January 18, 2003

It is difficult to trace how and when chemicals and biochemicals first came to be used as drugs. However, the history of drug development indicates that when humans began using herbs indistinguishably and indiscriminately as they developed the knowledge of normal and abnormal functioning of the human body.

Some of the substances cured the abnormality while others did not. With repeated attempts, or experimentation, a sort of therapeutic system came into existence and grew with time. In some instances the condition worsened, and people died from ignorant treatments. In primitive days, medical treatment was an ordeal. Patients had to gulp bowls full of black-brown concoctions, which was ugly to look at, displeasing to taste and nauseous in smell. As sciences progressed, many therapeutic systems were tried. The most successful one was based on the science of chemistry and biochemistry.

By 1870, some of the essential principles of chemical theories were laid. Avogadro’s atomic hypothesis had been confirmed and a periodic table of elements established. Elements were arranged according to their atomic numbers and weights. Theory of valency was established. Biological oxidation and reduction, concept of enzymes as biological catalysts and pH and energy-yielding processes within the living cells were established. These developments provided substantial understandings of elements of which all the living beings are composed. Their mishmash arrangement was considered the root cause of abnormalities within the body. In 1890, Friedrich August Kekule, a dedicated and devoted chemist, stumbled in his dream on to the structural formula of the benzene molecule, discovering the concept of aromatic hydrocarbon that gave rise to the new science of organic chemistry. Today benzene, a known carcinogenic, is considered one of the “dirty dozen” toxic substances.

This benzene theory provided a decisive impulse to do research on coal tar derivatives, particularly dyes and a base upon which many drugs were formed. The selective affinity of dyes for biological tissues led Paul Ehrlich (1874), at the University of Strasbourg, to postulate the existence of chemo-receptors. This is still exploited in the diagnosis of various diseases and subsequently it gave birth to the science of chemotherapy. Drug development thus began its career when chemistry had reached a point of culmination and maturity that allowed its principles and methods available for isolation, purification, structure elucidation and recognition of active ingredients of medicinal plants. Penicillin was discovered in 1929 from the penicllium mold and just after ten years of its discovery, Ernest Chain and Howard Florey found its antibiotic nature. That opened the doors to a new era in the treatment of bacterial infection. While some drugs were developed out of necessity, others were developed by chance. Today, as many as five hundred new organic and inorganic compounds are developed each year throughout the world. Some of them find their use as chemicals for laboratory reagents, most of them are used in industries but hardly five per cent of them find their use in medicine.

In the middle of the 20th century, genetics appeared on the horizon of medical science, and became the cornerstone of the knowledge upon which the scientists based their understanding of the disease processes. Subsequently, the development of drugs also revolutionized the scenario of pharmaceutical industries and therapeutic systems. Biochemical mechanisms of the action and the understanding of structure and functions of cells and tissues and their interaction with other elements has become the order to give rise to the creation of novel drugs which can hit the target and interact with diseased gene. Molecular biology also exerted profound influence on drug discovery, allowing the concept of genetic information to grow in biochemical and chemical terms for cloning and expressing genes that encode therapeutically useful proteins. About 70 protein drugs, including monoclonal antibodies, have been developed so far. They are often referred to as “biotech” drugs. In 1998, fifteen biotech products, most of them recombinant proteins, were introduced worldwide.

The human genome contains about 15,000 genes which can be encoded for therapeutic proteins-based drugs, (Jurgens Drew in Science, March 17, 2000)

Today, pharmaceutical science is developing under the influence of molecular biology with mutual consultation of chemists. It has been accepted that no drug can effectively be developed without knowing the disease and its cure at cellular and molecular (genetic) level. This enables us to understand life as a process in which information is copied from generation to generation, and expressed by producing bio-molecules, protected by compartments and repair mechanisms, and adapted by a balanced process of mutation and selections. Decoding the genome is thus, fundamentally, a problem of describing and modeling biological processes. The outcome will be a quantitative understanding of life processes, from molecular detail to macroscopic phenotype that is a new predictive biology. The quality and efficacy of an antibiotic or antiviral agent is based on its capability to bind with viral DNA by means of intercalation with DNA components of the infective agents; for instance, bacteria, viruses, etc. The DNA should then be regarded as a receptor in pharmacological sense. Drugs, which are not able to exhaust sequence information contained in DNA components, cannot act specifically on particular gene. This hard task seems to have been receiving attention of synthetic anti-sense oligonucleotides. This concept was proposed by Paul Zamecnik and Mary Stephenson in 1978 for therapeutic purposes. However, drugs based on specific antisense oligonucleotides in accordance with the genetic nature are also in the development stage, perhaps.

Thus, in historical perspective, the past of drugs traces back the roots of today’s pharmaceutical industry to the turn of 19th century and embraces the more recent impact of molecular biology and genome sciences so as to be called drugs of future requiring rising opportunities and escalating R&D costs.

The Human Genome Project, which has identified all the three billion nucleotide bases in human DNA, is yielding clues to thousands of new research targets for drug development. But following up those clues will be immensely expensive and will require a supersized scale of operation. The easiest way left for the pharmaceutical companies to achieve that magnitude quickly was to merge. This is the reason why merger of huge pharmaceutical industries is witnessed nowaays. In this regard the merger of Glaxo-Wellcome and SmithKline, with the aim to create the largest pharmaceutical R&D in the world, is worth a mention. Former GlaxoSmithKline chief Sir Richard Sykes had declared (Science, March 17, 2000) the end of traditional approach to drug discovery in which thousands of chemical compounds are screened to find one that works in these words: “The future of drug is in molecular genetics, cell biology and the modern sciences.”

A common man’s interest is to know whether the drugs developed by adopting genomic technology would be pure and 100 percent of the effort, would they be devoid of stereo-isomeric phenomena, side or adverse effects!

However, in Pakistan, Prof Atta-ur-Rahman has initiated joint projects between public sector institutions and private sector industries for technology based production of high value added goods is a good step (Dawn ScienceDotcom: Sept 7, 2002). Hopefully, through this partnership, if offered in pharmaceutical sector also, Pakistan would also be able to achieve the technological development required to produce biotech drugs and the drugs based on the diagnosis of diseases on molecular level, as envisaged in the merging of giant multinational pharmaceutical companies. The common man’s query remains intact until the drugs based on genomic technology are available therapeutically.

The writer is former senior research officer, PCSIR, Karachi

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