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Achim Kramer
Born18 May 1968
Friedrichshafen, Germany
CitizenshipGermany
Alma materUndergraduate: Free University of Berlin (1993)
Ph.D: Humboldt University of Berlin (1996)
Known forPost-translational modifications of the circadian clock
Circadian rhythm research
AwardsYoung Researchers Award- Charité (1998)
Brooks Fellow at Harvard Medical School (2001)
Heinz-Maier-Leibitz Award from German Research Foundation (2002)
Scientific career
FieldsChronobiology, chronomedicine, biochemistry
WebsiteAchim Kramer Lab

Achim Kramer (born May 18, 1968)[1] is a German chronobiologist and biochemist. He is the current head of Chronobiology at Charité – Universitätsmedizin Berlin in Berlin, Germany.[2]

Kramer's primary research interests include post-translational modifications of circadian clock proteins and the function of the circadian clock in the immune system. Some of his work includes identifying phosphorylation regions on mPER2 (mammalian PER2) and their implications for familial advanced sleep phase syndrome (FASPS), identifying circadian rhythms in macrophages, and investigating the necessity of heme degradation for circadian rhythms. Kramer's current projects include improving BodyTime (a method for identifying an individual's chronotype with a single blood sample), analyzing the coupling between peripheral circadian oscillators, and live cell imaging of circadian clock proteins. Along with being an important contributor to the field of chronobiology, he is also a certified piano teacher.[3]

Background

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Education

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Kramer completed his undergraduate degrees in biochemistry from Free University of Berlin in 1993 and in piano from Berlin University of the Arts in 1994.[3]  Kramer wrote his undergraduate thesis on peptide libraries used to identify tumor necrosis factor alpha (TNF-α) antagonists under the tutelage of Jens Schneider-Mergener. In 1996, Kramer completed his Ph.D summa cum laude in Biochemistry at Humboldt University of Berlin, again working under Schneider-Mergener.[1] His dissertation research focused on identifying peptides for studying antibody-antigen interactions.[1]

Academic career

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After graduating from Humboldt University of Berlin, Kramer held several postdoctoral positions.[1] From 1996 to 1998, he was a postdoctoral fellow at the Institute of Medical Immunology at Charité.[1] During this time, he investigated the structural basis of cross-reactivity and polyspecificity of anti-p24 (HIV-1) antibody to attempt to better understand the mechanisms of molecular recognition events.[4] He then was a postdoctoral fellow under Riccardo Cortese in 1998 at the Istituto di Ricerche di Biologia Molecolare (IRBM) in Rome, Italy.[1] During this year, he learned phase-display library technology, a technique that complemented his work on cross-reactivity and polyspecificity.[5] From 1999 through 2001, Kramer also completed a postdoctoral position at the Department of Neurobiology at Harvard Medical School under Charles Weitz, where he showed how rhythmic secretion of transforming growth factor alpha (TGF-α) by the suprachiasmatic nucleus (SCN) could encourage sleep via epidermal growth factor (EGF) signaling pathways.[6][7] TGF-α binding to its epidermal growth factor receptor (EGFR) was shown to decrease locomotor activity in hamsters.[8] Hamsters lacking EGFRs were shown to have increased activity during daytime, which indicated that TGF-α could be a possible inhibitor of locomotion.[8][1]

Kramer became an Assistant Professor of Chronobiology at Charité in 2002 and has been a full tenured Professor of Chronobiology at Charité since 2007.[3] He has also held several editorial positions. He serves as the associate editor of PLoS Genetics Journal since 2013, an Editorial Board member of the Journal of Biological Rhythms since 2013, and the editor of the Circadian Clocks: Handbook of Experimental Pharmacology. Kramer has also served on the executive board of the European Biological Rhythms Society.[3]

Research interests

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Kramer's undergraduate and Ph.D research was primarily biochemistry focused. Kramer became interested in chronobiology after reading about Chuck Weitz's discovery of the partnership of BMAL1 and CLOCK. He read about Weitz's work in a Berlin newspaper, Der Tagesspiegel, and soon after applied to work as a postdoc in Weitz's lab, joining in 1999.[9] Since then, Kramer has worked mostly in the field of chronobiology.

Post-translational modifications of the circadian clock

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Kramer and his lab currently investigate how post-translational and post-transcriptional mechanisms can affect oscillations in the mammalian circadian clock.[10] This has led his team to discover some of the underlying molecular mechanisms that could be responsible for FASPS in humans, namely a defect in PER2.[11] They found PER2 to be less stable and more easily degraded in the cytoplasm in FASPS but could become stabilized when phosphorylated at Serine 662 (S662).[12][13] Out of the 247 serine or threonine sites on PER2, Kramer and his lab were able to identify 21 of them as phosphorylation sites (including S662).[14] Mutation of S662 to glycine (S662G) showed PER2 could export out of the nucleus more easily and get degraded in the cytoplasm, suggesting that changing phosphorylation of PER2 can prevent it from remaining in the nucleus.[14] This finding not only led to a better understanding of the biochemical basis for the PER2 defect in FASPS, but also demonstrated how the half-lives of circadian genes can vary based on phosphorylation of proteins.[15]

Kramer has examined the role of casein kinase 2 (CK2) in the mammalian circadian clock, specifically in its ability to phosphorylate PER2.[16] He found that down-regulation of either CK2α or CK2β lengthened circadian period while knockdown of both CK2α and CK2β caused mice to be arrhythmic, indicating CK2 has a role in the circadian clock.[16] Furthermore, inhibition of CK2α caused a delay in PER2 accumulation in the nucleus, suggesting that CK2α has a regulatory role in allowing PER2 to enter the nucleus.[16]

Kramer has also investigated how CRY1 binding to PER2 can be modulated by zinc to form the CRY1:PER2 heterodimer.[17] In 2014, his lab, in collaboration with Eva Wolf's lab, published a paper that revealed an X-ray crystal structure of CRY1:PER2 with a Zn2+ ion thought to be stabilizing the complex.[18] Specifically, Kramer and his collaborators found that CRY1 had a zinc and PER2 binding site at Cysteine 414 (C414) and was unable to bind as effectively to PER2 when mutated to an alanine (C414A).[19] The findings suggest that the Zn2+ ion facilitates the reduction of an intramolecular disulfide bond on CRY1 so that it can bind PER2 more effectively, which would make the circadian clock zinc sensitive.[20][21]

Circadian clock in the immune system

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In addition to researching post-translation modifications of clock proteins, Kramer has also studied the function of the circadian clock in the immune system.[10] He has shown how TNF-α and IL-6 secretion by lipopolysaccharide (LPS)-stimulated murine splenic macrophages display circadian rhythms that are not dependent on either variations in glucocorticoid concentrations or the circadian changes that occur in the cellular constitution of the spleen.[22] This exhibits how the molecular clock in immune cells can remain functional regardless of systemic cues.[22] Kramer was also able to show that approximately 8% of the macrophage transcriptome in mice exhibits circadian oscillation, including genes (such as JUN and FOS) that are involved in LPS-induced responses.[23]

Chronomedicine

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Kramer's work has advanced sleep health and medicine. In response to Jeffrey Hall, Michael Rosbash, and Michael Young winning the 2017 Nobel Prize in Physiology or Medicine for their work on investigating the molecular mechanisms of the biological clock, Kramer noted that "Without this, we couldn't argue for later school times on evidence-based grounds; we couldn't look for the best time to take your medicine; we couldn't find an interrelation between metabolic disorders and clock disorders."[24]

In 2018, Kramer and his colleagues developed a method to determine an individual's circadian rhythm using transcriptomics of blood monocytes taken from a single blood sample. The method identifies transcript biomarkers for internal time in the blood samples.[25] This blood test provides information about an individual's chronotype.[26] This personal chronotype identification method, what Kramer and colleagues call BodyTime, is currently being used to improve patients’ quality of sleep.[27] The project is ongoing, aiming to advance chronomedicine.

Along with optimizing the BodyTime project, Kramer is currently investigating coupling between peripheral circadian oscillators and is working on live cell imaging of circadian clock proteins.

Summary of selected publications

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  • 2001 – Identified transforming growth factor-alpha (TGF-α) as an inhibitor of locomotion via the suprachiasmatic nucleus (SCN) and epidermal growth factor (EGF) receptors[28]
  • 2006 – Identified phosphorylation regions of mPER2 that stabilized it or led to its degradation, explaining the phenotype of familial advanced sleep phase syndrome(FASPS)[29]
  • 2009 – Discovered the protein casein kinase 2 (CK2) as being an important component in the cellular clock as a phosphorylating agent of PER2[30]
  • 2009 – Found that spleen, lymph node, and peritoneal macrophages exhibit circadian rhythms in and ex vivo in mice, impacting the oscillations of the immune system[31]
  • 2014 – Discovered a zinc ion on the mCRY1-mPER2 dimer and suggested importance of zinc and disulfide bond formation to the interaction of the two clock proteins[32]
  • 2017 – Showed that heme degradation is necessary for circadian rhythms through its generation of carbon monoxide (CO). CO lessens the CLOCK-BMAL1 binding to target promoters[33]
  • 2018 – Created a method for determining internal circadian time for individuals using a single blood sample[34]

Honors and awards

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  • 1998: Young Researchers Award- Charité[1]
  • 2001: Brooks Fellow at Harvard Medical School[3]
  • 2002: Heinz-Maier-Leibitz Award from German Research Foundation (DFG)[3]
  • 2010, 2011, 2013, 2015: Teaching Awards of the Charité Master Program in Medical Neurosciences[3]

References

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  1. ^ a b c d e f g h "DFG – Deutsche Forschungsgemeinschaft – Dr. Achim Kramer – Heinz Maier-Leibnitz-Preisträger 2002". www.dfg.de. Retrieved 2019-04-10.
  2. ^ Benninger, Harrald. "Person". Institut für Medizinische Immunologie (in German). Retrieved 2019-04-10.
  3. ^ a b c d e f g "Prof. Dr. Achim Kramer | TRR 186". trr186.uni-heidelberg.de. Retrieved 2019-04-10.
  4. ^ Wucherpfennig, Kai W.; Allen, Paul M.; Celada, Franco; Cohen, Irun R.; De Boer, Rob; Garcia, K. Christopher; Goldstein, Byron; Greenspan, Ralph; Hafler, David (August 2007). "Polyspecificity of T cell and B cell Receptor Recognition". Seminars in Immunology. 19 (4): 216–224. doi:10.1016/j.smim.2007.02.012. ISSN 1044-5323. PMC 2034306. PMID 17398114.
  5. ^ Kramer, Achim. E-mail interview. 25 April 2019
  6. ^ Yan, Lily; Smale, Laura; Nunez, Antonio A. (2018-09-30). "Circadian and photic modulation of daily rhythms in diurnal mammals". The European Journal of Neuroscience. 51 (1): 551–566. doi:10.1111/ejn.14172. ISSN 1460-9568. PMC 6441382. PMID 30269362.
  7. ^ Bringmann, Henrik (April 2018). "Sleep-Active Neurons: Conserved Motors of Sleep". Genetics. 208 (4): 1279–1289. doi:10.1534/genetics.117.300521. ISSN 1943-2631. PMC 5887131. PMID 29618588.
  8. ^ a b Blum, Ian D.; Bell, Benjamin; Wu, Mark N. (May 2018). "Time for Bed: Genetic Mechanisms Mediating the Circadian Regulation of Sleep". Trends in Genetics. 34 (5): 379–388. doi:10.1016/j.tig.2018.01.001. ISSN 0168-9525. PMC 5910202. PMID 29395381.
  9. ^ Kramer, Achim. E-mail interview. 24 April 2019
  10. ^ a b "achim kramer lab :research .interests". www.achim-kramer-lab.de. Retrieved 2019-04-11.
  11. ^ Ozturk, Narin; Ozturk, Dilek; Kavakli, Ibrahim Halil; Okyar, Alper (2017-10-17). "Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy". International Journal of Molecular Sciences. 18 (10): 2168. doi:10.3390/ijms18102168. ISSN 1422-0067. PMC 5666849. PMID 29039812.
  12. ^ Kim, Mikyung; de la Peña, June Bryan; Cheong, Jae Hoon; Kim, Hee Jin (July 2018). "Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2". Biomolecules & Therapeutics. 26 (4): 358–367. doi:10.4062/biomolther.2017.131. ISSN 1976-9148. PMC 6029676. PMID 29223143.
  13. ^ Lee, Euna; Kim, Eun Young (September 2014). "A role for timely nuclear translocation of clock repressor proteins in setting circadian clock speed". Experimental Neurobiology. 23 (3): 191–199. doi:10.5607/en.2014.23.3.191. ISSN 1226-2560. PMC 4174609. PMID 25258565.
  14. ^ a b Hallows, William C.; Ptáček, Louis J.; Fu, Ying-Hui (September 2013). "Solving the mystery of human sleep schedules one mutation at a time". Critical Reviews in Biochemistry and Molecular Biology. 48 (5): 465–475. doi:10.3109/10409238.2013.831395. ISSN 1549-7798. PMC 4089902. PMID 24001255.
  15. ^ Mermet, Jérôme; Yeung, Jake; Naef, Felix (2017-03-01). "Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World". Cold Spring Harbor Perspectives in Biology. 9 (3): a028720. doi:10.1101/cshperspect.a028720. ISSN 1943-0264. PMC 5334255. PMID 27920039.
  16. ^ a b c Lowrey, Phillip L.; Takahashi, Joseph S. (2011). "Genetics of Circadian Rhythms in Mammalian Model Organisms". The Genetics of Circadian Rhythms. Advances in Genetics. Vol. 74. pp. 175–230. doi:10.1016/B978-0-12-387690-4.00006-4. ISBN 9780123876904. ISSN 0065-2660. PMC 3709251. PMID 21924978.
  17. ^ Janjić, Klara; Agis, Hermann (2019-02-13). "Chronodentistry: the role & potential of molecular clocks in oral medicine". BMC Oral Health. 19 (1): 32. doi:10.1186/s12903-019-0720-x. ISSN 1472-6831. PMC 6375164. PMID 30760278.
  18. ^ Putker, Marrit; O'Neill, John Stuart (January 2016). "Reciprocal Control of the Circadian Clock and Cellular Redox State – a Critical Appraisal". Molecules and Cells. 39 (1): 6–19. doi:10.14348/molcells.2016.2323. ISSN 0219-1032. PMC 4749875. PMID 26810072.
  19. ^ Okano, Satoshi (2016). "Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreatic β-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1". Journal of Diabetes Research. 2016: 3459246. doi:10.1155/2016/3459246. ISSN 2314-6753. PMC 5220486. PMID 28105441.
  20. ^ Masri, S.; Orozco-Solis, R.; Aguilar-Arnal, L.; Cervantes, M.; Sassone-Corsi, P. (September 2015). "Coupling circadian rhythms of metabolism and chromatin remodelling". Diabetes, Obesity & Metabolism. 17 Suppl 1 (1): 17–22. doi:10.1111/dom.12509. ISSN 1463-1326. PMC 4732882. PMID 26332964.
  21. ^ Hoyle, Nathaniel P.; O'Neill, John S. (2015-01-20). "Oxidation-reduction cycles of peroxiredoxin proteins and nontranscriptional aspects of timekeeping". Biochemistry. 54 (2): 184–193. doi:10.1021/bi5008386. ISSN 1520-4995. PMC 4302831. PMID 25454580.
  22. ^ a b Rao, Rohit T.; Pierre, Kamau K.; Schlesinger, Naomi; Androulakis, Ioannis P. (2016). "The Potential of Circadian Realignment in Rheumatoid Arthritis". Critical Reviews in Biomedical Engineering. 44 (3): 177–191. doi:10.1615/CritRevBiomedEng.2016018812. ISSN 0278-940X. PMC 5915622. PMID 28605351.
  23. ^ Hsieh, Paishiun Nelson; Zhang, Lilei; Jain, Mukesh Kumar (2018). "Coordination of cardiac rhythmic output and circadian metabolic regulation in the heart". Cellular and Molecular Life Sciences. 75 (3): 403–416. doi:10.1007/s00018-017-2606-x. ISSN 1420-682X. PMC 5765194. PMID 28825119.
  24. ^ Gannon, Megan (2017-10-02). "Nobel Prize in Medicine Awarded for Work on Biological Clock". Live Science. Retrieved 2019-04-25.
  25. ^ Kramer, Achim; Kunz, Dieter; Kadener, Sebastian; Hummel, Michael; Herzel, Hanspeter; Lammert, Hedwig; Ashwal-Fluss, Reut; Bartok, Osnat; Zaleska, Mandy (2018-08-31). "High-accuracy determination of internal circadian time from a single blood sample". The Journal of Clinical Investigation. 128 (9): 3826–3839. doi:10.1172/JCI120874. ISSN 0021-9738. PMC 6118629. PMID 29953415.
  26. ^ "Chronobiology – adapting to biorhythms". Deutsche Welle. 2019-01-10. Retrieved 2019-04-11.
  27. ^ "Connecting Everyday Life to the Biological Clock". BodyTime. Retrieved 2019-04-11.
  28. ^ Kramer, A.; Yang, F. C.; Snodgrass, P.; Li, X.; Scammell, T. E.; Davis, F. C.; Weitz, C. J. (2001-12-21). "Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling". Science. 294 (5551): 2511–2515. Bibcode:2001Sci...294.2511K. doi:10.1126/science.1067716. ISSN 0036-8075. PMID 11752569. S2CID 41153720.
  29. ^ Vanselow, Katja; Vanselow, Jens T.; Westermark, Pål O.; Reischl, Silke; Maier, Bert; Korte, Thomas; Herrmann, Andreas; Herzel, Hanspeter; Schlosser, Andreas (2006-10-01). "Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS)". Genes & Development. 20 (19): 2660–2672. doi:10.1101/gad.397006. ISSN 0890-9369. PMC 1578693. PMID 16983144.
  30. ^ Maier, Bert; Wendt, Sabrina; Vanselow, Jens T.; Wallach, Thomas; Reischl, Silke; Oehmke, Stefanie; Schlosser, Andreas; Kramer, Achim (2009-03-15). "A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock". Genes & Development. 23 (6): 708–718. doi:10.1101/gad.512209. ISSN 1549-5477. PMC 2661607. PMID 19299560.
  31. ^ Keller, Maren; Mazuch, Jeannine; Abraham, Ute; Eom, Gina D.; Herzog, Erik D.; Volk, Hans-Dieter; Kramer, Achim; Maier, Bert (2009-12-15). "A circadian clock in macrophages controls inflammatory immune responses". Proceedings of the National Academy of Sciences of the United States of America. 106 (50): 21407–21412. Bibcode:2009PNAS..10621407K. doi:10.1073/pnas.0906361106. ISSN 1091-6490. PMC 2795539. PMID 19955445.
  32. ^ Schmalen, Ira; Reischl, Silke; Wallach, Thomas; Klemz, Roman; Grudziecki, Astrid; Prabu, J. Rajan; Benda, Christian; Kramer, Achim; Wolf, Eva (2014-05-22). "Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation". Cell. 157 (5): 1203–1215. doi:10.1016/j.cell.2014.03.057. ISSN 1097-4172. PMID 24855952.
  33. ^ Klemz, Roman; Reischl, Silke; Wallach, Thomas; Witte, Nicole; Jürchott, Karsten; Klemz, Sabrina; Lang, Veronika; Lorenzen, Stephan; Knauer, Miriam (January 2017). "Reciprocal regulation of carbon monoxide metabolism and the circadian clock" (PDF). Nature Structural & Molecular Biology. 24 (1): 15–22. doi:10.1038/nsmb.3331. ISSN 1545-9985. PMID 27892932. S2CID 41438780.
  34. ^ Wittenbrink, Nicole; Ananthasubramaniam, Bharath; Münch, Mirjam; Koller, Barbara; Maier, Bert; Weschke, Charlotte; Bes, Frederik; de Zeeuw, Jan; Nowozin, Claudia (2018-08-31). "High-accuracy determination of internal circadian time from a single blood sample". The Journal of Clinical Investigation. 128 (9): 3826–3839. doi:10.1172/JCI120874. ISSN 1558-8238. PMC 6118629. PMID 29953415.
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