Most of our researchers are biologists or chemists, while others are bioinformaticians, mathematicians, physicians, or physicists. For these experts, molecular medicine is about combining the different perspectives of physicians and scientists.
A steadily rising number of publications
The immediate result of a scientist's work are research papers which are published in scientific journals. These articles serve a central aspect of science: spreading knowledge across the world. Other researchers subsequently re-use and cite the results in their own work.
In 2016 the number of publications rose to 490 (from 432 in 2015), with 77 (2015: 68) appearing in outstanding journals with an impact factor above ten. Some 60 percent of all publications were co-authored by researchers from other countries.
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The most prestigious research grants in Europe
European Research Council (ERC) views the recipients of its highly sought-after funding as pioneers venturing into uncharted territory. The selection process for the grants is based on a single criterion – scientific excellence – and researchers are not constrained by any thematic or policy priorities. That's why receiving an ERC grant is a great honour and valuation of one's work.
As of end of 2017, 16 scientists who won ERC grants are currently working at the MDC. 20 ERC grants were raised directly at the MDC, four were awarded in 2016 alone. The MDC thus ranks 17th out of 128 German research institutions.
Examples of recent significant scientific discoveries
In the last two years, MDC labs made several noteworthy discoveries relevant for understanding diseases.
Together with the Screening Unit, which is jointly run by the FMP and the MDC, the scientists identified a previously unknown gene as an essential constituent of the volume-regulated anion channel (VRAC).
The gene is called leucine-rich repeat- containing 8 A (LRRC8A). Using a oneby- one approach in a large-scale cell culture experiment, Jentsch’s team transiently silenced approximately 20,000 human genes.
In an automated screening process the researchers also investigated which of the genes are responsible for the swelling activated chloride flux across the cell membrane. The approximately 130,000 time-dependent measurements were statistically analyzed with help from the Bioinformatics Group led by Miguel Andrade (until April 2014 at the MDC; now at the University of Mainz). Jentsch’s team went on to show that LRRC8A requires other members of the LRRC8 gene family to form VRAC.
DCM is marked by an enlarged, weakened heart and is responsible for about a third of deaths from congestive heart failure. MDC scientists have shown that mutations in the protein RBM20 (RNA binding motif protein 20) probably contribute to DCM by affecting the splicing of crucial molecules in the heart.
They provided a detailed account of the operation of RBM20, which is preferentially present in the heart and orchestrates a large number of target molecules. Studying RBM20’s target pattern revealed that it was located in introns, from where it tells the spliceosome to remove a nearby exon, thus shortening the molecule. But the defective RBM20 version fails to remove the exon and instead creates RNA with extra segments, resulting in proteins that are too long.
In the case of titin, an essential heart protein, this creates a molecular spring that is too slack and muscles that don’t contract efficiently. Ultimately, the heart is forced to work harder and becomes enlarged. Further study will show if these findings are clinically relevant.
To enable enzymes to grab ahold and start transcribing a gene at the right place, the DNA contains recognition sequences, so-called promoters, which are located immediately upstream.
Researchers at the MDC and the University of California in San Diego have discovered that this isn’t so. Their studies show that a central part of promoters, the core promoter, is intrinsically unidirectional, and that transcripts of the opposing DNA strand arise from their own core promoters.
Using high-throughput experiments and various analytical procedures, the researchers determined that in fact about 40 percent of the genes have two opposite core promoters at variable distances. Through the copy of the opposing strand a long noncoding RNA arises (lncRNA), i.e. a transcript, which is not translated into a protein and whose function has yet to be elucidated. Since reverse-directed core promoters are common but not universal, the researchers presume that these at least partially help to regulate gene transcription.
The CRISPR-Cas9 technology allows researchers to create DNA doublestrand breaks at specific locations within the genome. These are repaired in cells by using one of two naturally occurring mechanisms – either by homologous recombination, which allows researchers to make very precise changes to genome sequences, or by non-homologous end joining, which is more efficient but less precise, since it frequently deletes DNA sequences.
The BIH and MDC researchers have now used nature’s bag of tricks to suppress cellular non-homologous end joining, which makes it possible to increase the efficiency of homologous recombination and thus of precise genetic modifications using CRISPR-Cas9 by up to eightfold.
The team of scientists led by Friedrich Luft at the Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC and the Charité, have found the cause of a rare disease.
The affected individuals have hereditary hypertension, unusually short fingers and are small in stature. They typically die before the age of fifty if their hypertension goes untreated. This disease, which afflicts this and five other families not related to each other, causes six different point mutations in the PDE3A gene.
These mutations lead to high blood pressure and shortened bones of the extremities, particularly the metacarpal and metatarsal bones. The scientists have thus discovered the first Mendelian hypertension form not based on salt reabsorption in the kidneys, but instead is more directly related to the structure and function of the vascular wall.
The consortium “Targeting somatic mutations in human cancer by T cell receptor gene therapy” has made a major advance in the development of cancer immunotherapy. The researchers have successfully modified immune cells (T cells) to recognize and specifically target cancer cells in mice.
They were able to analyze the antigens and clearly distinguish between “good” and “bad” T cell targets by using a humanized mouse model. This animal model can be used to test the therapeutic suitability of T cell receptors and antigens, which is an important prerequisite for the development of clinical applications. Targeting human melanoma neoantigens by T cell receptor gene therapy.
Research leading to better therapy and diagnoses
Therapeutic fatty acid metabolites
Omega-3 fatty acids are found in oily fish such as salmon and are believed to protect against heart disease. But not all patients will benefit from a change of diet. This is because the omega-3 fatty acids first have to be converted into active metabolites in the body, as Wolf-Hagen Schunck’s team at the Max Delbrück Center for Molecular Medicine (MDC) has discovered.
The biochemist and his colleagues are now developing a substance called OMT-28 at OMEICOS, a MDC spin-off. It is supposed to bypass the intermediate step and act directly on the receptors of heart muscle cells. The researchers hope that this will prevent atrial fibrillation and reduce the risk of heart failure and strokes. The substance has already proved effective in animal models. A phase 1 study on healthy human volunteers began in March 2017.
Two recently approved drugs are based on MDC research
MDC researchers made a key contribution to two drugs that came on the market in 2015: VONVENDI (Baxalta Inc., now: Shire) and Blincyto (Amgen). VONVENDI is the only recombinant treatment for adults living with von Willebrand disease (VWD), an inherited bleeding disorder. Patients lack a protein – known as von Willebrand factor – that is crucial for normal blood clotting. VONVENDI provides a substitute and therefore helps control bleeding episodes.
Blincyto, on the other hand, is an immunotherapy against a very aggressive form of blood cancer (B-cell acute lymphoblastic leukemia). The bone marrow of these patients produces too many immature white blood cells. Rather than maturing into functional cells, these lymphoblasts rapidly reproduce, suppressing normal blood formation. The drug enlists the body’s own T-cells to destroy this cancer.