Achim Kramer

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

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. 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. He then was a postdoctoral fellow under Riccardo Cortese in 1998 at the Istituto di Ricerche di Biologia Molecolare (IRBM) in Rome, Italy. 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. TGF-α binding to its epidermal growth factor receptor (EGFR) was shown to decrease locomotor activity in hamsters. Hamsters lacking EGFRs were shown to have increased activity during daytime, which indicated that TGF-α could be a possible inhibitor of locomotion. Since then, Kramer has worked mostly in the field of chronobiology.

Post-translational modifications of the circadian clock Kramer and his lab currently investigate how post-translational and post-transcriptional mechanisms can affect oscillations in the mammalian circadian clock. 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. 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). 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). 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.

Kramer has examined the role of casein kinase 2 (CK2) in the mammalian circadian clock, specifically in its ability to phosphorylate PER2. 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. 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. 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). 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.

Circadian clock in the immune system In addition to researching post-translation modifications of clock proteins, Kramer has also studied the function of the circadian clock in the immune system. This exhibits how the molecular clock in immune cells can remain functional regardless of systemic cues.

Chronomedicine 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."

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. This blood test provides information about an individual's chronotype. This personal chronotype identification method, what Kramer and colleagues call BodyTime, is currently being used to improve patients' quality of sleep. 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

2001 – Identified transforming growth factor-alpha (TGF-α) as an inhibitor of locomotion via the suprachiasmatic nucleus (SCN) and epidermal growth factor (EGF) receptors 2006 – Identified phosphorylation regions of mPER2 that stabilized it or led to its degradation, explaining the phenotype of familial advanced sleep phase syndrome(FASPS) 2009 – Discovered the protein casein kinase 2 (CK2) as being an important component in the cellular clock as a phosphorylating agent of PER2 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 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 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 2018 – Created a method for determining internal circadian time for individuals using a single blood sample

Honors and awards

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