Technology

Gene Editing: The Promise and the Frightening Peril

Two women recently became Nobel Laureates for developing genetic scissors to re-write the code of life. What this means for the world.

Into the future: What if you could change the building blocks of life (DNA) of animals, plants, and microorganisms? Welcome to a revolution in the life sciences, one that is contributing to new cancer management strategies. Gene editing may allow us to cure inherited diseases that are not currently curable. Today we look at CRISPR, including its promise and its peril.

Gene editing came to the world’s attention recently. Drs. Emmanuelle Charpentier and Jennifer A. Doudna won the 2020 Nobel Prize in Chemistry. These brilliant scientists developed the so-called CRISPR/Cas9 genetic scissors. With this powerful tool, researchers can change the DNA of animals and more.

Looking more closely at CRISPR-Cas9

CRISPR (pronounced “CRIS-per”) is short for CRISPR-Cas9. More specifically, CRISPR stands for “clusters of regularly interspaced short palindromic repeats.” Let’s turn to the key players in the process.

  • CRISPR are specialized bits of DNA. These particular segments have an important characteristic — nucleotide repeats and spacers. You may recall that nucleotides are the building blocks of DNA. Spacers are tiny bits of DNA that are in-between the repeated sequences.
  • The protein Cas9 (or CRISPR-associated) is an enzyme that serves as molecular scissors. This protein can cut DNA strands.

Bacteria taught us how to do it

Scientists adapted the natural defense mechanisms of bacteria and archaea, the domain of microorganisms composed of a single cell. These organisms used CRISPR approaches to fight off attacks by foreign bodies such as viruses. The microorganisms using the CRISPR approach slice up and destroy the foreigner’s DNA.

Bacteria take spacers from viruses that have attacked the bacterium. In this way, the spacers can serve as a memory bank, allowing the bacteria to recognize the viruses and better battle them in future attacks. Voila: Bacterial immunity.

Once the CRISPR technology cuts the DNA, the cell’s natural repair mechanisms take action, inducing mutations to the genome. The repair happens in one of two ways, according to Huntington’s Outreach Project at Stanford (University):

  • One repair mechanism involves gluing the two cuts back together. In more fancy terms, this is “non-homologous end joining.” Alas, this method tends to introduce errors by accidentally inserting (or deleting) nucleotides.
  • The second type of repair involves fixing the break by filling in the gap with a sequence of nucleotides. The cell uses a small strand of DNA as a template, and scientists can supple a template of their choosing. In this way, we can write in any gene we want or fix a deleterious mutation.

CRISPR in action

In 2017, a research team led by Japanese investigators Shibata of Kanazawa University and Nishimasu of the University of Tokyo showed what the CRISPR process looks like in real-time.

Built-in safety mechanism

Does Cas9 make mistakes and cut the wrong part of a genome? There is a built-in safety mechanism. Short DNA sequences (protospacer adjacent motifs, or PAMs) are tags next to the target DNA sequence. If the Cas9 complex doesn’t see a PAM next to a target DNA sequence, it will not cut the DNA.

2020 Nobel Prize in Chemistry

Kudos to Jennifer Doudna and Emmanuelle Charpentier. They re-engineered the Cas9 enzyme into a more manageable two-component system. They fused two RNA molecules into a “single-guide RNA” that, when combined with Cas9, could discover and cut the DNA target specified by the guide RNA. Now we can program this artificial Cas9 system to target any DNA sequence for cutting.

How has CRISPR been used?

Now you know that CRISPR is a powerful tool for changing our genes. The technique is relatively easy and allows researchers to alter DNA sequences. The alterations in the genetic material, in turn, shift gene function. Here are some examples of its use:

  • Farming. For example, scientists have engineered probiotic cultures for yogurt. The technology is used in crops to raise yields and tolerance to drought.
  • Biofuels. CRISPR has been used to modify yeasts employed in making biofuels.
  • Treatment of human disease. In 2019, doctors used CRISPR to experimentally treat a young woman with a genetic disorder, sickle cell disease. In 2020, researchers injected a CRISPR-modified virus into a patient’s eye in an attempt to treat Leber congenital amaurosis. Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears early in life in affected individuals.
  • COVID. Researchers are exploring whether CRISPR platforms can facilitate the coronavirus’s detection (and inactivation), SARS-CoV-2.
  • Substance detection. Coupling CRISPR-based diagnostics to an enzymatic process can help aid in the detection of contaminants in the environment.
  • Gene drives to eliminate malaria. These genetic systems increase the probability of a particular trait passing from parent to child. Over generations, gene drives may help control diseases such as malaria (say, making the female Anopheles gambiae mosquito sterile).

CRISPR — The peril

Could CRISPR gene editing be used to create new species? Perhaps we can revive extinct species using closely related existing species. I am at once excited and terrified. Also, CRISPR technology is not 100 percent efficient, with editing efficiencies reported to be in the range of 50 to 80 percent or more. Moreover, CRISPR can cut DNA at unintended regions, leading to unwanted mutations.

What are the ecological impacts of gene drives? Could the introduced trait spread to unintended targets via crossbreeding? What about the genetic diversity of the target species? Given gene editing of human embryos or cells of reproduction (so-called germline editing) leads to genetic alterations passed on to subsequent generations, what are the ethical concerns?

Unintended consequences, with limits in our understanding of gene-environment interactions and intrapersonal gene-gene interactions? Also, we are affecting a future person without their consent. Finally, what are the implications of using gene editing as an enhancement tool — want a child with one green eye and one brown eye? Or an usually tall or intelligent child?

The US National Academies of Sciences, Engineering, and Medicine

Let’s end with a comprehensive report with guidelines and recommendations for genome editing. Although the Academies urge caution, it does not call for prohibition. Instead, the panel recommends that germline editing be performed only on genes that lead to severe disease and only when there are no other reasonable management alternatives. The scientists also call for following families involved in gene editing for generations.

Thank you for joining me today.

References

Basics

Landmark research

I have degrees from Harvard, Yale, and Penn. I am a radiation oncologist in the Seattle area. You may find me regularly posting at www.newcancerinfo.com

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