In March this year, six clinical trial volunteers ended up in a critical condition with multiple organ failure at Northwick Park Hospital. The Medicines and Healthcare products Regulatory Agency maintains that these events were unforeseeable but, nevertheless, the crisis highlights how precarious drug development can be.

Drug discovery and testing methods have come a long way in the past 25 years, but clearly not far enough. This is all about to change: in a radical departure from current drug screening, scientists are on the brink of harnessing the power of a new technology, better known for its involvement in therapeutic cloning technology - stem cell science.

Unlike the ambitions of therapeutic cloning, which are still some years away, the preliminary use of stem cells in drug screening is ready and waiting. In addition to enhanced testing of compounds and reduced risk to trial subjects, stem cell technology used as a tool in drug discovery should also keep the marketers and analysts happy.

More money is ploughed back into pharmaceutical R&D than any other research-based industry in the UK. The figure currently stands at an average 15.8% of sales . The reason for the high costs associated with drug discovery and development is simple; ever more stringent regulations are being combined with increasing costs and European price containment. Currently, only one in three drugs that make it to market actually recoup their costs and generate a profit.

Estimates put the cost of bringing a new molecule to the market at around $1 billion over 10-12 years.

Dr John McNeish is Senior Director of Genetic Technologies, Pfizer Global Research and Development in the US, and leads research into new methods of screening and pre-clinically evaluating potentially innovative compounds.

“The high cost associated with development evens out across the entire chain from early screening to clinical trials, so that the lower costs per molecule at the early stage are cancelled out by their high failure rate by the time they reach the clinical trial level. There is still much trial and error in drug discovery.” It is hoped that more reliable methods during the early stages will lead to additional certainty by the time compounds reach clinical trials, reducing attrition rates.

Ultimate drug discovery

Ultimately, drug discovery aims to find compounds that are highly efficacious against a carefully chosen target, have minimal side effects and can continue to deliver effectiveness and safety through clinical trials and eventually in patients. This is a tall order and few candidate molecules go the distance; for every medicine that is approved, many thousands are screened. Across the industry, attrition rates currently vary between 1%-5% of all candidate compounds.

Before the days of targeted screening and advances in medicinal chemistry, serendipity played a significant role in the drug production. Towards the latter half of the 20th century, a more systematic approach was adopted to drug discovery as pharmaceutical companies accumulated extensive libraries of reagents they began screening for potential therapeutic agents.

But this process is still relatively crude and screening technology has been limited by the quality of the material used to test the library of reagents on offer. Stephen Minger is a stem cell scientist based at King’s College, London, and together with research by industry, his fundamental work into stem cell science and the generation of cell lines promises to offer methods that have been hitherto unmatched in the world of drug discovery and development.

“Most drug discovery laboratories use animal or human tumour cell lines or animal models to test new compounds and evaluate potential targets. None of these methods are ideal, they fail to accurately reflect cellular activities in humans but, until now, they were the best available.”

“To obtain reliable results both in screening and in toxicology testing, a consistent source of high quality cells that can proliferate and differentiate into the appropriate cell types as needed are urgently required. Many labs use liver cells but, if these are derived from cadavers, then they naturally vary with each source; consequently the results reflect this inconsistency and error is introduced into the screening process,” adds Dr Minger.

The human response

Notwithstanding the benefits of high quality cells, what occurs in a suspension of cells is far removed from reactions in the body. Consequently, it is impossible to develop new medicines without using animal models for tests that cannot be conducted any other way.

However, ever wise to the need to replace animal models, drug companies believe that stem cells could provide part of the solution. Dr McNeish and his colleagues hope that the development of stem cell-based HTS will take drug testing systems one step nearer to the response in the human body, but will further remove science from the use of animal models.

“In fact, despite not being a whole body system, it will certainly be better than using primary cell lines and should be less expensive. In terms of pharmacology, the results will be much better and should cut costs," says Dr McNeish.

Embryonic stem cells are primal, undifferentiated cells that retain the ability to divide indefinitely and develop into any specific type of cell, for example neurone, cardiac or liver cell. They have great potential in HTS screening because many different cell types can be obtained from a single source.

“For example a single embryonic stem cell line can be expanded indefinitely and can differentiate into a wide array of cell types. So the same starting population can be used to generate liver, heart, brain, skin, and pancreatic cells,” reveals Dr Minger.

Government endorsement

The burgeoning efforts by industry and academic research have recently received endorsement from the government and, in December 2005, it welcomed a strategy for the UK to maintain its position as a world leader in the field. In response to a report by the UK Stem Cell Initiative, the government supported the first recommendation to establish a public-private consortium to use stem cells in enhancing drug discovery and development. Tied to this, the government has pledged up to £100 million between 2006-2008.

Add to this pledge the weighty funds and R&D resources held within the pharmaceutical industry and stem cell science is about to be propelled to a new level. Pfizer has already made substantial progress and scientists in the US are already using mouse embryonic stem cells in HTS.

Before long, the expectation is that stem cells will deliver a scalable, high quality resource of human cells that will improve candidate compound identification and survival in human trials.

“Stem cells offer considerable advantages compared with cells currently used for HTS. They are genetically normal and show normal physiological responses, can be maintained in culture for long periods of time and are grown at scale, all of which enhances their usefulness in screening processes. They can also be relatively easily genetically manipulated to produce cells with specific modifications relating to the disease under investigation,” explains Dr McNeish.

Human stem cells should offer superior methods to format predictive, HTS methods that shorten the timelines for the identification of new therapeutics and reduce the amount of in vivo testing. “The potential impact of these cellular systems is broad, and processes that could be affected include target identification and validation, chemical screening, secondary assays for drug efficacy, metabolism and safety studies, compound evaluation for human genetic variants and the identification of clinically relevant biomarkers,” says McNeish. The future beckons.