Once underestimated, now a beacon of hope

In the Corona pandemic, mRNA vaccines proved their effectiveness and safety. They mark the beginning of a new era in medicine, says Würzburg infection biologist Jörg Vogel. He will describe the triumph of ribonucleic acid in therapy at the GDNÄ Annual Meeting in Leipzig – and here in an interview. 

Professor Vogel, one of the main topics of the anniversary meeting in Leipzig is RNA medicine. What makes this new therapeutic direction so interesting?
The well-founded hope that previously incurable diseases can finally be treated. This was triggered by the great success of mRNA vaccines in the Corona pandemic. Not only could the vaccines be developed very quickly, but they also proved to be highly effective and safe. There is currently an incredible sense of optimism worldwide; some are even talking about a medical revolution. The task now is to transfer the active principle to as many diseases as possible. 

Which diseases could be considered?
There are hardly any limits. Research is currently focusing on cancer and cardiovascular diseases. But other common diseases such as dementia are also possible candidates. And for numerous rare diseases, especially when they are caused by defects in a single gene, RNA medicine could finally bring a breakthrough. Some RNA drugs are already on the market in the EU, and I expect to see many new therapies soon. 

RNA seems to be an all-rounder. How does it manage that?
It has to do with its many capabilities, which have long been overlooked. In the past, almost everything focused on messenger RNA, or mRNA for short, a messenger molecule that carries genetic blueprints from the cell nucleus to the protein factories in the cytosol. In addition to tRNA, which has also been known for some time and which transports amino acids to the protein factories, the ribosomes, and rRNA, which is a component of these protein factories, many other classes of RNA have been discovered in recent years. They have been given names such as miRNA for micro-RNA or siRNA for small interfering RNA. More than a dozen different RNA classes are now known, and new ones are being added all the time. What is clear today is that RNA controls vital processes in cells, and errors in this control can cause disease. Or, to exaggerate a bit: RNA is the real player in our cells and organs.

© SciGraphix/Sandy Westermann

Modern RNA medicine uses therapeutic mRNA, antisense strategies and CRISPR-Cas systems, among others, to treat various diseases.

How can the miracle molecule be used medically?
In two ways: in modified form as a drug and, when it comes to the body’s own RNA, as a target for tailored drugs. mRNA vaccines are a good example of the first mode of action. For example, Biontech/Pfizer’s Corona vaccine contains a laboratory-generated mRNA variant of the spike protein of SARS-CoV-2. After vaccination, the body generates this spike protein variant, which elicits a strong immune response. The vaccine functions as an antigen that triggers the production of antibodies by the immune system. Similarly, it is hoped to stimulate the immune system to produce antibodies against cancer cells with the help of specifically modified RNA. Several studies are already underway. The lung cells of cystic fibrosis patients could also be modified using the CRISPR-Cas method so that they produce a vital protein in the correct form. It is not yet possible to predict which of these therapies will prevail from a medical and cost perspective. 

Please also explain the second active principle with an example.
In cardiac medicine, for example, research is being carried out to prevent the production of pathogenic proteins by artificially produced siRNA. To do this, RNA snippets are created in the laboratory that have a structure exactly complementary to the sequence of the body’s own RNA – so-called antisense molecules. The idea is to couple them to small liposomes and inject them under the skin. These liposomes are to enter the heart to deliver their siRNA cargo into the cells. The cargo, the plan goes, docks with the body’s own RNA and paralyzes it. In a similar way, non-coding RNA, which does not make proteins in the body but regulates many processes, could be directed in the desired direction when it malfunctions.  

In short, what can RNA medicine do that conventional drugs cannot?
One major advantage is programmability: active ingredients can be designed exactly as needed. Another advantage is speed. You can design a therapeutic on screen in minutes and then manufacture it quickly if the production capacity is there. Just think about mRNA vaccines, which were available very quickly.

© RVZ

Old and new in aesthetic combination: The converted and expanded former Surgical Clinic of Würzburg University now houses two research centres, the Helmholtz Institute for RNA-based Infection Research and the Rudolf Virchow Centre for Experimental Biomedicine.

But do RNA therapies do exactly what they are supposed to?
They are very specific. Perhaps even more specific than conventional drugs that target proteins. This has to do with the exact base pairing in nucleic acids.

 And if serious side effects occur: Can the RNA be recovered?
We don’t know exactly yet. So far, it hasn’t been necessary because the mRNA quickly disappears from the body again. But we will have to think about something for the future. So far, it is only a research idea to create depots with replacement proteins in the body. But if this succeeds, we must of course have protective mechanisms ready in case of incompatibilities. However, I do not see a problem in principle, because an antidote could also be designed here. For example, an anti-CRISPR-Cas molecule that is administered on demand. 

Unlike today’s drugs, RNA is very unstable. How do you prevent it from rapidly decaying in the body and becoming ineffective?
To do that, you have to change its chemical structure. The mRNA vaccine again provides a fitting example. The fact that it works so well is thanks to biochemist Katalin Karikó. Together with immunologist Drew Weissmann, she incorporated a variant of the base uridine, pseudouridine, into the mRNA well in advance. This not only makes the molecule more stable and efficient, it also reduces the risk of immune system overreactions.  

A pioneering achievement that made the saving vaccines possible in the first place?
Yes, and certainly worthy of a Nobel Prize. If you contrast experiments with non-modified mRNA, it shows that it can’t be done without this modification. That’s the reason why some other vaccine candidates have failed so far.  

Let’s clarify a few technical issues. RNA molecules are large and very negatively charged. How do you get them where you want them in the body?
In the case of mRNA vaccination, this works very well: the vaccine injected into the upper arm muscle is taken up by certain immune cells in the muscle and from there leads directly to an immune response. However, as already mentioned, depots near target organs such as the lungs, liver or kidneys are also being considered. Sprays are also under discussion. Overall, this is a big research topic right now. Compliance is also always important: How well is the therapy accepted by patients and how do they stick to it – all this plays a role.  

Today, RNA molecules are mainly packaged in lipids in order to smuggle them into the cells. Is this the best method?
At present, yes. Nanocages, which can be thought of as cages made of DNA for transporting RNA, are also being tested. The most important thing is to protect the comparatively large RNA molecules from attacks by the immune system and degradation by enzymes – all methods must be measured against these criteria.  

How long does the effect of RNA therapy last?
That depends on the technology. In mRNA therapy, similar to Corona vaccination, the protein is produced for a few days after administration – after which the mRNA is degraded. The protein, in turn, can exist in the body for days to weeks and exert its effect until it is then also degraded. For example, in the treatment of spinal muscular atrophy SMA, the drugs that promote mRNA maturation must be given every two to four months.  

How far along is testing in humans?
Among the most advanced is a CRISPR-Cas trial of an RNA agent to treat the inherited disease beta-thalassemia. Until now, patients have required regular blood transfusions. If the new therapy proves successful, that will no longer be necessary. Then their bodies will produce the missing hemoglobin. New mRNA-based vaccines are also undergoing clinical trials, for example against influenza or malaria.

© HIRI / Luisa Macharowsky

At the anaerobic workbench in the laboratory of the Helmholtz Institute for Infection Research with Professor Jörg Vogel (left).

Why has RNA medicine only now become a big topic?
It took the pandemic to build up pressure. It provided the necessary push and showed that mRNA vaccines and RNA medicine as a whole are effective and safe. 

You are considered a pioneer in RNA medicine. What brought you in this direction?
I studied biochemistry and worked in molecular biology laboratories as a student, including in plant genetics. I then also did my doctorate there, on molecular mechanisms of catalytic RNA molecules in barley chloroplasts.

You have headed the Helmholtz Institute for RNA-based Infection Research for more than five years. Where do you stand today? The institute has developed magnificently, in parallel with the growing importance of RNA research. When we started out, the topic of vaccines was still primarily thought of as proteins as active agents, not RNA. That has changed dramatically in recent years. Today, innovations are expected primarily from RNA research. At our institute, we benefit greatly from high-throughput sequencing: This allows us to look inside the cells as if with a microscope and see which RNA is currently being produced. Meanwhile, we’re also pretty good at modifying RNA to make it medically useful.  

Is medical utility a big issue with you?
When it comes to new approaches, yes. But we are basic researchers. Further development is a matter for industry. 

Does your institute work with pharmaceutical companies?
So far, hardly at all, but that is set to change. We are currently preparing the first spin-off. It involves RNA-based diagnostics and tests that can detect many different pathogens simultaneously. 

There is still no cure for the common cold. Will RNA medicine be able to cope with it?
Why not? We already have ideas!  

A shorter version of this interview can be found in the publication for the 200th anniversary of the GDNÄ: Wenn der Funke überspringt, Leipzig 2022, ISBN 978-3-95415-130-1.

Now it’s up to the politicians, says Professor Jürgen Floege. He heads the University Clinic for Renal and Hypertension Diseases in Aachen, is committed to more research and likes to think outside the box – also in the GDNÄ.

Professor Floege, with what thoughts and feelings do you as clinic director look forward to the second pandemic winter?
I am relatively relaxed. I don’t expect the kind of strain we had at the beginning of the pandemic this winter. In the spring of 2020, there were many seriously ill patients on the wards, which also had to do with the geographical proximity to the then Corona hotspot Heinsberg. We are currently looking after about a dozen Covid 19 patients in our clinic. One hundred percent of them are unvaccinated. Some of them are young and have no previous illnesses, yet they now have to be artificially ventilated. This shows quite clearly that no immune system, no matter how strong, can help against this disease; the best protection is offered by vaccination.

Do the employees in your clinic also see it that way?
Yes, most of them have been vaccinated twice. In the meantime, many of them – including myself –have had a third vaccination. We don’t have any compulsory measures, but we appeal for common sense and consideration. So far, we have done well with this. We are currently concerned about a completely different issue.

Is it also related to the pandemic?
Directly. The pandemic has burdened us with high additional expenses and driven us deep into the red. Even before the pandemic, three quarters of the German university hospitals were running deficits, and now almost all of them are like us. Each of these hospitals treats patients that no other hospital can or wants to treat; in addition, we are responsible for training young doctors on a large scale. This costs time and money and is not sufficiently rewarded by the current remuneration system. Therefore, we urgently need supplements, which politicians have so far refused to grant. At my hospital, but also in many other hospitals, this has led to an investment backlog of the highest order. Important projects now have to wait.

© Peter Winandy

The University Hospital Aachen was founded in 1985 and today employs around 8,500 staff in 35 specialist clinics, 30 institutes and six interdisciplinary units. Every year, more than 50,000 patients are treated there as inpatients and a good 200,000 as outpatients. The hospital is located in the west of Aachen in the immediate vicinity of the municipality of Vaals in the Netherlands.

Your speciality is the kidney – an organ that medical laypeople do not necessarily associate with the coronavirus.
Yet the kidneys are one of the most frequently affected organs after the nasal mucosa and lungs. One third of all people who are severely affected by Covid-19 suffer from kidney failure. And it is not at all rare for an infection to lead to late damage in the kidneys that does not disappear.

How common is kidney damage in this country?
Very common. In about four million people, the kidney function is below 30 percent of its possible capacity. And in half a million people, kidney function has dropped to 15 percent or less. If the function drops to five to seven percent, those affected are dependent on dialysis as kidney replacement therapy, unless a new kidney is available for transplantation.

It is estimated that kidney disease will be the fifth leading cause of death worldwide by 2040. Yet in your field, nephrology, there are currently the fewest clinical trials for new therapies. Why is that?
It has to do with the complexity of kidney diseases. They are difficult to control and difficult to research. Very few patients only have kidney problems; most of them also suffer from diseases of the cardiovascular system, the lungs or the gastrointestinal tract, to name just a few diagnoses. People with pronounced kidney damage are often kept away from drug studies because these studies depend on a functioning organ – after all, the vast majority of active pharmaceutical ingredients are excreted via the kidneys. In addition, the treatment of kidney patients is highly individualised, there are hardly any standard prescriptions. And medicines that have the intended effect in healthy kidney patients can in some cases have a completely different effect in patients with severe kidney disease.

© J. Floege

Visiting dialysis patients is part of the daily work of Jürgen Floege’s team.

Nevertheless, there is a lot of research going on in your clinic. On which topics?
Apart from kidney diseases, it is about rheumatological-immunological diseases. We initiate and participate in clinical studies, but also do basic research. Just recently, the Collaborative Research Centre “Mechanisms of Cardiovascular Complications in Chronic Renal Insufficiency”, which we run together with the outstanding heart specialists at our university, was rated very highly and recommended for a second funding period. We are also involved in Covid-19 research: some colleagues are currently in the process of creating an artificial kidney in the test tube in order to test new therapeutic approaches on it. With my own research group, I want to find out whether high-dose administration of the coagulation vitamin K can help dialysis patients. There are indications that the K2 variant in particular protects the blood vessels that are under great strain in chronic kidney disease. K2 is only found in very few foods, for example in the Japanese soy product natto. For our study, we use synthetically produced vitamin.

What can we do ourselvesf for healthy kidneys?
It is important to have a normal weight, blood pressure values below 130/80 millimetres of mercury and little salt. The optimal salt intake is up to five grams a day, which corresponds to just one teaspoon – much more is unhealthy. In addition, diabetes is associated with a considerable risk of kidney disease: For this reason, too, the disease should be avoided if possible or the blood sugar should be well adjusted if the disease is present.

Allow me to ask you a personal question: How did you get involved in kidney research yourself?
It was clear to me early on that I wanted to do medicine. The decision also had to do with the early death of my father. In the 1970s there wasn’t much we could do about his heart attacks, fortunately there was a lot of progress. I spent my training years in Hanover, New York and Seattle and became more and more interested in renal medicine.

© Peter Winandy

The University Hospital of RWTH Aachen University (pictured front left) is one of the largest hospital buildings in Europe. North of it is the Melaten Campus with technology-oriented research facilities of RWTH and companies.

You have now been working in Aachen for more than twenty years. How does it feel to work as a medical doctor at a technical university?
Today I am doing very well here. It was different when I took up my post at the end of the 1990s. At that time, medicine was more of an appendage of the technical subjects here. The German Science Council took a look at that in 2000 and recommended that the state of North Rhine-Westphalia close the medical faculty. What followed was a huge jolt. Everyone made an effort, a lot of fresh research money was raised, good scientists were appointed and to this day great young people are vitalising the operation – we have become a highly esteemed and valued faculty within RWTH Aachen University.

How did you become a GDNÄ member?
I joined only recently, at the suggestion of the Würzburg cardiologist, Professor Georg Ertl. He also won me over to take on the task of group chairman for medicine.

As a clinician and researcher, you do not suffer from a lack of work. What made you decide to get additionally involved in the GDNÄ?
I like to look beyond the horizon of my discipline and am very interested in other areas of the natural sciences. The GDNÄ meets this need with its diversity of subjects. What also fascinates me is the great tradition – that is already unique.

Do you have any ideas for the future of the GDNÄ?
I think we need a “Young GDNÄ” parallel to the established Society of German Natural Scientists and Physicians. Role models could be the Young Internists within the German Society for Internal Medicine or the Young Academy of the Berlin-Brandenburg Academy of Sciences and the Leopoldina. It is important that the young people organise themselves and can be productive independently of their elders.