Ines Hochmuth married Hans Mandl when she was 19 years old in Vienna, Austria. By 1938 after Germany took over Austria they were living in England, and moved to Ireland in 1939. It was there that she attended University College Cork and studied chemistry. At the end of World War II, Ines and Hans Mandl flew to the United States to join Ines’s mother who had a job and an apartment in New York. They arrived in the US with only ten dollars in one-dollar bills hidden in their clothing. Ines began work as a translator for German scientific journals and then found a job as a chemistry technician in Elizabeth, New Jersey. She soon started to attend the Polytechnic Institute in Brooklyn (now a part of New York University) at night while working as an assistant to Carl Neuberg, the German Biochemist (the scientist who first used the term, biochemistry) at New York University. “Photochemistry of Amino Acids, Peptides and Enzymes” was the subject of her thesis for a PhD awarded in 1949. That same year, I was 11 years old and was just beginning to be interested in scientific subjects, although I was drawn more to biology than to chemistry. In 1949 I had no idea how important Ines Mandl would be in my life.
By 1950 Ines Mandl was employed by Columbia University as a research associate and was studying strains of clostridium histolyticum that had been discovered in World War II and was funded by the US Army. Her first appointments were in Surgery, then Medicine and Microbiology. In 1959 she had funding but no laboratory. I remember vividly her story of how she desperately searched for lab space near the 168th Street and Broadway campus. It turned out that Henry Clay Frick, Jr., a gynecologist who treated cancer patients, had available laboratory space which he let her use. It was this location for the laboratory that enabled her to have an appointment in the Department of Obstetrics and Gynecology. Her first publications describing the work with collagenase were in 1953 in the Journal of Clinical Investigation. One strain of this bacterium was rich in collagenase – a collagenase that broke down collagen in scars but did not harm healthy tissue. A topical collagenase ointment was developed for the treatment of burns and was also used for the treatment of decubitus ulcers. Gradually over time, her interest in the protein elastin developed and she focused on lung diseases and the role of elastin and elastases in these diseases, especially emphysema. She collaborated with an internist, Dr. Gerald Turino, but she remained in the Department of Obstetrics and Gynecology. She progressed slowly through the faculty ranks and was Assistant Professor for seventeen years, but eventually was full Professor and retired as Emeritus Professor of Reproductive Biochemistry in 1986. In 1972 Ines Mandl established and edited the professional journal Connective Tissue Research. Needless to say, Dr. Mandl has been awarded numerous honors; the one I admire the most is the Garvan Medal which is given to outstanding women chemists by the American Chemical Society. She received this award in 1982.
As Ines began to establish herself as a world renowned scientist at Columbia University, I graduated high school, went on to college and to Columbia University to study nursing and nurse-midwifery and finally, to Duke University Medical School. I arrived as a new teacher at Columbia’s College of Physicians and Scientists in the summer of 1979 right after completing my Obstetrics and Gynecology residency at Yale. The chair of the Obstetrics and Gynecology Department, Dr. Raymond Vande Wiele encouraged me to work with Ines Mandl and she became my mentor and PhD sponsor. I think Dr. Vande Wiele was happy to have a member of the Obstetrics and Gynecology Department involved in Dr. Mandl’s laboratory. While she was a member of his department, she was working on lung elastin and elastases. I received my PhD in 1986 on “Uterine Cervical Elastin in Normal and Abnormal Mammalian Gestation and Parturition” and was her last PhD student. Working and studying with Ines was intense, exhilarating and stimulating. She insisted on precise work, exceptional thinking and rigorous experimentation. She was also fun. I have wonderful memories of the large, fabulous Christmas Parties held each year by Ines and her husband Hans in the lobby of the science building on 168th Street. It seemed that every year every person in every laboratory at P&S attended that event. Dr. Mandl made sure that I attended scientific meetings with her and that I presented my work at these conferences. Over the years of my association with her I have attended numerous Gordon Conferences, European Connective Tissues Society meetings and Elastin meetings. She always made certain that I met her international colleagues and friends and that I stretched my scientific knowledge through them. It was at one such meeting that I first heard Donald Ingber discuss his concepts of “tensegrity” and Leslie Robert talk about cell-matrix interactions, among many others. The idea of a role for mechanotransduction in reproductive tract tissues was born at these meetings. In 2014 the Campion Fund held a scientific meeting in Durham, North Carolina on this topic. Along with a colleague at Johns Hopkins, Janice Evans, I published a review paper on this meeting in Connective Tissue Research. We titled it “Feeling the Force” in Reproduction: Mechanotransduction in Reproductive Processes.
I left Columbia and moved to the University of Rochester, then SUNY Buffalo and eventually to the NIH where I worked with my good colleague, Jim Segars on the basic biology of uterine fibroids. I became interested in the collagen contained in fibroids. To study this extracellular protein I spent countless hours in a basement electron microscopy facility looking at numerous slides (technically grids) to determine that the collagen in these benign tumors that are the cause of much morbidity such as pain and bleeding was considerably altered compared to that usually found in other tissues. The finding that the fibrils were shorter and disarrayed compared to the collagen in normal uterine myometrium led to many studies exploring the fibrotic nature of the tumors, and to the role of mechanotransduction in their growth. At first some were skeptical regarding these findings. One colleague who is an expert electron microscopist told me that the EMs we published were not very good, implying that artifacts were prevalent. Then he had a chance to repeat the experiments and found the same findings. He called me and told me that the collagen in uterine fibroids “is a real mess-all over the place”. This led us to the concept that the fibroid tissue itself was so firm that it would not easily be degraded by the collagenases found in the human body and that mechanotransduction was very much a mechanism of fibroid development.
After Ines Mandl retired she continued to attend scientific meetings, especially those in Europe and I would often meet her at those meetings. We met in Davos, Switzerland in 2010 at the Federation of the European Connective Tissue Societies where I presented work conducted at Duke University on the types of collagen expressed in uterine fibroids. Ines was interested in this work and suggested that I try the clostridia histolyticum collagenase she had isolated in 1953. It now had been highly purified and FDA approved as Xiaflex for Dupuytren’s contracture of the hand, as a possible treatment for uterine fibroids. The collagenase that Dr. Mandl had isolated is totally different from that found in mammals and consists of two isoforms, one which starts digesting the collagen at the ends of the molecule and the other that starts in the middle. Over time it digests all of the collagen until it is reduced to gelatin. At her urging I contacted Thomas Wegman, the President of BioSpecifics Techologies Corporation that had purified the drug and licensed it to a company, Auxilium, now merged with Endo. I met with him and began proof of principle studies to determine if this would be a feasible treatment option. We have published two papers now that do show that Xiaflex does indeed digest uterine fibroid collagen. A resident at the time, Dr. Lisa Bruenegraber and my colleague Dr. Friederike Jayes were my co-authors on the first paper and the co-authors of the second paper were Drs. Jayes, Betty Liu, Frank Moutos and Farshid Guilak. In the second paper we reported that 37-77% of the fibroids were made up of fibrotic tissue reflecting the collagen-rich nature of the tumors. The important aspect of mechanotransduction is that as tissue force is reduced, the cell behavior changes and the cells themselves become capable of dying off. We believe that this concept can work in fibroids. The exciting thing is the collagenase that Dr Mandl isolated so many years ago is now in a safety and tolerability clinical trial at Johns Hopkins where my good friend and colleague, Jim Segars is the Principal investigator. In this study the collagenase, Xiaflex, will be injected directly into the fibroids. Since human serum proteins inhibit Xiaflex, the drug would be inactivated quickly if it leaked out of a uterine fibroid. I am hopeful that Xiaflex will indeed be a treatment option for women with uterine fibroids. The drug has already been helpful in understanding the makeup of fibroids. By digesting the tumor with Xiaflex we confirmed that uterine fibroids are made up of 37-77% of fibrotic tissue containing altered disassociated collagen.
The story contained in this blog is a story of how basic science works, how ideas go from one generation of scientists to the next and how ideas lead to new applications. It suggests that discoveries made in basic science often take time to filter into translational research and clinical trials. Persistence and imagination count. Scientists who understand both fundamental science and clinical medicine are also important to advancing medical treatment. While it is desirable that all “bench to bedside” research should not take decades, this story does illustrate how scientific progress is often made and how it is transmitted from one generation of scientists to the next. The story also honors Ines Mandl, PhD for her discovery and for her mentorship and friendship.
Contributed by Phyllis C. Leppert, MD, PhD