Christoph Cremer

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Christoph Cremer (born July 12, 1944 in Freiburg im Breisgau ) is a German physicist and professor at the Ruprecht-Karls-Universität Heidelberg , honorary professor at the Johannes Gutenberg-Universität Mainz and research group leader at the Institute for Molecular Biology in Mainz, who specializes in conventional light-optical Has overcome the resolution limit (“ Abbe limit”) using different methods (1996 localization microscopy SPDM; 1997 spatially structured lighting SMI). In September 2014 he founded the non-profit organization LuciaOptics for the use of super resolution microscopy in the areas of molecular biology , biomedicine , microbiology , virology , pharmacy and diagnostics .

Life

Christoph Cremer comes from a family with a scientific and socio-theological background, his father Hubert Cremer was a professor for mathematics and large computer systems at RWTH Aachen University , his uncle Lothar Cremer is considered one of the leading scientists of the 20th century in the field of technical acoustics and his Aunt Erika Cremer , developer of the fundamentals of adsorption gas chromatography , was the first female physics professor at Innsbruck University in 1940 . As early as the 1930s, Cremer's mother Elisabeth Rahner described current forms of collaboration between parents and childcare facilities, whereas her brothers Karl Rahner and Hugo Rahner are considered to be extremely important theologians of the past century.

His brother Thomas Cremer is also a professor of medicine at the Ludwig Maximilians University in Munich, while the youngest brother Georg Cremer, professor of economics, is Secretary General of the German Caritas Association.

After a few semesters of philosophy and history at the universities of Freiburg and Munich , Christoph Cremer studied physics (supported by the German National Academic Foundation ) in Munich and did his doctorate in genetics / biophysics in Freiburg. This was followed by a postdoc at the Institute for Human Genetics at the University of Freiburg , a stay of several years in the USA at the University of California and the habilitation (Dr. med. Habil. For General Human Genetics and Experimental Cytogenetics, Medical Faculty University of Freiburg). Since 1983 he has been teaching as professor (2004 full professor ) for applied optics and information processing at the University of Heidelberg, at the Kirchhoff Institute for Physics . He is also a scientific member of the Interdisciplinary Center for Scientific Computing (IWR), the Institute for Pharmacy and Molecular Biotechnology , and the University's Bioquant Center.

Christoph Cremer is involved in three ongoing excellence projects (2007–2012) at Heidelberg University and is a partner in the biotechnology cluster for cell-based and molecular medicine, one of the five top German BMBF clusters approved in 2008 . As the elected second speaker of the Senate (since 2006), Cremer is also involved in university politics at Heidelberg University. In his function as an 'adjunct' professor at the US University of Maine and as a scientific member of the renowned Jackson Laboratory ( Bar Harbor / Maine, USA), where he does research for several weeks a year during the semester break, he is building one there biophysical center (Institute for Molecular Biophysics, IMB), which is connected with Heidelberg University in a 'Global Network' project. He is married to the architect and artist Letizia Mancino-Cremer, who has been chairwoman of the Goethe Society in Heidelberg since 1992.

  • Super resolution microscopy by Prof. Christoph Cremer

  • Breast cancer nanoscopy, 3D two-color super resolution microscopy from Her2 and Her3 & cluster studies

  • Localization microscopy of single blinking YFP molecules / SPDMphymod

  • Two-color localization microscopy SPDMphymod / Super Resolution microscopy with GFP & RFP fusion proteins

  • Marker / probe-free localization microscopy SPDM - previously invisible cell structures can be detected

  • Investigations on human Retinal tissue, suffering from macular degeneration AMD, 100nm resolution with structured lighting

  • Virus Super Resolution Microscopy SPDM Cremer / Ways labs

Fundamental developments

Conception of 4Pi microscopy

Cremer was involved early on in the further development of laser-based light microscopy . The first ideas for this came from his PhD student days in the 1970s. Together with his brother Thomas Cremer, meanwhile professor of anthropology and human genetics at the Ludwig-Maximilians University in Munich , Christoph Cremer proposed in a patent specification in 1971 the development of a hologram- based 4Pi laser scanning microscopy (DE Offenlegungsschrift 2116521). This patent specification already contains the first ideas for the use of photoswitchable molecules for an improved light-optical acquisition of nanostructural information.

The basic idea was to focus laser light from all sides (solid angle 4Pi) to a “spot” with a diameter smaller than with conventional laser scanning microscopy and to use this to scan the object point by point; so the optical resolution should be improved beyond the conventional limit (about 200 nm laterally, 600 nm axially). Since 1992, 4Pi microscopy using two opposing microscope lenses with a high numerical aperture has been developed by Stefan Hell (currently Director at the Max Planck Institute for Biophysical Chemistry, Göttingen ) into a powerful, high-resolution imaging process.

First DNA irradiation technology for living cells

At the beginning of the 1970s, the brothers Christoph and Thomas Cremer developed a laser UV micro- irradiation device which for the first time enabled the targeted irradiation of a partial area of ​​living cells in the absorption maximum of DNA (257 nm) and replaced the conventional UV partial irradiation that was common for 60 years. For the first time, DNA lesions could be caused in a targeted manner (i.e. at pre-selected locations in the nucleus of living cells) without disrupting the cell's ability to divide or survive. Specific small cell areas could be micro-irradiated and the dynamics of the macromolecules present there could be quantified. In addition, the high speed of the process of fractions of a second irradiation time allowed the targeted irradiation of moving cell organelles . This development formed the basis for important experiments in the field of genetic research (detection of " chromosome territories " in living mammalian cells) and led in 1979/1980 to a successful collaboration with the biologist Christiane Nüsslein-Volhard (today director at the Max Planck Institute for Developmental Biology Tübingen , Nobel Prize 1995). In this collaboration, Christoph Cremer used his laser UV micro-irradiation apparatus to produce cellular changes in the early larval stages of the fruit fly .

Development of confocal laser scanning microscopy for fluorescence

On the basis of the experience gained during the construction and use of the laser UV micro-irradiation apparatus, the Cremer brothers designed a light-optical laser scanning process in 1978 in which the three-dimensional object surface was scanned point by point by a focusing laser beam and specifically marked areas were stimulated to fluorescence . The image was then put together electronically point by point, similar to the scanning electron microscope or the Scanning Optical Microscope by Davidovits and Egger.

However, special attention was paid to a) the imaging of specifically fluorescence- marked structures b) the increase of the signal contrast in the axial direction with the aid of a small pinhole diaphragm placed in the image plane with the diameter of the diffraction disk created there by a punctiform fluorescent object; Marvin Minsky applied for a patent for this basic idea of confocal microscopy as early as 1957 , but without reference to laser light sources (these were not yet available at the time) and without consideration of fluorescence excitation. Another difference to related microscopy concepts is that, due to the experimental experience Cremer & Cremer has gained with highly stable gas lasers, the “excitation pinhole” was dispensed with in their microscopy process.

This construction plan of a confocal laser scanning fluorescence microscope (CSLM), which was the first to combine the laser scanning method with the three-dimensional (3D) detection of fluorescent objects, brought Christoph Cremer to his professorship at Heidelberg University. Confocal laser scanning fluorescence microscopy , which was technically mature for application in the following decade, especially by working groups at the University of Amsterdam and the Heidelberg European Molecular Biology Laboratory ( EMBL ) and the associated industrial partners , found a broad use in the molecular biological and biomedical laboratories in the later years and is now used remains the gold standard today as far as three-dimensional light microscopy with conventional resolution is concerned.

Super resolution microscopy

In many cases, the goal of microscopy is to determine the sizes of individual small objects. In conventional fluorescence microscopy , this is also only possible up to values ​​that are around the conventional optical resolution limit of around 200 nm (lateral). Christoph Cremer's working group has developed various super resolution microscopes, such as the Vertico-SMI , based on the different technologies and respective requirements. A resolution of 5 nm in 2D and a determinable molecular density of approx. 2.8 × 10 4 µm −2 are currently  achieved.

Structured lighting SMI

In the mid-1990s, Christoph Cremer began developing a light microscopic method that made it possible to significantly improve the size resolution of fluorescence-marked cellular nanostructures. This time he used the principle of wide-field microscopy in connection with structured laser lighting ( SMI : spatially structured illumination). A resolution of 30 - 40 nm (about 1/16 - 1/13 of the wavelength used) is currently achieved with this. In addition, this technology was no longer subject to the speed restrictions of focusing microscopy, so that the 3D analysis of whole cells is possible in short observation times (currently in the range of a few seconds).

Localization microscopy SPDM

Christoph Cremer has also designed and implemented fluorescence-optical methods of wide-field microscopy since the mid-1990s, which aimed to improve the effective optical resolution (in the sense of the smallest detectable distance between two localized objects) by a multiple of conventional resolution ( SPDM , localization microscopy, English . spectral precision distance / position determination microscopy).

SPMDphymod - localization microscopy with normal fluorescent molecules

In 2008, Cremer's research group found that under certain photophysical conditions, many “very common” dye molecules such as GFP, RFP, YFP, fluorescein or Alexa dyes and not just photoswitchable dyes can be used for optical nanoscopy. By combining many thousands of individual images of the same cell, “localization images” with significantly improved optical resolution were obtained with the help of laser-optical precision measurements. This extends the applicability of the SPDM method to numerous areas of biophysical, cell biological and medical research, as well as the high-resolution investigation of viruses.

LIMON: 3D Super Resolution Microscopy

LIMON (Light MicrOscopical nanosizing microscopy) was developed in 2001 at the University of Heidelberg and combines the two methods localization microscopy and structured lighting for 3D super resolution microscopy with a resolution of 40 nm in 3D. Using this two-color colocalization 3D super resolution microscopy, the spatial arrangement of the two genes Her2 / neu and HER3 active in breast cancer was determined with an accuracy of about 25 nm, and the cluster formation, which is probably relevant for cancer development, was analyzed at the single-molecule level.

Award

  • Heidelberg Innovation Forum 2009: The world's fastest light microscope named best business idea.

Fonts (selection)

  • Considerations on a laser scanning microscope with high resolution and depth of field. In: Microscopica acta . tape 81 , no. 1 , 1978, p. 31-44 , PMID 713859 ( uni-heidelberg.de [PDF]).

Individual evidence

  1. ^ Honorary Professorship for IMB's Christoph Cremer, press release .
  2. ↑ luciaoptics.org Microscopy Research Center LuciaOptics
  3. ^ Franz Weigl, Ludwig Battista, Anton Heinen, Elisabeth Rahner, Maria Montessori: Pedagogy and Didactics of the Age Levels. Kösel & Pustet, Munich 1931–1934.
  4. ^ Anton Heinen, Elisabeth Rahner, Maria Montessori: Family and Toddler Education. Kösel & Pustet, 1934.
  5. ↑ Elisabeth Rahner: The thought of mothers training in its development from Comenius to the present. Dissertation. 1936.
  6. ↑ Prof. Dr. med. Thomas Cremer. In: uni-muenchen.de. Accessed June 5, 2018 .
  7. ↑ a b C. Cremer, T. Cremer: Considerations on a laser-scanning-microscope with high resolution and depth of field. In: Microscopica acta . tape 81 , no. 1 , 1978, p. 31-44 , PMID 713859 ( uni-heidelberg.de [PDF]).
  8. ↑ T. Cremer, C. Cremer: Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present . In: European journal of histochemistry . tape 50 , no. 4 , 2006, p. 223-272 , PMID 17213034 ( ejh.it [PDF]).
  9. ↑ S. Hell, S. Lindek, C. Cremer, EHK Stelzer: Measurement of the 4pi-confocal point spread function proves 75 nm axial resolution. In: Applied Physics Letters . Volume 64, 1994, pp. 1335-1337, doi: 10.1063 / 1.111926 .
  10. ^ PE Hänninen, SW Hell, J. Salo, E. Soini, C. Cremer: Two-photon excitation 4Pi confocal microscope - Enhanced axial resolution microscope for biological research. In: Applied Physics Letters . Volume 68, 1995), pp. 1698-1700, doi: 10.1063 / 1.113897 ( uni-heidelberg.de [PDF]).
  11. ↑ C. Cremer, C. Zorn, T. Cremer: An ultraviolet laser microbeam for 257 nm / A laser UV micro-irradiation apparatus for 257 nm . In: Microscopica Acta . tape 75 , no. 4 , 1974, p. 331–337 ( uni-heidelberg.de [PDF]).
  12. ↑ Christoph and Thomas Cremer talk about 40 years of joint research into the functional genome architecture ( Memento from December 25, 2015 in the Internet Archive )
  13. ↑ M. Lohs-Schardin, C. Cremer, C. Nüsslein-Volhard: A fate map for the larval epidermis ofDrosophila melanogaster: localized cuticle defects following irradiation of the blastoderm with an ultraviolet laser microbeam . In: Developmental Biology . tape 73 , no. 2 , 1979, p. 239-255 , doi : 10.1016 / 0012-1606 (79) 90065-4 ( uni-heidelberg.de [PDF]).
  14. ↑ C. Nüsslein-Volhard, M. Lohs-Schardin, K. Sander, C. Cremer: A dorso-ventral shift of embryonic primordia in a new maternal-effect mutant of Drosophila . In: Nature . tape 283 , no. 5746 , 1980, pp. 474-476 , doi : 10.1038 / 283474a0 ( researchgate.net [PDF]).
  15. ↑ Patent US3643015 : Scanning optical microscope. Published June 19, 1970 , Inventors: Paul Davidovits, Maurice David Egger. ‌
  16. ↑ D. Baddeley, C. Batram, Y. Weiland, C. Cremer, UJ Birk: Nanostructure analysis using spatially modulated illumination microscopy . In: Nature Protocols . tape 2 , no. 10 , 2007, p. 2640–2646 , doi : 10.1038 / nprot.2007.399 ( uni-heidelberg.de [PDF]).
  17. ↑ Manuel Gunkel, Fabian Erdel, Karsten Rippe, Paul Lemmer, Rainer Kaufmann, Christoph Hörmann, Roman Amberger and Christoph Cremer: Dual color localization microscopy of cellular nanostructures. In: Biotechnology Journal. Volume 4 2009, pp. 927-938, doi: 10.1002 / biot.200900005 ( archives-ouvertes.fr [PDF]).
  18. ↑ C. Cremer, R. Kaufmann, M. Gunkel, F. Polanski, P. Müller, R. Dierkes, S. Degenhard, C. Weg, M. Hausmann, U. Birk: Application perspectives of localization microscopy in virology . In: Histochemistry and Cell Biology . tape 142 , no. 1 , 2014, p. 43–59 , doi : 10.1007 / s00418-014-1203-4 ( uni-heidelberg.de [PDF]).
  19. ↑ Qiaoyun Wang, Rüdiger Dierkes, Rainer Kaufmann, Christoph Cremer: Quantitative analysis of individual hepatocyte growth factor receptor clusters in influenza A virus infected human epithelial cells using localization microscopy . In: Biochimica et Biophysica Acta (BBA) - Biomembranes . tape 1838 , no. 4 , 2014, p. 1191–1198 , doi : 10.1016 / j.bbamem.2013.12.014 ( uni-heidelberg.de [PDF]).
  20. Jump up ↑ J. Reymann, D. Baddeley, P. Lemmer, W. Stadter, T. Jegou, K. Rippe, C. Cremer, U. Birk: High-precision structural analysis of subnuclear complexes in fixed and live cells via spatially modulated illumination (SMI) microscopy . In: Chromosome Research . tape 16 , no. 3 , 2008, p. 367–382 , doi : 10.1007 / s10577-008-1238-2 (free full text).
  21. ^ P. Lemmer, M. Gunkel, D. Badeley, R. Kaufmann, A. Urich, Y. Weiland, J. Reymann, P. Müller, M. Hausmann, C. Cremer: SPDM: light microscopy with single-molecule resolution at the nanoscale . In: Applied Physics B . tape 93 , no. 1 , 2008, p. 1–12 , doi : 10.1007 / s00340-008-3152-x (free full text).
  22. ^ Rainer Kaufmann, Patrick Müller, Georg Hildenbrand, Michael Hausmann, Christoph Cremer: Analysis of Her2 / neu membrane protein clusters in different types of breast cancer cells using localization microscopy . In: Journal of Microscopy . tape 242 , no. 1 , 2010, p. 46–54 , doi : 10.1111 / j.1365-2818.2010.03436.x ( uni-heidelberg.de [PDF]).
  23. ↑ Peter Saueressig: Heidelberger Innovationsforum: World's fastest light microscope named best business idea. European Media Laboratory GmbH, press release from October 21, 2009 from Informationsdienst Wissenschaft (idw-online.de), accessed on June 5, 2018.

literature

Web links

personal data
SURNAME Cremer, Christoph
BRIEF DESCRIPTION German physicist
DATE OF BIRTH July 12, 1944
PLACE OF BIRTH Freiburg in Breisgau