CRISPR: Gene editor, cancer weapon and harbinger of genetically engineered nightmares

Tyagarajan S February 14, 2017 11 min

Designer babies. Engineered warriors. Super bugs. Genetic casteism. The science fiction dystopia of genetic engineering (Gattaca, genetic glass ceilings and borrowed ladders: Is genoism inevitable?) is oozing out into our lives. So are utopian dreams of killing cancer, pre-empting genetic defects and eradicating malarial mosquitos.

All thanks to a revolutionary new technology being hailed as the biotech discovery of the century —  Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR, pronounced crisper).

A CRISPR way to evolve

CRISPR is the most precise, fastest and cheapest (a graduate student with access to a lab can get started for $75) method available (till date) to manipulate the genomes of any animal (or plant for that matter). In precision terms, CRISPR took gene editing from an era of blind bombing runs using rickety, old planes to laser-guided, target-seeking missiles.

It’s a technology that could one day revive the Woolly Mammoth.

Crisper can help revive woolly mammoth
The Harvard Woolly Mammoth Revival team has been working closely with Revive & Restore to recreate mammoths that that can fill up the tundra using CRISPR gene editing technology.

CRISPR has really gotten buzzing in the last few years. So much so that Merriam-Webster included it as one of the 1,000 new words added to the dictionary earlier this year.

Crispr mentions in scientific publications
Source: PubMed

So, what’s it all about?

Primordial bacterial defence to science fiction technology

Long before it became a revolutionary technology known to man (we’re talking millennia here), CRISPR was being used as a defence mechanism by bacteria against their evolutionary nemesis  —  the parasitic viruses.

The discovery started with some researchers noticing (quite accidentally) that bacterial DNA had some recurring sequences that were palindromic (hence the name: Clustered Regularly Interspaced Short Palindromic Repeats or CRISPR).

Crispr palindromic repeats
An over-simplified rendition of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) sequence in bacterial DNA

The second breakthrough was the discovery in 2007 that between the repeating DNA sequences, there lay embedded RNA strands of viruses as part of the bacterial adaptive immune system (Dr Rodolphe Barrangou is largely credited with this discovery).

CRISPR regions are composed of short DNA repeats (purple rectangles) and spacers (red and blue rectangles). When a new virus attacks a bacterium, a piece of its RNA is included into the existing spacers

The third and perhaps the most exciting breakthrough moment came when teams led by Jennifer Doudna and Emmnuelle Charpentier (both won the breakthrough prize in life sciences in 2014) fully decoded the defence mechanism. An extraordinary protein, now called Cas9, which attaches itself to the RNA strands, helps home in on the right part of the viral DNA and upon finding it, cuts if off effectively, neutralising the threat.

Crispr Cas9
Using CRISPR RNA, the bacterial molecular machinery (Cas9 enzyme) finds a matching target sequence in the invading virus and upon finding it, cuts it up and kills the attacking viral genome

Here’s the fun part if you are a biotech researcher: Assemble an RNA sequence (within limits) and fit it with the Cas9 enzyme and you have a programmable DNA cutter, with a map of where to hit in the DNA town, a built-in GPS, homing device and a scalpel all rolled into one.

Crispr Working
Source: Harvard University

CRISPR-Cas9 is a biotech revolution because the technique could work on the DNA of any damn living thing on the planet. This is also what makes it a potential goldmine.

Hunt for genetic gold

You know that there is serious excitement in the community when two institutes —  University of California, Berkeley and The Broad Institute of MIT and Harvard  —  are going at it in order to win a patent.

It’s a story worthy of a Hollywood drama. Feng Zhang of the Broad Institute of MIT currently owns the patent for the CRISPR-Cas9 technique. But the Doudna-Charpentier duo from Berkeley claim the first discovery and earlier application for the patent.

Crispr patent wars
Broad Institute of MIT and Harvard in Cambridge, Massachusetts and Berkley, are vying for patent rights to CRISPR-Cas9. In May 2012, Jennifer Doudna, a molecular biologist at Berkeley, applied for a patent after CRISPR–Cas9 was successfully used to alter parts of bacterial DNA. In December 2012, Feng Zhang, synthetic biologist of the Broad Institute, applied for a patent after demonstrating its use in human-like cells. Zhang requested  —  and got  —  an expedited approval for his patent application. After a challenge by Berkeley, a review of the patent is in progress and both the institutes have filed hundreds of pages of documents in court.

After all, there’s a $5.5 billion market at stake and investors have pumped in millions.

Riding on the CRISPR wave, three companies went for IPOs in 2016. Editas Medicine (of which Zhang is the founder and owner) raised $94 million, Intellia Therapeutics (in which Doudna is a founding member) raised $104 million and CRISPR Therapeutics (which owns Charpentier’s patent rights on the technology) raised $56 million. Before they went public, these companies had raised upwards of $100 million individually through private funding and partnerships.

There is a lot riding on the patents.

And clinical trials are yet to come. Last year, the US National Institutes of Health (NIH) approved the first proposed clinical trial from University of Pennsylvania. Editas has also announced that it will conduct clinical trials this year.

While patent wars are being fought in the US, things are moving at a frenetic pace across the world in China. After using CRISPR to edit monkeys in 2014 and human embryos in 2015 (causing an bio-ethical uproar and calls for slowing down), China announced that they’ve started on live human trials last October using CRISPR to fight cancer.

The competition brewing between the countries promises to accelerate the CRISPR trials and bring its resulting benefits quickly into the market.

Cure Cancer, fix genetic disorders and kill malarial mosquitos

A few months ago, I got acquainted with someone who had a condition in which his his body makes an abnormal form of haemoglobin. Every month, he checks himself into a hospital for a complete blood transfusion. This condition, called thalassemia, is a genetic blood disorder with no treatment  —  just lifelong, regular blood transfusions. Imagine that.

There are nearly 50 such major genetic diseases that get passed on to millions of people and CRISPR-Cas9, by making gene editing easier, offers immense hope. Jennifer Doudna believes that we’ll start by fixing the genetic diseases of the blood, liver and eyes to be followed by more complex ones like cystic fibrosis. It can also have a huge impact on cancer treatment by programming the patient’s immune cells to seek and destroy cancer cells.

Crispr india cancer
All the approved clinical trials today target cancer treatment. The gene editing focuses on programming a patient’s own immune cells to seek and destroy cancer cells

Beyond human applications, CRISPR offers a playground of options to leverage genetic modifications in organisms to plants to animals.

The most exciting (and dangerous?) possibility here revolves around influencing genetic traits across generations of large populations of creatures that can be favourable to humanity. Statistically, the possibility of any genetic trait propagating to the next generation is 50/50. But “gene drive” allows us to force certain traits to spread through to nearly all offspring  —  like resistance to malarial pathogen in mosquitos — making an entire population adopt the trait in just a few generations.

Crispr gene drive
Using ‘gene drive’, an engineered mosquito is likely to pass on malarial resistance genes to most of its offspring — defying the evolutionary 50% chance. As a result, the desired gene would pervade across an entire population rapidly.

There are worries about the unintended consequences of these changes. By eradicating entire populations, how does our ecosystem get affected? Also, what kind of unknown / unplanned mutations happen once we start messing around with the DNA?

Designer babies and genetic frankensteins

It isn’t a stretch to imagine that with the power of gene-editing, parents are going to want to edit their babies to perfection. With that scenario, a whole army of dystopian nightmares from science fiction come crashing into our narrative.

Crispr brave new world
A future of chronic, engineered and notional happiness. But it feels like the archetypal dystopia that we come to expect: the happiness is insipid

Here’s a small selection of the cheery possibilities:

  • A genetically engineered race of super soldiers built to fight our wars could end up becoming the ‘Frankenstein’ species we love to hate (Thirteen / Black Man — Richard Morgan)
  • We’ll create a genetically-engineered caste system of people (some intentionally stupid so they’ll do menial jobs) for the purpose of a more stable, satisfied society (Brave New World — Aldous Huxley).
  • Maybe we’ll genetically engineer ourselves into microscopic entities so we can live in the harsh conditions of an alien planet. (Surface tension (short story) — James Blish)
  • Bizarre hominids (half-ape, half-human) created as part of secret government-corporate genetic experiments could escape and predictable chaos could ensue (Chimera, Stephen Gallagher)
  • A bio-engineered plague that is gender specific (or race specific, if we want to extend the idea) could be unleashed and wipe out targeted sections of the population (The White Plague, Frank Herbert)

While the list may sound paranoid, they all point us to the two most common fears: Genetic classism and unintended consequences. Access to genetic engineering, when available commercially, will be driven by access to wealth, and therein lies the seed for social and cultural divisions.

Playing around with genes is a one-way road into the unknown given that we don’t understand the consequences enough  

The fear of unintended consequences is even more real and immediate. Playing around with genes is a one-way road into the unknown given that we don’t understand the consequences enough. Who’s to say that editing our the ‘buggy’ part of our genetic code won’t impact us in other ways?

There is also the fear of us losing our genetic heterogeneity, which is nature’s way of helping us survive sudden, shocking environmental changes. A highly homogenous species is more likely to get wiped out more easily.

With China starting to test genetic modification of human embryos using CRISPR, there are already murmurs that we should probably adopt the solution Richard Heinlein proposed in his novel Beyond the Horizon: Couples would be allowed to choose from among their own sperm and ova and not be allowed to edit them (you can get the best version of the baby you can produce naturally).

Crispr Heinlein solution
Broadly paraphrasing…

Maybe we do need science fiction solutions to deal with science fiction problems.

We’re nowhere close to designer babies yet

For all the noise, CRISPR is nowhere close to being perfect.

Back in 2015, a group of researchers from Sun Yat-sen University in Guangzhou conducted germline edits on human embryos as they attempted to modify a gene responsible for β-thalassaemia. Of the 86 human embryos injected with gene-edited cells, a very small fraction contained the new genetic material. A surprising number of ‘off-target’ mutations were also discovered, leading the team to conclude that the technology was too immature.

Even when CRISPR-Cas9 combo does its job, it works better as a precision scalpel, cutting off a required portion of the genes. Inserting another genetic sequence in its place is an entirely different problem. In the words of one frustrated researcher, “Burning a page of the book is not editing the book.”

Even when CRISPR-Cas9 combo does its job, it works better as a precision scalpel, cutting off a required portion of the genes  

Researchers are fast at work looking at other enzymes that could work with Cas9 and help with the “editing” problem. In parallel, several CRISPR-based variant techniques are being developed. We are in very early days, but the possibilities and fears loom with an immediacy that’s not necessarily there.

The ease and cost effectiveness of CRISPR is the game changer. DIY bio-hackers could now achieve results that were earlier possible for Phd’s in sterile labs causing governments to react with threats of prosecution.

The ease and cost effectiveness of CRISPR is the game changer. DIY bio-hackers could now achieve results that were earlier possible for Phd’s in sterile labs causing governments to react with threats of prosecution  

This has brought forth calls for highly restrictive regulations from certain scientists. Highly visible failures (due to hasty or amateurish approaches) may only end up hurting the field more in the long run, they believe. Others believe that its this very ease of access and experimentation that’s going to result in breakthroughs.

In any case, CRISPR-Cas9 is riding a silicon-valley style hype-wave right now — a tricky place to be in. The narrative could quickly degenerate into divisive social media-like rhetoric, with pro and anti groups lining up. In an age of regulation influenced through Facebook propaganda, this could result in governments creating regressive, inconsistent legislations. Then there is the big, pending patent decision that could potentially impact the future of millions of dollars of private investments funding the technology in the US.

For CRISPR, 2017 will be a key year.

Lead visual: Nikhil Raj

Inside graphics: Tyagarajan S

 


Updated on February 14, 2017, at 3.32pm to correct the credit for inside graphics. It earlier said Nikhil Raj but should be Tyagarajan S.