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Prof Lorraine O’Driscoll: Potential of EVs for benefit in health and disease

 Prof Lorraine O’Driscoll – Trinity College Dublin, Ireland

Lorraine ODriscoll

Prof Lorraine O’Driscoll is Professor in Pharmacology at the School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin. Following her PhD, Prof O’Driscoll undertook biotechnology/biomedical research for US and EU industry (including Berlex; Archport Ltd-Axonobel; MediSyn Ltd; MedaNova Ltd.) before returning to academic research and teaching. At post-doctoral level, she gained experience at the Dana-Farber Harvard Cancer Institute and the University of Miami. Prior to joining TCD in 2008, Prof O’Driscoll most recently held the position of Senior Research Programme Leader and Lecturer in School of Biotechnology, DCU. She has been a Principal Investigator (PI) on 5 cancer clinical trials with Cancer Trials Ireland, and on SFI-supported Molecular Therapeutics for Cancer Ireland; Strand Leader of Irish Cancer Society-supported Breast-PREDICT; PI on grants from Health Research Board, Enterprise Ireland, Breast Cancer Now, and PI and Founding Chair of the H2020-supported European Network Cooperation in Science and Technology focused on Exosomes & Microvesicles in Health & Disease (ME-HaD) which brought together researchers from 27 European countries, 3 US universities, Australia and 7 industry partners. She is also an Elected Member of the International Society for Extracellular Vesicles (ISEV). Prof O’Driscoll’s research group focuses on diagnostic, prognostic and predictive biomarkers; discovering new therapeutic targets; cancer cells communication via exosome and other extracellular vesicles (EVs); elucidating and circumventing resistance to targets agents and classical chemotherapy; metastasis; immune suppression in cancer; EVs in milk, their role and their potential for exploitation; EVs as therapeutic delivery vehicles and EVs in regenerative medicine.

Prof Lorraine O’Driscoll is the Coordinator and the Principal Investigator of the H2020-MSCA-ITN TRAIN-EV (Training in Extracellular Vesicles: for benefit in Health and Disease) program, supporting the training of 15 PhD students.

 

- What pushed you towards a career in science?

- I have been interested in cancer research since I was a very young child. I remember an elderly relative dying from cancer when, to me, there was nothing obviously wrong with the person; but then she suddenly died. She had died from cancer. So, I became interested in knowing more about cancer. At school I learned more about the different options that were available to study, and I remained very interested in cancer and different diseases and especially about what can be done to try to help with them. Of course, to try to best prevent or manage diseases such as cancer you must try to understand why they occur, what has gone wrong in the first place, and then try to see what the best way is to deal with that. So really, since my childhood I was driven by the hope of trying to do something to prevent deaths from cancer.

- What has been the most memorable moment for you during your research?

- It’s always memorable and very fulfilling when I see my students graduating with their PhD or post-doctoral fellows progressing to faculty positions, clinical posts or key positions in industry, but probably the most awarding thing is when we identified something at the bench in the laboratory and are able to progress it all the way to clinical trials towards better treatments and hopefully better outcomes for people who were suffering from diseases such as cancer.

- How was the idea of the TRAIN-EV program born?

- The idea of TRAIN-EV was conceived a number of years before being granted almost €4 Mi for this program in 2017. In fact, more than ten years ago me with my research group I was studying medium that was conditioned by cultured cancer and normal cells and also blood specimens from patients and from healthy volunteers and, just out of curiosity, we decided to look for messenger RNA. There had been no previous studies suggest messenger RNA would be extracellular and in fact the high concentration of RNAse H enzymes suggested that this could not be so. However, when we performed a large RNA study on nearly 60,000 gene transcripts, somewhat to our surprise we found that there were more that 400 of these transcripts apparently remaining intact in blood. After various filtration steps and re-analysis, we realised that the RNA was protected some way; we assumed it probably in vesicles or bound to something that was protecting it. Then, mining the literature that was emerging at that time I realised that some other people were talking about exosomes and other extracellular vesicles too. So, it was really curiosity and chance that brought us to study exosomes and other extracellular vesicles.

Now it’s obvious that this is a very exciting field of research, but back then there really were very few research papers on this topic emerging and it wasn’t nearly as topical as it is now. So, it was not obvious to search for the word “exosomes”. I thought, at that time, that it might make sense to contact other people publishing in this field. I first emailed Jan Lötvall in Gothenburg. He immediately and positively supported my idea to try to apply to H2020 for funding to establish a Consortium in this field. My vision was to initiate ME-HaD. Jan suggested I contact Clotilde Thery in France and, from that, I went on to contact researchers in several countries. At the time of the ME-HaD grant submission, there were 10 countries involved; very soon this increased to 27 countries and included 360 researchers from academic, clinical and industry settings; many of who were early-stage researchers. ME-HaD supported a lot of training schools, training networks, secondments, meetings, discussions about nomenclature, isolation methods, and also resulted in a number of highly cited publications in this field. I continue to look for opportunities to apply for Horizon 2020 funding, because I could see that as researcher in this field we can really work well together. Fortunately, I saw an H2020-MSCA-ITN Call and identified it as an opportunity to apply for an innovation training network to train 15 PhD students over the course of 4 years. Thankfully, people who were a part of the former ME-HaD which was come towards an end, and who were also working on cancer and immunology of cancer, were very interested in being a part of this TRAIN-EV application. Thankfully, TRAIN-EV was scored very high by reviewers and was successfully funded. TRAIN-EV brings together industry, academics and medical researchers to supervise 15 early-stage researchers who are working, in inter-related and collaborative projects, towards their PhD in industry or in clinical or academical institutes.

- What are the objectives of the TRAIN-EV program and what benefits could it bring to the EV society?

- TRAIN-EV aims to provide excellent and integrated multi-disciplinary and cross-sectoral training of a critical mass of 15 ESRs of outstanding potential in the academic, clinical, and industry/business components of exploiting EV, while performing novel cutting-edge research to address these gaps and generate new knowledge. The benefits to the EV community are to make further progress in the understanding and the application of EVs in conditions such as in cancer, and understanding how the immune system communicates and works with cancer cells. It is really important to improve the methods of EV isolation and characterisation, as well as to understand more about the physiological roles of EVs and what they are doing in pathophysiological conditions, such as cancer. This is to best exploit EVs for patients’ and societal benefits, for education and also for economic purposes.

- What potential might EVs have in cancer diagnostics and therapy?

- EVs have potential as diagnostic, prognostic and predictive biomarkers in cancer. Our studies indicate that they are involved in multiple drug-resistance, in metastasis, in suppressing the immune system in cancer. By understanding how and why this occurs, we hope to be able to prevent or circumvent this. EVs also have potential benefits as therapeutic delivery vehicles.

- What do you think about cell-free regenerative medicine?

- EVs as cell-free regenerative medicine is another purpose for which we are now embarking on another H2020 program called EVPRO. EVs have a lot of potential to represent their cells of origin. So EV will extensively evaluate EVs in the tissue engineering and medical devices space. The potential here is to for therapy where there is cartilage damage, damage to bones, to hips etc. I believe EVs have huge potential for many purposes and in many fields of medicine. Its such an exciting field of research!

Some although a substantial amount of my research groups’ efforts is focused on EVs in cancer; we are also working on understanding and exploiting the benefits of EVs as cell-free replacement in regenerative medicine; milk EVs and what benefits they are contributing for offspring; and EVs as therapeutic delivery vehicles.

- Looking to the future, where do you think the EV field is going over the next 5–10 years?

- I think because a lot of EV research community has been smart and cautious and make sure that their EV research is been done to a high standard, and with independent validation by collaborators, I think that a lot of what were fundamental EV findings should be translated into application over the next 5 to 10 years. Of course, there may be some studies that have not been performed to the same standards, and so making interpretation of their findings more difficult. But I’m optimistic that EVs as diagnostics for a range of conditions and as predictive biomarkers of response to therapy should be in clinical utility in the next 5 to 10 years. Additionally, I think their application in regenerative medicine should also be occurring within that time space. Because academics, industry and clinicians in the EV field are trying to work together, there is optimism for timely success.

The potential to deliver molecules within the body via EVs is very interesting idea as well. A challenge is to ensure that those EVs are delivering only to the places we want to deliver. There have been a number of studies, where individual groups have reported delivery a particular molecule to an organ in a pre-clinical model and shown affects there. However, other attempts to repeat the same have observed EVs in many other systems and organs of the body too. In our studies we have found that EVs will go to where we want them in vivo, but also to where we don’t want them to be delivered too as well. I believe that effects are now needed to establish if we can obtain specific targeted delivery to as to prevent or at least substantially minimize side- effects.

I believe that more inter-institutional and cross-sectoral collaborations and large clinical trials in this field are the best and fastest way forward to success in the EV field.

- What in your opinion are not-to-do things when working with EVs?

- It is important not to do EV research just because its “fashionable“. As with all research, its important to have a purpose and to do research to high standards. It is important to be sure that whatever techniques and methodologies you follow are really producing EVs. For example, you should be aware that with some methods you may isolate some EVs, but they may be substantially contaminated with lots of proteins and other moleucles too. I’d strongly suggest not doing this. Using established protocols, following MISEV2018 guidelines, and EV-TRACK are really important. Attending the ISEV Annual Meeting can be very educational. Taking to peopke outside your sector and e.g. ask what industrys’ EV needs are, ask what clinicians’ EV need are, so that you can plan and perform highly relevant EV research. Thankfully, many research groups are working to high standard and therefore we can be hopeful that results that are collectively been produced may be meaningful.

Potential of EVs for benefit in health and disease