Quinta Grande The Newsletter of the Instituto Gulbenkian de Ciência
April-May 2011 Issue 9
In this edition AXA funds neuroscience research - 3 IGC image on the cover of Science - 2 ROTRF Recognition Prize awarded to IGC researcher - 4
A mystery solved: How sickle hemoglobin protects against malaria
by Ana Godinho
In a study that challenges currently held views, Miguel Soares and his team at the IGC have unravelled the molecular mechanism whereby sickle cell hemoglobin confers a survival advantage against malaria, the disease caused by Plasmodium infection. This research, published in the latest issue of the journal Cell* is likely, not only, to help solve one of the long-standing mysteries of biomedicine but also open the way to new therapeutic interventions against malaria, a disease that continues to inflict tremendous medical, social and economic burdens to a large proportion of the human population.
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Normal and sickle red blood cells (Source: Wellcome Trust, UK).
The mystery Sickle cell anemia is a blood disease in which red blood cells reveal an abnormal crescent (or sickle) shape when observed under a conventional microscope. It is an inherited disorder – the first ever to be attributed to a specific genetic modification (mutation), in 1949 by Linus Pauling (two-times Nobel laureate, for Chemistry in 1954, and Peace, in 1962). The cause of sickle cell anemia was unequivocally shown to be a single base substitution in the DNA sequence of the gene encoding the beta chain of hemoglobin, the protein that carries oxygen in red blood cells. Only those individual that inherit two copies of the sickle mutation
(one from their mother and the other from their father) develop sickle cell anemia. If untreated, these individuals have a shorter than normal life expectancy and as such it would be expected that this mutation would be rare in human populations. This is however, far from being the case. Observations made during the mid-20th century and building on Pauling’s findings, revealed that the sickle mutation is, in fact, highly selected in populations from areas of the world were malaria is very frequent, with sometimes 10-40% of the population carrying this mutation. This observation lead scientists to propose that somehow this mutation is giving those individuals who carry it some
sort of survival advantage. E.A. Beep, a doctor in the British Colonial army in Rhodesia, is credited with the observation, made in the mid 20th century, that the number of cases of malaria in people who had sickle-shaped red blood cells was smaller when compared with individuals in the same population whose red blood cells were normal. This observation was later confirmed by another British doctor and biochemist, Anthony Allison, who, drawing on Linus Pauling’s findings, proposed that people who carry a single copy of the sickle mutation, are not only protected from sickle disease, but also from malaria, thus explaining the high prevalence of this mutation in geographical areas where malaria is endemic. These findings lead to the widespread belief in the medical community that understanding the mechanism whereby sickle cell trait protects against malaria would provide critical insight into developing treatment or a possible cure for this devastating disease, responsible for over a million premature deaths in sub-Saharan Africa. Despite several decades of research, the mechanism underlying this protective effect remained elusive. Until now.
The paper in Cell Several studies suggested that, in one way or another, sickle hemoglobin might get in the way of the Plasmodium parasite infecting red blood cells, reducing the number of parasites that actually infect the host and thus conferring some protection against the disease. The IGC team’s results challenge this explanation. In painstakingly detailed work, Ana Ferreira, a post-doctoral researcher in Miguel Soares’ laboratory, demonstrated that mice (obtained from Prof. Yves Beuzard’s laboratory), that had been genetically engineered to produce one copy of sickle hemoglobin similar to sickle cell trait, do not succumb to cerebral malaria, thus reproducing what happens in humans. When Prof. Ingo Bechman observed the brains of these mice he confirmed that the lesions associated with the development of cerebral malaria where absent, despite the presence of the parasite. Ana Ferreira went on to show that the protection afforded by sickle hemoglobin in these mice acts without interfering directly with the parasite’s ability to infect the host red blood cells. As Miguel Soares describes it, «sickle hemoglobin makes the host tolerant to the parasite». Through a series of genetic experiments, Ana was able to show that the main player in this protective Quinta Grande|April - May | 2
effect is heme oxygenase-1 (HO-1), an enzyme whose expression is strongly induced by sickle hemoglobin. This enzyme, that produces the gas carbon monoxide, had been previously shown by the laboratory of Miguel Soares to confer protection against cerebral malaria. In the process of dissecting further this mechanism of protection Ana demonstrated that when produced in response to sickle hemoglobin the same gas, carbon monoxide, protected the infected host from succumbing to cerebral malaria without interfering with the life cycle of the parasite inside its red blood cells. Miguel Soares and his team believe that the mechanism they have identified for sickle cell trait may be a general mechanism acting in other red blood cell genetic diseases that are also know to protect against malaria in human populations: «Due to its protective effect against malaria, the sickle mutation may have been naturally selected in sub-Saharan Africa, where malaria is endemic and one of the major causes of death. Similarly, other clinically silent mutations may have been selected throughout evolution, for their ability to provide survival advantage against Plasmodium infection ». In Portugal, sickle cell anemia is most common in the South of the country, with small pools in the town of Coruche, Alcácer do Sal and Pias - traditional rice growing areas, where malaria was endemic until the mid 20th century. Genetic studies on the origin and spread of the sickle hemoglobin mutation have shown that the mutation seems to have been brought into Portugal during the slave trade, between the 16th and 19th centuries. Today, near Alcácer do Sal, there remains a small group of people thought to be descendants of the slaves brought into the region. This research was carried out the at the IGC in collaboration with the Team of Prof. Yves Beuzard (Université Paris VII et XI, France), an expert in sickle cell anemia, and Prof. Ingo Bechman an expert in neuropathological diseases (Institute of Anatomy, University of Leipzig, Germany). Other IGC researchers involved in this study are Ivo Marguti, Viktória Jeney, Ângelo Chora, Nuno Palha and Sofia Rebelo. This project was funded by Fundação para a Ciência e a Tecnologia (Portugal), GEMI Fund Linde Healthcare and the European Commission’s Framework * Ferreira, A., et al. Sickle Hemoglobin Confers Tolerance to Plasmodium Infection. Cell, Doi: 10.1016/j. cell.2011.03.049
AXA funds post doctoral fellow research at Champalimaud Neurosciences Programme at the IGC
by Sílvia Castro
AXA research fund was created in 2008 and since then it has taken as a mission to finance basic research contributing to the understanding and prevention of environmental, life and socio-economic risks.
This year one of the winning projects was the one that Albino Oliveira-Maia has submitted under Life risk’s topic that funds projects related with aging and long term care; addictions and risky behaviours; emerging biomedical risks. The project was funded with 60 000 € and aims to understand eating habits and obesity. Undoubtedly, obesity has increased dramatically in occidental societies and it has become one of the greatest threats to public health in the developed world, with a big impact on health costs. The AXA Research Fund Post-Doctoral Grant valued the project in this area that
Mice dopamine neurons
Albino will develop under Rui Costa’s supervision. The study aims to investigate the role and activity of dopaminergic neurons during flavour-nutrient conditioning.
IGC research image on the cover of Science by Sílvia Castro
The cover Science’s April 22nd edition was an image from IGC scientists Leonor Boavida and José Feijó. On the cover of Science you can see a false-colored two-photon microscopy image showing green fluorescent protein–labeled pollen on the stigma (the top of the pistil) of Arabidopsis thaliana. The image resulted from the research firstly published online at Science Express, and sees now the light on the print edition of Science. IGC scientists found out that plant communicate during reproduction through a mechanism previous observed in the nervous system of animals. The Portuguese results open doors for a new line of research on how cell-cell communication is conserved between animals and plants. For more information you can see the press release sent on March 2011
Quinta Grande, Issue10 April-May, 2011
Coordinator: Ana Godinho Editor: Sílvia Castro Contributors: Ana Godinho, Maria João Leão, Sílvia Castro Address: Rua da Quinta Grande, 6 2780-156 Oeiras, Portugal Telephone: +351 214 464 537; Fax.: +351 214 407 970 www.igc.gulbenkian.pt
Have your say ‘Quinta Grande’ is a forum to communicate events and any news which may be of interest to those who work either at or with the IGC. If you have any suggestions of topics to be discussed here, please e-mail them to: quintagrande@igc.gulbenkian.pt Quinta Grande|April - May | 3
News in Brief
ROTRF Recognition Prize awarded to IGC research Miguel P. Soares
Organ transplantation is one of the most important medical advances of the past decades. Over the years, the Roche Organ Transplantation Research Foundation (ROTRF) an independent medical research charity has been providing funding for innovative research projects in this area, particularly where there is an unmet medical need. Last year the Trustees of this organisation invited all ROTRF grant recipients to presenting the results of their ROTRF-funded projects. The ROTRF Recognition Prizes were awarded to investigators whose projects, funded by this institution, had a major impact on the field of transplantation and whose achievements best exemplify the mission of the ROTRF. Now, in 2011 the 11 recipients were announced, and amongst them is IGC researcher Miguel P. Soares. The work for which he has been distinguished began while he was still in his previous host institution, Harvard Medical School, and focuses on tissue transplantation between different species. Miguel P. Soares used an experimental model to study the mechanisms involved in rejection of transplanted mouse hearts into rats, and in the study of an immunosuppressive protocol that protects transplanted mouse cardiac tissue from being rejected by the rat host. He found that the mechanism underlying this phenomenon relies on the expression, by endothelial cell (EC) lining the surface of mouse blood vessels, of a series of ‘protective genes’. He was specially interested in the cellular and molecular mechanisms by which one of these genes, heme-oxygenase-1 (HO-1) expressed in the EC, protects the mouse tissue from being rejected. The results of this project have a great clinical relevance since they can provide innovative new approaches to overcoming transplant rejection between different species, such as in transplantation of pig organs into primates.
IGC at OptimusAlive!Oeiras 2011 music and art festival
For the forth year running and for four day, 6-9 July, IGC will be at the music and art festival OptimusAlive!Oeiras 2011 - one of the major Summer music festivals in Portugal. The partnership between IGC and the music events company Everything is New was set up in 2008 and since then scientists take science to festival goers. This pioneering partnership has awarded four research fellowships for recent graduates, in biodiversity, genetics and evolution. Applications for 2011 will be opening next July.
Dates for your Diary May nd June IGC Seminars list is available here May 20th Biodiversity Day: A look beyond 2010 IGC and the French Embassy in Portugal, are holding a public meeting at the Fundação Calouste Gulbenkian, on 20 May. Biodiversity Day aims to be a space where conservation biologists, students, teachers and the general public may discuss some of the issues of greatest concern to biodiversity on the planet.
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May 15th- June 15th Registrations open for the Genome Biology and Evolution Summer School The Genome Biology Summer School is a joint initiative of the Volkswagen Foundation and the Calouste Gulbenkian Foundation, hosted at the IGC. is open to 40 students of any nationality who will have completed the first year of the Bologna Master’s degree or equivalent.
May 24-27th EMBO Workshop on “Biophysical Mechanisms of Development” The IGC will host the second edition of the EMBO Workshop on “Biophysical Mechanisms of Development”. The workshop will discuss recent advances and new mechanisms arising in the field of developmental biophysics, June 29th C2 talks Science and Art exchanges between the IGC and the Modern Art Centre, FCG: A scientist at CAM: walk-and--talk visit to Migue Palma’s exhibition “Linha de Montagem”