The Max Planck Institute

Barley is one of the most important cereal crops on a global scale. Many barley cultivars produce a toxic alkaloid called gramine that affects the suitability of barley as fodder, but also helps to protect barley from pathogens. So far, the potential of manipulating gramine levels has not been harnessed for plant breeding, because the genetic basis of gramine production has been unresolved. Research groups now disclose the complete biosynthetic pathway of gramine and demonstrate how gramine biosynthesis can be introduced into model organisms or removed from barley. Barley is one of the most important cereal crops on a global scale. Many barley cultivars produce a toxic alkaloid called gramine that affects the suitability of barley as fodder, but also helps to protect barley from pathogens. So far, the potential of manipulating gramine levels has not been harnessed for plant breeding, because the genetic basis of gramine production has been unresolved. Research groups from IPK Leibniz Institute and the Leibniz University Hannover now disclose the complete biosynthetic pathway of gramine and demonstrate how gramine biosynthesis can be introduced into model organisms or removed from barley. Today, the results were published in the journal Science. All plants mediate their environmental interactions via chemical signals. An example is the alkaloid gramine produced by barley, one of the world's most widely grown cereals. Gramine provides protection against herbivorous insects and grazing animals and inhibits the growth of other plants. Despite long-standing interest, the key gene for the formation of gramine remained elusive. The researchers discovered a cluster of two genes in barley for gramine biosynthesis. The first gene (HvNMT) had already been discovered 18 years ago. In their study the researchers from IPK and the Leibniz University Hannover now identified a second gene (AMI synthase, HvAMIS), and found out that both genes are located in proximity of each other on the same chromosome. With this discovery, the pathway of gramine biosynthesis is now fully elucidated. "We discovered that AMIS is an oxidase enzyme that carries out an unusual cryptic oxidative rearrangement of tryptophan, allowing us to revise the previous biosynthetic proposal from the 1960s," says Dr. John D'Auria, head of IPK's research group "Metabolic Diversity." Prof. Dr. Jakob Franke, head of the group "Biochemistry of Plant Specialised Metabolites" at Leibniz University Hannover, adds: "We were very surprised by the so far unknown enzyme mechanism by which gramine is formed. At the same time, we now have the possibility to produce biologically active alkaloids with sustainable biotechnological methods." The research team could produce gramine in yeast and model plants (Nicotiana benthamiana, Arabidopsis). "In contrast to many other protective metabolites from plants, production of gramine requires only two genes. Therefore, using our findings for practical applications is relatively straightforward," emphasises Ling Chuang from Leibniz University Hannover, one of the first authors. "Furthermore, genetic engineering of barley allowed us to produce gramine in a non-gramine producing barley variety, and eliminate gramine production in a gramine producing barley variety by genome editing," explains the other first author Sara Leite Dias, International Max Planck Research School funded researcher at the IPK. "The results set the basis to produce gramine in organisms without the native ability to synthesize it for purposes such as a natural plant protection agent, or to eliminate gramine from barley and other grasses to reduce toxicity towards ruminants," says Dr. John D'Auria. "Our findings set the ground for improving barley to increase its resistance to pests, reduce its toxicity to ruminants and contribute to sustainable weed management."

A new report uncovers how hydrogen gas, the energy of the future, provided energy in the past, at the origin of life 4 billion years ago. Hydrogen gas is clean fuel. It burns with oxygen in the air to provide energy with no CO2. Hydrogen is a key to sustainable energy for the future. Though humans are just now coming to realize the benefits of hydrogen gas (H2 in chemical shorthand), microbes have known that H2 is good fuel for as long as there has been life on Earth. Hydrogen is ancient energy. A new report uncovers how hydrogen gas, the energy of the future, provided energy in the past, at the origin of life 4 billion years ago. Hydrogen gas is clean fuel. It burns with oxygen in the air to provide energy with no CO2. Hydrogen is a key to sustainable energy for the future. Though humans are just now coming to realize the benefits of hydrogen gas (H2 in chemical shorthand), microbes have known that H2 is good fuel for as long as there has been life on Earth. Hydrogen is ancient energy. The very first cells on Earth lived from H2 produced in hydrothermal vents, using the reaction of H2 with CO2 to make the molecules of life. Microbes that thrive from the reaction of H2 and CO2 can live in total darkness, inhabiting spooky, primordial habitats like deep-sea hydrothermal vents or hot rock formations deep within the Earth's crust, environments where many scientists think that life itself arose. Surprising new insights about how the first cells on Earth came to harness H2 as an energy source are now reported in PNAS. The new study comes from the team of William F. Martin at the University of Düsseldorf and Martina Preiner at the Max Planck Institute (MPI) for Terrestrial Microbiology in Marburg with support from collaborators in Germany and Asia. In order to harvest energy, cells first have to push the electrons from H2 energetically uphill. "That is like asking a river to flow uphill instead of downhill, so cells need engineered solutions," explains one of the three first authors of the study, Max Brabender. How cells solve that problem was discovered only 15 years ago by Wolfgang Buckel together with his colleague Rolf Thauer in Marburg. They found that cells send the two electrons in hydrogen down different paths. One electron goes far downhill, so far downhill that it sets something like a pulley (or a siphon) in motion that can pull the other electron energetically uphill. This process is called electron bifurcation. In cells, it requires several enzymes that send the electrons uphill to an ancient and essential biological electron carrier called ferredoxin. The new study shows that at pH 8.5, typical of naturally alkaline vents, "no proteins are required," explains Buckel, co-author on the study, "the H-H bond of H2 splits on the iron surface, generating protons that are consumed by the alkaline water and electrons that are then easily transferred directly to ferredoxin." How an energetically uphill reaction could have worked in early evolution, before there were enzymes or cells, has been a very tough puzzle. "Several different theories have proposed how the environment might have pushed electrons energetically uphill to ferredoxin before the origin of electron bifurcation," says Martin, "we have identified a process that could not be simpler and that works in the natural conditions of hydrothermal vents." Since the discovery of electron bifurcation, scientists have found that the process is both ancient and absolutely essential in microbes that live from H2. The vexing problem for evolutionarily-minded chemists like Martina Preiner, whose team in Marburg focusses on the impact of the environment on reactions that microbes use today and possibly used at life's origin, is: How was H2 harnessed for CO2 fixing pathways before there were complicated proteins? "Metals provide answers,," she says, "at the onset of life, metals under ancient environmental conditions can send the electrons from H2 uphill, and we can see relicts of that primordial chemistry preserved in the biology of modern cells." But metals alone are not enough. "H2 needs to be produced by the environment as well" adds co-first author Delfina Pereira from Preiner's lab. Such environments are found in hydrothermal vents, where water interacts with iron-containing rocks to make H2 and where microbes still live today from that hydrogen as their source of energy. Hydrothermal vents, both modern and ancient, generate H2 in such large amounts that the gas can turn iron-containing minerals into shiny metallic iron. "That hydrogen can make metallic iron out of minerals is no secret" says Harun Tüysüz, expert for high-tech materials at the Max-Planck-Institut für Kohlenforschung Mülheim and coauthor on the study. "Many processes in chemical industry use H2 to make metals out of minerals during the reaction." The surprise is that nature does this too, especially at hydrothermal vents, and that this naturally deposited iron could have played a crucial role at the origin of life. Iron was the only metal identified in the new study that was able to send the electrons in H2 uphill to ferredoxin. But the reaction only works under alkaline conditions like those in a certain type of hydrothermal vents. Natalia Mrnjavac from the Düsseldorf group and co-first author on the study points out: "This fits well with the theory that life arose in such environments. The most exciting thing is that such simple chemical reactions can close an important gap in understanding the complex process of origins, and that we can see those reactions working under the conditions of ancient hydrothermal vents in the laboratory today."

Pancreatic cancer is one of the deadliest types of cancers in humans. It is the fourth leading cause of cancer-related deaths in the western world. The early stages of the disease often progress without symptoms, so diagnosis is usually very late. Pancreatic cancer is one of the deadliest types of cancers in humans. It is the fourth leading cause of cancer-related deaths in the western world. The early stages of the disease often progress without symptoms, so diagnosis is usually very late. Another problem: Advanced tumors -- and their metastases -- cannot be completely removed. Chemotherapies, in turn, attack not only the tumor cells but also healthy cells throughout the body. Innovative nanoparticles could be a new approach to treat cancer more precisely. The approach was developed by a research team from the Max Planck Institute (MPI) for Multidisciplinary Sciences, the University Medical Center Göttingen (UMG), and the Karlsruhe Institute of Technology (KIT). The therapy is now to be optimized for clinical application as quickly as possible. The method promises to treat pancreatic carcinomas with more accuracy and with fewer side effects than current cancer therapies. Using so-called nanoparticles, they transported the active substance Gemcitabine in large quantities directly into the tumor. "Targeting the drug in high concentrations into the tumor cells with the help of the nanoparticles increases the efficacy and spares healthy cells. This can reduce the severe side effects that occur with Gemcitabine," explains Myrto Ischyropoulou, lead author of the study recently published in the journal Advanced Materials. "Currently, patients are given the free drug. This is distributed throughout the body and can lead to toxic effects in all parts of the body. The nanoparticles, on the other hand, release the drug mainly in the tumor." Joanna Napp, scientist at the UMG and the MPI, adds: "Using imaging methods, we have already been able to demonstrate in mouse models that the nanoparticles accumulate in the tumors." The administration of nanoparticles also allows resistance mechanisms in the tumor to be circumvented. "Free Gemcitabine is often no longer taken up by the tumor very early on and is thus largely ineffective there. However, it still leads to considerable side effects, for example in the liver and kidneys," explains Claus Feldmann from KIT. "By using a different uptake mechanism in tumor cells, our nanoparticles could be a very effective new therapeutic approach here." The research success is an excellent example of successful interdisciplinary cooperation, says Frauke Alves, group leader at the MPI and the UMG. "From the idea to the development of the new nanoparticles to preclinical testing, chemists, biologists, pharmacists, and physicians have worked hand in hand." With a spin-off, the scientists are now working to bring their new nanoparticles out of the test phase and into clinical use as quickly as possible.