
near GM maize plots became ill when the GM maize came into flower . Terje
Traavik of the Norwegian Institute of Gene Ecology in Tromsø found
antibodies to Cry1Ab produced by the GM maize in the blood of 39 villagers
. The same illnesses recurred this year .
- Between 2001 and 2002, twelve dairy cows died on a farm in Hesse,
Germany, after eating Syngentas Bt176 GM maize, and others in the herd
had to be slaughtered on account of mysterious illnesses . The Spanish Food
Safety Authority has withdrawn authorisation for Bt176 cultivation .
- Arpad Pusztai and colleagues found that GM potatoes with snowdrop
lectin adversely affected every organ system of young rats, and the stomach and
small intestine lining grew up to twice the thickness of controls .
- Scientists in Egypt found similar results in the gastrointestinal
tract of mice fed GM potato with Bt toxin .
- US Food and Drug Administration had data since the early 1990s
showing that rats fed GM tomatoes with antisense gene to delay ripening
developed small holes in their stomach .
- Aventis (now Bayer) found 100% increase in deaths of broiler chickens
fed glufosinate-tolerant GM maize T25 compared to controls .
- Numerous anecdotes from farmers and others indicate that livestock,
wildlife and lab animals avoid GM feed, and fail to thrive or die when forced
to eat it [21, 22].
Different species of GM food or feed with different GM genes have caused
problems in many species of animals. You dont have to be a scientific
genius to suspect that there is something wrong with the GM process itself or
the GM insert common to them. One of these is the CaMV 35S promoter.
The CaMV 35S promoter
In 1999, two laboratories [23, 24] independently confirmed earlier
suspicion that the CaMV 35S promoter has a recombination hotspot, which
resulted in frequent breaks and rearrangements of the transgenic DNA and other
signs of increased transgenic instability.
My colleague Prof. Joe Cummins was the first to warn against using the
CaMV 35S promoter or any viral genes in plants because it had been shown that
such viral transgenes in plants could recombine with naturally occurring
viruses to generate, in some cases, super-infectious viruses. Subsequently, the
CaMV 35S promoter has been found to substitute for the promoter of many plant
and animal viruses to produce infectious viruses.
We wrote a review  drawing attention to the hazards of the promoter,
calling for all GM crops containing it to be withdrawn. We were viciously
attacked and vilified. We replied to all the scientific criticisms in a paper
 that was much longer than the original, and our critics never acknowledged
it. In the course of debating with our critics we uncovered even more damning
evidence: the CaMV 35S promoter is active in species across the living world:
bacteria, fungi, algae, plants, animal and human cells included . Again,
our critics never acknowledged this to themselves or to the public.
Because the CaMV 35S promoter is very aggressive and active in animal
and human cells, there is a possibility that it could trigger cancer by making
certain oncogenes over-express. The problem is worse, because in some cases,
the CaMV 35S promoter contains extra enhancer and booster
sequences; and none of these constructs has been tested for safety.
For example, the AGBIOS Database describes Mon 863 maize as follows
"The introduced DNA contained the modified cry3Bb1 gene from
B. thuringiensis subsp. kumamotoensis under the control of the
4-AS1 promoter (CaMV 35S promoter with 4 repeats of an activating sequence),
plus the 5 untranslated leader sequence of the wheat chlorophyll a/b
binding protein (wt CAB leader) and the rice actin intron. The transcription
termination sequence was provided from the 3 untranslated region of the
wheat 17.3 kD heat shock protein (tahsp17). The modified cry3Bb1
gene encodes a protein of 653 amino acids whose amino acid sequence differs
from that of the wild-type protein by the addition of an alanine residue at
position 2 and by seven amino acid changes."
Some of you may recall the headlines in 2000 on the first success of
gene therapy after some 12 years trying. Gene therapy is the genetic
modification of human cells, and use methods and constructs very similar to
those employed for genetic modification of animals and plants.
Bone-marrow cells from infants suffering from an X-linked Severe
Combined Immune Deficiency were genetically modified in a petri-dish, and the
transformed cells re-implanted into the patient.
Eleven infants were treated and nine were apparently successful.
However, among the nine successes, two developed leukaemia in 2002. It turns
out that the transgenic DNA jumped into a gene, that when over-expressed,
triggers cancer [29-32].
Box 1 summarises why GM is inherently hazardous. These concerns have
never really been properly addressed.
Whats wrong with GM?
- Breaks all the rules of evolution & short-circuits evolution
- Rampant recombination of DNA from different species that would never
have exchanged genes in nature
- GMOs unnatural because many can only be made in the laboratory
- Makes new genes and gene combinations that have never existed
- Introduces new genes and gene products to our food chain
- Uncontrollable and unpredictable
- Transgenic lines unstable and cannot be risk assessed
- Disease-causing viruses and bacteria are the main tools of GM as they
are for creating biological weapons
- Enhances horizontal gene transfer & recombination, the main route
to creating new disease-causing agents.
- Transgenic DNA designed to jump species & invade genomes
- Transgenic DNA invading genomes can cause inappropriate gene
expression and trigger cancer.
Yesterday, the representative of your research minister asked, "Which
science do we need for a precautionary politics?"
My answer is that we need a different kind of science, and the fluid
genome is pointing the way to it.
Beyond the fluid genome
IBM has been building a new supercomputer, Blue Gene, projected to be
complete in two years time, which will be the most powerful supercomputer on
earth . It will perform one quadrillion (10 to power 15) operations per
second. Even then, it will take a year to simulate an average protein folding
Our body contains some 100 trillion (10 to the power 14) cells, each
expressing a unique repertoire of the millions of proteins that could be made.
Not only do the proteins fold simultaneously to perfection in split seconds,
they also carry out millions of catalytic reactions at the rate of thousands to
hundreds of thousands cycles per second. And all the diverse activities are
orchestrated, from the molecular and microscopic through to the macroscopic
domain, from trillionths of a second to hours, days and years.
The organic whole is quintessentially diverse and pluralistic. The
organism is the antithesis to uniformity and homogeneity. It is truly
remarkable that we should habitually think of ourselves as "I" in the singular.
So what makes such a vast conglomerate of diverse molecules and cells a whole?
One way to think of the tens of thousands of genes and millions of
proteins that must work together as a whole, is that they constitute a
molecular democracy of distributed control, a phrase first
introduced by Henrik Kacser , who was in Edinburgh University.
Conventional biochemistry still tends to see enzymes and their
substrates bumping into each other as they wander about haphazardly and
randomly in a solution of water inside the cell. But since the early part of
the last century, evidence has been accumulating that the cell is intricately
organised, perhaps down to the level of individual molecules; much of that
evidence was reviewed by Joseph Needham, distinguished Cambridge biochemist
later turned historian of Chinese science, in his book, Order and Life,
first published in 1936 .
Not just enzymes and substrates, but even the water molecules are
organised in a liquid crystalline continuum, as Needham had predicted in his
remarkably prescient book, and as we discovered in my laboratory in 1992, when
we half stumbled upon a novel, non-destructive imaging technique that enabled
us to see the insides of live organisms in pure, vivid colours. It inspired me
to write a book  around what the colours mean, entitled,
The Rainbow and the Worm, The
Physics of Organisms. This book also explains why organisms are so
sensitive to low doses of toxic agents, by the way.
In this new vision of the organism as a liquid crystalline continuum,
electric and electromagnetic energies of all kinds enable the molecules to
intercommunicate and coordinate their activities. When intercommunication and
coordination are perfect, we get to a state of coherence or wholeness.
The living organism is so coherent that it looks like a dynamic liquid crystal
display, because all its molecules are moving coherently together.
I have referred to this dance of life as quantum jazz,
where every single player, however small, is improvising freely from moment to
moment, and yet keeping in beat and in sync with the whole.
Organisms are not controlled from the outside, that much is clear. They
are not even controlled from the inside. There is no master-gene
turning development on, nor armies of control genes that are not
themselves also controlled.
The ideal organic whole, quintessentially pluralistic and diverse, works
by total participation and intercommunication, and is at once most coherent and
most free, for the parts as for the whole.
In contrast, the dominant mechanistic culture reduces all to uniformity
and homogeneity, it operates in rigid hierarchies of controller versus the
controlled, and sees only inevitable opposition between the individual and the
collective, the public and the private. This failure to see nature as organic,
entangled wholes is the ultimate source of all wars and conflicts, and of the
lack of precaution. Science with precaution is also science with social
Taking the ideal organic whole seriously involves entirely new
programmes of scientific research in sustainable agriculture, holistic health
and sustainable energy use, with equal partnerships between scientists and
traditional health practitioners and farmers in the field. We have initiated a
discussion paper Towards a Convention on Knowledge , which has been
widely adopted by scientists and indigenous peoples organisations.
And to turn our words into deeds, we launched an Independent Science
Panel (ISP) to produce our own report ,
Case for a GM-Free Sustainable World, calling for a ban on GM crops and
a comprehensive shift to non-GM sustainable agriculture.
The ISP had a very successful briefing to the European Parliament on 20
October 2004, where we put this message across loud and clear [37, 38].
To live with the fluid genome is to leave behind the mechanistic culture
of death and destruction for a thoroughly organic paradigm that regenerates
life and creativity; that would truly nurture individual freedom and diversity
with universal love.
So let us work freely, creatively and coherently together, like the
dance of life that I am going to show you now.