Read/write access to your genomes? Using the past to jump to the future

Today’s guest author is Razib Khan, who is currently a graduate student in genomics at UC Davis. Outside of his scientific work he is interested in history, religion and philosophy, among other things. You can follow him on Twitter at https://twitter.com/razibkhan.

If the story of the last century was the maturation of physical science, the plot of the coming decades will be thick with biology. And genetics will be a key protagonist. In our initial rush of enthusiasm, we often over-hype the promise of new sciences and technologies in the short term—but in our all-too-human myopia, we also don’t truly grasp how innovation can transform our lives. The steam engines of the early 18th century were conceived of and implemented as powerful utilities to aid in the removal of water from mines. But this invention catalyzed an economic revolution that culminated in a century long “age of steam,” which transformed how people lived, worked, and travelled.

When launched in 2007, the iPhone was understood to be the next step in mobile voice technology. What it became was a tool which created and destroyed whole economic sectors—and wormed its way into our lives so seamlessly that it’s almost beneath notice. As science becomes engineering, its transformative power is unleashed. And yet it also (eventually) becomes banal. The fact that we talk about genetic engineering with both wonderment and concern is a sign that its time is still to come. We are moving rapidly into the era where “next generation sequencing” simply becomes the norm of how one accesses genetic variation of any organism. This will allow researchers to explore the branches of the tree of life at incredibly fine scale and to gain unprecedented insights into state of life on earth in earlier epochs. And it will allow the detection of even the most subtle fluctuations in genetic variation in contemporary populations.

But we are also witnessing the first steps in the long march to the age where genetic engineering will become a ubiquitous and workaday part of humanity’s toolkit. Our species will not only gain awareness of the past of life on earth, but we will acquire the power to mould the shape of the tree deep into the future. We are at an especially exciting time in genetics, with the maturation of one field and the birth of another, one allowing for a comprehension of the forces which shaped the past, and another that enables us to become a force which dictates the course of the future.

Past history teaches us that science can take centuries to ripen to the point where human existence is altered in some deep and fundamental manner. For example, Newtonian mechanics preceded the industrial revolution by over a century. Despite the genius of the achievement the material world and human condition were initially unperturbed. Only in the 19th century did physics begin to go from victory to victory and to birth new aspects of human experience by complementing a long parallel tradition of tinkerers and inventors. Electricity and nuclear power are just two applications of seemingly abstruse scientific models which were initially only of intellectual interest.

The origins of genetics date back to the 19th century, during the years that physics was at its peak of glamor. But Gregor Mendel’s ground-breaking work did not make any waves, its potential unrealized even by Charles Darwin, who would have chance to encounter the Austrian monk’s results. But by 1900, the inheritance debates had reached an impasse, and Mendelism stepped into the breach, first through the persuasive power of William Bateson, but ultimately due to the sheer predictive power of Mendel’s work. Mendel’s laws fit the patterns of inheritance many biologists were seeing and resolved paradoxes at the heart of evolutionary biology (e.g., the maintenance of standing variation over generations). Yet it took another 50 years for geneticists to glimpse the concrete manifestation of genes in our bodies, the double-stranded helix of DNA. And then still another 50 years for the human genome to be completed.

Over the past century, genetics has proceeded in the dark, leaping from isolated oases of illumination, traversing valleys in a landscape of daunting complexity in the faint light of poor data. Into this darkness, the intersection of methodology and computational muscle which we now term “next generation sequencing” exploded like a fusion reaction triggering a newborn sun. Today, in the “post-genomic era,” we are awash with data.

But at some point in the near future, the age of genomics will be over because it will become a conventional part of genetics. Whereas ten years ago a paper on the genome of a particular organism was notable; today it is simply a line on a c.v. and fodder for jokes among geneticists. It has become a paint-by-numbers approach to science. First, Sequence. Then, make grand but tendentious claims about the importance of the generated sequence. Finally, leave others to do follow up work and move on to the next sequence. Somewhere along the way, substantive biological significance was left by the wayside in the great rush to publish.

Of course genomics is more than a joke. It has opened up enormous possibilities. You can read Yaniv Erlich’s overview of what those might be in his vision for ubiquitous sequencing. To give a simple perspective, consider that just 15 years ago the publication of the draft of the human genome was a national accomplishment, touted by President Bill Clinton and the media. Yet now hundreds of thousands of people’s genomes have been sequenced, and you can get a good quality read out of your own genetic makeup for a few thousand dollars. Or, as Erlich puts it “in 1990, sequencing one million nucleotides cost the equivalent of 15 tons of gold.” Today? You can get one million nucleotides for the cost of “five breakfast sandwiches at a New York City food cart” according to his calculations.

Before the printing press, the production of manuscripts by reproducing from an original copy was a laborious process given over to professionals. Books were precious, and libraries were the privilege of the powerful. After the Gutenberg printing press was invented in 1440, literacy was democratized, and reading became an avocation of many. So while literacy dates back over 4,000 years, a broad and deep culture of literature only arrived with the printing press. Technology transformed a cultural instrument, deepening its impact. Over the course of its first century, genetics to a great extent has been the domain of a scholarly and medical priesthood. But with the increasing availability of genetic information to the general public, that will change. Already there are debates about the value in releasing medical genotype data to individuals when there is a sea of misinformation as to the implications. To have the genetics in front of you is one thing; to make it actionable through surveying the scientific literature and avoiding quackery is another. In the end a combination of public education and more user friendly interpretive technologies, rather than limiting data access, will be the two solutions for a problem which we wouldn’t have even been able to imagine ten years ago.

In The History and Geography of Human Genes, L. L. Cavalli-Sforza produced a work that summed up five decades of scholarship. The core results spanned several hundred autosomal classical markers. At the time, only Cavalli-Sforza, with his professional eminence and deep institutional ties, could have pulled off such a feat, distilling untold years of labor by innumerable people. Twenty years later, my own personal computer has thousands of samples with millions of markers, and other thousands of samples with hundreds of thousands of markers. The laborious process of data generation by classical genetic analysis techniques has been supplemented, often replaced, by a gusher of information freely available for the taking. If we were once trying to decode the “book of life” by assembling the odd word here and there, today we are printing multiple editions of the same book in full.

But just because you can read does not mean that you can make sense of what you read. Pure sequence information can only get you so far. As technology becomes widespread and ubiquitous, the excitement will fade over coverage, read length, and accuracy. All platforms will be good enough. Ultimately it will fall onto the shoulders of geneticists to make biological sense out of the morass of information, and traditional laboratory science will have to enlighten us. It does no good to have the biggest library in the world if we don’t bother to actually understand what the books tell us.

Population- and pedigree-level focus will be paired with a more fine-grained understanding of how genetic features give rise to variation in phenotypes. A concept such as recombination, implicit in Mendel’s law of independent assortment, will be understood as it plays out on a more precise individual scale, elucidated by structural genomic understanding of its mechanisms. The power of genetics will come to the fore in the intersection with the ubiquitous sea of data in which we already swim. A million flowers will bloom from the joining of data sets to smoke out the correlations therein. And from this field of correlations will emerge causations.

But just as literacy is powerful because you can write as well as read, so the century of biology will earn its name because of genetic engineering. We are literally in the first half-decade of the CRISPR/Cas9 era. For the next generation, genetic engineering will be so ubiquitous that the term will become passé and fade into the background of our lives. A world of pervasive sequencing will be paired with ubiquitous tinkering with genomes. As the human population adds another four billion over the next century, genetic modification of organisms is almost certainly going to become part of the arsenal of any agronomist. Genetic modification of mosquitos offers the possibility of insights into classical questions about behavioral variants. Combining CRISPR/Cas9 with gene drive in Drosophila shows us an exciting path toward eliminating pests via biological means. And the new methods are also increasing the number of fronts that mouse geneticists can work on in their battles to improve human health through better understanding of disease etiology.

Necessity is the mother of utilization. The existence of a class of Mendelian diseases which have grave mortality and morbidity consequences for sufferers, such as cystic fibrosis, means that there will likely be genetic modification of individuals in the near future, as gene therapy comes out of the shadows. As genetics becomes a thoroughly applied science, and CRISPR/Cas9 becomes affordable and easy to implement, it will democratize genetics.

It’s an exciting time to be involved in genetics. We should be prepared for adventures, both good and bad. Whenever humanity unleashes a technological revolution a Pandora’s box is opened and we can’t predict its social consequences. But each time we always release hope for a better future.