Boston Business Journal, October 25, 2002 Has Biotechnology Strayed From its Biological Roots? By focusing too closely on the molecular level, scientists may be missing the forest for the trees By Dr. Bruce Bach It is an article of faith among drug developers today that only with molecular detail will it be possible to tease apart the disease process and properly target drugs to maximize the likelihood of beneficial effect and minimize side effects. By doing so, researchers hope to identify unique structures that can be tested against libraries of candidate drugs using an industrial-scale, high-throughput process in the search for the elusive yet long anticipated "silver bullet." The original desire to reap the benefits contained in the forest has been translated into a massive effort to study all of the trees to find a molecule that will fit the selected mold. This reductive approach has had a few big successes, particularly in cases where the molecular details are the disease. Identifying HIV protease inhibitors is a shining example of this impressive but brute-force approach, as are custom anti-bacterial agents. Thus, no one can gainsay the process when it works, but it appears that the current yield is too low for the time, effort, manpower, and capital consumed by the process. At the same time, we still have few, if any, effective therapies for organ debilitating disease processes that are the result of chronic physiological stress, such as cardiac hypertrophy, liver cirrhosis, and end-stage kidney disease. Progress in cancer research remains frustratingly slow as the molecular diversity of cancers defeats our ingenuity in developing new cytotoxic agents. Systemic diseases expressed at the tissue level do not translate well into strategies that target a single molecule to achieve therapeutic control. The birth of biotech and its initial successes in providing restorative treatments, such as insulin, growth hormone and blood-cell enhancer erythropoietin created enormous financial returns and excitement about the potential for using proteins as a new class of drug agents to support novel approaches to disease control. After the first resounding successes, advances came at greater cost and with less certainty. Inevitably, biotech has gravitated towards the concept of the "silver bullet" and has become more driven by the philosophy of reducing disease to its molecular details. By doing so, we may have missed the forest for the trees, having disconnected biotechnology from its biological base. Perhaps it is time to reemphasize the "bio" part of biotechnology, concentrating more effort on understanding and controlling the interaction between normal and abnormal biological processes in disease. One of the major potential contributions of biotech companies to improving healthcare outcomes may be in providing more biologically based treatment strategies that will extend our ability to encircle diseases instead of eradicating "hot spots". Because of its biological roots, biotech may be able to make the most of the powerful advantage that comes from looking at disease as a process that evolves over time and space. Controlling disease by manipulating multiple elements of the body's response to the disease process may open the door to treating diseases that have no effective treatment today. Looking at unmet clinical needs in diseases expressed at the tissue level, we can see three approaches. An accepted approach is tissue replacement. In this approach, we wait for tissues to fail and then, where possible, we replace them with donor tissue. This approach is limited by the inadequate supply of donor tissue and by the problem of rejection of foreign tissue by the recipient. An emerging approach to these diseases is the field of cell replacement. Recent advances in cell separation, stem cell culturing and gene transferred technologies have moved the possibility of using cells as therapeutic agents into the realm of reality. Applications range from supplying new cells to producing necessary proteins (such as insulin for type I diabetes), to engineering cells for combating cancers. Companies like Alexion Pharmaceuticals Inc. of Cheshire, Conn., Diacrin Inc. of Charlestown, Los Angeles-based Proneuron Biotechnologies Inc. and StemCells Inc. of Palo Alto, Calif., are targeting neurologic disorders. And Genzyme Biosurgery Corp. of Cambridge is focusing on cartilage repair. The limitation of the cell replacement approach is that it has to be done outside the body and the cells have to know where to go. The next generation of tissue therapeutic agents may well be those that require no manipulation or production of cells outside the body, but rather harness the tissue developmental and repair programs that already reside in the diseased tissue. Discovering ways to activate or deactivate these programs therapeutically is not going to happen by breaking cells into their component molecules and looking at them one at a time. In order to reap the forest of biotech benefits, we have to look beyond the molecular details of the trees and advance our understanding of how nature has chosen to approach repair processes as the basis for advancing the field of regenerative medicine as well as other fields. Dr. Bruce Bach is the CEO of Collgard Biopharmaceuticals Ltd., a clinical-stage tissue therapeutics company with offices in Boston, Atlanta and Tel Aviv. Back