Predictive Toxicology: Stem Cell Characterization Must Mature
In this interview, Phillip Hewitt, Head of Early Investigative Toxicology at Merck KGaA analyzes new innovations in predictive toxicology
In this interview, Phillip will be sharing his thoughts on the latest innovations in predictive toxocology and the vital improvements needed to the application of Induced Pluripotent Stem Cells (iPSCs) in drug discovery today.
Give us a flavour of your work within predictive toxicology and a few trends you are noticing in the market?
Philip: “At the moment my work focused mostly towards in-silico and in-vitro toxicology, so predicting various endpoints related to drug safety and chemical safety. The trends [I am] seeing often relate to in-silico testing. There is a huge impetus now to improve our in-silico models, and at Merck we are doing a lot of work towards improving commercial tools by using in-house data, leading to a local Merck-specific in-silico model. There are a several large EU consortia related to gathering internal pharma data and putting it into improving in-silica prediction modelling. I see this as a big step-forward for the future; it will take years probably [to take effect] but it's definitely coming because our current in-silico predictivity, in my mind, needs to be improved a lot.
“When it comes to in-vitro models, obviously we have been using in-vitro tox testing for a very long time but overall they are not very predictive of human safety. So there has been a lot of work over the last few years related to 3D micro-tissues or “human-on-a-chip” / “organ-on-a-chip”. It is certainly easier said than done. There has been a lot of work towards liver and I still am yet to see a good 3D liver model. There are a lot of new 3Dmodels coming out on the market related to gastrointestinal, cardiac, kidney, mini-brains. This area is really gathering pace. We are starting to get involved as well in some of these models, GI, retina and liver for example. I see this as a key area where the market is heading and [this can be spotted] from what is being offered by SMEs and academics.
“Also, there is a lot of pressure in the industry to come up with new biomarkers for organ toxicity. This is not a new trend, but it has been, say seven/eight years since the kidney biomarkers were validated by the regulatory authorities and there has not really been much progress since then (from a regulatory perspective). There is a lot of money being pumped into looking for biomarkers, in-vivo biomarkers to predict specific target organs - of course with the aim [of being] translatable from the animal models we use in toxicology to the clinic. [This investment will increase] in the near future. I know the PSTC – the Predictive Safety Testing Consortium - have a lot of projects related to liver, testes, pancreas and several other organs looking for in-vivo biomarkers. These will come online, I'm sure, in the next few years.”
Please give us insight into the current perceptions which are for the use of IPSCs?
Philip: “I think the perception is different to reality. The perception, when I talk to some people, is that IPS cells are going to solve all our problems. If you are looking for pharmacology or disease-related models maybe there is a lot more success but from a safety perspective there is a very significant way to go yet before we really have a cell system which is at least vaguely similar to a human cell system.
“We at Merck are also working towards IPS-derived cell systems, including liver, cardiovascular and CNS systems, with continuous improvements ongoing. I think some organs are easier [to work with] than others. I see a great advance in CNS and cardiovascular models but for liver and kidney - not so much. It is just perhaps too difficult to differentiate an IPSC into a liver cell. The liver is a complicated organ and there is a lot we need to understand.
“The misconception is that IPSCs will generate liver cells, kidney cells and so on, but in the end you cant be totally sure with what you get; it is not a liver cell, it's not a kidney cell. I think for the near future this needs to be worked on.
“The differentiation protocols are being improved on a constant basis. So eventually we may reach a status where we can generate organ-specific cell models from the same donor of IPS cells. It’s an exciting technology and the potential is that you can take IPSCs from healthy donors but also diseased patients or patients that have strong toxicity, drug-induced liver injury patients for example. Perhaps they have a genetic component which makes them susceptible to drug-induced liver/kidney/cardiac injury. If you can generate in-vitro models for that then maybe [in the future] we can start screening our compounds against these sensitive patients.”
What sort of limitations exist with these cells in predictive toxicology?
Philip: “The main limitation is the cells that are being generated are not fully characterized. You have commercially available cells, IPS-derived cells and they have a few bits of information which depict - that's a liver cell, that's a cardiovascular cell, but it is [in fact] not enough. Those cell systems should have a huge amount of functional data, and that is forgotten/excluded. It is this extensive characterization of the cells that is missing.
“When we are looking at CNS, kidney, liver and heart IPS-derived systems they all seem to be very foetal-like. So we are good at pushing those adult IPSCs through to a different cell type but it is not fully differentiated, not adult-like and that's what's missing. We are not developing drugs for foetuses, we are developing them for adults. Of course, for some organ systems, like liver, there is a huge difference between foetal and adolescent and then adult states/functions.
“There is a long way to go before we get to a stage where we have cells with full adult phenotype. Although, I heard recently that for cardiomyocytes at least they are starting to have differentiation protocols where they are generating more adult-like and fully differentiated cells.
“So that is the biggest limitation – these IPSC based models are not what you think they are. So of course, as a result you are going to generate a lot of data which is potentially meaningless. My big worry is that these stem cell-derived models being developed, generating a lot of data which is fed back to predictive tox and building databases basically on a cell model which is, in fact, not predictive of anything.”
Looking ahead, what are your predictions for this method over the next few years?
Phillip: “IPSCs are here to stay and we will be active in this area as well. We need the improvement in differentiation protocols. I think it is important to have consortia and groups tackling this together because it is not only the differentiation protocol, but also the validation of the cells for a specific purpose. In our case it will be safety testing - so you need to be able to recapitulate those safety endpoints in multiple labs to really be convinced the model is worthwhile.
“The advantage of these cells is the fact that we can use generate organ systems from one cell source without having to rely on freshly available cells or cryopreserved cells. They will definitely improve and I am still hopeful that in the next five years we will have good models based on IPS-derived cells.”
To finish, name a few exciting innovations you have witnessed in the predictive toxicology industry as of late?
Phillip: “One big thing, which is a hot topic at the moment is bioprinting - printing cells into a specific format to give you a mini-tissue. I’m yet to be 100% convinced myself, but there is a huge impetus for bioprinting from the technological side, the engineering side, obviously the biological side but also the potential benefits that will transfer to the safety experts. There has been a lot of work in liver over the last few years and now Merck is expressing interest in bioprinting. Bioprinting is in its infancy: it could disappear in the next few years but if it really does take off that would be a very exciting innovation.
“Another (not so recent) innovation is seen with the 3D model tissues, I think we will see a lot of these developed in the near future. There are the 3D retinal models which are in development now, considering how complex a retina is and putting that into a 3D cell culture system is amazing to me.”