How CRISPR Works

CRISPR stands for ‘Clustered Regularly Interspaced Short Palindromic Repeats,’ which are segments of DNA that serve as a defense mechanism in bacteria against viral threats. Innovators like Emmanuelle Charpentier, Jennifer Doudna, and Feng Zhang have transformed this natural system into a groundbreaking genetic engineering tool known as CRISPR/Cas9.

An analogy for CRISPR/Cas9 is akin to editing a manuscript on a computer. Imagine you've written a lengthy novel and wish to remove a specific sentence but can't recall its exact location. By using the 'control-F' function, you can quickly find and delete it. Similarly, CRISPR acts as a search tool within our DNA, targeting a 20-letter sequence and guiding the Cas9 protein—referred to as molecular scissors—to eliminate unwanted genetic material.

What sets CRISPR apart is its capability to do more than just delete sequences. Researchers can also craft new DNA sequences to replace those that are removed, akin to editing a sentence and substituting it with a more suitable one. This versatility makes CRISPR/Cas9 a valuable tool for scientists across various fields.

Applications of CRISPR in Research and Industry

The advent of CRISPR/Cas9 has transformed scientific inquiry and experimentation. Jennifer Doudna, a pioneer of the technology, explains that it not only allows for gene manipulation but also facilitates the exploration of genomic organization and practical applications beyond mere research.

By altering specific gene sequences, researchers can better understand gene functions and their links to diseases like cancer and heart conditions. My own doctoral research on drug-resistant breast cancer heavily relies on CRISPR/Cas9 techniques for engineering mutations in cancer cells.

Furthermore, CRISPR aids in creating improved disease models by replicating known genetic disorders in animal subjects, thus enhancing our understanding of potential treatments.

Recently, CRISPR technology has been adapted for diagnosing COVID-19. Utilizing a Cas protein named Cas12, scientists describe it as a molecular shredder capable of detecting viral DNA and signaling its presence.

Beyond biomedical applications, CRISPR offers significant potential across various industries. Companies are experimenting with the technology to optimize production processes and enhance yields. For instance, CRISPR has been employed to increase the output of renewable biofuels by modifying the genetic makeup of certain microorganisms. In agriculture, research spans from developing tomato plants with higher yields to creating non-browning apple varieties.

A Scandal that Shook the World

The ethical implications of CRISPR technology were starkly highlighted in November 2018 when He Jiankui announced at an academic conference that he had genetically altered the embryos of twins, Lulu and Nana, using CRISPR/Cas9. He aimed to disable the CCR5 gene, which encodes a protein that HIV uses to enter white blood cells, theorizing that this would grant the girls immunity against the virus.

At the time, the technology was still being refined, and there had been no clinical trials conducted on humans or animals to understand the long-term ramifications of such genetic alterations. He also faced scrutiny over the ethicality of the consent process, as the couple was misled regarding the nature of the experiment, which was framed as an AIDS vaccine project.

His announcement was met with global outrage, with 122 Chinese scientists condemning his actions as detrimental to the reputation and future of Chinese science. He Jiankui's work involved human germline editing, meaning the genetic modifications were present in all of the individual's cells and could be passed on to future generations—a stark contrast to somatic editing, which affects only specific cells without inheritable effects.

While some scientists advocate for the potential of germline editing to treat inherited diseases, the ethical divide between therapeutic use and enhancement of human traits is concerning. Stringent regulations are essential to prevent misuse of this technology, especially given the uncertainties surrounding unintended genetic alterations that may have occurred in the twins' genomes.

The Future of CRISPR

In contrast, somatic gene editing holds significant promise for addressing genetic conditions, with several clinical trials currently in progress. For instance, Vertex Pharmaceuticals and CRISPR Therapeutics are conducting trials aimed at treating Sickle Cell Disease through CRISPR-edited blood cells that produce elevated levels of fetal hemoglobin. Preliminary results have been encouraging, indicating the potential for CRISPR to provide curative solutions for serious genetic conditions.

Other active clinical trials include treating patients with multiple myeloma using genetically modified white blood cells and HIV-positive individuals with cells edited to eliminate CCR5.

Ongoing research aims to enhance CRISPR editing techniques to improve safety and efficacy. A novel approach known as base-editing, developed by David R. Liu at the Broad Institute, offers increased precision and reduced DNA damage. Recent studies have successfully employed base-editing to partially restore hearing in deaf mice by targeting the TMC1 gene.

5 Notable CRISPR Startups

1. Mammoth Biosciences

   Co-founded by Jennifer Doudna, this company focuses on utilizing CRISPR technology to create portable and cost-effective diagnostic kits, known as the DETECTR platform, for detecting viral infections, cancers, and antimicrobial resistance.

2. Synthetic Genomics

   In partnership with ExxonMobil, this company employs CRISPR gene editing to engineer micro-algae for enhanced biofuel production, aiming to achieve a production rate of 10,000 barrels a day by 2025.

3. PlantEdit

   This CRISPR/Cas9-based enterprise is dedicated to producing sustainable genome-edited plant products, such as 'Solive,' a soy-based oil with greater shelf stability than traditional olive oil, achieved through genetic modification of the FAD2 gene.

4. Beam Therapeutics

   Founded by David R. Liu, this company aims to leverage base-editing technology for therapeutic purposes, including treatments for sickle cell disease and beta-thalassemia.

5. Sherlock Biosciences

   This company intends to use CRISPR/Cas12 for detecting genetic mutations. They gained attention for developing a rapid diagnostic test for COVID-19 and were recognized as one of the Top 100 Technology Pioneers of 2020 by the World Economic Forum.

As advancements in CRISPR continue, it is likely that these technologies will play an integral role in our future. Biologist Ellen Jorgensen has emphasized that the funding for such innovations comes from the public through various organizations. She notes:

> “That makes us all the inventors of CRISPR. We all have a responsibility. Only by learning about these types of technology will we be able to guide their use and ensure a positive outcome for both the planet and ourselves.”

While CRISPR editing holds tremendous potential, it also raises significant ethical questions. It is crucial for those in authority to engage in difficult conversations about the implications of CRISPR technology and enforce stringent regulations. As an informed public, we can contribute by educating ourselves and advocating for responsible decision-making.

In conclusion, let He Jiankui's imprisonment serve as a cautionary tale for researchers: just because you can alter human genetics, it does not mean you should.

References

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Yeh WH, Shubina-Oleinik O, Levy JM, et al. In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness. Sci Transl Med. 2020;12(546):eaay9101. doi:10.1126/scitranslmed.aay9101