Annual review 2017

Profound change; profound questions

From the frontline of scientific research, Assistant Professor Mitchell O’Connell offers a view of the huge benefits that could flow from the CRISPR gene-editing technology, and warns about its current limits and possible misuse.

Professor Mitchell O’Connell

Assistant Professor of Biochemistry and Biophysics, University of Rochester

The sudden emergence of CRISPR technology, with all its transformational promise, has, at times, led to the kind of hype that often greets a moment of profound scientific discovery.

But, says Assistant Professor Mitchell O’Connell, speaking from his research lab at the University of Rochester Medical Centre in New York state, it’s important to bring some balance to the conversation about this hugely important technology and the complex work that still needs to be done for it to reach its potential.

“If you have a good idea in science, no doubt ten others will have had the same idea, and five may have tried it already,” he says. “Ideas are generally easy. Implementation is harder.”

And many hurdles lie in the way of CRISPR achieving its potential – IP (“messy”), regulation (“very tough”), potential societal resistance, deep ethical questions and significant technological challenges.

The scientific community, Mitchell argues, needs to be real and open about these issues so that the technology can be developed and applied safely, backed by a broad and informed consensus among stakeholders.

Opening doorsRead more

But that, he makes clear, is not to underestimate the extent to which CRISPR is already opening new doors in scientific research.

“At a very fundamental level its ability to extend our understanding of biology and what genes and non-coding DNA do in everything from humans to all kinds of plants, animals, and bacteria etc. is extremely profound,” he says.

“In fundamental research CRISPR has really been able to help us begin to decipher the architecture of the genome and I think we will look back in 20 years’ time and think ‘wow, that’s how people were thinking about gene expression prior to CRISPR.’”

More importantly it is relatively easy to use and available to labs across the world. “There were gene editing techniques before, but they were only there for the 1%. Now anyone who runs a lab is able to take their favourite model organism(s) and modulate its genes to study their effects on growth, development, aging, cancer, cognition etc… you-name-it.”

In contrast to some of the patent disputes that have erupted as the technology is commercialised, sharing of ideas within the academic community is also helping to propel research. “We are all really focused on just pushing the field further forward,” he says.

From drug testing to foodRead more

He sees a number of key benefits coming from the technology, not least in the treatment of disease, in drug development and agriculture.

In the past, he notes, some drug development programmes have “struggled and failed spectacularly” because they have simply not reflected the vast genetic variation within and between different human populations. CRISPR could change that.

“It will allow us to create more complex disease models that will take account of the vast amount of genetic variation that exists in populations so that we can really understand how multiple gene variants are causing disease. That’s because we can now go in and target thousands of genes at once with pretty high efficacy. That’s where we see the technology going.”

But in terms of using CRISPR gene editing itself as part of a therapeutic intervention (and particularly in vivo gene CRISPR editing) it is still early days and key technical challenges are yet to be overcome, including delivery – getting it to the appropriate cells (and not to unwanted target cells), making precise edits at high enough efficiency to manifest a therapeutically beneficial phenotypic effect, and limiting the possibility that other regions in the genome will be affected, creating unwanted “off-target” mutations.

These challenges will be particularly challenging when using the technology on somatic (non-reproductive) cells within the body and Mitchell thinks that in the short-term the biggest advances in disease therapeutics will be seen in ex vivo (outside the body) research and in offering some relief to patients with terminal diseases.

He predicts much faster progress in applying CRISPR in food production. “I’d like to see more talk about the benefits we can make in agriculture and revisiting the genetic modification (GM) debate. This is where CRISPR researchers need to be very careful because scientists previously struggled communicating the benefits of GM to the general population, their voices were often drowned out by fearmongering and lots of falsehoods.”

Maintaining a secure food supply has been one of the great feats of civilisation, he argues. “Using CRISPR is a lot more precise and usually involves making only very minor changes to the genome compared with the hundreds and hundreds of imprecise changes that we have made to plants to get from a wild heirloom species to something that’s domesticated and can grow in a mono-culture.”

Some of the nuance of these debates is lost, he says, particularly when transformational technologies come into the media spotlight.

RenegadesRead more

Ease of access to CRISPR technology and its relative simplicity to use, without approval or oversight and “with a couple of years’ experience in molecular biology”, has clear downsides too. It means that regulation will, also, be a particular challenge in what is currently still something of a “Wild West” environment.

“The danger of a couple of renegade scientists coming out and doing stuff before it’s safe to do so, or doing it just because they can, is a real concern,” he says.

In common with a growing number of researchers, including Jennifer Doudna – a pioneer in the field and his former advisor at the University of California, Berkeley – Mitchell calls for a pause to allow for a “community conversation” to decide what should and shouldn’t be done with the technology.

“We need to reach out to the community and let people know that we are citizens too and might in some cases have an opinion that is potentially separate from our scientific opinion,” he says.

Such a conversation needs to be inclusive of all stakeholders and address people’s concerns – particularly on issues likely to be highly contentious, such as germ-line editing. Equally, real care needs to be taken to explain the medical and economic benefits the technology might bring in terms of human wellbeing and helping to curb soaring healthcare spending.

“It’s hard to bring everyone together to create a quorum. But we need to really lay it out and be clear about the benefits to humanity as a whole in terms of quality of life and economics of healthcare particularly given our aging population and the increasing costs associated with long-term healthcare”.

“There is a massive cost to a lot of healthcare and being able to treat diseases and cure and/or prevent serious disabilities could massively boost our ability as a population to thrive.”