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CRISPR: What the Future Holds For Mankind

Back in the early 2000s humanity was changed forever when the computer game The Sims was introduced.

Most of us spent long hours designing our tiny digital people, building their house on a low budget that had you thinking if they needed a bed or the fancy high-tech toilet instead.

Our creativity reached a whole new level through the cool features we gave our characters. Tall, short, three different skin tones (yep, it’s an old game), a variety of outfits and accessories.

We would even create the actual character’s character (if that makes sense), such as their personality, emotions, everything.

Of course, 19 years ago, the graphics were really not that great compared to the next generations of the game.

And let’s be honest, weird (yet hilarious) things would happen especially when glitches popped up.

Like this one time when this user had a “man-baby”.

Nevertheless, this game gave us some of the best childhood memories with technology.

But have you ever thought what it would be like if we could “modify” humans just like in The Sims?

Okay, obviously we don’t mean like the creepy “man-baby” glitch thing, but what if we could choose features?

What if we could “edit” current DNA to cure chronic diseases, or even better, prevent them from happening altogether?

Well, good news for you.

Thanks to technology once again, we might soon be able to do so!

This is CRISPR.

It may sound like a cereal brand, but CRISPR actually stands for: “Clustered Regularly Interspaced Short Palindromic Repeats” and is pronounced “crisper”.

According to Science Alert, this type of technology allows scientists to ‘cut’ and ‘paste’ genes into DNA.

This way, researchers can modify genes in living cells in order to someday be able to ‘correct’ mutations and treat genetic causes of diseases.

Um…Huh?!

Okay wait, let’s rewind a bit.

Our DNA is made up of molecules called nucleotides.

Each of these nucleotides, has a phosphate group, a sugar group and a nitrogen base.

There are four types of nitrogen bases with a ‘series of letters’ representing: adenine (A), thymine (T), guanine (G) and cytosine (C).

Based on the order in which these letters/bases are, we have the DNA’s genetic code.

Very, very, simply put: think of our DNA as a zipper. It has two long chains (of molecules) and the nucleotides are the teeth of that zipper.

What CRISPR does, is that with Cas9 (one of the enzymes produced by the CRISPR system) ‘cuts’ a part of the ‘zipper’ that might be ‘faulty’ and replaces it with one that isn’t.

Kinda like this:

The CRISPR journey

CRISPR has been around since the 1980s and this technology has been evolving ever since.

According to Board Institute of MIT and Harvard Feng Zhang: “CRISPRs were first discovered in archaea (and later in bacteria) by Francisco Mojica, a scientist at the University of Alicante in Spain. He proposed that CRISPRs serve as part of the bacterial immune system, defending against invading viruses.”

Here’s the timeline of this fascinating technology and it’s evolution so far, according to ark-invest.

1980s: First targeted gene-editing, performed on yeast cells in many laboratories.

1987: First report of clusters repeats in bacteria, discovery required for later CRISPR editing development.

1991: First insights into how zinc finger proteins recognize specific DNA sequences.

1994: Discovery that DNA breaks included by a nuclease can be repaired efficiently by homologous recombination, a key foundation of today’s gene-editing technology.

2002: First targeted gene edit made in a living organism.

2002: Clustered repeats discovered in 1987 renamed “Clustered Regularly Interspaced Short Palindromic Repeats” or CRISPR.

CRISP - Clustered Regularly Interspaced Short Palindromic Repeats

2009: Discovery of a simple code explaining how transcription activator-like effectors (TALE) can recognize specific DNA sequences, an important foundation for TALENs a year later.

2009: First US clinical trials of gene-editing in humans begins in patients with HIV.

2012: First reports of engineered CRISPR-Cas9 system that cut specific DNA sequences.

2013: First reports of engineered CRISPR-Cas9 systems to modify genes in human cells.

2014: New England Journal of Medicine report on the first human clinical trial using Zinc Finger Nucleases (ZFNs) to target and destroy the CCR5 gene in T-cells of 12 people with HIV.

2016: First AIDS patient treated with ZFN-edited blood stem cells.

2016: First cancer patient treated with CRISPR edited immune cells in China.

2017: First US FDA approval of CRISPR-based clinical trial.

You can find more information regarding the discovery of CRISPR here.

What’s Going On Today?

Although the CRISPR technology is relatively new, it’s made a huge impact in the field of biology.

According to Dr Jennifer Doudna, professor at the University of California, Berkeley, and co-discoverer of CRISPR-Cas9 gene-editing technology, there is still quite a lot that needs to be done in order to ‘perfect’ this technique.

“During CRISPR’s teenage years, we will look to expand the types of edits we can make, focus on advancing the safe and effective delivery of CRISPR genome-engineering tools, work through the first wave of Food and Drug Administration approvals and increase our exploration of a naturally occurring way to fine-tune CRISPR-based editing to improve accuracy” Dr. Doudna said.

Additionally, Lainie Ross who is a bioethicist at the University of Chicago, expressed her concern regarding the Chinese who are already using CRISPR on patients.

More specifically, Ross said: “My concern is: Are we really ready? There’s much about CRISPR that we don’t understand. We could be doing more harm than benefit. We need to be very, very cautious. This an incredibly powerful tool.”

Dr Shixiu Wu, who’s president of the cancer hospital in Hangzhou China, disagrees.

According to Dr Wu, doctors explain every possible risk to their patients in detail before proceeding with CRISPR. “We [are] just beginning. We should improve it to get more benefits for the patients. If you don’t try it, you’ll never know” Dr. Wu stated.

Who Will Have Access To This?

We know what you’re thinking…

Most probably this technology will be available mainly for the rich, as it will be extremely expensive as many other cures.

Eh, that depends.

Dr Doudna argues that everyone will have access to these new technologies.

More specifically, she said “We must ensure that in this future, everyone will have access to these new technologies and there’s a consensus on rules to regulate whether and how this technology is applied to the human germline. This must come from a collaborative effort that includes increased private and public investment, more commercial partnerships to reduce financial risk and scale the technology, and the political and regulatory nuance to allow widespread affordable access to safe, effective cures without stifling a technology that will underpin the health of future generations.”

What’s next for CRISPR?

One of the reasons why this technology cannot be used officially on humans yet (excluding China apparently), is because scientists are have not yet gathered enough data showing the frequency of “off-targeting”.

This means that there are high chances of malfunctions appearing.

Additionally, another reason is ethics.

Is it ethical to create a genetically edited generation who might not be happy that their existence is based on embryo modification?

What if we end up creating a whole new generation of superior humans (designer babies)?

Talking with The Pro’s

Whatever the subject may be, we like to research subjects to their core.

Since the CRISPR invention can be quite complicated, we reached out to a professional biologist to help us get an even better understanding of this technology.

Georgia Stavrou has a BSc in Biomedical Science (University of Surrey), MRes Cancer Informatics from the Imperial College London, MPhil Medical Science from the University of Cambridge, and is currently employed at the University of Cyprus as a Special Scientist in Epigenetics.

Here’s what went down.

Axios: What exactly is CRISPR?

Georgia Stavrou: Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR) are actually sections in a bacterial/archaeal genome (DNA/RNA) that correspond to sections of the genome of a virus that had previously ‘attacked’ the bacterium we are looking at.

Think of it as a form of natural defence mechanism that bacteria have developed against these invading viruses (bacteriophages). The idea is that once the bacterium is invaded by this bacteriophage and survives, short sections of the virus are incorporated in the bacterium.

If the same virus invades again, the bacterium can quickly fight back as it can recognise sections of in within its own genome and thus destroy the invading bacteriophage.

Think of it as a bacterial form of adaptive immunity.

Axios: When was this discovery made?

G.S: The CRISPR repeats were first discovered in E. coli in the 1980s but their actual function was only confirmed 12 years ago where studies showed that S. thermophilus could acquire resistance against a bacteriophage by integrating a piece of the genomic fragment of an infectious virus into its CRISPR locus.

Having said that, the research about using this feature of bacteria as a tool was actually being conducted by various labs at the same time (and as such several groups try to claim the fame).

In 2012, Jennifer Doudna and Emmanuelle Charpentier were the first to propose that CRISPR-Cas9 (enzymes from bacteria that control microbial immunity) could be used for programmable editing of genomes.

Jennifer Doudna  and Georgia Stavrou

Axios: What is CRISPR used for?

G.S: CRISPR-Cas9 (although there are newer tweaked versions of this technology constantly being developed) is one of the newer tools being added to the existing genome editing toolkit. One of the key advantages over its predecessors is its specificity.

Think of CRISPR technology as a pair of molecular scissors that are able, with the help of short given sequences (also known as guide RNA), to cut at specific locations in the genome.

There are several tools researchers are able to use to generate the optimal location and guide RNA sequences that would maximise the on-target activity of the enzyme (ie we cut where we intend to cut) and minimise the off-target activity (cutting at random places in the DNA).

This technology is often referred to as a swiss-army knife as it can help researchers do multiple things that can help scientific progress. A simple yet not trivial example is when researchers ‘discover’ a new gene and want to further understand its function, maybe in the context of cancer.

In order to shed some light, we often delete this gene to see what happens in the healthy cell and ultimately in cancer cells to see what happens and maybe how other genes may be affected.

We can use this CRISPR gene-editing technology. After careful research, we design guide RNA pairs that will bind and guide our Cas9 enzyme to a specific location in the DNA. Just like in bacteria, the modified RNA will recognise the DNA sequence and the Cas9 enzyme will cut at the specific sequence in the gene.

Once this is cut, the cell’s own DNA will try to repair this cut and can do so in different ways by either adding or deleting pieces of genetic material. 

If we intend to delete this gene, we can provide a ‘repair template’ to ‘fix’ the DNA in our own way with a sequence that we know will cause a disruption and ultimately will not allow the gene of interest to function and thus causing a so-called gene-knockout.

Think of it like a cut-paste mechanism.

Archive DNA vs Virus DNA

Axios: At what stage is CRISPR at the moment?

G.S: CRISPR technology is evolving rapidly. Its use as a genomic editing tool has coined it as a great way of transforming basic research, drug development and improving the understanding of human diseases.

To date, there are over 16,000 articles that have been published containing the term CRISPR and has even inspired Hollywood scriptwriters.

Despite the obvious buzz, scientists are still working on understanding the safety, efficacy and responsible potential use of the CRISPR technology in people.

As such, ethical concerns do arise when such genome editing tools are used to alter human genomes.

Based on concerns about ethics and safety, germline cell (egg and sperm cells) and embryo genome editing are currently illegal in many countries as such changes could be passed on to future generations.

The technology has been tested in several diseases.

More recently, scientists have attempted to use the technology to try and treat a person suffering from both leukaemia and HIV with mixed success.

After finding a suitable stem cell donor for the patient, they used the stem cells and edited them to contain a mutated version of a protein receptor that is key for the successful invasion of the cells by HIV.

In theory, once the patient received the transplant, the new blood cells produced would not only help ‘cure’ the patient’s leukaemia but also prevent any HIV entering the new cells.

HIV demonstration entering the cells

Unfortunately, due to several hindrances, these edited cells had to be mixed with unedited cells before transplantation. 19 months after the transplantation, the edited cells form only 5–8% of the recipient’s total stem cells, a very low percentage that although has lead to the patient’s leukaemia to be in remission, the patient is still infected with HIV.

Although this is not a 100% success story, the scientists have used it as a proof of concept and showed that the patient did not suffer any side-effects caused by the gene-edited cells. 

Moreover, when the genomes of those cells were sequenced, they did not find evidence of unintended genetic changes. This is just one of the multiple ways the technology can be used.

Axios: What is the goal? What are scientists trying to do with this method?

G.S: As we have mentioned previously, the technology is being used as a tool to better understand biology and potentially use it as part of the treatment of both genetic and non-genetic diseases.

Crisp

A study has looked at potentially using this technology to enhance the body’s own anti-tumour defence to combat cancer.

Specifically, trials in China are currently underway whereby researchers are utilising immune cells (T-cells) that have an edited form of the gene encoding for a protein responsible to keep cells in check.

Scientists have proposed that by deleting this gene in T-cells, can be activated to kill non-small cell lung cancer cells in patients with advanced disease. The trials are still in their infancy but preliminary results seem promising.

Apart from medicine, CRISPR has been used in an attempt to catch up with climate change and try to improve agriculture such as CRISPR-editing bananas to resist fungal growth.

The Future of Mankind

This exciting technology keeps evolving day by day, and it is headed towards changing our lives forever.

Someday (maybe even sooner than we thought) we might finally be able to cure deceases, or even prevent them from happening.

With the ethics topic still remaining, “editing” embryos is currently illegal in many countries as errored changes in an embryo’s DNA could be passed on to future generations.

Even so, we can only hope that if this ever happens, it won’t create a species of X-MEN-like good-looking humans to take our place!

X-men like humans
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