I actually wanted to become a football star… like almost every other boy at that time in Germany… fortunately, I was smart enough to realize that I wasn't talented enough for football… and I was also lucky enough to watch a movie that really inspired me… the movie is called Blade Runner (a must see!!!)… because of the movie I thought it must be super cool to become a genetic engineer trying to create artificial life forms… not knowing that science at that time was far away from even understanding the human genome (and still is!!!)… however, I studied biochemistry at the “Freie Universität Berlin“ and finished my studies with the synthesis of a photo-cleavable non-ionic detergent to improve the separation performance of complex protein mixtures in the 2 dimensional gel electrophoresis (see: Light-triggered conversion of non-ionic into ionic surfactants: towards chameleon detergents for 2-D gel electrophoresis)…
It was at the end of my studies when I became inspired a 2nd time… this time by a number of scientific articles about the capsaicin or TRPV1 receptor… the authors were able to show that the burning sensation or pain that we feel when we eat something spicy (chili peppers) or touch something hot was due to the activation of the capsaicin/TRPV1 receptor in sensory nerve terminals (see: The capsaicin receptor: A heat activated ion channel in the pain pathway. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. Nature 1997; Vol. 389, 816-824)… a little later the same group was able to demonstrate that thermal inflammatory hyperalgesia depends on the presence of the capsaicin/TRPV1 receptor in sensory nerve terminals (see: Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Science 2000; Vol. 288, 306-313)… this was – at least in my opinion – the beginning of a new area of pain research as it was the first clear demonstration that a painful sensation can be explained by conformational changes in a single protein… I remember that I was very fascinated by these findings… and that I decided to do my PH D thesis on pain research…
During my PH D thesis in the lab of Prof. F. Hucho I was trying to identify the molecule that renders a subpopulation of sensory afferent C-fiber nociceptors IB4 positive… IB4-binding C-fiber nociceptors constitute an important class of nociceptors and it is believed that their malfunctioning is responsible for the pain of people suffering from certain chronic inflammatory or neuropathic pain syndromes (although human C-fiber nociceptors do not react to IB4)… a better understanding of the biological function of IB4-binding C-fiber nociceptors is therefore essential for the development of new analgesics that can be used to treat chronic pain-syndromes resistant to classical opioid or non-steroidal anti-inflammatory drugs based therapies… during my PH D thesis I was able to identify versican as a) an IB4-binding molecule and b) one of the molecules that renders IB4-binding afferent C-fiber nociceptors IB4-positive (see: Identification of versican as an isolectin B4-binding glycoprotein from mammalian spinal cord tissue)… and one of the first things that I did when I started my postdoc in the lab of Prof. JD Levine at UCSF was to elucidate some of the biological functions of the IB4-binding versican (see: 1) GDNF hyperalgesia is mediated by PLCγ, MAPK/ERK, PI3K, CDK5 and SRC kinase signaling and dependent on the IB4-binding protein versican… and 2) Dependence of MCP-1 induced hyperalgesia on the IB4-binding protein versican)…
I also initiated work to analyze whether certain pain syndromes for which our lab has established animal models are dependent on IB4-binding afferent C-fiber nociceptors or not… the idea that different nociceptor subpopulations might have different functions and that certain pain syndromes are caused by the malfunctioning of only a few of them is quite old (see for example: Tackling pain at the source: New ideas about nociceptors. Snider WD, McMahon SB. Neuron 1998; Vol. 20, 629-632)… however, nobody before had analyzed whether certain pain syndromes are dependent on IB4-binding afferent C-fiber nociceptors or not… and over the last couple of years our group was able to show that certain pain syndromes are – indeed – dependent on IB4-binding afferent C-fiber nociceptors (see for example: 1) Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress dependent acute painful peripheral neuropathy… and 2) IB4-positive nociceptors mediate persistent muscle pain induced by GDNF)…
Understanding the pathophysiological mechanisms underlying chronic pain states will be a critical step in the development of new therapies to specifically target the distinct mechanisms of chronic pain… and our lab has developed an animal model for the transition from acute to chronic pain, called hyperalgesic priming, in which afferent C-fiber nociceptors that have been exposed to an inflammatory or neuropathic insult develop a long-lasting hyperalgesic response to a subsequent challenge by the proinflammatory cytokine prostaglandin E2 (PGE2, which is the target of the most commonly used class of drugs for treating pain, the nonsteroidal anti-inflammatory drugs; see: Critical role of nociceptor plasticity in chronic pain. Reichling DB and Levine JD. Trends Neurosci 2009; Vol. 32, 611-618)… and it was my idea to analyze whether hyperalgesic priming is dependent on a certain subpopulation of nociceptors (see: 1) Nociceptor subpopulations involved in hyperalgesic priming… and 2) Hyperalgesic priming is restricted to IB4-positive nociceptors. Joseph EK, Levine JD. Neuroscience 2010; Vol. 169, 431-435)… moreover, since hyperalgesic priming is still present months after the precipitating inflammatory or neuropathic stimulus, it must be associated with the formation of a molecular memory in IB4-binding C-fiber nociceptors. Based on my ideas (and inspired by the excellent work of the Eric Kandel lab) we were able to demonstrate that… a) a prion-like misfolding mechanism could be responsible for the chronification of pain (see: Generation of a pain memory in the primary afferent nociceptor triggered by PKCε activation of Cpeb)… and b) that hyperalgesic priming can be reversed by the inhibition of protein translation (see: Peripheral administration of translation inhibitors reverses increased hyperalgesia in a model of chronic pain in the rat)...
Right now I am interested in/working on the following three topics… 1) I am trying to elucidate the biological function of the IB4-reactivity of IB4(+)-C-fiber nociceptors (I have already an idea)… 2) I am trying to develop a method to selectively down-regulate the expression level of proteins in nociceptor subpopulations (first experiments were quite promising), and last but not least 3) I am trying to understand the molecular and cellular mechanisms underlying mechanical hyperalgesia/allodynia (I am planning to write a small review)…