We can Edit the Human DNA – What’s Next?

Almost two years ago I participated at a symposium on genomics at The New York Academy of Sciences. Dr. Jennifer Doudna of UC Berkeley presented a technology called CRISPR/Cas9 that allows for precise manipulation of the DNA.

CRISPR stands for a long sequence of words that you will most likely forget, but here it goes – Clustered Regularly Interspaced Short Palindromic Repeats. It is used by bacteria to protect themselves against invading pathogens.

When virus DNA invades bacteria, it leads to the production of two short RNAs. One of these RNAs matches the sequence of the virus. Together with Cas9 (an enzyme that can cut DNA), these RNAs form a complex that works like this:

1.The matching sequence (guiding RNA) looks for its target in the viral genome.
2.When it finds it, Cas9 cuts the target viral DNA. The virus is disabled.

Researchers found that they could engineer the system not only to cut viral DNA, but any DNA sequence they desire. To do this, they simply change the guiding RNA to match their target. This can be done in living cells too. Here’s how it works:

1.When CRISPR/Cas9 is put in the nucleus of a cell, it locks onto a sequence called PAM.
2.Cas9 unzips the DNA and matches it to the target RNA.
3.When the match occurs, Cas9 cuts both strands of the DNA.
4.Normally, the cell tries to repair the DNA. However, the process is prone to error.

When DNA is not repaired correctly, the resulting gene could be mutated or disabled. Its altered function allows researchers to better understand how it works.

If researchers want to be more precise and replace defective (mutated) genes with healthy copies, they add a piece of DNA (the template) to the complex that carries a healthy copy. So, in this case, resuming from step 3:

3.Cas9 cuts the DNA.
4.The DNA template (desired sequence) can pair with the cut ends.
5.The original defective sequence is replaced with the new one.

For a 2 minute explanation of this process, here’s Gene Editing with CRISPR-Cas9from Dr. Doudna herself.

Okay, we can edit genomes. But what are some practical applications for this?

1.Gene editing stops muscular dystrophy in mice. In humans, it could save numerous lives every year.
2.On the controversy side, Chinese use CRISPR to create more muscular livestock.
3.Creating genetic disease in animals to better understand them in humans. Creating more resistant crops (and numerous other potentially beneficial agricultural applications). Modifying mosquitoes so that they cannot spread malaria. Creating disease resistant human cells. More.
4.Of course, it can also lead to experiments that provoke massive tumult:

“In April, China became a lightning rod for criticism and anxiety when a team of Chinese scientists published a paper online in the journal Protein & Cell detailing attempts to use CRISPR to modify nonviable human embryos, obtained with consent from a fertility clinic. Their aim had been to delete a gene linked to a blood disorder called beta-thalassemia without creating other mutations, but the experiment failed on 85 attempted embryos.

The research was legal within China, which bans experiments on human embryos more than 14 days old, and was supported in part by government grants. (Such research is not banned in most U.S. states but is probably ineligible for federal funding.)”

5.It may be related to #4. UK researchers have received permission to edit genes in human embryos (second half of 2015)
6.And probably the most important so far, as of March 2016:

“Scientists have removed HIV from human immune cells using a new gene-editing technique. They’ve managed to shut down HIV replication permanently.

Using the much-touted CRISPR/Cas9 gene editing method, scientists have demonstrated how they can edit HIV out of human immune cell DNA, and in doing so, can prevent the reinfection of unedited cells too.”

For geeks, here’s the full study.

For a detailed insight into the history and the development of CRISPR/Cas9, here’s a paper by Eric Lander of the Broad Institute of MIT and Harvard, published in January 2016.

Doudna thinks that CRISPR/Cas9 should not be used in clinical applications today, but she sees how it could be used for research, even in adult cells. However, she ismuch more reserved when it comes to modifying embryos:

“Do we know enough about the human genome to understand the impact of making changes to it in a developing embryo?…I think that there I would like to see our society draw a line and say that we wont go there right now. We’ll take the time that we need to really think about this.”

In a December 2015 Ted Talk titled We Can Now Edit Our DNA. But Let’s do It Wisely she provides the current perspective on CRISPR/Cas9. She calls for caution and careful consideration before moving forward.

Now, you may see the numerous ethical concerns this technology raises. It is far from being perfect, it can be prone to error (more work to be done), and we are not sure of how vectors (delivery systems for the CRISPR/Cas9) work in humans compared to animals, both in terms of accuracy and specificity. Still, the present and the future look very promising.

“Cristi Vlad holds a Master of Science (M.Sc.) in Civil Engineering. He did not profess in the field yet. He got absorbed into self-experimentation and writing books about the details of his experiments. More, on his website.

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