Regulatory and Ethical Aspects

(Chapter 22)

Ethical considerations

Medical applications of biotechnology may have far-reaching ethical consequences. For example, in 1993 an announcement was made that "scientists had cloned human embryos"; three copies of human embryos were created outside the body, and were allowed to develop for six days. A more recent stir was the 2001 announcement by Advanced Cell Technology that cloned human embryos of 4-6 cells had been grown. In essence, human cloning qualitatively is not new, as identical twins are clones. However, the test-tube approach is different in that embryos are selected (which is not the case for identical twins) and can be divided many times, to create a large number of embryos with genetically identical makeup. Since then, developments have been rapid, and there no longer are technological reasons why one could not clone a human. The federal government has stipulated that federal money cannot be used for cloning research involving human embryos, but this is quite an ineffective measure as now much of the scientific work in the field is carried out by private firms. There is no informed consensus yet on cloning, but certainly this issue will need to be raised in the public arena. There still is a long way to go on this. A good web site is that of the Center for Genetics and Society (http://www.genetics-and-society.org/), which conducts research on the implications of the new human genetic technologies.

Bioethics also extend into the traditional medical arena. With the development of life-extending tools (including mechanical ventilators, exotic drugs, organ transplants, and artificial nutrition and hydration devices), one must ask the question whether we should keep a person alive just because we can. And who should answer that question? Also, should particular medical products (such as human growth hormone) be available to everyone, or what are the grounds for selection? Or who should have access to anyone's DNA fingerprint? And how ethical is the business standpoint of pharmaceutical companies, who invest a lot of money to develop "luxury" medicine and treatment for the rich in the Western world, but who have invested 100-fold less in new drugs for malaria, cholera, and other lethal maladies of the tropics? These are issues that clearly go beyond what is covered in the classroom, but important to think about and form an informed opinion about.

You may want to look at the web site of the Council of Responsible Genetics, which can be found at http://www.gene-watch.org/. This Council may seem a little overcautious, but many of the issues brought up are very valid regardless the position one takes on them.

Stem cell research

A related area with bioethics implications is human stem cell research. Pluripotent human stem cells are cells that are undifferentiated and that can develop into most tissues or types. An explanation on such stem cells is provided in http://www.nih.gov/news/stemcell/primer.htm, and a 1999 stem cell report from the American Association for the Advancement of Science is at http://www.aaas.org/spp/sfrl/projects/stem/main.htm. These stem cells come from a variety of sources, primarily human embryos (embryonic stem cells). Even though there is no instance where such embryo was used for stem cell generation when it was actually destined for implantation or other procedures that would allow the embryo to develop, the political decision was made in 2001 to limit embryonic stem cell lines to those lines that existed at that time (http://escr.nih.gov/). The text of the speech of President Bush on this issue can be found at http://www.washingtonpost.com/wp-srv/onpolitics/transcripts/bushtext_080901.htm. Moreover, funding was provided to allow research to shift to other stem cells (umbilical cord, placenta, etc.) that are thought to not be able to differentiate into as many different types of cells but that may be very useful as well. Stem cell research is moving quickly, and updates can be found at http://www.stemcellresearchnews.com/ and http://www.stemcellresearchfoundation.org/.

The "early" (1977-1983) applications of genetic engineering all involved expression of human genes (such as the insulin, growth hormone and interferon genes) in bacteria that were kept in the laboratory. The level of expression was up to a million protein molecules per bacterial cell, which means that about a mg of protein could be extracted from 100 ml of cell culture. This was a marked improvement over the traditional method of extraction of relatively rare enzymes from tissue. For many purposes, it suffices to grow genetically engineered organisms in the laboratory, and to obtain the desired product from them. However, laboratory containment of production-scale numbers of transgenic plants and animals is impractical, and such genetically altered species will need to be released. Therefore, it is important to consider the requirements that need to be met for a genetically modified organism to be released in the environment.

The first genetically engineered organism that was approved for release in the US in the early nineties was a bacterium, Pseudomonas syringii, which, in contrast to most of its naturally occurring kin, does not make a protein that acts as a nucleation site for ice formation during light freezing conditions. Thus, if the genetically engineered bacteria rather than the naturally occurring ones are sitting on (and in) a plant leaf, ice formation (leading to rupture of cell walls and to plant damage) will not easily occur. Natural Pseudomonas syringii strains with properties identical to the genetically modified one do occur, so one can argue that no new bacterial characteristics are added to the ecosystem.

Around the same time, field tests were done with genetically modified plants. In 1992, transgenic tomato that expresses the coat protein from a plant virus, the tobacco mosaic virus, was tested. Plants that express this coat protein (obtained by transforming tomato protoplasts with the virus coat protein gene, and regenerating the protoplast to an entire plant) are less sensitive to the tomato mosaic virus and the tobacco mosaic virus. The insertion and expression of the coat protein gene in tomato does not result in any loss of productivity of the plant, whereas virus infection of non-resistant plants can decrease yields by 20% or more. Thus, the insertion of the gene for the tobacco mosaic virus coat protein into tomato leads to an increased resistance against two viruses without affecting the yield of the crop. The reason why viral coat protein expression in the plant leads to increased resistance of the plant against the "real" virus is not yet understood.

As will become clear in the next few paragraphs, the rate of release of genetically engineered organisms during the past decade has been mindboggling. However, first we need to consider what may be the effects when one introduces genetically engineered organisms into the environment. In the first place, is there any risk to the environment (for example, an upsetting of the ecological equilibrium in the area)? Secondly, does the introduction of the organism make sense in the long term (for example, is it likely that weeds or insects will rapidly become resistant to the herbicide or pesticide upon extensive application)? Thirdly, do we know sufficiently about the nature of the genetically engineered organism to be released to be sure that there will be no side effects (like a higher sensitivity to certain diseases)? Fourthly, is the introduction of the genetically engineered organisms the best way to go, or is it used to temporarily fix other problems? In the case of insect-resistance, most genetic modifications of plants involve the introduction of an appropriate Bt toxin. For introduction of herbicide resistance, there are several possibilities: either (1) introduction of a gene whose product metabolizes the herbicide, (2) introduction of a highly expressed copy of the gene for the receptor protein (thus "catching away" all herbicide molecules, and still have enough receptor protein without herbicide to function with), or (3) introduction of a gene that contains a mutation in the receptor protein so that the receptor protein has a decreased affinity for the herbicide without affecting the functional activity of the protein.

In the United States, herbicide-tolerant soybeans became available to farmers for the first time in 1996. This has proven to be quite a success story. Within two years, over 4 million acres (40 percent of the U.S. soybean acreage) had been planted with herbicide-tolerant soybeans -- making soybeans the number one bioengineered crop in the United States. Why have U.S. farmers taken to the herbicide-resistant soybeans and similar crops? It is because they have found that using these bioengineered seeds reduces the need to plow their fields to control weeds; decreases the amount of chemical herbicide they need to use; produces higher crop yields; and can deliver a cleaner and higher quality harvest. Total herbicide sales have not increased, indicating that environmental impacts are limited. Pesticide tolerance has been introduced primarily by means of introducing the gene for Bt toxin into plants. Corn provided with genetic protection from the European corn borer by insertion of the appropriate Bt gene was approved in the United States in August 1995. Fields of corn with Bt protection, on average, have 7-11 percent increase in yield per acre in comparison to more conventional corn, and the amount of sprayed pesticide has decreased, thus decreasing the environmental impact of agriculture.

Companies want to safeguard their investments in generating new and "better" varieties of agricultural crops. An interesting development over the past few years is the appearance of "terminator technology" designed to prevent propagation of genetically engineered plants. This was developed to prevent farmers from using home-grown seeds of genetically engineered plants, and to force the farmers to buy seeds from the company who developed them. The principles of this technology are explained thoroughly in http://filebox.vt.edu/cals/cses/chagedor/terminator.html. The ethics of this approach clearly are multi-faceted: on one hand it is clear that the company needs to recapture the investment they made in developing the genetically engineered plants, but on the other hand poor farmers may not be able to afford going back to the company and buying seeds every year.

Use of genetically modified agricultural crops is widespread globally. The country with probably the most genetically engineered agricultural crops is Argentina, with 99% of the soybean crop there being of transgenic origin. In 2001, farmers planted biotechnology-derived seed on 46% of global soybean acres, 7% of global corn acres, and 20% of global cotton acres. Of the 130 million acres of biotechnology-derived crops planted in 2001, 77% were tolerant of specific herbicides, 15% were tolerant to specific insects, and 8% were both insect and herbicide tolerant. Thus far, there is no convincing evidence for negative effects of these transgenic crops on humans or the environment. In 1999, preliminary reports were published indicating negative effects of plants producing the Bt toxin on caterpillars of the monarch and other butterflies, but subsequent field research demonstrated that the Bt level and toxicity in the plants were insufficient to negatively impact butterflies (http://www.nature.com/nsu/010913/010913-12.html).

Release of transgenic crops and animals in some respects is similar to the release of a "new" organism into the environment. The effects may be difficult to predict: there are success stories (many agricultural crops are not native to where they are grown), but (often unintentional) introduction of new species into an ecosystem in some cases has led to huge disasters. For example, a fungus introduced into America from Asia killed almost all of North America's chestnut trees. Another fungus has eliminated most Dutch elm trees from the Eastern US. The myxomatosis virus introduced in Australia (by Australian scientists) almost completely annihilated that continent's rabbit population, where this species had become a major pest within a century after its introduction in Australia. However, it should be mentioned that the rabbit strikes back, and has become essentially resistant to the virus; another virus has now been "accidentally" introduced in Australia. More than half of the insect pests in the US today come from abroad. Similarly, starlings, house sparrows and gypsy moths are all introduced animals that America could have lived without. By the same token, most of the USA's major crops, including soybean, wheat and also rice, are not indigenous to America. Such arguments are valuable reminders of biotechnology's potential to do great good or great harm, and thus one should examine very carefully the potential effects of the release of genetically engineered organisms into the environment. On the other hand, it should be realized that in many cases hybrids with properties close to those of certain genetically altered organisms could be selected by repeated crosses, as has been done virtually throughout history. Thus, it makes no sense to over-react when encountering an organism that is genetically engineered; factors such as the nature of the introduced gene (and its product) need to be evaluated first before any judgment on its potential environmental danger or on its merits can be made.

One particular issue pertaining to the safety of release of genetically modified organisms is whether desired characteristics in crops can confer adaptive advantages to weedy species. Spreading of plant genetic material is very easy. For example, bees are important pollen vectors over a range of distances and farm-to-farm spread of plants such as canola (rapeseed) that have closely related wild relatives. Pollen can also travel for miles in the wind. If crossing with wild plants and native species, herbicide or pesticide resistant weeds might result. Indeed, in Canada canola-related weeds have been found that have become resistant to three types of herbicides. It is not only related plants that may receive the transgene. There is also a report of gene transfer from genetically engineered rapeseed to bacteria and fungi in the gut of honey bees. Therefore, it is clear that one cannot guarantee the absence of spreading of transgenes that have been introduced. The question that then needs to be addressed in the evaluation of the risks of release of a genetically modified organism is whether such a spread would pose unacceptable environmental risks.

Apart from a rational analysis of potential risks, public opinion is also an important factor in the fate and success of transgenic plants and animals. After a decade of research, development, testing, and approvals, Calgene's Flavr Savr^® genetically engineered tomato hit the market place in the nineties. This tomato is slow-ripening due to decreased ethylene production, and thus it can be picked later and still be sold in good shape in the grocery store. This was the first genetically engineered food product to be marketed. However, there was a concern about the public perception of the product, and the Flavr Savr^® tomato no longer is marketed commercially. Another example of where public perception had a major effect was the case of Starlink corn: In 2000, in tacos traces of a Bt corn variety (DNA fingerprinting in action!) were found that had not yet been approved for human consumption (pending the outcome of allergen tests) but had been approved for use as animal feed. A public outcry followed. Even though Starlink corn was approved for public consumption soon thereafter and no proven cases of allergies due to Starlink have been found, this was poor public relations for the biotechnology industry. Currently, no corn varieties will be approved for animal feed if they have not been approved for human consumption as well.

Guidelines have been prepared by both national and international institutions for screening and characterization procedures of recombinant DNA organisms. The most well-known are the 1976 NIH (National Institute of Health) guidelines for research involving recombinant DNA molecules, formulated after a meeting of scientists at Asilomar. These guidelines were very strict, since at that time there was not much experience with the potential hazards of biotechnology, and the guidelines were (rightfully) targeted at a "worst-case scenario". After a few years it became clear that many of the risks were initially overestimated, and the guidelines relaxed over the years. Today some 90% of the experiments involving recombinant DNA are exempt from the guidelines. However, now new regulatory concerns have emerged: in some cases the approval for various aspects of release of genetically engineered organisms or the production of drugs etc. by transgenic organisms is spread out over several federal agencies (Food and Drug Administration, the Environmental Protection Agency, and the US Department of Agriculture), so that product approval is a long and tedious process. Although obviously the streamlining of the approval process must not result in a loss of thoroughness and quality of this process, it is obvious that one single agency can do a better and cleaner job than several agencies that often work in parallel (or antiparallel) with respect to each other. In addition, the workload of some agencies has increased dramatically over the last few years (now biotechnology is coming of age), while the staffing of the agencies has not kept pace.

In an attempt to streamline the approval process for field testing of genetically engineered plants, the USDA no longer requires submission and approval of a description of the method for conducting the field tests before the tests actually take place. Now for routine tests, one only needs to notify APHIS (Animal and Plant Health Inspection Service, a branch of the USDA) as long as the field tests follow basic guidelines. Waiting for approval is not necessary in these cases. To qualify for this "express-lane treatment", the researcher must certify that (1) the transgenic plant is one of the following species: corn, cotton, potato, tomato, soybean, or tobacco; (2) the transferred gene is stable; (3) the process will not produce disease in the transgenic plant; (4) the process introduces no infectious material to the plant; (5) the process poses no significant risk of creating new plant viruses; and (6) the transgenic plant does not contain any functionally intact genes from human or animal pathogens. This new notification procedure reduces approval time, cuts cost, encourages biotechnology innovations, and focuses USDA resources on the areas of greatest complexity. In another move to limit unnecessary paperwork, USDA allows specific transgenic plants to be removed from regulation after adequate field testing has been completed.

Whatever one's view on the appropriateness of current rules on approval of genetically modified plants and animals in the environment, there is no doubt that such organisms are hard to avoid in the food that you eat or the clothing you wear. A web site with many links on genetically modified foods is http://special.northernlight.com/gmfoods/. Suitable web sites with additional information on government and regulatory resources are http://www.nbiap.vt.edu/ and http://www.nal.usda.gov/bic/.

Release of genetically engineered microbes

Thus far, release of genetically engineered microorganisms has not been looked upon favorably by scientists and regulatory agencies. Microbes cannot be easily tracked in the environment, and it is felt that risks associated with release of genetically altered microbes are too large. Instead, naturally occurring organisms may be fished out of their natural habitat, enriched in the laboratory, and released at a different location. This may be done, for example, in the case of in situ bioremediation.

When discussing the risks associated with biotechnology and the release of genetically engineered organisms, one has to keep in mind that there are risks involved with almost anything. We ride our bicycles or drive a car, use energy from a nearby nuclear power plant, live in a flood plain, get a suntan, or maybe we even smoke, and still may be worried more about genetically engineered foods than about any of the daily hazards we have chosen to take for granted. Our choices may be irrational because we may make decisions based on emotions rather than facts. Some of the factors triggering our emotions may have to do with whether the risks are voluntary (more acceptable) or involuntary (less acceptable), whether we are in control or not, whether the risks are familiar or not, and whether the risk is natural or man-made. However, this may be pretty misleading. For those of you who like(d) cabbage, mushrooms, and peanut butter: did you know that at least for bacteria the carcinogenic potential of these presumably healthy items is very high? Often the media are keen on just reporting "facts" that will draw the attention of the reader, but there is not necessarily a critical comparison with other items.

Risks and benefits need to be put together and compared. Are we prepared to take certain risks to enjoy particular benefits? Depends on the risks, and depends on the benefits, you may answer. The same may be true with genetically engineered materials. What are we comfortable accepting as risk, and what benefits do we expect from it? This may be an important question to consider.... it clearly may have a different answer for any of us individually, but we must think about it rationally.

http://photoscience.la.asu.edu/photosyn/courses/BIO_343/
This web site contains the syllabus for the MBB 343/BIO 343 course, describes the laboratory experiments, and covers materials that will be discussed in the lecture but that have not been covered sufficiently in the required textbook (B.R. Glick and J.J. Pasternak (1998) Molecular Biotechnology: Principles and Applications of Recombinant DNA, second edition).

Most of the material at this website has been compiled over the years by Wim Vermaas, a Professor in the Plant Biology Department. Instructors this year are Wim Vermaas (weeks 5-8, 12-13, and 15-16) and David Rhoads (weeks 1-4, 9-11, and 14).

Contact information: Wim Vermaas: office location: LS-E549; phone: (480) 965-3698; Email: wim@asu.edu; office hours for Fall 2002: M and TH 10:40-11:30.
David Rhoads: office location:LS-E511; phone (480) 965-2583; Email: david.rhoads@asu.edu; office hours for Fall 2002: T/TH 1:30-2:30 pm on the days that he lectures only.

Material at this site may be used freely by others as long as the source of the information is acknowledged. Contact the appropriate web master to learn about the rules of using materials contained at other web sites that are referred to at this site.