Whither The Next Generation of Medicines?
Professor Roger Foo of the Cardiovascular Research Institute ponders the brave new world of genomic medicine and molecular biology.
Most of us remember what we were doing on the day a global event happened. The day the two planes flew into the twin towers in downtown Manhattan, New York. The day the Berlin Wall came down. The day the tsunami hit the shores of some of our favourite beaches in Indonesia. The day we were told that our founding father LKY had died.
I remember it was a busy day of ward rounds in a busy university hospital unit in 2000, when Tony Blair and Bill Clinton announced that the full human genome was finally sequenced. It was fascinating to hear that the “blueprint” of humans had been revealed, but to the sick patients that were on my list, yet to be seen, yet to be discharged, yet to be assigned a review date, the meaning and relevance of a full human genome map could not have been more remote. Even so, what is not momentous is when events make incremental advance, and many smaller yet significant discoveries come together, to make the ground-breaking change that we cannot put a date or time to.
At some point since the first human genome was sequenced, we discovered that we have virtually the same number of about 20,000 coding genes as the worm or fish. The coding genome makes up only about one per cent of the whole three billion-bases of the single human genome. It is the section of the genome that encodes for all of the proteins that constitute all of the parts of our cells, and thence all of the parts of our tissues and organs, our hormones, receptors, cellular antigens and so on. These, all from the ~20,000 coding genes.
Coding genes turn out to be pretty much conserved across animal species. Instead, what makes us different from other animals is the vast, approximately 99 per cent non-coding portion of the genome, which turns out not to be “junk DNA” or simply relics from an evolutionary past, but are crucially are important and functional because they are regulatory segments of the genome that are responsible for fine-tuning and regulating how the coding genome is expressed.
This is how, even though every cell from different parts of our body carries the identical DNA blueprint, different sets of genes are switched on or expressed to make a skin cell function differently from a liver cell, or from a brain cell etc. Different sections of the regulatory genome are activated to turn on or off their corresponding genes. The circuitry is complex, intricate, full of feed-back and feed-forward. Complicated to say the least! The regulatory genome controls gene expression so that a cell manifests its identity.
At some point since the first human genome was sequenced, we discovered that we have virtually the same number of ~20,000 coding genes as the worm or fish.
But what regulates the regulatory genome remains the holy grail of genomic research, and it is a question that could easily turn into one that is philosophical. For now, Sir John Gurdon and Dr Shinya Yamanaka1 have at least shown us that if you pick the right regulatory factors (we can call these “molecular switches”), you can control the regulatory genome, and thereby control cell identities, for example by turning or transforming differentiated cell types into pluripotent stem cells. This is one of the many convergent discoveries that I suggest, will contribute to our next generation of medicines.
Some years after the first human genome was sequenced, Professor Sir Shankar Balasubramanian2 delivered the technology that turned out to revolutionise and democratise genome sequencing. Instead of needing $100m and 10 years to sequence one single human genome, as it did leading to the announcement from Blair and Clinton, Next Generation sequencing technology today allows the sequencing of a human genome within 48 hours, and at ever-decreasing fractions of the cost.
Another convergent moment in history was when one of our young and brightest A*STAR scholars, Dr Sarah Ng, while working in the lab of Dr Jay Shendure in Seattle, cracked a long-standing mystery and uncovered the gene responsible for Freeman-Sheldon syndrome, while making use of the Next Generation sequencing technology3. From thereon, scientists have made countless breakthroughs, resolving the genetic causes (if there were any) for unsolved diseases and afflictions of mankind.
Consanguineous families have the risk of manifesting rare recessive conditions among their offspring. This is again where sequencing families such as these have revealed “human knockouts”, whose recessive loss or gain of function of specific genes have explained why some of these communities are uniquely prone to, or conversely, protected against diseases4. The identity of these genes has pointed us to new pathways of biology: for example, rare families with mutations in the PCSK9 gene have exceedingly low levels of the LDL-cholesterol5, uncovering not just a previously unknown PCSK9 pathway of cholesterol processing, but pointing to the value of targeting PCSK9 for new-generation, cholesterol-lowering medication.
Anti-PCSK9 therapy is today6 one of the most potent and successful means of controlling hypercholesterolaemia. Besides pointing to worthy drug targets, the existence of living “human knockouts” of the respective genes (who do not have overt medical conditions and are protected against specific diseases), imply these specific gene products could be targeted with drugs. In effect, drug-makers see this as nature already performing the experiments for them, to validate drug safety and efficacy. It shouldn’t be surprising to hope then that this approach promises to deliver less tenuous and more fail-safe forms of drug discovery. This must explain why Verve Therapeutics launched with a $58.5m Series A financing round, led by GV (formerly Google Ventures).7 Verve plans to edit the adult genome, and confer lifelong protection against cardiovascular disease, mirroring the genes of people whose naturally occurring mutations have been associated with lowered risks of heart disease and heart attack.
The discovery of bacterial tools, translated now to successful editing of human genomes (CRISPR/Cas9) means that yet another convergent discovery has made what was once mere wishful thinking possible – to “mend” the human DNA template. Like Next Generation sequencing, CRISPR-editing technology is accessible, democratic, and hundreds (if not thousands) of labs around the world are today working to refine and adapt the tools. Dozens of biotech companies (such as Verve) are leveraging to deliver new generation gene therapy. CRISPR-based RNA editing has also broken the news,8 where editing is directed to the RNA transcriptional output of the genome and avoids the risk of heritable transmission. Another prominent company in the news recently has a pipeline of CRISPR-based RNA-targeting gene therapy.9
I remember being fascinated as a junior registrar by the notion of “molecular medicine”, and remember also being very curious about the Institute of Molecular Medicine at Oxford, founded in 1989 by Professor Sir David Weatherall. He championed the discovery and understanding of the α and β chains of haemoglobin and their relationship to thalassaemia. Some will say that the reductionist approach to discovery and research has inevitably beaten the path to where we are today, staring down at a very molecular compendium of next generation medicines.
Where single genes may be targeted for rare disease, CRISPR-editing and gene therapy seem the future. For complex conditions, multi-gene and multifactorial, the prospects are for targeting “molecular switches” to reprogramme cell identities, reversing the course of diseases, rather than simply slowing down disease progression, which is what nearly all medicines today do. Medical schools might do well to underline the importance of Molecular Medicine in equipping tomorrow’s doctors to effectively handle next generation medicines.