Genomics and beyond:
on the threshold of transforming medicine

It was the most fateful meeting of your life. An ovum, a sperm, with one thing leading to another, a nucleus fuses and a wholly unique combination of DNA comes into being: your genome. Your first cell becomes two, four, eight, sixteen, and with each division your genome gets closer to putting feet on the ends of legs, colouring eyes and developing an aptitude for drawing.

Characteristics influenced by your DNA are not limited to how you look or think. Genes also carry susceptibility to disease, and thus a perverse capacity to disrupt or end the life of the organism that bears them. Sometimes these faulty genes are inherited and sometimes they mutate spontaneously. Sometimes disease arises from a single malfunctioning gene, sometimes it arises from a subtle layering of multiple genes and environmental influences. Sometimes, we simply don’t know what causes a disease, but that doesn’t stop us trying to find out.

Such discoveries seem tantalisingly close as advances in technology enable comprehensive study of the genome and propel medicine into a wholly different future. “There’s no doubt in my mind that genomics will transform medicine. It will convert it from being the art of crisis management, based on limited information and with a one-size-fits-all approach, to the science of good health,” says Professor John Mattick, Garvan Institute of Medical Research’s Executive Director.

Upon assuming his position in January 2012, Mattick established genomics as the keystone of Garvan’s research program. This ambition crystallised in 2014 when Garvan was among the first to acquire the Illumina HiSeq X Ten sequencing platform, which decodes a DNA sample – all six billion of its bases – at high volume and low cost.

So why sequence the whole genome, given that conventional protein-producing genes only occupy about two per cent? “Why would you just rip out the coloured pages from the book?” counters Mattick. “It might be cheaper to look at just the coloured pages, and there’s a high value there for traditional genetic disease, but if you’re thinking about the future of clinical diagnoses then you want to have all of the information because you want to be able to explore its dimensions and understand it in full. Indeed the genetic factors underpinning complex diseases, which are the major health problems, lie mainly outside of the protein-coding genes.”

A complete account of genomic information, moreover, is not limited to DNA alone. Enter the field of epigenetics, where the Greek prefix “epi” indicates “upon”, “above”, or “in addition to”. The epigenome is an essential additional layer of chemical information that orchestrates which parts of the genome are active in different cell types. It accounts for why one cell might manufacture keratin to build fingernails, while another cell with identical DNA creates haemoglobin so that red blood cells can transport oxygen.

DNA underpins all the body’s activities and processes, just as it does for Garvan’s research.
Professor Susan Clark, who heads Garvan’s Genomics and Epigenetics Division, elaborates on Mattick’s book analogy. “Imagine a book with six billion letters, but there are no chapters, no paragraphs and no grammar to aid the reader to interpret the story,” she says. “Epigenetic information provides the grammar to allow our DNA to be read in context to ensure that all our fingers and toes end up in the right places.” Alongside its role in development, epigenetics also tweaks gene expression according to environmental signals. Consider a pair of identical twins, who have the same DNA but distinct appearances and personalities due to their individual life experiences.

As with the genome, the epigenome is susceptible to faults, whether inborn or acquired, such as health impacts from smoking or exposure to toxins. Though problematic, such a situation does have an upside. “Unlike genetic mistakes, epigenetic mistakes have the potential to be reversed,” says Clark. “In the future we aim to generate sequence maps of both our genome and our epigenome to provide a new toolbox of diagnostic tests and therapies to treat disease.”

With technology having advanced so quickly, genomics and epigenetics can finally start improving and extending lives. The first stop is tackling genetic disease, particularly in children who are born with a previously undiagnosable physical or intellectual disability. The other initial target is cancer, where genomic analysis can guide drug choice through uncovering a tumour’s specific mutation, and where epigenetic therapies are showing promising results. Though remarkable, such achievements represent only the beginning of the beginning. Ultimately, as genomics and epigenetics affect every part of human biology, it stands to reason that they should affect every part of medicine too.

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