Design and biotechnological production of new peptide-based active ingredients
FRANKFURT. Microorganisms often produce natural products in a step-by-step manner similar to an assembly line. Examples of such enzymes are non-ribosomal peptide synthetases (NRPS). Researchers at Goethe University Frankfurt have now succeeded in designing these enzymes in such a way that they can produce completely new natural products.
Many important therapeutics, such as antibiotics or immunosuppressant and anti-cancer drugs, are derived from microorganisms. This is also the case for several different peptides which are produced in the microbial cell with the help of the NRPS enzymes. An NRPS functions like an assembly line in a modern car factory: new parts are added to the basic chassis at each workstation until a finished car rolls out of the plant at the end. In the case of the NRPS, a certain amino acid is selected, activated and processed at each station (known as modules) so that linear, cyclic or further modified peptides emerge at the end that can also carry unusual amino acids.
Although the fundamental principles of NRPS are long known, to date it was hardly possible to modify these enzymes. In the few cases where single modules were successfully exchanged, production of the modified natural products noticeably decreased. Assembling completely new enzymes, which in turn would produce completely new natural products, seemed totally impossible. The research group led by Professor Helge Bode, Merck Endowment Professor for Molecular Biotechnology at Goethe University Frankfurt, has now achieved this.
“In principle, we use natural NRPS systems from bacteria only as building blocks which we reassemble in a new way using new interfaces we’ve identified,” says Bode, explaining the research approach. Yields are comparable with the natural production of these natural substances.
The method is meanwhile so sophisticated that even beginners can use it to produce new peptides and thus potential drugs shortly after a basic introduction. However, it has been a long road. “I was lucky that I had a team working with me on this project that did not allow itself to become discouraged, was very diligent and able to think outside the box,” says Bode. “The interface we finally selected to assemble the individual building blocks is such that the classical modular order of the biosynthesis is no longer respected.”
The next step is to modify first clinical drugs with this method and use biotechnology to produce them. Moreover, new information regarding the structure of these NRPS will be gathered as part of the LOEWE research focus MegaSyn led by Bode and Professor Martin Grininger, also from Goethe University Frankfurt. This will make it possible to further improve the method in order to allow the modification of related classes of natural products or even to produce whole libraries of natural products. First results are very promising.
Kenan A. J. Bozhüyük, Florian Fleischhacker, Annabell Linck, Frank Wesche, Andreas Tietze, Claus-Peter Niesert, Helge B. Bode: De novo design and engineering of non-ribosomal peptide synthetases, Nature Chemistry, https://www.nature.com/nchem/, DOI: 10.1038/nchem.2890
A picture can be downloaded from: http://www.muk.uni-frankfurt.de/69511536
Caption: Schematic diagram of the “toolbox system” of the NRPS enzymes for the production of new active ingredients. Fragments from natural systems (green, magenta, blue) are reassembled in a new order (centre) and then produce a natural product which has not formed like this in nature before (right).
Further information: Professor Helge B. Bode, Merck Endowment Professor for Molecular Biotechnology, Faculty of Biological Sciences, Riedberg Campus, Tel.: +49(0)69-798- 29557, email@example.com.
Scene knowledge makes the processing of visual impressions more efficient
FRANKFURT. Our environment is composed according to certain rules and characteristics which are so obvious to us that we are scarcely aware of them. Professor Melissa Lê-Hoa Võ, psychologist at Goethe University Frankfurt, is studying this “scene knowledge”, amongst other topics of visual cognition in a virtual reality laboratory. In the current issue of the “Forschung Frankfurt” research journal, journalist Jessica Klapp tells readers about her virtual trip to Italy and explains why we don´t look for the milk under the bed or for our pillow in the bathtub.
“When we search for a specific object in a scene, we seem to have developed a precise idea of where to look for and find certain things,” explains Melissa Võ. What she finds particularly interesting in her investigation of these naturalistic scenes is how we perceive our environment. In which circumstances are we especially attentive? And what will we remember later? To find this out, Professor Võ uses eye tracking and virtual reality scenarios in her laboratory, alongside measurement of brain potentials.
“We use eye tracking to measure which parts of a picture the observer finds interesting or important, how fast his gaze settles on specific objects in a scene and how long it dwells there,” explains Dr. Dejan Draschkow, a member of Professor Võ’s research group. Eye tracking is very important due to the close relationship between eye movement and cognitive processes. The video-based systems used by the researchers register eye movements with the help of a camera. Both head-mounted systems that resemble a pair of spectacles as well as remote eye trackers installed in a computer monitor together with a camera and infrared LEDs are used. With the mobile system, the test participants can move around in the room, search for objects and interact with them.
With the virtual reality headset, the computer simulates a virtual 3D world in which the test person moves about. With simulated settings, such as an Italian piazza in the centre of which brown boxes are unexpectedly floating around, the researchers check whether the results identified on two-dimensional monitors are also valid in a realistic, three-dimensional environment. They want to understand which rules people use to compose their environment and interact with the objects in it.
Investigating scene knowledge in children is one of the topics that the research group is tackling in particular depth. The aim of the “SCESAM” project, which was launched with the support of IDeA, an interdisciplinary research centre, is the early detection and treatment of possible cognitive disorders such as dyslexia. Tests are conducted in a mobile laboratory right outside the nursery school: The researchers show children “ungrammatical” pictures, for example a shoe on the cooker instead of a saucepan, and watch their reactions with the help of an eye-tracking camera. If one of the children in a large group behaves differently, they are interested to see whether there is a correlation between language development and attention behaviour.
Other fields, such as medicine, also benefit from the results. For example, the researchers measured the eye movements of radiologists when studying x-rays and analysed which strategies they use to recognize tumours and how successful these strategies are. The research results are also important for the security control of hand baggage at airports. How do staff decide which baggage needs a more thorough check? Why wasn’t a dangerous object found? Didn’t the baggage inspector look at this area? Or did he look but didn’t consider the object important?
And finally, people with dementia could also profit from scene knowledge research, since Võ and her team have discovered that the ability to recall pictures in a scene increases if the test persons have previously looked for and found individual objects. In a surprising memory test, they performed far better than participants who were supposed to memorize objects explicitly. “What this means for us is that in the case of a visual search there is more interaction with the scene and the participants commit objects better to memory,” explains Professor Võ.
A picture can be downloaded from: www.uni-frankfurt.de/69396691
Caption: A picture from the SCEGRAM database which shows objects in unusual places. Melissa Võ’s research group is investigating how the brain reacts.
Further information: Professor Melissa Le-Hoa Võ, Dr. Dejan Draschkow, Scene Grammar Lab, Institute of Psychology, Faculty of Psychology and Sports Sciences, Westend Campus, Tel.: +49(0)69-798-35342, firstname.lastname@example.org, Tel.: +49(0)69-798-35310, email@example.com.
Goethe University is a research-oriented university in the European financial centre Frankfurt The university was founded in 1914 through private funding, primarily from Jewish sponsors, and has since produced pioneering achievements in the areas of social sciences, sociology and economics, medicine, quantum physics, brain research, and labour law. It gained a unique level of autonomy on 1 January 2008 by returning to its historic roots as a "foundation university". Today, it is among the top ten in external funding and among the top three largest universities in Germany, with three clusters of excellence in medicine, life sciences and the humanities. Together with the Technical University of Darmstadt and the University of Mainz, it acts as a partner of the inter-state strategic Rhine-Main University Alliance. Internet: www.uni-frankfurt.de
Publisher: The President of Goethe University Editor: Dr. Anne Hardy, Referee for Science Communication, PR & Communication Department, Theodor-W.-Adorno-Platz 1, 60323 Frankfurt am Main, Tel: (069) 798-13035, Fax: (069) 798-763 12531.
For a clear picture please hold your breath – Gentle diagnostics make early-stage heart disease visible
FRANKFURT. By no means are only elderly people at risk from heart diseases. Physically active individuals can also be affected, for example if a seemingly harmless flu bug spreads to the heart muscle. Should this remain undetected and if, for example, a builder continues with his strenuous job or an athlete carries on training, this can lead to chronic inflammation and in the worst case even to sudden death. The latest issue of the “Forschung Frankfurt” journal describes how modern non-invasive examinations using state-of-the-art imaging technology can reduce such risks.
Professor Eike Nagel and his 12 coworkers at the Institute for Experimental and Translational Cardio Vascular Imaging of Goethe University Frankfurt are developing better ways to predict and diagnose heart diseases. In recent years, the researchers have taken the lead in the development of a procedure that is still very new in heart scans. Nagel explains the advantages: “With the help of magnetic resonance imaging, we can look right inside the heart muscle.” Blood flow to the heart muscle is visualized and shows whether there are any constrictions of the arteries supplying the heart. Experts can also spot whether the heart muscle is scarred, inflamed or displays any other anomalies.
The comparatively fast method makes it possible to examine patients at an early stage and may prevent cardiac insufficiency or even a heart attack. “Diseases such as HIV, kidney damage, rheumatic diseases or tumours often affect the heart either directly or as a side effect of therapy,” says Nagel, describing groups potentially at risk. The cardiologist is convinced: “Nowadays we can treat or even cure so many diseases, but the heart suffers too and this should be carefully monitored as it mostly remains undetected.”
MRI is a non-invasive and gentle examination technique, which is less risky but just as efficient as an examination using a conventional heart catheter, where a thin tube is pushed in the direction of the heart through an artery. Nagel’s research group was recently able to demonstrate this in a large international multi-centre study that was met with international acclaim.
The Institute for Experimental and Translational Cardio Vascular Imaging also has state-of-the-art computer tomography equipment at its disposal that can produce three-dimensional images of the heart. These especially reveal calcium deposits and plaques in the artery walls which could rupture and trigger a sudden heart attack. “This allows us to determine the risk of a heart attack and the need for therapy fast and at an early stage, which can then be non-invasive,” says Nagel. Which technique is best for which patient is one of the research topics Nagel’s group is evaluating. In some patients, both may be needed and the Institute is optimally equipped to answer most aspects of heart disease thanks to its deep insight into the heart.
Nagel finds these rapid advances in imaging over the last decades fascinating: “Nowadays we can spot the slightest changes and literally get a clear picture of the heart’s condition.”
Many further articles on “Image and Imagery” can be found in the current issue of “Forschung Frankfurt” and show the fascinating use of image material in scientific applications.
Images and captions can be downloaded from: www.uni-frankfurt.de/69481709
Further information: Professor Eike Nagel, Institute for Experimental and Translational Cardio Vascular Imaging, University Hospital Frankfurt, Department of Medicine III / Cardiology (House 23 A), Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Tel.: +49-(0)69-6301-87200, Eike.Nagel@kgu.de
Journalists can order the current issue of “Forschung Frankfurt” free of charge from Helga Ott, firstname.lastname@example.org.
“Forschung Frankfurt” subscriptions: http://tinygu.de/ff-abonnieren
Study at Goethe University Frankfurt: In intelligent persons, some brain regions interact more closely, while others de-couple themselves
FRANKFURT. Differences in intelligence have so far mostly been attributed to differences in specific brain regions. However, are smart people’s brains also wired differently to those of less intelligent persons? A new study published by researchers from Goethe University Frankfurt (Germany) supports this assumption. In intelligent persons, certain brain regions are more strongly involved in the flow of information between brain regions, while other brain regions are less engaged.
Understanding the foundations of human thought is fascinating for scientists and laypersons alike. Differences in cognitive abilities – and the resulting differences for example in academic success and professional careers – are attributed to a considerable degree to individual differences in intelligence. A study just published in “Scientific Reports” shows that these differences go hand in hand with differences in the patterns of integration among functional modules of the brain. Kirsten Hilger, Christian Fiebach and Ulrike Basten from the Department of Psychology at Goethe University Frankfurt combined functional MRI brain scans from over 300 persons with modern graph theoretical network analysis methods to investigate the neurobiological basis of human intelligence.
Already in 2015, the same research group published a meta-study in the journal “Intelligence”, in which they identified brain regions – among them the prefrontal cortex – activation changes of which are reliably associated with individual differences in intelligence. Until recently, however, it was not possible to examine how such ‘intelligence regions’ in the human brain are functionally interconnected.
Earlier this year, the research team reported that in more intelligent persons two brain regions involved in the cognitive processing of task-relevant information (i.e., the anterior insula and the anterior cingulate cortex) are connected more efficiently to the rest of the brain (2017, “Intelligence”). Another brain region, the junction area between temporal and parietal cortex that has been related to the shielding of thoughts against irrelevant information, is less strongly connected to the rest of the brain network. “The different topological embedding of these regions into the brain network could make it easier for smarter persons to differentiate between important and irrelevant information – which would be advantageous for many cognitive challenges,” proposes Ulrike Basten, the study’s principle investigator.
In their current study, the researchers take into account that the brain is functionally organized into modules. “This is similar to a social network which consists of multiple sub-networks (e.g., families or circles of friends). Within these sub-networks or modules, the members of one family are more strongly interconnected than they are with people from other families or circles of friends. Our brain is functionally organized in a very similar way: There are sub-networks of brain regions – modules – that are more strongly interconnected among themselves while they have weaker connections to brain regions from other modules. In our study, we examined whether the role of specific brain regions for communication within and among brain modules varies with individual differences in intelligence, i.e., whether a specific brain region supports the information exchange within their own ‘family’ more than information exchange with other ‘families’, and how this relates to individual differences in intelligence.”
The study shows that in more intelligent persons certain brain regions are clearly more strongly involved in the exchange of information between different sub-networks of the brain in order for important information to be communicated quickly and efficiently. On the other hand, the research team also identified brain regions that are more strongly ‘de-coupled’ from the rest of the network in more intelligent people. This may result in better protection against distracting and irrelevant inputs. “We assume that network properties we have found in more intelligent persons help us to focus mentally and to ignore or suppress irrelevant, potentially distracting inputs,” says Basten. The causes of these associations remain an open question at present. “It is possible that due to their biological predispositions, some individuals develop brain networks that favor intelligent behaviors or more challenging cognitive tasks. However, it is equally as likely that the frequent use of the brain for cognitively challenging tasks may positively influence the development of brain networks. Given what we currently know about intelligence, an interplay of both processes seems most likely.”
Publication: Hilger, K., Ekman, M., Fiebach, C., & Basten, U. (2017). Intelligence is associated with the modular structure of intrinsic brain networks. Scientific Reports. (DOI:10.1038/s41598-017-15795-7)
Basten, U., Hilger, K., & Fiebach, C. J. (2015). Where smart brains are different: A quantitative meta-analysis of functional and structural brain imaging studies on intelligence. Intelligence, 51, 10-27.
Hilger, K., Ekman, M., Fiebach, C., & Basten, U. (2017). Efficient hubs in the intelligent brain: Nodal efficiency of hub regions in the salience network is associated with general intelligence. Intelligence, 60, 10-25.
Contact Information: Dr. Ulrike Basten, email@example.com, see also Laboratory for Neurocognitive Psychology, Department of Psychology, Goethe University Frankfurt, Germany; http://fiebachlab.org
Theoretician at Goethe University Frankfurt calculates effect of magnetic sails
FRANKFURT. With a miniaturised space probe capable of being accelerated to a quarter of the speed of light we could reach Alpha Centauri, our nearest star, in about 20 or up to 50 years. However, without a mechanism to slow it down the space probe could only collect data from the star and its planets as it would zoom past. A theoretical physicist at Goethe University Frankfurt has now examined whether interstellar spacecrafts can be decelerated using “magnetic sails”.
For a long time, the idea of sending unmanned space probes through the depths of interstellar space to distant stars was purely utopian. Recent research on new concepts - amongst others within the “Breakthrough Starshot” project – has shown that miniaturised space probes could be accelerated by means of powerful lasers. Slowing them down again seems more challenging, since they cannot be fitted with braking systems for weight reasons. However, according to Professor Claudius Gros from the Institute for Theoretical Physics at Goethe University Frankfurt, it would be possible to decelerate at least comparatively slow space probes with the help of magnetic sails.
“Slow would mean in this case a travel velocity of 1,000 kilometres per second, which is only 0.3 percent of the speed of light, but nevertheless about 50 times faster than the Voyager spacecraft,” explains Gros. According to Gros’ calculations, we require a magnetic sail in order to transfer the spacecraft’s momentum to the interstellar gas. The sail consists in a large, superconducting loop with a diameter of a about 50 kilometres. A lossless current induced in this loop then creates a strong magnetic field. The ionised hydrogen in the interstellar medium is then reflected off the probe’s magnetic field, slowing it down gradually. This concept works, as Gros was able to show, despite the extremely low particle density of interstellar space (0.005 to 0.1 particles per cubic centimetre).
Gros’ research shows that magnetic sails can decelerate ‘slow’ spacecrafts weighing up to 1,500 kilograms. However, the journey would take historical periods of time, for example about 12,000 years to reach the seven known planets of the TRAPPIST-1 system. Surprisingly, slower cruising probes of the size of a car could be launched by the same laser which would allow to send, according to current planing, high-speed space probes weighing just a few gram to Alpha Centauri.
Missions to distant stars taking thousands of years are out of the question for exploratory missions. But the situation is quite different in cases where the cruising time is irrelevant, such as missions that open up alternative possibilities for terrestrial life. Such missions, like Gros proposed in 2016 under the name of ‘The Genesis Project’, would carry single-celled organisms, either as deep-frozen spores or encoded in a miniaturised gene laboratory. For a Genesis probe, it is not the time of arrival which is important, but the possibility to decelerate and then orbit the target planet.
Publications: Claudius Gros: Universal scaling relation for magnetic sails: momentum braking in the limit of dilute interstellar media, Journal of Physics Communications 1, 045007 (2017)
Claudius Gros: Developing Ecospheres on Transiently Habitable Planets: The Genesis Project, in: Astrophysics and Space Science 361, 324 (2016)
Further information: Professor Claudius Gros, Faculty of Physics, Institute for Theoretical Physics, Riedberg Campus, phone: +49(0)69-798 47818, email: gros07[@]itp.uni-frankfurt.de
New Scientist, 13 November 2017: Should we seed life through the cosmos using laser-driven ships?