Roger Foo: Genetic research holds out new hope in battle against heart disease

SINGAPORE

Many of us remember what we were doing on the day of a significant global event. The day that airliners were  flown into the World Trade Center and the Pentagon. The day that the Berlin Wall came down. The day that a tsunami hit the shores of Indonesia.

As a physician, I remember one day during  my ward rounds in 2000 when then-British Prime Minister Tony Blair and then U.S. President Bill Clinton announced that the full human genome was finally sequenced. While it was inspiring to hear that the “blueprint” of humans was now known, I still had sick patients on my list yet to be seen and discharged. For them, the relevance of the discovery could not have felt more remote.

Not every advance is momentous. Most ground-breaking changes cannot be pinpointed to a single press conference. They are instead the result of many smaller, incremental advances, as we cardiologists would be soon be reminded.

Around the time we first understood the human-genome sequence, we discovered that humans have virtually the same number of coding genes (roughly 20,000) as a worm or fish.

What makes us different are the 3 billion remaining base pairs of the non-coding genome. In these, we find what are called gene regulatory elements. They are more easily visualized as “switches” that control when and how much our genes are expressed.

The blueprint of the human genome can be thought of as a songbook. Different musical notes are sung by different cells, often in unison. And so, we have lung cells performing differently from heart or liver cells even though they all have the same blueprint. The circuitry involved is intricate. 

Despite this complexity, now is a fantastic time to be working in genomic research. Technological advances reveal how different sections of the genome and its switches underpin cellular functions throughout the body. With technology, doctors can sequence our patients’ genomes at accessible cost, control their gene expression and even edit their blueprint. This lets us target the root cause of diseases. 

Indeed, such technology has already informed life-saving new therapies for cancer. When cardiologists watched Mr Blair’s and Mr. Clinton’s 2000 announcement, it kindled hopes for new cures and therapies. Now, we’re finally moving closer to such solutions for complex and multifactorial heart diseases.

For example, mapping out the genes that cause high cholesterol has had a huge impact. We now think that it may be possible to safely edit such genes in adult genomes, giving people a reduced risk or even lifelong protection against heart disease. In the meantime, suppressing gene expression related to heart disease using twice-yearly injections of gene-targeting medicines will be far more effective than the daily oral doses of statins that patients currently take.

A new generation of medicines is emerging as a result of our ever-deepening understanding of the genomic map. Targeting genomic switches in order to reprogram gene expression would reverse the course of disease rather than simply slow its progression. The latter is what nearly all medicines today do. 

The future of cardiology glows with excitement as we pursue a solution to the scourge of heart disease, which blights the lives of many – particularly those at elevated risk, such as the elderly and sufferers of metabolic diseases and diabetes. These risk factors are at an all-time global high. For cardiology, the next generation of ground-breaking medicines is firmly on its way and could not be welcomed sooner.

Roger Foo , M.D., is Sheikh Zayed bin Sultan Al Nahyan Professor in Medicine at the National University of Singapore.

Human genes by function of the transcribed proteins, as number of encoding genes and percentage of all genes

Yap Seng Chong/Swaine Chen: Get ready for the next pandemic

SINGAPORE

Outbreaks of infections have long plagued humanity, and changed history. The Black Death ripped through Europe in the middle of the 14th Century, killing a third of the population. Smallpox brought by European explorers helped seal the fate of the Americas 400 years ago. And in a mere four months, COVID-19 has transformed much of life in the 21st Century.

The mortal impact of infections is undeniably important. But even more dramatic are the victories that humanity has won against them. These are less sensationalized, likely because they require sustained, steady effort.

The understanding of aseptic technique began a long battle against surgical bacterial infections; the modern fruits of our success in this battle range from life-saving organ transplantation to cosmetic day surgery. Vaccines have slashed rates of childhood mortality from bacterial and viral infections; this provides reproductive security, driving modern economic development by enabling couples to have fewer children while increasing their education and productivity.

Thus, infectious diseases continue to be enormously significant. Not only can they disrupt cultures and countries, but countering them is a necessary prerequisite to unleash society’s innovative and productive capacity. It behoves us, then, to learn diligently from all infectious diseases.

COVID-19 is the most powerful infectious disease we have seen in the past 100 years. We refer to “power” here not as the speed with which it kills, but its integrated impact on society and the economy. Whole continents have been locked down. The energy of entire industries is being redirected to combat the SARS-CoV-2 virus. This response has been inspiring and further testifies to COVID-19’s unique position in the compendium of infectious threats.

This sweeping mobilization is again supported by sustained past investments in research and technology. In the next pandemic, we will have even more tools at our disposal, some generated during this period. Our response will be even swifter and more definitive, hopefully, but only if we learn from the current crisis, for there will indeed be a next outbreak, a next pandemic, and then others after that. We need to continue steady investment in research and technology. We also need full alignment within society, including politics and economics.

Several large-scale trends have contributed to COVID-19, trends that will make future outbreaks and pandemics more frequent and, possibly, more severe. One such trend is larger urban populations, increasing both density and interactions. A second is increasing global connectivity – both digital and physical. Finally, urban development drives two further complementary trends -- encroachment on previously undeveloped areas, where indigenous animals, plants and microbes previously held sole dominion; and increased demand for and specialization of food production, driving increased agricultural density and efficiency, and the search for alternative foods. There are doubtless other biological and non-biological factors that contributed to COVID-19, but we focus on these as they highlight aspects of a formula that cannot be ignored: Density + Mobility + Ecological Disruption = Outbreak Risk

Looking forward, then, what lessons can we take from COVID-19?

Researchers and policy makers should look at pandemics as a negative externality in which we all suffer the consequences. Countries have used diverse strategies to tackle the COVID-19 pandemic. Even within countries, such as the United States, different regions have responded in dramatically different ways, ranging from vigorously active measures to rather passive ones.

In the short term, we will learn which policies were most effective. In the longer run, we need to incorporate the strategies that worked best into preparations for future pandemics. We observe that, among the many policy debates occurring across the globe, economic imperatives are often placed in opposition to the advice of medical and scientific professionals. We believe that the recognition of negative externalities provides a path towards alignment of the economic and medical perspectives, which could then better recruit political support.

To cement the global learning curve and drive these policy innovations, we further propose that the World Health Organization be deliberately bolstered to organize the global infrastructure for pandemic preparedness in the “peacetime” when COVID-19 subsides. Emerging infectious diseases are a global problem, and we must act collectively as a planet. The next pandemic is just around the corner. We must learn, quickly, from the past and the present to ensure our collective future. 

Yap Seng Chong is Lien Ying Chow Professor in Medicine and Dean of the National University of Singapore Yong Loo Lin School of Medicine.

Swaine Chen is an associate professor at the National University of Singapore Yong Loo Lin School of Medicine, and group leader for infectious diseases at the Agency for Science, Technology and Research’s Genome Institute.

Yong Loo Lin School of Medicine