Dr. Rudolph’s comes to us all the way from Jena, Germany. He is currently the Scientific Director of the Leibniz Institute for Age Research at the Fritz Lipman Institute. His research focuses on the molecular mechanisms underlying the aging process, especially the aging of stem cells. One of his areas of study is telomeres. Telomeres are the “caps” at the ends of chromosome arms that prevent chromosome degradation during replication. Telomeres are made up of hundreds of DNA nucleotide repeats with the sequence TTAGGG. These caps help protect the loss of vital DNA information by serving as “buffering” sequences whose gradual shortening during chromosome replication has minimal effect. As a person ages, their cells undergo numerous cellular divisions which require chromosome replication. During replication, a small portion of the telomere is lost each time. When a telomere gets too short, a cell typically stops dividing in order to avoid the risk of losing vital gene sequences, which could be detrimental to the health of the organism.
Dr. Rudolph’s laboratory studies the role of telomeres in stem cells and mice. Dysfunction of telomeres can have several severe side effects including reduced lifespan, tumor formation, cirrhosis in humans with liver disease, and reduced function of stem cells. From a therapeutic perspective, the Rudolph lab has shown that the deletion of specific DNA damage checkpoints can improve stem cell function, organ maintenance, and the lifespan of telomere dysfunctional mice without increasing tumor formation. Dr. Rudolph’s seminar focused on hematopoietic stem cells (blood stem cells) and the changes that occur in them during the aging process. Hematopoietic stem cells regenerate over a person’s lifetime and can differentiate into all the different blood cell types found in humans, such as T-cells and B-cells. Studies have shown that stem cells are often the origin of many cancers. Due to their long lives and high replication rate, when compared to somatic cells, stem cells have an increased risk of acquiring DNA mutations that can cause cancer and other diseases. When studying hematopoietic stem cells, it is possible to isolate them from a simple blood sample. These cells can then have their DNA sequenced for possible mutations that might lead to cancer. With a better understanding of these mutations, new cancer treatments that are genetically designed and targeted for those mutations can be created, and then used in a patient specific manner.
Q: Can you detect stem cell mutations that cause cancer in vivo?
KLR: Yes, you can for the hematopoietic stem cells (blood stem cells), by taking a blood sample. You can then analyze these cells by next-generation sequencing and identify the mutations. The problem is that although you may be able to test for these predictive mutations in other tissues, it is very difficult to obtain tissue samples from various organs. One must also keep in mind that a mutation detected in blood cells is not always present in other organs. The mutations that we are detecting are not always those that one is born with but also those that occur over a person’s lifetime due to continual DNA damage and repair. So different cells and organs will have different mutations that occur over time. People are now developing nanotechnologies to take measurements from different cells.
Q: Are there any preventative measures that can be taken after detecting mutations to delay or prevent the onset of leukemia?
KLR: Yes, scientists are just starting to develop these therapies. Many of these cancers are a product of multiple gene mutations, so if you have gene “A” mutated to survive, you need gene “B” to be intact. But if you can design something to disrupt gene “B”, then the cell mutation in gene “A” cannot survive, and therefore it doesn’t become cancerous. The problem is that cells that are cancerous are so highly mutagenic that it is possible for another mutation to occur in that cell that would allow it to still survive the disruption of gene B. It’s a complicated problem, and you also want to be careful about inducing mutations in healthy cells.
Q: As your body ages you mentioned that hematopoietic stem cells keep differentiating to repopulate other cell types. Is the pool of hematopoietic stem cells able to regenerate themselves, or is that pool finite?
KLR: In principal, the hematopoietic stem cell can regenerate from a single cell. So in theory a single transplanted cell can repopulate the pool.
Q: Have scientists looked on a large genomic scale if there are anti-cancer mutations in specific genes or mutations common in people that never get cancer?
KLR: People have been looking into this, specifically in centenarians and what makes them so successful. They have tried to find specific versions of genes or mutations in genes that contribute strongly to their longevity and cancer resistance. These studies have not yielded many specific gene, but it’s not that simple. It could be instead due to a combination of genes or specific versions of these genes. I think there is more room for discovery. Multiple genes and versions of those genes contributing to the phenotype should be taken into consideration.
Q: How did you become interested in telomeres?
KLR: So I started as a medical doctor in hematology studying liver disease. These patients are diagnosed, but they live twenty to thirty years and then start to show effects of the disease, followed by cirrhosis, and eventually liver failure. I became interested in why the patients were fine for those twenty years and what limits liver regeneration after that many years. Around the time I was pondering this question, the first telomerase knockout mice were made, producing mice with shortened telomeres. This model helped us to understand what the effect of shortened telomeres was in an animal. These studies influenced my trajectory towards studying telomeres in the context of stem cell differentiation.
Q: Is there any reason why one can’t have hematopoietic stem cells injected into the liver of liver disease patients for liver regeneration?
KLR: We have tried to do this in the hematopoietic system of old mice by taking hematopoietic stem cells from young mice and transplanting them into old mice, and the result was disappointing. The new stem cells did not integrate well and the aged in vivo environment did not allow for the newly introduced stem cells to function properly. In terms of using induced pluripotent stem cells (IPS cell) there are additional risks involved. IPS cells can transform and become cancerous, and they need to be generated and differentiated in culture, which is both time consuming and costly. I think trying to better understand why endogenous stem cells stop functioning and then adjusting the environment in vivo to keep them active, is a promising alternative avenue of treatment.
Q: How has having an MD influenced your perspective and approach toward research?
KLR: Having medical training changes the perspective on how you look at basic science. It allows one to see the potential therapeutic applications of very basic scientific discoveries that might not otherwise be observed.
Q: What are some of the best aspects of being a director of an entire institute?
KLR: I think what is great about being a director of an institute, especially if it’s one that focuses on the research you are interested in, is that you can build up a team of researchers and individuals that all have similar interests but from different angles. I think it’s a lifetime opportunity. Of course it takes away time from your research. However, with a good team, you have people to help you and can achieve more together than alone. You need the input from various angles, to understand a field as complex as aging.
For more on Dr. Rudolph’s research, check out the Rudolph Research Group website.