Download The benefits of performing studies in fresh human tissue -De

The benefits of performing studies in fresh human tissue -De-risking
the drug discovery process. By Laura Kurth
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.
© Biopta Group 2014
Tel: +44 (0) 141 330 3831
Email: [email protected]
www.biopta.com
The benefits of performing studies in fresh human tissue -De-risking the
drug discovery process.
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.
© Biopta Group 2014
Tel: +44 (0) 141 330 3831
Email: [email protected]
www.biopta.com
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.
© Biopta Group 2014
Tel: +44 (0) 141 330 3831
Email: [email protected]
www.biopta.com