What if you could rewrite the story of your genes? Erase hereditary diseases, boost your immunity, or even enhance your capabilities? This isn’t the plot of a futuristic movie – it’s the promise of CRISPR, a revolutionary gene-editing tool that’s making waves in labs and headlines worldwide. But as we stand on the brink of this genetic frontier, we’re faced with questions that go beyond science. Should we play ‘editor’ with the human genome? Where do we draw the line between healing and enhancing? In this article, we’ll explore the incredible potential of CRISPR and navigate the ethical maze it’s created. Ready to dive into the fascinating world of genetic scissors and moral dilemmas?

Article originally prepared in Italian for my personal podcast Disruptive Talks (read it here).
This content is also available as a self produced video documentary, here, and in audio podcast, available here.

You may have heard about it, but do you really know what it is and how it works? In this article, I will explain it in a clear and accessible manner, without excessive technical jargon. You’ll see that CRISPR is a groundbreaking discovery that could change the future of humanity. However, it’s not all smooth sailing! There are also very delicate ethical issues to address. Let’s proceed systematically and start from the beginning.

What is CRISPR?

CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, represents a groundbreaking discovery in the field of genetics. This complex name belies a fascinating biological mechanism that has opened up new frontiers in genetic engineering.

The story of CRISPR begins in 1987 when Japanese scientist Yoshizumi Ishino stumbled upon unusual repetitive DNA sequences in E. coli bacteria. At the time, these sequences were a mystery, their purpose unknown. For nearly two decades, these curious genetic elements remained an enigma, occasionally noted by researchers but largely unexplored.

It wasn’t until the early 2000s that the scientific community began to unravel the true nature of CRISPR. A pivotal moment came in 2005 when three independent research teams, led by scientists like Alexander Bolotin, Eugene Koonin, John van der Oost, and Francisco Mojica, published groundbreaking findings. They revealed that CRISPR was part of a sophisticated adaptive immune system in bacteria, a natural defense mechanism against viral invaders.

This discovery set the stage for a monumental leap forward in 2012. Two scientists, Emmanuelle Charpentier and Jennifer Doudna, made a breakthrough that would change the landscape of genetic research. They demonstrated that the CRISPR system, particularly when coupled with a protein called Cas9, could be repurposed as a precise genetic editing tool. This insight transformed CRISPR from a curious bacterial feature into a powerful technology with the potential to revolutionize medicine, agriculture, and our understanding of genetics itself

CRISPR demystified: the mechanics of genetic editing

CRISPR technology operates on a principle that’s both elegant and revolutionary. At its core, it functions as a highly sophisticated genetic editing tool, often described as “molecular scissors” for DNA. However, this analogy only scratches the surface of its complexity and precision.

The CRISPR system consists of two main components: a guide RNA (gRNA) and a Cas enzyme, most commonly Cas9. The guide RNA acts as a molecular GPS, programmed to locate a specific DNA sequence within the vast genome. This gRNA is custom-designed to complement the target DNA sequence, ensuring pinpoint accuracy.

Once the gRNA finds its target, it guides the Cas9 enzyme to the precise location. Cas9 then performs a double-stranded break in the DNA, effectively ‘cutting’ the genetic material at the designated spot. This process is analogous to a precision surgical instrument, making an incision at an exact point determined by the surgeon (in this case, the scientist).

After the DNA is cut, the cell’s natural repair mechanisms spring into action. This is where the true power of CRISPR as an editing tool comes into play. Scientists can exploit this repair process in two primary ways:

1. Gene knockout: if the goal is to disable a gene, the cell’s somewhat error-prone repair mechanism, known as non-homologous end joining (NHEJ), often introduces small mutations when mending the break. These mutations can render the gene non-functional.
2. Gene editing or insertion: alternatively, scientists can provide a template DNA sequence along with the CRISPR components. In this case, the cell may use a more precise repair mechanism called homology-directed repair (HDR). This process can incorporate the provided DNA template, effectively replacing the original sequence with a corrected or modified version.

The versatility of CRISPR extends beyond simple cuts and repairs. By modifying the Cas enzyme or using multiple guide RNAs, researchers can achieve a variety of genetic alterations, including deletions, insertions, and even complex rearrangements of DNA sequences. What set it apart is its unprecedented combination of precision, efficiency, and versatility. Unlike earlier gene-editing techniques, it can be easily programmed to target almost any DNA sequence, making it adaptable to a wide range of applications in medicine, agriculture, and biotechnology.

As our understanding grows, so does our ability to refine and expand its capabilities, opening up new frontiers in genetic engineering and therapeutic interventions.

CRISPR’s ripple effect: transforming science and society

The applications are numerous and are leading to concrete progress in various fields.

For example, it is used to create animal models, such as mice or monkeys, with genetic mutations identical to those causing human diseases like Huntington’s disease or cystic fibrosis. These “model organisms” allow for more in-depth study of disease mechanisms and testing of new drugs or gene therapies.

In the field of somatic gene therapy, it has been successfully used to correct mutations underlying severe diseases such as beta-thalassemia, sickle cell anemia, and Duchenne muscular dystrophy by modifying the DNA of patients’ somatic cells.

CRISPR also makes germline and embryo editing possible. For instance, harmful genetic mutations could be corrected before a child is born, ensuring a life free from severe pathologies. However, the long-term impacts of such interventions are unpredictable and pose delicate ethical questions.

Here is a list of recent update about CRISPR updates:

1. CRISPR Therapeutics receives FDA approval for sickle cell treatment (December 2023):
   the FDA approved CASGEVY, the first CRISPR-based gene therapy for sickle cell disease, marking a significant milestone in CRISPR applications.
2. CRISPR used to create malaria-resistant mosquitoes (October 2023):
   researchers successfully used CRISPR to create mosquitoes resistant to the malaria parasite, potentially offering a new approach to combat the disease.
3. CRISPR technology advances in cancer treatment (August 2023):
   clinical trials using CRISPR to enhance CAR-T cell therapy for various cancers have shown promising results, potentially improving cancer immunotherapy.
4. CRISPR-edited wheat approved for consumption (July 2023):
   the UK approved a CRISPR-edited wheat variety with reduced levels of asparagine, marking a significant step in gene-edited crop regulation.
5. New CRISPR techniques improve precision (May 2023):
   scientists developed enhanced CRISPR methods, including prime editing refinements, offering greater precision and reduced off-target effects.

The moral maze of gene editing

While correcting genetic defects in embryos could eradicate terrible diseases, modifying the germline can transmit unforeseen alterations to descendants, with implications that go far beyond the individual. Moreover, cosmetic or human enhancement applications raise concerns about eugenics.

In the future, if adequately regulated, CRISPR could truly defeat debilitating genetic diseases before birth. But given the unpredictability of long-term effects, caution is necessary.

For this reason, in 2015, an international group of scientists called for a moratorium on the use of CRISPR in human embryos intended for implantation, due to the risk of rash approaches and undesired effects. Despite this, in 2018, Chinese researcher He Jiankui announced the birth of the first children with DNA modified through CRISPR, causing controversy and resulting in his three-year prison sentence.

The debate has also ignited in Italy. In 2017, the National Bioethics Committee expressed its opinion recommending a ban on any experimentation on embryos, while considering admissible basic research on germ cells not intended for pregnancy.

Navigating the genetic frontier: key considerations

It will be important, at the right time, to open a public debate to decide where to draw inviolable boundaries on the use of CRISPR technology.

For example, is it right to modify the human embryo? And if one day it were possible to create genetically modified human beings, would we allow it?

The issues that could lead to debate following the potential commercial development of this science are numerous:

• Eugenic drift, with “designer babies” selected by parents
• Social inequalities, with access at high costs and more advanced countries potentially excluding developing countries
• Discrimination against genetically unmodified people
• Genetic doping in sports, with genetically enhanced athletes
• Militarization and use for creating biological weapons

These are ethically complex issues that don’t have easy answers. CRISPR is a technology with enormous potential but poses delicate ethical questions. If addressed with an open mind, empathy, and rationality, such questions can lead us to reconcile scientific progress and protection of human dignity.

In short, the future of CRISPR is in our hands. It’s up to us to decide how to use it for the common good. I am optimistic and believe that this technology can truly improve the lives of many people.

What do you think?

Let me know in the comments below, I’m curious to know your opinion!

For further inquiries or assistance with technologies, feel free to reach out.

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Notes and Further Reading

For those interested in delving deeper into CRISPR, here are some valuable resources and recent articles:

CRISPR Therapeutics Official Website

• https://crisprtx.com/: latest updates on CRISPR-based therapies and clinical trials.

Nature CRISPR Collection

• https://www.nature.com/subjects/cas9-endonuclease: curated research articles and news on CRISPR technology.

Broad Institute CRISPR Resources

• https://www.broadinstitute.org/research-highlights-crispr: educational materials and research updates from a leading CRISPR research institution.

CRISPR Journal

• https://home.liebertpub.com/publications/crispr-journal/642: peer-reviewed journal dedicated to CRISPR research and applications.

WHO Expert Advisory Committee on Human Genome Editing

• https://www.who.int/groups/expert-advisory-committee-on-developing-global-standards-for-governance-and-oversight-of-human-genome-editing: updates on ethical guidelines and governance of human genome editing.

Other links

• What is CRISPR: https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr
• Discovery history: https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/crispr-timeline
• Biomedical applications: https://www.mdpi.com/1422-0067/21/3/715
• Ethical implications: https://theconversation.com/crispr-gene-editing-controversy-shows-old-ideas-about-east-and-west-still-prevail-66918
• Gene therapy with CRISPR: https://www.nature.com/articles/d41586-019-03350-5
• CRISPR for cancer treatment: https://www.cancer.gov/news-events/cancer-currents-blog/2017/crispr-immunotherapy
• Human embryo modification: https://www.nature.com/articles/d41586-019-00673-1