The American Society for Pharmacology and Experimental Therapeutics (ASPET) awarded Dr. Krzysztof Palczewski from the University of California, Irvine, the 2022 Goodman and Gilman Award in Receptor Pharmacology. The Louis S. Goodman and Alfred Gilman Award in Receptor Pharmacology was established in 1980 to recognize and stimulate outstanding research in pharmacology of biological receptors. Such research might provide a better understanding of the mechanisms of biological processes and potentially provide the basis for the discovery of drugs useful in the treatment of diseases.
Dr. Palczewski is receiving this award in recognition of his innovative and pathfinding studies on mechanisms of activation of G protein-coupled receptors that have advanced understanding of receptor structure, signaling mechanism, defects that lead to disease, and treatments that preserve vision.
Dr. Palczewski is a Donal Bren Professor and Distinguished Professor at the University of California, Irvine, holds the Irving H. Leopold Chair of Ophthalmology, and is the Director of the Center for Translational Vision Research at the Gavin Herbert Eye Institute. He received his PhD in biochemistry at the Technical University of Wroclaw, Poland and did postdoctoral training at the University of Florida.
Dr. Palczewski’s research utilizes a variety of multidisciplinary approaches to study phototransduction and the visual cycle to characterize the visual system in health and disease. Pursuit of such a comprehensive understanding of vision, including gene expression and transcriptional regulation, is essential to combat genetic defects, metabolic aberrations, and environmental insults leading to blindness. He has identified elements of the signaling pathways of the visual system, through targeted structural biology at different levels of resolution, obtained with classical and time-resolved crystallography, cryo-electron microscopy, and cellular cryo-electron tomography. By studying a precise structural and functional account of the participating retinal cells and their intracellular organization with two-photon in vivo and ex vivo microscopy, his work has made groundbreaking advances to recognize biochemical perturbations for early diagnosis of ocular diseases and stratification of patients for the discovery and validation of pharmacological treatments and to prevent retinal degenerative diseases.
Dr. Palczewski has been a member of ASPET since 2015.
The award will be presented at the ASPET Business Meeting and Awards Presentation during the ASPET Annual Meeting at Experimental Biology 2022 on Saturday, April 2 at 4:30 pm in Philadelphia. Additionally, Dr. Palczewski will deliver the award lecture titled G Protein–coupled Receptor Signaling in Phototransduction at the 2022 annual meeting on Sunday, April 3 at 1:00 pm in Philadelphia.
Professor K. Palczewski is the Co-Founder of ICTER. We sincerely congratulate him on receiving this prestigious award.
On March 9, 2022, we held the ICTER ISC 2022 Annual Meeting and Review. We met in hybrid mode, physically at Varso Place, downtown Warsaw, and online via Zoom. We summarized our scientific and research activities in 2021 for the experts of the International Scientific Committee, and presented strategic goals for our future research program. Invited guests from Poland and abroad delivered talks.
Dr Colin Chu from the Institute of Ophthalmology at University College London gave a lecture entitled: “Imaging Immune Responses in the Retina”. Dr Colin Chu is a Clinical Senior Research Fellow at the University of Bristol and Moorfields Eye Hospital, London. He has recently been awarded a Wellcome Trust Fellowship to start his lab at UCL Institute of Ophthalmology. He did his PhD at UCL before post-doctoral training with Prof Andrew Dick in Bristol and with Dr Ron Germain at the US National Institutes of Health. As a clinician-scientist and ophthalmologist his focus is on improving the care of patients with retinal diseases and studying fundamental immunology by applying in vivo and ex vivo imaging techniques to the eye.
Dr Alice Davidson from the Institute of Ophthalmology at University College London gave a talk entitled “Corneal Endothelial Dystrophies: A Paradigm for Non-Coding and Repeat Expansion-Mediated Disease Mechanisms”. Associate Professor Alice Davidson is a UKRI Future Leader Fellow Professor at the University College London Institute of Ophthalmology (UCL IoO), London, UK. Dr Davidson started her scientific research career at the University of Manchester where she undertook a PhD in Molecular Genetics and Cell Biology (2006-2010), investigating the role of bestrophin-1 in ocular disease. She subsequently worked as a postdoctoral scientist at UCL IoO (2010-2015). In 2015 she was awarded a Fight for Sight Early Career Investigator Award to initiate her own independent research programme at UCL IoO and later a prestigious UKRI Future Leader Fellowship (2019) to further advance her inherited corneal disease research program.
Prof. Pearse Keane from Moorfields Eye Hospital in London gave a lecture entitled: “Artificial intelligence in ophthalmology – going from code to clinic”. Pearse Keane is Professor of Artificial Medical Intelligence at UCL Institute of Ophthalmology, and a consultant ophthalmologist at Moorfields Eye Hospital, London. He is originally from Ireland and received his medical degree from University College Dublin (UCD), graduating in 2002. In 2016, he initiated a formal collaboration between Moorfields Eye Hospital and Google DeepMind, with the aim of developing artificial intelligence (AI) algorithms for the earlier detection and treatment of retinal disease. In August 2018, the first results of this collaboration were published in the journal, Nature Medicine. In May 2020, he jointly led work, again published in Nature Medicine, to develop an early warning system for age-related macular degeneration (AMD), by far the commonest cause of blindness in many countries.
Prof. Krzysztof Palczewski of the University of California, Irvine gave a visionary lecture entitled: “Precise genome editing in the eye”. Prof. Palczewski is a co-founder of ICTER. He is a biochemist and a globally renown expert in biochemistry of vision – employed in the Medical School at the University of California Irvine, USA. Author of more than 500 scientific papers published in the leading magazines, including “Science,” “Nature” and “Molecular Cell” – filled over 10 patents and patent applications. His significant achievements include crystallizing and describing the structure and function of rhodopsin, as well as discovering the mechanisms leading to retinal degeneration and, in consequence, to vision loss.
At the meeting, representatives from the following authorities also attended and delivered presentations:
Polish Academy of Sciences: Vice President Prof. Paweł Rowiński,
Institute of Physical Chemistry of the Polish Academy of Sciences: Deputy Director for Scientific Affairs Dr. Adam Kubas, Professor of the Institute,
Foundation for Polish Science: President of the Board Prof. Maciej Żylicz.
Podcast hosts Piotr and Aleksandra Stanisławscy, creators of the Crazy Nauka science popularizing blog, talk about vision, ocular diseases, and eye health with their guest, physicist specializing in applied optics and medical and experimental physics, leader of the Physical Optics and Biophotonics group at ICTER.
Even mild head injuries can mean serious consequences for brain function at its most basic level. Research published in Communications Biology shows that neuroplasticity, too, has its limits.
Injuries to the posterior occipital cortex are common in humans. Traumatic brain injury (TBI) can lead to long-term visual impairment (like loss of visual acuity). For example, estimates suggest that as many as 75% of current or former soldiers live with permanent visual dysfunction or cortical blindness. TBI is associated with mechanical brain damage and a wide range of neuronal abnormalities.
The human brain is characterized by surprising plasticity. Even when one part is injured, the functions of the damaged neurons can be taken over by other cells. This is because neural tissue has a remarkable ability to form new connections to reorganize, adapt, change, and self-repair the entire organ.
Such neuroplasticity is also characteristic of the sensory areas of the visual cortex. This region of the brain is the final component of the visual pathway, responsible for receiving and processing visual impressions. The primary visual cortex (V1) is reached by the nerve fibers of the optic radiation, which carry nerve impulses from the retinas of both eyes.
Until now, scientists knew little about the effects of TBI on long-term visual circuit function. A team of researchers led by John C. Frankowski and Andrzej Foik examined in vivo (in adult mice) how neurons respond to visual stimuli two weeks and three months after mild injury to the primary visual cortex (V1). V1 neurons normally show sensitivity to different features of a visual stimulus, such as color or direction of movement. The preprocessed data is transmitted to subsequent areas of the visual cortex. This study showed that although the primary visual cortex remained largely intact after the brain injury, there was a 35% reduction in the number of neurons. This loss largely affected inhibitory neurons rather than excitatory neurons, which, as their names indicate, inhibit or stimulate action in the target cells, respectively.
After TBI, less than half of the isolated neurons were sensitive to visual stimuli (32% at two weeks after injury; 49% at three months after the event), compared with 90% of V1 cells in the control group. There was as much as a threefold decrease in neuronal activity after the brain injury, and the cells themselves had worse spatial orientation. The overall results mean that even minor, superficial brain injuries cause long-term impairment in the way visual stimuli are perceived, persisting several months after the event.
A deeper understanding of the functional impairments in damaged visual cortex is important because it can provide a basis for developing circuit-level therapies for visual cortex damage.
The biochemistry of vision is a complex process. The molecules supporting the visual pigments that allow us to see our surrounding reality have remained essentially invisible for scientists for a long time. The team led by Prof. Maciej Wojtkowski from the International Centre for Translational Eye Research (ICTER) has changed that, thanks to an innovative state-of-the art imaging device that they have developed.
It is commonly said that eyes are the mirror of the soul; however, they are undoubtedly our window on the world. The retina of the eye represents the first and very important processing station for the path of light as it is converted into an image. Molecular reactions occurring in the retina are crucial for the perception of visual stimuli from the environment.
For many years scientists and doctors have not been able to observe molecules present in the natural milieu of the retinal photosensitive cells in vivo. The team of scientists led by Prof. Maciej Wojtkowski from ICTER at the Institute of Physical Chemistry, Polish Academy of Sciences (IPC PAS) have developed a two-photon excited fluorescence scanning laser ophthalmoscope (TPEF-SLO). It is an instrument that remarkably allows viewing the biochemistry of vision in the living eye in real time. Prof. Wojtkowski points out that “thanks to close collaborations with biochemist Prof. Kris Palczewski from the University of California Irvine and the laser group of Prof. Grzegorz Soboń from the Wrocław University of Science and Technology, we can quickly and effectively demonstrate the capabilities of the new imaging method and validate its utility for diagnosing disease progression and treatment, leading to its use in clinical practice.”
How does it happen that we see?
The human eye is one of the most precise organs of our body, capable of distinguishing about 200 pure colors. Mixing these colors produces about 17,000 different hues, and taking into account our ability to distinguish about 300 intensities of color associated with light intensity, we get a staggering 5 million perceived colors.
The retina, the part of the eye that receives visual stimuli, contains photosensitive cells, cones and rods. The cones enable us to see and distinguish colors in bright light, while the rods are sensitive to single pulses of visible light at dusk or night. Visual impressions are transmitted via the optic nerve to the primary visual cortex in the brain, but the signals that carry the visual impressions are the result of biochemical processes that occur in the photoreceptors. “Simplifying, we can say that the human eye is a biochemical factory whose activity depends on biochemical transformations of a single molecule, retinal. This molecule is indispensable for the function of the visual pigments, namely rhodopsin in rods” – says Prof. Maciej Wojtkowski.
Rhodopsin, the visual pigment in rods is a light sensitive G-protein coupled receptor (GPCR). Absorption of a quantum of radiation causes isomerization of 11-cis-retinal within the rhodopsin binding pocket and subsequent hyperpolarization of the photoreceptor membranes. In this manner the visual impulse is initiated and transmitted to the brain. A deficiency of vitamin A, precursor of retinal, reduces the ability to see at night, known as night blindness or nyctalopia.
Unfortunately, the molecules indispensable for sustaining visual pigments are undetectable by scientific instruments during virtually the entire visual cycle in living humans. “However, there is one instant in the visual cycle when the molecules can be seen; we can’t detect them with UV light, but we can observe them thanks to so-called fluorescence with two-photon excitation,” adds Dr. Jakub Boguslawski, a main researcher on the project.
Two-photon process, color palette
Ophthalmic imaging techniques are fundamental in diagnosing retinal pathologies. With optical tomography (OCT), scanning laser ophthalmoscopy (SLO), and fundus autofluorescence, we have made advances in understanding mechanisms of eye diseases. This collection of advanced technologies, however, is an insufficient arsenal for full insight into the chemistry of vision. Non-invasive assessment of metabolic processes occurring in retinal cells (visual pigment regeneration) is essential for the development of future therapies. In the case of age-related macular degeneration (AMD), which is one of the most common diseases causing blindness, cells within a disease-altered retina cannot be distinguished at an early stage from cells of a normal healthy retina. However, the differences can be picked up by biochemical markers, if these markers can be fluorescently induced.
This is the idea behind two-photon fluorescence imaging (TPE). It is an advanced technique for measuring compounds that support the function of visual pigments and are not visible in other tests.
Compared to traditional imaging methods based on single-photon fluorescence, TPE allows the metabolites of vitamin A that are involved in vision, such as retinol or retinol esters, to be viewed. “The eye is an ideal organ for multiphoton imaging,” says Prof. Wojtkowski, whose team is responsible for the discovery. Eye tissues such as the sclera, cornea, and lens are highly transparent to near-infrared light. This, in turn, penetrates retinal tissues in a non-invasive way.
Images obtained with TPEF-SLO have confirmed that this is an effective way to view the molecules that sustain visual function. Comparison of data from humans with retinal degeneration with mouse models of the disease revealed a similar rapid accumulation of bisretinoid condensation products. “We believe that visual cycle intermediates and toxic byproducts of this metabolic pathway could be measured and quantified using TPE imaging,” says Dr. Grazyna Palczewska, one of the project’s main investigators.
This new age instrument, enabling non-invasive assessment of the metabolic state of the human retina, opens numerous therapeutic possibilities for degenerative diseases of the retina, including the testing of new drugs. By understanding the biochemistry of vision and the alterations that occur in disease, physicians will be able to pinpoint precise locations of the lesions and assess the impact of therapy. The research on TPEF-SLO was published in The Journal of Clinical Investigation.
Authors: Jakub Boguslawski, Grazyna Palczewska, Slawomir Tomczewski, Jadwiga Milkiewicz, Piotr Kasprzycki, Dorota Stachowiak, Katarzyna Komar, Marcin J. Marzejon, Bartosz L. Sikorski, Arkadiusz Hudzikowski, Aleksander Głuszek, Zbigniew Łaszczych, Karol Karnowski, Grzegorz Soboń, Krzysztof Palczewski, and Maciej Wojtkowski.
For many years visual inspection of fundus photography and examination of images acquired with optical coherence tomography (OCT) have been used by ophthalmologists for eye disease diagnosis and monitoring therapy progress thanks to their ability to detect morphological biomarkers of pathophysiology. However, early retinal degeneration might affect photoreceptor physiology and their functional response to light stimuli long before disrupting retinal morphology at a scale visible by clinical instruments. The anomalies in physiological response can be measured with Electroretinography (ERG), by recording the electrical currents generated directly by retinal neurons in combination with contributions from retinal glia. The drawback of ERG is that it measures an average response from large portions of the retina, and it might miss physiological changes occurring only in small areas. This issue can be partially solved by multifocal ERG, which measures the response from specific retinal regions. However, discriminating photoreceptor degeneration from that of the neural retina remains a problem.
More recently, a new technique called optoretinography (ORG) has been developed. In this technique, the physiological response to a single pulse light stimulus is measured with the use of OCT. In our work, we focus on the development of ORG that can measure response to a flicker stimulus. Similar measurements have been performed with ERG multiple times, and they have proven instrumental in the analysis of retinal light adaptation and critical flicker frequency (CFF) variations between the macula and periphery.
Our results have already demonstrated that we could detect the photoreceptor response to different flicker frequencies in a repeatable fashion. We also demonstrated the ability to spatially detect the response to a patterned stimulus with light stripes flickering at different frequencies. These results highlight the prospect for a more objective study of CFF variations across the retina or complete characterization of the spatially resolved temporal frequency response of the retina with flicker ORG perimetry and other novel accurate retinal functional studies for early detection of retinal degeneration and therapy monitoring.
ICTER delegation composed by Prof. dr hab. Maciej Wojtkowski, dr Andrea Curatolo – IDoc Research Group leader, and Managing Director Anna Pawlus, represented the Institute of Physical Chemistry and our Research Centre at the Back2business, Polish Research and Innovation networking event, on Tuesday, November 9, 2021 in Brussels.
The authorities present at the event were: dr Wojciech Kamieniecki – Director of NCBR, Andrzej Sadoś – Permanent Representative of Poland to the EU Signe Ratso, Deputy Director-General, DG Research and Innovation, European Commission, Ewa Kocińska-Lange – Director of NCBR Office in Brussels / BSP, Agnieszka Ratajczak – National Centre for Research and Development – moderator, prof. dr hab. Zbigniew Błocki – National Science Centre, Przemysław Kurczewski – National Centre for Research and Development, Malwina Górecka – National Agency for Academic Exchange, Michał Pietras – Foundation for Polish Science, prof. dr hab. Paweł Rowiński – Polish Academy of Sciences, dr Piotr Dardziński – Łukasiewicz Research Network, and prof. dr hab. Elżbieta Żądzińska – Conference of Rectors of Academic Schools in Poland.
Our delegation presented the Institute’s of Physical Chemistry, Polish Academy of Sciences and ICTER’s achievements and research results, and made some valuable connections for the future.
Keratoconus is an eye disease that affects the cornea, the clear transparent lens outside our eyes. Keratoconus is a progressive disease that affects 1 in 1000 people and, if untreated, might lead to blindness. However, the early detection of keratoconus is still a clinical challenge.
This work was developed in the frame of MAiCRO project, financed by National Science Center, at ICTER in collaboration with colleagues from Volantis, from the Antwerp University Hospital in Belgium.
In this paper a reinterpretation of already available clinical data to enhance the early detection of keratoconus is proposed. During a standard ophthalmologist examination, doctors focus mainly on analyzing macroscopic data: corneal shape, thickness, radius, and other geometrical parameters. The analysis of this information allows the ophthalmologists to diagnose different eye diseases, but it has repeatedly proven to be not enough for a proper diagnosis, specially in the early cases.
What innovation brings the approach proposed by Consejo, Jiménez-García, Issarti & Rozema? The authors define a diagnostic tool based not only on traditional macroscopic parameters, but also on microscopic data of the cornea’s tissue, combining both approaches (macro- and microscopic information) in a methodology denominated MAiCRO. In particular, in this article, corneal tomographies of sixty right eyes were obtained from the Department of Ophthalmology at the Antwerp University Hospital. The patients were divided in three study groups: controls (20 eyes), clinical keratoconus (20 eyes), and subclinical keratoconus (20 eyes) – subclinical keratoconus are eyes that have not developed the disease yet. The study defined biomarkers that account for tissue transparency and compared these biomarkers between study groups. To define those biomarkers different techniques of image processing and statistical modelling of light intensity distribution (in other words, using information of the journey of the light through the cornea) were applied.
The results of the study validated with a ROC analysis confirmed a discrimination success of 97% when differentiating between subclinical keratoconus and control eyes, which is a much higher clinical diagnosis rate success than clinical standards.
One of the benefits of this methodology is the reinterpretation of commonly available hospital data obtained through non-invasive ophthalmological tomography based on Scheimpflug technology. Using MAiCRO methodology, doctors do not need to take more measurements, or perform additional tests in order to be able to diagnose Keratoconus more effectively than before.
Dr Alejandra Consejo is a Postdoctoral fellow collaborating with ICTER.
Supported by funding from the National Science Centre (Poland) under the OPUS 19 funding scheme (project no. 2020/37/B/ST7/00559).