RNA and the frontier of personalised medicine

Europe must invest in RNA research to unlock the potential of personalised medicine says Professor Jörg Vogel

Europe needs to invest much more in fundamental research into the RNA molecule in order to develop more effective medical treatments tailored to the individual needs and genetic makeup of each person. This would be done best by creating a virtual Europe-wide RNA research institute linking separate centres in each country, according to a new report RNA World: a new frontier in biomedical research from the European Science Foundation (ESF).

RNA has emerged from the shadow of its sibling DNA as a major player in biomedical research with huge potential for creating a new generation of drugs that are more specific to a given disease and can be tuned to the needs of individual patients. This has been recognised in other parts of the world, especially the US, where dedicated RNA research is already well established, creating an urgent need for Europe to catch up.

RNA, like DNA, is composed of nucleic acids that encode the genes of all life forms. In plants and animals DNA provides the permanent source of genetic information residing mostly in the nucleus of each cell. The role of RNA molecules is as temporary carriers of that information when it is translated from the DNA source. For over a century after its discovery in 1869, it was thought that RNA’s role in plants and animals was just as a messenger, carrying the information from the DNA in the nucleus of each cell to the biochemical assembly plants called ribosomes where proteins are made.

But now it is known that there are different types of RNA molecule, including so-called microRNAs and other small or long RNAs that do not code for proteins and directly regulate the activity of genes. RNA mechanisms can even determine what proteins each gene makes by altering the way the critical parts of a gene, known as exons, fit together. One gene is known to be capable of producing as many as 38,000 different proteins, and it is through the machinery of RNA that the decision is made over which one to make. This would have seemed revolutionary to biologists even 50 years ago, when it was thought each gene coded for just a single protein.

The implications of these recent discoveries are profound for the future of biomedical research, according to Professor Jörg Vogel from the University of Würzburg, Germany, who co-chaired the ESF report. “RNA research has become a very important field, and needs to be funded in its own right,” said Vogel. “The problem has been that as the molecule has got sexy, loads of people come in from other areas, get funding, but then move out again when their project is over, with no dedication to teaching or creating lasting expertise in RNA.”

At present, RNA research within Europe has been occurring in a piecemeal fashion as a side-benefit of other more specific medical research projects. This is creating a duplication of effort and a failure to build up a solid body of knowledge and expertise that the whole continent can draw upon. “By contrast the US was extremely quick at coming up with RNA centres throughout the country, and have been totally ruthless in terms of funding.”

Meanwhile all the world’s big biomedical companies have come to realise that RNA research holds the keys to successful and lucrative therapies. “Every major pharmaceutical company has started a program on RNA based therapeutics,” said Vogel.

But Vogel emphasised that these are very early days for RNA based biomedical research, with few proven therapies and everything to play for. Providing substantially more funding for pure RNA research comes through soon, Europe can catch up and may even benefit from its more collaborative approach to research. “I think the European way will work better in the long run. The US is very active but it’s all down to individuals who say, ‘we’ll turn this centre into a hot bed for RNA research’. Europe works differently, much more through structured measures.”

For this reason the ESF report has hit the right note by identifying not just the need for a more coordinated approach to fundamental RNA research but also a focus on key areas of priority that will later lead to clinical benefits. “I have always seen the ESF as the think tank for European science, and they have done a great job here identifying the priorities,” said Vogel. 

One of the highest priorities is to create more specialists in bioinformatics, which is the application of computation and mathematics to the life sciences. Biomedical research in all areas including RNA relies increasingly on advanced analytical and statistical techniques to make sense of vast amounts of data relating to expression of genes in different circumstances. “A new generation of bioinformaticians needs to be trained to meet future demand, to work closely with RNA biologists and researchers in many other areas of the life sciences,” said Vogel.

The idea of a virtual centre arose because it would enable different countries firstly to set up their own multidisciplinary centres specialising in particular aspects of biomedicine. Then these centres in turn would be linked up to achieve critical mass in all the disciplines needed for a large scale RNA research programme, including biology, biochemistry, chemistry, genetics, biophysics, structural analysis, microbiology, plant sciences and clinical medicine, as well as bioinformatics.

This distributed research environment would be conducive to training a new generation of young scientists, PhD students and postdoctoral researchers in the skills required for RNA research. It would also be best placed to exploit existing mechanisms for funding in Europe, combining specific EU calls with approaches to the national research councils in each member country, as well as seeking grants from private sources including charitable foundations like the Wellcome Trust in the UK.

The overriding message of the ESF report is that the current drip feed approach whereby RNA research is conducted only as it becomes necessary to support a specific clinical goal needs to be underpinned by a fundamental program concentrating on the underlying RNA science. This is essential not just for the sake of the science, but because clinical advances rely absolutely on fundamental knowledge, insisted Vogel. “Hardly any big medically important discovery with RNA of the last 20 to 30 years was made by studying organisms that appeared to be relevant at the time,” said Vogel. “They almost all came out of fundamental research. Therefore we need to adopt a dual strategy combining fundamental research with translation of that research into clinics.”

Of course this all begs the question of why there should be a major expansion in RNA research, rather than DNA, or for that matter proteins which after all are the end products of gene expression and are involved in almost all pathways. Firstly the discovery of RNA interference in the 1990s revealed that RNA molecules play a crucial role in the regulation of gene expression and therefore of proteins and other compounds that govern all the critical metabolic pathways, the series of chemical reactions involved in processes such as energy production within the cell. Subsequently it became clear that RNA molecules are particularly suitable candidates for medical intervention because they allow flexible treatment by tuning the dose to the patient, they are relatively safe, and are easy to produce in large quantities.

DNA molecules are less suitable because they are less flexible, involving changes in at least one of the chromosomes where genes reside. Equally making proteins is complex because the molecules involved are sometimes very large, and their properties harder to predict because they depend on the subtle way they are folded into their final shape. By contrast, RNA molecules are becoming easier to manufacture in large quantities through chemical synthesis. And they are relatively safe since they degrade readily and are usually not mutagenic, meaning that they do not cause genetic changes that could lead to cancer.

Above all, RNA molecules are potentially capable of evoking highly specific responses with doses capable of being tuned to individual requirements, bringing true personalised medicine. The aim to is provide a specific cocktail of compounds that can be adjusted both to the needs of the patient and the nature of the condition, without causing significant side effects in the process. RNA fits this bill exactly, according to Vogel. “Many diseases need a combinatorial approach where you interfere with several pathways at once in a dose dependent manner adjusted to the patient,” said Vogel. “RNA can do that.”

Although the science is very promising, it is reasonable to object that we need more firm evidence than RNA can deliver. So far, there is only one proven therapy based on Pegaptanib (trade name Macugen), a so-called aptamer to treat age-related loss of vision by macular degeneration. Aptamers are RNA molecules that like antibodies bind to other molecules including DNA, RNA and proteins, and can potentially be used to disrupt the course of many diseases. There are early clinical trials for more aptamers to target cancer, diabetes, and other diseases. Therapies based on other classes of small RNA molecules are also being developed.

Meanwhile the scientific argument for stepping up RNA research is accumulating fast and becoming overwhelming, identifying RNA as the mediator in the middle of just about every important set of chemical reactions in all complex organisms. It is not too late for Europe in turn to become a major actor in this drama, but there is an urgent need now for serious strategic planning – and funding.

The Author: Professor Jorg Vogel