BBI Contributing Writer
In the beginning there was DNA, the software for the human body. But the function of DNA is to carry the instructions for the design and manufacture of proteins; and it became apparent in the last years of the 20th century that the study of the genome alone did not provide a totally meaningful picture of what goes on in the body – especially in disease.
Proteomics is the systematic analysis of the proteins that are present in cell and tissue samples obtained from humans or a variety of other species. Samples of healthy human tissue are typically compared with diseased specimens, enabling disease-specific proteins to be comprehensively documented. Until very recently, analyzing the proteins in just a single tissue sample would have involved months, or perhaps years, of labor by an entire research group. Now the new automated technologies of proteomics allow complex protein profiles to be analyzed within hours and days, rather than weeks and months.
Proteomics offers to biomedical research a powerful new means of identifying molecular markers of disease and novel therapeutic targets. In the pharmaceutical industry, proteomics promises enhanced drug discovery, reduced research and development costs, reduced clinical development times and increased revenues.
Filling a gap in biotechnology
During the past few years the performance of the biotechnology industry has failed to live up to its early promise, a problem exemplified by the sluggish commercial performance of the sector. In medicine, for instance, biotechnology has not yet yielded novel diagnostic markers and therapeutic targets at the rate many had originally predicted.
Among factors that may be blamed for this are the limitations of genomics, and specifically in determining patterns of gene activity within specific tissues associated with particular diseases. To date, progress in this branch of genomics, known as functional genomics, has not met expectations. This, at least, is the view of the proponents of proteomics, and they have some impressive arguments in their dossier.
The main limitation of functional genomics, they aver, is that the pattern of gene activity within a cell does not provide an accurate picture of the distribution and activity of the cell proteins. There are a number of reasons for this. Firstly, a time lag frequently occurs between gene expression and protein production. The observation that a gene is active does not determine whether the protein it encodes is being produced abundantly, at low levels or even at all. RNA splicing at a single gene transcript may also produce many RNA variants, generating a variety of different proteins. Most importantly, nearly all newly translated proteins undergo post-translational modifications, such as proteolytic cleavage and glycosylation, which are vital determinants of shape and function. Also, the functional interactions and metabolism of proteins generate a wealth of protein complexes and metabolic intermediates.
For all these reasons, a cell's full profile of proteins, or "proteome," is not explicitly coded by the genome and cannot be elucidated by analysis at the genetic level alone. The fact that functional genomics cannot predict protein structure and distribution is a crucial limitation, because most disease processes are primarily manifested at the level of proteins, not genes. Proteins form the integral machinery of cellular activity, for instance, by regulating which genes are activated, relaying intracellular and intercellular signals, and driving metabolic processes. It is these activities that are dysfunctional in disease, and it is upon these mechanisms that drugs act. Much of the data emerging from functional genomics does not have sufficient physiological meaning to enable conclusions to be drawn on the molecular mechanisms of disease or to allow diagnostic markers and therapeutic targets to be identified. The excitement surrounding proteomics stems from the fact that it focuses directly upon this crucial protein level – greatly enhancing the ability to analyze the molecular basis of disease and identify new leads for R&D.
Two is better than one
By focusing on the complementary roles of DNA and protein, proteomics and genomics are natural collaborators in the molecular analysis of living systems. The two fields have an interdependent and synergistic relationship in which each reinforces the other. The information obtained from genomics is compiled into DNA sequence databases that dramatically accelerate the process of protein identification. Proteomics identifies precisely which genes are associated with important protein changes, sifting the data of genomics to identify the functional elements and giving them physiological meaning.
The analytical and commercial potential in bringing the twin forces of genomics and proteomics into harness is now being recognized by leading players in both fields. Recently, Oxford GlycoScience (OGS; Abingdon, United Kingdom) and Incyte Genomics (Palo Alto, California), the U.S.-based genomics company, announced a collaboration that will lead to the construction of combined proteomics/genomics databases, available to pharmaceutical and biotechnology companies. Collaborative programs of this kind are likely to become commonplace in the biotechnology sector
The proteomics industry
Commercial proteomics is a young industry. Indeed, the term "proteomics" was only coined in 1995. The field evolved out of the well-established and highly dynamic worldwide protein research community. Although some major pharmaceutical companies such as Glaxo Wellcome (London), Parke-Davis (Ann Arbor, Michigan) and AstraZeneca (London) have developed new proteomics units, this sector of industry is driven by specialist proteomics and biotechnology companies, led by companies such as OGS and Proteome (Beverly, Massachusetts), now part of Incyte Genomics.
A number of other genomic and biotech companies are now investing in proteomics technology and generating novel proteomic data, including Amgen (Thousand Oaks, California), Millennium Pharmaceuticals (Cambridge, Massachusetts), PerSeptive Biosystems (Framingham, Massachusetts) and Genetics Institute (Cambridge, Massachusetts). In Europe, the Ludwig Institute (in collaboration with OGS) and Pharmagene Laboratories (Royston, United Kingdom) both have developed human biomaterial banks for use in proteomics.
Proteomics and the pharmaceutical industry
It is in the pharmaceutical industry that the impact of proteomics is likely to be most strongly felt. Its most important contribution may be in the discovery of diagnostic markers and therapeutic targets, and, in addition, the new field has the capacity to improve the analytical power and cost efficiency of nearly every stage in the pharmaceutical development process.
Proteomics has several preclinical applications, including the validation of therapeutic targets and the elucidation of drug modes of action. It also is likely to have an increasing role in the selection of lead candidates for further development. Proteomic analysis is more powerful than traditional biochemical analysis techniques in this regard, because it allows the effects of an agent on an entire system of interacting proteins to be monitored simultaneously.
Proteomics also will prove particularly useful in toxicology studies and in clinical development, where it can provide clinical markers for monitoring patient progress and identifying responders at an early stage. It also can be used to identify subgroups of patients who are likely to respond to treatment (or, conversely, to react adversely) according to phenotypic differences in the proteomes of different individuals. Proteomics could significantly reduce the cost and number of patients required for clinical trials and the time taken for new drugs to reach the marketplace. Following a product's launch, proteomic analysis will be able to identify differences between competitor drugs with similar actions, supporting product differentiation and post-launch marketing.
The potential market for proteomics-related products should probably be seen in the context of the in vitro diagnostics (IVD) market, because this is where the first applications of proteomics will be developed. These applications will take the form of biochips used to determine the identity of proteins in samples from patients, so that particular variants of diseases can be pinpointed, or the patient's response to specific drug interventions can be determined.
The IVD market is large and mature, with worldwide revenues totaling some $21 billion in 1999. Despite overall stability, several emerging sectors, including biochips, image analysis, point of care testing, and automated immunohistochemistry, represent solid growth opportunities. The market is essentially static, with revenues having grown in real terms by only 4% to 5% per annum in recent years. Total sales of nucleic acid tests (primarily DNA-based tests) for in vitro diagnostics last year were only an estimated $250 million.
Biochip sales are expected to grow from $12 million in 1997 to $184 million in 2000, and then enter a phase of meteoric growth approaching 30% a year, to reach almost $650 million by 2005. The greatest need for biochips may exist, at least at first, in the pharmaceutical industry, where DNA chips and protein chips offer pharmaceutical companies new technologies that they can use to streamline drug development. Compared with current technology where the drug screening cost-per-target is $1 to $2, biochips can bring the cost down as low as $0.0001. Medical diagnostics and academic research already are beginning to use the chips for studying gene expressions and biological mechanisms. Protein chip development is still at an earlier, largely experimental stage.
It is estimated that DNA chips accounted for 94% of the 1999 market and protein chips for the remaining 6%. Lab chips have just begun to be available and are expected to hold an 18% share by 2005. Protein chips will then have a 10% share and DNA chips 72%. The expectation that sales of DNA and protein chips will balloon during the next five years is based on the premise that the technology to produce them will undergo dramatic improvements over the next two to three years. Market growth will be stimulated by new DNA and lab chips and the introduction of diagnostics and forensics biochips.