How the first iRNA therapy developed (Part One)

Posted March 21, 2020 by Bonnibelle

It once gained the glory of the Nobel Prize and was once considered a big bubble in the pharmaceutical industry.

It once gained the glory of the Nobel Prize and was once considered a big bubble in the pharmaceutical industry. From the award of Nobel Prize many years ago to the approval of the first new drug today, RNAi technology has gone through a difficult and tortuous development path. In this article today, we will review the story of the birth of the first RNAi therapy in human history.

The unexpected Nobel Prize

At 2:30 am on October 2, 2006, Professor Andrew Fire of Stanford University received a call. At the other side of the phone, a slightly accented voice congratulated him. The Nobel Committee decided that Professor Fire, along with Professor Craig Mello of the University of Massachusetts, would share the 2006 Nobel Prize in Physiology or Medicine.

Like many Nobel Laureates, Professor Fire's first reaction was "very surprised" and even suspected that the other party had dialed the wrong number. Because since the 1980s, the average age of Nobel Laureates in Physiology or Medicine is over 60. But he was only 47 years old, and Professor Mello was only 45 years old. Moreover, it is only 8 years before the important papers published by them. It all came too fast and unreal.

Many biologists point out that these unusual numbers just reflect how unusual their work is. "Their discovery worth a Nobel Prize," said Nobel laureate Professor Thomas Cech.

This unusual discovery is the discovery of RNA interference (RNAi) mechanism. This is a method for silencing genes with double-stranded RNA. The Nobel Prize Committee said that this is a fundamental mechanism for controlling the flow of genetic information. It exists in plants, animals, and humans, and has broad application prospects in the fields of biotechnology and medicine.

What is RNAi?

Interestingly, these two scientists were not the first to discover the phenomenon of RNAi. Before them, botanists had observed some phenomena that were difficult to explain. In 1990, two botanists reported a surprising discovery—chalcone synthase is a rate-limiting pathway in the anthocyanin synthesis pathway in petunia flowers. Researchers speculate that if the expression of this enzyme is increased, the anthocyanin synthesis will be accelerated and the petunia flowers will become darker.

But the experimental results were quite contrary to their expectations. After overexpression of chalcone synthase, the color of petunia flowers did not become darker, but also became lighter! Looking at the white flowers in front of them, botanists were extremely confused. Subsequent research found that the content of chalcone synthase was 50 times lower in wild petunia than in the modified petunia. This has also led researchers to speculate that the introduction of RNA from outside the body would "silence" genes with homologous sequences.

Although these botanists have made important observations and proposed potential mechanisms of action, they have not been able to translate this discovery into practical applications. This is where Professor Fire and Professor Mello contributed. In C. elegans, they found that only by injecting double-stranded RNA that coincided with the gene sequence, or with a close proximity, could the gene be silenced effectively. This may have been an organism's antiviral mechanism, but it has been used as a means of regulating its own genes in the long river of evolution. This discovery of the two scientists also allows us to use a very simple method to regulate the genes of organisms.

It can be said that this breakthrough technology has opened a door to a new world. This innovative tool has been favored by many biological laboratories and has also accelerated the development of biology. More importantly, it shows us hope for treating diseases through "gene silencing." As stated in the official Nobel prize press release, "RNA interference has been widely used in basic scientific research to study the function of genes. It is also expected to bring new treatments in the future."

"I believe this technology will be widely used in the field of anticancer therapy in the next 10 years," said Dr. Bruce Stillman, then the chairman of Cold Spring Harbor Laboratory and a member of the American Academy of Sciences.

The industry situation

5 years before the Nobel Prize was awarded, people have completed the sequencing of the draft human genome. Many researchers have long begun to use RNAi in mammalian cells, and biotechnology companies have sprung up one after another, vying to be the inventors of the first new RNAi drug.

The logic behind this is also easy to understand. Many diseases are caused by the emergence of pathogenic proteins, and the mechanism of action of conventional small molecule drugs is to bind these proteins and inhibit their function. The use of RNAi technology is expected to inhibit their expression, stifling these pathogenic proteins in the bud. Because double-stranded RNA is very easy to synthesize, if this treatment idea can be successful, people will no longer need to perform tedious drug screening and avoid the "non-drug-free" problem of pathogenic proteins. Therefore, the biopharmaceutical industry has a very high enthusiasm for R & D of RNAi therapy, and some well-known pharmaceutical companies have also begun to get involved. The whole field is full of enthusiasm, and the advent of the first RNAi therapy seems to be just around the corner.

To be continued in Part Two…
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Last Updated March 21, 2020