Investigating Telomeres: Using High-Performance Microscopy for Understanding Cancer
• Carl Zeiss, Inc.
Experts from the scientific community convened at the German Center for Research and Innovation to discuss the use of high-resolution imaging when investigating telomeres during cancer research. Telomeres are repetitive DNA sequences at each end of each chromosome that protect them from deterioration or fusion with neighboring chromosomes.
Dr. Sabine Mai, Senior Investigator at the Manitoba Institute of Cell Biology and Director of The Genomic Centre for Cancer Research and Diagnosis, set the stage by introducing the topic of genomic instability, a feature in cancer cells that describes what changes when a cell becomes a tumor cell, i.e. how the genomes, genes, and chromosomes rearrange and change.
Dr. Mai then proceeded to explain how 3-D telomere profiling can be used to diagnose, prognose, and monitor cancer patients to aid clinicians in staging and treating patients. 3-D telomeric signatures in cancer can help clinicians understand what is unique about each patient, knowledge that can help enhance personalized medicine. She then gave a brief overview of the history of cancer cell research, looking back at research efforts by German scientists David von Hansemann and Theodor Boveri. While they lacked the proper technological instruments back in their day, these scientists were nonetheless able to correctly describe the malignant origin of cancer over 100 years ago.
Dr. Mai then shared insights from her years of cancer cell research aided by 3-D imaging. Using telomeres as indicators in lymphoid and non-lymphoid cancers, she observed that the 3-D telomere organization in cancer cells is different than in normal cells and is also predictive of a patient’s disease as well as treatment response. A quantitative assessment of 3-D telomeric profiles in both cell types is now possible thanks to the software TeloView. Dr. Mai described her clinical studies on Hodgkin’s lymphoma and the effects of super-resolution imaging: For the first time in a blind study, Dr. Mai in collaboration with Dr. Hans Knecht at McGill University Health Centre, were able to successfully predict the clinical behavior of patients undergoing chemotherapy by looking at the 3-D profiles of telomeres at diagnosis. Dr. Mai and her team aim to use this technology in the future to monitor treatment success and to design the best treatment plan for each patient.
Dr. James Fitzpatrick, Senior Director of Advanced Biophotonics and Strategic Technologies at the Salk Institute for Biological Studies, then spoke, giving an overview of the microscopy techniques and high-performance tools currently available that have been used to create detailed models of telomeres. From multi‐scale microscopy and super-resolution fluorescence imaging to structured illumination microscopy, Dr. Fitzpatrick provided a variety of examples of the cell structure images that these tools enable researchers to visualize. For example, one can look at a CRF2 receptor localizing to a cell membrane in a dividing cell or at leading and lagging strand telomeres in a metaphase spread. Other images that Dr. Fitzpatrick showed included motor neuron reconstruction in a mouse spinal cord segment as well as telomere relocation to nuclear periphery during mitosis.
With these detailed images in mind, Dr. Fitzpatrick reminded audience members about an inherent caveat to light – namely that there is an intrinsic limit to optical resolution. Citing the German physicist and optical scientist Ernst Abbe, Dr. Fitzpatrick described in layman’s terms how the diffraction limit of light is essentially proportional to half the wave length. The problem here is that many of the items researchers are interested in imaging are smaller than the diffraction limit. This makes it difficult to look inside cells to discriminate objects because very small objects appear bigger ‘optically.’ Super-resolution fluorescence imaging, for example, makes use of innovative optical and mathematical methods to image beyond the diffraction limit.
Dr. Bernhard Zimmermann, Senior Director of Global Marketing Life Sciences for Carl Zeiss Microscopy GmbH, concluded the evening by revealing a new microscope and innovative technology from Jena designed to further scientific advancements in cancer research. Dr. Zimmermann cited confocal laser scanning microscopy (LSM) as the most popular optical sectioning microscopes in the life sciences and the single most important technology in scientific imagining today. He then introduced a new technology designed to overcome the “classical limitations” of confocal laser microscopy: the new Zeiss LSM 880 with revolutionary Airyscan technology. He compared conventional non-confocal imaging with the Airyscan technology, illustrating how the Airyscan, for example, is able to take advantage of spatial information not recorded with conventional LSMs. Moreover, he demonstrated how the Airyscan can reveal more details in samples by increasing the resolution of LSM 880 up to 1.7 times. Additionally, it can deliver high-quality images previously impossible with LSMs, achieving good image quality in a shorter period of time. According to Dr. Zimmermann, LSM 880 Airyscan technology performs multi-color imaging of samples, enhances resolution, increases signal-to-noise ratio, and thereby enables more accurate quantification.
A lively discussion with the audience, moderated by James Sharp, the President of Carl Zeiss Microscopy, LLC, and President and CEO of Carl Zeiss, Inc., ensued. Among the topics discussed were the challenges and opportunities of high-resolution microscopy, its broad range of applications in biomedical research, and its role in helping researchers and clinicians better understand cancer in the future.