About 1.3 million people in the EU die of cancer each year, which accounts for around a quarter of all deaths. To counteract this, Professor Markus Morrison, Director of the Institute of Cell Biology and Immunology (IZI), initiated an international research and training program for young cancer researchers. Since then it has become a model for two more doctoral student networks, each of which is receiving about four million euro of funding from the European Commission’s Marie-Sklodowska-Curie Program.
“The more we understand about the cellular processes within the tumour, for example about why it isn’t reacting to treatment” says Markus Morrison, “the better our ability to intervene”. His “Cellular Biology and Applied System Biology" research group is studying the complex intracellular signal paths that decide whether a cell dies or, as is the case in cancer, begins to multiply exponentially. That is not a task that a lone scientist in an ivory tower could solve, which is why the EU networks are reaching out to doctoral candidates even while they are still in training. As the biologist emphasises: “the idea behind it is that young researchers are brought into contact with researchers from other countries and learn to work in both academic, clinical and corporate environments”. The objective is to expand the horizon beyond disciplinary and cultural boundaries to find new solutions in cancer research. Up to 15 doctoral candidates will receive funding for three years within the networks.
Each of these doctoral student projects is run in conjunction with an academic institution, a hospital and a European and occasionally, a non-European company: the members of the network spend some time in each of these, which is why they spend up to nine months travelling during their respective funding periods. “This isn’t like it is in traditional research consortia where I would ask a given collaboration partner to take some measurement or other and have them send me the result”, says Morrison.
Far from Home
International movement has also come about due to the fact that master’s graduates were only able to apply to participate in projects outside of their home countries. One of the candidates was the bioinformatician, Nivetha Krishna Moorthy. “I was over the moon when I was selected”, says the Indian, who holds a Master’s in Biomedical Technology from the renowned Sorbonne in Paris, “after all, Marie-Curie doctoral programmes are extremely prestigious. So, she packed her bags and relocated to Stuttgart at the end of January 2018 where she began her doctoral studies within the GLIOTRAIN network at the Institute of Cell Biology and Immunology at exactly the same time as an Italian woman.
Launched in September 2017, this is the newest of the three networks: its 21 collaborating partners from eight countries are targeting glioblastomas, the most common and most lethal brain tumours. About 85 per cent of all sufferers fail to respond to treatment and succumb within two years. Morrison explains the dilemma: “it's a huge research challenge, but because brain tumours are relatively rare among the populace as a whole, it has been difficult to get funding in the past”.
Passport for the Brain
Krishna Moorthy will be using computer simulations to design and experimentally test a brain penetrating variant of an active agent previously refined at the institute. The compound in question is a fusion antibody designed to initiate the programmed cell death of the cancer cells. To enable the substance to cross from the bloodstream into the brain, Moorthy will add a molecular tail that will function as a kind of passport for the bloodbrain barrier.
Krishna Moorthy is learning how to produce bespoke human antibodies at YUMAB, a biotech company based in Braunschweig, Germany. Her second trip will take her to the Royal College of Surgeons in Dublin, Ireland, where she will be investigating the distribution of the active substance in the bodies of laboratory mice. “I don't think I’ll ever get the chance to learn so much after I get my doctorate”, says Krishna Moorthy, “but it's definitely possible with this doctoral student program, which enables me to gather experience in the private and public sectors and to make loads of contacts so that I’ll eventually be able to choose where I’d prefer to work”.
Krishna Moorthy’s supervisor, Morrison, knows the GLIOTRAIN coordinator at the Royal College of Surgeons from his own time in Dublin. Morrison, a native of Osnabrück, spent 13 years researching and teaching at the same department before accepting a professorship at the University of Stuttgart in 2016. The first doctoral student network, MEL-PLEX, which served as a model for the other two, was founded by Morrison in Dublin in 2014. The young researchers in the network are studying malignant melanoma, sometimes known as black skin cancer. This type of cancer is becoming more widespread, particularly among fair-skinned Europeans. Morrison has managed to recruit 17 partners from eleven countries into the network.
It was by no means a foregone conclusion that the EU would provide funding for the network, which will continue its work till November 2018: “competition is fierce within the life sciences”, explains Morrison, who has been coordinating the skin cancer network since its inception, “and there are many exclusion criteria that could result in an application being turned down”. Morrison is convinced that the other doctoral student networks have also received funding due to the fact that the concept has proved successful. More than 400 young researchers applied for a place in the MEL-PLEX programme when it was first launched, which may be due, in part, to the fact that the salary offered in the Marie-Curie programme is slightly higher than the usual remuneration for doctoral students in this country.
Forecasting Cancer
The initial objective of the MEL-PLEX network is to gain a better understanding of skin cancer, which spreads to other organs at a relatively early stage, where it forms lethal metastases. Until recently, patients first diagnosed in this advanced stage faced certain death. Whilst such patients do survive a bit longer today, thanks to new therapies, they are still a long way from being cured. That is why the scientists want to develop new therapeutic agents and to be able to use biomarkers to predict the likely course of a given case of cancer or whether the tumour will be amenable to treatment with a particular therapy. “We want to be in a position to immediately identify those patients, who will benefit from a given therapy”, says Morrison. The remainder will be spared undergoing a course of treatment that would be ineffective in their cases, but would be associated with unpleasant side effects. “Because modern therapies are getting more and more expensive”, Morrison continues, “the costs would otherwise cripple any health service”.
One member of Morrison's research group, the Italian Cristiano Guttà, is focusing on such predictive models for malignant melanoma. His initial work within the MEL-PLEX network involved determining whether the formation of certain proteins that play a role in cellular quality control processes is increased or decreased within tumour tissue. “This so-called autophagy enables cells to digest any organelles and proteins that may be damaged or no longer required, and to recycle the molecules” Guttà explains. The process can even result in the complete self-consumption and, therefore, death of the cell in cases of severe damage.
“I populate mathematical models with data relating to the proteins and clinical pathology and with information about how the proteins are internetworked then test the predictive potential of the models” says the molecular biologist with a penchant for computer science. In this way he was able to confirm that the cancer progresses at a faster pace in patients in whose cells this autophagic mechanism is wound down in the early stage of the disease. Guttà gained the knowledge of statics needed to analyze the protein data when working with Oncomark, a Dublin-based company specialising in cancer biomarkers, where he spent two months.
Creating networks is also important for us as a research hub
Josip Soko, doctoral student at University of Stuttgart
“There's a huge transfer of knowledge”
Guttà is currently collaborating with pathologists at the University Hospital of Bern to quantify two other proteins involved in the autophagic sequence in tumor biopsies. “In this context, I get to see how the data I use is obtained – from the biopsy to data collection”, says Guttà enthusiastically. “At the same time, my Swiss colleagues need someone to teach them about systems biology. There's a huge transfer of knowledge and expertise”. Later, Guttà wants to investigate the protein profile of advanced skin tumors, as there is evidence to suggest that the cellular recycling program actually fuels the cancer in this stage.
Apart from Guttà, a Croatian woman and a colleague from Bangladesh are collaborating in the skin cancer network at the Institute of Cell Biology and Immunology. “You meet the whole world sitting round the lunch table”, enthuses Guttà, “this cultural melting pot is something I encounter throughout the science community". The doctoral students participating in one of the networks meet every six months, either to present their results or to take part in advanced training courses coordinated by Morrison. “Whenever we all meet up”, says Josip Skoko, “it's as if we've known each other forever. You've got one research group here and another right across Europe in which you discuss your project and come up with new ideas”.
Like Guttà, Skoko is also researching malignant melanoma. He is part of the TRAINERS network that is coordinated by one of Morrisons researcher friends in Galway, Ireland. Skoko, a Croatian, came to Stuttgart at the same time as Morrison. The doctoral students in the TRAINERS group, which was inaugurated in 2014 and will run until 2019, are interested in general with the quality control processes of intracellular proteins, which can be impaired in various diseases. In neurodegenerative diseases such as Parkinson's or Alzheimer's, for example, misfolded proteins are no longer broken down and tend to clump together, causing nerve cells to die off. That is precisely the effect the scientists hope to achieve in tumours by blocking the breakdown of proteins, which will ultimately cause the cancerous cells to die.
Junk Overload Kills Cancer Cells
Substances that inhibit activity in the proteasome, the cell's protein dismantling centre, have already been approved. Skoko has discovered that cancer cells also die off when he treats them with the same agent. However, before they die, the cells send out signals that also mobilize the body's own immune system against the cancer. “Our hope is that a proteasome blocker will boost the efficacy of the existing immunotherapies or targeted therapies used to treat skin cancer, as an immune response can be delayed in the former and the tumor can rapidly develop resistance to targeted therapies”, says the biologist.
Yet, Skoko is not satisfied with that: he wants to further accelerate the programmed cell death triggered by the proteasome blocker as well as boosting the immune-system response by seeking out key proteins within the protein quality control process and switching them on or off in a targeted manner. The extent to which the immune system’s messenger substances, which the treated skin cancer cells then secrete, activate the immune system is still an open question. To this end, he initially plans to use biochips at one of the field offices of the diagnostics specialist, Randox, in Ireland, to detect all secreted immune system messenger substances. With the results in his pocket, he will then travel to the Catholic University of Leuven in Belgium to discuss his findings with experts in the subject of immune-system- induced cell death.
Future Perspectives
And, what will he do after his doctoral studies? “Well, we’ll see”, says Skoko, considering his options, “I might take up a post-doctoral post in a country I've never been to before. The most important thing”, he adds, “is that, through the network, I get to hear about vacancies and new research projects before they've even become public knowledge”. “Creating networks is also important for us as a research hub” says institute director Morrison. On the one hand, the doctoral students contribute new knowledge to the institute and, on the other, they function as ambassadors for the University of Stuttgart. “When our collaboration partners see that the doctoral students we send them are trained to the highest levels” he adds, “then their willingness to collaborate with us on other projects is significantly increased”. As such, the doctoral student networks are beneficial to both sides.
Helmine Braitmaier