Future Directions

The availability of a large collection of secreted proteins has enabled us to look at physiology and pathology from a new viewpoint. However, our assays are always

Fig. 17.6. Combining the power of the human secretóme and human genetics gives us a unique platform for drug discovery in the future. The secretóme is a list of proteins that are by definition drug targets, since they can be administered to patients (not all proteins are druggable - see Hopkins et al. 2002). Genetics gives us the candidates which correlate best with disease. Where these two worlds intersect, then we have the best chance of finding a new therapeutic. Often the worlds do not intersect directly, and so it is important to understand the metabolic and protein-protein interaction pathways that link them

Fig. 17.6. Combining the power of the human secretóme and human genetics gives us a unique platform for drug discovery in the future. The secretóme is a list of proteins that are by definition drug targets, since they can be administered to patients (not all proteins are druggable - see Hopkins et al. 2002). Genetics gives us the candidates which correlate best with disease. Where these two worlds intersect, then we have the best chance of finding a new therapeutic. Often the worlds do not intersect directly, and so it is important to understand the metabolic and protein-protein interaction pathways that link them

limited - either we are studying human cells in culture, or we are studying the in vivo activity in animal models. Although both give us a glimpse of the possible clinical use, neither gives us a complete picture. Before we get into clinical testing it is essential to know that our protein targets are actually linked with the human disease. Typically we look at this from three viewpoints. First, is the target actually expressed in the tissue during disease? Second, is there evidence that the protein will have an effect on cells from patients with the disease. This is typically only straightforward if the target is present on leukocytes, or if it is present in the skin or on tissue which is surgically resected as part of the treatment of advanced stage disease (such as arthritis). The third piece of data comes from the human genetics. We now live in the era of the whole genome scan (see Klein et al. 2005 for an example) - where it is possible to look at as many as 500,000 single nucleotide polymorphisms. Since we are studying the DNA of a large number of patients, we can try to detect whether SNPs in the gene of interest can correlate with the severity, speed of onset, or even subtype of disease. This is only a correlation, but it does enable us to take a look at molecules associated with the disease, and to see which of our proteins might play a role in the real human pathology. We have completed scans in the autoimmune diseases multiple sclerosis, psoriasis and SLE - allowing us to see which of our secreted proteins can be prioritized based on the genetic data.

Combining these three viewpoints is a very powerful approach (Fig. 17.6) - protein discovery gives us a list of proteins - all tractable (easily made) - but with no a priori correlation with disease. Whole genome scan analysis of human genetics gives us a list of the genes which link to disease - but with no a priori correlation as to whether they are tractable as targets (whether a drug could ever be made against them). Sometimes these two worlds will overlap directly - but in most cases they will not. To link the two worlds we have to make the most of pathway databases, which look at which proteins can and do interact with each other and to understand which tractable protein can be used to modulate the activity of a protein whose gene correlates with development of disease.

The technologies of the genome era have enabled us to start to master the human secretome and to understand the biology of its members in much more depth. The bulk of the challenge still lies ahead of us - picking those proteins that will be of the greatest clinical benefit to our patients. This is a challenge which will keep us busy for many decades to come.

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