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Witness Testimony
Dr. Lance A. Liotta M.D.,Ph.D.
NIH Ethics Concerns: Consulting Arrangements and Outside Awards.
Thank you Chairman Greenwood and Members of the Committee for the opportunity to appear before you today to discuss my role as a scientist at the NIH and my various collaborative efforts. I grew up loving science. My father was a science high school teacher. Both of my parents encouraged my inquisitiveness and creativity. I began inventing things at an early age. By college I was spending my summers working and inventing solutions for the Dupont Corporation at its Experimental Station in Wilmington, Delaware. I have always had a passion to be an inventor, and today I have over 80 patents and patents pending, which list me as an inventor. My interest in medical diagnostics and pathology began during my undergraduate years (1965-1969). At that time I began doing research that led to patents for diagnostic test technology for infectious disease, as well as, general blood and body fluid testing methodologies. While in medical school, I was employed part time as a medical laboratory technician for the medical student health clinic. I was responsible for blood, culture and urine analysis, including the report generation. This training allowed me to gain exposure and expertise within the broad field of diagnostic testing methodology, and pathology diagnostic service labs. I received my Ph.D. in Biomedical Engineering from Case Western Reserve University ("CWRU") in 1974. Two years later, I graduated from CWRU's M.D./Ph.D. program with my M.D. My Ph.D. work focused on mathematical modeling and experimental analysis of cancer invasion and metastasis. Cancer metastasis is the very definition of malignancy and causes this disease to be lethal. My Ph.D. allowed me to gain broad expertise in instrumentation, computer algorithms, mathematical modeling, and experimental animal models of cancer and analysis of clinical pathologic material. The results of my research convinced me that a major medical need was an improved understanding of when and why cancer becomes malignant. Because I was enrolled in the M.D./Ph.D. program, my Ph.D. research was supervised by both the Pathology Department of the Medical School and the Biomedical Engineering Department. In parallel with my Ph.D. studies, I worked to achieve an M.D. with an eye toward a career as a research pathologist. For this reason, I took special clinical rotations in diagnostic monitoring and diagnostic pathology laboratory services. When I considered the next stage of my career, the NIH intramural program offered a superb environment that would support my creative freedom to pursue research contributions that could benefit public health. Within 7 years of joining the NCI, as a pathology resident, I became Chief of the Laboratory of Pathology and Chief of the Section of Tumor Invasion and Metastasis, now part of the Center for Cancer Research. In these capacities I have three types of intramural duties: clinical service, training of research and clinical fellows, and cancer research. I am very proud of the outstanding clinical service provided by my laboratory staff to the NIH. We are responsible for all anatomic pathology service for the entire NIH. Our Lab hosts a world-class residency program. Here we recruit and train research-oriented pathologists who become academic leaders. My research contributions, supported by the NCI program, have generated more than 500 scholarly publications. This productivity is only a reflection of the wonderful colleagues and collaborators working in the special environment of the NIH, as well as the vision and support of the NCI and NIH leadership. I am proud to have further served the NIH as the Deputy Director for Intramural Research under NIH Director, Dr. Bernadine Healy. I played a major role in setting up the Intramural Human Genome Program. This job gave me a great appreciation of the significant ways in which the NIH environment has continued to attract top-notch minds. My research accomplishments to date span a wide range of scientific and clinical disciplines, including: Cancer Metastasis My work along with my collaborators is recognized as a groundbreaking effort to investigate the process of tumor invasion and metastasis at a molecular level. In the mid 1970s, we proposed and experimentally demonstrated the linkage between angiogenesis onset and tumor invasion and metastatic dissemination. We proposed the concept of metastasis suppressor genes. Consequently, scientists in my Laboratory of Pathology discovered a series of novel genes and proteins, which regulate cancer invasion and metastasis, thereby providing new strategies for cancer diagnosis and treatment. As a demonstration of the originality of these discoveries, all are covered by U.S. government-owned patents, both issued and filed. New Technology for Micro Analysis of Tissue My laboratory has invented technology in the fields of pathology diagnosis, microdissection and proteomics. Our group invented Laser Capture Microdissection (LCM), which was developed through a research CRADA (Cooperative Research and Development Agreement) with Arcturus, Inc. and, thereby, rapidly commercialized. This technology is now in use in more than 1000 labs worldwide. The technology has enabled investigators for the first time to make broad discoveries in genomics, functional genetics, and is now extending into personalized medicine. This partnership is a prime example of what the NIH CRADA mechanism is designed to do: turn bench research into practical applications. Clinical Proteomics Program We created the first joint agency initiative between the NCI and the FDA in 1998 to develop new technology for the discovery of proteins important for cancer diagnosis and therapy, using actual human tissue and body fluids. Dr. Emanuel Petricoin of the FDA and I serve as co-directors. This initiative is now called the NCI/FDA Clinical Proteomics Program (CPP). Individualized Cancer Therapy Under the CPP, we proposed that LCM, combined with a new type of protein array, also developed in the CPP, constituted a new paradigm for patient-tailored medicine. The promise of this approach is improved therapeutic efficacy with lower toxicity, using a panel of drug treatments, individualized for the patient's tumor. This technology has already been translated to use in patients. It is being applied to patient tissue biopsies, conducted before, during and after experimental therapy, as part of ongoing NCI Clinical Center Trials. Diagnostic Tools for Detection of Early-Stage Cancer Another major initiative has been in the field of early detection of cancer. In 1997, based on our initial studies, we hypothesized that a large number of previously undiscovered and unknown protein markers were generated in the tissue and spilled into the blood, as a record of the disease state or the physiologic state. This hypothesis predicted that cancer developing in the tissue contained or shed proteins, which could be used as a test for early diagnosis. Our challenge was not knowing the identities of these molecules. Proteomic Pattern Diagnostics In 1998, in order to explore the potential existence of this new list of diagnostic markers, we applied mass spectrometry for fingerprinting analysis of tissue and blood. This was a well-established technology, but had not yet been applied to microdissected tissue. Even though we did not know the identity (name, sequence) of the molecules underlying the pattern fingerprints we recognized that this data supported our hypothesis that a large treasure-trove of previously unknown diagnostic markers existed. In our early studies, we analyzed our mass spectral data using visual graphing and the pattern recognition software that was commercially available. As we reported publicly at the American Association of Cancer Research in 1999, our results indicated the existence of a rich source of unknown markers in cancer tissue. We also reported on the first evidence of mass spectral fingerprinting diagnosis of cancer. Prior to this public disclosure, the U.S. government filed patents on this concept. Our next step, during the fall of 1998 and spring of 1999, was to look in great depth at human serum samples from cancer and non-cancer patients, using a variety of analytical methods. We realized, based on our previous findings and expertise, that a large number of pattern recognition approaches existed for spectral analysis, including applications to mass spectrometry. Subsequently, under a government material transfer agreement, Correlogic Systems software was employed to analyze our mass spectral data. The result was a publication in the LANCET, describing the potential research feasibility of using mass spectral fingerprints in serum for early stage ovarian cancer detection. Based on this reduction to practice, a patent jointly owned by the U.S. Government and Correlogic was filed. I am named as an inventor on this application. This promising research collaboration was extended to explore additional research applications under a research CRADA. This CRADA did not include the identity of the molecules themselves, nor did it constrain the U.S. government from its ongoing evaluation and use of other pattern recognition methods. Instead, the CRADA was aimed at evaluating the use of Correlogic's software for additional research topics. The impact of this work from 1998 to 2002 is best exemplified by the fact that at the latest meeting of the American Association of Cancer Research, hundreds of scientists reported on exploring this field of proteomics pattern recognition, using a variety of methods. An Abundance of New Diagnostic Marker Candidates Our lab's consistent goal has been three-fold. 1) identification of the proteins predicted to exist by our original hypothesis, 2) continuous posting of our raw mass spectral data in the public domain, as a public service and with unfettered, full access (i.e., others have analyzed our raw data with their own pattern recognition methods and have published excellent results); and, 3) translation of these discoveries to patient benefit with the highest degree of scientific rigor, as rapidly as possible. To that end, under the CPP, we have recently invented next-generation technology (patent applications solely owned by the Government and advertised in the Federal Register), which allows us to amplify and identify the new molecules we proposed to exist. Through the use of this government technology, and in collaboration with colleagues in the NCI-Fredrick proteomics facility, we have now identified thousands of specific proteins with diagnostic potential, which were previously unknown to exist in the blood. Because the U.S. government is the steward of this information, we believe that it can have broad public health benefits and will stimulate the large diagnostic industry of the U.S. I have been the recipient of over 30 awards for achievement in cancer research and translational medicine. In addition, I have received numerous PHS Commissioned Corps awards, including the NIH Director's award, the Merit Award, the Distinguished Service Medal, the Meritorious Service Medal, the Surgeon General's Medallion, and the Surgeon General's Exemplary Service medal. Mr. Chairman, with the committee's permission, I would like to include my C.V., which provides further details concerning my publications, patents, and related career information. According to published information, this committee is investigating outside activities by NIH scientists. Because I have had outside activities during the course of my career, let me address this issue. I take my job as a dedicated public servant very seriously. I believe that I have upheld and maintained the highest ethical standards in all of my official capacity over the years as Chief of the Laboratory of Pathology, Chief of the Section of Tumor Invasion and Metastasis, and former Deputy Director for Intramural Research. At all times, I have endeavored to follow the regulations governing outside activities. I have consulted with the appropriate personnel within the NIH when guidance was needed with respect to such regulations. I would never knowingly engage in any conflict of interest and would immediately cease such activity if there were a change in circumstance that would lead me to believe that an approved outside activity had become one which involved a conflict. The research CRADA with Correlogic was signed in April 2002. At that time, Correlogic was a software company with an established proprietary pattern recognition software using a genetic algorithm with a lead cluster analysis. The purpose of the CRADA was to study the application of Correlogic's specific algorithm to analyze spectral data that had been generated and would be generated by the NCI/FDA Clinical Proteomics laboratory ("the Lab") from blood samples run on the commercially available SELDI-TOF mass spectrometer that the Lab had purchased in 1998. The CRADA's goal was to find unique discriminating patterns of unknown entities revealed by Correlogic's proprietary algorithm applied to raw mass spectral data the Lab had generated, and would generate. I began an NCI approved consulting with Biospect in December, 2002. My understanding was that Correlogic was a software company, in contrast with Biospect, that I understood to be a scientific instrument company. When I began consulting with Biospect, I understood Biospect was in the early stages of developing a new instrument and scientific technology which employed its proprietary chemistry to separate and identify molecules. I understood Biospect desired to explore the use of blood and body fluids from animal and human sources with the goal of discovering molecules for biological and medical applications. In view of new information obtained within the last week, I ended my outside activity with Biospect. This activity had been approved repeatedly by my supervisor and the NCI Deputy Ethics Counselor. During this past week I specifically learned that Biospect requested certain information from the NIH. For me, this caused concern. As a result, I terminated my relationship with Biospect effective immediately. When I first came to the Cancer Institute at the NIH in 1976 to join the pathology residency program, I was fresh out of medical school. I so loved the climate of intellectual freedom there, that I decided to stay. Here it is 28 years later. I am very proud to be a part of the NIH and the NCI. I am humbled in my hope that any of my contributions may have added to the international renown of those institutions. I have always been thrilled to work with colleagues who are so very dedicated to save lives and reduce suffering through the advancement of scientific knowledge. In closing, Mr. Chairman, I wish to express my gratitude to the CCR, NCI, NIH and PHS for giving me the opportunity to serve the public benefit within a special creative environment that respects its scientists as individuals. Here at the NIH a critical mass of scientists from multiple agencies can work together to further scientific knowledge and employ this knowledge for the common goal of saving lives. Related Documents |
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