Commentary

Medical professionals in 2080 will look back on the early part of the 21st century and be reminded of Charles Dickens’ opening words from A Tale of Two Cities: “It was the best of times, it was the worst of times …” ¹ Mr Dickens was describing in 1859 the French Revolution that took place 70 years earlier. Like the French Revolution in the late 1700s, medicine today is in the midst of a revolution, and it is no surprise that toxicology is part of it. Today’s revolution is different from the one that took place in France. The current evolution is poised to save many more lives than the French Revolution took.

Although patients of today have diseases, the “best of times” still belongs to them, thanks to personalized medicine. Personalized medicine, the product of today’s revolution, is the antithesis of the “sheep dip” approach that has been used to protect sheep against disease perpetuated by vermin. Individual sheep from a herd are immersed, one by one, in a pesticide cocktail where they receive the same treatment of the same dose for the same amount of time. Although that may be an effective dosing regimen for farm animals, equality in treatment, like many other circumstances involving humans, does not assure the most desirable outcome.

The “best of times” in the revolution of today has its foundation in the genomic explosion which is bringing new techniques, tools, and knowledge to the practice of medicine. Consequently, medicine is at the cusp of understanding diseases at the molecular level and is progressing to the point where diseases can be predicted and treated on an individual basis, thanks to genomics. Therapeutic interventions brought about by genomic personalization will result in more rapid cures with less unwanted side effects. Therein lies the revolution of today.

The “worst of times,” to their chagrin, belongs to the large and established pharmaceutical industry because the “one size fits all” approach for drug discovery and development does not have a promising future. When one considers the success rate, the egalitarian framework of ignoring individual differences cries out for an alternative approach. Treating those afflicted with a disease using the same drug at the same dose for the same duration is going the way of the buggy whip and is being replaced by the individualism of personalized medicine. Consequently, the pharmaceutical industry is taking note. Effective implementation of a new drug discovery paradigm is necessary to increase the productivity of the pharmaceutical industry as much as the new paradigm of personalized medicine increases the optimism of industry’s customer patients.

These “best of times” couldn’t come any too soon to offset the “worst of times” for the pharmaceutical industry. The purveyors of therapeutics are facing serious challenges on several fronts. Unquestionably, health care delivery efficiency, due to governmental intervention and health insurance reimbursements, is a challenge to the practice of medicine. Whether the reimbursements are governmental or private, they are moving targets, usually heading in a downward direction. The flow through pipelines of candidates to replace blockbuster drugs that are going off patent is reduced to a trickle. The current paradigm for drug discovery is inefficient, costly, and outdated. What else could go wrong?

Sustainability, so that the pharmaceutical industry can continue to deliver medicines in the future, requires an enabling technology or a dramatic event, preferably an economically positive one. Enter genomics—the very tool that shifts the focus from using an egalitarian approach for treating disease to one that is individualized with a personalized medicine framework. Could genomics solve the pharmaceutical industry’s woes?

The identification of a diseased state and doing something therapeutically about it is the task at hand. Combining genomics with biomarkers creates the tool for achieving the “best of times” for both patients and the pharmaceutical industry. Consequently, the combination effectively manages the task at hand for both patients and the pharmaceutical industry. This is the foundation of personalized medicine. When genomic biomarkers are developed they, in addition to making medicine more personal, also become the tools of the enabling technology for drug discovery, development, and diagnosis. Genomic biomarkers set the stage for a revolutionary efficiency that brings down the cost of not only drug developments but other types of product developments as well.

It is clear from Genomic Biomarkers for Pharmaceutical Development—Advancing Personalized Health Care (In press) and Predictive Toxicology in Drug Safety ² that biomarkers have seen dramatic growth in their identification and in their use within pharmaceutical discovery and development. ^2,3 Biomarkers are on the path to become the drivers for and an integral part of increased efficiency and value, both social and economic, in pharmaceutical developments. ⁴ Biomarkers, especially those that are derived from genomics and at the same time associated with therapeutics, are being accepted and are considered an extension of the drug therapy. Furthermore, the therapeutic biomarkers are being codeveloped as companion diagnostics and are in the early stages of being inculcated into the drug discovery and development process. ^5,6

Most therapeutic biomarkers that are developed concurrently with drugs are done so to complement the drug therapy and therapeutic biomarkers are part of the disease healing process. For the most part, therapeutic biomarkers support the drug by either detecting the early onset of the disease ⁷ or by identifying patients, usually with a genomic-derived biomarker that would most likely benefit from the drug, ergo, personalized medicine. ⁸ Consequently, it is not surprising that these therapeutic biomarkers are intentionally connected to drugs and treatments and are perceived as part of the therapeutic process to cure the disease and restore homeostasis.

Biomarkers are not new nor are they complex. Simply put, biomarkers are molecular indicators of the functioning status of a biologic system. In fundamental terms, biomarkers indicate whether or not a biologic system had its homeostatic condition disturbed. Legions of toxicologists have dedicated their careers to identifying and quantifying incidents of disrupted homeostasis; that is what they do. Toxicologists, in their job descriptions and career objectives, have used biomarkers for the early detection of eminent pathology, determining the time-course onset along with the progression of the distorted homeostasis, and establishing whether the shift in homeostasis is reversible or irreversible. However, toxicity biomarkers, while not directly the cause of, are nonetheless associated with problems that cause or result in an adverse structural or functional state or condition.

Biomarkers have been, are, and will be an essential component of toxicology, whether toxicology is practiced for the benefit of pharmaceutical development or for any other products to which humans are exposed and for which human health risk assessments are made. However, when toxicity biomarkers are used outside pharmaceutical developments, their use must be done with eyes wide open. Toxicity biomarkers are viewed differently than therapeutic biomarkers because they function differently.

Toxicity biomarkers are sentinel indicators that identify, and at times quantify, early warnings of distorted homeostasis resulting from both therapeutic and nontherapeutic xenobiotics. Furthermore, a toxicity biomarker identifies a potential problem while a therapeutic biomarker is the first step to solve a problem. Toxicity biomarkers that are used for nonpharmaceuticals to monitor toxicology testing and to assist in research and product development may not be perceived as having as much value as those biomarkers associated with pharmaceuticals that ultimately resolve problems. Consequently, for low benefit/risk perceptions, toxicity biomarkers are positioned to be perceived as effectively lowering the toxicological no-effect level in the minds of the nontoxicologists by considering a biomarker response as toxicity and not a sentinel to it.

Mapstone et al ⁷ states “Biomolecules of preclinical disease will be critical to the development of disease-modifying or even preventive therapies.” The key phrase in the Mapstone quote is “preclinical disease.” If therapeutic biomarkers for detecting a disease are important before a disease is clinically evident, then why wouldn’t toxicity biomarkers be important before toxicity is clinically evident? Following this reasoning, it can be argued that the toxicological no-effect level is not the lowest dose at which any alteration in structure (pathology) or function (physiology) is seen but rather the dose below which toxicity biomarkers are not affected. This downward shift of the no-effect level is not trivial.

Thinking that a response from a toxicity biomarker is outright toxicity creates a conundrum for toxicologists. However, the conundrum is readily solved by understanding that toxicity biomarkers have a different objective when compared to therapeutic biomarkers. Therapeutic biomarkers determine preclinical changes caused by disease that is not the result of a toxicant or toxin. Toxicity biomarkers, on the other hand, identify changes in homeostasis that are caused by toxicants and toxins.

Preclinical changes using therapeutic biomarkers before a disease is clinically evident are desirable so that therapies can disrupt the disease process as early as possible. Toxicity biomarkers are used to detect homeostatic changes that precede toxicity. Toxicity only becomes evident when the changes go beyond distortions in homeostasis and result in structural or functional changes. Consequently, toxicity biomarkers are pretoxicity indicators and are not toxic responses. Furthermore, toxicity biomarkers can be used to verify the return to the original homeostatic state which arguably can be described as reversibility of adverse reactions.

In addition to the differing purposes between therapeutic and toxicity biomarkers, the term “biomarker” itself is vague and has many different meanings. The meaning of biomarker is so broad and greatly overused that the word is a candidate for cliché status. It is a word whose specific meaning in the mind of the user does not necessarily have the same meaning in the minds of those who hear the word. At some time, the word “biomarker” may acquire sufficient clarity through modifiers and descriptors so there will be no misunderstanding across disciplines. That time has not yet come.

Biomarkers, which may be considered new tools for some, are merely a renaming of tools that have long been in the toxicologists’ tool box. Toxicologists’ biomarkers are more readily recognized when their other more familiar names are used, for example, clinical chemistries, organ function tests, serum enzymes, and so on. The familiar names can be identified in more specific ways with more precise descriptors such as blood glucose, blood urea nitrogen, alanine amino transferase, and so on.

If Aristotle had been a toxicologist, he would have argued that the ability to detect and quantify is the essential property of a biomarker, and the name “biomarker” is a descriptive or accidental property; and make no mistake, essential properties trump accidental properties. What toxicity biomarkers do is more important than what they are called. Toxicologists would be wise to make haste slowly to become part of the “biomarker frenzy.” Calling every peek into an organism a “biomarker” or search for new “biomarkers” for the sake of having more biomarkers does not change the fundamental activity of the toxicologist.

In addition to the functional diversity, therapeutic versus toxicity, and definitional vagueness of the word “biomarker,” there is also a misappropriated focus that is best described as a “tool versus task” distinction. Toxicity biomarkers are tools; developing and using them is not an end unto itself. The task that is desired is the best human health risk assessment, whether it is for pharmaceuticals or for any other types of products or human exposures. Toxicologists must continue to do what they have done well for so long: use the tools (toxicity biomarkers) to accomplish the ultimate task (human health risk assessment).

The well-established principles of dose–response, homeostasis, reversibility of toxicity, changes in blood clinical chemistries and hematological parameters, metabolite profiling of excreted xenobiotics and their metabolites, and so on, have both guided and served the toxicologist well. Until the definitional dust on “biomarkers” settles and the functional difference and purpose between therapeutic and toxicity biomarkers are widely acknowledged, toxicologists will continue to methodically do their tasks. They will determine hazards, define how xenobiotics change living organisms, and how living organisms change xenobiotics. It is less important to call the tool that one is using a shovel or a scoop or a spade or a trowel than it is to accomplish the task of digging the hole.