Who was voted among Top 20 Most Influential Medical Researchers? Michael Sheetz Was!

Nov 7, 2019 by

Michael F. Shaughnessy –

1) Professor Varela, we have to recognize one of the most influential medical researchers- currently teaching at the University of Texas in Galveston- Michael Sheetz- But we need some background- where was he born and educated?

Dr. Michael Patrick Sheetz is a world-renowned biochemist and cell biologist who is best known for his remarkable pioneering investigations in biomechanics and mechanobiology. In particular, he is an expert in the extracellular matrix machinery of the cell, especially in motor-based motility of cells and of organelles, especially those involving kinesin. Dr. Sheetz has been credited as a co-discoverer of kinesin. He is also an expert in the cell division-engaging protein called dynein, plus muscle cell biology involving actin and myosin and of the membrane-cytoskeleton adhesion system. One of his famous discoveries has to do with the use of so-called “optical tweezers” to manipulate and measure the forces associated with cell movement and the activity of proteins like kinesin. His body of scientific research relates directly to the biomedical sciences.

Dr. Sheetz was born on the 11th day of December in the year 1946. He took his undergraduate degree in 1968 at a private liberal arts-based institution called Albion College, which is located in the town of Albion, Michigan, in the U.S. He took his Ph.D. degree in 1972 from the California Institute of Technology, which is in Pasadena, CA, in the U.S.

2) He pioneered mechanobiology and biomechanics–For the layperson or student- how would you summarize these two areas?

Mechanobiology is a burgeoning and essential new field that combines the biological sciences with those of physics and engineering. The area is concerned with examining biological systems from a mechanical perspective, such as the physical forces involved in the physiology of growing, developing, and differentiating cells and tissues. As such, mechanobiology focuses on the physical properties that control the biological behavior of living cells and tissues.

One important sub-field of mechanobiology is referred to as mechanotransduction. Here, the cells detect outside stimuli and then respond to such stimulation by converting the external signals into specific physiological processes, which, in turn, conduct a behavioral response in the cells. The method of mechanotransduction involves first a so-called mechanocoupling system. This system transduces mechanical forces into cellular sensory signals via a mechanism that detects the individual messages. Next, a biochemical-based coupling system takes over. Here, the method involves converting the mechanical signal into a biochemistry-based reaction for the purpose of influencing a cellular behavior, such as turning on a gene to produce a specific protein. The mechanotransduction process also involves communicating the message from the cells that detected the signal onto other cells, which can then respond with the desired behavior.

Biomechanics is another vast field of scientific study. It deals with exploring the structure and function of biological systems from a physical-mechanical perspective. The area also explores the movement of biological systems, such as organelles, cells, tissues, and organisms. The discipline focuses on the mechanics of these living systems.

There are many different aspects of biomechanics. One of these points includes kinesiology, which studies movements of the body from physiological, mechanical, and dynamic perspectives. Another element of biomechanics is the control of tissue behavior based on the nervous system. Biomechanics also involves sports medicine, in which orthopedics and therapy are carefully examined. One exciting sub-field is referred to as forensic biomechanics, which includes the investigation of accidents using biomechanical engineering to determine the causes of injuries.

3)  His research focuses on cell motility, motor molecules, and integrin-cytoskeleton interactions. Can you tell us why each of these are important?

Cell motility refers to the migrations of organelles, cells, and tissues within the body, such as dividing healthy cells, muscle fibers, growing cancer cells, and bacteria. Motor molecules are generally proteins that produce the movements of the organelles, growing live cells, and tissues, and they then function within cellular structures to assemble the cells and tissues in the body. Such motor proteins can use biological energy to generate forces and motions of the cells or living tissue masses within the individual.

The integrin-cytoskeleton refers to the protein called integrin and its association with structures inside of the cell, called the cytoskeleton. The internal cytoskeleton is composed of smaller proteins called filaments and tubules, and they can serve to determine the shape and integrity of cells. The integrin molecules function to connect the cytoskeleton to the extracellular matrix, a substance that resides outside of cells. The integrin-cytoskeleton axis participates in the junctions between neighboring cells as sort of a cellular glue, keeping cells stuck together to form larger masses and tissues. The integrin-cytoskeleton axis also participates in cell growth and helps such cells to survive. These cell components often work by signaling other cells to aid in these functions.

The integrins have many essential functions in cells. For instance, in addition to attaching a live cell to a matrix, the integrins also participate in cell signaling mechanisms to modulate cellular behaviors along these matrices. When matrix parts bind to integrins of cells, they form integrin clusters to initiate assemblages of cell-matrix junctions, further triggering cells to bind other arrays, and then grow and become motile.

Integrins function to connect a cell with another cell, forming so-called cell-cell junctions, which then create larger assemblages of cellular masses. These cell-cell connections respond to mechanical forces by recruiting additional integrins to accommodate the stresses induced by the applied forces. Thus, the integrins that are associated with the cell-matrix junctions can perform the processes involved in mechanotransduction.

Integrin molecules also work in the membranes of cells that are migrating along a substratum to form so-called focal adhesions, upon which the proteins actin and myosin function to accommodate cell crawling. Integrin uses adaptors connected to the actin that is located within the cytoskeleton of the cell to bind the substratum, permitting myosin to serve as a force transmitter so that actin filaments can grow longer bringing a protruding living cell with it. The protrusion formed by the growing actin polymers confers the cell migration along the substratum.

Interestingly, bacteria can exploit integrin on human and animal cells to bind and initiate bacterial entry into such cells by reorienting the actin polymers to do so. This mechanism is called zippering because integrin is used to help zipper actin molecules together in long chains in order to mediate phagocytosis of bacteria. But in this case, the bacterial entry occurs in cells which are not equipped to kill the bacteria, and they can wreak havoc inside such non-phagocytic cells, causing damage and pathogenesis.

4) How are they linked to cancer?

Cancer cells often grow at a phenomenal rate, and as quick growers, they need to assemble new structures that permit this rapid pace of growth. For example, they may need cell division machinery, like DNA synthesis, or mitotic mechanisms, in order to mediate the separation of newly made DNA into the freshly made tumor cells. As tumor and cancer cells grow, sometimes the extracellular matrix machinery is re-shaped or even sacrificed to permit their rapid growth rates or to permit metastasis.

Tumor and cancer cells also exhibit a growth behavior that involves cytoskeleton modulation in which their mechanosensory machinery is abnormal. Therefore, such tumor and cancer cells have broken mechanosensory systems that lack the ability to sense neighboring cells or substratum. Whereas healthy cells can detect their neighbors or substrate and thus stop growing as necessary, tumor and cancer cells are under no such mechanosensory control. Tumor masses may then overgrow their micro-environments, possibly leading to malfunction of such cells, tissues, or organs and consequently causing cancerous tumors.

Cancer cells are abnormal in their motility behaviors. For instance, cancers can, on occasion, become motile, breaking off of the larger original tumor mass and migrating to other locations in the body to initiate new tumor masses elsewhere. The term that’s used to describe this type of tumor cell mobility and growth is metastasis. A great deal of biomedical science research is focused on these cellular systems as targets for modulation in order to curtail tumor metastasis.

5) Mechanosensing in myofibrillogenesis- why is this important, and what does it mean?

In heart muscle cells, called cardiomyocytes, disease can occur in which their extracellular matrix composition is altered, leading to abnormal cross-linking and stiffening of the heart cells’ so-called microenvironments. Furthermore, damage from a heart attack and cardiomyopathy, a condition in which the heart has to work with a more significant amount of work in order to pump blood through the circulatory pathway, leads to the formation of scar tissue called cardiac fibrosis. This abnormal condition influences the behavior of the heart muscle cells.

In heart cells, a protein called talin serves as a so-called mechanosensitive adaptor, which senses muscle oscillations and the tensions generated during their contractions. The mechanosensing system can detect differences inherent in healthy cardiac muscle versus cardiac fibrosis.

Myofibrillogenesis refers to the generation of so-called myofibrils of the heart. These myofibrils function to contract and relax during heart contractions for blood pumping. During cardiac muscle cell development, early embryonic cardiomyocytes lack a specific stiffness and thus, lack tension. The talin-based mechanosensory system can even distinguish between these younger muscle cells versus more mature heart cells, based on their inherent stiffness properties.

6) Apparently, he has been studying how cells differentiate and regenerate tissues or, sadly, metastasize. Why are each of these important?

The cellular differentiation process involves the conversion of a non-functional primordial stem cell into a specialized cell with a specific biological role to play. Part of the character of stem cells is their immense capacity to differentiate into specialized cells, a property called pluripotency.

Dr. Sheetz and his colleagues studied cellular differentiation in his laboratory, starting in the mid-1990s when they examined developing and growing nerves. They found that integrin played an essential role in the nerve growth cone emergence by interacting with the neuronal cytoskeleton. One exciting finding was their discovery that during axonal growth cone emergence, specific mechanical forces were generated. As these forces came about, individual players were identified in the process. One of these players is called vinculin, which is found in the focal adhesion segments of the cells and which binds to the protein called talin. During the growth cone movement, the talin protein is actually stretched, which then exposes vinculin binding sites for its recruitment to the focal adhesion sites.

The process of regeneration refers to the healing manner of biological systems. Often, the healing process repairs damaged tissue by replacing the wounded tissue with fibrous extracellular matrix material that is not as functionally or structurally as good as the original tissue that it replaced. Dr. Sheetz developed an interest in this area shortly after the turn of the 21st century.

Some of the first investigations included his analysis of myosin assembly and its changes during the closure of epithelial tissue wounds. They developed a technique in which they used lasers to damage cellular layers of kidney cells, and they then measured the activities of actin and myosin. When complexed together, the actin and myosin connections are referred to as actomyosin. The Sheetz team found that the actomyosin machine attached to the tight junctions between the damaged epithelial cells forming a ring made by the myosin portion of the actomyosin during the closing up of the wound. They also strongly implicated the role of another enzyme called Rho-kinase in placing the cellular machine in its proper location and turning it on.

As I mentioned earlier, metastasis involves the breakage of a tiny portion of a larger tumor mass and the movement of these tumor pieces to different locations in the body where they can establish new tumor masses. Often metastasis is the most undesirable outcome for a patient who has a tumor. A metastatic tumor can interfere with the normal functioning of the body and make therapies difficult. Dr. Sheetz began studies of metastasis in the early 2000s. His laboratory focused on the rates of tumor movements and the forces involved in the tumor traction properties. He found that both of these processes worked by distinctive cellular mechanisms.

Next, he focused on the role of integrin. He discovered that integrin moved laterally within the membranes of tumor cells and clustered together during cellular migrations. His team then found out that the clustered integrins prompted actin molecules to assemble together, which then permitted myosin to act upon the actin assembly to mediate the generation of contractile forces.

These newly produced forces, in turn, stimulated the activation of a so-called signal transduction system call Src kinase, which then mediated the cell movement along in new directions. The clustered formation of integrin molecules also played a role in bringing together other players, such as proteins like talin, and paxillin, or even vinculin. Dr. Sheetz’s work clearly established the functional importance of integrin in the chemistry and biology of the cell.

7) The Cell as a Machine– seems to be one of the most provocative books and essential books of the last 10 years- What do you know about the book?

Dr. Sheetz published The Cell as a Machine in 2018, having co-authored the book with Dr. Hanry Yu, who has held principal investigator positions at the National University of Singapore at Singapore and at the prestigious Massachusetts Institute of Technology, in Cambridge, the U.S.

Their book covers a vast array of topics pertaining to the chemistry and biology of the cell from an energy-transducing, mechanical perspective. That is, Drs. Sheetz and Yu view the cell as a specialized living device, complete with an extensive assortment of biological gadgets for implementing its enormous collection of functions necessary for life.

Living cells are remarkable entities, and as a cellome, marvelous functions can be accomplished by their mind-boggling pieces of machinery. The insides of the cells that belong to the living cellome harbor sub-structures that are considered tiny technologies of their own.

Such sub-cellular apparatuses include those for mediating the various developmental stages of a cell, the multiplication of the cell, its evolution, and the integration of these disparate systems into a collection of sensory mechanisms that regulate its adaptable behaviors. The book also addresses how a cell manages to maintain and energize its mechanical functions and then discusses the players involved in the design of the cellular machine. The authors further survey the various pieces of machinery of the enclosed cell from the standpoint of their molecular structures.

The book covers how a cell senses its outside environment and then communicates this external data to its internal cellular workings in order to make decisions on how to respond appropriately. The publication also includes how cells die and the associated ramifications. Lastly, the authors deal with topics pertaining to the multiple ways in which the cell malfunctions, such as in disease, especially in the case of cancer. The book is beautifully written, and, thus, I believe it is definitively geared to become an enduring classic.

8) Back in 2012- Sheetz shared the very prestigious Albert Lasker Basic Medical Research Award. First of all, who was Albert Lasker, and what did Sheetz win the award for?

Indeed, the accolade is widely deemed as a sort of preamble to the Nobel. Approximately 50% of the Albert Lasker Basic Medical Research Award beneficiaries go on to acquire the Nobel, especially in the physiology or medicine category. The Lasker awards are considered an extremely prestigious honor, and it is bestowed to individuals who make outstanding contributions in any one of several fields, such as in biology, clinical medicine, human health, and education. The Lasker Awards were established by Mary Woodward Lasker and Albert Davis Lasker in 1945. Albert Lasker was a successful advertising business person.

Dr. Sheetz gladly shared the honor with colleagues, Drs. James Spudich and Ronald Vale, the latter of whom I had had the great pleasure of meeting briefly at the MBL in the summer of 1991 at Woods Hole, MA. Each of these great investigators have collaborated with each other in a considerable number of scientific projects. Dr. Spudich is well known amongst cell biologists, biochemists, and biomedical scientists for his works dealing with myosin and actin in muscle. Dr. Vale is widely known for his works concerning axon movement and co-discovering kinesin with Dr. Sheetz and others. In fact, Drs. Vale and Sheetz coined the term kinesin. Dr. Vale also determined the crystal structure of the motor domain of kinesin in 1996, publishing the work in Nature.

The trio of investigators received their Lasker honors together for having made outstanding scientific discoveries pertaining to motor proteins that make up the internal cytoskeleton, energized cellular machines that transport organellar-based cargoes along microtubules, for the contractile behavior of actin and myosin motors within the muscles and especially for their tremendous contributions towards the mechanisms involved in the movements of cells. Their scientific achievements are exceptionally relevant in the field of cancer biology.

As recipients of the Lasker Award, Dr. Sheetz and his two honorees are in good company. Other Lasker Laureates include many of the investigators we have considered in our book-writing collaborations. Such luminaries include Drs. Tu Youyou (2011), John Gurdon (2009), Barry Marshall (1995), Stanley Prusiner (1994), Nancy Wexler (1993), Leroy Hood (1987), Rita Levi-Montalcini (1986), Joseph Goldstein (1985), César Milstein (1984), Harold Varmus (1982), Frederick Sanger (1979), Rosalyn Yalow (1976), Gobind Khorana (1968), Albert Sabin (1965), Renato Dulbecco (1964), Francis Crick (1960), James Watson (1960), Alfred Hershey (1958), Peyton Rous (1958), Jonas Salk (1956), John F. Enders (1954), Hans Krebs (1953), Selman Waksman (1948), Carl Cori (1946), and Karl Landsteiner (1946), to name a few!

9) What have I neglected to ask about this scientist who is still active and researching away?

Indeed, as of this writing, Dr. Sheetz is 75 years old and still a busy biomedical investigator. He recently moved to Galveston, TX, in the U.S., in 2019, to become a full professor at the Medical Branch of the University of Texas at the Molecular MechanoMedicine Program. His position is sponsored as the Robert A. Welch distinguished chair in chemistry. Prior to this, Dr. Sheetz had been at Columbia University in New York, U.S., since 1990. Before Columbia, he had been living in Missouri, where he was at Washington University in St. Louis, having arrived there in 1985. He has also held adjacent positions at the Singapore National University in the Mechanobiology Institute, starting in 2010, and at Duke University Medical Center in Durham, North Carolina, in the U.S., beginning in the early 1990s.

I had the fortune of having met Dr. Sheetz, however briefly, during the summer of 1991, at the famous Marine Biological Laboratory, located in Woods Hole, Massachusetts, when I was a graduate student participating in summer research as a young ASCB fellow. During our brief conversation, Dr. Sheetz was a totally good-natured person. I believe then that he had previously injured his leg and was hobbling around all summer with crutches and a cast around his leg. It did not seem to slow him down in the least.

I also recall that summer that his MBL seminar was fascinating. Dr. Sheetz spoke about the beautiful molecular machines, like dynein or kinesin, and the translocation of organelles along intracellular protein microtubules within axons. It had been the first time I had heard about the concept of the inner workings of a cell operating like an energized motor machine!

It had also been the very first time that I had ever heard about optical tweezers! He had shown those of us in the audience that day about his amazing images from his microscope of cells or smaller sub-cellular particles that were ensnared within a so-called single-beam optical gradient trap system, or optical tweezers! We watched in amazement how he had managed to manipulate an individual cell in its trap, at will!

10) Blown away- are the only words I can use to describe Michael Sheetz’s work as documented on Research Gate, which indicates: 464 research works with 38089 citations and 2,514 reads. Is there any single book or article which stands out in your mind?

Indeed, Dr. Sheetz’s written collection of scientific literature is vast. He has delivered an astonishing wealth of biological literature to the field of biomedical science, and in particular, to cell biology as well as the fields he established, biomechanics and mechanobiology.

It is my firm conviction that his remarkable citation record is a tribute to the relevance of his scientific work. It is quite clear that his work is tremendously appreciated by an enormous magnitude of biomedical investigators. In fact, I surmise that the article you referenced above regarding Dr. Sheetz, having been listed in 2013 as a member of the top-twenty most influential biomedical scientists in the world, is a testament to the immense popularity of his written works.

Dr. Sheetz is in an extraordinary esprit de corps. In the same top-twenty list, Dr. Sheetz is connected with other great scientists featured in our own books, including the present one. Such scientific luminaries include Drs. Tim Hunt, James Watson, Harold Varmus, Gerald Edelman, Tu Youyou, and the inimitable Sir John B. Gurdon, taking the number one spot on the list.

A few years after his remarkable MBL seminar during the summer of 1991, I had read with wonder his newsworthy publication in my newly delivered issue of Science in April of 1993. In the new paper, he revealed how he had trapped the kinesin mechanomotor within the clutches of his optical tweezer apparatus. I was astonished! With a single molecule of the famous kinesin caught in the trap, he had actually measured the forces involved to the pico-Newton level for the mechanical activity of a single motor protein! The mechanical force findings for the individual kinesin motor had direct applications towards the eventual construction of behavioral models for tissue contraction, such as those seen in muscles, developing cells, neuronal axon cone growth, and cancer cell movements.

For interested readers- Here is Prof. Michael Sheetz speaking about his research and interests:

Interview with Michael Sheetz – MBI and DBS, NUS and Columbia U. – YouTube www.youtube.com Michael Sheetz talks about his research program.
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