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Faster and simpler production of high-resolution, three-dimensional electron microscopy images of biomolecules
FRANKFURT/JENA. An interdisciplinary team from Frankfurt and Jena has developed a kind of bait with which to fish protein complexes out of mixtures. Thanks to this “bait", the desired protein is available much faster for further examination in the electron microscope. The research team has christened this innovative layer of ultrathin molecular carbon the “smart nanosheet". With the help of this new development, diseases and their treatment with drugs can be better understood, for example.
“With our process, new types of proteins
can be isolated from mixtures and characterized within a week," explains Daniel
Rhinow from the Max Planck Institute of Biophysics in Frankfurt. “To date, just
the isolation of the proteins was often part of a doctorate lasting several
years." Together with Andreas Terfort (Goethe University) and Andrey Turchanin
(Friedrich Schiller University Jena), the idea evolved a few years ago of
fishing the desired proteins directly out of mixtures by equipping a nanosheet
with recognition sites onto which the target protein bonds. The researchers
have now succeeded in making proteins directly available for examination using
electron cryo-microscopy through a “smart nanosheet".
Electron cryo-microscopy is based on the
shock-freezing of a sample at temperatures under -150 °C. In this process, the
protein maintains its structure, no interfering fixing and coloring agents are needed,
and the electrons can easily irradiate the frozen object. The result is high-resolution,
three-dimensional images of the tiniest structures – for example of viruses and
DNA, almost down to the scale of a hydrogen atom.
In preparation, the proteins are
shock-frozen in an extremely thin layer of water on a minute metal grid. Previously,
samples had to be cleaned in a complex procedure – often involving an extensive
loss of material – prior to their examination in an electron microscope. The electron microscopy procedure is only successful
if just one type of protein is bound in the water layer.
The research group led by Turchanin is now
using nanosheets that are merely one nanometer thick and composed of a cross-linked
molecular self-assembled monolayer. Terfort's group coats this nanosheet with a
gelling agent as the basis for the thin film of water needed for freezing. The
researchers then attach recognition sites (a special nitrilotriacetic acid group
with nickel ions) to it. The team led by Rhinow uses the “smart nanosheets" treated
in this way to fish proteins out of a mixture. These were marked beforehand
with a histidine chain with which they bond to the recognition sites; all other
interfering particles can be rinsed off. The nanosheet with the bound protein
can then be examined directly with the electron microscope.
“Our smart nanosheets are particularly
efficient because the hydrogel layer stabilizes the thin film of water required
and at the same time suppresses the non-specific binding of interfering
particles," explains Julian Scherr of Goethe University. “In this way,
molecular structural biology can now examine protein structures and functions
much faster." The knowledge gained from this can be used, for example, to
better understand diseases and their treatment with drugs.
The team has patented the new nanosheets
and additionally already found a manufacturer who will bring this useful tool
onto the market.
Publication: Smart Molecular Nanosheets for Advanced Preparation of Biological
Samples in Electron Cryo-Microscopy, ACS Nano 2020, https://doi.org/10.1021/acsnano.0c03052
Julian Scherr, Zian Tang, Maria Küllmer,
Sebastian Balser, Alexander Stefan Scholz, Andreas Winter, Kristian Parey,
Alexander Rittner, Martin Grininger, Volker Zickermann, Daniel Rhinow, Andreas Terfort
und Andrey Turchanin; Department of Structural Biology, Max Planck Institute of
Biophysics, Max-von-Laue-Str. 3, 60438 Frankfurt am Main; Faculty of
Biochemistry, Chemistry and Pharmacy, Goethe University, Max-von-Laue-Str. 7,
60438 Frankfurt am Main; Institute of Physical Chemistry, Friedrich Schiller University
Jena, Lessingstr. 10, 07743 Jena
A
picture can be downloaded under: www.uni-frankfurt.de/
Caption: The new nanosheet process: The
protein complex to be examined (yellow) is attached to the smart nanosheet via
a nickel complex with the aid of a marker (red chain with pentagons). Unwanted
proteins (gray) are repelled by the hydrogel (black grid). After freezing the
entire structure, including a thin film of water, this can be irradiated with
electrons to obtain images of the bound proteins, from which a computer can then
calculate the 3D structure of the protein.
Further
information:
Professor
Andreas Terfort, Institute of Inorganic and Analytical Chemistry, Goethe University,
Max-von-Laue-Str. 7, 60438 Frankfurt am Main, aterfort@chemie.uni-frankfurt.de,
+49-69-798-29181, https://www.uni-frankfurt.de/53459866/terfort
Professor Andrey Turchanin, Friedrich
Schiller University Jena, Lessingstr. 10, 07743 Jena, andrey.turchanin@uni-jena.de,
+49-3641-48370, www.apc.uni-jena.de
X-ray structure analysis gives detailed insights into molecular factory
Mystery about the cancer drug nelarabine solved after decades
FRANKFURT. Acute
lymphoblastic leukaemia (ALL) is the most common kind of cancer in children.
T-ALL, a subtype that resembles T-lymphocytes, can be treated successfully with
the drug nelarabine. The drug has not been successful, however, with B-ALL, a
subtype resembling B-lymphocytes. Since the 1980s, oncologists have been puzzled
as to the cause of this difference. Now, an international research team headed
by Goethe University and the University of Kent has discovered the reason:
B-ALL cells contain the enzyme SAMHD1, which deactivates the drug.
In the current issue of “Communications
Biology", Professor Jindrich Cinatl from the Institute for Medical Virology at
Goethe University and Professor Martin Michaelis from the School of Biosciences
at the University of Kent report on their investigations with nelarabine on
different cell lines. “Nelarabine is the precursor of the drug, a prodrug, that
does not become effective until it is combined with three phosphate groups in
the leukaemia cell," explains Professor Cinatl. “In studies of various ALL cell
lines and leukaemia cells from ALL patients, we have been able to demonstrate
that the enzyme SAMHD1 splits the phosphate groups off so that the medicine loses
its effect." Because B-ALL cells contain more SAMHD1 than T-ALL cells,
nelarabine is less effective with B-ALL.
These results could improve the treatment
of ALL in the future. In rare cases, B-ALL cells contain very little SAMHD1 so
that treatment with nelarabine would be possible. On the contrary, there are
also rare cases of T-ALL exhibiting a lot of SAMHD1. In such cases, the
otherwise effective nelarabine would not be the right medication. Professor
Michaelis observes: “SAMHD1 is thus a biomarker that allows us to better adapt
treatment with nelarabine to the individual situation of ALL patients."
Tamara Rothenburger, whose doctoral
dissertation was funded by the association “Hilfe für krebskranke Kinder
Frankfurt e.V“, is satisfied when she looks back at her research. “I hope that
many children with leukaemia will benefit from the results." The research was
also supported by the Frankfurt Stiftung für krebskranke Kinder. Additional
members of the research group are Ludwig-Maximilians-Universität Munich, and
University College London.
Publication:
Tamara Rothenburger, Katie-May McLaughlin,
Tobias Herold, Constanze Schneider, Thomas Oellerich, Florian Rothweiler,
Andrew Feber, Tim R. Fenton, Mark N. Wass, Oliver T. Keppler, Martin Michaelis,
Jindrich Cinatl. SAMHD1 is a key
regulator of the lineage-specific response of acute lymphoblastic leukaemias to
nelarabine, in: Communications Biology, DOI
10.1038/s42003-020-1052-8, https://www.nature.com/commsbio/
Further
information:
Prof. Dr. rer. nat. Jindrich Cinatl
Institute for Medical Virology
University Hospital Frankfurt
Tel.: +49 69 6301-6409
E-mail: cinatl@em.uni-frankfurt.de
Researchers from Frankfurt produce tsetse attractants in yeast to contain sleeping sickness
FRANKFURT. Because the tsetse fly can transmit
sleeping sickness, it is commonly combatted with insecticides or caught in
traps. Bioscientists at Goethe University have now developed a method for
producing the attractants for the traps in a biotechnological procedure. The Frankfurt
scientists hope that in the future, the attractants can then be produced
locally in rural areas of Africa at low cost (Scientific Reports, DOI:
10.1038/s41598-020-66997-5).
The tsetse fly occurs in large regions of sub-Saharan
Africa. The flies feed on human and animal blood, transmitting trypanosoma in
the process – small, single-cell organisms that use the flies as intermediate
host and cause a dangerous inflammation of the lymph and nervous system in both
animals and humans. There is no vaccination for this sleeping sickness;
untreated, it usually ends in death. In agriculture, particularly cattle
breeding, sleeping sickness – or trypanosomiasis – causes enormous damages in
the form of sick and dead animals.
In addition to the use of insecticides,
the insects are also caught in traps. The attractants used include substances
that also occur in cattle urine and which attract tsetse flies. These
substances (3-ethylphenol and 3-propylphenol, or 3-EP and 3-PP for short) are
synthesized out of oil derivatives or also extracts from cashew nut shells
through chemical processes. However, both processes are complex and neither
practical nor affordable for rural communities in Africa.
In the LOEWE collaborative research
project MegaSyn, molecular biologists at Goethe University have now succeeded
in producing 3-EP and 3-PP in genetically modified brewer’s yeast (Saccharomyces cerevisiae). They used a
yeast strain into which they had previously introduced a new metabolic pathway,
and changed its sugar metabolism. This enabled the yeasts to produce similarly
high concentrations of 3-EP and 3-PP as those which occur in cow urine.
Doctoral student Julia Hitschler from the Institute
for Molecular Biosciences at Goethe University explains: “Our yeasts could
ideally grow in Africa in nutrient solutions on the basis of plant waste
products, food rests or fodder rests. This would make production of the
attractant almost cost-free. We are currently looking for partners to help us test
our yeasts locally and provide them to the local population.”
The potential for the new yeasts go beyond
the tsetse attractants, add Professor Eckhard Boles, who heads the project. In
the future, other substances that have been previously won through oil or coal
could be produced through the new yeasts: “Our yeasts could be developed to
produce other alkylphenols besides 3-EP and 3-PP. These alkylphenols could be
used for the production of lubricant additives or surface-active substances in
cleaning agents.”
Publication:
Julia Hitschler, Martin Grininger, Eckhard
Boles: Substrate promiscuity of
polyketide synthase enables production of tsetse fly attractants 3-ethylphenol
and 3-propylphenol by engineering precursor supply in yeast. Scientific
Reports, https://doi.org/10.1038/s41598-020-66997-5
Further
information:
Prof. Dr. Eckhard Boles
Institute for Molecular Biosciences
Goethe University Frankfurt
Tel:
+49 69 798 29513
e.boles@bio.uni-frankfurt.de
http://www.bio.uni-frankfurt.de/boles
A game theoretical study shows that envy coupled with competition divides society into an upper and lower class
FRANKFURT. Can class differences come about endogenously, i.e. independent of birth and education? Professor Claudius Gros from the Institute for Theoretical Physics at Goethe University pursued this issue in a game theoretical study. He was able to show that the basic human need to compare oneself with others may be the root cause of the formation of social classes.
It's generally recognized that differences
in background and education cement class differences. It is less clear when and
under what circumstances individual psychological forces can drive an initially
homogenous social group apart and ultimately divide it. Claudius Gros,
professor for theoretical physics at Goethe University, investigated this
question in a mathematical precise way using game theory methods. “In the
study, societies of agents – acting individuals – are simulated within game
theory, which means that everybody optimises her/his success according to
predetermined rules. I wanted to find out whether social differences can emerge
on their own if no one starts off with advantages – that is, when all actors
have the same skills and opportunity," the physicist explains.
The study is based on the assumption that
there are things in every society that are coveted but limited – such as jobs,
social contacts and positions of power. An inequality is created if the top
position is already occupied and someone must therefore accept the second-best
job – but not, however, a societal division. With the help of mathematical
calculations Gros was able to demonstrate that envy, which arises from the need
to compare oneself with others, alters individual behaviour and consequently
the agents' strategies in characteristic ways. As a result of this changed
behaviour, two strictly separate social classes arise.
Game theory provides the mathematical
tools necessary for the modelling of decision situations with several
participants, as in Gros' study. In general, constellations in which the
decision strategies of the individual actors mutually influence each other are
particularly revealing. The success of the individual depends then not only on
his or her own actions, but on others' actions as well, which is typical of
both economic and social contexts. Game theory is consequently firmly anchored
in the economy. The stability condition of game theory, the “Nash equilibrium",
is a concept developed by John Forbes Nash in his dissertation in 1950, using
the example of poker players. It states that in equilibrium no player has
anything to gain by changing their strategy if the other players do not change
theirs either. An individual only tries out new behaviour patterns if there is
a potential gain. Since this causal chain also applies to evolutionary
processes, the evolutionary and behavioural sciences regularly fall back on
game theoretical models, for example when researching animal behaviours such as
the migratory flight routes of birds, or their competition for nesting sites.
Even in an envy-induced class society
there is no incentive for an individual to change his or her strategy,
according to Gros. It is therefore Nash stable. In the divided envy society
there is a marked difference in income between the upper and lower class which
is the same for all members of each social class. Typical for the members of
the lower class is, according to Gros, that they spend their time on a series
of different activities, something game theory terms a “mixed strategy".
Members of the upper class, however, concentrate on a single task, i.e., they
pursue a “pure strategy". It is also striking that the upper class can choose
between various options while the lower class only has access to a single mixed
strategy. “The upper class is therefore individualistic, while agents in the
lower class are lost in the crowd, so to speak," the physicist sums up.
In Claudius Gros' model, whether an agent
lands in the upper or lower class is ultimately a matter of coincidence. It is
decided by the dynamics of competition, and not by origin. For his study, Gros
developed a new game theoretical model, the “shopping trouble model" and worked
out a precise analytical solution. From
it, he derives that an envy-induced class society possesses characteristics
that are deemed universal in the theory of complex systems. The result is that
the class society is beyond political control to a certain degree. Political
decision-makers lose a portion of their options for control when society
spontaneously splits into social classes. In addition, Gros' model demonstrates
that envy has a stronger effect when the competition for limited resources is
stronger. “This game theoretical insight could be of central significance. Even
an 'ideal society' cannot be stably maintained in the long term – which
ultimately makes the striving for a communistic society seem unrealistic," the
scientist remarks.
Publication: Claudius Gros, „Self induced class stratification in competitive societies of agents: Nash stability in the presence of envy“, Royal Society Open Science , Vol 7, 200411 (2020).
Link: https://royalsocietypublishing.org/doi/10.1098/rsos.200411
Further information: Professor Claudius Gros, Institute for
Theoretical Physics, Riedberg Campus, E-Mail gros07@itp.uni-frankfurt.de