The benefits of performing studies in fresh human tissue: De-risking the drug discovery process. By Dr Laura Antos
The use of fresh human native tissues and cell lines are essential to research advancements. Both have their unique benefits. Cell lines are easy to grow and maintain, amend for genetic manipulation and generally are uniform in their responses in assay systems. These benefits have made them invaluable for drug screening programs, allowing numerous compounds to be tested in the search for drug candidates. Cell lines are, however, a contrived experimental system and one should be cognizant of the risks in extrapolating the properties of a compound in these systems relative to that in the native human setting. This is particularly true for receptor agonists where the potency of a molecule is the product of the compounds property and that of the tissue in which it is tested. Clearly, native intact human tissue would be advantageous in this situation; however, for most experimentalists, human tissue availability is limited and comes with viability concerns. Biopta, through its extensive network of quality tissue suppliers and highly committed staff, (10 years’ expertise in the logistics of accessing human tissue, and highly specialised scientists on-hand 24/7) have solved these issues and for the past decade have led the way in human tissue research.
By using human fresh tissue, both healthy and diseased, Biopta have de-risked the drug discovery programs of numerous companies. Furthermore, by embracing the inherent intrinsic variation between patient responses, we can now advance the utility of human fresh tissue in providing functionality (phenotyope) linked to genotype, a key step in the development of personalized medicines. The decision to use either cell lines or native fresh tissue should ideally depend upon the question one is trying to answer. If the question centres on intrinsic functionality of a single protein, potential binding partners or specific defined signalling pathways, cell lines have been the standard choice; however, if one wishes to look at drug compounds in a complex system representative of the clinical physiology, then fresh human tissue research is a must.
Why should is fresh human so important when translating drug responses to the clinic?
Having a drug target in its native setting allows the following:
- The target is in its natural environment, coupled to its pathways as it would be in a clinical setting;
- The potency of an agonist is dependent on receptor number/efficiency of the resultant coupled system. The potency value for an agonist in this system is more akin to the potency in humans and is more accurate for defining the dose required for clinical efficacy. High expression cloned systems will report higher potency values;
- The inaccuracies of cell lines will be compounded if disease tissue shows different coupling from healthy tissue; something that Biopta can often compare.
- Few compound/target interactions are neutral in effect. Antagonists can show internalization properties (act as agonists for switching receptors off) and so pathway coupling holds true for these antagonists as well as conventional agonists.
In tissue, targets exist in a complex cellular system that encompasses interactions from many cell types. Therefore, even while co-culture experiments may tell us nicely of the changing biology between cell interactions between differing cell types, the correct ratio of cell types and often the need for appropriate extracellular matrix can affect the outcome of these experiments.
Cell lines demonstrate what can happen whereas native tissue shows what does happen.
There is no arguing that cell lines are a stable system when defined in particular terms. However, events such as genetic variation occurs when cells are cultured such that gene and protein expression patterns vary with passage number, causing diversion, not only from native physiology, but also between the cell lines themselves. Even when using primary cells, de-differentiation and changes in morphology and pharmacology can occur in a matter of days or even hours and, still, important interactions between various cell types which exist in tissue are lost. Nevertheless, the ability of cell lines to grow continuously with an unlimited lifespan makes them a cost effective and relatively uniform system with which to test drug compounds and cofactor interactions. They are also highly susceptible to transient gene transfer (transfection), allowing researchers to better understand specific protein/gene function.
Native human tissue, however, represents the most physiological experimental system available short of clinical trials. It allows direct investigation into human tissue functionality and pharmacology, thus giving the most accurate data regarding drug efficacy or mechanism of function not just on an individual, but throughout a population. Only in human tissue is it possible to measure drug effects in vitro on systemic processes such as muscle tone modulation and true multicellular inflammatory processes. As not all individuals respond similarly to drug treatments, having tissue that characterizes this inter-patient variance best demonstrates how a drug will affect the general populace overall. Through use of diseased tissues, researchers also get the most accurate representation of varying human pathologies allowing for treatment identification. As tissue has a limited lifespan, experiments must be done promptly or on preserved tissue.
At Biopta, we only use fresh, not frozen, tissue, to create the most physiologically relevant drug-testing systems available to the pharmaceutical industry.