Six years ago, the chair of the newly formed Department of Molecular and Medical Pharmacology at the University of California, Los Angeles, convinced the dean of the medical school to put nuclear medicine into pharmacology as a division within the department.
The fact that he succeeded in accomplishing this radical reconfiguration was aided no doubt by the fact that the request came from one of the inventors of positron emission tomography (PET), Michael E. Phelps, PhD.
Since that time, this department has evolved into what Phelps describes as a self-contained culture of medicine. It incorporates the old pharmacology department and includes the Division of Nuclear Medicine, the Crump Institute for Biological Imaging, the UCLA/Department of Energy Laboratory of Structural Biology and Molecular Medicine, and the Ahmanson Biological Imaging Center.
“It does make sense,” explains Johannes Czernin, MD, board certified in nuclear medicine and director of the Ahmanson Biological Imaging Center. “The biological imaging probes we are using are radiopharmaceuticals that typically originate from pharmacology and the pharmaceutical industry. We can use these radiopharmaceuticals to image biological processes of living organisms.”
Phelps, whose doctorate is in chemistry, uniquely holds six academic positions at UCLA and has been on the faculty of the University of California since 1976. In addition to serving as the chairman of the Department of Molecular and Medical Pharmacology and holding an endowed professorship-the Norton Simon-he is also the director of the Crump Institute for Biological Imaging, professor of biomathematics, the associate director of the Laboratory of Structural Biology and Molecular Medicine, and the chief of nuclear medicine. He also has published more than 500 scientific articles, books, and book chapters and spearheaded, as principal investigator, more than $120 million in grants.
This past February, President Clinton announced Phelps as a winner of the Enrico Fermi Award, given for a lifetime of achievement in the field of nuclear energy. The Fermi award is the government’s oldest science and technology prize. Phelps earned the award for his invention and use of PET. Recently, he was elected to the National Academy of Sciences.
It is unusual for nuclear medicine to be a part of pharmacology, but the nature of the research performed in this department is not routine. “Medical research is creating a new discipline of in vivo analysis,” Phelps explains. “It is our belief that merging biology and genetics with pharmacology and imaging is fundamental in integrative biology and in vivo research. With this department, we have the technology and the knowledge to begin exploring the life-sustaining biological mechanisms that regulate organ functions of the body, to investigate the molecular errors of disease, and to work on creating the pharmacological means to correct them.
“Biological imaging provides the means to watch and measure the integrated organization and function of organ systems and whole organisms, ranging from the molecular assembly of viruses to the biological function of organ systems in humans in health and disease.
“We can build imaging technologies within the Crump Institute, we can build imaging or drug molecules through pharmacology, we can expand our research within the Laboratory of Structural Biology and Molecular Medicine, and we can produce novel biological imaging examinations for our patients in our clinic, all within the organization we have assembled.”
CREATING A NEW DISCIPLINE
The structure of Phelps’ department is based on the hypothesis that all disease is caused by some factor that alters the expression of the genome. “The new field of molecular medicine resulting from the merger of biology and medicine works on the hypothesis that disease is caused by an interaction of the genome with the environment: the environment, or aging, introduces changes in the instructions to cells from gene expression that change their phenotypic function to those of disease processes,” Phelps begins. “Molecular medicine seeks to reset, block, or terminate these instructions, or errors of disease, that cause organ systems to fail. In the nuclear medicine clinic, we use labeled molecules-sugars, amino acids, proteins, nucleic acids, the life-sustaining molecules of our body-to take pictures of the living biological and genetic processes within the organ systems in our body to identify the fundamental nature of disease, its early detection, and biological characterization, to guide the design and use of therapeutic intervention.
“Nuclear medicine now forms alliances with genetics, pharmacology, and molecular biology. This is one of the ways we are different from radiology, which has tended to be more oriented to physicists and computer scientists. while nuclear medicine includes a lot of biologists, chemists, and physicists. We, of course, are also closely affiliated with the Department of Medicine. Radiology, however, is beginning to work towards the concept of biological imaging as well, but what is unique to us is that we actually label molecules, which biologists, geneticists, and pharmacologists and the pharmaceutical industry study and use.”
Although it made sense in the context of science and the overall structure of the UCLA School of Medicine, moving nuclear medicine into pharmacology was painful for radiology. “It was initially hard for our colleagues in radiology at UCLA to accept moving nuclear medicine out of radiology and into pharmacology,” Phelps says. “Since then, we have developed our own school of thought and our own vision. Now we work hard to be good partners with radiology, to work together to build a broader community of medical imaging.”
BUILDING A NEW DEPARTMENT
The Department of Molecular and Medical Pharmacology is one of UCLA’s most successful research departments. The faculty has research funding in excess of $20 million dollars per year. Research is conducted within all components of the department, from basic molecular and cellular biology to pharmacology, virology, immunology, gene therapy, and biological imaging and nuclear medicine.
The Crump Institute, a science and technology center, merges biology and genetics with imaging to develop new imaging technologies and procedures of biological imaging in a broad context. Included are such state-of-the art technologies as three-dimensional image reconstruction with cryo-electron microscopy, confocal fluorescent microscopy, autoradiography, and micro-PET scanners in an imaging environment that includes viruses and cells to rodents and monkeys.
The Laboratory of Structural Biology and Molecular Medicine, which has been supported by the Department of Energy since 1951, merges biology and genetics with medicine and focuses on the biological imaging of mice to man. A large basic and clinical research program operates within the confines of this laboratory. The focus of research includes investigation into the basic biomedical sciences including protein structure and function, receptor systems, biosynthetic and metabolic enzymes, design of molecular probes and drugs, development of PET scanners for humans, and the study of human diseases, from Alzheimer, epilepsy, and Parkinson to cardiovascular disease and various cancers.
The Ahmanson Biological Imaging Center, directed by Czernin, operates as a nuclear medicine clinic where biological imaging procedures are used in the study and care of patients with a wide variety of diseases. This clinic serves as a bridge between the research and technology developed within the Department of Molecular and Medical Pharmacology, and the Laboratory of Structural Biology and Molecular Medicine, and is the place where the research is used to define and advance the role of nuclear medicine in the care of patients.
THE CLINICAL MISSION
The focus at Ahmanson is to conduct clinical research and trials and to provide optimal patient care utilizing the most modern technology. “I am leading the PET oncology research,” Czernin explains. More specifically, that includes research regarding the utilization of PET in lung and breast cancer and the impact of PET imaging on the management of patients with cancer. The resulting data have provided Phelps with the evidence required to help widen indications for the use of PET approved by the Health Care Financing Administration (HCFA), where Phelps is a well-known and frequent visitor.
Regarding rates of reimbursement, the clinic is doing better with PET than with conventional nuclear medicine now that Medicare is paying for approved PET scans. HCFA recently has approved reimbursement for three new oncological indications for PET procedures: detection and localization of recurrent colorectal cancer; staging and characterization of both Hodgkin and non-Hodgkin lymphoma; and staging melanoma, expanding existing coverage for lung cancer and cardiovascular disease.
“Collection rates for conventional nuclear medicine are 25% to 30% of what we charge,” Czernin explains. “With PET, it is closer to 60%: With a Medicare rate of about $2,000 and 45 to 50 minutes for a whole body scan, we work conscientiously to use PET in the most cost-effective manner to improve patient care. Although expensive for a single test, this scan can help to avoid or reduce the number of other diagnostic tests, reduce surgeries, and change patient management in a cost-effective manner that also provides better patient care. Numerous clinical trials have shown that PET can substantially reduce the costs of diagnostic evaluations and treatments and improve the quality of patient care. For example, in numerous cancers, PET has been shown to have an accuracy that is 15% to 20% higher than conventional workups for detection and staging, and to change the management in about 30% of the cases. However, since you need more time to study each patient, and since the procedure is costly, you must be very selective and utilize PET wisely.”
About 8,000 patients are seen at the clinic annually, according to Czernin. Of these, approximately 1,500 are examined with PET. The remainder are imaged with conventional nuclear medicine techniques, such as planar gamma camera imaging and SPECT (single photon emission computed tomography). Dual head gamma camera systems with coincidence detection also are utilized.
According to Czernin, the most frequently performed procedures at the clinic are (in order): 1) stress-rest myocardial perfusion studies with SPECT; 2) bone imaging; 3) renal imaging; 4) thyroid imaging; 5) tumor imaging; 6) brain perfusion imaging; and 7) lung perfusion ventilation imaging. The most frequently performed PET studies are for cancer, dementia, cardiovascular disease, and epilepsy and Parkinson disease.
As the clinic director, Czernin straddles the rarefied world of research and the real world of health care today, albeit in a relatively sheltered academic environment. “The technology of medicine is advancing rapidly,” he notes. “What is gloomy about medicine right now is the health care business and administration. Many physicians are disillusioned because they have been robbed of their freedom to decide what is best for their patients. Also, reimbursement rates in nuclear medicine have dropped by a factor of 3 over the previous 5 years on the professional side. The professional component of a PET scan ($2,000) ranges from $79 to $110. Eventually, patients will demand reform in health care management.”
STRAIGHT TO THE SOURCE
Historically, drugs and other medical treatments are developed to modify the symptoms of disease since the source of the problem is often unknown. Phelps believes that the focus of medicine is shifting from treating symptoms to identifying and correcting the molecular errors that have produced the disease. “In molecular medicine we have entered a new world,” Phelps asserts. “Molecules are being developed as drugs that will be designed with the growing knowledge of identifying the original errors of disease and correcting them. Biological scientists are coming together with medicine in a way that will change medicine forever. PET is one of the biological imaging techniques of the new molecular medicine.”
PET’s efficacy in determining whether cancer has metastasized was acknowledged by HCFA’s recent approval of three new indications for PET. “With PET we developed ways to identify the metabolic basis of disease by observing a labeled analog of glucose, one of the most common substrates in our body, used to generate energy for cellular function,” Phelps notes. “PET provides metabolic images of the entire body, that is, all organ systems of the body can be inspected for the presence of disease in a single examination. Cancer biologists learned that with tumor cells, the more malignant they are, the higher the glycolytic rates, establishing a relationship between the rate of metabolism and the aggressiveness of the tumor. This provides the means to identify disease, differentiate benign from malignant lesions, determine the degree and extent of metastases, including silent asymptomatic disease, and evaluate therapeutic responses by separating tumor from edema and necrosis.
“Cancer is a systemic disease because it metastasizes, causing cancer to change from a local treatable disease in most cases to a very complicated medical problem with poor prognosis. When the gene expression allows cells to migrate, this changes the whole picture. We take labeled molecules of glucose and inspect the lungs, colorectal system, breasts, ovaries, brain, kidneys, lymphatic system, bones, and other organ systems to identify the primary tumor as well as the distributed sites of metastases. Most metastases give no symptoms and can remain asymptomatic for a long time. Because we inspect all organ systems and do not need symptoms to direct our procedure to an organ system, we identify silent disease routinely, providing more accurate staging. New biological imaging probes are now being developed to identify cancer before cells become highly malignant and the signal in the genome comes on to instruct the cancer cells to migrate into metastatic disease.”
The development of techniques that allow researchers to image gene expression in vivo could greatly accelerate medical research and drug development. A current focus of coordinated research at the Crump Institute for Biological Imaging and the Laboratory of Structural Biology and Molecular Medicine centers on the development of such a technique. Scientists there created micro-PET, a miniaturized high-resolution PET scanner for mice and monkeys. “We know that molecular errors occur that produce disease by altering and maintaining a change in the patterns of genes expressed in the genome, which provide instructions of disease via messenger RNA,” Phelps explains. “By imaging the patterns of gene expression within organ systems of the body in vivo, we will be able to identify and understand the early, even asymptomatic and silent changes, as diseases begin their insidious process of organ dysfunction.
“Although hereditary disease potentially produces genetic abnormalities in all cells, most diseases result from alteration within specific organs by interactions with specific agents in the environment, such as carcinogens, viruses, and bacteria. Thus, imaging is ideally suited because individual organ systems can be examined. This information can be used to guide the development and use of gene therapies, as well as other approaches to correct the problem.”
UPHEAVAL IN HEALTH CARE
At a time when much of medicine is facing an economic crisis, Phelps observes a tremendous social and economic upheaval occurring in health care. “Seventy percent of the research and development from all sources in the United States is going into computers, electronics communications technology, and biotechnology,” Phelps notes. “The biotechnology efforts are in the areas of material sciences, agriculture, medicine, forensics, and health. The portion of biotechnologies that is focusing on identifying the errors of disease and producing new therapies is now coming together with the computer and communications industries to produce new devices and technologies that can rapidly identify genes, read out patterns of gene expression and protein products, and produce molecules that can modify or correct the errors of disease.
“All of these efforts are of great benefit to biological imaging because they identify the molecular targets of disease and produce candidate biological imaging probes that can be used to study and diagnose disease. A synergy is developing between the pharmaceutical imaging industries, in which molecules that result from this effort can be used in near massless quantities as probes to image the function of a target molecule of disease, and the mass of the same molecule can be increased to modify the function of the target as a drug, be it conventional or gene therapy.”
Phelps’ biological imaging concept for the UCLA School of Medicine’s Department of Molecular and Medical Pharmacology was revolutionary when it was introduced 6 years ago. However, other major medical institutions are beginning to follow suit. According to Phelps, the California Institute of Technology, Pasadena, recently started a program in the Beckman Institute for Biological Imaging. The Whitehead Institute at the Massachusetts Institute of Technology, Cambridge, one of the leading biological institutes in the United States, also started a program called Biological Imaging. “The Howard Hughes Medical Institute, which funds the Hughes Investigators, a group of some of the most distinguished biological scientists in the United States, is now talking about bringing the physical sciences together with the biological sciences to understand how organ systems work within organisms,” Phelps adds. “Biological imaging is a part of the concept they are developing. Congress and the National Institutes of Health are debating the formation of a new Institute for Biological Imaging.”
When asked about the future of nuclear medicine, both Phelps and Czernin see a continued merging of nuclear medicine and biology to further the biological imaging concept of nuclear medicine. “It has been a difficult and long process,” Phelps says. “The revolutionary concept of molecular medicine is moving forward and PET is part of this movement, in its scientific foundation and in the biological imaging examinations it provides in implementing these new concepts in health care.”
Sabine Kremp is a contributing writer for Decisions in Axis Imaging News.