Written by: Ashley Koca

The Defense Advanced Research Projects Agency, DARPA, is an organization out of the United States Department of Defense whose primary purpose is to progress the development of military technologies, first inspired and motivated by the Soviet threat “Sputnik.” Within this agency resides a program, the PReemptive Expression of Protective Alleles and Response Elements (PREPARE), designed to counteract four major categories of human ailments: opioid overdose, organophosphate poisoning, exposure to gamma irradiation, and influenza infection. PREPARE strives to design new methods of identification and development of medical countermeasures to promote genes that assist in protection against the ailments aforementioned—but with one major rule: the medical countermeasures must affect the genome without permanent alteration.  

DARPA, most recently, has employed five teams to address influenza immunity and radiation protection within the gut. Each team strives to reach the end goal of producing at minimum one product to be reviewed by the U.S. Food and Drug Administration. Representing Columbia University, Dr. Harris Wang and members of the Wang lab comprise one team of DARPA’s PREPARE initiative, pursuing a 9.5 million dollar study attempting to reduce the impact of radiation on the gut and blood through preventative therapy.

Although the focus on the blood and gut is seemingly oddly specific, the reasoning boils down to the fact that, in Homo Sapiens, the ionizing effects of radiation predominantly impact the stem cells housed in both those regions. The risk of radiation impacting the gut/bloodstream not only would impact soldiers, the main interest of DARPA, but would affect those using radiotherapy as a cancer treatment option—thus expanding the benefits of this technology outside the realm of warfare.  

Current technologies attempting to combat the issue, unfortunately, fall short. Common practices now work to regenerate blood cells, but only if delivered immediately after exposure to radiation. Prophylactic treatments have yet to be a reality, but, with the work of Dr. Wang and colleagues, they will hopefully soon become commonplace. 

The Wang lab plans to design a programmable gene modulator capable of oral introduction. Gene modulators are tools that alter the expression of genes. These tools are designer molecules like triplex-forming molecules, synthetic polyamides, and zinc finger proteins. Several mechanisms exist when utilizing these different molecules. The triplex-forming molecules bind to the DNA helix and form a triple helical structure, allowing for a reduction in the gene’s transcription. Synthetic polyamides inhibit transcription with sequence-specific minor groove DNA recognition. In that, they are a small collection of molecules that hydrogen bond to the minor groove of DNA through the specific recognition of base pairs.  Zinc-finger proteins bind instead to the major grooves of DNA. The modulation of zinc-finger proteins is more complicated, in that it can perform in a multitude of ways. In the case that the sequence the protein is targeting is an exon, transcription will be obscured. Another example of the range of zinc-finger motifs would be if the sequence is a methylase domain, in which case zinc-finger binding will only increase the methylation of the surrounding sequence. 

 The lab anticipates that the modulator will take hold in both the intestines and the liver. After which, the modulator should then induce the protection and regeneration of cells through regulating gene expression—which, in turn, changes protein production. This then causes the liver cells to prompt the regeneration of red blood cells within the bone marrow. Risk of gastrointestinal injury due to radiation has been suggested by scientists to be linked to genotypic variations, hence the importance of gene modulation as a treatment option. 

When contemplating systems of genetic alteration, those in control must consider the ethics and potential implications of their actions. The genetic manipulation of any organism risks complications that could permanently alter the environment or the entire population of the organism that the method of manipulation was designed to affect. Although this modulator is not designed to change the genes themselves merely their expression, certain alterations or increases in frequencies of expression could spell doom for an organism. Alternatively described as an “extinction tool,” gene drives and other instruments of gene alteration have been recognized for their potential benefits to society as well as their potential for extreme consequences. The equal potential for harm as well as good by these gene devices must be taken into consideration when developing new tech. 

The support of organizations such as DARPA is crucial to the progression of science as it provides researchers with a plethora of financial opportunities and the support needed to conduct their science. Additionally, the interest of the Department of Defense is monumental in and of itself as it signifies the relevance of such research outside of the niche scientific community—the research has valuable, real-world applications that transcend the borders of pure academia. The continued support of these agencies provides hope to the scientific community, the US’ need for the advancement of science has not faltered since the origins of DARPA—the Sputnik scare has yet to be forgotten.

Citations:

Defense Advanced Research Projects Agency. (n.d.). Retrieved from https://www.darpa.mil/news-events/2019-06-27.

Defense Advanced Research Projects Agency. (n.d.). Retrieved from https://www.darpa.mil/program/preemptive-expression-of-protective-alleles-and-response-elements.

Shadad, A. K. (2013). Gastrointestinal radiation injury: Symptoms, risk factors and mechanisms. World Journal of Gastroenterology, 19(2), 185. doi: 10.3748/wjg.v19.i2.185

Systems Biology Home Columbia University Department of Systems Biology. (2019, July 2). Retrieved from https://systemsbiology.columbia.edu/tags/genome-engineering.

Uil, T. G. (2003). Therapeutic modulation of endogenous gene function by agents with designed DNA-sequence specificities. Nucleic Acids Research, 31(21), 6064–6078. doi: 10.1093/nar/gkg815