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In Context #17 (Spring, 2007, pp. 3-4); copyright 2007 by The Nature Institute

Putting Genetic Miscalculation on the Record
Craig Holdrege

At The Nature Institute we are beginning a project to investigate and make widely known the unintended effects of genetic manipulation. Here we describe briefly the need for the project and give two concrete examples. You can expect to hear more from us on this topic in the coming year.

In science labs and biotech companies around the globe, organisms—bacteria, plants, and animals—are being altered every day in new ways by genetic engineering, from goats that make silk proteins in their milk to bananas that produce a cholera vaccine, from glow-in-the-dark monkeys to plants that produce pesticides. A Pandora's box of opportunity has opened up in the past twenty years to manipulate organisms in virtually any way the genetic engineer's or venture capitalist's fantasy envisions. The experimental organism is treated as a means to an end, as a medium to realize an intention. The only limiting consideration is: does it work? What is remarkably absent from consideration is the question whether the experiments might be impinging upon the biological integrity of the manipulated organisms themselves. This question seems irrelevant as long as you view organisms as mechanisms to be altered or as commodities to be improved upon.

Genetic engineering is often portrayed as an exact and precise method to alter organisms. In reality, the moment a novel gene construct is put into a host organism, biotechnologists have little understanding of the observed effects. Occasionally the effect is the one intended, but more often than not, other effects arise that are totally unexpected and may even be the opposite of the intended effect. Only the small number of "successful" results make the news. Even then the successful trait may coexist with many unrecognized side-effects, and further unintended effects may be triggered only after the organism is exposed to a different environment.

It is not only that genetic engineering induces changes in organisms that would naturally never occur (no strawberry would ever become frost-resistant by taking up flounder DNA); the manipulation ramifies into the organism as a whole in uncontrollable and mostly unknown ways. Genetic manipulations reveal, paradoxically, the integrity of the whole organism by disturbing it.

The widespread occurrence of unintended effects of genetic modification on the whole organism is largely overlooked or ignored, and genetic engineering is marketed as a scientifically based, precise means of manipulation that is safe to the consumer, the host organism, and the environment. U.S. regulatory agencies (FDA, USDA, EPA) encourage the development of biotechnology and when they declare that genetically modified crops are safe, their opinion is in the vast majority of cases not based on agency-directed tests, but on those carried out by the companies marketing the crops. A 235-page report, "Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects" (2004) by the National Research Council plays down the effects of genetic engineering and mentions only five examples of unintended effects in plants.

As we see it, a massive and relatively uncontrolled experiment with life is being played out in labs and farms around the world. This experiment cannot be addressed if people are not even aware of its existence, its scope or its gravity. It is therefore imperative to make the unintended effects of genetic modification on organisms more widely known.

We believe that the far-reaching implications of genetic manipulation of life will become clear only when the widely dispersed information concerning unintended effects is bundled together and made accessible to the public in an understandable way. In our project we will (1) research the primary scientific literature for genetic engineering experiments that show unintended effects on the host organism's physiology, morphology, or behavior; (2) create a comprehensive document summarizing and giving references for the examples found, grouping them in categories that will emerge in the course of the research; (3) write one or more reports, commentaries, and articles, and give talks summarizing our findings in a language understandable to the general public; (4) publish our report(s) along with the examples of unintended effects on our website and make this information resource known to over eighty organizations, journalists, and key individuals nationally and internationally concerned with biotechnology.

Following are two examples of the kind we will be researching and describing.


EXAMPLE 1

Goal: Transgenic plants that make a biodegradable polyester (polyhydroxybutyrate = PHB). Three genes (isolated from bacteria) needed for PHB production were transferred via Agrobacterium into the mustard Arabidopsis.

Expected Result: Six transgenic lines were produced that accumulated PHB in their chloroplasts. The greatest amount was 4% PHB of total plant fresh weight.

Unintended Effects:

  • The more PHB in a transgenic line the smaller the plants—growth retardation was evident even in those plants that accumulated very little PHB.
  • The plants with the most PHB never produced seeds.
  • The plants showed slight chlorosis (yellowing of leaves).
  • Metabolic profiling of 60 metabolites "suggest that severe changes in metabolism result from the production of PHB in these lines." The amounts of sugars, alcohols, amino acids and organic acids changed markedly while—to the researchers' surprise—the amounts and composition of fatty acids did not change.

Source: Bohmert, K., I. Balbo, J. Kopka, et al. (2000). "Transgenic Arabidopsis Plants Can Accumulate Polyhydroxybutyrate to Up to 4% of their Fresh Weight," Planta vol. 211, pp. 841–45.

EXAMPLE 2

Goal: Different lines of transgenic potatoes were created to break down the sugar sucrose in different ways. This entailed making a small genetic change that is associated with the production of a specific enzyme in each of the transgenic lines. The scientists wanted to know if additional changes were being effected, so they carried out a so-called metabolic profile.

Intended Result: As expected, there were changes in amounts of the substances that were connected to the sugar breakdown pathway that had been affected by the genetic manipulation.

Unintended Effects: The scientists investigated a total of 88 different substances and found, to their surprise, that there were changes in the amounts of most of these substances in the transgenic potatoes and that many changes seemed unrelated to the sucrose breakdown pathway. The transgenic lines differed both from each other and from the non-manipulated potatoes. For example, the transgenic potatoes often produced more amino acids than the non-manipulated potatoes, and nine substances were found in the transgenic potatoes that could not be detected in the non-manipulated potatoes.

Additional Comments: A review article remarks that the above study "revealed a massive elevation in the content of each individual amino acid. This was particularly surprising since it had previously been thought that the majority of the tuber's need for amino acids was met by supply from the leaves, and that the tuber did not possess the necessary machinery for de novo synthesis of amino acids. It, furthermore, demonstrates the need for considering the effect of genetic manipulation on pathways other than those targeted" (Carrari 2003).

Primary Source: Roessner, U., A. Luedemann, D. Brust, et al. (2001). "Metabolic Profiling Allows Comprehensive Phenotyping of Genetically or Environmentally Modified Plant Systems," The Plant Cell vol. 13, pp. 11-29.

Comment Source: Carrari, F., E. Urbanczyk-Wochniak, L Willmitzer, et al. (2003). "Engineering Central Metabolism in Crop Species: Learning the System," Metabolic Engineering vol. 5, pp. 191–200.

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