Chances are, you’ve probably looked into a microscope at least once in your life. Whether it was to look at cells of an onion skin, to visualize colonies of growing bacteria, or to determine the presence of immune cells in 5 micrometre thin sections of human tissue. Today, our ability to visualize the invisible is something we don’t think twice about. As scientists, microscopes are often part of our daily lives. But there was a time when this invention, albeit as simple as combining two different lenses, was revolutionary. The invention of the microscope changed the landscape of what was scientifically possible. What does this piece of equipment mean to us today?

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When we think of microscopes, we often picture the giant slide-scanning or confocal microscopes that we have access to today. However, this invention has just as humble beginnings as any other. In the late 1400s, spectacle makers discovered that the rays of the sun could be focused using a special piece of glass, and that if this glass was held over an object, the object would appear larger. They named their invention “lenses” due to the fun fact that the glass resembled a lentil bean. These new lenses were not very powerful and could only magnify objects up to 10 times. It was not until almost 100 years later in the 1590s that the theory of a “lens” was used to create what we now know as the compound microscope. A father-son team of spectacle makers named Hans and Zaccharias Janssen found that if they put several of these lenses in a tube, the magnification of each lens was amplified and whatever object was at the end of the tube appeared significantly larger. Not long after, a scientist by the name of Anthony Leeuwenhoek further improved on the Janssens’ invention and created lenses that were smaller but had greater curvatures, allowing them to focus light even more. Suddenly, he had created a microscope that could magnify up to 270 times! Leeuwenhoek was arguably the first to see things that no man had seen before, such as bacteria living in tiny water droplets, nematodes and yeast. Leeuwenhoek was also the first to visualize human cells, such as blood cells and sperm. In the following decades, many scientists continued to improve upon the microscope, lending to both its design as well as its visualization capabilities. In 1665, English scientist Robert Hooke published Micrographia, a book in which he described in great detail the different things he was able to see using his microscope, including feathers, the eyes of houseflies and thin slices of corkscrews. He used his observations to coin the term “cell” to describe what we now know as the building blocks for all biological organisms.   

By the late 1800s, the microscope had gone through dozens of changes to make it more powerful, stable and sharper. The simple set up of a stage, light source, eyepiece, and a few objective lenses changed the face of science and research as we know it.  Suddenly, we were able to study, understand and manipulate worlds which were once invisible to us. We saw the birth and rise of microbiology, virology and immunology. Microscopy even became a science of its own, earning scientists critical acclaim and Nobel prizes, an example being chemist Richard Zsigmondy who became interested in glass and its coloring in the late 1800s. Up until this point, the power of the microscope was limited to objects that could be visualized within the visible light spectrum. However, in 1908, Zsigmondy was able to develop the ultramicroscope which removed the bounds of light absorption and reflection, and instead allowed particles to be viewed via light scattering. This meant that if an object fell below the wavelength of visible light, it could still be captured and seen! But what about objects that couldn’t be seen because they were either colorless or transparent? This problem was solved by Dutch physicist Frits Zernike who won the Nobel prize in 1953 for his invention of the phase-contrast microscopy technique. When light passes through any medium, the amplitude and phase of the light wavelength may change. Our eyes are capable of detecting changes in amplitude, but phase changes are invisible. With the changes that Zernike made to the structure of the microscope, researchers could now see cellular structures that were invisible with basic light microscopy. This meant that biologists could now study living cells, since the extra staining steps that would normally kill them were no longer necessary. For example, scientists could now visualize cell division without using DNA-damaging dyes such as propidium iodide. Around the same time, scientists were using fluorophores to help stain biological tissues and bacteria. With the discovery of fluorescent labeling in the 1940s by Elinger and Hirt, it was now possible to stain tissues in a controlled and specific manner, leading to the birth of fluorescent microscope. The fluorescent microscope itself was developed 20 years earlier as an extension of the UV microscope, and was used to observe autofluorescence in animal and plant tissues. However, with the discovery that antibodies could be tagged with fluorescent dyes, it was now possible to observe individual proteins and cell structures.

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So much of what is possible today in terms of scientific research has stemmed from these initial inventions that made it possible for us to see hidden worlds. Before we could see the microorganisms that cause illness, the general belief was that infectious diseases came from God or evil spirits. Today, when a person presents at a hospital with an unknown illness, diagnosing them is as easy as taking a swab and looking through the lens of a microscope. Once viruses were discovered as disease-causing agents, one major goal of scientists has been to understand their structure and function. In the context of the current COVID-19 pandemic, this has never been more important considering that understanding the structure of a virus is critical to understanding how to prevent infection. This is where another update to the microscope has become handy. The electron microscope (EM) was first developed by Ernst Ruska and Max Knoll in 1931, but it wasn’t used to visualize viruses until 1939 when Kausche and Pfankuch used it to study the tobacco mosaic virus. Since then, the electron microscope has aided in the discovery of numerous novel viruses. This microscope works by manipulating the wave-like properties of electrons rather than light to magnify an object’s image. Just imagine, without the EM we wouldn’t know that the virus that causes smallpox is different from the virus that causes chicken pox. We also wouldn’t understand the way the poliovirus interacts with its host, thereby making it much more difficult to design a vaccine. In fact, we wouldn’t even have known something as simple as the fact that the hepatitis B disease is caused by a virus. Today, electron microscopy has become essential in helping us understand the recently discovered coronavirus. This has allowed scientists all over the world to use this knowledge to categorize the SARS-CoV-2 shape and morphology, understand how it interacts with its human hosts, and develop vaccines to protect against the virus.

From its humble beginnings to the magnificent role it plays in the scientific world today, the microscope is easily one of the most life-changing inventions of the last few centuries. What started as a simple light source and a couple of lenses has turned into endless possibilities and a portal to hidden worlds. So, the next time you have the chance to use one, even just a simple light microscope, remember that centuries of innovation and creativity have made your research possible.

References

  1. 2020. History of Microscopes. Microscope.com
  2. 2020. Microscope History. Microscopeworld.com .
  3. Falkowski, P. 2020. Leeuwenhoek’s Lucky Break. Discover Magazine .
  4. Noe, A. 2020. The Hooke Microscope. The Scientist Magazine®
  5. Sella, A. 2020. Classic Kit: Zsigmondy’s ultramicroscope. Chemistry World.
  6. Murphy, D., R. Oldfield, S. Schwartz, and M. Davidson. 2020. Introduction to Phase Contrast Microscopy. Nikon’s MicroscopyU .
  7. Ellinger, P. 1940. FLUORESCENCE MICROSCOPY IN BIOLOGY. Biological Reviews 15: 323-347.
  8. Rüdenberg, R. 2010. Origin and Background of the Invention of the Electron Microscope. Advances in Imaging and Electron Physics 171-205.
  9. Goldsmith, C., and S. Miller. 2009. Modern Uses of Electron Microscopy for Detection of Viruses. Clinical Microbiology Reviews 22: 552-563.
  10. Bowler, J. 2020. This Is What The COVID-19 Virus Looks Like Under The Microscope. ScienceAlert.
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Salma Sheikh-Mohamed

Salma Sheikh-Mohamed is a second year Master's student in the Immunology department at UofT, researching the use of Imaging Mass Cytometry (IMC) for immunophenotyping human tissue. Her recent work using IMC in the human brain can be found in a manuscript entitled Multiplex Imaging of Immune Cells in Staged Multiple Sclerosis Lesions by Mass Cytometry. When not working in the lab, she enjoys reading, baking, and working on her food photography skills.
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