On December 12th Vadim Gladyshev from the Harvard Medical School, Boston, USA, gave a conference in a packed room at the PRBB invited by Roderic Guigó from the CRG. Gladyshev investigates the molecular basis for natural changes in longevity and the biological mechanisms involved in aging.
The first part of the conference focused on the mechanisms of aging. Gladyshev’s main question was: why and how do things go wrong with age?
At the beginning he introduced several aging theories that have contributed most significantly to the aging debate in the research community. Some of them were built in the 50s based on 19th century insights, whereas others are very recent. According to him, these theories are very different, each of them touching on a particular aspect of the aging process and, within that context, each has its merit, but all are incomplete.
He continued with his own view about aging. He suggested that imperfectness of biological processes leads to inevitable damage accumulation – called deleteriome – causing aging. His research group is now characterizing properties of cumulative damage and its impact on the aging process. They also study cancer as a disease of aging.
While the mechanisms of aging and the process of lifespan control may seem highly related topics, he maintained that they are different areas. To explain the difference, he used a metaphor of a river, where a lifespan would be equivalent to the time needed for the water to flow from the mountain to the ocean. According to him, the route of the river can be changed to make the journey longer, just like lifespan of humans can be extended. However, the fact that the river flows because of gravity can’t be changed, just like we cannot change the fact that the aging process occurs because of imperfectness. So the cause of aging is different from the determinants of longevity.
The second part of the conference was about mechanisms of lifespan control, trying to answer the questions: why do cells and organisms live as long as they do? and how does Nature adjust lifespan?
Gladyshev’s research team uses multiple approaches to address this question. One methodology involves studying the genes of exceptionally long-lived mammals, such as the naked mole rat, the Brandt’s bat and the bowhead whale. The Brandt’s bat (Myotis brandtii) is found throughout most of Europe and parts of Asia, and it often lives more than 40 years.
The naked mole rat (Heterocephalus glaber) is a burrowing animal commonly found in East Africa, well-adapted to their underground existence. They are characterized by small eyes, short and thin legs, hairless body (hence the common name) and wrinkled pink or yellowish skin. Their large front teeth are used to dig. This animal can live up to 31 years, the record for the longest living rodent.
Gladyshev’s group recently sequenced and analyzed the genomes of these animals, and they discovered some of the adaptations that contribute to their long lifespans. They also identified general gene expression and metabolic changes that associate with longer life.
In addition to the evolutionary study of long-lived animals, Gladyshev’s lab focuses on cell types that have different lifespan and in long-lived mouse models. They also do analysis across species and cell culture-based profiling in order to find unique and common mechanisms of longevity. Longevity signatures (based on gene expression) identify candidate interventions for lifespan extension. Ultimately, the researchers would like to find treatments or some other approaches which would help extend life span and diminish the consequences of age-related diseases.
At the end of the talk the public showed great interest on Gladyshev’s research, posing many questions about aging in yeast, epigenetic drift in aging and the relation between lifespan and maturity. In a fruitful and interesting conversation, some in the audience also suggested research approaches such as studying aging in single cells or focusing on the physics of aging. We’ll have to wait for Gladyshev’s next talk to see if some of these suggestions gave their fruits!
A report by Mari Carmen Cebrián
Congratulations to Núria López-Bigas at the GRIB (UPF-IMIM) for her lab’s latest paper in Nature describing why there’s an increased mutation rate in Transcription Factor Binding Sites (TFBS) in melanomas and lung tumors!!!!
You can read more about the experience publishing this paper in this post from her lab’s blog, where she explains how, after a long process of reviewing, they felt they “had the responsibility to describe our finding as soon as possible to the community”, and decided to publish the manuscript in bioRxiv. Later on, the paper was accepted and published by Nature.
Here’s for this success story!
You can read the paper here:
Radhakrishnan Sabarinathan, Loris Mularoni, Jordi Deu-Pons, Abel Gonzalez-Perez & Núria López-Bigas. Nucleotide excision repair is impaired by binding of transcription factors to DNA. Nature 532, 264–267 (14 April 2016) doi:10.1038/nature17661
Manolis Kogevinas, Codirector of CREAL, one of the centres within the PRBB, has written this post recently in the “Health is Global” blog about how external factors play a major role in most cancers. He also talks about the new edition of the European Code Against Cancer, published by the International Agency for Research on Cancer (IARC) and addressed to all European citizens.
If you want to know more about the European Code against Cancer and the workings behind it, you can read the interview to Joachim Schüz, head of the environment and radiation section at the IARC and one of the principal investigators involved in its updating. He visited the PRBB a few months ago, and you will find the interview here, in page 4 of the Ellipse newspaper – the monthly publication at the PRBB.
The Biomedical Genomics group led by Núria López-Bigas at the Pompeu Fabra Unviersity have recently published a paper in Cancer Cell describing the landscape of anti-cancer targeted therapeutic opportunities across a cohort of patients of twenty eight of the most prevalent cancers. They first looked for all the driver mutations (mutations that ’cause’ the cancer) for each individual cancer, then collected information on all the existing therapeutic agents that target those mutations, and finally, combining both datasets, came up with anti-cancer targeted drugs that could potentially benefit each patient. You can read more about this paper on their blog post.
Coinciding with the publication of that paper, the lab has crafted a new IntOGen interface which presents the results of this analysis. You can see it and learn more about it here.
“Cancer prevention requires the vision, courage, and political leadership to make long term decisions”
Christopher Wild has been the Director of the International Agency for Research on Cancer (IARC), the cancer agency of the World Health Organization (WHO), since 2009. Married to a neuroscientist and father of three, this epidemiologist and Man United fan came to the PRBB in March to give the 3rd Global Health session co-organised by ISGlobal, CRESIB, and CREAL.
How has the burden of cancer changed over recent years?
The incidence of cancer globally has increased: there were 14 million new cases in 2012 and it is expected we will reach 24 million new cases by 2035. Also, about 70% of the world’s cancer deaths occur in low- and middle-income countries. This is due to the rise in population sizes and average life expectancy in general, particularly in these countries, but also because they are shifting towards ‘industrialised’ lifestyle habits such as increased smoking, alcohol consumption, unhealthy diets, obesity and lack of physical exercise, which we know are linked to cancer.
Who should ensure decisive action is taken against these known risks?
First the researchers need to provide reliable scientific evidence on which to base decisions. Once the scientific evidence is available it is down to national authorities to make informed regulatory decisions. However, scientists can probably explain the interpretation of their findings more clearly when presenting them to decision-makers.
Why is prevention so hard?
There are different elements involved. First, intervention may require co-ordination across different parts of government and society. Second, there are often infrastructural, economic or cultural barriers. For example, in some developing countries, vaccinating against human papilloma virus to prevent cervical cancer might be interpreted as a signal of sexual promiscuity. This is why I think much more research has to be conducted on the factors which affect the implementation of prevention in routine healthcare settings. This is an often neglected area.
Finally, sometimes the case is not made politically and there is a failure to translate scientific evidence into guidelines. One of IARC’s important jobs is to evaluate prevention strategies, to find out what works. This research must be independent of vested interests, and here the position of the Agency within the UN has a major advantage. It also gives us the opportunity to improve the translation of knowledge into action at the level of individual countries.
Where do we need to invest more in the fight against cancer?
Prevention is central to reducing the rising trend of cancer, and we know that more than 50% of cases could be prevented if what is currently known were to be implemented efficiently; if governments took strong action, such as enforcing anti-tobacco controls, ensuring vaccination against HBV and HPV, promoting healthier lifestyles and improving access to health care including the early detection of breast, cervical, and colorectal cancers. But investment in prevention requires the vision, courage, and political leadership to make decisions and financial commitments that will bear fruit, often many years in the future.
You can read a related post here.
The director of the International Agency for Research on Cancer (IARC), Christopher Wild, celebrated his birthday in style this year. On that special day, February 21, he gave a talk to a full auditorium at the PRBB, in what was the 3rd Global Health session co-organised by ISGlobal, CRESIB and CREAL. This was his second visit to the park, the first one being six years ago, when the building was pretty much empty. “It’s great to see how now everything is thriving!”, he said.
Wild started pointing out the three aims of the IARC, the cancer agency of the World Health Organization (WHO): describing occurrence of cancers, evaluating prevention strategies, and supporting implementation in clinical settings. He highlighted particularly the low-income countries where cancer cases are increasing exponentially, with 60% of cancers worldwide now being in developing countries.
The role IARC is crucial if we take into account that 30% of non-transmissible diseases in 30-70 years-old are due to cancer. And especially so if we look at the predictions based on demographics: according to the agency’s director, by 2030 there might be 21.7 million cases of cancer, when in 2012 there were 14 million.
“Cancer patterns are not static; as countries develop, so they do. We need to think forward”
As Wild pointed out, we cannot treat our way out of cancer, so what we need is prevention. Half of the cancers could be prevented by the knowledge we currently have. And taking into account that most cancers have environmental or life style causes, the potential to act is even greater. We have known for years that tobacco, infections, alcohol, lack of physical activity and obesity are factors that can increase your risk of cancer. And we know prevention works, as proven by the decrease of lung cancer cases in countries such as Finland of the UK after tobacco bans were introduced. But it takes a long time. Take the example of cervix cancer: screening and vaccinations against the papilloma virus can decrease its incidence, but at least 20 to 30 years have to pass before we can see an effect on the population! So, as Wild stressed, political vision and leadership is essential in order for prevention to work.
But if prevention is proving difficult, there’s an area which is even more neglected: implementation. The speaker explained some successful cases. One involved aflatoxin, a known carcinogen produced by a fungus that grows on peanuts and corn. In 2005, intervention in some 20 villages in Africa, where simple resources were given to reduce exposure to the fungus (by using mats to reduce humidity, etc.), lead to 60% reduction in exposure. In turn, this lead to only 2% of the villagers having the toxin in blood, as opposed to 20% of people in villages in which intervention hadn’t taken place.
But despite the success of this proof of concept, eight years later nothing has been implemented at a general level.
It is clear that there is a lot of work to do in this area. When asked how far the IARC should go in terms of pushing for this kind of actions, the director was cautious. “Once you become an advocate, your science is under suspicion”, he declared. Sadly, this is the reality faced by some scientists working in the health sector, whose research result can be seen as the outcome of hidden interests if they are too active in pursuing policy changes. Should scientists then just publish their results, perhaps act as advisors in some committees, and then sit back patiently and wait until politicians decide is time to take action? Hearing some of Chris Wild’s arguments and examples, I personally think not. But his point about the dangers of advocacy was a good one. The debate is open….
A report by Maruxa Martinez, Scientific Editor at the PRBB
The 2nd CEXS-UPF Symposium on Evolutionary Biology that took place in November at the Barcelona Biomedical Research Park (PRBB) opens this edition of El·lipse, the park’s monthly newspaper.
Also on the topic of evolution, Salvador Carranza (IBE) tells us about his research on reptile phylogeny. Other news include new findings on senescence and embryo development, lung cancer diagnosis, ‘mini-kidneys’ created from human stem cells, the benefits of long-term breastfeeding, new molecules involved in metastasis or computational models to decipher biological problems. On a more personal note, Baldomero Oliva (UPF) tells us about his scientific career and the secret to become a good scientist: patience and stubbornness. The current-affairs debate deals with a very topical question, raised by a recent article in The Economist: is there a reliability problem in science? Find out the different opinions of four researchers at the park!
Cervical cancer represents the second most frequent gynecological malignancy in the world. It is caused by a persistent virus infection by the high-risk human papillomavirus (HR-HPV) but no cervical cancer vaccine has been marketed to date. In a paper published in PLoS, Juan Martin Caballero, director of the PRBB animal facility, together with colleagues from a pharmaceutical company have generated a virus-like particle (VLP)-based vaccine to treat this cancer and have tested it in humanized transgenic mice.
The researchers took a long C-terminal fragment of the HPV-16 E7 protein – one of the two viral proteins necessary for induction and maintenance of malignant transformation – and introduced it into the infectious bursal disease virus (IBDV) VLP. The combination of tumor antigens and IBDV-VLPs has been shown as a good strategy to boost the immune response and direct it against different types of cancer.
The authors tested the therapeutic potential of their new vaccine, VLP-E7, in HLA-A2 humanized transgenic mice grafted with TC1/A2 tumor cells. They performed a series of tumour challenge experiments demonstrating a strong immune response against already formed tumors, including its complete eradication. Remarkably, therapeutic efficacy was obtained with a single dose without adjuvant and it persisted when the mice were re-challenged with a second tumor cell inoculation. As the authors state, this indicates a high immunogenic potential and in vivo efficacy of their cervical cancer candidate vaccine, VLP-E7, although further studies will be necessary to investigate the potential of the IBDV VLP carrier and its applications to other human diseases.
Martin Caballero J, Garzón A, González-Cintado L, Kowalczyk W, Jimenez Torres I, Calderita G, Rodriguez M, Gondar V, Bernal JJ, Ardavín C, Andreu D, Zürcher T, von Kobbe C. Chimeric Infectious Bursal Disease Virus-Like Particles as Potent Vaccines for Eradication of Established HPV-16 E7-Dependent Tumors. PLoS One. 2012;7(12):e52976
Cancer is generally caused by a combination of many specific mutations, called drivers. But cancer cells contain many other mutations that are not the cause of the cancer, but rather a consequence (passenger mutations). Also, high-throughput genome projects are identifying a huge number of somatic variants. Which ones are cancer-causing? How to distinguish the needle in the haystack?
A new computational method recently published in Genome Medicine by the research group led by Núria López-Bigas at the GRIB (UPF-IMIM), can help. Called transformed Functional Impact Score for Cancer (transFIC), it improves the assessment of the functional impact of tumor nonsynonymous single nucleotide variants (nsSNVs) by taking into account the baseline tolerance of genes to functional variants.
Other methods predicting the functional impact of cancer-causing somatic variants employ evolutionary information to assess the likely impact of an amino acid change on the structure or function of the altered protein. However, according to the authors, the ultimate effect of this amino acid change on the functioning of a cell depends on other factors as well, such as the particular role played by the altered protein in the cellular machinery. The more critical that role is, the less tolerant will the protein be to an amino acid change.
Their new method takes this feature into consideration, and has been shown to outperform previous ones. They distribute their new tool as a PERL script that users can download and use locally, and they have set up a web server which can be queried to obtain the transFIC of somatic cancer nsSNVs.
Gonzalez-Perez A, Deu-Pons J, Lopez-Bigas N. Improving the prediction of the functional impact of cancer mutations by baseline tolerance transformation. Genome Med. 2012 Nov 26;4(11):89
Anna Bigas and Lluís Espinosa, of the Stem Cell and Cancer group of the IMIM are two principal investigators who have joined forces to investigate different aspects of cancer development. Together with their jointed group of 14 researchers, Bigas focuses on hematopoietic stem cells, while Espinosa concentrates on solid cancer and intestinal stem cells.
Bigas aims to understand how a pluripotent stem cell becomes a hematopoietic stem cell during embryogenesis. `It is a great challenge in the regenerative medicine field to understand where these stem cells come from and how they conserve this self- renewing capacity which enables them to maintain a tissue´, she explains. She focuses on a major signalling pathway controlling decisions in both normal and leukemic cells and which is also important for tissue maintenance: the Notch pathway.
Searching for Notch target genes
In order to specify the molecular mechanisms driving an undifferentiated cell towards the hematopoietic lineage or to the leukemic phenotype, the group’s current objective is to find Notch target genes and to describe their mechanism of function.
The researchers use techniques like such as chromatin precipitation and promoter arrays. This results in lists of possible candidate genes from which the real targets have to be isolated and validated in a series of experiments, including FACS to isolate the cells of interest and to determine whether the candidate gene is expressed. Further molecular and biochemical analysis, as well as experiments using mutant mice, help define possible interactions of the target molecules and their effect in the organism.
One target gene is GATA2, an important hematopoietic transcription factor that is not expressed in Notch mutant mice and is altered in human leukaemia. The Bigas group have characterized the GATA2 promoter and found that Notch exerts both positive and negative signals that restrict the intensity and the duration of GATA2 expression in hematopoietic cells.
In parallel, Espinosa is studying whether Notch cooperates with other signalling pathways in different contexts. He found that specific elements of the NF-κB pathway, which is involved in cancer development, directly regulate the transcription of genes which are known to be Notch-dependent.
In a common work Bigas and Espinosa identified a new role of the Notch signalling pathway in the maintenance of leukemic stem cells. Previous studies had shown that both the NF-κB and the Notch pathway are involved in T-cell acute lymphoblastic leukaemia, and future therapeutical strategies may employ both Notch and NF-kB inhibitors to fight this leukaemia.
However only the recent findings of Bigas and Espinosa describe the exact mechanism by which Notch activates the NF-kB transcription factor. These new insights published in Cancer Cell, could be translated to clinical trials and result in better pharmaceutical treatments with less side effects.
Despite all the advances in the field, it is not yet known whether Notch is also important for the leukaemia initiating cells, a question that Bigas would like to answer in the close near future. These cells are of major interest, since they are resistant to standard leukaemia treatments, remain in the organism and ultimately are the source of a recurrent outbreak.
Bigas and Espinosa maintain collaborations both inside and outside of the PRBB. `It is a great advantage to have so many scientists within a few square metreers´ Bigas states, `and we just have a great collaborative work in progress, including involving scientists from the CRG, the UPF, Hospital del Mar and others´.
This article was published in the El·lipse publication of the PRBB.