A new age of discovery for biology

An age of discovery is in prospect for biology, predicts Feng Zhang, neuroscience professor at MIT and co-inventor of CRISPR

Science

In the era of modern science, hardly a week goes by without a big advance in biology. Although such progress will continue in 2018, it will not bring a cure for cancer, a remedy for Alzheimer’s or a pill to slow ageing. That is because biology, as a field, is largely still about exploring and not yet about engineering.

Some of the greatest scientific successes of the past century have come by marrying science and engineering, from the Apollo mission to the Large Hadron Collider. Similarly, the Human Genome Project required both basic research and technology development. The disciplines at the heart of these successes—mathematics, engineering, and material and computer sciences—have propelled the technology economy, giving rise to nearly all of the most dominant companies in the world today.

Biology, meanwhile, is still largely about testing to see what happens when various strings are pulled. Biologists are doing important and difficult work that provides critical insight into the fundamental principles of living organisms. But as we build new tools to understand biology at an increasingly high resolution, we are nearing the limits to the knowledge that our traditional approaches will allow.

Chief among these limits is that life requires an inherent complexity. In 2016 scientists reported the creation of a minimal synthetic bacterial genome, containing just 473 genes (for comparison, the human genome contains about 20,000). Of those 473 genes, 149 were of “unknown function”, but leaving out any one of them was lethal. Even in a controlled laboratory setting with the simplest set of instructions to build a living organism, nearly a third of the content of those instructions remains a mystery.

In classical genetics and molecular biology, figuring out what genes do is typically accomplished by knocking out the gene and then studying what goes wrong. This approach has led to powerful insights, from revealing oncogenes, which when mutated can lead to cancer, to uncovering the network of proteins involved in patterning the structure of the body during development. This type of work is predicated on a tenet of biology, put forth in 1941 by George Beadle, that each gene contains the instructions for one protein. Although this is largely true, proteins frequently form large complexes that function together, muddying the one-to-one relationship. It thus becomes necessary to probe the function of genes in a combinatorial fashion. Doing this for the 149 genes of unknown function in the synthetic minimal genome using classical tools is a daunting task. Doing this for the human genome is impossible.

However, with new technologies that speed up the processes of reading and writing biology, scientists can now interrogate the function of genes at a much greater scale. As data about gene function accumulate, this information can direct the combinations of genes to study, greatly reducing the dimension of the problem. A number of consortia have been formed to tackle the large-scale experiments needed to catalogue the regulatory elements of the human genome, map all the types of human cells, draw up comprehensive lists of all the variants in the human genome found in the population and create a circuit diagram of all the connections in the brain. All of these data can be fed back into research programmes focused on understanding the function of individual or related sets of genes in specific contexts, such as disease or ageing.

Expect the unexpected

This type of basic research is necessary to advance our understanding of the living world. Precisely because biology is not yet an engineering discipline, it is imperative to support the work of scientists who are exploring the molecular world, driven by curiosity and a tinkerer’s desire to know how things work. These explorations have a rich history of leading to unexpected discoveries and unanticipated applications, a recent example of which is the adaptation of microbial CRISPR-Cas systems for genome-engineering tools.

Basic research is also providing the fuel for new disease treatments, improvements in agriculture and novel biotechnologies. These, in turn, are driving a biotechnology boom. It is not just the biological findings that are driving the life-science economy. Associated developments in software, hardware, materials science and engineering also contribute. Opportunities for those with PhDs are extending beyond academia into biotech startups, law and investment. All this progress, though, is built on the output of basic research, as well as funding from public and private sectors, without which the discovery pipeline will run dry.

Armed with vast banks of information, could we design a synthetic minimal genome in which every single gene was chosen to fulfil a specific function? Could we treat any cancer or slow down ageing? Perhaps. But what might be more interesting are the as yet unimagined discoveries made along the way.

Credit: Lauren Crow
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