Ann Nguyen: | Hi there. This is Ann Nguyen, Associate Conference Producer with Cambridge Healthtech Institute. We're here for a podcast interview for the Engineering Expression Systems conference, part of the 2015 PEGS Europe Summit happening in Lisbon, Portugal, this 2nd to 6th of November. We now have live from Ireland, Dr. Niall Barron, Program Leader of Mammalian Cell Engineering at the National Institute for Cellular Biotechnology at Dublin City University. What was your path towards CHO cell line engineering and ultimately to Dublin City University and what's the environment there like for conducting your research? |
Niall Barron: | Originally, I did a Ph.D. in Applied Microbiology in looking at ways of producing bioethanol from waste cellulose material. So I've always had an interest in applying biology to solve scientific problems. I went on to do postdoctoral studies in Baylor College of Medicine at Houston in the area of genome engineering. Upon my return to Ireland, I joined the staff at the National Institute for Cellular Biotechnology in Dublin City University to begin research in the area of biopharmaceutical production. My interest in molecular biology and genetic engineering is what attracted me to the area in the first place. It's also an extremely important industry here in Ireland. We're one of the major manufacturing locations globally for biopharmaceuticals so most of the big biopharma companies have activity here, predominantly in biomanufacturing. Less so cell line development which is usually done at headquarters or other sites typically in North America or on mainland Europe. It is an extremely important industry in Ireland and our group in Dublin City University attempts to support that important industry by undertaking the type of research we do in order to support it. So that the industry here are actively seeking collaborations with locally based researchers to bolster their own reputation within their own organizations. So DCU has a quite a broad program in biotechnology generally, with a particular focus on this area. My group predominantly focuses on improving various CHO cell characteristics so that we can improve the efficacy of them making recombinant protein therapeutics. |
Niall Barron: | I suppose, there's obviously been a lot of improvement in the CHO platform for biomanufacturing in the last few decades and in particular, I suppose, in the last number of years we've had a draft genome sequence available. A lot of that has helped us gain a better understanding of the basics, I suppose, of CHO cell biology. However, a lot of the older, I suppose, original challenges still remain. So for example, CHO cell lines are notoriously genomically and phenotypically unstable. The biggest challenge that most companies face in finding good producers is just that, finding them within a large heterogeneous population of transfected cells. And once they have found a good producer with the characteristics that they're looking for, whether it be the particular critical product attributes or cell line behavior, it's often a concern that the cell line will continue to display those characteristics over time because instability is an ongoing problem and that problem, as I say, still continues today. Predictability also is a challenge. If a cell line development department is having more and more products being pushed on to it to develop cell lines to manufacture for early tox studies or early phase clinical trials, predictability is important to ensure that they can meet the demands internally of the company so that they can guarantee cell lines being available within a particular period of time. Reproducibility also is a problem so regulators as we know don't like to have any variance in the product that's being produced. Ideally the ... I suppose the Holy Grail will be to develop a cell line where whatever the product is, particular class that you get a reproducible molecular entity out at the other end of your process. So a lot of those things are very aspirational still. There are a lot of groups, both in the industry and academia, attempting to put essentially sets of tools and approaches together to try and address those challenges. Older, I suppose, challenges like productivity and cell growth are probably not as critical as they were. Many companies, except at maybe the level of monoclonal antibodies in particular, that they're able to get from their processes are probably adequate. I don't believe any of them would refuse to accept higher levels if they could get them but probably the levels of mAb production are reasonably okay. It's some of the newer [inaudible 00:04:24] fusion protein and bispecifics and things like that that will really probably form the challenge going forward. I suppose, again, looking towards medicines of the future that the term personalized medicine has been around for a number of years now and in particular, I suppose, nowadays we think about that being more stratification rather than personalization where we can identify cohorts of patients that will benefit from a particular drug or a particular form of a drug more so than other cohorts depending on the classification of disease they have. In order to meet that kind of market where you may have multiple products, it would be highly desirable to perhaps have continuous production platforms, continuous downstream processes to purify your product and essentially convert the existing manufacturing infrastructure into genuinely multiproduct sites, so not just sites that will produce two or three different products but perhaps tens of different products to meet market demand. |
Niall Barron: | I suppose the main theme that I would like to convey to the audience, and most of the audience I think are probably going to be aware of this, is that the biological system that is CHO cells that we've chosen to use for the production of these recombinant proteins is an inherently complex system. It's a higher eukaryotic system which means it's extremely complicated with multiple systems, multiple networks interacting and indeed many of the challenges I just mentioned come from that level of complexity. So one of the things I would try to convey in my talk because I focus really on using a particular type of regulatory element known as a microRNA to manipulate a particular phenotype of interest to the industry and the manipulation that I'm talking about ultimately results in improved protein productivity. The question is how do we do that. In this particular microRNA, which is known as microRNA-23, based on our research appears to enhance mitochondrial function within cells when its levels are depleted. So if you deplete microRNA-23, in particular CHO cell lines, you enhance their ability to make protein and we believe it's by enhancing the mitochondrial activity of those cells. If you think about mitochondria, you're really taking about the engine room of the cell and to me, it makes sense that boosting the efficiency or the output of the engine room should ultimately result in a boost of productivity one way or the other. Whether it be via cell growth or a specific protein productivity. That's one aspect of one of the ways we can look upon improving CHO cells is to look at the engine. Other people believe that we should also look at other instrumentation within that particular platform, if you like to use the analogy of a car. Indeed all those approaches coming together I believe are what the way forward is including some of the more advance systems biology approaches. There's a lot of interest in now and really tweaking networks and building small artificial networks within the cells to, again, reach that goal of more efficient production systems. |
Ann Nguyen | That was Dr. Niall Barron of Dublin City University. He'll be speaking during the Engineering Expressions Systems conference at the 7th Annual PEGS Europe in Lisbon, Portugal happening the 2nd to 6th of November. To learn more from Dr. Barron, visit www.pegsummiteurope.com for registration info and enter the keycode “Podcast”. This is Ann Nguyen. Thanks for listening. |