What makes the discovery of aliskiren particularly compelling is the fact that it comes more than a century after the discovery of renin itself. In the 109 years since Swedish doctors Robert Tigerstedt and Per Bergman showed that kidney extracts containing renin increased blood pressure, medical researchers have strived to control high blood pressure by inhibiting renin’s effects with varying degrees of success. Until aliskiren, however, no medicine was available to doctors and patients that worked directly on renin to control high blood pressure.

Norman K Hollenberg MD, PhD Professor of Medicine at Harvard Medical School Director, Brigham and Women's Hospital, Boston, USA

So why did finding an effective direct renin inhibitor take so long? Why despite so many setbacks, did researchers continue pursuing renin? With more than 40 years’ experience in renin research, Professor Norman Hollenberg of Harvard University offers some helpful insight to these questions and explains why he agrees with The Wall Street Journal’s decision to give aliskiren its top prize for innovation.

Dr Hollenberg, how did you become interested enough in renin to devote most of your career to studying it?
Until the late 1960s, many people including myself thought the Renin System had already seen its pinnacle and was on the decline. So as I conducted my kidney research on the causes of high blood pressure, I focused on areas other than the Renin System. However, to my surprise, the leading theory at the time – which is where I was focused – turned out to be wrong.

When this happened, I immediately made a list of other possible explanations - including the Renin System. As I tested these different approaches, I made a remarkable discovery about a protein in the Renin System. Using an extremely small dose in animals – just 1 percent of what was believed to be needed – blood pressure started rising, and I have been chasing renin ever since!

Why was the time between renin’s discovery and actually having medicines to control it so long?
Dr Tigerstedt and his partner Per Bergman were extraordinarily good scientists, and Dr Tigerstedt edited leading medical textbooks. After their discovery that renin increases blood pressure in 1898, other scientists quickly started to study renin in their labs. For some reason, these other researchers were not able to replicate Tigerstedt’s results and eventually gave up.

Then in the late 1930s, a Cleveland scientist, Harry Goldblatt, reignited interest in renin by showing that restricting blood flow to kidneys caused high blood pressure. This meant that Tigerstedt and Bergman were right about renin being linked to blood pressure. So, Dr Goldblatt started a whole new wave of research that led to medicines affecting the Renin System like ACE inhibitors and angiotensin receptor blockers (ARBs). However, until just recently we have not had a direct renin inhibitor (DRI) that acted on renin.

While these medicines work at different points in the Renin System, DRIs inhibit the starting point. So, why weren’t DRIs developed first?
If you want to block the Renin System, it’s logical to start at the beginning with renin, but frankly DRIs have historically been difficult to make. Several early DRIs were made but were either very short-acting, weren’t effective for blood pressure, or were too expensive. In the meantime, renin research went in other direction that led to ACE inhibitors and ARBs which act further down in the Renin System. Despite having these wonderful medicines, we still haven’t seen the full efficacy that patients need. For this reason, renin research continued and recently produced the first DRI capable of overcoming these earlier challenges.

As a doctor, what is your opinion about The Wall Street Journal’s decision to give its top award for innovation to aliskiren?
It is very deserving, because DRIs are the first major development for treating high blood pressure in well over a decade. For more than a century, we’ve speculated that renin plays a critical role in disease and now doctors finally have the first medicine to directly inhibit it. It is certainly a very important innovation in medicine.

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