• The DaVinci

A Response to Paul Berg, Jennifer Doudna, and Recombinant DNA

Updated: 5 days ago

E. Smith

3.30.21


To read the Berg Letter: Potential Biohazards of Recombinant DNA Molecules

To read the Doudna Letter: A prudent path forward for genomic engineering and germline gene modification


(THEDAVINCI-CHARLOTTESVILLE) - Berg Letter and Doudna Letter Responses

Introduction

The Berg Letter, written and published in 1974, was a set of rules put in place for the use of recombinant DNA. This letter then led to a conference the following year where the technology and safety measures were discussed. More recently, in 2015, Jennifer Doudna wrote a letter of similar structure highlighting the potential hazards of CRISPR. An article was written by Leah Ceccarelli of the University of Washington in 2018 that compared these letters and critiqued them. In this paper, I will describe the Berg Letter regarding recombinant DNA safety, the 1975 Asilomar Conference on Recombinant DNA, the Doudna Letter regarding CRISPR safety, the critique on both letters, and then respond with my own opinions/ideas.


The Berg Letter

In 1973, Paul Berg discovered recombinant DNA. Realizing the potential power that this technology could hold, he wrote a letter outlining its capabilities and what cautions should be taken when using it (Berg, Baltimore, Boyer, Cohen, Davis, Hogness, Nathans, Roblin, Watson, Weissman, & Zinder, 1974). In this letter, he talks about the use of recombinant DNA to make a RNA strand in E. Coli that is complementary to the Xenopus laevis ribosomal DNA strand as an example of a use of recombinant DNA (Berg, et. al 1974). Following this, he then mentions that E. Coli can have some strains that will infect humans, so there needs to be caution around the use of E. Coli with recombinant DNA. He continues in this letter by describing two types of experiments that should not be undergone until “adequate methods are developed” for the prevention of the spread of the recombinant DNA (Berg, et. al 1974). After a few more precautionary measures are mentioned, the letter explains that they base their precautions off of judged potential and that these precautions will disrupt the progress of scientific advancements made using recombinant DNA, so safety can be ensured (Berg, et. al 1974).

The Berg Letter does refer to E. coli as a useful source for the applications of recombinant DNA, as it can effectively produce RNA in relatively simple conditions. However, this bacteria poses a few risks, as it has some strains that can be found in the human gastrointestinal system, and these strains have the capability to “exchange genetic information with other types of bacteria” (Berg, et. al 1974). This capability is risky because some of these “other types of bacteria” are pathogenic, therefore, being harmful to humans (Berg, et. al 1974). It’s really thoughtful for this to be pointed out in the Berg Letter, especially since there has been a large amount of biological experimentation that utilizes E. coli since then. This could have helped the evolution of sterile procedure, which is an essential methodology in experimentation.

The section that explained the two types of experiments that should be delayed until further understanding was a very key point in this paper. The two types of experiments were described as “construction of new, autonomously replicating bacterial plasmids that might result in the introduction of genetic determinants for antibiotic resistance or bacterial toxin formation […] or construction of new bacterial plasmids containing combinations of resistance to clinically useful antibiotics” and “linkage of all or segments of the DNA's from oncogenic or other animal viruses to autonomously replicating DNA elements such as bacterial plasmids or other viral DNA's” (Berg, et. al 1974). It was smart for them to provide specific examples of what should not be approached yet, so it’s clear to all readers. Shortly following this section, the letter stated, “the director of the National Institutes of Health is requested to give immediate consideration to establishing an advisory committee” which would have three main tasks including “overseeing an experimental program to evaluate the potential biological and ecological hazards of the above types of recombinant DNA molecules” and “developing procedures which will minimize the spread of such molecules within human and other populations” and “devising guidelines to be followed by investigators working with potentially hazardous recombinant DNA molecules” (Berg, et. al 1974).

Overall, I think this was a very strong and precise letter. It got its point across without taking an abundance of pages, but still held a necessary amount of detail and explanation. The way it was written demonstrated a genuine concern about the possible hazards of this recombinant DNA technology while also acknowledging that it’s also an important tool in the advancement of biology. The letter even suggests that an “international meeting of involved scientists from all over the world” should be held to further discuss the topic (Berg, et. al 1974).


1975 Asilomar Conference on Recombinant DNA

In early 1975, the suggested meeting took place in Asilomar, California, in which scientists from around the world gathered to discuss biohazards with recombinant DNA molecules (Mukherjee, 2016). During this meeting, the scientists decided on a way to rank the recombinant DNA experiments by their risk value. This ranking was used as regulation for the development of future projects and experiments with recombinant DNA molecules. The resulting agreement of the conference was that, in order to prevent interference from the government, such experiments could be “self-regulated” (Mukherjee, 2016).


The Doudna Letter

Many years later, in 2015, Jennifer Doudna published her letter, “A prudent path forward for genomic engineering and germline gene modification,” regarding safety measures around CRISPR-Cas9 technology (Baltimore, Berg, Botchan, Carroll, Charo, Church, Corn, Daley, Doudna, et al., 2015).

The Doudna letter starts off with an Abstract section describing a meeting that was held beforehand in January of 2015, followed by a brief description of CRISPR-Cas9 and what it does. After the Abstract section, there is a section that describes their current applications of CRISPR-Cas9, which outlined some of CRISPR-Cas9’s many potentials like replacing mutated genes or changing genes in embryonic stem cells (Baltimore et al., 2015). This is then followed by a “Moving Forward” section, which recommended discussion in the science community and then brought up some questions about responsible usage of CRISPR-Cas9 (Baltimore et al., 2015). Following this section is a Recommendations section, which suggests further research into CRISPR and ethics needs to be done. Additionally, there are four provided steps that in summary suggest further debate among the scientific and ethical community as well as to not proceed with this technology in humans while the ethics are still in question (Baltimore et al., 2015).

This letter referenced its predecessor, the Berg letter, at a few points throughout which I thought was smart. Having a model for a rulebook/warning letter is quite helpful in the mostly unknown world of science, so the Berg letter set a good precedent. The letter feels like it was written with a lot of worry, as it mentions many times how this could be exploited and would result in ethical and biological chaos. Overall, I think it was not bad of a warning letter and said what it needed to say, but some sections could have been a bit clearer and less anxiously-written. However, this may be a biased opinion of sorts since I lived for the few years that have been after this letter and have witnessed violations of it.


Doudna and Berg Letters in Juxtaposition

The Berg Letter and the Doudna Letter each had their own successes and downfalls. The Berg Letter was one of the first of its kind and, therefore, had nothing to base itself upon. I do not think there are any specific flaws with the Berg letter- I actually find it a bit easier to comprehend than the Doudna letter. The Doudna letter was able to use the Berg letter as an example, and did so well structurally. However, I think the Doudna letter was a bit less clear than the Berg letter, which leads me to question if perhaps modern scientific writing uses a bit more jargon than scientific writing in the past does. Overall, both were informative, well-put, and good cornerstones for the progression of genetic science.


Ceccarelli’s Critique on Berg/Doudna Letters

The introduction to this critique is very interesting as it lists magazines and articles that have featured CRISPR (Ceccarelli, 2018). Ceccarelli describes the Berg and Doudna letters as “calls for responsible research,” which is a good summary of them (Ceccarelli, 2018, p3). She then analyzes the Berg text a bit, which very much demonstrates her strength in communications. At the beginning of the section where she analyzes and critiques Doudna’s letter, she says “significantly, none of these terms (construct, create, link, or join) appears in the Doudna essay, even though CRISPR is often attached in public discourse to synthetic biology, a field that is filled with metaphoric vehicles of construction, manufacturing, and creative work,” which shows that she is very apt at critiquing this letter (Ceccarelli, 2018, p6). Ceccarelli talks a lot about Doudna’s uses of certain terms, which made it feel a bit awkward to read.

After judging the vocabulary in the Doudna letter, Ceccarelli states that the biggest difference between these two texts is the conception of the subject technology as an agent (Ceccarelli, 2018, p6). Basically, the Doudna letter seems to personify the subject technology, in this case CRISPR, significantly more that Berg does with recombinant DNA. This could be the source of what made Doudna’s letter sound so worrisome- the question of does the technology itself have more control than the scientist.

Overall, I think she does slam Doudna a bit on the vocabulary, but then does point out the very intriguing point of seeing CRISPR as an agent that has control and capabilities. This was something I had not even recognized in Doudna’s writing, but now it sticks out. This brings up more ethical questions, especially after seeing the violation of these regulations with the CRISPR babies. Is CRISPR itself the agent for human genome editing, or is CRISPR just the vector for human nature and curiosity to use to break established ethical rules?


Conclusion

It was very interesting to examine these texts side by side. These texts raised a lot of questions- scientific, but mostly philosophical or ethical. The Berg letter was a strong work that helped set some of the first guidelines about genetic editing. The Doudna letter was a modern example of the Berg letter, and showed the more anxious side of scientists (regarding ethical concerns and power). The Ceccarelli critique outlined a terrifying metaphor of a personified CRISPR-Cas9, which opened more questions about the motives of the scientist. In conclusion, I think having conversations that include as many voices as possible is very important regarding ethics in human genetic science, and these conversations need to continue whenever there is a significant new discovery.



References

Baltimore, D., Berg, P., Botchan, M., Carroll, D. R., Charo, A., Church, G., Corn, J. E., Daley, G. Q., Doudna, J. A., et al. (2015). A prudent path forward for genomic engineering and germline gene modification. Science. 2015 April 3; 348(6230): 36–38. doi:10.1126/science.aab1028.

Berg, P., Baltimore, D., Boyer, H. W., Cohen, S. N., Davis, R. W., Hogness, D. S., Nathans, D., Roblin, R., Watson, J. D., Weissman, S., and Zinder, N. D. (1974, July 26). Potential Biohazards of Recombinant DNA Molecules. Science, New Series, Vol. 185, No. 4148 (Jul. 26, 1974), p. 303. American Association for the Advancement of Science. Retrieved 3/7/2021 from http://www.jstor.org/stable/1738673

Ceccarelli, L. (2018). CRISPR as agent: a metaphor that rhetorically inhibits the prospects for responsible research. Life Sciences, Society and Policy Vol. 14, No. 24. Department of Communication, University of Washington. https://doi.org/10.1186/s40504-018-0088-8

Mukherjee, S. (2016). The Gene: an intimate history. New York: Scribner, 2016. Print.





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