Chapter Two

Medicine through the Millennia

To understand the importance of the latest medical breakthrough, it would be helpful to understand where we come from as human beings, trying to heal ourselves from whatever ails us.

But although it’s easy to track the beginning of the current revolution in medicine, when and how did we start ingesting foreign substances to restore our vitality?

The story doesn’t start with us humans.

Don’t worry; I’m not talking about creatures from outer space.

It started with apes. Not just apes. Primates.

In today’s world, local tribesmen have been observed to watch and copy what plants primates eat. Then they use the same plants for the same anti-parasitic reasons. So we humans have been learning from our primate cousins for many millennia. The truth is, animals have an uncanny instinct for knowing the curative properties of plant extracts and making brilliant use of them. Chimpanzees in Africa (Figure 2.1 #1), for instance, routinely seek out and consume plants with antibiotic and antiparasitic properties. They even mix plant extracts and soil rich in the clay mineral, kaolinite, a chemical that improves the potency of the plant extracts. It was also an ingredient in the original version of Kaopectate, until the 1980s. The clay also binds the toxins released by fungi and bacteria that the chimps may have ingested, thus offering protection from potentially harmful foods. Furthermore, kaolin enhances the beneficial effect of the consumed leaves from native plants.

Gorillas in Africa and other primates in South America (Figure 2.1, #1) have also been observed to self-medicate, in some cases consuming poisonous leaves from plants that they normally avoid to cure constipation or protect against gastrointestinal parasites.

But it’s not just primates who have an instinct for medicinal products. Elephants trek over dangerous terrain to a cave in Mount Elgon in Kenya to excavate and then grind up particular rocks rich in sodium to counteract toxins found in the plants that they feed on.

Closer to home, you may have noticed your dog or cat chewing on grass to make themselves vomit, expel the grass, and presumably other ingested products which some sense warned them were potentially harmful. So our initial understanding that plants could improve our health initially came from animals.

Then we took the ball and ran with it.

Whatever you think of primitive folk medicine, a lot of it worked. Pharmacologists have now identified active ingredients in poppy (opium), coca (cocaine), foxglove (digitalis), and many more plant extracts all of which were used in primitive folk medicine, and are familiar to doctors even today.

Medicines derived from active plant extracts have been employed by every society from every corner of the globe since ancient times.

The Far East

In ancient China, where acupuncture has been practiced for upward of five thousand years, herbalism has had a similar length of documented use. Recent pottery shards have been found in a Chinese cave dating back twenty thousand years (Figure 2.1, #2). Perhaps these shards were from pots used to store medicinal herbs, as humans moved from hunter-gatherers to settler-farmers?

One of the earliest recorded proponents of herbalism was Emperor Shen Nung who wrote “Pen Ts’ao,” or Great Herbal, in ~ 2700 BC describing 365 herbs, many of which it is believed he tested on himself. He is also credited with discovering tea, which acts as an antidote against the poisonous effects of some seventy herbs, which he first tasted in 2737 BC by accident. He was burning tea twigs, with the leaves still on them, when the burning leaves floated up from the fire born by the hot air, landing in his cauldron of boiling water which he subsequently drank. Shen Nung is venerated as the Father of Chinese medicine as well as the first tea drinker.

The Middle East

In Egypt by about two thousand BC, medical prescriptions recorded on papyri were based on plant matter and made reference to the herbalist’s combination of medicines and magic for healing. Perhaps the best known of these is the Papyrus Ebers, the most complete and extensive of surviving ancient herbals which dates from 1550 BC (Figure 2.1, #3). The Papyrus Ebers in turn is based on sources, now lost, dating back a further five hundred to two thousand years.

The earliest Sumerian herbal dates from about twenty five hundred BC. In Babylon, many early Arabs were also enthusiasts for herbal remedies. Inscribed Assyrian tablets dated 668–626 BC list about 250 vegetable-based drugs, including many familiar herbs and spices such as saffron, cumin, turmeric and sesame, that are still in use today – and familiar to most cooks.

Figure 2.1. Wherever mankind has set foot, so the desire to take medicine to combat disease has followed. See text for flags numbered 1-10. #11 is Harvard University, Boston where Professor Paul Zamecnik first conducted an “antisense experiment.” And #12 is Bothell, Washington, the corporate office of my former company, AVI BioPharma (now Sarepta Therapeutics) who have pioneered spliceswitching oligomers.

India

Traditional herbal medicine dates back in India at least to the second millennium BC, where it is known as Ayurveda (Figure 2.1, #4). One authentic textbook is the Sushruta Samhita, a book of 184 chapters describing 1,120 illnesses and 821 preparations based on plant, mineral, and animal sources. Sushruta is credited with writing the Sushruta Samhita in Sanskrit, which is a redacted text on all of the major concepts of Ayurvedic medicine with innovative chapters on surgery, then considered the most important branch. Cataract surgery was performed by Sushruta before eight hundred BC.

Europe

From Ancient Greece (Figure 2.1, #5), Hippocrates (460–377 BC) arguably had the greatest influence on modern medicine, and was known to use approximately four hundred different drugs, mostly of plant origin. He is referred to as the father of Western medicine and credited with greatly advancing the systematic study of clinical medicine, summing up the medical knowledge of previous schools.

The First Millennium

Pliny the Elder (Gaius Plinius Secundas, 23-75AD) was a Roman author, naturalist, and natural philosopher. He wrote seven books (as part of a thirty-seven book treatise entitled Naturalis Historia) describing medicinal plants that were often cited in other later texts. Naturalis Historia became the earliest printed herbal when it was subsequently produced in 1469.

The Islamic World

In the medieval Islamic world, Muslim botanists and physicians made a major contribution to the knowledge of herbal medicines. The most prominent of these is Rhazes (865-925), a Persian physician, alchemist, philosopher, chemist, and scholar. He was the first to differentiate smallpox from measles and discovered kerosene. He has been considered “probably the greatest and most original of all the physicians, and one of the most prolific as an author.”

There were many other Persian herbalists, and herbs and chemical compounds were so important that the first known drugstore was opened in Baghdad in 754 AD (Figure 2.1, #6).

The Second Millennium

The Americas

Herbs were also being used in the Americas, by indigenous Aztecs in the South especially. An illustrated herbal published in Mexico in 1552, Libellus de Medicinalibus Indorum in the Aztec Nauhuatl language (“Book of Medicinal Herbs of the Indies”), was written by a native physician, Martín de la Cruz (Figure 2.1, #7). The formal illustrations in this book resemble European ones, suggesting that the artist was influenced by his Spanish masters. The book was translated into Latin by Juan Badianus and illustrated the tlahçolteoçacatl, tlayapaloni, axocotl, and chicomacatl plants, which were used to make a “remedy for a wounded body” in Aztec herbalism.

Native Americans in North America likely also developed primitive medicines from roots, herbs, and plant extracts but passed the information down through the generations by verbal means rather than written documentation. The healing skills of ancient native peoples have only relatively recently started to be recognized, let alone documented with a written record.

Europe

During the Middle Ages and then the Renaissance, when many sciences progressed considerably in Western Europe, the study and advancement of medicine and drugs did not. Prescriptions generally followed the herbal remedies of ancient cultures, or worse, used bile, animal dung, ground up sexual organs, urine and sweat.

The stimulus for herbalism to become more systematic was the invention of the printing press with a movable typeface, which took place in Germany in 1440. The new printed herbals were more detailed with greater general appeal, often with Gothic script and the addition of woodcut illustrations that more closely resembled the plants being described.

William Turner (1508 to 1568) was an English naturalist, botanist, and theologian who, after studying at Cambridge University, eventually became known as the “father of English botany” (Figure 2.1, #8). He achieved botanical notoriety with his 1538 publication Libellus de re herbaria novus, which, despite its title, was the first essay on scientific botany written in English. His three-part A New Herball of 1551, 1562, and 1568, was noted for its original contributions and extensive medicinal content and for being written in vernacular English. The woodcut illustrations he included however were taken from an earlier work by the German botanist, Leonhart Fuchs (1501-1566). Turner described over two hundred species of plants native to England and his work had a strong influence on later eminent botanists such as John Ray and Jean Bauhin.

John Gerard (1545–1612) was the most popular of the English herbalists due to his publication, in 1596, of Catalogus. This was a list of 1033 plants growing in his Elizabethan English garden at Holborn, where he introduced exotic plants from the New World. In 1597, he published the large and heavily illustrated Herball, or Generall Historie of Plantes, which went on to be the most widely circulated botany book in English in the seventeenth century.

In the seventeenth century, greater interest in medicine in England was stimulated by the English physician, Thomas Sydenham (1624-1689). Sydenham fought for the Parliamentarians under Oliver Cromwell throughout the English Civil War, and, at its end, resumed his medical studies at Magdalene College, Oxford. He published widely on medical topics and gave the needed boost to pharmacology and was posthumously accorded the title of “English Hippocrates.” Among Sydenham’s many achievements was the discovery of a disease, Sydenham’s Chorea, also known as St. Vitus Dance. This is a disease of characteristic jerky movements of the limbs and grimacing of the facial muscles, often occurring in children and caused by an infection with the Streptococcus bacterium that was often associated with rheumatic heart fever.

John Parkinson (1567–1650), a founding member of the Worshipful Society of Apothecaries, was apothecary to King James I of England, who was also King James VI of Scotland. Parkinson was an enthusiastic and skillful gardener, stocking his garden in Long Acre, in Covent Garden, London, with many rare plants. Parkinson was the last of the great English herbalists and one of the first of the great English botanists.

Parkinson was an active correspondent with important English and Continental herbalists and botanists, and imported many new and unusual plants from overseas, in particular from the Mediterranean coast of the Middle East and from Virginia on the U.S. East Coast. Parkinson is celebrated for his two monumental works, the first Paradisi in Sole Paradisus Terrestris in 1629. This was essentially a gardening book for which Charles I awarded him the title Royal Botanist. The second was his Theatrum Botanicum or Theatre of Plants, of 1640. This was the largest herbal ever produced in the English language and was the most complete and beautifullypresented treatise on plants of its time.

Another British example from the period is the astrologicallythemed Complete Herbal written in 1653 by the physician and astrologer Nicholas Culpeper (1616-1654), based on his experience cataloging English herbs. Culpeper’s book was reprinted many times and remained popular with many even into the twentieth century. However, by including astrological themes the book never gained scientific authority and credibility with all physicians then or since.

Culpepper, a radical republican, fought for Cromwell during the English Civil War and performed heroic surgery while battles raged about him. Culpeper was no friend of the medical establishment at the time, believing physicians overcharged for their services and by not publishing work, or publishing in Latin, were deliberately trying to keep their patients in ignorance. So while many were preoccupied with the war he set about publishing his work in vernacular English, outraging the Royal College of Physicians. He also charged little for his printed leaflets further upsetting his professional brethren. Culpepper’s main work, The English Physician, was published in 1708 in Boston. It became the most successful non-religious English text of all time, with many readers in colonial America, and remains in print today at $35 for the 94 page hardback edition.

However, despite the efforts of such enlightened physician herbalists as Sydenham, Parkinson, and Culpeper in both Britain and mainland Europe, treatment of illness often involved administering poisons, bleeding or “cupping” and application of clysters, what we know as enemas, purges and sudorifics to increase sweating. Today, nobody would be surprised at the lack of efficacy of these barbaric measures, which did little to endear physicians to their gullible patients.

In the nineteenth century, there were efforts to identify, isolate and purify the medicinal extracts from plants. Friedrich Serturner (1783-1841), a German pharmacist, was the first to isolate any plant extract, an alkaloid from the poppy plant in 1804. He found the extract induced dream-like states in people, so he named the extract morphium after Morpheus, the Greek god of dreams. Serturner subsequently purified the extract and marketed it as morphine, from his pharmacy in Einbeck in 1817 (Figure 2.1, #9).

An Italian chemist, Raffaele Piria (1814 – 1865) isolated and prepared salicyclic acid from salicin – originally from willow trees. Later, in 1853, a French chemist, Charles Gerhardt (1816-1856) synthesized the derivative acetylsalicylic acid, with later refinements to the process by Karl-Johann Kraut in 1869 and Hermann Kolbe in 1874. It wasn’t until 1899 when the German company, Bayer, introduced the compound as aspirin that it became the first fever reducing, widely marketed, pure drug.

The 20th Century

The development of drugs became an established science in 1909 when Paul Ehrlich (1854-1915), a Prussian Jew, discovered an arsenicbased drug, called Salvarsan, to treat syphilis. Ehrlich was awarded the Nobel Prize for Physiology or Medicine for his work on infectious disease and Salvarsan became the best selling drug in the world between 1910 and the 1940s when it was eventually replaced by penicillin.

These early drugs were developed by a chemical synthetic process, in test tubes on a small scale and in big vats on a larger scale. Soon, drugs would be created by biological processes using living cells. Yeasts or bacteria were initially used to produce the product. More recently, biological drugs have been produced in tissue cultures. The biologic products are generally much bigger molecules, often complex, and can be protein, sugar, nucleic acid or a combination of these. If the biologic is a protein made by cells from an animal, it may create an allergic reaction to the foreign animal protein once given to humans.

The first biologic drug was insulin, which was first isolated by Frederick Banting and Charles Best in Toronto in the 1920s (Figure 2.1, #10). That was followed by cortisone, isolated by Edward Kendall at the Mayo Clinic in Rochester, Minnesota. Kendall won a Nobel Prize in 1950. Thereafter small molecule drugs, and to a lesser extent biologics, began to establish a greater potential place in medicine. By the early twentieth century, modern pharmaceuticals had arrived, less than one hundred years ago.

The First Biologic Drug

Dr. Frederick Banting and Charles Best, then a medical student, conducted experiments with insulin in dogs who had had their pancreas removed, to make them diabetic. Pancreatic extract was injected into a diabetic dog in the summer of 1921. The dog’s elevated blood glucose level dropped, and it seemed healthier and stronger. The intrepid duo kept their diabetic dog in healthy condition by injecting it with the extract several times a day. In late 1921, biochemist Bertram Collip joined the team that was now tasked with purifying the insulin extracted from the pancreas of cattle so that it would be clean enough for testing on humans. In January 1922, in Toronto, a 14-year-old boy was the first human diabetic to receive insulin. Before the insulin shots he was near death. But the test was a success and he rapidly regained his strength and appetite. Soon, Eli Lilly started largescale production of the extract and by 1923 was producing enough insulin to supply the entire North American continent.

Drugs aimed at specific targets, which are the direct antecedents to medicines that target genes, began to emerge in 1935 with Sulfanilamide. This was an antibacterial drug discovered by Gerhard Domagk (another Nobel laureate) and Therese Trefouel. It was in all likelihood the first drug that reacted with a specific protein receptor. Then in 1940, Thaddeus Mann and David Keilin in Cambridge, UK, discovered that sulfanilamide encouraged urinary excretion by blocking the enzyme carbonic anhydrase, thus working as a diuretic as well as an antibiotic.

This led to the successful search for more potent carbonic anhydrase inhibitors, which act to reduce elevated blood pressure and are called anti-hypertensives.

Other small molecules began to be sought in order to target other specific protein receptors.

The Placebo Effect

In 1955, it was discovered that if a patient believed in a substance, it could create a healing effect even if it had no actual pharmacological value. Henry Beecher wrote about the “Powerful Placebo” in the Journal of the American Medical Association. He noted that a dummy drug, the placebo, worked in about a third of cases. This was true even when it was prescribed by a physician. And it was true for a range of diseases too, from an upper respiratory infection to a headache.

Given the wide diversity of patients treated with any one pharmacologically active compound, the diversity of responses, and our still limited knowledge about how drugs work in some cases, a response rate of 33% is not very different from the response rate seen with some drugs. Thus, over the last fifty years, and especially recently, drugs are compared with the placebo effect when evaluating how effective they are. That is not to say that the drug’s mechanism of action is unknown or incorrect. It is just that the interaction between disease and patient is far more complex than was previously thought.

Once a potential drug has been identified, then making it, purifying it and ensuring its stability can commence. Testing in the laboratory, so called in vitro testing, to see if the drug does indeed interact with the target receptor, is the next step. These target receptors are often obtained in a blood test or biopsy from a patient with the disease in question. This in vitro work takes place prior to any work being conducted in whole animals, called in vivo work.

By now the potential drug is called a New Chemical Entity, NCE or New Molecular Entity, NME. Confirming that this potential drug does indeed interact with the target can be a lengthy process, called Proof of Principle. Once convincing proof has been obtained in the laboratory which is another complex process, preliminary safety testing in animals can start.

It was hoped that modern technology and knowledge would alleviate the need to test NCEs in animals (see Chapter 9); however, that hope has not been realized yet. That is despite computerization and the greater understanding about the various drug classes, chemical subgroups and modifications and their predictable effects, that nowadays go into building an NCE.

The process of discovering, developing and licensing medicinal drugs has become much more complex and costly. This trend is likely to continue, with animal testing remaining an integral and gatekeeping part of that process before any testing in humans is allowed. The regulatory hurdles for NCEs get higher because the public expects new drugs to be marketed that are effective but represent zero risk of adverse effects. This is currently impossible to guarantee, but what is seemingly expected. Attorneys line up to sue any company unlucky enough to market a drug that subsequently is shown be unsafe even in a tiny proportion of patients treated.

Penicillin, the first of the wonder antibiotics, was discovered by Sir Alexander Fleming (1881-1955) in 1928. Fleming, a Scottish biologist and pharmacologist, wrote many articles on bacteriology, immunology, and chemotherapy. He discovered the enzyme lysozyme in 1923. He was a brilliant researcher who fortunately kept an extremely messy laboratory. In August 1928 he stacked all his cultures of the staphylococcus bacteria on a bench in a corner of his laboratory before going on vacation with his family. On returning, on 3rd September, Fleming noticed that one culture was contaminated with a mold that had killed the colonies of staphylococci that immediately surrounded it. Other colonies farther away were normal.

Fleming grew the mold in a pure culture and found that it produced a bacteria-killing substance. He identified the mold as being from the Penicillium genus, and, named the substance it released “penicillin.”

Penicillin had to wait for better synthetic manufacturing processes before it could be widely distributed. It initially reached U.S. servicemen in 1941, and then the general public after World War II ended in 1945.

Interestingly enough, it is likely that penicillin had been used for centuries beforehand with the ancient Egyptian practice of using poultices of moldy bread.

Penicillin heralded the “New Age of Antimicrobials,” but there has always been one problem with the entire drug category. As fast as new classes of antibiotics have been developed, the microbes against which they are pitted evolve to become resistant to them.

Other major classes of drugs were serendipitously discovered or scientifically developed based on better disease understanding. These advances include the first beta-blocker, propranolol, created by Sir James Black in 1962. Black’s work built on the discovery of the adrenoreceptor by George Oliver and Edward Schafer at University College, London who showed that adrenal extract, when injected, would raise blood pressure. The active ingredient, adrenaline was discovered in 1904. However the actual molecular target of adrenaline, called epinephrine in the U.S., was only demonstrated to be two classes of protein receptors in 1948, so called alpha and beta receptors. More about the beta receptor, a G-protein coupled receptor, in Chapter 4. Black went to work for ICI Pharmaceuticals in 1958 and it was while there that he developed propranolol, for the treatment of high blood pressure and heart disease.

Other new drug classes, developed in the late twentieth century, based on better disease understanding, include:

•   antimigraine triptan drugs to block the 5-hydroxytryptamine receptor

•   histamine H2 receptor antagonists to reduce stomach acid

•   proton pump inhibitors to reduce stomach acid

•   selective serotonin receptor antagonists to combat depression

By the end of the twentieth century, medicines were classified into Anatomical Therapeutic Chemical (ATC) classes according to what body system they acted on and/or their therapeutic or chemical characteristic. The classification system is “owned” by the World Health Organization Collaborating Centre who established the 14 main ATC groups and they have published updates since the first edition that appeared only as recently as 1976.

Third Millennium

By the end of the first decade in the twenty-first century, there is information available on over thirty thousand medicines that can be prescribed or purchased over the counter. But, as mentioned previously, there are approximately 150,000 proteins in the body, so only a small fraction of these have successfully been targeted by the drugs developed so far. And many of these thirty thousand drugs have been developed by modification of an existing drug and share the same target. More than twenty-five thousand of these drugs have been available for many years and are now off patent. As new targets and small molecule drugs to target them are getting harder to find, some people fear that we are reaching the limit of what is druggable.

Moving into the second decade of this millennium, more research and developmental effort is being focused on the rare diseases that until very recently were considered to be untreatable. Members of the Pharmaceutical Research and Manufacturers of America, America’s biopharmaceutical organization, invested an estimated $45.8 billion in 2009 to discover and develop new medicines. Much of this money is being spent on rare diseases, which are both devastating to patients and complex for researchers. By early 2011, a record 460 medicines for rare diseases were in late stages of the drug development pipeline, either in clinical trials or awaiting U.S. Food and Drug Administration (FDA) review.

A rare disease is defined by the U.S. government as one that afflicts fewer than two-hundred thousand Americans. There are approximately seven thousand rare diseases. Half of these afflict children. Eighty percent of these rare diseases affect fewer than six thousand U.S. patients. However, in total, approximately thirty million Americans suffer from one rare disease or another, that’s one in every ten of us.

Taken together, rare diseases are common. Across the world, as many as six hundred million patients now suffer from a rare disease. Often, patients suffer from untreatable diseases for years before getting a correct diagnosis. Then they get the news that there is very little or nothing that modern science and medicine can do to help them. However, as this book will demonstrate, there is now hope for some of these six hundred million suffering patients, or at least the next generation of patients who are destined to suffer like them.

The Future of Conventional Drugs

What’s the future of conventional drugs in the twenty first century?

In the last thirty years, blockbuster drugs have come and gone. Many have enjoyed enormous peak sales, reflecting their efficacy or benefit and safety. That has provided for a favorable benefit-risk ratio and popularity. The sales have rewarded the marketing machines of the companies that manufactured them. A list of the top twenty drugs by sales is given in Appendix A. Drug marketing has become big business with significant amounts spent on advertising to the medical profession, and in some countries such as the U.S., to the general public as well.

One of the most recognizable of these blockbuster drugs is Ventolin for treating the bronchospasm of asthma. Ventolin is also known by its active chemical name, albuterol in the U.S. or salbutamol in the rest of the world. Ventolin was the first stimulator of the adrenergic beta receptor. It was launched in 1968 by Allen & Hanburys.

Allen & Hanburys is the oldest pharmaceutical company, established in London in 1715. It is now part of the GlaxoSmithKline family. Allen & Hanburys was the company I joined from UK family practice in 1993. So I regard it as my industrial alma mater, as well as Glaxo in general, and I am more familiar with the stories about their blockbuster drugs.

The active ingredient in Ventolin, albuterol/salbutamol, has remained the most frequently prescribed inhaled asthma-reliever medication for approximately 45 years. The patent has long since expired on the salbutamol/albuterol molecule but with Ventolin inhaler having to be reformulated with HFA (hydrofluoroalkane), a different propellant, into a CFC-free (chlorofluorocarbon) inhaler, the brand is once again protected from generic alternative competition until 2015. The new propellant was required to reduce the harm done to the protective ozone layer in our atmosphere by the older CFC propellants. The HFA propellants also have less global warming potential than the older CFC ones. Ventolin is the asthma reliever medication that you may still reach for when you feel your chest go tight or you start wheezing.

Stomach ulcers and excessive stomach acid were at one time treated with cimetidine, a drug used to block the stomach acid-producing histamine H₂ receptor, developed by James Black. Black then refined cimetidine, and in doing so developed another of Glaxo’s blockbuster drugs, ranitidine (Zantac), that had fewer adverse drug reactions, was longer-lasting in action, and had ten times more activity than cimetidine. Black was awarded the Nobel Prize for Medicine in 1988 for work leading to the development of propranolol and cimetidine.

Zantac was initially launched in 1981 and by 1988 was the top selling prescription drug in the U.S. It has now become available “Over the Counter” (OTC) in many countries as the long and large safety database established suggests its use no longer needs to be overseen by a physician. The patent on the drug ranitidine expired in 1997 and many generic manufacturers rushed their versions of ranitidine on to the market to capitalize on its popularity, while new classes of drugs, such as the proton pump inhibitors or PPIs were developed and found to be even more effective in treating excessive gastric acid.

Prozac, fluoxetine is the generic name, is another blockbuster drug, developed by Eli Lilly as a selective serotonin reuptake inhibitor, or SSRI. It is perhaps the best known SSRI used for treating major depression, but it was only the fourth to reach the market. Two of the first three SSRIs, zimeldine, indalpine and fluvoxamine, had to be withdrawn because of adverse side effects. Prozac became available in the U.S. in 1987 and became a major blockbuster and the subject of the book “Prozac Nation” by Elizabeth Wurtzel published in 1994, as well as a subsequent film, before its patent too expired in 2001.

Summary

For 4,900 of the last five thousand years, mankind has been limited mostly to using herbs and plants for medicinal purposes.

As science has evolved and brought greater understanding to disease, especially over the last half century, so have new synthetic or natural chemicals been discovered and developed. More recently, biological products have arrived. Both classes have had the goal of “correct or cure”, and the science of drug development has exploded onto the scene.

Drugs can be broadly characterized into falling into one of three “platform technologies”:

• Small molecules, which can nevertheless be very large

• Biological products, first developed under a hundred years ago

• The “Nucleic acid-based-therapeutics”, in the last thirty years.

The dividing line between these platforms is occasionally blurred, but the remainder of this book will focus on the Nucleic acid basedtherapeutics which will eventually become established as a major breakthrough for medical science and a source of many new medicines.