Tag Archives: Technical University of Munich (TUM)

Optimizing mRNA nanoparticles

The process of continuously working on scientific improvements is not always appreciated by outsiders such as myself. A December 28, 2021 news item on Nanowerk highlights research published (from 2019 and 2020) on improving delivery of mRNA used in vaccines (Note: A link has been removed),

The research neutron source Hein Maier-Leibnitz (FRM II) at the Technical University of Munich (TUM) is playing an important role in the investigation of mRNA nanoparticles similar to the ones used in the Covid-19 vaccines from vendors BioNTech and Moderna. Researchers at the Heinz Maier-Leibnitz Zentrum (MLZ) used the high neutron flux available in Garching to characterize various formulations for the mRNA vaccine and thus to lay the groundwork for improving the vaccine’s efficacy.

A December 27, 2021 TUM press release, which originated the news item, delves further into the science of improving something that already works well,

The idea of using messenger RNA (mRNA) as an active ingredient is a brilliant one: The molecule contains the specific blueprint for proteins which are then synthesize by the cell. This makes it generally possible to provide a very wide spectrum of different therapeutically effective proteins.

In the case of the Covid-19 vaccine, these are the proteins of the characteristic spikes on the surface of the Corona virus which are used for vaccination. The proteins are presented on the surface of immune cells; then the human immune system triggers defenses against these foreign proteins and thus against the Corona virus. The mRNA itself is completely broken down after only a few hours, a fact which is advantageous to the safety of these vaccines.

The road to the best packaging

The mRNA has to be packaged appropriately in order to keep it from being broken down on the way to the cell by the ubiquitous enzymes of the human body. This is done using nanoparticles which can consist of a mixture of lipids or polymers.

The lipids are fat molecules similar to the molecules of the cell membrane and help deposit the mRNA in the interior of the cell. Lipids and biopolymers are then broken down or excreted by the body.

To this ends, the BioNTech formulation team led by Dr. Heinrich Haas worked together with the group led by Prof. Peter Langguth of the Pharmaceutical Technology department at the Johannes Gutenberg University Mainz’s Institute of Pharmaceutical and Biomedical Sciences. They developed a series of formulations in which the nanoparticles consisted of various mixtures of lipids and biopolymers already proved in pharmaceuticals.

In the light of neutrons

In order to compare the properties of variously composed nanoparticles with one another, the researchers subjected the nanoparticles to a wide range of investigations. In addition to x-ray and microscopic analyses, these investigations included radiation with neutrons using the instrument KWS-2, operated by the Forschungszentrum Jülich at the FRM II of the Technical University of Munich in Garching.

The neutrons are scattered in the interior of the nanoparticles, inter alia, on the hydrogen nuclei and are deflected from their paths in a characteristic way. This is the basis for conclusions about their distribution. If the hydrogen atoms of certain components – for example of the lipids only – are exchanged with heavy hydrogen, the chemical properties and the pharmaceutical efficacy do not change, but the scattering pattern of the neutrons does.

“This method makes it possible to selectively highlight parts of a complex multi-component morphology without changing the physical chemistry of the sample,” says Dr. Aurel Radulescu of the Jülich Centre for Neutron Science (JCNS), who is responsible for the instrument KWS-2 and who led the evaluation of the measurement results. “This makes it possible to depict structural properties which other methods can only barely render visible, if at all.”

The right degree of order is the key

In these analyses the research teams were interested in how efficiently the various formulations were able to transmit the mRNA into the cell, referred to as transfection. The researchers thus found out that the highest transfection rates were achieved with nanoparticles that are characterized by a certain type of internal arrangement.

“High levels of biological activity were registered whenever ordered and less ordered areas alternated in the interior of the nanoparticles in a characteristic manner. This could be a generally valid concept of structure-activity relationship which can be applied independently of the systems investigated here,” Dr. Heinrich Haas of BioNTech points out. A similarly low degree of order had also been found previously by the research teams using x-ray radiation in other lipid nanoparticles.

An improved procedure

In order to receive the desired structural properties lipids and biopolymers had to be combined with the mRNA using exactly defined procedures. Here the research team was able to show that the nanoparticles for packaging the mRNA could be produced in a single step, which means a significant simplification compared to the two-step procedure which was originally also investigated.

Thus a simplified method for the creation of mRNA nanoparticles with improved activity was ultimately found. “Such questions of practical producibility represent an important prerequisite for the possibility of developing pharmaceutical products,” says Prof. Langguth. In the future such concepts could be taken into account in the development of new mRNA-based therapeutic agents.

Here are links to and citations for the papers (Note: This is not my usual way of setting the links),

Hybrid Biopolymer and Lipid Nanoparticles with Improved Transfection Efficacy for mRNA by Christian D. Siewert, Heinrich Haas, Vera Cornet, Sara S. Nogueira, Thomas Nawroth, Lukas Uebbing, Antje Ziller, Jozef Al-Gousous, Aurel Radulescu, Martin A. Schroer, Clement E. Blanchet, Dmitri I. Svergun, Markus P. Radsak, Ugur Sahin and Peter Langguth. Cells 2020, 9(9), 2034 – DOI: 10.3390/cells9092034

This paper appears to be open access.

Investigation of charge ratio variation in mRNA – DEAE-dextran polyplex delivery systems by C. Siewert, H. Haas, T. Nawroth, A. Ziller, S. S. Nogueira, M. A. Schroer, C. E. Blanchet, D. I. Svergun, A. Radulescu, F. Bates, Y. Huesemann, M. P. Radsak, U. Sahin, P. Langguth. Biomaterials, 2019; DOI: 10.1016/j.biomaterials.2018.10.020

This paper is open access.

Polysarcosine-Functionalized Lipid Nanoparticles for Therapeutic mRNA Delivery by S S. Nogueira, A. Schlegel, K. Maxeiner, B. Weber, M. Barz, M. A. Schroer, C. E. Blanchet, D. I. Svergun, S. Ramishetti, D. Peer, P. Langguth, U. Sahin, H. Haas. ACS Appl. Nano Mater. 2020, 3, 11, 10634–10645 – DOI: 10.1021/acsanm.0c01834

This paper is behind a paywall.

Democracy through mathematics

Prime Minister Justin Trudeau promised electoral reform before he and his party won the 2015 Canadian federal election. In February 2017, Trudeau’s government abandoned any and all attempts at electoral reform (see Feb. 1, 2017 article by Laura Stone about the ‘broken’ promise for the Globe and Mail). Months later, the issue lingers on.

Anyone who places the cross for a candidate in a democratic election assumes the same influence as all other voters. Therefore, as far as the population is concerned, the constituencies should be as equal as possible. (Photo: Fotolia / Stockfotos-MG)

While this research doesn’t address the issue of how to change the system so that votes might be more meaningful especially in districts where the outcome of any election is all but guaranteed, it does suggest there are better ways of changing the electoral map (redistricting), from a June 12, 2017 Technical University of Munich (TUM) press release (also on EurekAlert but dated June 23, 2017),

For democratic elections to be fair, voting districts must have similar sizes. When populations shift, districts need to be redistributed – a complex and, in many countries, controversial task when political parties attempt to influence redistricting. Mathematicians at the Technical University of Munich (TUM) have now developed a method that allows the efficient calculation of optimally sized voting districts.

When constituents cast their vote for a candidate, they assume it carries the same weight as that of the others. Voting districts should thus be sized equally according to population. When populations change, boundaries need to be redrawn.

For example, 34 political districts were redrawn for the upcoming parliamentary election in Germany – a complex task. In other countries, this process often results in major controversy. Political parties often engage in gerrymandering, to create districts with a disproportionately large number of own constituents. In the United States, for example, state governments frequently exert questionable influence when redrawing the boundaries of congressional districts.

“An effective and neutral method for political district zoning, which sounds like an administrative problem, is actually of great significance from the perspective of democratic theory,” emphasizes Stefan Wurster, Professor of Policy Analysis at the Bavarian School of Public Policy at TUM. “The acceptance of democratic elections is in danger whenever parties or individuals gain an advantage out of the gate. The problem becomes particularly relevant when the allocation of parliamentary seats is determined by the number of direct mandates won. This is the case in majority election systems like in USA, Great Britain and France.”
Test case: German parliamentary election

Prof. Peter Gritzmann, head of the Chair of Applied Geometry and Discrete Mathematics at TUM, in collaboration with his staff member Fabian Klemm and his colleague Andreas Brieden, professor of statistics at the University of the German Federal Armed Forces, has developed a methodology that allows the optimal distribution of electoral district boundaries to be calculated in an efficient and, of course, politically neutral manner.

The mathematicians tested their methodology using electoral districts of the German parliament. According to the German Federal Electoral Act, the number of constituents in a district should not deviate more than 15 percent from the average. In cases where the deviation exceeds 25 percent, electoral district borders must be redrawn. In this case, the relevant election commission must adhere to various provisions: For example, districts must be contiguous and not cross state, county or municipal boundaries. The electoral districts are subdivided into precincts with one polling station each.
Better than required by law

“There are more ways to consolidate communities to electoral districts than there are atoms in the known universe,” says Peter Gritzmann. “But, using our model, we can still find efficient solutions in which all districts have roughly equal numbers of constituents – and that in a ‘minimally invasive’ manner that requires no voter to switch precincts.”

Deviations of 0.3 to 8.7 percent from the average size of electoral districts cannot be avoided based solely on the different number of voters in individual states. But the new methodology achieves this optimum. “Our process comes close to the theoretical limit in every state, and we end up far below the 15 percent deviation allowed by law,” says Gritzmann.
Deployment possible in many countries

The researchers used a mathematical model developed in the working group to calculate the electoral districts: “Geometric clustering” groups the communities to clusters, the optimized electoral districts. The target definition for calculations can be arbitrarily modified, making the methodology applicable to many countries with different election laws.

The methodology is also applicable to other types of problems: for example, in voluntary lease and utilization exchanges in agriculture, to determine adequate tariff groups for insurers or to model hybrid materials. “However, drawing electoral district boundaries is a very special application, because here mathematics can help strengthen democracies,” sums up Gritzmann.

Although the electoral wards for the German election were newly tailored in 2012, already in 2013, the year of the election, population changes led to deviations above the desired maximum value in some of them (left). The mathematical method results in significantly lower deviations, thus providing better fault tolerance. (Image: F. Klemm / TUM)

 

Here’s a link to and a citation for the paper,

Constrained clustering via diagrams: A unified theory and its application to electoral district design by Andreas Brieden, Peter Gritzmann, Fabian Klemma. European Journal of Operational Research Volume 263, Issue 1, 16 November 2017, Pages 18–34 https://doi.org/10.1016/j.ejor.2017.04.018

This paper is behind a paywall.

While the redesign of electoral districts has been a contentious issue federally and provincially in Canada (and I imagine in municipalities where this is representation by districts), the focus for electoral reform had been on eliminating the ‘first-past-the-post’ system and replacing it with something new. Apparently, there is also some interest in the US. A June 27, 2017 article by David Daley for salon.com describes one such initiative,

Some people blame gerrymandering, while others cite geography or rage against dark money. All are corrupting factors. All act as accelerants on the underlying issue: Our winner-take-all [first-ast-the-post]system of districting that gives all the seats to the side with 50 percent plus one vote and no representation to the other 49.9 percent. We could end gerrymandering tomorrow and it wouldn’t help the unrepresented Republicans in Connecticut, or Democrats in Kansas, feel like they had a voice in Congress.

A Virginia congressman wants to change this. Rep. Don Beyer, a Democrat, introduced something called the Fair Representation Act this week. Beyer aims to wipe out today’s map of safe red and blue seats and replace them with larger, multimember districts (drawn by nonpartisan commissions) of three, four or five representatives. Smaller states would elect all members at large. All members would then be elected with ranked-choice voting. That would ensure that as many voters as possible elect a candidate of their choice: In a multimember district with five seats, for example, a candidate could potentially win with one-sixth of the vote.

This is how you fix democracy. The larger districts would help slay the gerrymander. A ranked-choice system would eliminate our zero-sum, winner-take-all politics. Leadership of the House would belong to the side with the most votes — unlike in 2012, for example, when Democratic House candidates received 1.4 million more votes than Republicans, but the GOP maintained a 33-seat majority. No wasted votes and no spoilers, bridge builders in Congress, and (at least in theory) less negative campaigning as politicians vied to be someone’s second choice if not their first. There’s a lot to like here.

There are other similar schemes but the idea is always to reestablish the primacy (meaningfulness) of a vote and to achieve better representation of the country’s voters and interests. As for the failed Canadian effort, such as it was, the issue’s failure to fade away hints that Canadian politicians at whatever jurisdictional level they inhabit might want to tackle the situation a little more seriously than they have previously.

A method for producing two-dimensional quasicrystals from metal organic networks

A July 13, 2016 news item on ScienceDaily highlights an advance where quasicrystals are concerned,

Unlike classical crystals, quasicrystals do not comprise periodic units, even though they do have a superordinate structure. The formation of the fascinating mosaics that they produce is barely understood. In the context of an international collaborative effort, researchers at the Technical University of Munich (TUM) have now presented a methodology that allows the production of two-dimensional quasicrystals from metal-organic networks, opening the door to the development of promising new materials.

A July 13, 2016 TUM press release (also on EurekAlert), which originated the news item, explains further,

Physicist Daniel Shechtman [emphasis mine] merely put down three question marks in his laboratory journal, when he saw the results of his latest experiment one day in 1982. He was looking at a crystalline pattern that was considered impossible at the time. According to the canonical tenet of the day, crystals always had so-called translational symmetry. They comprise a single basic unit, the so-called elemental cell, that is repeated in the exact same form in all spatial directions.

Although Shechtman’s pattern did contain global symmetry, the individual building blocks could not be mapped onto each other merely by translation. The first quasicrystal had been discovered. In spite of partially stark criticism by reputable colleagues, Shechtman stood fast by his new concept and thus revolutionized the scientific understanding of crystals and solid bodies. In 2011 he ultimately received the Nobel Prize in Chemistry. To this day, both the basic conditions and mechanisms by which these fascinating structures are formed remain largely shrouded in mystery.

A toolbox for quasicrystals

Now a group of scientists led by Wilhelm Auwärter and Johannes Barth, both professors in the Department of Surface Physics at TU Munich, in collaboration with Hong Kong University of Science and Technology (HKUST, Prof. Nian Lin, et al) and the Spanish research institute IMDEA Nanoscience (Dr. David Écija), have developed a new basis for producing two-dimensional quasicrystals, which might bring them a good deal closer to understanding these peculiar patterns.

The TUM doctoral candidate José Ignacio Urgel made the pioneering measurements in the course of a research fellowship at HKUST. “We now have a new set of building blocks that we can use to assemble many different new quasicrystalline structures. This diversity allows us to investigate on how quasicrystals are formed,” explain the TUM physicists.

The researchers were successful in linking europium – a metal atom in the lanthanide series – with organic compounds, thereby constructing a two-dimensional quasicrystal that even has the potential to be extended into a three-dimensional quasicrystal. To date, scientists have managed to produce many periodic and in part highly complex structures from metal-organic networks, but never a quasicrystal.

The researchers were also able to thoroughly elucidate the new network geometry in unparalleled resolution using a scanning tunnelling microscope. They found a mosaic of four different basic elements comprising triangles and rectangles distributed irregularly on a substrate. Some of these basic elements assembled themselves to regular dodecagons that, however, cannot be mapped onto each other through parallel translation. The result is a complex pattern, a small work of art at the atomic level with dodecagonal symmetry.

Interesting optical and magnetic properties

In their future work, the researchers are planning to vary the interactions between the metal centers and the attached compounds using computer simulation and experiments in order to understand the conditions under which two-dimensional quasicrystals form. This insight could facilitate the future development of new tailored quasicrystalline layers.

These kinds of materials hold great promise. After all, the new metal-organic quasicrystalline networks may have properties that make them interesting in a wide variety of application. “We have discovered a new playing field on which we can not only investigate quasicrystallinity, but also create new functionalities, especially in the fields of optics and magnetism,” says Dr. David Écija of IMDEA Nanoscience.

For one, scientists could one day use the new methodology to create quasicrystalline coatings that influence photons in such a manner that they are transmitted better or that only certain wavelengths can pass through the material.

In addition, the interactions of the lanthanide building blocks in the new quasicrystals could facilitate the development of magnetic systems with very special properties, so-called “frustrated systems”. Here, the individual atoms in a crystalline grid interfere with each other in a manner that prevents grid points from achieving a minimal energy state. The result: exotic magnetic ground states that can be investigated as information stores for future quantum computers.

The researchers have made an image available,

The quasicrystalline network built up with europium atoms linked with para-quaterphenyl–dicarbonitrile on a gold surface (yellow) - Image: Carlos A. Palma / TUM

The quasicrystalline network built up with europium atoms linked with para-quaterphenyl–dicarbonitrile on a gold surface (yellow) – Image: Carlos A. Palma / TUM

Here’s a link to and a citation for the paper,

Quasicrystallinity expressed in two-dimensional coordination networks by José I. Urgel, David Écija, Guoqing Lyu, Ran Zhang, Carlos-Andres Palma, Willi Auwärter, Nian Lin, & Johannes V. Barth. Nature Chemistry 8, 657–662 (2016) doi:10.1038/nchem.2507 Published online 16 May 2016

This paper is behind a paywall.

For anyone interested in more about the Daniel Schechter story and how he was reviled for his discovery of quasicrystals, there’s more in my Dec. 24, 2013 posting (scroll down about 60% of the way).