Research

The Computational Genomics Laboratory at a glance

The Computational Genomics Laboratory develops research in the area of Evolutionary Cell Biology, and its translation in the context of human and animal health. The problem we study is the origin of intracellular compartmentalization, including the origins and evolution of cellular organelles, functional modules, and the evolution of cytoplasmic organization . This work has led to the identification of novel drugs, and is now helping us uncover cancer biomarkers to aid clinicians treating cancer patients. We have developed several novel bioinformatics and medical informatics platforms to deal with data integration problems raised by our work, for example in the areas of epidemiology of infectious diseases and the molecular basis of genetic diseases. We use mostly computational approaches in our work (Bioinformatics, Systems Biology), and more recently started also to conduct experimental work, for example testing our computational predictions on patient material arising out of cancer biopsies, and getting involved in genome sequencing projects.

Current research questions and projects

Evolution of cytoplasmic organization

Cells compartmentalize their biochemical functions in a variety of ways, notably by creating physical barriers that separate a compartment via membranes or proteins. Both Eukaryotes and Prokaryotes have a wide diversity of membrane-based compartments, many that are lineage- or tissue-specific. We are interested in understanding how organelles arise in evolution and how they develop new, specialized functions. We have been focusing Rab small GTPases, markers of distinct pathways and compartments within the Eukaryotic endomembrane system, to address the following questions:

  • When did each organelle and pathway emerge in evolution 
  • Did it involve the co-option of existing components, duplication followed by subfunctionalization, or the ‘invention’ of novel functions and/or components?
  • What is the nature of the mutations involved in the emergence of Rab functions in the evolution of the endomembrane system

We are also interested in protein based organelles and use as a model organelle the microtubule organizing centers (MTOCs), the major organizer of the Eukaryotic cytoskeleton. MTOCs have a clearly defined structure to study that allows us to study the interplay between the molecular components and the morphological properties of the cell. We are addressing the following questions:

  • How many different types of MTOCs exist in nature and are they homologous or analogous? (diversity and variation) 
  • What constraints does function impose of structure? 
  • What is a normal MTOC morphospace and what is its relationship to the pathological morphospace how does morphological variation maps to genotypic variation?

Both internal membrane systems and MTOCs are organized by proteins that frequently have coiled coil domains. These domains  form rods and spacers and are also protein interaction platforms. Coiled coils pose several problems for bioiformatics and molecular evolution analyses, in particular the difficulty in distinguishing homology from analogy. We are seeking to understand the evolutionary dynamics of these domains in order to address the questions raised above about endomembrane systems and MTOCs.

'Cell inside cells' - Evolution of endosymbionts, parasites and development pathways

One of the most fascinating aspects of cellular life is how cells have found replication niches inside other cells. Mitochondria and chloroplasts represent one extreme of full integration between endosymbiotic organelle and host. At the opposite end of the spectrum are compartments formed by intracellular parasites that invade and parasitize eukaryotic cells for several resources, occupying different intracellular niches (phagosomes, lysosomes, cytosol, etc.) and having a deleterious effect on the host. In between these two extremes, we find multiple independent cases of endosymbiosis of bacteria from diverse taxonomic groups with various degrees of integration with organisms from the majority of eukaryotic taxa. Similarly, there are multiple examples of Eukaryotes that found replication niches inside other eukaryotes, forming permanent endosymbiotic associations or as parasites. Less appreciated is that bacteria also found replication niches inside other prokaryotes, which lends support to the idea that the endosymbiotic event that resulted in mitochondria did not necessarily require a pre-existing internal membrane systems. Our current projects in this topic include:

  • Characterizing the adaptation of protozoa to intracellular life, using the facultative parasite of clams and oysters, Perkinsus olseni, as a model system
  • Characterizing the adaptation of bacteria to intracellular replication niches

 

Another way by which a cell may be found inside another cell is in the context of specific developmental programs. We are interested in the development program that in some Firmicutes gives rise to a specialized cell type, a spore, that is engulfed by the mother cell - a process termed endosporulation. This development program gives rise to the most resistant cell type known to man. We wish to understand:

  • when did the sporulation program emerge in evolution and what is its relationship to other (exo) sporulation programs in bacteria?n
  • what is the origin of the endosporulation machinery - how much represents novel structures and functions and how many represent co-options or subfunctionalization of existing components?
  • what is the role of endosporulation - a stress response or an alternative replication strategy for varying environments?
  • what is the molecular basis of spore resilience?

 

Bioinformatics methods and databases for Evolutionary Cell Biology

Our work in evolutionary cell biology is raising problems for which we don’t have the adequate tools to address. This has led us to develop such bioinformatics tools and resources. In the past we developed:

RabDB and the Rabifier - a database and sequence classifier for functional assignment of Rab proteins

HCO - a database and sequence classifier for Heme-copper oxygen reductases 

We are currently working on:

MTOC-Explorer a database and analysis framework of morphological diversity for MTOCs; and the MODI  the MOrphological Diversity Index, a metric for the comparison of cellular structures 

A substitution model to study Coiled-coil -forming proteins, and a homology detection pipeline for proteins containing these domains.

 

Translational Bioinformatics and Evocell

Translational bioinformatics is a term that describes the use of bioinformatics methods in translational research, i.e. aimed at solving medical problems (diagnosis,  prognosis, new therapies, personalized medicine, etc.). To us it is the ultimate test ground of the sometimes very abstract research that we do in evolutionary cell biology.

Currently, our main research lines are:

Dissecting numerical and structural centrosomal abnormalities in tumor progression as potential prognostic markers and therapeutical targets. This is a collaborative project with the labs of Monica Betencourt Dias (IGC, PT), Paula Chaves (IPO, PT), David Pellman (Dana Farber Inst., USA), funded under the Harvard Medical School - Portugal program.

Drug repositioning for infectious diseases: Drug development pipelines are drying, and few new drugs are reaching the market. There is however some indication that current drugs may have broader uses than currently known. We are exploring bioinformatics and evolutionary approaches to find new antibacterial and antiprotozoal uses of existing drugs. We focus on understanding the adaptation of intracellular parasitic bacteria to the host cells. This research line has given rise to one spin-off company - Comparagen.

Understanding the epidemiology of the intracellular parasite M. tuberculosis, the causative agent of tuberculosis. In the course of this project we developed a new typing framework for M. tuberculosis  and developed a new, open source, data integration platform to manage and analyse clinical, epidemiological, molecular typing and socio-demographic data - inTB. This work is a collaboration with the lab of Gabriela Gomes (IGC, PT).