Even the smallest discovery can revolutionise science, and a tiny molecule can have a big impact.
Professor Sir David Baulcombe’s and his colleagues’ research in plants led to the ground-breaking discovery of a unique type of biological mechanism. This plays a critical role in how our genes are controlled (gene regulation) and led to drugs that can ‘turn off’ or ‘silence’ disease-causing genes. This includes ones associated with conditions that are difficult or impossible to treat.
While this research started in plants, it has had far-reaching impacts on human health. This includes the production of six therapeutic drugs designed to treat serious genetic disorders, affecting many thousands of patients worldwide. The patents on Professor Baulcombe and colleagues’ invention have also generated over £11 million in licensing income, with the market value of these therapeutics increasing year-on-year.
About our genes and our DNA
Our genes act as code and determine various characteristics like eye colour and height. Our genetic blueprint directs the production of proteins, which are essential for all our biological processes, including growth and our overall health. But did you know that only about 1% of our DNA codes for proteins? The other 99% is referred to as ‘non-coding’ DNA, long considered by scientists to have no known function, leftover from the long journey of evolution.
Over the years, geneticists have discovered that some of this non-coding DNA plays critical roles, including producing special RNA molecules. RNA chemically differs slightly from DNA (think sisters, not twins), but it is still genetic information.
In 1998, the process of RNA interference (RNAi) was discovered in a species of worm used in research (C. elegans, a type of roundworm). It involves small interfering RNA (siRNA), tiny fragments of RNA that play an important role in regulating gene expression and protein production.
So why is siRNA important?
siRNA regulates genes through RNA interference (RNAi), which is where the siRNA targets another type of RNA molecule called messenger RNA (mRNA), breaking it down. mRNA is like a messenger pigeon, flying across a cell carrying protein recipes. If you break down the mRNA, the recipe cannot be sent, and the protein is never made. In summary, siRNA stops protein production by blocking the instructions.
This makes siRNA a great candidate for therapeutics. Proteins are involved in practically every human, animal, and plant disease. Sometimes the protein itself goes wrong, and sometimes proteins are critically involved in biological processes that have become overactive or underactive, causing disease. So, if you stop the protein, you can help treat the disease.
Engineering siRNA to target particular proteins via mRNA has, therefore, become an exciting field for drug discovery.
Ground-breaking discoveries in genetics
Professor Baulcombe and his colleagues were instrumental in the characterisation of siRNAs and RNAi in plants, while based at The Sainsbury Laboratory. His early work established that:
- some RNAs could break down mRNA or interfere with protein production
- these RNAs were likely to be incredibly small, which is why no one had found them yet
In 1998, Andrew Fire and Craig Mello’s Nobel Prize-winning work in roundworms defined our understanding of RNAi. A year later, in 1999, Professor Baulcombe and Dr Andrew Hamilton, a post-doc in Baulcombe’s lab, found tiny RNA fragments that stopped mRNA activity in plants. BBSRC funded Professor Baulcombe’s early research, alongside pivotal funding from the Gatsby Charitable Foundation.
Professor Baulcombe’s and Dr Hamilton’s research was patented by Plant Bioscience Ltd (PBL, the technology management company jointly owned by The Sainsbury Laboratory, John Innes Centre, and BBSRC.) This patent protected both the method of using siRNA to turn off genes and stop proteins from being produced, and the small RNA molecules themselves. Cover extends to all types of living organisms.
In 2012, the patent was licensed by PBL to Alnylam Pharmaceuticals (which already had an additional fundamental patent portfolio in the RNAi space), as well as to certain other companies. The patent has since generated over £11 million in licensing income. PBL has funnelled this revenue back into science, innovation and technology investment, helping to support the translation of pioneering life science research.
In 2024, the global RNAi technology market was estimated to be worth $2.9 billion.
siRNA therapeutics
Building on this fundamental science discovery, Alnylam has used siRNA to produce six successful pharmaceuticals.
ONPATTRO® (Patisiran) and AMVUTTRA® ▼ (Vutrisiran)
Patisiran and Vutrisiran treat a rare progressive hereditary disorder, hATTR (hereditary transthyretin amyloidosis). hATTR causes an unstable protein to clump together. These clumps get deposited all over the body, stopping organs and tissues from working properly, including heart and nerve damage. Along with hATTR, there is age-associated ATTR, which Vutrisiran additionally targets.
GIVLAARI® ▼ (Givosiran)
Givosiran treats acute hepatic porphyria (AHP) in adults. AHP is a group of four inherited diseases of the liver with a wide range of debilitating (and sometimes life-threatening) symptoms, including abdominal pain and vomiting.
OXLUMO® ▼ (Lumasiran)
Lumasiran treats primary hyperoxaluria type 1 (PH1), a rare genetic disease that causes a build -up of oxalate. Our kidneys get rid of excess oxalate through urine, but when we have too much, it can bind to calcium to form crystals and kidney stones. PH1 causes chronic kidney stones and urinary issues but can also damage other organs and lead to kidney failure.
LEQVIO® ▼ (inclisiran) and Qfitlia™ (Fitusiran)
Alnylam has collaborated with Novartis on inclisiran and with Sanofi on fitusiran. Inclisiran treats primary hyperlipidemia, where high cholesterol is genetic and caused by a range of mutations. Fitusiran treats haemophilia, which is caused by a missing or non-working blood-clotting protein. This means bleeding for longer, bruising more easily, and being at increased risk for joint or brain bleeds.
Next steps
Alnylam was one of the first companies founded to harness the power of RNAi and has played a major role in establishing RNAi therapeutics as a revolutionary new class of medicines. Now, additional companies have joined the field to provide therapeutics for many diseases of major concern, including:
- certain cancers
- type 2 diabetes
- Alzheimer’s
- Parkinson’s
The research conducted by Professor Baulcombe and his colleagues was critical to the development of this new therapeutic area. Professor Baulcombe has won the prestigious Lasker Award and the Wolf Prize in Agriculture for his plant RNAi research.
The impact of this research isn’t limited to the direct translation of research into RNAi therapeutics. Following Professor Baulcombe’s work, researchers at The Sainsbury Laboratory used RNAi to engineer plants, making them better hosts for producing pharmaceuticals. This technology was also licensed to several companies. BBSRC has continued to fund Professor Baulcombe’s research until 2024, after which he became Regius Professor of Botany Emeritus at Cambridge University. He continues to contribute to bioscience as the Biological Secretary and a Vice President of the Royal Society.
Disclaimer: Alnylam has had no editorial control over the content but has performed a technical check for accuracy.
Further information
Professor Baulcombe’s 1999 paper: A Species of Small Antisense RNA in Posttranscriptional Gene Silencing in Plants