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August 10, 2000


Mae Wan and Joe Cummins reply on Hull paper criticism of


The following was circulated on the gentech@gen.free.de server. Readers of
Agbioview may care to reply.

On 9 Aug 2000, at 12:37, jcummins wrote:

Dear Dr. Tribe,

I am sorry that I cannot spend enough time answering e-mails,
especially the ones from people like yourself who offer reasoned
criticisms of our position. I have posted our reply to Hull et al, in
the reply to your other e-mail. Let me paste another concerning the
CaMV promoter containing reference to another paper that confirms
the reality of the recombination hotspot, and the fact that the promoter
is active also in animal systems, contrary to conventional wisdom
among plant molecular geneticists. It was submitted to Nature
Biotechnology, but they have refused even to acknowledge receipt
of the communication. We are not as interested to get it published as
to draw attention to these crucial findings, so please circulate it

The issue of natural versus artificial genetic engineering takes a
much more considered reply which we are preparing. This subject
is so important that I really feel it is up to people who defend the biotech
industry or are exploiting the technology to convince us that it is
beyond reasonable doubt safe. It should not be up to people like
myself and my colleagues, who would much prefer not to have to
do it.

I do not retract anything that we have said in our article concerning
infectious diseases, because we are aware of no substantial reply
to the points we raised, especially in the conclusion, where we listed
the circumstantial, inductive and deductive evidence linking genetic
engineering to the recent resurgence of infectious diseases. We are
not saying that genetic engineering is solely responsible, as we
made clear. Overuse and abuse of antibiotics, environmental degradation,
increase in travel and so on, all have contributed. We would be
reassured by actual empirical investigations, for example,
systematic comparisons of bacterial strains pre and post genetic engineering
era. Meanwhile, we should prevent the release/escape of GM
constructs, vectors, and other naked/free nucleic acids into the environment.
We do not want to block research. Quite the contrary is the case. Why
do genetic engineers find it so difficult to accept common sense

Matzke et al (1) suggest that pararetroviral promoters such as the
CaMV 35S are not exotic to plant genomes as they already
contain many integrated pararetroviral sequences. The crucial question is
whether the CaMV 35S promoter in transgenic constructs poses special

Kumpatla and Hall (2) analyzed a transgenic rice locus and
confirmed that fragmentation and recombination occur frequently within the
CaMV 35S promoter, but not in the wheat plant ubiquitin promoter used in
another transgenic cassette. This indicates that the CaMV
promoter is not like any other promoter. Six out of seven recombination
junctions in the CaMV promoter map near the 19 basepair palindrome
identified as a recombination hotspot by Kohli et al (3).

The conventional wisdom among plant molecular geneticists is that
plant promoters, such as the CaMV 35S, are not active in animals
(4). In fact, the CaMV 35S promoter was found to support high levels of
reporter gene expression in mature Xenopus oocytes (5), and to
give very efficient transcription in extracts of HeLa cell nuclei (6). The
CaMV promoter worked at least as well as the SV40 promoter in
Xenopus oocytes, and better than the major late promoter of the adenovirus-2
in HeLa cell extracts.

So, while the CaMV is specific for plants in the cruciferae family,
its isolated promoter is promiscuous across domains and
kingdoms of living organisms. It is the genetic (and evolutionary) context that
makes all the difference. There is no justification for claiming that
the promoter in transgenic constructs is as safe as the promoter in
the intact viral genome, nor to consider it equivalent to the promoter
of proviral sequences in the plant genome.

1. Matzke, M.A. et al. Nature Biotechnology 18, 579 (2000)
2. Kumpatla, S.P. and Hall, T.C. IUBMB Life 48, 459-467 (1999).
3. Hull, R. et al. Microbial Ecology in Health and Disease (in press).
4. Kohli, A. et al. Plant J. 17, 591-601 (1999). 5. Ballas, N. et al.
Nucleic Acid Res 17, 7891-7903 (1989). 6. Burke, C. et al. Nucleic
Acid Res 18, 3611-3620 (1990).

Mae-Wan Ho, Angela Ryan
Institute of Science in Society and
Dept. of Biological Sciences
Open University
Milton Keynes, MK 7 6AA, UK
Joe Cummins
Dept. of Plant Sciences,
University of Western Ontario
----- Original Message -----
From: To:
Sent: Wednesday, August 09, 2000 12:56 PM
Subject: RE: more on 35S, archive 2575

> Dear Joe,
> I forward this from another list. It is on the paper from Hull et al
> which I assume you have. best regards wytze

> On 9 Aug 2000, at 9:51, Ranch, Jerry wrote:
> I'd like to make some observations on the CaMV 35S issue:
> One point that Hull et al did not make was that the construct used by
> Kohli et al was designed specifically to elicit recombination.
> There would be very few transgenics produced in the industry for
> COMMERCIAL use that would use the same element several times
> tandemly. In this case the 35S promoter was used three times
> tandemly. It is common knowledge in the art that these kind of
> constructs are unstable. So the industry does not use them widely,
> except for experimental use. So while Kohli et al can make use of
> these types of construction for experimental use, they have little
> relevance to the real world of GMOs.
> Now Hull et al and Tepfer et al review the claims of Ho et al on
> the recombinogenic nature of 35S as suggested by Kohli et al paper.
> To my mind Kohli is a a very poorly designed experiment. It is
> poorly designed because the results are subject to different
> interpretations. There are better ways to identify hotspots in
> sequences than by junction analysis. Also, they evaluated 19
> transgenics. If I were to make such broad sweeping claims based on
> the evaluation of only 19 transgenic events, I'd lose my job.
> Because of the variability of integration, most commercial
> enterprises evaluate hundreds of events for each gene construct
> introduced to identify the ones that express properly, are safe
> (through rigorous compositional analysis), and are genetically
> stable.
> Also, the existence and function of hotspots is arguable. In Wahls
> et al Cell 60:95-103 (1990) a hotspot from the human genome was
> identified with the sequence d(AGAGGTGGGCAGGTGG)6.5. Now this
> sequence was used by Engel and Meyer (Plant Journal, 2:59-67(1992))
> in petunia and tobacco assays in search of sequence mediated
> homologous rcombination...they found none caused by the supposed
> human SAT sequence. Now some will argue that one might not expect a
> human SAT sequence to function in a plant...then why would you
> expect a viral sequence to function in a plant? In the art,
> recombination hotspots remain a contentious issue, and there is no
> wide consensus that they really exist. If they did exist and
> function as predicted, the industry would be using them extensively
> to increase transformation frequency, or integration site.
> Thats all for now.
> Jerry Ranch
> R. Hull, S.N. Covey and P. Dale
The 35S promoter, derived from the common plant virus, cauliflower
mosaic virus (CaMV),
is a component of transgenic constructs in more than 80% of genetically
modified (GM) plants. Alarming reports have suggested that the 35S promoter
might cause accidental activation of plant genes or endogenous viruses,
promote horizontal gene transfer, or might even recombine with mammalian
viruses such as HIV, with unexpected consequences. In this article,
we discuss the properties of CaMV and the 35S promoter and the potential
risks associated with the use of the promoter in GM plants,
concluding that any risks are no greater than those encountered in
conventional plant breeding.
(Clipped for brevity)