Einsteins on the Beach: A Response to Doudna, Berg, and the Evolution of CRISPR
(THE DAVINCI - CHARLOTTESVILLE) - In 1975, over one hundred scientists, writers, and lawyers gathered in Pacific Grove, California, at the Asilomar Conference Grounds. They met to discuss the biological consequences and benefits of the rapidly developing recombinant DNA technology used in many genetic experiments at the time (Mukherjee, 2017). The conference was orchestrated by Paul Berg, the geneticist who discovered recombinant DNA in 1973, and was meant to serve as a forum on the potential evolutionary and biological risks of the new technology (Mukherjee, 2017). Asilomar has since been referred to as a “graduation ceremony for the new geneticists.” It marked a turning point in genetic engineering and helped define the future of biology (Mukherjee, 2017, p. 235).
In 1973, Paul Berg created the first gene hybrids—two segments of DNA from different bacteria stuck together to create a single strand of genetic material (Mukherjee, 2017). To do this, he used DNA from SV40—an oncogenic virus that infects primates (Vilchez, 2004, p. 498). Berg used the enzyme ligase to fuse the entire SV40 genome with a section of DNA from another bacteria, phage λ (Mukherjee, 2017). This experiment would instantly expand the field of genetic engineering, allowing scientists to create new genetic “chimeras” and organisms formerly implausible and unheard of (Mukherjee, 2017). However, this level of evolutionary power could have dangerous consequences—both ethical and biological. The Asilomar conference attempted to establish safe and efficient guidelines for genetic experiments, while allowing scientists some freedom to pursue innovations in the new science (Mukherjee, 2017). The Gene nicely lays out the structure and major elements of the conference, from its diverse attendants to its uncomfortable conclusion and the document that started it all: the Berg Letter.
The one page, all-encompassing response to the hazards of recombinant DNA and genetic modification gets right to the point: “Although [recombinant DNA] experiments are likely to facilitate the solution of important theoretical and practical biological problems, they would also result in the creation of novel types of infectious DNA elements whose biological properties cannot be completely predicted in advance” (Berg, 1974). The creation of brand new genetic entities could result in increased pathogenicity, antibiotic resistance, and uncontrollable viral outbreaks (Mukherjee, 2017). Any experimental missteps could lead to a pandemic, and government intervention could effectively hamper the science for decades. In an attempt of self-governance, the Berg letter outlined several recommendations that might prevent the need for government interference. Firstly, the letter called for a halt on genetic experimentation “until the potential hazards of such recombinant DNA molecules have been better evaluated or until adequate methods are developed for preventing their spread,” limiting the risk of creating a non-pathogenic viral strain (Berg,1974). Additionally, the Berg letter called for an international committee of scientists to meet early in 1975 to discuss the progression of the field and the use of recombinant DNA (Berg, 1974). This conference would become Asilomar - and helped lay out guidelines for scientists and their experiments (Mukherjee, 2017). Many of these same questions and concerns would be mirrored forty years later in Jennifer Doudna’s 2015 letter in response to CRISPR-Cas9 technology (Doudna, 2015).
In 2012, Jennifer Doudna used another genetic manipulation tool—CRISPR Cas-9—to target and edit a specific gene sequence (Rogers, 2020). Although it has been almost 50 years since Asilomar, many questions and concerns from the conference are still prevalent. Should scientists be regulated in their experiments (Mukherjee, 2017)? What are the potential evolutionary and ethical consequences of gene editing (Berg, 1974)? How can we evaluate these risks (Mukherjee, 2017)? Though the Berg Letter and the Asilomar conference did provide some guidelines for genetic manipulation experiments, they failed to address many of the moral and ethical issues that the field is faced with today.
In 2015, Doudna, along with seventeen other scientists (including Paul Berg and David Baltimore, authors of the Berg Letter), penned a statement imposing restrictions similar to those laid out in the Berg letter:“A Prudent Path Forward for Genomic Engineering and Germline Gene Modification” (Doudna, 2015). These included a) a discouragement of germline modification experiments until the ethical implications of these changes could be discussed, b) a call for transparent research around the efficacy of CRISPR, and c) a request for an international discussion on the morals of gene alteration (Doudna, 2015). Many of these considerations are modern adaptations of the requests in the Berg letter, and attempt to prevent the same biological hazards.
Already, the similarities between Doudna and Berg and their views of genetic manipulation are becoming apparent. Both of them are pioneers in the field of genetic engineering, and both won the Nobel Prize in Chemistry for their work (Athni, 2019). Then, they both shifted their focus to preserving the integrity of the science, though it may have hampered their careers. When Doudna originally published the Doudna letter in 2015, Paul Berg was one of the leading contributors—a sign that many of the same issues discussed at Asilomar are still prevalent in the field today (though the technology has advanced) (Doudna, 2015). However, after the international moratorium requested in the Doudna Letter was not held, Doudna shifted her viewpoint yet again (Athni, 2019). “I don’t think we want to drive people into hiding over this,” said Doudna in an interview with NPR (Stein, 2019). “I would like to have a much more open, transparent international conversation. I don't like the word moratorium because it kind of goes against that spirit.” (Stein, 2019). The worry that an all-out ban on these experiments could hamper the field was a prime concern at the Asilomar conference in 1975, although the attendants reached a different conclusion than Doudna (Mukherjee, 2017). “The most important lesson of Asilomar,”said Berg, “was to demonstrate that scientists were capable of self-governance” (Mukherjee, 2017).
Given the rampant development of the field of genetic engineering in the past forty years, it’s surprising how similar the ethical and biological issues facing the field are. Both Berg and Doudna and their respective letters are asking for the same things, and the scientific community seems unable to deliver on these promises. Though Asilomar helped address the ethical aspects of recombinant DNA technology, it did not discuss any moral or ethical issues associated with the science (Mukherjee, 2017). However, the genetic modification of twin girls by He Jainkui in 2019 has launched these difficult questions into the spotlight (Cyranoski, 2019). Germline gene editing—which affects the future generations of genetically modified humans—has many dangerous consequences and ethical roadblocks, such as unintended mutations and the uncontrollable creation of “better” humans, which is often subjective and can fuel systemic racism and bias (Cyranoski, 2019). The 2015 Doudna Letter was trying to prevent experiments like Jiankui’s, but the international conference promised by Doudna and Berg never occurred—possibly allowing the Jiankui experiment to continue. I believe that, in the future, more scientists will lean towards tighter, international regulations on germline editing, just as more scientists continue unsupervised with experiments like Jiankui’s. I expect that Doudna and Berg will be among the former.
A comparison of Doudna and Berg was written in 2018 by Leah Ceccarelli that remarks on one key difference between the Berg Letter and the Doudna Letter: the attitude of scientists at the time (Ceccarelli, 2018). This is also discussed in The Gene. Scientists in 1974 viewed themselves as “in control” of recombinant DNA technology, and believed that, if necessary, they could halt the progress of the science at any time (Ceccarelli, 2018). More modern scientists, such as Doudna, predict that experimental gene editing is an unstoppable force, and that the technology will continue to be developed despite action by the scientific community (Ceccarelli, 2018).
The comparison by Ceccarelli focused on many of the literary aspects of the two letters and their tones, which I think is an interesting response to a scientific paper. “In [the Doudna Letter], the technology in question is often situated as the subject of the sentence, [... while] the [Berg Letter] uses subject-predicate pairings that more often portray the scientists who are using the biotechnology as the subject of sentences” (Ceccarelli, 2018, p. 3). As someone who is fascinated by language, I believe that this comparison comes from a unique angle, and reflects on an aspect of the letters not previously discussed. The shifted mindset of the scientists certainly contributes to their actions, and their responses to “breaches” in the letters’ requests, such as the experiments by He Jiankui. I expect this attitude played a part in Jennifer Doudna’s new opinion on an international moratorium: rather than trying to stop an unstoppable scientific force, it is better to study it’s aspects and attempt to move with it. Although this viewpoint may have dangerous consequences (such as increased germline editing), the tone of her letter reflects this position (Ceccarelli).
Both Paul Berg and Jennifer Doudna are geneticists dedicated to preserving the morality of their fields, though they disagree on the best method of doing so. From The Gene’s cohesive chronicling of the discovery of recombinant DNA and the work of Paul Berg to the modern discoveries of Doudna and the scientists who collaborated on the Doudna Letter, the similarities between these two scientists are extremely evident. Despite their technical disagreements, both are trying to maintain the ethical and biological pursuits of genetic engineering, a rarer occurrence in the age of genetically modified embryos and unstoppable science.
Athni, T. (2019, March 14). Professor and Nobel Prize recipient Paul Berg joins call for global halt on gene-edited babies. The Stanford Daily. https://www.stanforddaily.com/2019/03/14/professor-and-nobel-prize-recipient-paul-berg-joins-call-for-global-halt-on-gene-edited-babies/
Baltimore, D., Berg, P., Botchan, M., Carroll, D., Charo, R. A., Church, G., Corn, J. E., Daley, G. Q., Doudna, J. A., Fenner, M., Greely, H. T., Jinek, M., Martin, G. S., Penhoet, E., Puck, J., Sternberg, S. H., Weissman, J. S., & Yamamoto, K. R. (2015). A prudent path forward for genomic engineering and germline gene modification. Science, 348(6230). https://doi.org/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., & Zinder, N. D. (1974). Potential Biohazards of Recombinant DNA Molecules. Science, 185(4148). https://doi.org/10.1126/science.185.4148.303
Ceccarelli, L. (2018). CRISPR as agent: a metaphor that rhetorically inhibits the prospects for responsible research. Life Sciences, Society and Policy, 14(1). https://doi.org/10.1186/s40504-018-0088-8
Cyranoski, D. (2019, February). The CRISPR-baby scandal: what’s next for human gene-editing. Nature. The CRISPR-baby scandal: what's next for human gene-editing
Mukherjee, S. (2017). The Gene: An Intimate History (Reprint ed.). Scribner.
Rogers, K. (2020). Jennifer Doudna | Biography, Facts, & Nobel Prize. Encyclopedia Britannica. https://www.britannica.com/biography/Jennifer-Doudna
Stein, R. (2019, March 13). Scientists Call for Global Moratorium on Creating Gene-Edited Babies. National Public Radio. https://www.npr.org/sections/health-shots/2019/03/13/701549223/call-for-global-moratorium-on-creating-gene-edited-babies
Vilchez, R. A., & Butel, J. S. (2004). Emergent Human Pathogen Simian Virus 40 and Its Role in Cancer. Clinical Microbiology Reviews, 17(3), 495–508. https://doi.org/10.1128/cmr.17.3.495-508.2004