Chips in

Why falling costs and maturing technology mean biochips can revolutionise drug discovery.

The future of drug discovery is looking increasingly like it will be less about laboratories and more about microarrays. Since the emergence of microarray technology – or biochips – in the late 1980s, there has been great excitement amongst the medical community about its implications for human health. And the latest reports certainly suggest that the hype has been justified. New research from global growth consulting firm Frost & Sullivan concludes that biochips have “revolutionised and added a new dimension” to drug discovery, and forecasts that after accruing nearly US$126.9 million in Europe last year alone the biochip market will grow at a compound annual growth rate of 25 percent over the next six years.

Back in its early beginnings, biochip technology was a high-end, expensive product aimed almost exclusively at genetic research. The technology required a small glass slide (about the size of a finger nail) with biological material printed on it and a reader. For a typical experiment, a researcher would place a sample of diseased tissue, tagged with fluorescent dye onto a gene-laden chip, which was subsequently read by the scanner. Should any DNA in the sample match any of the genes on the chip, that part of the chip would light up, providing clues about the role of that specific gene in a particular disease. In addition to DNA biochips, protein biochips simultaneously emerged.

“The microarray appears as literally an array of several thousand dots, each with a particular sequence that reacts with a sequence on the DNA so that the type of gene present can be detected from the pattern,” explains Tony Owen, Marketing Manager for Liquid Phase Analysis Products at Agilent Technologies. “As such it is possible, for example, to compare healthy tissue with diseased tissue and see what the differences are between them from a genetic point of view.”

Progress in genomics has had a large hand in the emergence of the technology in the last decade. “Biochips have been made possible by the advances in genomics and following on from the Human Genome exercise,” suggests Anthony D. Baxter, Chief Executive Officer of deltaDOT. “It’s simpler to produce and successfully use a comparative technology like most genomic chips when you can compare with the template – the human genome. Equally, once you have a better understanding of the proteome – which is coming along now – then protein biochips become ever more useful.”

Drug discovery

Biochip manufacturers have subsequently found their major customers to be largely pharma firms, with scientists employing the technology to search for new molecular targets for drugs by, for instance, analysing the subtle changes in genes when a cell is infiltrated by a virus or becomes cancerous. With most drug targets being proteins, protein biochip producers in particular have found a burgeoning market in drug discovery. Furthermore, biochips can perform in a fraction of a minute an analysis that would take hours using traditional methods, and duplicate systems can be added to increase sample throughput.

“This is a very important area because drug companies need to analyse large quantities of different chemical compounds,” says Hywel Morgan, a University Microelectronics Group Professor and strategic consultant for Innos. “The current method of doing this is very serial, it is one at a time. Now if we can do many, many different analyses in parallel and process the information, and in fact the information has to be processed in quite a different way, then obviously a whole range of biomolecular analyses such as drug discovery, can be speeded up by orders of magnitude.”

Nevertheless, the innovative nature of this technology meant companies have been initially wary of investing in such untried equipment and techniques. Furthermore, the costs are significant. Each reader costs hundreds of thousands of dollars and even the slides themselves are priced at upwards of a thousand dollars. However, with costs continually decreasing and streams of very encouraging data emanating from the technology, any doubtful pharma firms have been forced to have a rethink.

“The prices are coming down while simultaneously the complexity of the biochips are increasing,” explains Wamadeva Balachandran, Professor of Electronic Systems at Brunel University in the UK. “The microengineering technology is advancing rapidly and the use of microelectromechanical (MEMS) technology as well as the microelectronics combined with that means that it is much cheaper and easier to make them. In the future lots of these biochips are going to come into the market and they are probably going to be disposable devices. I forecast that you will have biochips almost at the price of microprocessor chips. It is some way away but that is the way it is moving.”

In addition, the limitations of existing technologies have also forced the hand of some firms according to John Hassard, Chief Technology Officer at deltaDOT. “A fundamental reason spurring growth is that old technologies like gels simply cannot do the work,” he explains. “Most of the low-hanging fruit of new molecular entities have been taken and new developments require greatly increased sophistication. The resolution of old technologies is poor, reproducibility execrable and time to analyse very slow. Finding subtle correlations between, say, disease indications, genomics and proteomics is difficult.”

Technical evolution

It has been a string of recent technical developments and strategic alliances, however, which has most noticeably boosted the biochip market recently according to the new Frost & Sullivan report. The latest technical advances in particular – such as miniaturisation and multi-parameter testing – have meant that drug discovery companies are increasingly evolving to adapt innovative biochip technology into their product pipeline with the aim of slashing attrition rates, reducing time-to-market for drugs and ultimately revolutionising drug discovery.

Biochips employed in tandem, with improved bioinformatics techniques and high throughput screening, for instance, has enabled a dramatic increase in sample throughput in target identification and target validation, offering higher information content on the small chip surface. Miniaturisation and high throughput solutions have further added value to gene expression analysis, which accelerate drug discovery by slashing the attrition rate of drugs that do not pass clinical trials. Biochips have streamlined the identification and prioritisation of the drug targets by corroborating many gene expressions in parallel.

Expression profiling with the use of biochips is helping identify drug targets and pathways for complex disease mechanisms. To evaluate a drug target during drug design, the disease pathway of the particular drug is chosen before genome expression profiling influences different possible genes and analyses the effects on the pathway. After selective identification and validation of drug targets, the biochips are then used to screen the collection of compounds to identify targets that disrupt the expression of diseased genes.

“Many drug companies have realised the need for implementing biochips from a research model to a value chain process in their product manufacturing process,” explains Charanya Ramachandran, Research Analyst in Drug Discovery & Clinical Diagnostics at Frost & Sullivan. “Therefore, it is a steady growth period for chip products especially after the completion of the Human Genome Project. Multi-parameter testing is speeding up the identification and prioritization of drug targets through parallel gene expression profiles. And with the current improvements in silicon micromachining and lab automation, as well as the development of software packages that empower biological researchers to understand the different data in a meaningful manner, are expected to advance the proliferation of biochips to unprecedented heights in drug discovery.”

Elsewhere, outside of technical matters, strategic alliances have also nurtured the growth of biochip use in the drug discovery process. Companies are forming strong alliances, melding business expertise and key intellectual properties. Chip companies are collaborating with firms owning biocontent, while alliances between chip companies and pharmaceutical firms are also becoming more commonplace.

“Frost & Sullivan research indicates that key strategic alliances between the biochip manufacturers and the pharma companies will surely nurture the growing trend of biochips in the drug discovery sector,” continues Ramachandran. “Through distributorships and licensing agreements, niche suppliers are continuing to be competent in the dynamic market by affiliating themselves with the larger, well-recognised suppliers.”

Biochip implications

The biochip sector is far from fully matured, however, and some barriers to a more significant microarray presence in drug discovery are still to be cleared. The deluge of biological data is necessitating robust infrastructure for streamlining the drug discovery process, and despite the surfeit of software tools for data handling there is an urgent need for devices that can encode data knowledge in a format easily understood by biologists according to Ramachandran.

“More than making novel applications, time has come for companies to ensure that the tools are reliable enough to make biochips to find their way into routine drug development processes,” she emphasises. “A synergistic approach is suggested wherein academic research institutions come up with path breaking research and companies brings forth feature rich implementations through appropriate technology transfer and thus meet end-user requirements. Consistency in the array data read-outs will bring in statistical validation for drug companies to boldly introduce this high enabling technology into the routine drug discovery pipeline.”

The increasingly large volumes of compounds being pushed through the drug discovery pipeline has, however, created a large consumer base for biochips in Europe including academic research units and industrial research bases in addition to pharma and biotech companies. And as the industry buy-in becomes more significant so the optimism surrounding biochips will become a self-fulfilling prophecy, with the capital pumped into the technology continuing to simultaneously herald technical evolution and drag down costs. Looking at the bigger picture, all of this can only serve to benefit human health at large, as the time-to-market for new innovative drugs is slashed.

“There is still a considerable amount of research being done in implementation and development of lab–on-a-chip technology,” concludes Morgan. “But I think looking five to ten years ahead, the technology will have a major role to play in large number of biochemical, chemical and life sciences laboratories and will be a dominant force in driving research in these areas. These devices will revolutionise the way that we can carry out research and experiments in the same way that electronics and personal computers have revolutionised the way that we can do complex calculations.”

The potential of biochips continues to surprise. And just as biochips are revolutionising drug discovery, so many are now equally confident that it will soon be making waves in other fields in the future. “This type of technology is a cutting-edge in our sector and the potential is enormous to develop this area further and to work within our sector to improve the care and increase the possibilities to cure or treat medical conditions,” stresses Caroline Ruggieri, Deputy Manager at Emerging Biopharmaceutical Enterprises, part of the European pharmaceutical federation, EFPIA. “Some of the possible implications for this field are not just genetic applications, however, but it also furthers or helps support the toxicological and biochemical research. Healthcare is one of the areas of course of emphasis but the biochip technology could potentially be used anywhere and everywhere. The implications are huge for healthcare but they also expand to all sorts of other areas of research and science.”

Biochips: the background

The first example of an analytical device on a chip was developed by researchers at Stanford University, in the US, in the 1970s. The Stanford GC, as it is now known, was a complete working gas chromatograph on a silicon wafer, including column, injector and detector.

It wasn’t until the late 1980s, however, that the first ‘biochip’ was introduced – by Affymetrix.

Formally known as DNA microarrays, a biochip is a glass or silicon wafer that is designed for the purpose of accelerating genetic research. It may also be able to rapidly detect chemical agents used in biological warfare so that defensive measures could be taken.

A biochip is designed to ‘freeze’ into place the structures of many short strands of DNA and in a sense it is a form of test tube for real chemical samples. A specially designed microscope can determine where the sample hybridised with DNA strands in the biochip.

However, as researchers’ interests have become more varied and nuanced, chipmakers have come up with new iterations of biochips. Over the past decade, the power of these chips has multiplied rapidly. At present, a single chip can hold the contents of an entire human genome – 30,000 to 100,000 genes. Just two years ago, it took two chips to hold that amount of data – while a decade ago it took five.

Emerging use of protein microarrays

A recent study of 842 proteomics researchers reveals the increasingly use of biochips by scientists.

• 34 percent currently use protein microarrays
• 48 percent plan to use protein microarrays in the future
• Of those who plan to use protein microarrays in the future, 69 percent plan to use them in the next 12 months

This emerging group also plan to use protein arrays with greater density than existing users.

• 68 percent of respondents already using protein microarrays focus on subsets of proteins, usually fewer than 100 per array.
• Only 54 percent of future users intend to utilise arrays with fewer than 100 proteins printed on them.