Gebhard Schertler is head of the research division Biology and Chemistry at the Paul Scherrer Institute PSI and professor for Structural Biology at ETH Zurich. In this interview he talks about biological research at PSI and the future of drug development.
Using X-ray laser technology, a team led by researchers of the Paul Scherrer Institute PSI has recorded one of the fastest processes in biology. In doing so, they produced a molecular movie that reveals how the light sensor retinal is activated in a protein molecule. Such reactions occur in numerous organisms. The movie shows for the first time how a protein efficiently controls the reaction of the embedded light sensor.
With a new method for modifying antibodies, Philipp Spycher, winner of a Founder Fellowship at the Paul Scherrer Institute PSI, wants to develop drugs that are more stable and, thus, have fewer side-effects.
The Nobel Prize in Chemistry 2017 has been awarded to Jacques Dubochet of Switzerland, U.S.-based German scientist Joachim Frank, and Richard Henderson of the United Kingdom for the development of structural analysis of single biological molecules by means of cryo-electron microscopy. The awarding of the prize underscores the fundamental significance of structural analysis of biomolecules for modern biology – a research area where the Paul Scherrer Institute PSI plays a leading role in Switzerland.
A pharmaceuticals manager at Roche for a long time, now he is the founder of a biotech firm on the campus of the Paul Scherrer Institute PSI: Michael Hennig knows the trends in the medical sector. In this interview he explains why the medicine of the future needs the innovation power of publicly funded research, and why he chose to locate his start-up leadXpro so close to PSI.
2016 and older
Bacteriorhodopsin is a membrane protein that harvests the energy content from light to transport protons out of the cell against a transmembrane potential. Nango et al. used timeresolved serial femtosecond crystallography at an x-ray free electron laser to provide 13 structural snapshots of the conformational changes that occur in the nanoseconds to milliseconds after photoactivation. These changes begin at the active site, propagate toward the extracellular side of the protein, and mediate internal protonation exchanges that achieve proton transport.
At the PSI, researchers work with radioactivity every day in order to develop advanced treatment methods for patients. Naturally, they take special safety precautions working with a material that decays. It's a race against time. To make sure everything functions smoothly, a dedicated work group takes care of the infrastructure.
Proteins are indispensable building blocks of life. They play a vital role in many biological processes. Researchers have now been able to show how the ultrafast processes by which proteins do their work can be studied with free-electron X-ray lasers such as SwissFEL at the Paul Scherrer Institute PSI. Free-electron X-ray lasers generate extremely short and intense pulses of X-ray light. Currently there are just two such facilities in operation, worldwide. The results were published in the scientific journal Nature Communications.
Researchers at the PSI have for the first time used a cyclotron to produce the radionuclide scandium-44 in a quantity and concentration as needed for medical treatment. With that, they have achieved the first precondition for scandium-44 to be used one day for medical tests in hospitals.
PSI researcher Kurt Ballmer-Hofer is concerned with the question of how tumours could be
starvedby preventing the development of blood vessels. After 40 years of research that yielded many fundamental insights about the formation of blood vessels, one of the key molecules has been found; further research is expected to enable clinical applications.
Researchers at the Paul Scherrer Institute PSI are now investigating a new method to channel radioactive substances directly into the nucleus of a cancer cell. Through this approach, the radiation source remains inside the cell and works in a more targeted way, because it gets closer to the cell's genetic information.
3. March 2016Medical Science Human Health Radiopharmacy
At PSI, scientists are developing new medicines against cancer. These contain radioactive substances that can be injected into the patients and thus make their way to the tumour. There, in direct contact, their radiation should destroy the cancer cells. Before such a radioactive medicine can be tested on patients in the first clinical trials, however, its safety must be guaranteed to ensure that the patient will not be harmed. Therefore every agent is produced at the PSI under sterile conditions and tested – separately for each patient, and only on the doctor's order.
17. February 2016Medical Science Human Health Radiopharmacy
Researchers at the Paul Scherrer Institute PSI have developed a drug to trace and treat a particularly malignant strain of thyroid cancer more effectively. One advantage of the new drug is that it can be used to treat a strain of thyroid cancer where the established treatment is ineffective. The researchers at PSI have developed the new drug to such an extent that an initial study conducted on cancer patients at the University Hospital Basel can now get underway.
3. February 2016Media Releases Biology Human Health Medical Science
New insights into the workings of important drug receptors
Many medical drugs operate on specific receptors located in the outer walls of our body’s cells. One of these is called the beta-1 adrenergic receptor. Among other things, it is responsible for palpitation, the racing pulse that we feel with stage fright or infatuation. How it transmits signals to the cellular interior can now be revealed in detail. These findings could help scientists better understand many drugs' mode of action.
10. August 2015Media Releases Biology Human Health Medical Science
Researchers unveil new details of how cells in a living organism process stimuli. So-called G-proteins, which help conduct external stimuli that reach a cell into its interior, play a central role here. For the first time, the study shows which parts of the G-proteins are vital for their function. Researchers from the Paul Scherrer Institute PSI, ETH Zurich, the pharmaceutical company Roche and the British MRC Laboratory of Molecular Biology report their results in the journals Nature and Nature Structural and Molecular Biology.
26. May 2015Research Using Synchrotron Light Large Research Facilities SwissFEL Human Health
Decoding biomolecules at SwissFEL and SLS
Proteins are a coveted but stubborn research object. A method developed for x-ray free-electron lasers and PSI’s future SwissFEL should now help researchers to make good headway in this field. It involves x-raying many small, identical protein samples consecutively at short intervals, thereby avoiding the main problem that protein research has faced thus far: producing samples in a sufficient size.
Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent beta - emitters: In vitro and in vivo study of a 44Sc-DOTA-folate conjugateResearch Division Biology and Chemistry (BIO), Folate Receptor Targeting Group, Head Cristina Müller. In recent years, implementation of 68Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of 44Sc (half-life = 3.97 h, average β+ energy [Eβ+av] = 632 keV) as a valuable alternative to 68Ga (half-life = 68 min, Eβ+av = 830 keV) for imaging and dosimetry before 177Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced 44Sc and its in vitro and in vivo comparison with the 177Lu-labeled pendant. Methods: 44Sc was produced via the 44Ca(p,n)44Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 μA, 30 min) using an enriched 44Ca target (10 mg 44CaCO3, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of 44Sc-cm09 was tested in human plasma. 44Sc-cm09 was investigated in vitro using folate receptor–positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice Results: Under the given irradiation conditions, 44Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of 44Sc from 44Ca targets allowed formulation of up to 300 MBq of 44Sc in a volume of 200–400 μL of ammonium acetate/HCl solution (1 M, pH 3.5–4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, 44Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor–specific binding to KB tumor cells. PET/CT images of mice injected with 44Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with 44Sc and 177Lu revealed almost identical pharmacokinetics. Conclusion: This study presents a high-yield production and efficient separation method of 44Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of 44Sc for PET imaging. Thus, 44Sc is a valid alternative to 68Ga for imaging and dosimetry before 177Lu-radionuclide tumor therapy.
17. November 2013Media Releases Biology Research Using Synchrotron Light Human Health
Botox is a highly dangerous toxin that causes paralysis. In cosmetic applications it is used to temporarily eliminate wrinkles and in medicine as a treatment for migraine or to correct strabismus. An international research team has now established how the toxin molecule binds to the neuron whose activity is then blocked by the poison. The findings may be useful for the development of improved drugs with a lower risk of overdosage.
DOTA conjugate with an albumin-binding entity enables the first folic acid–targeted 177Lu-radionuclide tumor therapy in miceResearch Division Biology and Chemistry (BIO), Folate Receptor Targeting Group, Head Cristina Müller The folate receptor (FR) has proven a valuable target for nuclear imaging using folic acid radioconjugates. However, using folate-based radiopharmaceuticals for therapy has long been regarded as an unattainable goal because of their considerable renal accumulation. Herein, we present a novel strategy in which a DOTA–folate conjugate with an albumin-binding entity (cm09) was designed with the aim of prolonging circulation in the blood and therewith potentially improving tumor-to-kidney ratios. Methods: The folate conjugate cm09 was radiolabeled with 177LuCl3, and stability experiments were performed in plasma. Cell uptake studies were performed on FR-positive KB tumor cells, and an ultrafiltration assay was used to determine the plasma protein–binding properties of 177Lu-cm09. In vivo, 177Lu-cm09 was tested in KB tumor–bearing mice using SPECT/CT. The therapeutic anticancer effect of 177Lu-cm09 (20 MBq) applied as a single injection or as fractionated injections was investigated in different groups of mice (n = 5) by monitoring tumor size and the survival time of treated mice, compared with untreated controls. Results: Compound cm09 was radiolabeled at a specific activity of 40 MBq/nmol, a radiochemical yield of more than 98%, and a stability of more than 99% over 5 d in plasma. Ultrafiltration revealed significant binding of 177Lu-cm09 to serum proteins (∼91%) in plasma, compared with folate radioconjugate without an albumin-binding entity. Cell uptake and internalization of 177Lu-cm09 was FR-specific and comparable to other folate radioconjugates. In vivo studies resulted in high tumor uptake (17.56 percentage injected dose per gram [%ID/g] at 4 h after injection), which was almost completely retained for at least 72 h. Renal accumulation was significantly reduced (28 %ID/g at 4 h after injection), compared with folate conjugates that lack an albumin-binding entity (∼70 %ID/g at 4 h after injection). These circumstances enabled SPECT imaging of excellent quality. Radionuclide therapy (1 × 20 MBq) revealed complete remission of tumors in 4 of 5 cases and a significantly prolonged survival time, compared with untreated controls. Conclusion: The modification of a folate radioconjugate with an albumin-binding entity resulted in a significant increase of the tumor-to-kidney ratio of radioactivity, enabling for the first time, to our knowledge, the preclinical application of folic acid–targeted radionuclide therapy in mice.
14. February 2013Media Releases Biology Human Health
Numerous processes taking place within our body, such as sight, smell or taste, are accomplished by an important family of sensors on cell surfaces, which are known as G protein-coupled receptors (GPCR). Researchers have now compared the hitherto known structures of GPCRs and discovered a stabilising framework of fine struts that is characteristic for the architecture of the entire GPCR family. Knowledge about this constructional feature, which has been conserved over the course of evolution, can be of significant assistance in the development of new pharmaceuticals.
3. January 2013Media Releases Human Health Biology Research Using Synchrotron Light
Anti-cancer drugs are used under the heading of “Chemotherapeutics” to prevent cells from dividing. Because the cells in a growing tumour divide more frequently than others, tumour cells are damaged more severely. Scientists at the Paul Scherrer Institute and the ETH Zurich have now clarified the exact mechanism of action of one class of these drugs. The data acquired is so accurate, that targeted drugs could now be developed that are even better suited to fulfil their task.
10. October 2012Media Releases Biology
Der Nobelpreis für Chemie geht in diesem Jahr an Robert J. Lefkowitz und Brian K. Kobilka. Sie haben herausgefunden, wie eine Familie von Rezeptoren funktioniert, die man G-Protein-gekoppelte Rezeptoren (GPCR) nennt. Auch am PSI leisten Wissenschaftler Beiträge auf diesem Forschungsgebiet.
This news release is only available in German.
Efficacy of a novel 177Lu-chCE7 radioimmunotherapeutic agent for disseminated ovarian cancer therapyResearch Division Biology and Chemistry (BIO), Center for Radiopharmaceutical Sciences,Tumor Targeting Group, Head Eliane Fischer. The L1-cell adhesion molecule is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1-CAM and exhibits anti-proliferative effects on L1-CAM-expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel 177Lu-chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth-inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl,an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10-tetraazacyclododecane-N-N′-N′-N‴-tetraacetic acid (DOTA) and labeled with the low-energy β-emitter 177Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 μg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of 177Lu-chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 ± 8.1% ID/g at 168 h postinjection. A single treatment with 177Lu-DOTA-chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted 177Lu-immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of 177Lu-DOTA-chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1-CAM.
21. December 2011Media Releases Human Health Biology Research Using Synchrotron Light
Lebende Zellen empfangen dauernd Informationen von aussen, die über Rezeptoren in das Zellinnere weitergeleitet werden. Genetisch bedingte Fehler in solchen Rezeptoren sind der Grund für zahlreiche Erbkrankheiten darunter verschiedene hormonelle Funktionsstörungen oder Nachtblindheit. Forschern des Paul Scherrer Instituts ist es nun erstmals gelungen, die exakte Struktur eines solchen fehlerhaften Rezeptors aufzuklären.
This news release is only available in German.
The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapyResearch Division Biology and Chemistry (BIO), Radionuclicde Development Group, Head Konstantin Zhernosekov. The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents.
9. March 2011Media Releases Matter and Material Biology Research Using Synchrotron Light
At the beginning of the process of sight, light interacts with a protein molecule called Rhodopsin. This molecule contains the actual light sensor that is stimulated by the incoming light and changes its form, in order to trigger the rest of the process. Researchers have now managed to determine the exact structure of the Rhodopsin molecule in its short-lived, excited state. From this, they have obtained a precise picture of the first step of the process of sight.
18. January 2010Media Releases Biology Research Using Synchrotron Light Human Health
Researchers at Biomedicum Helsinki, Finland, and the Paul Scherrer Institute (PSI) in Villigen, Switzerland, have determined the crystal structure of the ligand-binding domain of a vascular endothelial growth factor (VEGF) receptor in complex with one of its ligands (VEGF-C).
1. December 2009Human Health Biology Research Using Synchrotron Light
Proteins are the building blocks of all living organisms. In the living cell these complex molecules perform countless tasks. The precise function a protein performs is directly related to its structure. Researchers at the PSI investigate a wide range of proteins, in order to understand their structures and functions, often to lay the foundations for developing new drugs. In addition, researchers explore new techniques for determining protein structure – in particular with synchrotron light at the Swiss Light Source (SLS).
24. July 2009Media Releases Biology Human Health Research Using Synchrotron Light
Cell. Forscher entdecken Mechanismus für wesentliche Erkennungsvorgänge in lebenden Zellen. Über ihre Ergebnisse berichten die Forscher in der neuesten Ausgabe der Fachzeitschrift Cell.
This news release is only available in German.