Professor of Genomics, The Scripps Translational Science Institute; Author, The Patient Will See You Now
The 6 Billion Letters Of Our Genome

In 2015, we crossed the threshold of the first million people who had their genomes sequenced. Beyond that, based on the fast pace of progress in sequencing technology, it is projected that we’ll hit 1 billion people sequenced by 2025. That seems formidable, but quite likely given that the velocity of DNA reading innovation has exceeded Moore’s Law. However, the big problem we have is not amassing billions of people’s genome sequences. It is how to understand the significance of each of the 6 billion letters that comprise a human genome.

About 98.5% of our genome is not made of genes, so it doesn’t directly code for proteins. But most of this non-coding portion of the genome influences, in one way or another, how genes function. While it’s relatively straightforward to understand the tiny portion of the genome—genes—that code for proteins, the non-coding elements are far more elusive.

So the biggest breakthrough in genomics—Science Magazine’s 2015 Breakthrough of the Year—is the ability to edit a genome via so-called CRISPR technology with remarkable precision and efficiency. While we’ve had genome editing technologies for several years, including zinc finger nucleases and TALENS, they were not straightforward to use or could achieve a high rate of successful editing in the cells that were exposed. The precision problem also extended to the need to avoid editing in unintended portions of the genome, so called off-target effects. Enter CRISPR and everything has quickly changed.

Many genome editing clinical trials are now underway or will soon be to treat medical conditions for which treatment or a cure has proven remarkably challenging. These include sickle cell disease, thalassemia, hemophilia, HIV, and some very rare metabolic diseases. Indeed, the first person whose life was saved was a young girl with leukemia who had failed all therapies attempted until she had her T cells genome edited (using TALENS) with a very successful response. George Church and his colleagues at Harvard were able to edit 62 genes of the pig’s genome to make it immunologically inert, such that the whole idea of transplanting an animal’s organ into humans—xenotransplantation—has been resurrected. A number of biotech and pharma companies (Vertex, Bayer, Celgene and Novartis), have recently partnered with the editing company startups (CRISPR Therapeutics, Editas Medicine, Intellia Therapeutics, Caribou Biosciences) to rev up clinical programs.

But the biggest contribution of genome editing, and specifically with CRISPR, is to catapult the field of functional genomics forward. Not understanding the biology of the DNA letters is the biggest limitation of our knowledge base in the field. So many interesting DNA sequence variant “hits” have been discovered but overshadowed by uncertainty. Determining functional effects of the VUS—variants of unknown significance—has moved as a very sluggish pace, with too much of our understanding of genomics based on population studies rather than on pinpointing the biology and potential change in function due to an altered (compared with the reference genome) DNA letter.

Now we’ve recently seen how we can systematically delete genes to find out which are essential for life. From that we learned that only about 1600 (8%) of the nearly 19,000 human genes are truly essential. All of the known genes implicated in causing or contributing to cancer can be edited, and indeed that systematic assessment is well underway. We have just learned how important the 3-D structure of DNA is for cancer vulnerability by using CRISPR to edit out a particular genomic domain. What’s more is that we can now generate a person’s cells of interest (from their blood cells, via induced pluripotent stem cells)—be make heart, liver, brain, or whatever the organ/tissue of interest. When this is combined with CRISPR editing, it becomes a remarkably powerful tool that takes functional genomics to an unprecedented level.

What once was considered the “dark matter” of the genome is about to get illuminated. The greatest contribution of genome editing will ultimately be to understand the 6 billion letters that comprise our genome.