We change through every viral attack: genetically, epigenetically, immunologically

Prof. Dr. Martin Simon, cell biologist at the University of Wuppertal, on new directions in RNA research and the use of specifically modified genomes in cancer therapy

Research is essential for survival! This is now clear to all of us, at least since the global pandemic which has been limiting our lives increasingly for a good year now.The flood of information is overwhelming. The rapid search for answers represents an unprecedented challenge for science. A key role is played by ribonucleic acid (RNA), whose essential function is to convert genetic information into proteins in the biological cell. The cell biologist Prof. Dr. Martin Simon from Wuppertal has been head of the Molecular Cell Biology and Microbiology Division in the Faculty of Mathematics and Natural Sciences at the University of Wuppertal since 2018. He explains the task of RNA like this: "RNA is structured similarly to DNA (deoxyribonucleic acid). DNA is our conservative genetic material; it is stable in the cell nucleus and exists in duplicate copies to create a backup. RNA is sort of an intermediary." RNA makes a transcript of DNA, so to speak, whose information is then transferred into the protein. The code of the base sequence is thus translated into the code of the amino acid sequence. The mechanism of so-called protein synthesis has been known for a long time. "But this function has undergone a complete rewrite," Simon immediately adds, because for the past 20 years, many new classes of ribonucleic acids have been identified that have a regulatory effect through which they can switch genes on and off.

The software of the genome serves as a vaccine basis

"Today we have reached a point where we experience or recognize RNA as an extremely variable substance. It is much more mutable than DNA and it has much more functions since it can regulate, switch on and switch off. It actually represents the software of the genome." For the first time, RNA vaccines are being tested against Corona. In the process, physicians plan to inject their patients with a small piece of RNA that triggers human cells to produce the antigen of Sars-CoV-2. "It is an elegant mechanism," says the scientist, describing the process. "In principle, the process of this immunization, this vaccination, is the same as with all vaccines, except that you do not inject a protein here, but you inject an mRNA, also called messenger RNA, which is a matrix for protein synthesis. We ourselves produce the antigen and thus activate our T-cells, [T-cells make up a group of white blood cells that serve as the immune defense (editor's note)], which means we actually get in at a slightly later stage." Other vaccination principles are based on viral vectors that bring genetic material, i.e. DNA or RNA, into our cells. This is now superfluous. Here, he said, the big advantage is that development is faster. "That is exactly what we now need in the Corona situation," he says, explaining the approach. "Now, the biotech companies do not have the time to put together long viral vectors that we are then immunized against, because that is relatively complicated. It is much faster now, since you only need to synthesize one mRNA molecule. In the beginning, I was a bit puzzled, too. I had to read up, because the information policy was also sluggish. In the future, we will certainly be in a situation where viruses threaten us more often, so this is a method for the future. The development time is simply much shorter." However, the problem that still has to be solved, is the enormous quantity that has to be produced and the necessary cooling temperature, because mRNA is a very short-living factor.

Concern for DNA and our genome

Not all scientists support the faster route in pandemic times, out of concern for long-term damage to our DNA. Simon talks about a low probability of side effects from today's perspective, saying, "There is no data on this yet. But as with any vaccine, you inevitably have to weigh the risks against the benefits. That is the eternal discussion when a new technology comes along. In that case, especially with the threat that we see now with Corona, we definitely have to address that. I, myself would not have any concerns about being vaccinated with it now either. There is no risk of genetic transformation." With any single viral infection, Simon makes clear, all viruses introduce a plethora of mRNAs into us. With the Corona vaccine, it is just one. "Basically, every viral infection alters our cells genetically because the virus adds its genetic material to ours" he says, explaining it using the herpes virus as an example. "About 80% of the population is infected with herpes. We all have this virus in us and it has added its genetic material to ours. This is not directly integrated into our genome, but it can be called a genetic modification. Also, every flu virus produces its own proteins in our body, for this purpose, it adds its RNA to our cells. It uses us, as all viruses do, as a host." This is a very common process.

The genome editing method Crispr/Cas9

By many people, the term "genetic manipulation" is perceived as unnatural, since the intention behind it is often to bring about targeted changes or to develop new combinations of hereditary traits. There are many ways of modifying the genome of plants, animals or humans. A method that will receive a Nobel Prize in 2020 could open up completely new avenues in cancer therapy in the future. The two scientists Emanuelle Charpentier from the Max Planck Institute in Berlin and her American colleague Jennifer Doudna developed the so-called genome editing method Crispr/Cas9. This first possibility of changing a genome specifically. "The Crispr Cas system simply specifies an enzymatic activity by dragging it to a particular place in the genome," Simon explains. Normally, nucleases (group of enzymes) work nonspecifically, meaning they target DNA and randomly chop everything down. "The way the Crispr Cas system works is that there is a nuclease that is specified by a small RNA molecule. And that RNA molecule binds to the DNA and says, 'Cut here and nowhere else.' That is the trick of it." The variety of potential applications are based on the fact that with this engineered process, individual sites in the genome can be targeted for modification. "Similar to a text, I can remove, add or change letters," Simon explains, "it is a process that accelerates research extremely, including the medical applications that result."

New paths in cancer therapy

"We will all see a great benefit from the Crispr Cas technology since it will be the tool of the future in cancer therapy," Simon clarifies. He adds that cancer or other diseases can be approached differently. You now have ways to target, inactivate or alter are growth factors and proteases activated in the cancer that lead to metastasis. "You can use different strategies," the researcher explains, "you can try to correct this mutation, that would be the simplest principle. But you can also change the T cells. To do that, you look at the tumor, you analyze it, you can sequence it and see what is happening in there. Then you can design T cells and program them to recognize tumor cells. We can use our immune system to find the cancer cells and kill them." Simon also sees this as a long-term advantage of personalized medicine, which makes it possible to look at a cancer with its diverse subtypes individually, and introduce specific T-cell receptors into the T cells for that one person. Although this leads to a change in the genome of the T cells, it does not change the germ cells.

Germline manipulations alter the human gene pool

The fact that changes in the germ line are taboo but technically possible and that some researchers defy this ethical prohibition is shown by the case of a Chinese scientist who genetically manipulated human twins in 2018, so that the children were born HIV-resistant. This manipulation is fundamentally different from what we call somatic gene therapy. Here, individual cells of the adult body are transformed in the sense of cancer therapy. In the 2018 example, embryos were manipulated. In this way, all cells of the body are changed, including germ cells.

This work has been condemned worldwide, Simon reports. It is perfectly clear that science is concerned with somatic therapies and that research on the germline is always ethically questionable. "On the other hand, the Chinese researchers also worked on T cells, and they directly removed a protein that binds to HIV." However, the T-cell system is very complex, Simon explains. No protein that is removed is there just for fun. It is known that people who do not have that protein are much more susceptible to flu infections. "If I work on the immune system and remove individual components, then the HI virus has lost its docking site, but it always has an impact on other functions of the immune system as well." Another serious aspect of this "experiment" is that every change in the germ line is automatically inherited. This could mean a change in the human gene pool worldwide and thus represents a massive risk and a fundamentally ethically questionable approach.

Due to the technical possibilities, there are no limits to the imagination. There are enough examples in literature and film. That is why Simon is adamant: "Legislators must also take action here. There is the potential that this technology is being misused. There are researchers and users who do not adhere to ethical principles. However, one must differentiate germline transformation from somatic manipulation. It will be very important to not simply generalize these two very different aspects as genetic manipulation."

Clafirication is the key

The topic of genetic manipulation has even made its way into the cinema. The film "Human nature" summarizes many pro and con arguments and provides an interesting overview. Simon appreciates the good transfer of knowledge, which is now also evident in various television and radio formats. "At the moment, we have a very good reappraisal of these scientific aspects, which could, perhaps, be timed even more audience-friendly," he smiles and continues "I think we have learned that we have to invest in the transfer of information, because that is the only way we can get the skeptics on board. Fear and skepticism does not come from ignorance, but from fragments of knowledge. One just reads the headline, immediately has an opinion and puts it in a drawer. You follow one and distrust the other." More basic information and individual consideration by an independent commission made up of more scientists and fewer lobbyists and politicians would be a viable path for Simon.

In response to the final question as to where, for him, human repair ends, the 44-year-old spontaneously replies: "The germ line is taboo! That is clear in any case, there can and must not be any manipulation.

Uwe Blass (Interview on January 14, 2021)

Martin Simon studied at TU Kaiserslautern until 2005 and then became an assistant professor at Saarland University in 2012. Since 2018, he has been head of the Molecular Cell Biology and Microbiology Division in the Faculty of Mathematics and Natural Sciences at the University of Wuppertal.