Max Planck Society Yearbook Highlights

_{The following articles are the selected exemplary scientific research reports from the Max Planck Institute for Biology Tübingen. They highlight the breadth of research conducted at the Institute. These are then included in the annual report compiled by the Max Planck Society.}

For many years, it was unclear how the transmembrane protein ACD6 contributes to immunity in the plant Arabidopsis thaliana. By studying natural genetic variation, we discovered two small proteins that bind to ACD6, with one positively regulating the standard version of ACD6 and the other negatively regulating a naturally hyperactive version of ACD6. These insights in turn spurned experiments that revealed ACD6 to be an ion channel. Together, these experiments highlight how the study of genetic variation can reveal new biology that is not accessible to standard genetic screens.

Understanding why individuals differ from each other is a major goal in evolutionary biology. We study the genome of fruit flies to uncover which and how many genes regulate phenotypic variation, and integrate environmental perturbations to answer a key but still unresolved question: does the function of a given gene depend on the environment? Using whole-genome sequencing of thousands of individual fruit flies we identify the genes that regulate lifespan in low and high sugar diets and ask: are the genes that determine how long an individual lives the same ones in both diets?

What are the origins of new disease outbreaks in agriculture? How do pathogens evolve to infect new hosts and adapt to agricultural environments? These are some of the questions we are tackling, while pursuing disease outbreaks in kiwifruit orchards across South Korea and in banana grown across the Indonesian Archipelago.

Symbioses with microbes span a gradient of interaction outcomes across the mutualism-to-parasitism continuum. But how stable are these designations? Are mutualists beneficial under all conditions? And are parasites destined to always harm their hosts?

Many biological processes are studied in great detail in laboratory settings. However, their ecological relevance and significance is often hard to study because the way back from the lab to nature is difficult. My team and I study how nematodes compete for short-lived resources at scarab beetle carcasses. This work is carried out on small tropical island in the Indian Ocean with unique conditions. This work allows laboratory findings to be tested in “real life”, providing strong evidence for the importance of developmental plasticity and the organisms’ response to fluctuating environments.

In order to generate haploid gametes, eukaryotes can undergo a specialised form of cell division called meiosis. During the first round of meiosis, homologous chromosomes - one from each parent) - must be linked together so they can be properly segregated. In order to do so, most organisms use meiotic recombination to generate crossovers between homologous chromosomes. We describe our recent work that has used biochemical reconstitution to understand parts of the protein machinery that ensures faithful segregation of homologous chromosomes during meiosis.

Brown algae are multicellular eukaryotes that have been evolving independently from animals and plants for more than a billion years. Brown algae have invented a fascinating diversity of body patterns and reproductive characteristics, whose molecular basis remains totally unexplored. We are using the richness of morphological and sexual features of these enigmatic organisms to shed light into the origin of multicellularity and the evolution of sex determination across the eukaryotic tree of life.

Though we are in the era of thousand genome projects, the genes predicted within these genomes still leave much to be desired. In particular, some of the simplifying assumptions result in errors as soon as the peculiarities of molecular biology come into play. Thus, there is a continued need to improve the machine learning and other algorithms used in gene prediction. In the course of assembling and annotating new genomes, we developed a program, Intronarrator, to overcome the gene prediction inaccuracy due to tiny introns by direct intron predictions from deep RNA sequencing.

Genome sequencing holds the key to fighting disease and understanding biodiversity. However, current techniques only produce sequence fragments and omit its context, sometimes causing misleading results. We have developed haplotagging, an improved method for highly accurate sequencing at low costs while preserving the sequences context. Haplotagging can be applied to identify a single gene present in two different butterfly species living between the Amazon and the Andes which creates a unique wing pattern.

Controlled protein degradation plays a crucial role for the correct progression of cell cycle, signal transduction, gene expression or programmed cell death. In eukaryotes, organisms with a nucleus, a complex machinery of enzymes handles this highly regulated process. Recently, the existence of related enzyme systems has also been found in prokaryotes, organisms without a nucleus. The analysis of these nanomachines provides insight into the evolution of cellular protein degradation and the origin of the eukaryotic degradation machinery.

We use an interdisciplinary approach combining computational chemistry, biophysics, and developmental biology to create new signaling activators and inhibitors. We have designed novel hematopoietic growth factors and antagonists of cancer-relevant signals, and their structures are in atomic-level agreement with our theoretical predictions. Strikingly, the growth factors are highly active and can induce the differentiation of blood cells in living zebrafish embryos. This strategy holds great promise to engineer signaling molecules with novel functionalities for future clinical applications.

The transition to a sedentary lifestyle with agriculture and livestock breeding during the Neolithic left genetic traces. Scientists at the Department of Microbiome Science have found that differences between people at the level of genes involved in starch and milk metabolism play an important role in the composition of the microbiome in the intestine. The recent adaptation of humans to new eating habits has led to genetic variations which are still reflected today in differences in modern microbiomes.

Genetic variation is the basis of biodiversity, and is the key substrate of evolution. We are studying meiotic recombination, a key source of genetic variation, to elucidate on the role it plays while organisms adapt to new environments. Using linked-read genome sequencing technology, we have developed a method of studying recombination in individuals, and are using this to identify its molecular basis. Research on this fundamental process has implications for our understanding of first trimester abortion, genome function and how molecular mechanisms shape evolution in natural populations.

How do wild species respond to the climate change we currently experience? Scientists from the institute have discovered that the ability to adapt to extreme climate events is not uniformly distributed even within a single wild plant species. Hence, predictions of the future distribution of species are only meaningful if differences both between and within species are taken into account.

Sexual reproduction requires the generation of special cells called gametes, i.e. eggs and sperms, which carry half the genome of the parent. Meiosis is the process by which the parental genome is divided. In order to segregate the genome in a controlled way, novel linkages between sequentially similar chromosomes need to be created. Linkages are made by making programmed breaks in the DNA, followed by controlled repair of these breaks. Understanding the process of breakage and repair in detail at the molecular level will provide new insights into human fertility and genetic diseases.

Connectomes are wiring diagrams of neural networks showing the specific connections between neurons. The research group Neurobiology of marine zooplankton is working on the complete wiring diagram of a small marine larva to understand how neuronal circuits mediate behaviour.

Organisms are responsive to environmental variation. However, little is known on how genetic regulation of development is linked to environmental changes. Phenotypic plasticity, the property of a single genotype to produce distinct phenotypes dependent on the environmental conditions, provides a unique opportunity to study organismal-environmental interactions. The nematode Pristionchus pacificus is a new model for studying phenotypic plasticity. P. pacificus forms two distinct mouth-forms and is accessible to an unbiased studying of phenotypic plasticity.

How species differ from each other is a key question in biology. But genetic mapping between species has been challenging, because hybrid crosses are typically sterile. Combining latest stem cell and genomic techniques, the research group has pioneered in vitro recombination to circumvent breeding and directly cause gene exchanges in cells. In this way they have mapped differences between mouse species within weeks and created mouse embryos carrying hybrid mosaic genomes. By circumventing species barriers that prevent interbreeding this work sheds light on the genetic basis of trait variation.

The basic features of the body organisation of adult plants are established during embryogenesis. This process starts from the fertilized egg cell (zygote), which divides into an apical embryonic cell and a basal extra-embryonic cell. How this initial difference originates with input from the YODA pathway is briefly discussed. These cells give rise to embryo and extra-embryonic suspensor, respectively. The embryonic cells then generate, in response to the plant hormone auxin, a signal that stimulates the adjacent extra-embryonic cell to initiate the formation of the embryonic root meristem.

We are surrounded by microorganisms that adapt in their struggle to persist. In contrast to animals or plants, such adaptations don't take thousands of years but sometimes happen within weeks. To understand such rapid evolution, we need new theoretical frameworks and direct observations of the evolutionary dynamics. The research group develops such theory and uses it to analyze sequence data from influenza and human immunodeficiency virus populations. The results provide insight into the properties of the evolutionary process and allow predicting the composition of future virus populations.

The Max Planck Research Group Systems Biology of Development studies how signaling molecules transform a ball of cells into a patterned animal embryo. The scientists use an interdisciplinary approach combining genetics, biophysics, mathematics, and computer sciences. The results may help inform new regenerative medicine approaches for the generation of tissues from stem cells.

The attachment of ubiquitin (ubiquitination) to proteins is one of the most abundant protein modifications and targets proteins for degradation. We aim to understand how the ubiquitination reaction works on a structural level, how ubiquitination enzyme activities are regulated, and how ubiquitination regulates cellular processes and behavior. Since dysregulation of ubiquitination is associated with many human diseases, our studies also offer starting points for novel drug design strategies aimed at manipulating ubiquitination enzyme activities with small molecule inhibitors.

Today it is possible to retrieve genomes from organisms that perished thousands of years ago. Millions of desiccated plant specimens are stored in museums and contain DNA suitable for genome sequencing. These specimens harbor an untapped record of global biodiversity spanning the last 450 years. The combined use of historical and modern plant samples introduces a temporal scale to evolutionary studies, allowing the interrogation of allele frequencies through time. The research group studies the evolution of plants, their pathogens, and the associated microbiome using modern and ancient DNA.

Organisms across the world show unique adaptations that enable them to survive and flourish in distinct environments. Researchers at the Friedrich Miescher Laboratory are studying stickleback fish to unravel the genetic changes which allow organisms to adapt and speciate in new environments. Marine sticklebacks have undergone an adaptive radiation with freshwater forms evolving repeatedly and independently at many different places. Using these powerful replicates of the evolutionary process, research is identifying the common molecular changes underlying adaptation and speciation.

In eukaryotic cells DNA and transcription of RNAs are separated from protein biosynthesis occurring in the cytoplasm. Nucleus and cytoplasm are only connected via the nuclear pores. Transport between the compartments is aided by dedicated shuttling proteins, the karyopherins. Most karyopherins carry cargo only in one direction, either into (importins) or out of the nucleus (exportins), and then return empty handed. Importin 13 is an unusual karyopherin that can both import and export cargo. Our work revealed how Imp13 recognizes its cargoes and functions as a bidirectional transport factor.

MicroRNAs are genome-encoded, around 22 nucleotide-long RNAs that silence gene expression post-transcriptionally by binding 3′ untranslated regions of messenger RNAs. Although recent years amassed a wealth of information about their biogenesis and biological functions, the mechanisms allowing miRNAs to silence gene expression is not fully understood. Our long-term goal is to understand in molecular terms how miRNAs repress hundreds of mRNA targets in animal cells.

House mice from the Faroe Islands are among the largest mice in the world. Researchers at the Friedrich Miescher Laboratory try to understand how they come to settle in the Faroe and how they have evolved island gigantism so rapidly in the last thousand years by sieving through their genomes. Hidden in the tapestry of the mouse DNA is a complex history resulting from hundreds of years of mixing between mouse subtypes. Efforts are now underway to uncover the genetics of island gigantism.

As central elements of life, proteins fulfill a plethora of functions in cells and organisms. Not only their synthesis, but also their degradation has to be carefully regulated. Networks of ring-shaped AAA ATPases use energy to unfold proteins and deliver them into the interior of cylindrical proteasome complexes, where the disentangled proteins get degraded down to their basic components. Biochemical, bioinformatic and structural methods allow a deeper understanding of these processes on a molecular level and give insight into the evolution of complex protein nanomachines.

Each cell contains thousands of different proteins, and each of these proteins fulfills a specific task. To ensure that the exact amount of individual proteins is produced at the right time, the cell tightly regulates the expression of genes. During this process, messenger RNA (mRNA) molecules transfer the genetic information to the cellular location of protein production. The group studies the molecular machinery that degrades these mRNA molecules - which provides the cell with an efficient means to terminate the production of proteins that are no longer required.

Plants and animals independently evolved multicellularity. To orchestrate the growth and development of their tissues and organs, both kingdoms of life use hormones. The research group investigates how plant receptor proteins sense a growth-promoting steroid hormone by combining structural biology and biochemistry with genetics utilizing the model plant Arabidopsis thaliana.

Darwins theory on the origin of species by means of natural selection rests on the assumption that in every generation the progeny are not exactly alike, but vary slightly. Those that fit best to the conditions survive and propagate their kind. In order to identify genes that when mutated cause the variation of animal morphology in evolution, it is necessary to understand growth and development of  shape and form. In the department of genetics muscle stem cells, as well as the development of integumentary structures and the pigment pattern of the zebrafish are investigated.

The world’s oceans are teeming with microscopic animal life, with myriads of tiny critters, collectively called zooplankton, swimming and swirling in the water. These organisms sense and react to their environment, are able to sense where the light is coming from, how cold the water is, or how deep they are. They achieve this with nervous systems of surprising simplicity. The research group is trying to understand, using the marine annelid Platynereis as a model, how these nervous systems are wired up and function.

The nucleus, the command center of the eukaryotic cell, is separated from the cytoplasm by the nuclear envelope. At the beginning of cell division the nuclear envelope breaks down and DNA massively condenses to form chromosomes. The chromosomes are then equally distributed to the two emerging daughter cells. After this process is completed, chromosomes decondense and a new nuclear envelope is formed. The formation of the new nuclear envelope is a complex interplay of cellular membranes and proteins which scientists at the Friedrich-Miescher-Laboratory in Tübingen now try to understand.

Modern approaches and discoveries in developmental biology have a major influence on the understanding of evolutionary patterns and processes. Developmental control genes are highly conserved throughout the animal kingdom. How, nevertheless, biological diversity was generated despite the conservation of developmental control genes is subject of research in the area of evolutionary developmental biology (evo-devo). Recent studies in evo-devo aim for an integrative approach involving population genetics and ecology.

How a single cell gives rise to a complex multicellular embryo is a fascinating question in biology. This process involves coordination of cell division, differentiation and migration. We investigate the embryonic development of the fruitfly, Drosophila melanogaster, and focus on studies of cell migration and in particular of germ cells, the cells that give rise to sperm and egg cells. This report describes how lipids play a crucial role in regulating the survival and migration of Drosophila germ cells and which biological principles we can learn from this research.

During cell division, a multitude of changes has to occur concomitantly. Kinases, which have the ability to modify proteins by adding phosphate groups, play a crucial role during this process. Researchers at the Friedrich Miescher Laboratory have examined which proteins are modified by the Aurora kinase. This kinase is crucial for proper inheritance of the genetic information during cell division, and inhibitors of this kinase are currently tested in clinical trials. Elucidating the substrates of the Aurora kinase is therefore of both scientific and clinical relevance.

The basic features of the body organisation of adult plants are established during embryogenesis. This process starts from the fertilised egg cell (zygote), which divides into an apical embryonic cell and a basal extra-embryonic cell. This report describes how the embryonic cells generate, in response to the plant hormone auxin, a signal that stimulates the adjacent extra-embryonic cell to initiate the formation of the embryonic root meristem. In addition, attempts to study the origin of the very first difference between apical and basal cell fate are briefly discussed.

The diversity of today’s universe of proteins has developed via a multitude of small changes. Gene duplication provides the material for mutation and selection, while recombination contributes to the creation of diversity. These mechanisms are the basis for many successful protein engineering experiments. The amount of available sequence and structural data enables general assumptions about important factors in structure-function relationships. These findings are used in rational and computational design to build proteins with desired new properties.

The development of novel high-throughput sequencing technologies allows the determination of the complete set of RNA-transcripts expressed under a given condition. Accurate and efficient computational methods are needed to uncover the full potential of the immense amount of data that is generated by these technologies. Our research group focuses on the analyses of transcriptome data using modern „Machine Learning“ algorithms, providing a better insight into the relation of genetic information and phenotypic traits of individuals.

Abstract Mouse ear cress, Arabidopsis thaliana, is the workhorse of plant genetics, and currently only second to humans when it comes to information about genomic variation within the species. In the past two years, there has been a revolution in sequencing technology, and A. thaliana is an ideal object for exploiting the dramatic improvements in sequencing speed and cost. This report describes the beginning of the 1001 Genomes Project, which has as its goal the complete description of the genomes of 1001 wild strains of A. thaliana.

DNA is packed into chromosomes. During cell division two daughter cells must receive identical sets of chromosomes containing the genetic information. Missing or extra copies of chromosomes might result in cell death and diseases, hence, complex cellular mechanisms ensure the equal distribution of genetic information during cell division. Scientists at the Friedrich Miescher Laboratory are trying to understand how the two halves of a chromosome are held together and subsequently are distributed to daughter cells.

Animal embryos specify four early cell types. Determining the underlying mechanism is one central question of developmental biology. At present, it is studied how the crustacean Parhyale hawaiensis manages such developmental program at the eight-cell stage. Specification of germ cells, e.g., depends on the genes vasa and nanos, however, in a different way than in Drosophila melanogaster , demonstrating change of gene function during evolution.

MicroRNAs (miRNAs) are genome-encoded, about 22 nucleotide-long RNAs that silence gene expression post-transcriptionally by binding to 3’-untranslated regions of messenger RNAs. Although much information has been obtained about miRNA biogenesis and biological functions, the mechanisms allowing miRNAs to silence gene expression in animal cells remain controversial. Our goal is to understand the molecular mechanism of miRNA-mediated gene silencing.

The nucleus, the command centre of the eukaryotic cell, is separated from the cytoplasm by the nuclear envelope. How the nuclear envelope is disassembled at the beginning of cell division and how it is reassembled at its end, is largely unknown. The process is a complex interplay of cellular membranes and proteins. Scientists at the Friedrich-Miescher-Laboratory in Tübingen try to understand the underlying mechanisms.

Understanding how external signals are transduced across cellular membranes is a formidable challenge for molecular biologists. Through the structure of an archaeal HAMP domain, which was determined by nuclear magnetic resonance spectroscopy, we gained more insight into this process. The HAMP domain connects extracellular sensory to intracellular effector domains in a large number of transmembrane receptor proteins and hence is thought to play a crucial role in signal transduction. The structure reveals an ability to switch reversibly between two conformations with similar energy levels, whose balance is affected by ligand binding. A cogwheel-like rotation of helices, triggered by ligand binding to the sensory domain, appears to underlie the conformational change that mediates transduction of extracellular information into the cell.

When cells divide, the genomic information is duplicated and becomes symmetrically distributed to the daughter cells during division. Errors in the distribution of the genomic DNA can lead to cell death or promote tumor growth. Researchers at the Friedrich Miescher Laboratory use yeast to examine how cells ensure the extremely low error rate in the distribution of the genomic information.

The long-term goal of our research is to understand how social systems adapt to variable environments. Thorough understanding of the adaptive process, however, requires detailed knowledge of the mutational basis of adaptations, the fitness and phenotypic effects of those adaptations, and the selective environments in which they conferred fitness advantages. Towards this end, we employ both laboratory-based evolutionary studies of the social bacterium Myxococcus xanthus, as well as studies of fine-scale phenotypic and genomic variation among natural isolates. Here we highlight some of our ongoing studies of laboratory-evolved genotypes.

Cell migration in organisms is a complicated process, which is accomplished by the finetuned activity of the cytoskeleton in different regions of the cell. In vertebrates, cell migration plays a fundamental role as the three dimensional structure of organs is built by the migration of many different cell types: for example during the development of the nervous system and the blood vessels. It is obvious that these movements of cells from different origins have to be coordinated to ensure that each cell reaches its destined place. However, very little is known about how an embryo manages this huge logistic task. Embryos of the zebrafish, Danio rerio, harbour many characteristics making them the ideal model organism to study this dynamic cell behaviour in vivo: The embryos develop extremly fast outside the mother organism: 24 hours post fertilisation all important organ systems have started to form. Moreover, fish embryos are transparent, allowing high resolution time lapse microscopy to study and examine living animals.

Novel technologies allow for many measurements on biological systems, leading to fast-growing amounts and variety of data. In order to tap the full potential of the available data a thorough analysis is demanded. Apart from the electronic data organisation, an efficient and automatic analysis is a great conceptual challenge. Using modern Machine Learning Methods, researchers at the Friedrich Miescher Laboratory are analysing for example the complex phenomenon of cellular messenger RNA splicing. Their particular interest is the prediction of alternative splicing and a deeper understanding of its regulation mechanisms.

All multicellular organisms in the animal kingdom share a surprisingly high number of molecular building blocks and many of the same regulatory pathways. Yet, we still do not know how the various organisms use and modify these pathways to generate the nearly endless diversity of biological form. Evolutionary developmental biology tackles this problem by comparing the development of one organism to another, related organism. We have established the nematode Pristionchus pacificus as a satellite organism in “evo-devo”. After the generation of a molecular toolkit, we now address multiple questions ranging from developmental biology, neurobiology and genomics all the way to ecology.

Learning and memory are fundamental properties of higher organisms. While learning is the ability to acquire knowledge, memory refers to the ability to store acquired information and recall it in a novel context. In the last 50 years, it became clear that different forms of memories can be attributed to distinct regions within the brain. A region called hippocampus plays a crucial role in this process: it contains cells which are responsible for explicit forms of memories. Explicit memory represents conscious knowledge about the world, objects and people. Implicit memory, in contrast, represents unconscious procedures. Primarily we are interested in understanding the molecular mechanisms underlying learning and memory.

Membrane and protein transport are essential processes in the cell. Proteins have to be delivered to the correct cellular target compartment to fulfill their function. Most of the cellular organelles are surrounded by membranes in order to prevent uncontrolled mixing of their content with the cytoplasm. Communication between the organelles is mediated by vesicles that travel between different compartments. We investigate the regulation of membrane and protein traffic in different organisms. In the baker’s yeast Saccharomyces cerevisiae, we focus on the life cycle of a transport vesicle that is formed at the Golgi apparatus destined for the endoplasmic reticulum. In contrast, in the nematode Caenorhabditis elegans, we study membrane delivery into the division plane during cytokinesis. Cytokinesis is the last step in cell division: After DNA has been equally duplicated and distributed onto two poles, new membrane is inserted in between the poles at the plasma membrane which divides the cellular content, resulting in two cells.

Our long-term goal is to understand the mechanisms underlying variation in adaptive traits. As a prerequisite, the genes that are used by wild plants and animals to create phenotypic diversity need to be defined. By integrating a mechanistic understanding of genetic networks with an understanding of the adaptive significance of trait variation, it should be possible to identify functionally divergent alleles in natural populations. This knowledge can be used to understand the genetic mechanisms underlying adaptive change, and to predict the performance of natural populations under changing environmental conditions.

The availability of a large number of microbial genomes from a broad range of organisms has shaped our understanding of the dynamics of genome structure from pathogenic and non-pathogenic bacteria. The close adaptation towards a host in a symbiotic or pathogenic relationship results in small, minimalist genomes. The genomes from related host-adapted and potentially free-living bacteria are studied to gain insight into the molecular mechanisms that have driven the speciation process from free-living last common ancestors to the obligatory pathogenic species that we see today.

The research group is working on two main areas of interest of Cognitive Developmental Psychology. On the one hand , there are studies being carried out to show how children process the multitude of information in the environment and whether changes in processing occur with increasing age (Information Processing). On the other hand, we aim to find out what kind of knowledge children have in the course of development and how they acquire this (Knowledge Acquisition).

Membrane and protein transport are essential processes in the cell. Proteins have to be delivered to the correct cellular compartment where they function. Most of the cellular organelles are surrounded by membranes in order to prevent uncontrolled mixing of the content of the compartment with the cytoplasm. The communication between the organelles is mediated by vesicles that travel between different compartments. We investigate the regulation of membrane and protein traffic in different systems. In the baker’s yeast Saccharomyces cerevisiae, we focus on the life cycle of a transport vesicle that is formed at the Golgi apparatus and destined for the endoplasmic reticulum. In contrast, in the nematode Caenorhabditis elegans, we study the membrane delivery into the division plane during cytokinesis. Cytokinesis is the last step in cell division. After the DNA has been equally divided and has been distributed onto two poles, new membrane is inserted in between the two poles at the plasma membrane, which divides the cellular content resulting in two cells that can start a cell-cycle anew.