Milestone-Proposal:Super Resolved Microscopy
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Docket #:2024-09
This proposal has been submitted for review.
To the proposer’s knowledge, is this achievement subject to litigation? No
Is the achievement you are proposing more than 25 years old? Yes
Is the achievement you are proposing within IEEE’s designated fields as defined by IEEE Bylaw I-104.11, namely: Engineering, Computer Sciences and Information Technology, Physical Sciences, Biological and Medical Sciences, Mathematics, Technical Communications, Education, Management, and Law and Policy. Yes
Did the achievement provide a meaningful benefit for humanity? Yes
Was it of at least regional importance? Yes
Has an IEEE Organizational Unit agreed to pay for the milestone plaque(s)? Yes
Has the IEEE Section(s) in which the plaque(s) will be located agreed to arrange the dedication ceremony? Yes
Has the IEEE Section in which the milestone is located agreed to take responsibility for the plaque after it is dedicated? Yes
Has the owner of the site agreed to have it designated as an IEEE Milestone? Yes
Year or range of years in which the achievement occurred:
1992
Title of the proposed milestone:
Super-Resolved Fluorescence Microscopy, 1992
Plaque citation summarizing the achievement and its significance; if personal name(s) are included, such name(s) must follow the achievement itself in the citation wording: Text absolutely limited by plaque dimensions to 70 words; 60 is preferable for aesthetic reasons.
The first super-resolution image of a biological sample was obtained in 1992 by exciting and collecting light diffracted in the near field of the sample. This breakthrough achievement, called super-resolved fluorescence microscopy, exploited the properties of evanescent waves and made single-molecule microscopy possible. Its successful use in imaging single fluorophores inspired applications in cell biology, microbiology, and neurobiology.
200-250 word abstract describing the significance of the technical achievement being proposed, the person(s) involved, historical context, humanitarian and social impact, as well as any possible controversies the advocate might need to review.
In 1992, Betzig developed methods based on single-molecule localization microscopy (SMLM), where fluorescent molecules are switched on and off, allowing their positions to be determined with nanometer precision. Researchers led by Betzig, building upon the advancements made with Near-Field Scanning Optical Microscopy, successfully obtained a super-resolution image of a biological sample. This breakthrough, achieved using a tapered fiber probe and advanced imaging techniques, demonstrated the ability to overcome the diffraction limit and visualize microscopic structures with unprecedented detail. These techniques have revolutionized biological imaging, enabling scientists to visualize structures and processes within cells at unprecedented detail. Super-resolved fluorescence microscopy has opened up new avenues for research in fields such as neuroscience, cell biology, and materials science, providing invaluable insights into the fundamental workings of life. In 2014, Eric Betzig received the Nobel Prize in Chemistry, jointly with Stefan W. Hell, and William E. Moerner for their groundbreaking work in developing super resolved fluorescence microscopy. This revolutionary technology overcame the diffraction limit of light, which had previously restricted optical microscopes to a resolution of about 200 nanometers.
IEEE technical societies and technical councils within whose fields of interest the Milestone proposal resides.
Solid-State Circuits , Electron Devices
In what IEEE section(s) does it reside?
North Jersey
IEEE Organizational Unit(s) which have agreed to sponsor the Milestone:
IEEE Organizational Unit(s) paying for milestone plaque(s):
Unit: North Jersey Section
Senior Officer Name: Hong Zhao
IEEE Organizational Unit(s) arranging the dedication ceremony:
Unit: North Jersey Section
Senior Officer Name: Emad Farag
IEEE section(s) monitoring the plaque(s):
IEEE Section: North Jersey
IEEE Section Chair name: Emad Farag
Milestone proposer(s):
Proposer name: Theodore Sizer
Proposer email: Proposer's email masked to public
Proposer name: David Neilson
Proposer email: Proposer's email masked to public
Please note: your email address and contact information will be masked on the website for privacy reasons. Only IEEE History Center Staff will be able to view the email address.
Street address(es) and GPS coordinates in decimal form of the intended milestone plaque site(s):
40.684031,-74.401783
Describe briefly the intended site(s) of the milestone plaque(s). The intended site(s) must have a direct connection with the achievement (e.g. where developed, invented, tested, demonstrated, installed, or operated, etc.). A museum where a device or example of the technology is displayed, or the university where the inventor studied, are not, in themselves, sufficient connection for a milestone plaque.
Please give the address(es) of the plaque site(s) (GPS coordinates if you have them). Also please give the details of the mounting, i.e. on the outside of the building, in the ground floor entrance hall, on a plinth on the grounds, etc. If visitors to the plaque site will need to go through security, or make an appointment, please give the contact information visitors will need. Intention is to have the plaque just outside the main entrance to the Nokia Bell Labs Facility in Murray Hill, NJ. It is both a corporate building and a Historic Site as other historical markers are already on site both inside and outside the building.
Are the original buildings extant?
Yes
Details of the plaque mounting:
Outside the building on a rock or other permanent structure.
How is the site protected/secured, and in what ways is it accessible to the public?
The plaque will be placed prior to entering the building and thus visitors do not need to pass through security.
Who is the present owner of the site(s)?
Nokia America
What is the historical significance of the work (its technological, scientific, or social importance)? If personal names are included in citation, include detailed support at the end of this section preceded by "Justification for Inclusion of Name(s)". (see section 6 of Milestone Guidelines)
Introduction
Optical microscopy, the use of light to visualize objects, has been a cornerstone of scientific discovery for centuries. However, for over a century, its resolution was fundamentally limited by the diffraction limit, a physical constraint imposed by the wave nature of light. This limit dictated that two objects closer than half the wavelength of light could not be distinguished, effectively blurring fine details and hindering the study of microscopic structures. This limit prevented researchers from resolving structures smaller than approximately 200 nanometers, effectively obscuring the fine details of cellular processes and molecular interactions.
The Diffraction Limit and its Implications
Ernst Abbe, in the late 19th century, formulated the diffraction limit, which states that two objects closer than half the wavelength of light cannot be distinguished as separate entities. This limit effectively restricted optical microscopy to resolving structures larger than approximately 200 nanometers. While electron microscopy offered higher resolution, it was not suitable for studying living cells due to its invasive nature. The diffraction limit hindered the ability to visualize crucial biological processes, such as the intricate organization of cellular components, the dynamics of molecular interactions, and the mechanisms of disease development.
Breaking the Diffraction Barrier: The Birth of Near-Field Scanning Optical Microscopy (NSOM)
In the late 1980s and early 1990s, a revolutionary technique emerged that challenged the diffraction limit: Near-field Scanning Optical Microscopy (NSOM). Unlike conventional microscopes that rely on far-field light, NSOM operates in the near field, exploiting the properties of evanescent waves. These waves, which decay exponentially with distance from the source, can interact with objects at a much smaller scale than the wavelength of light.
Pioneering Work at Bell Labs: Eric Betzig and the Tapered Fiber Probe
Eric Betzig, a researcher at Bell Labs in Murray Hill, New Jersey, played a pivotal role in the development of NSOM. He and his colleagues developed a novel approach using a tapered fiber probe, which allowed for significantly higher resolution and signal intensity compared to previous NSOM designs. This breakthrough, published in Science in 1991, demonstrated the potential of NSOM for high-resolution imaging of various materials, including biological samples.
A Pivotal Moment in 1992: The First Super-Resolution Image of a Biological Sample
A pivotal moment in the history of microscopy occurred in 1992. Researchers led by Betzig, building upon the advancements made with NSOM, successfully obtained a super-resolution image of a biological sample. This breakthrough, achieved using a tapered fiber probe and advanced imaging techniques, demonstrated the ability to overcome the diffraction limit and visualize microscopic structures with unprecedented detail. This achievement marked a significant shift in the field, inspiring future applications in cell biology, microbiology, and neurobiology.
Single-Molecule Localization Microscopy (SMLM) and the Quest for Even Higher Resolution
While NSOM offered a significant improvement in resolution, the quest for even higher resolution continued. The development of single-molecule localization microscopy (SMLM) techniques, such as Photoactivated Localization Microscopy (PALM) and Stochastic Optical Reconstruction Microscopy (STORM), further revolutionized the field. These techniques, inspired by the early work on NSOM, allowed for the localization of individual fluorescent molecules with unprecedented precision, pushing the resolution limit to the nanoscale.
Path to a Nobel Prize
In 2014, Eric Betzig, along with Stefan W. Hell and W.E. Moerner, were awarded the Nobel Prize in Chemistry for their groundbreaking work in developing super-resolved fluorescence microscopy. Betzig's development of PALM (Photo-Activated Localization Microscopy), which uses photo-switchable fluorescent molecules to overcome the diffraction limit, was a key factor in this recognition. PALM has enabled scientists to visualize the intricate organization of cellular components, track the dynamics of molecular interactions, and uncover the mechanisms of disease development with unprecedented detail.
Impact and Applications of Super-Resolved Fluorescence Microscopy
The development of super-resolved fluorescence microscopy, inspired by the early work on NSOM and culminating in the Nobel Prize-winning work of Eric Betzig, Stefan W. Hell, and W.E. Moerner, has revolutionized our understanding of biological systems. This breakthrough has enabled scientists to see beyond the diffraction limit, revealing the intricate details of life at the molecular level. Super-resolved fluorescence microscopy is a powerful tool that continues to transform our understanding of life and inspire new discoveries and technological advancements. Super-resolved fluorescence microscopy has had a profound impact on various fields of science, including cell biology, microbiology, neurobiology, and medicine. It has enabled researchers to:
• Visualize the intricate organization of cellular components: Super-resolution microscopy has revealed the precise arrangement of proteins within cells, providing insights into the complex machinery of life.
• Track the dynamics of molecular interactions: By visualizing the movement of individual molecules, researchers can now study the intricate dance of proteins and other biomolecules within cells, revealing the mechanisms of cellular processes.
• Uncover the mechanisms of disease development: Super-resolution microscopy has provided new insights into the molecular basis of diseases, such as cancer, neurodegenerative disorders, and infectious diseases.
• Develop new diagnostic and therapeutic tools: The ability to visualize cellular processes at the nanoscale has opened new avenues for developing more precise diagnostic tools and targeted therapies.
What obstacles (technical, political, geographic) needed to be overcome?
Lenses and optical microscopes have been employed for centuries to examine small objects including biological samples. However, the resolution of these optical devices had been limited by the diffraction limit or 1/2 the wavelength of the light being used to examine the object.
The fundamental obstacle (and achievement) was how to be able to image beyond the diffraction limit of imaging which was accomplished in two ways: first, it used near field exploiting evanescent waves for imaging; and second, it used a novel tapered fiber to scan across the sample to develop the image.
What features set this work apart from similar achievements?
Near Field Optical Microscopy was a significant advance in the state of the art in imaging at the time it was discovered (1992) which when exploited with novel fluorescence excitation techniques established the Super-Resolved Fluorescence Microscopy breakthrough. First, it dramatically increased the resolution as compared with optical microscopes using lenses in the far field for imaging. For the first time, details of objects were revealed as never before. And second, it did not use electron microscopes for imaging which avoided damaging the samples under test, especially living biological samples, allowing the discovery to have wide use in bio-imaging ever since.
Why was the achievement successful and impactful?
The discovery of Super-Resolved Near Field Optical Microscopy allowed, for the first time, the imaging of objects including live biological samples, with a resolution beyond what had long been assumed to be the fundamental resolution -- the diffraction limit. Biological research now had a tool to explore structures at ever smaller dimensions allowing for greater understanding of these structures. Super-resolution microscopy has allowed for greater understanding and manipulation of biological systems is now used as a drug discovery tool.
Supporting texts and citations to establish the dates, location, and importance of the achievement: Minimum of five (5), but as many as needed to support the milestone, such as patents, contemporary newspaper articles, journal articles, or chapters in scholarly books. 'Scholarly' is defined as peer-reviewed, with references, and published. You must supply the texts or excerpts themselves, not just the references. At least one of the references must be from a scholarly book or journal article. All supporting materials must be in English, or accompanied by an English translation.
Harris T. D. et al., "Super-Resolution Imaging Spectroscopy" Applied Spectroscopy, v. 48, no 1, 1994 pp 14A-21A
Betzig, Eric; Chichester, Robert J. (November 26, 1993). "Single Molecules Observed by Near-Field Scanning Optical Microscopy". Science. 262 (5138): 1422–1425.
Betzig, Eric; Trautman, Jay K. (July 10, 1992). "Near-Field Optics: Microscopy, Spectroscopy, and Surface Modification Beyond the Diffraction Limit". Science. 257 (5067): 189–195.
Papers on beyond diffraction limit and 1992 observation of single molecules:
• Betzig, E., & Trautman, J. K. (1>Supporting Texts992). Near-field optics: Microscopy, spectroscopy, and surface modification beyond the diffraction limit. Science, 257(5075), 189–195. (This paper describes Betzig's early work on near-field microscopy.)
• Betzig, E., & Chichester, R. J. (1993). Single molecules observed by near-field scanning optical microscopy. Science, 262(5138), 1422–1425. (This paper demonstrates the ability to image single molecules using near-field microscopy.)
Eric Betzig's Work on PALM
• Betzig, E., Patterson, G. H., Sougrat, R., Lindwasser, O. W., Olenych, S., Bonifacino, J. S., ... & Hess, H. F. (2006). Imaging intracellular fluorescent proteins at nanometer resolution. Science, 313(5793), 1642–1645. (This landmark paper describes the development of PALM.)
Other Key Super-Resolution Microscopy Techniques:
• Hell, S. W. (2003). Toward fluorescence nanoscopy. Nature Biotechnology, 21(9), 1347–1355. (This paper describes the development of STED microscopy.)
• Rust, M. J., Bates, M., & Zhuang, X. (2006). Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nature Methods, 3(10), 793–795. (This paper describes the development of STORM.)
General Background on Super-Resolution Microscopy:
• Schermelleh, L., Heintzmann, R., & Leonhardt, H. (2010). A guide to super-resolution fluorescence microscopy. Journal of Cell Science, 123(21), 3791–3797. (This review provides a comprehensive overview of super-resolution microscopy techniques.)
• Huang, B., Bates, M., & Zhuang, X. (2009). Super-resolution fluorescence microscopy. Annual Review of Biochemistry, 78, 993–1016. (This review discusses the principles and applications of super-resolution microscopy.)
Nobel Prize Information:
• The Nobel Prize in Chemistry 2014. (2014). NobelPrize.org. Retrieved from https://www.nobelprize.org/prizes/chemistry/2014/summary/ (This page provides information about the Nobel Prize)
- Betzig, E; Trautman, J.K.; Harris, T.D.; Weiner,J.S. "Breaking the Diffraction Barrier: Optical Microscopy on a Nanometric Scale" Science 251 (5000)1468
- Nobel Lecture "Single Molecules, Cells, and Super-Resolution Optics", December 8, 2014
Supporting materials (supported formats: GIF, JPEG, PNG, PDF, DOC): All supporting materials must be in English, or if not in English, accompanied by an English translation. You must supply the texts or excerpts themselves, not just the references. For documents that are copyright-encumbered, or which you do not have rights to post, email the documents themselves to ieee-history@ieee.org. Please see the Milestone Program Guidelines for more information.
Media:R1_SRM.pdf Media:R2_SRM Media:R3_SRM Media:R4_SRM.pdf Media:R5_SRM.pdf
Please email a jpeg or PDF a letter in English, or with English translation, from the site owner(s) giving permission to place IEEE milestone plaque on the property, and a letter (or forwarded email) from the appropriate Section Chair supporting the Milestone application to ieee-history@ieee.org with the subject line "Attention: Milestone Administrator." Note that there are multiple texts of the letter depending on whether an IEEE organizational unit other than the section will be paying for the plaque(s).
Please recommend reviewers by emailing their names and email addresses to ieee-history@ieee.org. Please include the docket number and brief title of your proposal in the subject line of all emails.
