Academic Entrepreneur and Founder in the Field of Nanotechnology: Mauro Ferrari of the Methodist Hospital Research Institute, Houston, Texas

Mauro Ferrari is the executive vice president of Houston Methodist Hospital (a U.S. News and World Report Honor Roll Hospital, 2016) and the president/CEO of the

Mauro Ferrari in front of the Houston Methodist Research Institute he inaugurated in 2011.

Houston Methodist Research Institute, where he is the Ernest Cockrell Jr. Presidential Distinguished Chair. He also serves as the senior associate dean of the Weill Cornell Medical College, the primary academic affiliate of Houston Methodist. He has served as a special expert and advisor to the director of the National Cancer Institute (2003–2005), leading the establishment of the Alliance for Nanotechnology in Cancer, the world’s largest program in nanomedicine to date.

Dr. Ferrari is a member of the National Academy of Sciences of Italy and the European Academy of Sciences and is a fellow of the American Academy for the Advancement of Science, the American Institute for Medical and Biological Engineering, and the American Society of Mechanical Engineers.

His current duties include executive responsibilities over all research and education programs at Houston Methodist, with over 1,200 research employees and accredited clinicians executing more than 1,000 clinical trials and protocols. During his academic journey, his research work primarily focused on drug delivery, cell transplantation, implantable bioreactors, and other innovative therapeutic modalities. He has contributed several firsts in the course of his career, including the first nanofluidic systems (1992), microchip-cell hybrid therapeutic implants (1995), silicon-based therapeutic particles (1998), nanostructured surfaces for proteomics and peptidomics (2005), multi-stage vectors for systemic therapy (2008), formulation of transport oncophysics (2011), and injectable nanoparticle generators (2016) for the therapy of lung and liver metastases of mammary carcinomas.

With his wife, Paola, after completing his sixth Houston Marathon, with his personal record, in 2016.

Dr. Ferrari earned his degree of Dottore in mathematics at the University of Padova, Italy (1985) and then completed M.S. (1987) and Ph.D. (1989) degrees in mechanical engineering at the University of California, Berkeley, while also serving (1988–1990) at the University of Udine in Italy as an assistant professor of theoretical and applied mechanics. He was appointed to the faculty of the University of California at Berkeley, where he served as an assistant and then tenured associate professor of materials science, civil engineering, and bioengineering (1991–1998). From 1999 to 2006, he served at Ohio State University as the Edgar Hendrickson Professor and Director of Biomedical Engineering and a professor of internal medicine, mechanical engineering, and materials science, as well as the associate vice president for health science technology and commercialization. While at Ohio State he also attended medical school (2002–2003). Before joining Houston Methodist Research Institute in 2010, he served as a tenured professor of nanotechnology and internal medicine at the University of Texas Health Science Center for four years (2006–2010), where he was the founding chairman of the first department of nanomedicine in any medical school. During his academic and industrial career, he has published more than 350 papers and seven books.

He is the inventor of more than 40 issued patents, with about 30 more pending in the United States and internationally. His personal career research and development portfolio as a principal investigator totals over $100 million, including support from the National Cancer Institute (NCI), National Institutes of Health, NASA, National Science Foundation, Defense Advanced Research Projects Agency, U.S. Department of Energy, the FDA, the state of Texas, the state of Ohio, and several private enterprises.

He was the recipient of the prestigious CRS Founder’s Award at the 38th Annual Meeting & Exposition in 2011. His contributions have received a variety of other accolades, including the Wallace H. Coulter Award for Biomedical Innovation and Entrepreneurship, the ETH Zürich Stodola Medal, the Blaise Pascal Medal in Biomedical Engineering from the European Academy of Sciences, and the Innovator Award from the Breast Cancer Research Program of the Department of Defense. He received the Robert Heinlein award for microgravity research, and his experiments have flown on the International Space Station. He holds honorary doctorates in electrical engineering and biotechnology from the University of Palermo and the University of Naples “Federico II,” respectively, and adjunct or visiting faculty positions at many prestigious academic institutions worldwide.

Q With an academic background spanning mathematics to mechanical engineering, what inspired you to join the field of biomedical nano- and microtechnology and make a significant impact in the field?

A Well, back in those days there wasn’t a “field” yet, just a few people here and there that were starting to see the opportunity for breakthroughs based on interdisciplinary perspectives. The word BioMEMS originated in my lab at Berkeley in the early 1990s, and the words nanotechnology and cancer had not been used in the same sentence just yet. I guess that’s another way to say how old I am getting! But, seriously now, the reason why I got started in this direction was that my wife, Marialuisa, got sick with cancer and died. I knew nothing about medicine, so the only thing I could bring to the fight against cancer was what I knew something about: microtechnology, which over time became nanotech, and some mathematical physics.

Q Do you still maintain an active research lab? What are some of the important projects you are involved in?

A Yes, I maintain a very active lab. I just could not be without a lab. I have passed on to some of my younger collaborators some of my research lines—and they are doing better with them than I ever could have! The nanofluidics work is now directed by Alessandro Grattoni, who has actually gotten it on the International Space Station, among other things. The bone regeneration platform, BioNanoScaffold, is worked on by an interdisciplinary team taking it to the clinic under the guidance of our chief spinal surgeon, Brad Weiner. Tony Hu is taking the proteomic nanotechnology in new, fully independent directions. There are about 100 people at Houston Methodist alone working on different variants of our multistage vector therapeutics. I remain mostly involved in novel designs, such as our new injectable nanoparticle generator drugs (iNPG-pDox), in close collaboration with Haifa Shen, Elvin Blanco, and Joy Wolfram. We recently published back-to-back papers in Nature Biotechnology. The last one showed for the first time in history that it is possible to completely cure lung and liver metastases in animal models—this we are taking to the clinic with a great sense of mission, since it could dramatically change the way we deal with cancer. We were recently awarded a multi-investigator U54 center by the NCI, to study how transport oncophysics and nanotechnology can lead to improvements in cancer immunotherapy. This is my third NCI center grant as a principal investigator, and seventh overall; I believe this shows our commitment to multidisciplinary teamwork.

Q What is the current and future focus of research and development at the Houston Methodist Research Institute?

A We focus on the clinical translation of transformational discoveries like the new drug for cancer metastases, or innovative ways to rehabilitate stroke patients even a long time after their injury, as well as methods to fully restore cardiac functions following ischemic damage. We have many teams on these and other cutting-edge problems in medicine, with a supra-disciplinary approach. We are a hospital, so we always put patients first, and that is why we are so focused on clinical translation. We build GMP facilities and perform GLP safety tests for the most promising of our discoveries. We even have an internal development fund that we use to support our most advanced programs, so that they can make it across the valleys of death of translation and into the clinic in the most efficient manner, safely, and as rapidly as possible.

Q Please tell us in brief about companies that you either founded or were involved with during their inception. Please give any words of wisdom for aspiring entrepreneurs.

A Entrepreneurship is essential for the process of translation of true innovation. I have started several companies; currently, I am on the board of Arrowhead Pharmaceuticals (NASDAQ: ARWR), which has among other products a potentially curative, nano-based, RNAi therapeutic against hepatitis B in phase II trials. I am also on the board of NanoMedical Systems. Academic entrepreneurship has become almost “mission impossible,” so my recommendations to academic investigators are these: Don’t try to be CEO. Don’t take money from folks that are unable to lead in the next round. Don’t start your company too soon (you will spend the rest of your life in zombified mode, or worse, if you do). Fully identify and derisk your product first! And make sure your lab is an institution that helps you do all of the above. Did I mention that we are always open for business, when it comes to recruiting extraordinary innovators?

Q Please elaborate on the current state of BioMEMS technology. What are some of the commercial successes with the technology?

A Frankly, diagnostic BioMEMS have not lived up to expectations, not because of the lack of technology excellence, but rather because of the financial dynamics of healthcare, where there is limited if any premium for screening and early detection, which is where BioMEMS offer the greatest advantages. And now we have to deal with the Theranos scandal, which will cast a negative light upon microfluidics and BioMEMS, in the impressionable eyes of the uninformed, although it has nothing to do with these fields and the underlying technology platforms developed by serious scientists that have given decades of their lives to these endeavors, with extraordinary successes. While Theranos, on the other hand…

Q Could you please highlight a few research articles from your work that you believe have made the most impact in the field?

A I will pick just articles that have gotten cover honors in Nature journals, from the many that we published there over the years.

This is the first article in a major journal anywhere that ties together nanotechnology and cancer:

Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 5: 161-171 (2005).

The following two articles demonstrate the first multi-stage delivery systems for systemic injection and highlight the importance of physics and geometry in the rational design of nanoparticles:

Tasciotti, E, Liu, X, Bhavane, R, Plant, K, Leonard, AD, Price, BK, Cheng, MM, Decuzzi, P, Tour, JM, Robertson, F, Ferrari, M. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nat. Nanotechnol. 3: 151-157 (2008).

Ferrari M. Nanogeometry: Beyond drug delivery. Nat. Nanotechnol. 3: 131-132 (2008).

By studying the transport properties of nanosystems inside cancers, we made a more general discovery: mass transport in cancer is truly different from its counterpart in healthy tissues, for all types of mass, including biological molecules, cells, conventional drugs, and so on. Based on this, I formulated the framework of transport oncophysics: cancer really is a proliferative disease of mass transport dysregulation, which occurs primarily because of pathologic evolution of the biological barriers inside the body. This opens up a whole world of opportunities for novel drug delivery systems!

Michor, F, Liphardt, J, Ferrari, M, Widom, J. What does physics have to do with cancer? Nat. Rev. Cancer 11: 657-670 (2011).

This last article could be the most important result I have ever worked with, for it provides the unprecedented opportunity to cure lung and liver metastases. These are the most prevalent cause of death in cancer.

Xu, R, Zhang, G, Deng, X, Mai, J, Segura-Ibarra, V, Wu, S, Shen, J, Liu, H, Hu, Z, Chen, L, Huang, Y, Koay, EK, Huang, Y, Liu, J, Ensor, JE, Blanco, E, Liu, X, Ferrari, M, Shen, H. An injectable nanoparticle generator enhances delivery of cancer therapeutics. Nat. Biotech. 34: 414-418 (2016).

Q Could you please highlight a few publications from other prominent researchers that you believe have made the most impact in the field of nanotechnology?

A Sure, with pleasure! In strict alphabetical order…

Mark E. Davis at Caltech developed CALAA-01, the first RNA-carrying nanoparticle to be evaluated in a clinical trial for solid cancers. This human trial involved systemic delivery of siRNA with a targeted delivery system to treat patients with metastatic melanoma.

Davis, ME, Zuckerman, JE, Choi, CHJ, Seligson, D, Tolcher, A, Alabi, CA, Yen, Y, Heidel, JD, Ribas, A. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464: 1067-1070 (2010).

Robert Langer is the maestro of biomaterials and drug delivery—and many other fields! Among his zillion exceptional contributions, here is perhaps the one I remember most fondly, since it struck me between the eyebrows like a bolt of lightning and really got my inspiration going in a way that shaped much of my work to follow.

Langer, R, Vacanti, J. Tissue engineering. Science 260(5110): 920-926 (1993).

Chad A. Mirkin is known for many inventions, including his development of nanoparticle-based biodiagnostics. Dip-pen nanolithography—which can be used to transfer molecules and materials to surfaces with sub-50 nm resolution to study nanoelectronics, surface assembly, cell-surface interactions, and catalysis—has been recognized in a 2012 special issue of National Geographic as one of the top 100 scientific discoveries that changed the world.

Piner, RD, Zhu, J, Xu, F, Hong, S, Mirkin, CA. Dip-pen nanolithography. Science 283(5402): 661-663 (1999).

Nicholas A. Peppas published numerous seminal papers. In particular, his publication entitled “Mechanisms of Solute Release from Porous Hydrophilic Polymers” helped set the groundwork for research in the development of microparticle delivery systems. Dr. Peppas also published the influential article “Opsonization, Biodistribution, and Pharmacokinetics of Polymeric Nanoparticles,” which contributed to the U.S. FDA approval of the covalent attachment of poly(ethylene glycol) (PEG) to drugs to improve their pharmacokinetic properties.

Korsmeyer, RW, Gurny, R, Doelker, E, Buri, P, Peppas, NA. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 15: 25-35 (1983).

Owens, DE, Peppas, NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307: 93-102 (2006).

George M. Whitesides has pioneered so many important areas, but I will just cite two of my favorites. His highly impactful manuscript “Molecular Self-Assembly and Nanochemistry: A Chemical Strategy for the Synthesis of Nanostructures” led to the development of low-cost diagnostics and tools for global health. In “Self-Assembly at All Scales” he introduced the notion of nested information systems and the communication within them—a crucial concept for nanotechnology and nanomedicine.

Whitesides, GM, Mathias, JP, Seto, CT. Molecular self-assembly and nanochemistry: A chemical strategy for the synthesis of nanostructures. Science 254(5036): 1312-1319 (1991).

Whitesides, GM, Grzybowski, B. Self-assembly at all scales. Science 295(5564): 2418-2421 (2002).

With his dog Camillo, volunteering at the ALS clinic at Houston Methodist Hospital.

Q Please tell us about some of the successful ventures that came out of nanotechnology research in the last two decades.

A Far and away the crown goes to the company that introduced Abraxane (paclitaxelvectoring albumin nanoparticles) to cancer clinics, Abraxis BioScience, which has since been acquired by Celgene. It was the first-ever blockbuster drug to emerge from the nano-world; most importantly, it was the first drug even to be approved by the FDA with a mechanism of action based on the transport properties! This really ushers in a brave new world.

Q Where do you see the science of nanotechnology heading from its current state in the future?

A I am not interested in nanotechnology per se; my interest is in serving patients. Thus, I hope that nanotechnology will disappear, in the sense that it will become so successfully pervasive in the clinic that there will be no need for special identifiers. Just the natural thing, merged into other natural components of new solutions for the age-old problems of cancer: early detection, screening, prevention, therapy of metastases, enhancement of quality of lives—and better access for all, through a massive reduction of prices for cancer diagnostics and treatment!

Q Please tell us about your hobbies. What are your favorite activities in free time?

A My life is fully dedicated to family, work, and community service. I don’t do “free time”—it is all woven into the same texture of life. I travel with my wife, Paola, and our five (grown-up!) kids. I volunteer at the hospital, sometimes play saxophone and write, but without any real successes to report…I like to run marathons and ultramarathons, and they are certainly more restful than a typical day at the office!