Monday, 8 April 2013

Interview with Professor Marko Mihovilovic

About a month ago, researchers from the Bioorganic Synthetic Chemistry group at the Vienna University of Technology issued a press release, saying that they have developed certain chemical substances that turn the body’s own stem cells into cardiomyocytes, the cells the cardiac muscle is comprised of. The press release states that “This discovery could open the door to a new kind of regenerative medicine”.

After reading the press release, I decided to contact Prof. Marko Mihovilovic, leading researcher, to learn more about their research to which he agreed. I would really like to thank him, for taking the time to answer all my questions in such a great detail.

StemCellsFreak (SCF): Hello Professor. Could you first tell us a few things about yourself and your work?

Prof. Marko Mihovilovic: I am currently Associate Professor in Bioorganic Chemistry at the Institute of Applied Synthetic Chemistry, Vienna University of Technology (VUT). I am actually an organic chemistry by training during my predoctoral education at VUT, and later expanded my expertise into biochemistry and molecular biology during postdoctoral stays in Canada and the US. My major research interest is at the cross-roads of synthetic chemistry and biology. Within several research programs, my team tries to exploit bioorganic chemistry to solve relevant scientific questions in biology; along this line we develop pharmacological tools as well as focused compound libraries. (Editor's note: You can read more about Prof. Mihovilovic’s here and at the end of the interview)

Professor Marko Mihovilovic, source 
SCF: Can you tell us more about the type of stem cells you use in your research? Are the derived heart cells healthy and functional?

Prof. Marko Mihovilovic: Within our recent work on cardiogenic small molecules we have been working initially with embryonic stem cells; however, we could later extend the transdifferentiation capacity of our compounds also toward lineage committed pluripotent cell lines. Employing several of our compounds induced a differentiation process towards cardiomyocytes, which ultimately resulted in functional and independently and synchronously beating cardiac bodies. However, all results obtained so far are based on Mouse cell models; the next major milestone of the project will be to translate the effect also to human cell lines.

SCF: Have you tested the heart cells on living specimens and if yes did you observe any improvements and/or adverse effects? If not, are there any plans to begin animal studies in the near future?

Prof. Marko Mihovilovic: As stated above: so far our results are based on Mouse cell models in cell cultures with a confirmation of the differentiation capacity to be yet established on human cell lines. A detailed toxicological study of the compounds is currently planned. However, as the treatment for the transdifferentiation process is presently conducted in cell culture (i.e. outside of the organism), we understand compound toxicity (which we did not observe with our compounds in the concentration range to trigger the target effect) as a minor issue.

In addition, an important next milestone will be to demonstrate that re-implantation of transdifferentiated cells actually leads to tissue regeneration in the living organism.

SCF: In the press release, you say "The new triazine derivatives we are using are much more efficient at turning the stem cells into heart cells than any other substances ever tested before". Is there any published evidence to back up this claim?

Prof. Marko Mihovilovic: Due to IPR issues we have only recently started to publish our results also in scientific journals. There is a number of manuscripts under peer review, at present. As soon as the publications are accepted I would be happy to provide the detailed results.

SCF: Do you believe that your work has implications in other fields, other than the development of heart cells for regenerative purposes?

Prof. Marko Mihovilovic: There is a number of additional small synthetic molecules reported in the literature to also affect differentiation processes towards neuronal cell lines, pancreatic beta-cell regeneration etc. We are also investigating some candidates from our own compound libraries for such additional differentiation effects.

It seems to me that with recent progress in screening technology especially for large numbers of chemical compounds, we are discovering previously undetected effects especially related to cell differentiation end epigenetics. Such hit structures may serve as interesting lead compounds for developing pharmacological probes to obtain a better understanding of the biological processes. Moreover, some of such leads (as hopefully is the case for our candidate molecules) may very well serve as starting points for the development of novel therapies towards regenerative medicine.

Professor Marko Mihovilovic with Thomas Linder, PhD-student at the Vienna University of Technology, source

SCF: How long do you think it will take for your research to find its way in human applications?

Prof. Marko Mihovilovic: We are currently still very much in the beginning of the process of developing a broadly applicable therapy. We only have a vague idea about the molecular mechanism to trigger the observed differentiation process by small molecules. In order to make significant progress towards true application, we have to further study the involved mechanisms and identify the critical target(s) in order to tailor even better compounds.

However, with the identification of synthetic small molecules (SySMs) to affect differentiation processes in general, we have opened a new door in regenerative medicine. As a medicinal chemist, I am convinced that a SySM based treatment in regenerative medicine will overcome regulatory obstacles more facile than any gene-therapy approach (on the prerequisite on equal efficiency), as our expertise in handling small molecule drug candidates is much more advanced and can rely on an ample diversity of success stories exemplified by the pharmaceutical industry during the past decades. Under such circumstances, development of a novel drug candidate usually requires 7-10 years.

SCF: Have you participated in other stem cell-related studies?

Prof. Marko Mihovilovic: Our project related to cardiomyogenesis is currently most advanced; there are other targets (as outlined before) where we are currently in a less mature state of development.

SCF: What is your opinion about embryonic stem cells. Are you for or against ?

Prof. Marko Mihovilovic: I consider research on ESC as certainly troublesome from an ethical point of view; still, if new insights are obtained enabling advances in science for the benefit of humans, this can be justified.

There is an additional issue in context of regenerative medicine: Promoting differentiation of ESC (or other progenitor cell types) towards otherwise difficult to regenerate tissue is only half of the story. Such an effect may be complemented by the “de-differentiation” of already more mature cell types. During the recent couple of years, small molecules were also reported to initiate such dedifferentiation effects from mature cells towards a state of enhances “plasticity” in further cell differentiation.

Consequently, tailor-made cocktails for SySM-associated regenerative medicine are receiving substantial interest among the community, at present. The Holy Grail in the field would be to “harvest” easy-to-obtain tissue material, treat it with such a cocktail for de- and trans-differentiation, and finally re-implanting the obtained tissue material into the damaged area with minimum danger of rejection (since the original tissue came from the same patient).

Sounds still like science-fiction, but we didn’t even dare to think about small molecule associated tissue regeneration some 10 years ago …

SCF: Is there anything else you would like to add?

Prof. Marko Mihovilovic: I think recent developments in regenerative medicine could demonstrate, that ideas from science fiction stories dating back some 10 or more years have now reached a true scientific level. I am confident that in particular the discovery of small molecule chemical compounds to efficiently affect cell differentiation is currently opening up doors to both pushing our understanding of the underlying biological processes on molecular level as well as providing perspectives for highly novel therapies.

It is yet too early to say if these approaches will in fact reach the patient, ultimately. However, they provide new visions to scientists to advance the field and potentially new hope to patients currently suffering from organ failures incapable to regain complete functional restoration.

About Marko Mihovilovic
Marko was born in Steyr, Upper Austria, Austria in 1970. He is married to Dr. Barbara Krumpak-Mihovilovic (14.7.2001) and has two children, Gregor and Martin. After the A-levels in Linz, he started to study Technical Chemistry / Organic Chemistry in 1988 at the Vienna University of Technology (VUT), Vienna, Austria. His diploma Thesis was entitled 'Synthesis of Thieno[2,3-d]thiadiazole Derivatives' and was supervised by Prof. Peter Stanetty. He started his PhD thesis in 1994 ('Synthesis of Azasteroid Partial Structures as Potential Inhibitors of the Ergosterol Biosynthesis') again in the group of Prof. Peter Stanetty and finished this work in June 1996. From 1994-1998 he was research assistant at the Institute of Organic Chemistry (IOC). He was then on two postdoctoral stays as Erwin Schrödinger Fellow of the FWF (Project no. J1471-CHEM 'Designer Yeasts - New Bioreagents in enantioselective Synthesis') with Prof. Margaret M. Kayser University of New Brunswick, Saint John, N.B., Canada and Prof. Jon D. Stewart University of Florida, Gainesville, Florida, USA. From 1999-2003 he was again university assistant at the Institute of Applied Synthetic Chemistry (IAS, former IOC), VUT. In November 2003 he received his Habilitation (venia docendi) in the field of Bioorganic Chemistry and was promoted to 'University Dozent' (Assistant Professor) at the IAS, VUT. Since March 2004 he is Associate University Professor at the IAS, VUT. In May 2008 he declined the appointment to Full Professor in Bioorganic Chemistry at Johannes Kepler University Linz, Austria. From 2009 up to now he coordinates the Graduate School Program AB-Tec (Applied Bioscience Technology) at Vienna University of Technology. Since January 2013 he is the Head of Institute at the Institute of Applied Synthetic Chemistry (Vienna University of Technology, Vienna, Austria). (source)

A list of publications made by Prof. Mihovilovic and his research group can be viewed here

A list of all publications and contributions made by Prof. Mihovilovic is available here

1 comment:

  1. quote
    "usually requires 7-10 years."

    I wanted this now to treat my bad heart :(


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