Interview with Sebastian Diecke
Dr. Sebastian Diecke received the Paper of the Month Award for July 2019. We talked to Dr. Diecke about his excellent publication:
Dr. Diecke, your paper dealt with an inherited form of heart failure known as dilated cardiomyopathy. What is this disease? And who is affected?
Diecke: In this particular case, it is a family that includes about five patients. From the same family, we were also able to obtain two control subjects who display no abnormality of the nuclear structure.
What does “nuclear structure” mean?
Diecke: The nuclear structure, in this case, is the genetic information in the heart muscle, which is located in the nucleus.
The cell nucleus?
Diecke: Exactly. The morphology, or shape, of the nucleus is usually very round. But for these affected patients, the particular change in the genome alters this form so that it no longer appears round. This change is accompanied by differences in gene expression that affect various genes in the heart muscle cells and cause the muscle not to have enough strength to pump blood through the body.
How did you find this family? What brought them to your attention?
Diecke: They came forward in the usual course of clinical examinations being conducted at Stanford University, in the USA, by my boss at the time. Afterwards, an email was sent around saying, “We have an interesting disease that we don’t yet understand. Who would be interested in joining our research network?”
So you replied saying you were interested?
Diecke: Yes, and that’s how it came about. I was more from a basic research background, and the whole reason I went to Stanford was because I wanted to conduct really tangible translational research in a top institute. So I was very grateful for this email and thought, “I’ll now focus on this heart disease.”
Then what happened? Did you examine the family and remove heart muscle cells from the patients? Or how did you get the tissue?
Diecke: No, the next step was to enlist the patients and take skin and blood samples. We took these samples into the lab to obtain primary cells, which we then genetically manipulated in such a way as to produce so-called induced pluripotent stem cells. These are cells that are virtually identical to embryonic stem cells, and the characteristic feature of embryonic stem cells is that they can develop into all of the body’s various tissue types. We were therefore able to mature these cells into heart muscle cells and then compare them with the cells of the family members who are not affected by the disease.
And what did you discover? Do the heart cells from the affected patients actually look different? Do they beat differently?
Diecke: This is when we saw that the cell nuclei had a different appearance. And, with this change, we also saw associated deviations in the calcium signaling pathway and in the beat frequency of the cells.
The cells actually beat? You can see this under the microscope?
Diecke: Yes, exactly. This is one of those phenomena that science really brings you closer to – you can see the beating heart muscle cells. And if you have really good cells, you don’t even need a microscope. It looks like a wave motion.
And this means they beat differently?
Diecke: They beat arrhythmically, whereas usually you would see a constant rhythm. The cells that we obtained from the patients always displayed a small interbeat, which practically triggers a cardiac arrhythmia that can, in turn, lead to cardiac arrest.
So, the cells in the petri dish displayed cardiac arrhythmias?
Diecke: Yes, exactly. And a unique aspect of this study was that we also had access to material taken directly from one of the patient’s hearts. It is usually a limiting factor that you can’t get close to the tissue itself. In this study, however, it was very helpful for us that one of the patients had to be fitted with a pacemaker. This enabled us to obtain heart tissue from the patient and thus map out the entire cycle: from the disease model at the cellular level to material from the patient and his medical history. We were therefore also able to identify a drug, which is actually used to treat cancer, that ameliorates the arrhythmic phenotypes described.
How did you come across this medicine? Why did you try it in the first place?
Diecke: The analysis was carried out by sequencing the genetic material. This showed us which signaling pathway in the cells was deregulated. We knew from previous scientific studies which drugs have an effect on this signaling pathway, so that was when we tried various existing medications.
And is it really the case that this signaling pathway plays a role in both cancer and cardiac arrhythmia?
Diecke: The drug actually has a different effect on cancer cells, but a second mechanism affects cardiomyopathies. This is also the case with drugs for breast cancer. For example, doxorubicin is used to treat cancer, but also triggers major changes in the heart. A drug never has just one mechanism of action – there are always side effects. It is therefore unlikely that this drug will be used in patients right away. For now, it simply serves as a helpful indicator. Now, we might be able to modify this drug so that it only targets cardiomyopathies and no longer affects the signaling pathway that also plays a role in cancer.
So, the cancer drug itself wouldn’t be prescribed to heart failure patients?
Diecke: Not necessarily, the risks would be too great. At the moment, we are testing drugs that are currently used to fight cancer on the heart muscle cells produced in the petri dish.
You have studied a family in which five members are affected by this heart muscle disease. To what extent do your results help the thousands of other heart patients who also suffer from dilated cardiomyopathy?
Diecke: We suspect that there is a similar mechanism of action that is not unique to this one family. We obtained another patient sample that had a similar, though not identical, mutation. And there, too, we were able to ameliorate the phenotype. But, of course, it will not play a role in all dilatative diseases.
But for now, based on your results, you will be looking specifically at certain drugs that help with such diseases?
Diecke: Yes, indeed.
The general population believes that dilated cardiomyopathy is a result of high blood pressure. How often is the disease actually the result of genetic factors? And how often is it due to bad lifestyle choices? Can people sit back and say: “Well, if I have the wrong genes, then there’s no point me doing exercise?” Or is it a combination of the two factors?
Diecke: I don’t want to go out on too much of a limb, as I’m not a clinician. But I would say that the two factors work together. There is definitely a genetic basis, but lifestyle clearly also plays a role. If the heart muscle is overstrained, the onset of the disease occurs and is influenced by genetic modifications. So this certainly indicates an interaction between both factors.
Diecke: You’re welcome.