Microscopes at Mayo Clinic
Volume 8, Issue 1
Editor's note: The following contribution is an original work by molecular biologist Jeffrey L. Salisbury, Ph.D., head of Mayo Clinic's Microscopy and Cell Analysis Core.
Jeffrey Salisbury, Ph.D., Mayo Clinic's maven of microscopy.
Hermes, the messenger, also the Greek god of invention, with a microscope on the doors of the Plummer Building at Mayo Clinic.
Louis Wilson, M.D., father of modern laboratory medicine at Mayo Clinic.
"Modern medicine may be said to have begun with the microscope."
— Dr. William J. Mayo
According to the history Mayo Roots by Clark Nelson, pioneer physician William Worrall Mayo received his early formal training at the La Porte Medical College in Greencastle, Ind., in 1850. While there, he took a course on pathology and physiology that included the "use by nearly 100 students of a single microscope imported from England at great expense." This early exposure to the microscope had a lasting affect on Dr. W.W. Mayo's later practice and was further enhanced by the collection of books on microscopy that made up a substantial portion of his medical library.
His son, William James Mayo, recounted a legendary story from his youth to the American Medical Association in a talk in Detroit in June 1930. He was 10 at the time, and Charles, his brother, was 6.
The story unfolded in 1871, when his father had returned from several months of study at Bellevue Hospital in New York City. At breakfast, W.W. Mayo declared, "I saw in New York a microscope made in Germany, and I would like so much if I could have one like that. But I have spent all the money." He spoke of the wonders that could be seen with this microscope, and he proposed to the family that he mortgage the house for $600 to purchase it. So, with the consent of his wife, Louise Abigail, he did. By popular accounts, it took nearly 10 years to pay off the lean.
This early history attests to an extraordinary interest in microscopy that not only endured but also played an important part in the education of William and Charlie. Dr. Will made this point clear in a speech to the American Medical Association in 1930, when he said, "We understood then that what could be seen would be the truth. ... That microscope (the one purchased though the mortgage) ... is one of the prized instruments in our clinic today."
Indeed, this notion was so deeply ingrained that depictions of microscopes became a common feature of architectural inlays, sculptures, stained glass panels, paintings and museum pieces throughout the Mayo Clinic campus in Rochester, Minn.
Mayo Clinic develops a method for rapid microscopic diagnosis
Pathologist Dr. Louis Wilson joined the practice in 1905 to develop Mayo Clinic's research laboratories and became the first director of what is now called the Mayo School of Graduate Medical Education. It was Dr. Wilson who answered the call from the Mayo brothers to develop a rapid method to assess surgical specimens before the procedures were completed in the operating room. He developed a technique to rapidly freeze surgical tissues with carbon dioxide and to cut sections using a specially modified freezing microtome. After the material was stained with polychrome methylene blue, a pathologist examined it under the microscope and made the critical diagnosis, entering the results in the patient's record before he or she left the recovery room.
A century later, this technique is performed on 80 to 100 cases daily at the two Mayo Clinic hospitals in Rochester, and it has been adapted by other leading medical institutions throughout the world.
The electron microscope comes to Mayo Clinic
Stained glass window from the Plummer Building depicting microscopy.
Detail of exterior wall of the Plummer Building showing Dr. Plummer peering into a microscope.
Mayo Clinic physician, researcher and artist Dr. Hugh Butt first learned of the advances brought about by the electron microscope as an NIH National Advisory Cancer Board member in the early 1950s. He shared his enthusiasm in an equipment proposal to the Mayo Clinic board of governors: "You're talking about electron microscopes and organelles of the cell that I've never seen before. ... Only a few academic institutions have these machines. They magnify things hundreds of thousands of times. It is just a different world ... from the ordinary optical microscope, which magnified a few hundred times, but now you are talking about thousands. A simple cell becomes the size of a football field."
Initially, the board rejected Dr. Butt's proposal because of lack of interest among practicing pathologists on staff. However, within a few years the value of the electron microscope became more broadly recognized in the diagnosis of several human diseases. The board decision was reversed, and Mayo Clinic obtained its first electron microscope, an RCA EMU-3, the only instrument manufactured in the United States available at the time.
Pathologist Dr. Arnold Brown made the first electron micrograph at Mayo Clinic of a thin section of liver on an RCA EMU-3 on June 12, 1959. By the end of that year, 310 micrographs were recorded. Today, Mayo Clinic's Microscopy and Cell Analysis Core operates four state-of-the-art electron microscopes and is one of the largest in the country for imaging clinical and research samples, making more than 140,000 electron micrographs in the past year.
State-of-the-art microscopy methods
A freeze frame of moving mitochondria.
A cancer cell dividing.
Microscopes of many different types and capabilities can be found throughout Mayo Clinic — in operating rooms, offices, laboratories and classrooms. Microsurgery plays a broad role, allowing surgical repair of fine-tissue damage and vascular tissue. Mayo Clinic's Department of Laboratory Medicine and Pathology houses hundreds of microscopes, some of which have multiple headpieces so that six or more fellows or medical students can follow the observation of a senior pathologist.
In the research arena, new microscopy techniques give Mayo Clinic investigators an extraordinary look into the inner workings of cells and tissues.
For example, neurology researcher Eugenia (Jania) Trushina, Ph.D., and her colleagues recently published an important study on cellular defects from a mouse model of Alzheimer's disease. They discovered that mitochondria, the cell's energy powerhouse, showed altered structure and abnormal movement in neurons of mice carrying the defective human proteins of Alzheimer's disease. They used a microscopy method to analyze movements of many different mitochondria simultaneously.
Computer processing displayed mitochondrial movement (see mitochondria image) as parallel tracks that either remain relatively straight (red in the image), representing mitochondria that were not moving, or making zigzag paths (green in the image), while the diagonal (zigzag) lines represent mitochondria that are moving. By analysis of the angle of these zigzag tracks, the frequency of stops and starts and mitochondrial velocity can be measured. Using these methods, the Trushina team is testing drugs that revitalize mitochondrial movement in the mice and reverse the devastating consequences of the disease.
A second example is from the author's laboratory in collaboration with Antonio B. D Assoro, M.D., Ph.D., and Wilma L. Lingle, Ph.D. In the lab, a human cancer cell (see cancer cell image) is caught in the act of dividing, with DNA of the daughter cell nuclei labeled blue, centrioles labeled yellow-green and microtubules labeled red.
Finally, three new optical microscopes are being installed in the research Microscopy Core of Mayo Clinic's Guggenheim Building in Rochester. Two are sophisticated laser-powered instruments that have the capacity to excite fluorescent molecules and image deep within animal tissues, allowing researchers to view cells within their normal tissue environment for extended periods of time. Using these instruments, investigators will be able to examine real-time cellular processes in living animals and to study complex cellular responses in neurons in the brain, cardiac muscle cells in the beating heart and cancer cells in tumors.
The third microscope — purchased with a grant from the Minnesota Partnership for Biotechnology and Medical Genomics — will be used by the Microscopy and Cell Analysis Core at Mayo Clinic and at its sister facility at the University of Minnesota. This new superresolution microscope will allow researchers to view cellular processes at extremely high resolution to study interactions of individual molecules, even reaching below the previously insurmountable lower limit set by the diffraction of light. This instrument also uses powerful lasers to excite single fluorescent recombinant proteins within cells and, together with advanced computer processing, allows their precise location to be determined. By labeling up to four or five different proteins at the same time, the spatial relationships between single molecules can be mapped, in both living and fixed tissue.
While the more experimental of these microscopy methods may be found only in research laboratories today, the history of microscopy at Mayo Clinic predicts their inevitable advance into the medical practice.