Nature's chemicals. The natural products that shaped our world

Natural Products (NPs) is the term used to describe the hundreds of thousands of chemical compounds or substances that are continually produced by living organisms (plants and microbes). Hundreds of millions of tons of these chemicals are generated annually, and the trade in just a few of these has dominated human economic activity for thousands of years. Indeed the current world geopolitical map has been shaped by attempts to control the supply of a few of these compounds. Every day of our lives each human spends time and money trying to procure the NPs of their choice. However, despite their overwhelming influence on human culture, they remain poorly understood. Yet a knowledge of NPs can help in our search for new drugs, further the debate about GM manipulation, help us address environmental pollution, and enable a better understanding of drug trafficking.

Nature's Chemicals is the first book to describe Natural Products (NPs) in an evolutionary context, distilling the few simple principles that govern the way in which organisms (including humans) have evolved to produce, cope with, or respond to NPs. It neatly synthesizes a widely dispersed literature and provides a general picture of NPs, encompassing evolution, history, ecology, and environmental issues (along with some deeper theory relevant to biochemistry), with the goal of enabling a wider section of the scientific community to fully appreciate the crucial importance of Natural Products to human culture and future survival.

Richard Firn grew up on a farm near Edinburgh, went 3 miles to university to study agriculture but found chemistry more challenging. Using a scholarship to get to Australia, by chance he began research in plant physiology which he continued in the UK and the USA. In 1973 he joined the Biology Department at the University of York and by a series of chance events he was joined by his first graduate student, Clive Jones, who enjoyed speculating about the evolutionary significance of the many diverse chemicals in plants. Not only did Clive help Richard in the laboratory, he was even called upon to help Richard build the timber house in which he still lives. Some years later, while Richard was really trying to understand how plants sense and respond to gravity and light, Clive and Richard met up again and came up with the radical idea on which this book is based. Richard Firn died in May 2010.

 

The desirable qualities of spices, stimulants, intoxicants, perfumes and medicines are attributable to our sensing of what Richard Firn has chosen to call natural products (NPs), otherwise known as secondary metabolites. These bland, unappealing terms, with no obvious handy alternatives, hide the vital importance of NPs in our everyday lives. Alcohol, caffeine, nicotine, aspirin, heroine, anti-oxidants, flavours, pigments and penicillin are just a few obvious examples of NPs, almost all being made by plants or micro-organisms. This book tells their fascinating story with an impressive integration of much widely dispersed information. The approach challenges conventions and cuts across traditional boundaries whilst adopting the old-fashioned virtues of rational argument and historical analysis. There is an overarching consideration of Darwinian evolution and also of the evolution of ideas. Sadly, Richard Firn died shortly after the book was completed. Its contents reveal much about the author as a writer, teacher, philosopher and research worker. His quest for clarity, capacity for lateral thought, and ever-present scepticism are apparent from the core content and also from the structure. Each of the ten chapters is headed by an apposite quote from a notable author, scientist or historian, continues with an extensive summary of chapter content and, after the main body of text, there is an idiosyncratic and pithy ‘What does this chapter tell us about the way science works?’. 

Chapter 1, ‘What are natural products’ explains how the author came to settle on ‘natural products’ as the collective term. Firn uses this explanation as a vehicle to describe how chemistry, as studied in universities, came to diverge during the 18th, 19th and 20th centuries in ways that left NPs largely marooned in chemistry departments, thereby loosening their links with studies of biology and evolution. 

Chapter 2, ‘The importance of NPs in human affairs’ is probably the highpoint of the book. Its broad historical sweep and emphasis on the high monetary value of NPs compared with that of mere foodstuffs make a riveting story. Empires were won and lost as the major European countries competed to control the trade in NP-containing commodities such as tea, coffee, opium, rubber, spices and chocolate. Monopoly of supply was the goal but we learn that no hard-won monopoly lasted for long. A role emerges for the large botanical gardens in breaking these monopolies. 

Chapter 3, ‘The main classes of NPs’ tries to help the reader come to terms with the large number of known NPs (about 170 000). Firn steps back from this overwhelming diversity to identify a small number of basic pathways used in their synthesis (e.g. isoprenoid, alkaloid, glucosinalate); the diversity being the outcome of relatively minor fusions, additions and subtractions to a few basic molecular structures. There are heavy hints suggesting evolutionary advantage to such chemical diversity. These are built upon in subsequent chapters. The writing here is let down by some dim and poorly explained figures. 

Chapter 4, ‘Are NPs different from synthetic chemicals’ is mainly aimed at helping the lay-reader stop believing that naturally made chemical are all good while unnatural, man-made chemicals are mostly bad. However, skipping what may seem a fatuous or unscientific chapter would be a mistake since the question posed has hidden depths that are explored with a light but telling touch. The finale highlights what the author sees as the tragedy of so much scientific data being locked away in the databases of commercial companies and the confusion over who owns the results from publically funded research labs. 

Chapter 5, ‘Why do organisms make NPs?’ takes on the difficult task of identifying the roles of NPs in the lives of the plants or micro-organisms that produce them. A fascinating backdrop is constructed comprising the huge diversity of NPs, their presumed role (now or in times long past) in protecting against specific competitors and enemies, coupled with the failure of massive commercial screening programmes to find more than a handful of useful insecticides, fungicides, antibiotics, etc from the multitude of NPs. Resolution of the apparent contradiction is made all the more pressing by our need, as disciples of evolution, to hold to the notion that successful organisms are unlikely to create large numbers of NPs with no obvious biological or nutrient value. We are introduced to the notion that a large bank of mostly inactive NPs has evolutionary advantages. This is based on the belief that it constitutes a reserve from which bioactive compounds may be derived at minimal cost when selection pressures become intense. This is a rewarding chapter for the tenacious reader. 

Chapter 6, ‘NPs, chemicals and the environment’ is about the fate of NPs when they are released into the environment. In other words, it is about metabolic breakdown of NPs. This is mostly carried out by micro-organisms. It is argued that the diversity of NPs has led to the evolution of a comparable diversity of degrading enzymes with catholic tastes. Firn suggests that their low substrate specificity lies at the heart of the impressive microbial clean-up of the numerous man-made toxins continuously being released into our surroundings. The great diversity of natural NPs may thus have led, indirectly, to a much cleaner and safer modern world. 

Chapter 7, ‘Natural products and the pharmaceutical industry’ contains a pitch by the author for the pharmaceutical industry to put past failures behind it and resume mass screening for useful NPs. The immense commercial value for new or improved medically useful substances is the driver. This complex chapter uses the history of the discovery of penicillin to illustrate why standard screening methods, even if fast and automated, rarely identify new blockbuster drugs from amongst existing NPs. Firn has interesting ideas on how the bioprospecting might be improved. 

Chapter 8, ‘The chemical interactions between organisms’ deals principally with the competitive advantage that NPs confer on the plants and micro-organisms that make them. Since huge numbers of NPs were produced by micro-organisms long before plants and animals evolved it is presumed that microbial interactions drove much of their evolution. Roles for NPs in the co-evolution of plants and animals are also explored, as is self-immunity to an organism's own NPs. 

Chapter 9, ‘The evolution of metabolism’ expands on the Darwinian view of NP content as an inherited trait conferring competitive advantage and repeats the proposal that such advantage does not spring from ever-greater specificity of enzymes as mutation alters DNA sequences. The gibberellin hormones are used to illustrate the importance of NP diversity (there are a great many gibberellins). Such diversity is thought to raise the probability that one or two possess the appropriate molecular geometry to allow docking with key pre-existing proteins (e.g. a hormone receptor), thereby changing their structure and thus cellular function. 

Chaper 10, ‘The genetic modification of NP pathways’ expands the notion that there is much commercial potential in using genetically modified micro-organisms to make new and desirable NPs. The now familiar concept of low substrate specificity of NP-forming enzymes and the synthetic networks these can set up is developed into a strategy for generating large numbers of unpredictable NPs in culture using genetically modified and readily cultured micro-organisms. The resulting NPs, in turn, could then be screened for a wide range of biological activities using established high-throughput screening methods. 

Creating a satisfyingly integrated whole out of the widely disparate literature on NPs is a considerable intellectual achievement. However, a relentless working through of the logic underlying every issue and conclusion inevitably risks descending into tedium and turgidity. Happily, this is mostly avoided thanks to a liberal supply of historical notes, personal and often sharply critical opinions and an enlivening ability to broaden the context. Richard Firn's book is thus something of a page-turner and one a latter day Sherlock Holmes might conceivably have written. It is recommended reading. 

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