An interview with Markus Huth
A research article in the February 2015 issue of the JCI demonstrates that modification of a class of antibiotics known as aminoglycosides reduces detrimental side effects affecting hearing by blocking entry of the drugs into sensory hair cells via mechanotransduction channels. This work suggests that modifying antibiotics and other commonly used drugs based on their biophysical properties may be effective in reducing their side effect profile and enable their use when other options are limited. We asked the lead author, Markus Huth, about his work.
How did you first get interested in pursuing both medical and graduate research training in your career path?
Medical education in Europe is structured differently from that in the United States, so I first have to explain how our system works. After 13 years of pre-university schooling, I matriculated directly into in a six-year program: two years of preclinical coursework and four years of clinical studies. In Germany, where I went to medical school, doing some research is part of the curriculum, though I spent extra time on my project, which is where my interest in research first began.
I knew early on that I was interested in otolaryngology due to the delicate anatomy, so I sought to do research in this field. After visiting the various otolaryngology labs at my university, I was immediately interested in the ear because of the complexity of the system. It’s a central organ, yet it is still a black box in many respects. You have this extremely fragile sensory organ that is highly sensitive to mechanical stimulation, yet it is situated in the hardest bone of the human body. This problem of accessibility might be one of the reasons why our knowledge of the ear is limited, with many questions remaining to be answered, so I felt and still feel challenged. At the same time, I love working and interacting with patients as well as the dexterity skills required during surgery, as these motivated me to choose medicine in the first place. So, I guess pursuing both is due to the desire to fulfill both of these interests.
What are your observations after having trained in both the European and American medical systems?
They are really hard to compare because of the different education timelines. In Europe, our medical education and training are much more theoretical. We are taught surgeries at a much later stage in our residency and even as attending physicians. After two to three years of being an attending in Switzerland, any differences with American colleagues probably wash away. In this respect, we still have a lot to learn from the American system when you look at the education and training at a resident level in the US.
What did you expect when you first worked with these designer antibiotics?
This is a good question, because I actually came to Stanford with another project in mind. While trying to get this other project started and dealing with the delay of arrival of the necessary equipment, I had a lot of down time. At that time, there was an ongoing project on aminoglycoside ototoxicity in my lab, which needed some additional experiments to complete the study. I started to get involved in the aminoglycoside ototoxicity project just to acquire the technical skills necessary to ultimately conduct my own research. This is why, at first, I actually had no expectations at all. This project essentially identified the mechanotransduction channel as the mode of aminoglycoside entry into inner ear hair cells. My work started from there, and with all the hours put in, the results we found, and the ideas that evolved, it eventually became my baby. And now having an idea of the aminoglycoside pathway through the mechanotransduction channel, we next wanted to see if we could modify the aminoglycoside such that it could not fit through. We started out with nine compounds, and of course you hope that one of them would prove our hypothesis to be right. But research has taught me to be humble and not set expectations of initial experiments too high, so my hopes were not incredibly high. The initial experiments were done relatively quickly, and luckily, we found one non-ototoxic compound that continued to work as an antibiotic within the first series of our newly synthesized compounds.
Do you see any challenges in translating your methodology or findings into human trials or therapy?
I think it is always a challenge to bring a drug on the market given the necessary quantity of safety requirements and the present possibility that one of them might not be met. In retrospect, if you look at the side effect profile of aminoglycosides today, they probably would not have made it to the market. But they were discovered as the long-sought treatment for tuberculosis in 1944. As such, ototoxicity, a side effect shown in the very first clinical trial, was the lesser burden and deemed acceptable compared to the disease burden of tuberculosis. Today, due to their ototoxicity and nephrotoxicity, the indication for aminoglycosides is still very limited, although they are cheap and potent broad-spectrum antibiotics. This might be a reason for the relatively limited bacterial resistance to aminoglycosides compared to other antibiotics that are overprescribed today. Our findings provide the opportunity to extend the indications for an antibiotic that has good efficacy, and so far, the experiments as done in our paper are promising in respect to translating our findings into human therapy.
What do you see as future research directions from this work?
I see several. I think the most direct future direction is bringing this to a licensed drug, which is still a long way away. We have to overcome several safety studies and the requisite clinical trials. On the other hand, our hypothesis of modifying the aminoglycosides in a way that they do not fit through the mechanotransduction channel, or at least not in the quantity they used to, provides other possibilities for modifying molecules in ways that they don’t fit through to cause toxicity. For example, there are other drugs like cisplatin, a chemotherapeutic agent that is also known for its ototoxic side effects, which is another possible target for modification.
What advice do you have to other trainees who are pursuing research?
My biggest benefit was from going abroad and leaving my comfort zone. Seeing how things are done differently at another place really widened my perspective. Finding a good mentor is definitely the other thing. I was incredibly lucky to find great mentors. I have a great clinical mentor here in Switzerland, but I think my most influential mentor was Dr. Anthony Ricci at Stanford. I learned so much from discussing research with him, seeing how he designs research projects and how he approaches research data. But probably the most I learned was simply from listening to him and benefiting from his experience. I think those were the two main points that contributed to why my career had progressed the way it has.
About the First Author
Markus Huth, M.D., is currently in his final year of residency in otolaryngology at Lausanne University Hospital in Switzerland. During residency, he spent two years as a postdoctoral research fellow in the lab of Anthony Ricci at Stanford University School of Medicine. He undertook his preclinical coursework at Ludwig Maximilian University of Munich and obtained his M.D. from Technische Universität München.
About the interviewers
Freddy T. Nguyen is an M.D./Ph.D. candidate at the University of Illinois at Urbana-Champaign. He is the Founder of the American Physician Scientists Association and served on the Associate Member Council of the American Association for Cancer Research, His research interests currently lie at the intersection of biomedical optics and cancer research. He received his B.S. in Chemistry and B.A. in Mathematics from Rice University.
Chirag Patel earned his M.D. and Ph.D. from the University of Texas Medical School at Houston. He completed a preliminary year of residency training in internal medicine at East Tennessee State University and is currently a resident physician in neurology at the University of California at Los Angeles David Geffen School of Medicine. Dr. Patel received his B.S. and M.S.E. in biomedical engineering from Johns Hopkins University.
Related articles
Abstract
Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of
Authors
Markus E. Huth, Kyu-Hee Han, Kayvon Sotoudeh, Yi-Ju Hsieh, Thomas Effertz, Andrew A. Vu, Sarah Verhoeven, Michael H. Hsieh, Robert Greenhouse, Alan G. Cheng, Anthony J. Ricci
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