From AAV to CRISPR: Era of hacking our bodies is just beginning

1 Jun 2017

Cutting segment of DNA. Image: tdhster/Shutterstock

Methods such as CRISPR have started a new revolution in the human body, one in which the very fabric of our being can be altered at whim.

In the 1997 film Gattaca, the future society depicted has achieved mainstream genetic modification, so much so that before a child is born, their physical features can be chosen and hereditary conditions eliminated.

When the movie was released 20 years ago, genetic modification was still in its infancy, with the first complete mapping of the human genome only occurring six years later.

Now, with the advent of more powerful online machines, supercomputers and artificial intelligence (AI), the price of mapping an entire human genome has fallen from hundreds of millions of dollars, to potentially as low as $100 in the near future.

For science, this is game-changing, as researchers can now conduct very affordable research that could potentially unlock the answers as to why our genes behave the way they do, and why some horrific diseases – such as Parkinson’s and Alzheimer’s – develop.

Within Ireland alone, major players in the life sciences sector are teaming up to invest huge amounts of time and effort into research for genomics as part of a 15-year partnership at the beginning of this year.

So, two decades after it was first brought to popular attention on the big screen, genetic editing is not only here, it is now increasingly available.

Fixing diabetic blindness

Take the example of Dr Philip Cummins, a researcher at the School of Biotechnology, Dublin City University (DCU).

He is currently leading a major international project to solve a condition that affects millions of people globally: diabetic retinopathy, otherwise known as diabetic blindness.

Caused by high blood sugar levels damaging the blood vessels in the retina, the condition is one of the leading causes of ‘new’ blindness in the world.

For those who live with it, existing therapies – such as monthly injections or laser treatment – are by no means 100pc effective, and, in some cases, the side effects can lead to permanent damage.

This is where one of the most promising and clinically proven gene therapy treatments comes in: adeno-associated viruses, more commonly referred to as AAV.

While we tend to think of viruses as the bearers of bad news, they are actually the most effective method of getting modified genes into the human body.

By mutating the affected gene with this harnessed virus, Cummins and his fellow researchers will hopefully be able to ‘trick’ the damaged eye vessels into allowing the delivery of an engineered protein.


Image: Sergei Drozd/Shutterstock

Called COMP-Ang1, this protein could then be injected into the eye, restoring vision once again to those with diabetic retinopathy.

“With our drug, one of the benefits is that if it works optimally, [a patient] would see a profound improvement in their visual acuity that should last for between three and six months,” said Cummins in conversation with

“Eventually, the system will expel viruses and their foreign loads from the body. It’s an unpleasant thing getting an injection into your eyeball, but if it’s the difference between walking around half-blind and getting an injection, you’ll get the injection.”

Unravelling DNA like a ball of wool

Another way that science is manipulating our genes is through the work of the European-wide ClickGene project, currently being led by another DCU researcher, Dr Andrew Kellett.

Like other tested gene therapy methods, the process of actually modifying our genes can have unintended consequences, but, through clever editing techniques, a gene might be mouldable to our will.

Using a specially developed metallodrug, such as copper, and attaching it to nucleic acid (essential to all forms of life), a hybrid form is created.

This mutated nucleic acid could then directly bond to a cancer-causing gene (called an oncogene), with its metal centre precisely targeting the affected areas.

The current method of delivery being analysed by Kellett and his team is using opiates, particularly a morphine derivative with three molecules.

“If you have a ball of wool and you unravel it, you can imagine it being something similar to the structure of DNA taking up quite an amount of space,” Kellett explained.

“What these molecules do is cause the DNA to become compacted back to a very condensed size, like converting the unravelled wool back into a compacted structure.

“This is really interesting because it’s the first time that opiates have been shown to have alternative properties aside from their current uses, which are obviously well known.”

This method could soon allow Kellett and his team to carry out gene editing that would open up a whole new area in the field, allowing them to spawn new therapeutic or gene editing applications.

The question of ethics

While both Kellett’s and Cummins’s fields of research in gene editing are providing exciting results, they both share the limitation of not yet being fielded in human trials, despite their methods of delivery being demonstrated as effective in the past.

The simple reason is that when it comes to editing the very fabric of our being, researchers want to be absolutely sure that their positive results will not lead to unintended side effects to the detriment of the patient.

That is why trials remain ongoing in petri dishes and on mice, with the hope that they can eventually gain approval for human testing and achieve the results they have dreamed of.

There are ethical questions when it comes to tinkering with genetics, though, particularly in the new and potentially game-changing method of clustered regularly interspaced short palindromic repeats, or CRISPR for short.

Perhaps unlike any other method of gene editing, CRISPR has captured the imagination of the public because of its ability to precisely cut out segments of genes and replace them with another.

So, in theory, the gene that leads to the development of Huntington’s disease later in life can be cut out and replaced with a healthy gene, thereby ending thousands of years of natural genetic evolution.

Mouse embryo

A mouse embryo in vitro. Image: Jan Dunst/Shutterstock

CRISPR: A step too far?

Another example from last year showed how a team from Temple University was attempting to use CRISPR to ‘cut’ HIV from human cells. In the future, however, this method could also be expanded to cutting out and replacing natural and harmless features such as skin or eye colour.

Those fears portrayed in Gattaca have suddenly become a lot more real, and scary.

Both Kellett and Cummins admit that they are very interested in seeing where the technology goes, but they are steadfast in their demand to see more evidence before jumping on any CRISPR bandwagon.

“Right now, ethically, there’s huge issues with using CRISPR in any human work and that’s completely understandable,” Cummins said.

Kellett added: “I think one has to exercise a certain amount of caution, and I think there are a lot of reports out there of the speed at which it is being deployed in biological systems in human patients.

“From my point of view, it is very exciting, but that has to be balanced with a long-term view of the ethics and also the potential side effects from some of these, and they won’t be seen for a long number of years.”

Only scratching the surface

As it turns out, though, Kellett was a little off the mark.

Shortly after speaking with him, news broke that Columbia University Medical Center researchers found startling evidence of CRISPR creating hundreds of unintended mutations in the genome.

Within the genomes of two independent gene therapy subjects, they found more than 1,500 single-nucleotide mutations and more than 100 larger deletions and insertions, none of which had been predicted during computer simulations.

Despite this new knowledge, researchers in various parts of the world are expected to ramp up research into CRISPR, with China already confirming it has conducted tests on human embryos.

Whether we are heading towards a utopian world free of disease, or a hellish, dystopian society of genetic inequality and eugenics remains to be seen.

What is clear, however, is that we are only now scratching the surface of what is possible with gene editing.

Colm Gorey was a senior journalist with Silicon Republic