The future

The Future

Henry N. Wagner, Jr

Within the next 20 years, nuclear medicine could become a major focus of medical practice and biomedi- cal research as medicine enters a new age of certainty, in which surgery, radiation, and chemotherapy wi l l only be used when a benefit is certain to result from the treatment. Not only in neuropsychiatric disease, but also in other diseases, such as cancer, disease wi l l be v iewed as molecular dissonance, or, a communica- t ion disorder. Cells become cancerous and people become anxious, neurotic, or even psychotic because specific tissue cells or neurons either do not get the r ight messages because of a deficiency in DNA transcription and wrong messages are produced, or because of a failure in reception of the correct messages carried to cells. Nuclear medicine makes i t possible to characterize these transmitters and receptors as they are distr ibuted throughout various parts of the l iving human body. No field of clinical medicine is better equipped to transfer the advances in molecular biology and genetics to the care of the sick. Nuclear medicine takes a physiological and biochemical, rather than an anatomical or ontological, v iew of disease. Disease is characterized as a statistically defined devia- t ion of one or more functions or regional biochemical processes from those of healthy people under circum- stances as close as possible to those of a person of the same sex and age as the patient. The emission of photons from radioactive tracers that can penetrate

from the inside of the body to external radiation detectors is what makes it possible to examine molecular interactions involving picomolar concentrations of molecules involved in biochemical interactions between macromolecular recognit ion sites, enzymes, and substrates wi th in different parts of the living body. Perturbations (stress tests) wi l l be increasingly used to detect abnormal responsiveness to external forces early in the course of a disease. Movement of the diagnostic process from an orientat ion toward anatomy to a more fundamental level, the molecular level, wi l l be the hallmark of medicine in the next mil lennium. Gross or histopathologic changes wi l l no longer suffice. Radiotracers wi l l be able to characterize plasma membrane and intracellular recognit ion sites and wi l l also provide in v ivo probes, making it possible to identify changes in specific genes, as well as their molecular expression, even before the disease or disorder has manifest itself by symptoms and physical signs. Such molecular characterization of disease in situ wi l l make i t possible to t reat the patient as an individual and not just as a representative member of a group of patients who have similar problems and have been labeled as having a particular disease. Diagnosis wi l l become increasingly specific despite the heteroge- neity of the present diagnostic labels. Copyright �9 1996by W,B. Saunders Company

W LL NUCLEAR MEDICINE remain the best kept secret in medicine? Or will its

principles and practice become a major force in the health care system of the next millennium? Up to now, the existence of nuclear medicine has required a certain amount of resistance to being ignored. Its proponents must now pro- claim its unique contribution to medicine by making it possible to examine the dynamic state of body constituents as reflected in every organ of the body. The emission of -/photons, which can be measured by radiation detectors outside of the living human body, remains the only successful way to measure regional function and its underlying biochemistry. Today, most measurements are of body fluids or biopsy speci-

From the Johns Hopkins Medical Institutions, Baltimore, MD.

Address reprint requests to Henry N. Wagner, Jr, MD, Johns Hopkins Medical Institutions, 600 North Wolfe St, Baltimore, MD 21287.

Copyright �9 1996 by W.B. Saunders Company 0001-2998/96/2603-000855. 00/0

mens. In the future, measurement of in vivo chemistry will become commonplace. Mol- ecules will become a focus, which will extend present studies of circulating cells, tissues, and organs.

One can hope (and expect) that the science and practice of nuclear medicine will continue its exponential growth that began 35 years ago and still shows no signs of plateauing, as is evident by the excellence of the presentations made at the annual meetings of the Society of Nuclear Medicine over the past two decades.

In his book, The Phenomenon of Man, the philosopher, Teilhard de Chardin, wrote: "The history of the living world can be summarized as the elaboration of ever more perfect eyes within a cosmos in which there is always something more to be seen." The history of nuclear medicine is characterized by the elaboration of ever more perfect tracers to examine regional body chemistry in the living human body, in which there is always something more to be seen.

Whenever one can measure a biochemical

194 Seminars in Nuclear Medicine, Vol XXVl, No 3 (July), 1996: pp 194-200

THE FUTURE OF NUCLEAR MEDICINE 195

process within the body, there is, in theory, at least two diseases, one in which the process is abnormally slow and the other in which the process is abnormally fast.

By defining disease on the basis of chemistry, nuclear medicine is in an excellent position to characterize the biochemical reactions involving thousands of different molecules that comprise the living human body. In the socioeconomic domain, no field of medicine is better able to respond to the new demands of the public and health care providers for more certainty in diagnosis and in treatment.

Uncertainty is what makes medical care so expensive. Nuclear medicine increases certainty by increasing specificity and quantifiability of diagnosis, better decision making about treatment, and a way to quickly monitor whether the treatment is or is not helpful.

In his best-selling book, How We Die, Ameri- can surgeon, Sherwin Nuland, has written:

Some believe that doctors always know exactly what they are doing, that uncertainty is utterly alien to the superspecialists who treat the most seriously ill people in the hospital. They are convinced, and the more high-tech the doctor, the more their patients are convinced that the men and women who treat them always have very good scientific reasons for recommend- ing the courses of action they do . . . Sometimes it is really to maintain his own hope that the doctor deludes himself into a course of action whose odds of success seem too small to justi~ embarking on it.

Today, patients, their families, the public, and those responsible for funding health care want to be more certain about the value of diagnostic and therapeutic procedures. They are insisting on knowing whether a diagnostic study performs according to its specifications, whether it measures what it is supposed to measure, and whether decisions based on the information provided by the procedures are the correct ones.

More than ever before, nuclear medicine physicians will have to answer these questions: What is nuclear medicine? What does it do? How do specific nuclear medicine procedures help solve a clinical problem? How do they affect the entire health care system?

We must educate not only those physicians who have the primary responsibility for the care of the patient, but we must also educate the

public, the political leaders, and the health planners on how the data that nuclear medicine provides effect patient care and how the data help in decision-making and outcomes. We will have to address the fact that, in many cases, nuclear medicine procedures eliminate the need for other studies, some of which are in wide- spread use despite their poor performance in addressing specific problems, such as the diagnosis of metastatic cancer or the effectiveness of surgery. The most valuable studies are those that change conventional wisdom, leading to better, more certain treatment and improved patient survival or quality of life.

The use of radioactive tracers in medicine is comparable with the invention of the chemical balance and the discovery of x-rays. The tracer principle, that is, the monitoring of molecules as they participate in the dynamic state of body constituents, led to a whole new approach to biology and medicine, characterizing the chemistry of growth, development, and maintenance of life in experimental animals and living human beings. No other method has the sensitivity, specificity, and quantifiability in the characterization of in situ chemistry.

The great experimental physiologist, Claude Bernard (1813-1878), devoted his life to try to understand, in terms of physics and chemistry, the processes by which we live, by which we become ill, by which we are healed, and by which we die. The ability to trace the chemistry of cells and extracellular fluid of every organ of the body made Bernard's philosophy the founda- tion of biology and medicine. Bernard argued that chemistry holds the secret of health, that the human body is a mass of interacting chemicals, that its diseases are essentially chemical disorders, and that their remedies lie in chemistry.

Bernard taught that, "All the vital mechanisms of the body have but one object: to preserve constant conditions of life in the inter- nal environment." The invention of radiotracers proved that this apparent constancy of body fluids was, in fact, a dynamic equilibrium in which the rate of formation and the rate of breakdown of body constituents are in a deli- cate balance, constantly maintained in the battle against the second law of thermodynamics de-

196 HENRY N. WAGNER

spite the continual need to take in oxygen and food to provide energy; they make it possible to produce the molecules that make up the struc- ture of the body and coordinate its innumerable processes through thousands of different chemical messengers, some acting locally and others traveling throughout the body until they "bump, fit, and stick" against the sites that specifically recognize them.

No other field of medicine has a greater ability to define disease as a problem in the coordinating and balancing of the billions of chemical reactions involved in the normal func- tioning of ceils and tissues of the body. Histori- cally, whenever a biological or clinical finding has been made, whether the finding be physiological, pathological, or clinical, scientists try to interpret the observed phenomenon in terms of chemistry. As modern medicine becomes molecular as well as cellular in its orientation, nuclear medicine can move into the forefront and can increasingly be defined as molecular nuclear medicine.

As in the past, advances in nuclear medicine will require advances along two principal lines: the development of improved radiation detection, data processing, and display systems; and the production of new radiotracers.

Consider the example of Parkinson's disease. Since the first imaging of dopamine receptors in 1983, there has been a steady increase in the characterization of how the dopaminergic system is involved in patients with movement and other disorders. It is now possible to examine all aspects of dopamine neurotransmission: the synthesis of dopamine with fluorine-18 levo- dopa; the secretion of dopamine from the presynaptic neurons; the metabolism of dopamine by the monoamine oxidase enzyme system; and the reuptake of unbound dopamine from the synapse by the presynaptic dopamine trans- porter. Such measurements can sort out from the heterogeneous sea of patients with movement disorders those with senile Parkinson's disease, striatonigral degeneration, traumatic Parkinson's disease, progressive supranuclear palsy, and idiopathic Parkinson's disease. In classical Parkinson's disease, even in its earliest stages, there is a deficiency of the dopaminergic presynaptic neurons. This finding makes it possible to select specific patients for putative

pharmacological treatment to arrest or reverse the disease, to monitor the effect of the treatment in drug design and development, and, subsequently, to select those patients who will benefit from specific chemotherapy. In patients with idiopathic Parkinson's disease, D1 and D2 dopamine receptors are normal; in striatonigral degeneration, there is degeneration of postsynaptic dopaminergic neurons. Early studies with the neurotoxin MPTP injected into a carotid artery of baboons left postsynaptic receptors intact, but destroyed presynaptic neurons. In the earliest stage of Parkinson's disease, when only half of the body is involved, there are major deficiencies in presynaptic neurons on both sides of the brain documenting that the radiotracer studies are more sensitive than clinical manifestations. Using the tracer 11C WIN 35428, even in patients with stage I Parkinson's disease (when half of the body function remains normal), there are striking reductions in the bind- ing of the tracer to the transporters in the anterior and particularly the posterior putamen compared with normal persons. The striking abnormalities in the biochemistry of both sides of the brain in patients with hemi-Parkinson's disease, even though one side remains unaf- fected in terms of physical signs and symptoms, illustrates the better sensitivity of chemical versus clinical characterization of the patients.

The clinical manifestations of Parkinson's disease are correlated to the degree of impair- ment of dopaminergic presynaptic neurons. Be- cause drugs, such as monoamine oxidase inhibitors, are effective if treatment is begun early in Parkinson's disease, the finding of the great sensitivity of a molecular diagnosis before symptoms of Parkinson's disease represents one of the most important advances in neurology in the past two decades. The accumulation of both positron and single-photon-emitting radiotracers that bind to dopamine transporters can be used as markers to examine the role of genetic and environmental factors in Parkinson's disease.

This regional molecular approach to diagnosis is being taken in studies of patients with other neuropsychiatric diseases, including cogni- tive disorders, depression, and others. The ini- tial results are equally interesting and important.


Cancer can also be viewed as a communication disorder. Not only mental health, but life itself is maintained because atoms and molecules can recognize each other. Radioactive tracers are "molecules with messages," starting with radiolabeled mRNA and extending up to radiolabeled hormones and neurotransmitters. They make it possible to characterize disease in the light of information transfer within and between ceils and to examine what happens to chemical substrates, which provide the enormous amount of energy required to resist increasing entropy.

The process of communication amongst the cells of living human beings evolved from the molecules that play similar roles in unicellular organisms. One way of looking at cancer is that it is a process of dedifferentiation of the aerobic biochemical processes back to a more primitive anerobic state reflected in the avid accumulation of deoxyglucose by tumor cells. It is also becoming increasingly clear that primitive membrane receptors are often expressed in great numbers in cancer cells, which is again probably the result of dedifferentiation. The fact that so many neuroreceptors have been found on so many different types of neoplasms leads one to view the human nervous system as having evolved from unicellular organisms to facilitate intercellular molecular communication.

Many types of cancer can be detected by the increased expression of these plasma membrane receptors to substances such as somatosta- tin (SS) or vasoactive intestinal peptide (VIP). It is likely that it will soon be possible to characterize intracellular communication systems, beginning with DNA and nRNA, in addi- tion to membrane-recognition protein systems and their specific messengers. Cells become cancerous because they do not get the correct messages, either because of mutations in the DNA transcription process or because of a failure in execution of the molecular instruc- tions. Studies of small peptide molecules and oligonucleotides are underway in research labo- ratories in industries and universities throughout the world. The effects of antisense oligonucleotides and the molecular deficiencies in gene "knock out" experiments are also subjects of current research.

Hippocrates wrote, "It is disgraceful in every

art and more especially in medicine, after much trouble, much display and much talk, to do no good after all." The practical value of radiotracer studies in the care of patients with cancer can be summarized as follows: (1) detecting an unknown primary site of cancer in a patient found to have metastases, eg, in lymph nodes; (2) differentiating benign from malignant le- sions; (3) grading the degree of malignancy; (4) staging the extent of disease; (5) assessing the response to treatment; and (6) detecting recur- rent disease.

Pharmacologist Louis Lasagna wrote, "Often we don't know how to tailor specific drugs to specific patients very well; we could do that better and make a quantum jump in efficacy without even coming up with any new drugs." Nuclear medicine procedures make this possible.

A German colleague expressed it differently, "If two patients receive the same treatment, at least one of them will be treated wrongly." People are unique individuals and must be cared for as individuals, not according to statis- tical criteria.

In the future, detection systems will extend from whole-body nuclear imaging systems to the use of a small region of interest imaging systems that can be used within the operating room itself. In patients with cancer, whole-body imaging is frequently needed.

History repeats itself because no one listens the first time. My image of nuclear medicine is that of a tree, the trunk of which rests on an infrastructure soil of basic sciences. The trunk is molecular nuclear medicine, regional physiol- ogy, and regional biochemistry, from which branches extend to other specialties, such as cardiology, oncology, radiology, and others. For the tree to bear fruit in its greatest abundance, both the trunk and the branches must be strong.

The difficulty lies not in new ideas, but in escaping the old ones. In the early days of nuclear medicine, we defined radioisotope scanning as "the visualization of previously invisible organs by means of radioactive tracers"--an anatomical orientation. Today, nuclear medicine can be defined as topographic physiological chemistry resting on an infrastructure of physics, mathematics, and communication sciences.

The fundamental principles of nuclear medi-

198 HENRY N. WAGNER

cine were established by pioneers such as Georg Hevesy, Ernest and John Lawrence, and their many collaborators and intellectual descen- dants. The biochemical orientation of the field was interrupted by an orientation toward anatomy in the 1950s because radioisotope scanning made possible for the first time the visualization of organs that could not at the time be examined by conventional radiography. Ra- diotracers, such as carbon 11, were put on a back burner and technetium 99m was moved into prominence, with great success. Today, and in the next millenium, regional chemistry will be the essence of the field with the data displayed as functional or biochemical images.

Nuclear medicine is becoming more and more oriented toward genes as the principal determi- nant of human biology and the study of human disease. Genes not only affect the transmission of heredity, but also the expression of body constituents in response to the environment. The principles and technology of nuclear medicine make it possible to examine the effects of genetic expression in health and disease. In essence, genetics is a whole new way to view disease and nuclear medicine is a whole new way to view genetics.

Nuclear medicine was the first clinical spe- cialty to draw on the use of computers and information technology to examine the enormous numbers of information-bearing photons coming from radiotracers within the living human body. Information sciences will be increasingly important in taking advantage of the hundreds of millions of pieces of such data coming from within the body to reveal and characterize regional biochemistry and function within all the organs of the body. Modern information technology must remain in the forefront of every nuclear medicine program.

To be able to bring about a whole new way of practicing medicine, nuclear medicine academi- cians and practitioners must develop clearly stated, highly targeted goals and then pursue them vigorously and collectively. Only then will the standing of nuclear medicine rise in the eyes of the medical and scientific communities and the public. Enormous changes are now taking place in the scientific and political environment and in the face of increasingly limited resources in any one particular country. We must better

present the case for nuclear medicine to the public and to physicians all over the world~ Only then will nuclear medicine become a major force in medicine for future generations. We need to ask ourselves: What should we be doing that is different from what we have done in the past?

TEN PREDICTIONS

Prediction #1

Advances in molecular and physical genetics will be translated into medical practice using measurements of regional biochemistry and function by means of radioactive tracers, as well as by use of recombinant DNA methods and other genetic techniques. Just as molecular genetics will revolutionize the practice of medicine, so also will nuclear medicine revolutionize the practice of molecular genetics.

Prediction #2

Regional measurements of the biochemistry of the entire body with radioactive tracers wilt make it possible to assess the response of celts and organs to stimulation by function promot- ers, such as SS or growth factors, or function inhibitors, such as VIP or growth inhibitors. Measurement of in vivo chemistry will become as prevalent as biochemical examination of blood and urine is today.

Prediction #3

Characterization of abnormal regional chemistry will play a major role in the design and development of drugs and in the planning and monitoring of drug treatment in individual patients.

Prediction #4

After the mapping of the human genome has been completed, diseases will be linked to genetic mutations in human beings by radiotracer measurements of the functions of the products of the specific genes in living human beings. Chemotyping will link genotyping and phenotyping.

Prediction #5

The relative roles of genetic and environmental factors in specific diseases, such as hyperten- sion, diabetes, and mental illness, will be clari-


fled using radiotracers to measure homeostatic processes to serve as genetic markers. Genetic analysis based on quantitative measurements of in situ chemical reactions and the effects of perturbations of these chemical reactions will be commonplace in medical practice. Homeo- static processes characterized by radiotracer studies will make it possible to examine the genetics of these homeostatic mechanisms, re- pair processes, and other functions.

Prediction #6

Molecular nuclear medicine will define diseases as abnormal regional chemistry and not just as abnormal molecules, identifying patients by molecular phenotypes. Radiotracer studies will be used to tell us directly, after a gene mutation has been found to be associated with the clinical manifestations of disease, how the abnormal gene functions.

Prediction #7

Characterization of diseases will be much more precise, based on quantifiable, biochemical regional abnormalities. Up to now, the definition of disease has often been imprecise. Radioactive tracer studies, particularly when combined with perturbations, can provide precise characterization of disease. Genetic analysis requires an exact definition of disease that can form the basis of a gene hunt. An abnormal- ity will be identified as the failure to respond properly to a standardized perturbation, such as the administration of a nutritional substrate or a drug. Study of the genetics of these homeostatic deficiencies calls for analyses radically different from those of classical quantitative genetics, in which one searches for an abnormal molecule resulting from a mutation. Homeostatic processes operate at many levels of organization extending from molecules to the whole body. Breakdown in any feedback process can be considered a disease. As E.A. Murphy stated:

The ability of radioactive tracers to measure in situ biochemical processes and their response to perturbations can provide the measurements that can be used as markers in genetic studies. Genetically determined homeostatic processes can be affected by mutations that affect the lag time or the strength of the correcting process . . . the ubiquity of physiological homeostatic processes explains why classical quantitative and popu- lation genetics have done so little to clarify the causes

of human disease and may have even obscured genetic components . . . the neurosciences and psychiatry are ripe for studying physiological homeostasis. Radioac- tive tracers can be used to detect those persons with subclinica ! regional as well as global defects and can be appropriate markers for family studies and gene mapping.

Prediction #8

The war on cancer, which began with the signing by President Nixon of the National Cancer Act in 1971, is not over. Within 10 years, nuclear oncology will have the same impact on oncology as nuclear cardiology has had on cardiology. More will be known about whether environmental toxins or random errors in DNA replications are the causes of cancer. For example, it is now known that ultraviolet light mutates skin-cell p53 genes that normally sup- press skin-cell growth.

Within several decades, we will be able to target specific drugs to specific cancer-causing genes and determine the effects using radiotracer methods. Treatment will be directed toward the biochemical effects produced by cancer-causing mutations.

Prediction #9

Nuclear medicine will provide a whole new way of looking at disease. Most diseases are not invasions of the body, but normal defense mechanisms that have gone wrong. Today, most physicians think of disease as a biologically unique entity caused by identifiable, specific causes. Modern nuclear medicine looks at the whole person and views disease as an imbalance in regional biochemistry brought about by the expression of genes. The body will be increasingly viewed as an orchestra of chemicals that determine the symphony of our thoughts and behavior.

Prediction #10

Nuclear medicine will be able to detect chemical correlates of behavioral traits and diseases, as well as somatic diseases, and focus on neuro- biological as well as socioeconomic and political factors in neuropsychiatric diseases.

WHAT NEEDS TO BE DONE

Lincoln admonished us, "If we can first determine where we are and whither we are tending,

200 HENRY N. WAGNER

then we will best know what to do and how to do it." A basic question in genetics today is the relationship between genotype and phenotype. What happens when a gene is activated or inactivated? Mapping of chromosomes makes it possible to relate traits and certain diseases to chromosomal segments. From a library of DNA segments, it is possible to fish out the genes related to human traits and diseases. Nuclear medicine can tell us the biochemical function of specific genes.

Of the 12,000 genes and 120 million base pairs in fruit flys, 4,000 different mutations and the expression known for many of the genes have been identified. Nuclear medicine makes it possible to derive the same information for human beings; that is, to identify the function of many of the 3 billion human base pairs to be identified within the next 20 years.

To meet the needs of the future, nuclear medicine needs to continue to develop new approaches to radioisotope production, rapid syntheses of new radiopharmaceuticals, both positron emitters and single-photon emitters, specialized medical-imaging instruments, such as those for use in surgery, and new clinical applications of regional biochemical and function measurements. We need quantitative assess- ment of the effectiveness of nuclear medicine procedures in diagnosis, prognosis, and in the planning and monitoring of treatment. The goal must include continued studies of how the concepts, resources, and technologies being de- veloped in structural and molecular biology and human genome research can be applied to the study, diagnosis, and treatment of disease.

FEAR OF RADIATION

To many persons, the word technology con- jures up images of Three Mile Island, Cher- nobyl, thalidomide, Exxon Valdez, Challenger, and atomic bombs. The word radiation strikes a negative response in almost everyone. Technol-

ogy in general and radiation in particular are perceived to be the problem, not the solution to problems, and something to be avoided at all costs rather than to be embraced. Therefore, innovators in nuclear medicine must deal with societal and political forces as well as science and technology. They must deal with the laws of the land as well as the laws of nature.

Not understanding the role of science and the scientific method and not understanding that ionizing radiation is a part of life itself, most people are beset by anxiety and feelings of insecurity. They become victims of propaganda rather than participants in the debate of ideas. They feel increasingly impotent and unhappy as society is more and more dominated by technology. They eventually succumb to popular cul- ture, their lives dominated by television and sports.

Recent advances in understanding the effects of radiation on biological systems can improve our thinking, feeling, and behavior with respect to radiation issues. We are beginning to learn what it means to use radiation safely and effectively, we can see better the positive aspects of radiation and controlling our brain chemistry, instead of simply lecturing our chil- dren about the negative aspects.

The truth is that radiation is never inherently good or bad, safe nor dangerous. Too often people follow the policy, "do not prohibit what I want, prohibit what I do not want." Society has always been involved in establishing rules that govern the use of potentially harmful substances or activities. Decisions and actions must always be based explicitly or implicitly on ethi- cal and moral foundations.

In Tragic Choices, Guido Calabresi and Philip Bobbitt stated, " . . . it is by the values that are foregone no less than by those that are pre- served at tremendous cost that we know a society's character."

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