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Sandy Starr

The great leap forward in Genomic Medicine

Of all the reasons to be optimistic, medical advances with the human genome could prove awe-inspiring

In the early years of this millennium, our species made an unprecedented step. We became able to read more or less the entirety of our genetic code.

With the completion of the Human Genome Project in 2003, we had the first (nearly) complete human genome sequence – a string of billions of letters, representing the composition of the DNA molecules that are replicated throughout the trillions of cells in our bodies.

Since then, we’ve built on this achievement in remarkable ways. We’ve been able to make the human genome sequence even more ‘complete’, sequencing obscurer portions of DNA that had to be omitted the first time around because our technology wasn’t sufficiently advanced.

We’ve also made whole genome sequencing far more affordable and efficient. It originally took an international consortium more than a decade and billions of dollars of funding to sequence a whole human genome. The same thing can now be achieved by a single laboratory within a single day, at a cost of mere thousands of dollars (and falling).

And that’s not the half of it. In tandem with this increasing ability to read our genetic code, we’ve also been developing the ability to edit this code – to make precise and intentional changes to our DNA, as well as to the DNA of animals, plants and micro-organisms.

Genome editing – the deliberate alteration of selected DNA sequences in living cells – was first achieved in mammalian cells in the mid-1980s. Different approaches to genome editing were developed in subsequent decades, and these made it easier to achieve desired DNA edits more reliably. But the field has been drastically transformed during the past decade, with the advent of CRISPR.

CRISPR is a phenomenon that was originally discovered in the 1980s in prokaryotes – single-celled organisms, whose DNA is arranged in circular chromosomes. There, CRISPR acts as a defence mechanism against invading viruses. But in 2012, researchers discovered a way to adapt this phenomenon for use in eukaryotes – multi-celled organisms such as humans, whose DNA is arranged in linear chromosomes. In this new context, CRISPR became an extremely powerful approach to genome editing.

CRISPR genome editing involves introducing components into cells that break and alter specified portions of DNA, but then enlist the cells’ own natural repair mechanisms to join the broken DNA back together. Effectively, we took two natural phenomena – prokaryotic defence mechanisms and eukaryotic repair mechanisms – and juxtaposed them to our own advantage. This is a juxtaposition that nature herself never achieved, in the three billion years since prokaryotes and eukaryotes first diverged down different evolutionary paths.

It originally took an international consortium more than a decade and billions of dollars of funding to sequence a whole human genome. The same thing can now be achieved by a single laboratory within a single day.

How does this help humanity? To begin with, genome editing is an enormous boon to basic research. CRISPR genome editing is so practical and affordable that researchers around the world now use it routinely – indeed, there are now whole areas of life sciences research where CRISPR genome editing is all but ubiquitous.

This technology also has far-reaching potential for use in medicine. This was illustrated dramatically in 2015, when doctors at Great Ormond Street Hospital in London successfully used genome editing (not CRISPR but an older approach) to reverse advanced leukaemia in two infants, thereby saving their lives.

Perhaps the most contentious use of this technology is to edit the genomes of human embryos. This is permitted in a research context in countries including the UK, where it provides precious opportunities to understand the biology of early human development. But using genome-edited embryos to establish a pregnancy is a very different proposition, and at present would be illegal in many countries.

In 2018, we saw the first children (twin girls) ever to be born with edited genomes, after Chinese scientist Dr He Jiankui established a pregnancy with embryos on which he had used CRISPR genome editing. Unfortunately, Dr He did his work secretively and in breach of numerous scientific and ethical standards. His actions therefore prompted an understandable international outcry.

Fortunately, there are now two important initiatives – one conducted by the World Health Organisation, one conducted jointly by the USA’s National Academies and the UK’s Royal Society – which will be working throughout 2020 to establish international standards in this area. This work will clarify the criteria that need to be met before the clinical use of genome-edited human embryos is scientifically and ethically justified, thereby setting out a safer and more responsible path than the one embarked on by Dr He.

Meanwhile, exciting new variations and elaborations of genome editing – such as ‘base editing’ and ‘prime editing’ – are now emerging, and could add further to the advantages of the CRISPR approach.

Humanity’s ability to understand and intervene in its own DNA continues to expand steadily. The benefit that this technology has brought to us – and the greater benefit it could yet bring to us, if our science is rigorous and if our policies are sound – is awe-inspiring.

Sandy Starr is Deputy Director of the Progress Educational Trust - www.progress.org.uk - a charity whose vision is to improve choices for people affected by infertility or genetic conditions.