Crossing the Rubicon in Genetics

Originally published on Dr. McLaughlin's LinkedIN channel October 31, 2023.

I recently read Jurassic Park by Michael Crichton.  My favorite character was Malcolm, the mathematician who predicted the failure of Hammond’s experiment.  The following passage Crichton published in 1990 that struck me as prescient.

"We are witnessing the end of the scientific era. Science, like other outmoded systems, is destroying itself. As it gains in power, it proves itself in capable of handling the power. Because things are going very fast now. Fifty years ago, everyone was gaga over the atomic bomb. That was power. No one could imagine anything more. Yet, a bear decade after the bomb, we begin to have genetic power. And genetic power is far more potent than atomic power. And it will be in everyone’s hands. It will be in kits for backyard gardeners. Experiments for school children. Cheap labs for terrorists and dictators. And that will force everyone to ask the same question---What should I do with my power? ---which is the very question science says it cannot answer."

Indeed understanding of the genetic code has advanced at a feverish pace in recent years, with the possibility of genetic engineering on a mass scale looming as a boon or bane to humankind. As science and controversy clash, it’s worth reviewing the evolution of our understanding of how genes determine who we are…and what we may become.

In 1859, Charles Darwin sent shock waves through the scientific community with his landmark book, On the Origin of Species. According to his theory of natural selection, all living things evolve over time in accordance with their ability to survive and procreate in a particular habitat. Darwin’s theory [Marsh] was supported by observations of species such as finches living in the Galapagos Islands. Although the finches had mostly similar traits, they had different beaks depending on the island where they lived. When seeds were the main source of food, they tended to have blunt beaks. If the source was insects, they had long, pointy beaks. Better odds of survival had increased the likelihood of mating, thereby passing on the favorable traits to the next generation.

Knowledge of heritability advanced significantly thanks to Gregor Mendel, [Miko] a nineteenth century monk known as the “Father of Genetics.” By breeding and crossbreeding peas, Mendel learned that traits were passed on from two parents into the next generation, and that some traits may remain hidden in one generation but then expressed in the next one. Mendel also discovered that traits are determined by discrete units—what we now call genes.

Other brilliant scientists moving us into the future of genetics included the Swiss chemist Friedrich Miescher. [Pray] In 1869, he first identified nucleic acids in human cells and saw that they possessed chemical properties unlike those of other proteins. In the early twentieth century, the Russian biochemist Phoebus Levene [Pray] discovered the three major components of a nucleotide. Around 1950, the Austrian biochemist Erwin Chargaff [Pray] found that nucleotides were not arranged in the same order in different species.

Then, in 1953, the American biologist James Watson and English physicist Francis Crick rose to the science pantheon with their discovery of the double helix structure of DNA. [NIH] Their research showed that DNA can produce exact copies of itself and deliver genetic instructions. Crick later built on this finding by revealing that DNA creates a specific code by which genetic data can be stored and transmitted. In 1972, scientists first combined DNA from different species to create recombinant DNA molecules. This technology enables us to manufacture proteins for medical treatments, and even replace defective genes.

Today, a technological advance with perhaps the greatest impact on genetics is within our grasp: CRISPR technology. [Kararoudi] CRISPR—which stands for “clustered regularly interspaced short palindromic repeats”—is a type of gene discovered in 1987 that is part of the immune system in bacteria; it disarms viruses that enter bacteria by slicing up their DNA. We’ve learned how use CRISPR to selectively snip and alter bits of DNA in order to make specific deletions, insertions or modifications to genes.

Pivotal research on CRISPR by the American biochemist Jennifer Doudna and French biochemist, microbiologist and geneticist Emmanuelle Charpentier earned them the 2020 Nobel Prize in Chemistry. There’s a great book about Doudna and CRISPR that I strongly recommend. Entitled The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race,  by Walter Isaacson, it’s a thrilling story of how Doudna and her collaborators turned a phenomenon of primitive life forms into a technology that could transform life on earth.

CRISPR helped accelerate the development of CORONAVIRUS vaccines, and that’s the only beginning. As noted in the New York Times review [Sobel] of The Code Breaker, it “has the potential to control future pandemics — either by outwitting the next viral plague through better screening and treatment or by engineering human beings with better disease resistance programmed into their cells.” Recent advances in CRISPR technology [Chen] have helped us better understand the dynamics of specific genes and even individual chromosomes, label DNA in different species and track RNA in living cells. CRISPR is now a common tool [Leonova] for modeling human diseases, which has enhanced our ability to diagnosis conditions and formulate personalized treatments.

Just a few years ago, we witnessed the perils of genetic manipulation when Chinese biophysicist He Jiankui [Cyranoski] and his team modified the embryos of nonidentical twins whose father was HIV-positive. They deactivated a gene that can be a doorway to the HIV virus, then implanted the embryos in the mother’s uterus for gestation. Many concerns arose at the time about the quality of the research and its implications. The modifications had never been done in humans before, so there was no way to know the potential long-term consequences. Moreover, modification was incomplete in one of the embryos but it was implanted anyway. He Jiankui was condemned for his research and sentenced to three years in prison.

As the cliché goes, with great power comes great responsibility. It doesn’t take much imagination to conceive of a cabal of evil scientists using CRISPR to create a race of superbeings that dominate the world. In 2015, the U.S. Congress enacted legislation to help prevent abuse of genetic manipulation: a ban on the transfer of any genetically modified embryo for gestation. Some scientists argue that the restrictions on genetic modification are too severe and will greatly curtail genetic research, while others contend that such modification crosses an ethical line.
Unlocking the secrets of the atom was considered a high-water mark for science…, but as Malcolm states in Jurassic Park it also gave us the atomic bomb. Clearly, we need a lot more assessment of genetic modification by thought leaders in genetics, ethics, the law and national security before we attempt to play God. I wish I had more answers.  And the start of any answer begins with understanding how the problem originated.

References
Chen B, Niu Y, Wang H, et al. Recent advances in CRISPR research, Protein & Cell. 2020;11:786–791.
https://link.springer.com/article/10.1007/s13238-020-00704-y

Cyranoski D. WHAT CRISPR-BABY PRISON SENTENCES MEAN FOR RESEARCH. Nature. January 3, 2020.
https://www.nature.com/articles/d41586-020-00001-y
 
Kararoudi MN, Hejazi SS, Elmas E, et al. Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Gene Editing Technique in Xenotransplantation. Front Immunol. 2018;9:1711
https://www.frontiersin.org/articles/10.3389/fimmu.2018.01711/full

Leonova EI, Gainetdinova RR. CRISPR/Cas9 technology in translational biomedicine. Cell Physiol Biochem. 2020;54:354-370.
https://www.cellphysiolbiochem.com/Articles/000224/PDF/000224.pdf
 
Marsh G. Darwin's finches get their genomes sequenced. Nature. 2015;518:371−375.
https://www.scientificamerican.com/article/darwin-s-finches-get-their-genomes-sequenced/
 
Miko I. Gregor Mendel and the principles of inheritance. Nature Education. 2008;1:134.
https://www.nature.com/scitable/topicpage/gregor-mendel-and-the-principles-of-inheritance-593/
 
National Institutes of Health. Francis Crick. The Francis Crick Paper. The Discovery of the Double Helix, 1951-1953.
https://profiles.nlm.nih.gov/spotlight/sc/feature/doublehelix
 
Pray LA. Discovery DNA structure and function: Watson and Crick. Nature Education. 2008;1:100.
https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397/
 
Sobel D. A Biography of the Woman Who Will Re-Engineer Humans. New York Times. March 8, 2021.
https://www.nytimes.com/2021/03/08/books/review/walter-isaacson-the-code-breaker.html