Mechanobiology Institute, Singapore

PROFESSOR MICHAEL SHEETZ PROFESSOR

A moving story

Distinguished mechanobiologist Professor Michael Sheetz describes the research that has made him an eminent fi gure in his fi eld, as well as discussing the fi ner points of his more recent work towards building an innovative research institute

movements and laser tweezers led us How important is collaboration to MBI? to look at membrane diffusion again, and subsequently matrix-cytoskeleton We strongly believe in collaborations where interactions. Our current interests lie in the there is good complementarity. For example, mechanical signalling that occurs in matrix- we have a major collaboration with the Italian cell adhesions. Foundation for Cancer Research Institute of Molecular Oncology, a leading cancer research Can you elaborate on the successes for institute based in Milan, Italy, where they have which you were awarded the 2012 Albert experience in cancer biology and we have an Lasker Basic Medical Research Award? interest in understanding how the alterations in cancer cells affect their mechanical Spudich, Vale and I were awarded the communication with their environment and Albert Lasker Basic Medical Research lead to inappropriate growth. In the case of Award for research that developed in vitro L’Oreal – one of our main partners – they have assays for myosin and led to the discovery considerable expertise in skin biology and we of kinesin. It was a very great honour to have the mechanical tools to determine how receive the award for this area of research. stretching forces and other manipulations can Many others contributed to the discovery, alter basic biological parameters. and we feel that it is important to promote To begin, could you brieﬂ y outline your science in this fi eld as a consequence of Most of our partnerships are based at the research career to date? the award. single investigator level, and we encourage our investigators to bring collaborators to My graduate work was on the nuclear You are Director of the Mechanobiology Singapore to use our facilities and get things magnetic resonance of membranes and Institute (MBI) in Singapore. What are done. This helps both us and the collaborators. lipids and emphasised the importance the main aims and objectives of MBI? of membrane curvature on the physical How are you working towards achieving Can you provide an insight into properties of lipids. That investigation was these goals? some of your graduate programme’s then followed by a postdoctoral position success stories? with Professor Seymour Jonathan Singer The main objective of MBI is to bring on membrane shape in red blood cells together scientists and engineers with Our graduate programme has been a major through the bilayer couple hypothesis. diverse backgrounds in order to develop new success and is becoming more competitive My independent career focused initially approaches and knowledge around the most for admission over time as people learn on control mechanisms for the lateral important aspects of mechanobiology. We more about the MBI programme. One of diffusion of membrane glycoproteins via have an open lab environment, with open our faculty has described it in terms of the cytoskeletal corrals. During a sabbatical access to central facilities in microscopy, maturity that comes from interacting with with Professor James Spudich, I developed micro- and nanofabrication, cloning and many different laboratory environments an in vitro motility assay for myosin that protein expression, as well as computational and being forced to explain your approach subsequently stimulated a collaboration support. This is all to encourage students and to people outside your research area, who with Professor Ron Vale. In concert postdocs from diverse backgrounds to share will question your basic assumptions. That with Vale, who was a graduate student ideas and develop innovative approaches learning process is very important and occurs at that time, I looked for the vesicular to important biological questions. MBI much faster in an open lab environment than transport motor in squid axoplasm – work has so far done very well in attracting an in an isolated single lab. We also encourage that eventually led to the discovery of international group of excellent students and the students to use whatever tools they need kinesin. The analysis of motor mechanics postdocs as well as faculty, and many new to solve a problem rather than relying on the using super-resolution tracking of bead projects are now being published. tools of their own lab alone. WWW.INTERNATIONALINNOVATION.COM 27 PROFESSOR MICHAEL SHEETZ Mechanicell

The Mechanobiology Institute established at the National University of Singapore in 2009 supports cutting-edge research in this emerging field, being responsible for a number of interesting discoveries and important recent advances

IN THE SECOND half of the 20th Century, the AN INNOVATIVE INSTITUTE and to affect training with an innovative life sciences have undergone what might be philosophy. “The general concept is to provide described as a molecular biology revolution. Although mechanobiology is an emerging field, excellent facilities for all investigators in an open At the interface of biology and chemistry, the concepts behind it are by no means new; not lab environment that encourages discussion molecular biology has helped to reveal the only has it long been recognised that mechanical of problems by researchers with different biochemical pathways that underlie many of stimulation can play a role in many forms of backgrounds,” he explains. life’s essential processes, with concomitant medical treatment, but the mechanical aspects advances in genetics, proteomics and of cells have also been of interest to biologists for MOLECULAR INSIGHTS medicine. Bolstered also by technological some time. It is only relatively recently, however, innovation, scientists have expanded the that the advancement of biological imaging and Perhaps Sheetz’s best known achievement is understanding of development, physiology nanotechnology have reached a tipping point that which won him the Albert Lasker Basic and disease in many species through the that allows mechanobiologists to examine the Medical Research Award in 2012 – his landmark chemical relationships they have observed in pathways of mechanotransduction – the process discovery of the molecular motor kinesin, and cells and tissues. whereby mechanical force is translated into the development of methods for studying this chemical signals – on a molecular level. In light and other cytoskeletal motor proteins. The basic Biochemistry is certainly a valuable lens of these new developments, it seems that now is purpose of these motor proteins is to convert through which biological processes can the right time to begin building infrastructure in chemical energy into mechanical work, and be viewed, but while it has made a great this field – and, in particular, to begin training the transport certain cargo such as macromolecules contribution to fields like medicine, there next generation of interdisciplinary scientists to or chromosomes from one part of the cell to are other equally potent approaches waiting tackle future challenges. another. Kinesin does this by ‘walking’ along a to be exploited. In the emergent field of particular component of the cytoskeleton, the mechanobiology, for example, scientists Professor Michael Sheetz, Director of the National microtubule, and dragging behind it whatever examine how mechanical rather than University of Singapore’s Mechanobiology intracellular components are too large as chemical aspects of biology have an impact on Institute (MBI), is a pioneer in this field. A complexes to be transported by diffusion. life processes. The biophysics of interactions distinguished research scientist, Sheetz has between cells and the intercellular matrix, won a number of awards for his significant CONTINUED CONTRIBUTIONS as well as between neighbouring cells, not contributions to the scientific understanding of only governs the development of organs mechanical processes in biology – but perhaps This groundbreaking work was conducted in and the organisms that they form, but also his greatest accomplishment has been his the early 1980s, and since then Sheetz has controls the parameters of many biochemical success in leadership of MBI. Established in not only continued to carry out productive reactions, playing a role in the onset of cancer, 2009, this facility was designed to provide all research, but has also played a leading role in the heart disease and ageing. the necessary resources for effective research, establishment of an important research institute.

28 INTERNATIONAL INNOVATION INTELLIGENCE MECHANOBIOLOGY INSTITUTE, The Mechanobiology Institute has developed into a fully NATIONAL UNIVERSITY OF SINGAPORE operational multidisciplinary open lab housing around 200 OBJECTIVES To study how mechanical forces are investigators led by 20 principal investigators controlled in biological systems at a molecular, cellular and tissue level, and MBI was initially set up with block funding from proteins are released from specifi c pathogenicity translate these fi ndings to understanding Singapore’s National Research Foundation, sites and fi nd that infection involves sensing the disease progression. which provided two-thirds of the projected cost host environment through alterations in the KEY COLLABORATORS of the Institute over its fi rst 10 years of operation. folding of DNA. These elaborate systems for Within three years, the facility had developed producing pathogenic bacteria are being exploited National University of Singapore, into a fully operational multidisciplinary open to develop new antibacterials that alter the Faculty of Science • National University lab housing around 200 investigators led by mechanics of DNA. Thus, the MBI is developing of Singapore, Faculty of Engineering • 20 principal investigators (PIs). “We wanted to a new area of mechanopharmacology, or small National University of Singapore, Yong create an environment in which investigators molecules that alter cellular mechanochemistry Loo Lin School of Medicine • Institute could solve scientifi c problems – not build lab and function. of Molecular and Cell Biology (IMCB), empires, companies or clinics,” Sheetz reﬂ ects. Agency for Science, Technology and A number of exciting technologies are also at Research (A*STAR), Singapore • Italian An important part of this process has been the various stages of development within the MBI, foundation for Cancer Research (FIRC), implementation of an open lab environment, including the celebrated CTChip®, a device that Institute of Molecular Oncology (IFOM), whereby researchers from different projects and can retrieve circulating tumour cells in blood. Italy • Le Centre national de la recherche disciplines sit side-by-side, and desks are assigned Another MBI project led by Dr Benoit Ladoux, scientiﬁ que (CNRS), France • National on a lottery basis. Although many of the PIs were investigates the mechanisms of wound healing. Centre for Biological Science (NCBS), initially resistant to this idea, in time an integrated In a series of experiments using epithelial cells, India • L’Oréal, France and Singapore approach has led to increased interdisciplinary researchers examined how cell monolayers FUNDING collaboration and a heightened sense of respond to being wounded, colonise surfaces, community – as well as to the acceleration of the and employ mechanical measures to accomplish National Research Foundation, Singapore cutting-edge projects being undertaken there. both functions. Interestingly, the team was Ministry of Education, Singapore responsible for discovering a previously unknown process that cells use to heal a wound: by SUCCESS STORIES National University of Singapore supporting other cells. When cells close in to seal At a very basic level, MBI researchers are analysing a wound, they pull at the cells around and below CONTACT how 2 mm of bacterial DNA is packaged into a them – and the response of the supporting cells Professor Michael Sheetz 1 mm bacterium such that the proteins needed contributes to the healing process. Director for bacterial infection can be produced when the bacterium senses the host. Dr Jie Yan, a Projects such as these, which deal with Mechanobiology Institute, Singapore physicist, and Dr Linda Kenney, a microbiologist, cancer and wound healing, are examples of National University of Singapore are collaborating to determine how DNA-binding mechanobiological research with a clear medical 5A Engineering Drive 1 impact – but such studies need not focus on Singapore 117411 actual disease to be relevant. In another branch T +65 9827 2429 of research, MBI scientists are collaborating E [email protected] with medical groups in Singapore and L’Oréal to improve the basic scientifi c understanding of www.mbi.nus.edu.sg how skin ages, thins and wrinkles, and the role that mechanical processes play here. “It is an PROFESSOR MICHAEL SHEETZ received his ideal system to study because of the availability PhD (Chemistry) in 1972 from the California of patient samples and the cells can be grown Institute of Technology and postdoctoral readily in vitro,” Sheetz enthuses – and what training at Professor Seymour Jonathan is more, joining forces with the local medical Singer’s laboratory at the University of community and L’Oréal opens up access to new California, San Diego, USA. In 1982 he, resources and expertise. together with Professor James Spudich and then graduate student Professor Ron Vale, developed the fi rst quantitative in vitro TRENDSETTING motility assay and the discovery of kinesin. Sheetz and his colleagues are hopeful that the For this work, the trio received the 2012 successes of their new institute will encourage Albert Lasker Basic Medical Research Award. facilities in other fi elds to adopt a similar approach, increasing the focus on innovative Sheetz is now Director and Distinguished experimentation in science across the board Professor at the Mechanobiology Institute, and presenting a different kind of opportunity National University of Singapore, to young investigators. In Singapore, the subject and Emeritus Professor at Columbia of the next fi ve-year budget and the level of University, USA. support it will provide to basic science is a topic of current debate – but Sheetz remains confi dent that MBI will continue to provide an excellent and competitive environment for students and postdoctoral fellows for some years to come.