Science has now identified more than 8,000 rare diseases, many of which have one thing in common: A diagnosis takes time and a therapy or even a cure does not yet exist. This poses special challenges for all those involved, such as relatives, physicians and the affected persons themselves. Today, modern genetic and genomic testing makes it possible to identify a large number of these genetic diseases, often referred to as the "orphans of medicine," at an early stage. However, where are the limits of these technologies and why should they not be exceeded - human geneticist Prof. Martin Zenker, MD, talks about this in the podcast.

Today’s Guest

Prof. Dr. med. Martin Zenker heads the Institute of Human Genetics at the University of Magdeburg. The pediatrician has been researching the human genome and the molecular causes of "RASopathies," a group of very rare diseases, for a good 20 years. The aim of his research is to better understand the disease mechanisms and to develop concrete treatment methods.

*the audio file is only available in German

The Podcast to read

Intro voice: Know when you want. The podcast about research at the University of Magdeburg.

Friederike Süssig-Jeschor: Hello and welcome to our science podcast from the University of Magdeburg. In this episode, we get into the grand and interesting topic of genetics and want to talk about a very special group of diseases, the so-called rare diseases, most of which are genetically determined. Today, modern genetic testing makes it possible to identify a large number of these genetic diseases at an early stage. However, what are the limits of these technologies and why should they not be exceeded? This is what I would like to talk about with our guest today.

This is Professor Martin Zenker, MD. He is a specialist in pediatrics and director of the Institute of Human Genetics here at the University of Magdeburg. His research focuses on one of the most common rare diseases - the group of RASopathies - and the mechanisms of these diseases. For this purpose, he also leads the Germany-wide research network GeNeRARe. My name is Friederike Süssig-Jeschor. I am the press officer of the Medical Faculty of the University of Magdeburg.

Professor Zenker, we are pleased to have you here. A warm welcome to you!

Prof. Martin Zenker: Good Morning!

Friederike Süssig-Jeschor: Human genetics - When you hear the term, the first thing that comes to mind is Dolly, the famous cloned sheep, or the twins Lulu and Nana, the first two genetically engineered babies born in China in 2018.

Enlighten us for once, please! What is this field about and what is your task as the Institute of Human Genetics here at the University of Magdeburg?

Prof. Martin Zenker: Yes, what you are referring to are experiments or interventions on embryonic stem cells that have attracted a great deal of media attention and that some people see as the primary representative research for human genetics. And they are rightly viewed very critically. In fact, it has relatively little to do with the reality of working in a human genetics institute. As a medical discipline, human genetics is concerned with the genetic basis of human diseases. And we have made enormous progress in this area in recent years.

Today, we know a great many diseases and, of course, for the large number of genetic diseases, the genetic causes and genetic factors that predispose to diseases. And this research basically flows directly into the diagnostic procedures at the moment when a new gene for a disease is known. Of course, it is also available to us as diagnostics.

In addition, what we do practically at the institute is, on the one hand, in patient care, genetic counseling for questionable and suspicious genetic problems in a family and the laboratory testing. And of course as a university institute we do research, which we will talk about later. And teaching, training for students is of course also our area of responsibility.

Friederike Süssig-Jeschor: You mentioned it. You operate at the intersection of research and patient care. How can that benefit the patient? Why is that so important?

Prof. Martin Zenker: Well, in principle, genetics is research in root cause of a disease. In other words, we are really at the root of a particular disease. Recognizing the fundamental basis of a disease, naturally also helps us to understand the disease and then possibly to develop more targeted therapies. And that, of course, has enormous significance for patients. Quite apart from the fact that clarifying a genetic disease naturally plays a major role for the family, for assessing the likelihood of recurrence in the family.

Friederike Süssig-Jeschor: You take a close look at one of these diseases. For more than 20 years, you have now been researching the human genome and the molecular causes of RASopathies. This is one of these special groups of very rare diseases. What does it mean to have a rare disease? Perhaps you could try to explain that briefly and succinctly to our listeners.

Prof. Martin Zenker: Yes, we speak of a rare disease in purely formal terms when the frequency of the disease in the population is less than 5 in 10,000, i.e. 1 in 2,000. And some of these are rare and extremely rare diseases, some of which affect only five or ten people in the world. A large proportion of these, not all, i.e. about 80 percent, are genetic diseases.

Conversely, one can say that almost all genetic diseases are rare diseases. And they do have many things in common. They are often chronic diseases, which means that they are present throughout life. In other words, they are diseases that often affect several organ systems and can significantly reduce quality of life and life expectancy. And there is also the aspect that there can be several sufferers in the family due to the hereditary nature of this disease.

Friederike Süssig-Jeschor: Can you give us some examples so that we can get an idea?

Prof. Martin Zenker: Well, maybe a term you've heard of: Cystic Fibrosis. A lung disease in which the mucus is so tough that it leads to chronic destruction of the lungs. The wife of the former German President, Mrs. Herzog, was also the patron of this cystic fibrosis association. Then there are inborn errors of metabolism. Those that are detected in the newborn screening of every child belong to these rare diseases.

Also, many forms of mental retardation are actually rare genetic diseases. And last but not least, one must not forget that there are also rare variants for some common diseases, for example rare genetic forms of dementia, rare tumor diseases associated with hereditary tumors, such as hereditary breast cancer, or similar even rarer forms of disease. For example, extreme short stature is also usually a rare disease and the list could be extended indefinitely.

Friederike Süssig-Jeschor: Expressed in numbers: 4 million people in Germany suffer from one of these rare diseases, in Europe there are 30 million. Nevertheless, one often speaks of the "orphans of medicine", why?

Prof. Martin Zenker: Well, with the diseases, the one point is already that most doctors do not know these diseases. And you can often only make a diagnosis if you have seen a disease before. Pure book knowledge is often not enough. This leads to the fact that the diseases are diagnosed much later, sometimes only after years. Once a diagnosis has been made, it is difficult to find a real specialist, and many patients are left alone with a diagnosis but no adequate treatment. Then the development of therapies that really get to the root of the disease is much, much slower than with other diseases. The pharmaceutical industry understandably has only a limited interest in dealing with diseases and drug development where there are only 100 affected patients in a country. In addition, that just makes this disease these orphans.

Friederike Süssig-Jeschor: Let's get back to your research focus. Among other things, you are specifically concerned with Noonan syndrome. This syndrome is one of the RASopathies mentioned at the beginning. In Germany, it is estimated that 20,000 people are affected. What is known about this disease?

Prof. Martin Zenker: Yes, this is a disease first described since the 60's and it is characterized as a clinical profile. The main features are certain congenital heart defects, growth retardation leading to short stature. External features by which you can recognize the disease in part or very often, at least if you have the expertise and already know the disease. In addition, there are developmental abnormalities, also a certain increased tendency to tumors, quite serious complications that can occur.

The picture is very broad. There are people who have the disease and do not get a diagnosis in their life, even do not feel sick. There are very mild manifestations, but especially in variants of this disease, which is a group of overlapping clinical profiles, there are also, for example, serious developmental disorders leading to mental retardation or other serious complications.

Friederike Süssig-Jeschor: What exactly did you investigate in your research and what have you already been able to find out?

Prof. Martin Zenker:Well, we have been involved in the search for the genes for Noonan syndrome and related diseases since the early 2000s, first in my work in Erlangen and then in Magdeburg. This search has led to the fact that today we can actually find the genetic cause in almost all patients who have this disease and can thus detect the disease. In other words, we can make a reliable diagnosis.

We are also very much concerned with the question of the extent to which the very different manifestations of the disease are related to the individual genetic alteration. Because we believe that it is not a coincidence, that one patient has a severe expression and severe complication, while the other patient is very mildly affected. We already know, and of course this picture still needs to be sharpened, that it is precisely certain mutations, certain genetic changes, that are associated with particular complications, particular manifestations of the disease.

In this way, we will be able to better control the prognosis and perhaps also the screening of patients in the future if we know the genetic alteration. Then research is now simply moving in the direction of better understanding what actually happens in the cells, what happens in the affected organs when such a mutation is present. Because this knowledge about the actual mechanisms in organs and cells is important in order to find the starting points for targeted treatment.

Friederike Süssig-Jeschor: How do we have to imagine this? You have found a very specific starting point, a target. Whatever you want to call it now. You have identified a target and there is a defect. Is that right?

Prof. Martin Zenker: Yes. What unites this group of diseases is that all the genes that we know today have to do with a cellular signaling pathway, the so-called Ras-MAP kinase or RAS signaling pathway, which is responsible for the transmission of signals from the cell surface into the nucleus. And we can say with that nowadays that in principle Noonan syndrome are related diseases of the RAS signaling pathway.

That is why they have been given this collective term RASopathies. Moreover, this knowledge is of course enormously important, because we say that they have a common biological mechanism. That means that they probably have, even if you can treat it specifically, you can use the same approaches for the whole group.

Friederike Süssig-Jeschor: And to describe that a little bit figuratively: Is this a defect in a power line or how should we imagine it?

Prof. Martin Zenker: Well, it is not quite like that. In cells, signals are not transmitted by current pulses, but the cell has facilities for this in principle, which runs like a chain reaction of activation steps of signal molecules. That is, a signal on the surface of a cell encounters a hormone, a growth factor, any signals from the environment. Otherwise, the cell stands on its own, cannot communicate, and the binding of the signal to its receptor then triggers the activation of a downstream molecule in the cell, which in turn activates the next one, and so on. Until finally the signal is passed through to the cell nucleus. In addition, of course it is very important that these activated signal molecules fall back into the inactivated state. Otherwise, once switched on, you would have a permanent signal. It is like when your accelerator pedal is stuck in a car and you press it once and then it continues to drive at full speed and there are other regulatory devices, so that overall it is a very finely balanced system.

Moreover, the interesting thing in Noonan syndrome related diseases is just that it is not a defect in the sense of this system, but an over activation. That is, these mutant signaling proteins fall back into their inactive state more slowly. That is, it is simply an increased signaling flux and that simply interferes with many cellular processes. We know that this RAS signaling pathway is used by every cell, for very different purposes. Control of metabolism, of differentiation, of cell growth and the like. However, the defect in this fine control, in the reliability of the system is the problem that we have identified.

Friederike Süssig-Jeschor: In 2001, the first causative gene for Noonan syndrome was discovered. Together with researchers from Freiburg and San Francisco, you yourself discovered the second gene. There are now about 20 genes for Noonan syndrome and related diseases, most of which you were also involved in discovering. This discovery was made possible by the enormous technical changes that the field has experienced in recent decades.

Can you give us a brief insight? What has happened in terms of genetic diagnostics and treatment?

Prof. Martin Zenker: Yes, you have to bear in mind that the decoding of the human genome took more than ten years and cost billions of euros until the human genome sequence was finally known in the early 2000s. Nowadays, the genome of a human being can be analyzed in a week, and it still costs about €500 in purely material terms. Of course, this has changed the possibilities in diagnostics enormously.

In the past, if you wanted to make a genetic diagnosis, you first had to have a very clear idea of what kind of disease it was. Therefore, you had to ask a very specific question. Then the gene for it had to be known, or a very specific examination of this one gene could be carried out. Today we can, even if it is just a suspicion, it could be a genetic disease. I cannot pinpoint them. Many are so non-specific that you cannot even put a name to them right away. However, I can practically do a broad genetic analysis and then just look to see where is a change. Moreover, if I find something, then of course it is again: does it fit the appearance of the child, the patient and then you can say: yes, we have found the cause.

Friederike Süssig-Jeschor:You just mentioned that the field, i.e. the speed, has changed enormously. So how important is the timing of diagnosis? Using Noonan syndrome as an example.

Prof. Martin Zenker: Yes, that is very important, because the point is to be able to better classify the symptoms when they occur, so that other examinations that are always performed when a child has abnormalities that cannot be explained, a large number of examinations are performed that also burden the child with the genetic diagnosis. Once the diagnosis has been made, many of these additional examinations can be dispensed with. Then to do metabolism, then to do an MRI of the organ or of the brain. I think that is important. Of course, it is also important to assess the prognosis, to be able to tell the parents what the disease means, and, if necessary, to do more targeted preventive examinations. Then, of course, there are certain serious complications in this group of diseases where it is now possible to start more targeted therapies, which now are still off-label, that is, without approval. For example, severe cardiac involvement in Noonan syndrome, severe lymphatic problems, or tumors and leukemia. Finally yet importantly, for example, growth hormone treatment is a treatment that can be done to improve short stature once the diagnosis is made.

Friederike Süssig-Jeschor: What would you say? As a rule, it is the pediatrician or later the family doctor who knows his patients and their family history best. Are they sufficiently sensitized to human genetics or how do patients get to you?

Prof. Martin Zenker: We cannot expect pediatricians or family doctors to know all rare diseases, and Noonan syndrome is actually still one of the more common ones among the rare ones. There are often only rudimentary ideas of what it is and great uncertainty as to whether a child is really the one who qualifies for this diagnosis. However, we can already see that the sensitivity and also the recognition that human genetics can solve and clarify things today that could not be clarified in the past has already increased.

In addition, it is actually enough for us if the colleagues, pediatricians, general practitioners are so attentive and say: There is something unusual in the family, there could be an underlying genetic disease and the patients come to us. In the case of Noonan syndrome, for example, the heart defect is that of the child, which can lead to the diagnosis. It may then be the growth retardation later on. Children come from growth consultations with unexplained short stature, where we then find a Noonan syndrome or also in rarer cases sometimes the occurrence of such an early childhood leukemia, which leads to the diagnosis.

Friederike Süssig-Jeschor: Now the patients or affected families have found their way to you. How exactly does human genetic counseling work? Moreover, what is actually necessary for the diagnosis? A blood sample?

Prof. Martin Zenker: Yes, first of all about counseling. On the one hand, genetic counseling involves reviewing the previous findings to really get a comprehensive picture of the disease in question. A family tree is always obtained to check whether there are similar diseases in the family or other genetic risks that could be significant. And, of course, a normal clinical examination is also carried out in order to fully assess and document the clinical picture.

For genetic laboratory diagnostics, a blood sample is possible, but is from any body cell. We occasionally do it from saliva samples in children to save the blood sample. We can also do genetic diagnostics from tissue samples for certain issues.

So any material that just contains DNA is important for diagnostics. Then, that there is consent. The legal regulations are very clear that genetic tests can only be carried out with the legally valid consent of the patient or guardian, parental guardian. Yes, these are the conditions.

Friederike Süssig-Jeschor: And what happens after the diagnosis is made? Because if I understood you correctly, genetic diagnostics offers something like a glimpse into the future, so that the risks for certain diseases can of course be detected earlier.

Prof. Martin Zenker: Yes, the task really begins with the genetic diagnosis, because it is important that we do not abandon the patients with this information. This means that it is important to provide patients with a specialized care service for this disease. If such a service exists, it is of course available, even if not for every ultra-rare disease.

In the case of RASopathies, we are of course the experts and can take care of that. Then we simply try to control which examinations are done, to advise the family, but of course also the doctors in charge. Because not everything can really take place on site in Magdeburg, but also involves a lot of communication with the attending physicians, if necessary specialist conferences that are set up to discuss a particular problem with the attending physicians on site.

For the diseases that we diagnose, where we ourselves do not have such a specialized range of services and are not experts, a network of centers for rare diseases has developed in Germany, which are well networked and in principle have the task of really finding the clinic, the facility, for patients with a given diagnosis, which has the special expertise and at least provides comprehensive care for the patient and helps to manage the treatment and care.

For the diseases that we diagnose, where we ourselves do not have such a specialized range of services and are not experts, a network of centers for rare diseases has developed in Germany, which are well networked and in principle have the task of finding the clinic, the facility, for patients with a given diagnosis, which has the special expertise and at least provides comprehensive care for the patient and helps to manage the treatment and care.

Friederike Süssig-Jeschor: Why is this assistance still important? Because it is not just about understanding the disease. What is it doing to me? It also has an impact on your entire life in case of doubt. How do you support this as an MKSE or as an institute?

Prof. Martin Zenker: Yes, that is correct. As I said at the beginning, these are lifelong diseases. It has to be said that the patients themselves or the families actually often become the experts on the disease. That is why we have to make sure that the patients themselves are also well informed about the disease. Because not every doctor who is then involved with the patient has the knowledge. In addition, it is important that we ensure that patients really do have scientifically sound knowledge about their own disease.

Friederike Süssig-Jeschor: Living with the knowledge of a probable future disease outbreak can be very stressful. How important is it, therefore, to handle the knowledge you gain from genetic diagnostics with care? How do you deal with these ethical problems of modern human genetics?

Prof. Martin Zenker: Yes, that is right, that the knowledge of a genetic disease or a genetic risk for a disease that develops later, things that you cannot even see now, can of course be very stressful. For us, it is important that genetic testing be only really done with an indication. That means I have to know for what, for which symptom or for which disorder I am really looking for a cause.

I would not consider broad genetic testing without a cause to be ethically justifiable. Nevertheless, it is of course not one hundred percent feasible, because especially when the children are still very young, they may have a reason for the genetic examination, but it suddenly answers questions that go far into the future and concern matters, such as development, that are not even in front of their eyes at the moment.

In this respect, it is to some extent a stressful diagnosis to be diagnosed with such a genetic disease, with all the consequences, with the lifelong nature of this diagnosis and the possible long-term impact, which is much more significant than what actually prompted the examination.

Friederike Süssig-Jeschor: Does the use of genetic diagnostics also entail risks? On the other hand,, are there red lines that should not be crossed?

Prof. Martin Zenker: Yes, the risks in diagnostics lie in the fact that in some cases we are answering questions that have not yet been asked. And that it raises the ethical dilemma that we have just discussed. In comprehensive examinations, where the entire genome is more or less combed through, one can sometimes come across random findings that one has not even looked for, such as a predisposition to cancer.

However, there is also an obligation in the consent process to discuss this with the persons concerned and to say: If we see such findings that have nothing to do with the actual question, but may have relevance for the family, should we communicate them? Should they not be communicated? These are the - yes, if you will - perhaps risks.

Red lines, I think in the diagnostic field, I see them where extremely broad examinations are performed without any reason or when the connection is not clear, which then produce any findings or at least unclear results with a high probability. I think especially in the prenatal-diagnostic area, i.e. before birth, it has to be well considered and there have to be red lines what to examine and what not to examine.

What is very clearly regulated is, for example, that no genetic tests should be carried out on children for late manifesting diseases, i.e. those that only become relevant in adulthood, such as dementia or cancer. The individual should be allowed to decide for himself, when he is an adult, whether he wants to have this information or not.

In the field of treatment of genetic diseases or interventions in the genome, I think one principle is that the intervention must also have a prospect of being beneficial to the patient.

This does not mean, for example, to transfer a serious disease that may end in an early death to a long-lasting disease that nevertheless leads to a severe disability and then to death. I think that this so-called gene scissors CRISPR/CAS, which is also talked about a lot, that it can do so much but at the same time, it is not yet mature enough, at least for the application in the living organism, because it can also, so to speak, make changes at other places than the actual target sites in the genetic material.

What we also discussed at the beginning: Interventions in the reproductive tract, i.e. the manipulation of the genetic material of an embryo produced in a test tube through artificial insemination, is something that I consider to be fundamentally unacceptable from an ethical point of view. And to be honest, I don't see any reason to do something like that. You have to say about this, what was done in China at that time and, by the way, was only presented at a congress, never published. You simply have to say that this was only done because it was technically possible. There was no medical reason at all for this intervention and I see no reason for it in the future. Simply for the reason that if I create an embryo in the test tube by artificial insemination and have a genetic disease in the family, then it is still easier to examine the embryos and implant only those that do not have the genetic defect than to try to correct the others that have the genetic defect.

Friederike Süssig-Jeschor: On the other hand, there are already procedures, gene therapies and genetic procedures for treatment that are already being used successfully. Perhaps you could give us a few more examples.

Prof. Martin Zenker: Yes, hopes have been very high for many years that genetic engineering methods could be used to treat genetic diseases. This has also suffered many setbacks. It is simply fundamentally difficult to introduce a specific gene into many cells or to make a targeted change. Nevertheless, there are now actually initial successes. I think one of the most well known therapies, which has also gone through the press as the $1 million therapy, is gene therapy treatment for spinal muscular atrophy. This is a muscle disease where there is a very rapid breakdown of muscle in the child and there is an approved therapy that is actually already being used very widely. Nevertheless, we still do not know where these patients will actually end up. It is not going to be a complete cure. It will be an improvement of the disease. There have also been successes with certain blood diseases and immune diseases, where it is possible to deliver the bone marrow cells in the test tube, so to speak, to the gene therapy treatment and then return them to the patient in the sense of an autonomous bone marrow transplant.

That is where you accept the fact that you can expose the entire organism to these gene therapy procedures. I think what has a great future in any case, perhaps not so much in the field of human genetics, are procedures that are used in tumor therapy, for example, with modified immune cells that then make the immune system fight the tumor. This is called CAR-T cell therapy. That is also, where most of the gene therapy procedures that have been approved so far are.

Yes, and many things are in the pipelines either in research or already in the approval process, so we will see a lot more in the next few years.

Friederike Süssig-Jeschor: Let us come back to syndromal diseases. What do you think of technologies like Face2Gene? That is, an artificial intelligence or an app that promises to be able to recognize certain syndromes based on facial features.

Prof. Martin Zenker: In principle, artificial intelligence is of course something that will change society, many areas and of course medicine, and will gain a lot of influence. Moreover, it is quite clear that human genetics with the large data sets that we have to deal with, a genome is in principle a large data set, but also a phenotype, i.e. an appearance like a face is a data set and AI methods can actually be helpful there.

The software mentioned above, which is capable of recognizing the syndromic features of a face and saying that this could be Noonan syndrome, that this is Down syndrome, that this is another syndrome, is definitely helpful for the diseases that manifest themselves through characteristic features in the face. Not all diseases do that by far, but where there is a typical face, they actually have a hit rate that probably exceeds even the very good human geneticist.

At least for those diseases that are not his deepest field of expertise that he has already seen a hundred times. In the meantime, there is also the integration of such facial recognition procedures, if you will, or of these data from the facial analysis, into such automated evaluation algorithms, with which one then filters the genetic information from pure genetic diagnostics. So, you don't just enter the data that the person has a heart defect, a short stature, a developmental delay, but also the score from the facial analysis, so to speak. Then the algorithms can say: Yes, we have found a change in a gene, everything fits. Both the physical characteristics and the face are well matched.

Friederike Süssig-Jeschor: So I do notice an enthusiasm when it comes to tools with you. Is that what you would like to see as the next achievement for genetics? Alternatively, is it more networked data, for example?

Prof. Martin Zenker: I do not believe that there is a universal tool that will provide solutions for all questions in genetics, for diagnostic questions or other things. But I do believe that we, as human genetics, have to participate in these innovations that exist and use them for ourselves, and I believe that in the area of finding treatments, it will remain a slow and complex puzzle, because there will be no universal treatment for all genetic diseases.

It depends a lot, on what the mechanisms really are. Just as an example, like the RASopathies. Here, gene therapy that replaces the gene would not do anything at all, because we have over activation. Now they are adding more of the genes. That would tend to exacerbate the problem. In contrast to other diseases, we have to consider how we can reverse this activation.

In addition, here we are suddenly faced with completely different procedures, which in our case, for example, involve inhibitors of this signaling pathway. These are not gene therapeutics at all, but perhaps chemical drugs.

Friederike Süssig-Jeschor: Very exciting field. We are all curious to see how this will develop. Last question: How long will the designer baby with defined eye color, high intelligence and certain talents remain science fiction? With a smirk, of course.

Prof. Martin Zenker: I hope that it will remain science fiction forever. And I also think that for such characteristics that you mention: Eye color, body size, intelligence, which are inherited in a complex way and have many genetic influences, I don't see the possibilities at all to do that, so to speak, to upgrade, really effectively, without taking all the risks of interfering with the genetic material. That's why I really believe and hope that this will never become relevant.

It is quite different to improve a serious genetic defect by an intervention than to try to tweak some small genetic trait to optimize people.

Friederike Süssig-Jeschor: Absolutely. That brings us to the end of our interesting discussion. Many thanks to you, Professor Zenker. Bye and see you next time.

Prof. Martin Zenker: Yes, thank you.

Outro Voice: Know when you want. The podcast about research at the University of Magdeburg