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PHILIPS MEDICAL SYSTEMS

Molecular Imaging and Diagnostics – realizing preventive medicine

A positioning paper for Philips Medical Systems in MID Abstract: The rapid development of clinical diagnostic imaging technology, in tandem with medical and pharmaceutical research, has led to some major advances in healthcare. One truly remarkable example is molecular imaging, which together with its associated discipline of molecular diagnostics, is showing great potential for early detection of disease states, to the extent that clinicians can almost literally halt the development of illness occurring in a human being. Understandably, manufacturers of diagnostic equipment and software, pharmaceutical companies and other specialized industries are working togeth er – and competing – in the race to bring molecular imaging and diagnostic products and services to market. Moreover, clinical research centers in close co-operation with the other major players have a very important role. Philips Medical Systems, a world leader in medical diagnostic and healthcare equipment is making the investment to become a major force in helping to realize the potential of molecular imaging and diagnostics. This paper discusses the development of this field of medicine, the further potential and benefits, the players and Philips’ global involvement. INTRODUCTION The discovery of the structure of DNA by Crick and Watson(1) in 1953 was one of the major scientific events of the twentieth century. It had such an impact on biochemistry that it transformed the field and triggered a huge number of research projects. Now, almost 50 years later, discoveries in molecular biology resulting from such research seem likely to lead to another breakthrough in life science almost equal in importance and effect to that of the finding of the DNA double helix. These discoveries are in the areas of molecular imaging and diagnostics (MID), which alongside molecular biology and gene therapy, allow the monitoring and treatment of disease symptoms before they become systemic or established, the ultimate aim being the diagnosis and treatment of disease prior to the occurrence of secondary symptoms. In other words, paving the way toward predictive and preventive medicine. The identification of the DNA structure and its role in heredity processes led to rapid advances in molecular biology of which one key area is genomics, the study of human genes and their expression into proteins (a genome is the total complement of chromosomes of a species, including all genes and connecting structures). Through this, much greater understanding of the genetic blueprint was reached, until finally the draft sequence of the human genome was successfully decoded in 2000(2), a milestone at the turn of the new millennium. This remarkable discovery is revealing the secret of disease processes and how to intercept them, although it will take many more steps to achieve the ultimate goal.

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The flow of Genetic Information

Is knows as: “The central Dogma of Molecular Biology”

(Figure 1 – the central dogma of molecular biology)

It does not take much imagination to picture what impact preventive medicine could have on human health. Effectively, it means that it will be possible to visualize changes in body and metabolic functions at the onset of disease before the symptoms actually occur and to treat or halt the disease at a very early stage, making the expression ‘prevention is better than cure’ a reality. The effect on the healthcare industry will be just as dramatic. Time and cost savings are expected to be considerable. At the same time, many new opportunities will be opened up for manufacturers of imaging devices, drugs and contrast agents. In short, far-reaching changes will be made in society and industry that will greatly improve the quality of life. Today the knowledge, technologies, devices and chemical and biological reagents are available to enable increasingly accurate molecular imaging and diagnostics. However, although much has been achieved the medical science and industry are still at the threshold of truly effective and widespread predictive and preventive medicine. What electronics did for healthcare in the last 50 years genomics will do for the next 50 years.

IMPACT ON HEALTHCARE New imaging, diagnostic and therapeutic techniques arising from MID will cause a paradigm shift in healthcare procedures. Through time, much more emphasis will be placed on diagnosing and treating symptoms – even providing a cure – before secondary symptoms occur, rather than diagnosing from late symptoms and treating the disease after it has taken hold. Patient management broadly comprises four main procedural steps: screening, diagnosis and staging, treatment and monitoring, and follow -up. Traditionally, a first screening is done at the family doctor’s office. If disease symptoms are suspected or found the patient is referred to a hospital or medical centre for further examination (e.g. imaging), diagnosis and/or treatment. This procedure can be lengthy and costly (for 2001, the total medical costs for the treatment of cancer in the US, were estimated at 56.4 billion US

WHAT IS MID? Various definitions of molecular imaging have been formulated that cover different disciplines. The definition most commonly used is: “molecular imaging is the exploitation of specific molecules for image contrast” (Weissleder(3) and refers to the in-vivo measurement and characterization of cellular and molecular level processes in animal or human subjects). Similarly, molecular diagnostics is defined as the analysis of biomolecules to screen, diagnose and monitor the human health status and to assess potential risks.

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dollars (source: The National Institutes of Health)). In contrast, with molecular diagnostics, highly sensitive devices will permit the screening of initial symptoms and that will change the scenario for the next 10 to 20 years, where the family doctor will be able to screen for very early symptoms, or even treat before symptoms occur. Then, if required, the patient will be referred to a hospital or medical centre for further diagnosis and staging, using molecular imaging and targeted contrast agents that can interact with processes in a ‘pre-disease’ state. If treatment is required, new pharmaceutical procedures will allow patient-specific drug delivery, resulting in the ‘prevention rather than the cure’ of a (potential) disease. In the more distant future (after 20 years) screening, staging and treatment will, as can be expected, all be performed at the molecular level, and probably by the family doctor. It is also feasible that screening for certain selected symptoms may be performed at home by the individual without professional medical assistance. The effect of MID, along with successful developments in molecular biology, genomics and gene therapy, on the entire healthcare chain will therefore be far -reaching, particularly in the longer term. Most importantly, the cost consequences will be enormous. On the one hand, substantial savings in the cost of healthcare and medical insurance can be expected, with major changes in the reimbursment structure. On the other hand, greater investments will need to be made in the research, development and manufacture of hardware and software for new screening and imaging equipment, as well as for contrast agents, therapy drugs and related products. The potential market for MID is forecast to be about USD 45 billion by 2010. In genomics alone, billions of dollars are being invested by government and medical institutions and private companies in both the USA and Europe. In short, all parties involved in MID, directly or indirectly, recognize that huge investment needs to be made in its future. Spend on gene-related drug research by the top 18 pharmaceutical companies worldwide is estimated to rise from about USD 2.5 billion in 2000 (approximately 5 per cent of their R&D spend) to more than USD 12.6 billion by 2010 (or 24 per cent of R&D) (source: Parexel’s Pharmaceutical R&D Statistical Handbook, 2001).

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Molecular Diagnostics market $12B in 2010**$1.5B in 2001 source-The Gray Sheet

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(Figure – diagram of molecular diagnostics market values 1997 – 2007. Source: EAC ) PROBING DEEPER Each human cell comprises a nucleus containing two connected DNA molecules, each of which comprises 23 chromosomes. Each chromosome has between 30,000 and 80,000 genes, the basic units of heredity, evolution and the characteristic processes of growth, development and reproduction that distinguish each species. Each gene carries a ‘code’ for a number of proteins that are responsible for cellular structure and function. The human body contains between 500,000 and a million different proteins. It is this knowledge of human genes and their expression into proteins that is brought to light in genomics. However, more focus is now being turned to the study of proteins themselves in order to understand their structure, roles and interactions. This study is known as proteomics and is applied in understanding the relationships between genes, proteins, disease causes and effects of drugs. If intracellular processes cause the expression of a defective gene it will provide a code for a defective or ‘wrong’ protein. ‘Wrong’ proteins or the over-expression of a gene, e.g. as manifested in a tumour, can be the cause of disease. It is the make-up of such proteins in a molecule which can be visualized in molecular imaging and analyzed in molecular diagnostics. Molecular imaging can also visualize ‘good’ proteins as in apoptosis (the natural process of programmed cell death), for example. However, too high a level of apoptosis can also indicate disease or sub-effective treatment. Proteins are an important target for drug research and development. The comparison of proteins, and their levels, from diseased and healthy cells provides valuable information for drug treatment. The study and therapeutic treatment of ‘wrong’ genes or proteins is known as pharmagenomics, while pharmacogenomics is the knowledge of the particular gene codes of proteins that allow development of specific molecules to block a gene or protein or stimulate gene expression. Currently, about 500 different drugs, targeted at selected proteins or other receptors, are available on the market. Because of differences in different individual’s genes the same drug or combination of drugs that works for one person may not necessarily work for another. In practice, this means that drug treatment is only effective for about 30 per cent of patients. Moreover, since adverse side effects of drugs kill thousands of people every year worldwide, pharmaceutical companies are anxious to find ways to not only develop new and more effective, targeted drugs with less harmful side-effects, but to seek different approaches in administering agents and performing therapy. Currently, most research and development on MID is focusing on clinical applications in cancer and cardiovascular disease (the two most prevalent causes of death in humans in developed countries), and a number of common infectious diseases. Infectious disease and cancer are the fastest growing and largest application areas for molecular diagnostics, primarily because they are treated with drugs (antibiotics) at the molecular level. The intensive care unit (ICU), where more than half of mortality is caused by infectious diseases, is one area where molecular diagnostics can make a contribution. Because human genotyping and defining gene expression for a number of different cancers are starting to become successful, molecular diagnostics will play an important role in the screening, localization and therapy of cancer lesions at an early stage. Molecular imaging, which is only commercially available for PET (positron emission tomography) scanning, could be used during and after cancer therapy to track its effect. In cardiovascular disease, where, in addition to interventional procedures, drugs are also used to relieve symptoms and

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treatment is by surgery, MID could be mainly applied in the areas of artherosclerosis and congestive heart failure. In addition, angiogenesis – the growth of new blood vessels – is a major application area in vascular and cardiovascular disease. Drug therapy, e.g. vascular endothelial growth factor (VEGF), used to stimulate angiogenesis, first affects the capillaries, which are so small (typically less than 100 microns) that conventional imaging modalities are not capable of their visualization. But MID could image and measure the results of therapy at a microvascular level, so that the effects of both angiogenesis and anti-angiogenesis (the inhibition and destruction of blood vessels to halt the growth of malignant tumours, and applied in oncology) can be measured. Molecular imaging can also play an important role in monitoring gene therapy planning and follow-up in oncology, where it can permit molecular analysis of the receptor status and gene expression profiling.

The acquisitions of ATL Ultrasound, Agilent’s Healthcare Solutions Group, ADAC Laboratories, Marconi Medical Systems and MedQuist have not only expanded and strengthened Philips’ competencies and portfolio of imaging modalities, but have allowed the company to have a presence in other markets like patient monitoring and resuscitation. Philips is dedicated to improving healthcare, reflected in its vision and its theme of ‘clinical excellence without compromise’ and is adjusting its business model as medicine becomes more personalized. In fact, entr y into MID very much impacts the future of personalized healthcare as this paper has already shown, and even as far as telemedicine from the home.

The Philips’ Vision in Healthcare To make healthcare better through medical technology that enables: • Earlier diagnosis • Optimized workflow • Highly effective treatment • Empowered consumers • Personalized care

Philips’ MID Research Project Philips recognises that MID calls for a new diagnosis and treatment model. The company is building core clinical research competence both inte rnally and with outside institutions. Philips’ MID research projects are aimed at investigating the impact on its current businesses and identifying opportunities. Specifically, the project includes: • participation in the state-of-the-art in gene-based therapy and molecular imaging • definition of specifications of different imaging modalities • development of new technology to improve the imaging or molecular diagnosis process • designing new equipment for molecular imaging, such as a combined, open PET-CT

scanner • expanding the number of luminary sites for research collaborations • partnerships with other companies involved in MID • making alliances that qualify for public funding. • Building a consortium for the advancement of MID technologies Philips initial clinical focus is on angiogenesis, anti-angiogenesis, apoptosis vulnerable plaque (i.e. atherosclerosis).

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Jouko Karvinen, President and CEO of Philips Medical Systems, emphasizes the significance of MID on the company’s healthcare policy: “I am convinced that molecular imaging and diagnostics are essential to our long-term success. They will, therefore, become key elements in realizing our mission of becoming the world leader in healthcare solutions and in emphasizing our dedication to clinical excellence without compromise. We are reviewing our entire imaging and point-of-care business to see how these fascinating techniques can best be developed and integrated.” IMAGING TECHNOLOGY Molecular information can be obtained using some of the imaging technologies available today. Modalities differ with respect to spatial resolution and sensitivity, which are usually mutually exclusive. Suitability of an imaging modality for molecular imaging is judged on the criteria of spatial resolution, anatomical coverage, reproducibility, potential for quantification, support of image -guided drug delivery and, finally, the ability to image molecular targets and gene expression. The four modalities considered to be the most promising in molecular imaging are PET/CT, SPECT, MR and ultrasound, activities in which Philips has a long-term commitment and substantial investment. In addition, the majority of contrast media manufacturers agree that nuclear imaging is the most important and are developing targeted agents especially for this area. Commenting on this, David Rollo, CMO and Program Manager, Nuclear Medicine and Molecular Imaging at Philips Medical Systems, said: “One of the reasons we acquired ADAC Laboratories in 2000 was to strengthen our portfolio in nuclear medicine, including PET. Molecular imaging is the basis of nuclear imaging and the ADAC acquisition, in addition to help complete our imaging portfolio, is also a means to gaining a foothold in MID.” Commenting on the role of ultrasound in molecular imaging, Jeff Powers, Director of Contrast and Functional Imaging at Philips Medical Systems, said: “There are a number of exciting applications for ultrasound contrast in molecular imaging, including agents targeted to specific tissue types, as well as enhanced gene therapy in which microbubble vibrations actually increase expression of genes for therapeutic purposes. Prior to joining the Philips family, ATL and Agilent had each been leaders in the ultrasound contrast field since its inception. The new Philips Ultrasound activity is investigating all of these areas of research and is committed to being a leader in whatever proves clinically viable.” Jacques Coumans, MR Global Marketing Director at Philips Medical Systems, added: “MR is expected to play an essential role in the clinical use of molecular imaging, for screening, targeted drug delivery and therapy evaluation. In all these areas, Philips has, with our worldwide network of MR clinical luminary research partners, focused efforts on developing new technologies and implementing them in our products. Examples include the evaluation of molecular imaging contrast agents like those co-developed with Kereos, routine whole -body MR screening, targeted delivery in oncology and cardiology in an XMR setting, and non-invasive control of gene expression with focused ultrasound. We also believe that our strong position in cardiac, interventional and whole-body 3.0 T MR imaging is an essential platform for the introduction of molecular imaging in the clinic.” An overview of available imaging modalities and their applicability to molecular imaging is given below.

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X-ray/CT offer excellent spatial resolution for whole-body imaging and recent advances in the integration of navigation functionality and image processing allow accurate reproduction of scan location and image-guided drug delivery. However, there are limitations in imaging with the use of contrast agents and in assessing molecular information and gene expression. Conversely, high spatial resolution makes x-ray-based imaging important for hybrid systems such as PET-CT (see below). Ultrasound has a wide range of applications but is restricted to certain anatomical regions. It can quantitatively assess physiological information and be used for image-guided drug delivery (mainly in the abdomen, chest and legs) and enhancement of (gene-) therapy. Ultrasound does allow the use of microbubbles as a contrast agent that burst and release a therapeutic load when encountering a focused ultrasound beam. This is particularly useful in measuring blood flow at the arteriolar or capillary level, and can therefore be applied in following angiogenesis treatment. Other, smaller, ultrasound contrast agents have recently been developed that allow imaging of smaller molecular targets than in the vascular system. Another application is enhancing gene delivery with the acoustic effects of sonified microbubbles. Magnetic Resonance (MR) can visualize anatomy with good spatial resolution, is applicable to all body regions and will allow reproducible and quantitative imaging. It can also be used for intravascular and needle image-guided drug delivery, but not for a broad range of drugs due to safety aspects. MR can partly assess molecular information, for example through spectroscopy, but is limited by sensitivity. However, highly sensitive contrast agents have recently been used to allow imaging of molecular targets and gene expression. Since MR allows reproducible quantitative imaging without radiation it has quite some potential for follow-up studies. Nuclear Imaging, comprising PET (often combined with CT) and SPECT is a molecular imaging technique with excellent sensitivity and whole-body applications with good reproducibility and quantitation. However, its poor spatial resolution makes it unsuitable for image-guided drug delivery, and it requires relatively long scan times. Using nuclear imaging with radiopharmaceutical agents enables drugs tracing, including the study of pharmacokinetics in-vivo. Recently, PET has produced images of gene expression that show promise for future applications in monitoring of gene therapy. Optical Imaging is a relatively new imaging technique that, because of its lower penetration depth, is currently limited to endoscopic and microscopic applications in humans and animals. Optical imaging may eventually be used to retrieve information from deeper areas. Potential is seen in screening applications where only a yes/no answer is required rather than spatially resolve d information.

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Summary Anatomy

HiRes

Cov. Reprod

Quant.

Image-guided drug

delivery

Imaging of Molecular

Targets

Imaging of Gene

Express.

X-Ray/CT

++ ++ + + + + − − − −

US + +/− − + + + − MRI + ++ + ++ + + +/−

Nuclear − − + + ++ + ++ ++ Optical + − − + + − + +

Table 1: Classification of imaging modalities regarding the most important demands for molecular imaging.

(Figure – table showing classification of imaging modalities)

THE MARKET PLAYERS To enter and maintain a foothold in the MID market requires high stakes and is not without risk. Only those companies with considerable scientific and clinical knowledge and expertise, as well as significant financial resources can afford to invest in MID to any appreciable degree. Research alone requires major investment and not all players have such means. Players include medical diagnostic imaging equipment manufacturers, contrast agent and pharmaceutical companies, private and government research organizations (including clinical research centers) and numerous other large or small, specialized companies. Clearly, there is much to be gained by companies working together, and a number of alliances have already been formed between large imaging equipment manufacturers and contrast agent producers. Companies also work closely together, whether indirectly or directly as members, within the framework of a governmental or other non-profit organization, such as USA-based National Institutes of Health (NIH), which is contributing massive financial and other resources. The leading edge work in genomics and imaging is heavily weighted toward Academic Medical Centers, and the majority of biotech is currently in the US. PHILIPS’ ROLE IN MID Philips decided to invest heavily in MID and has embarked on an ambitious and exciting program. The company recognizes the paradigm shift that MID will cause not only in its own area of competence – imaging, in which it has a leading position in most of the modalities discussed above – but also in the areas of contrast agents, drugs and related peripheral equipment like DNA and protein arrays. Taking its current imaging modalities into MID, and concentrating initially on infectious diseases in the ICU, and cardiology and oncology, Philips is building competence in human clinical biochemistry. It has defined an optimized four-step workflow solution for screening, staging, therapy and monitoring that will provide predictive early diagnosis and innovative preventive treatment programs. Implementing the solution involves high-level research and development and co-operation with contrast agent and drug companies. One such company with whom Philips has an R&D agreement is Kereos Inc. and involves the development of molecularly targeted contrast agents for ultrasound, MR and nuclear imaging. Dr. Samuel

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Wickline, Professor of Medicine, Biomedical Engineering, and Physics and Co-Director, Cardiovascular Division at Washington University School of Medicine in St. Louis, U.S.A., is the project leader in the collaborative molecular imaging program. Commenting on the program, Dr. Wickline said: “My colleagues and I are very excited about this program and we are certain that it will lead to major breakthroughs in advancing contrast agent and scanner technology for molecular imaging and targeted therapeutics. Our research laboratories at Barnes-Jewish Hospital at Washington University School of Medicine in Missouri are working closely with both Philips and Kereos, which has an exclusive licensing agreement with Barnes-Jewish Hospital relating to ligand-targeted emulsions for medical diagnostic and therapeutic use and which were developed by our team.”

Philips has established an in-house dedicated MID Project Office to manage and supervise its research and development programs. Carmen van Vilsteren, newly appointed Program Manager of Philips’ MID Project Office, outlined some of the objectives: “We will detail our strategy further and manage and co-ordinate our program in MID. Some projects will be in association with other companies, and some will be carried out as a member of the European Consortium on Molecular Imaging, when it is officially formed, working in close co-operation with our own research, clinical science and development facilities.” Also to support Philips’ efforts in becoming established in MID, the company has appointed a Scientific Advisory Board, whose director is John Hart: “Our main role here is to evaluate and guide Philips’ future directions in the areas of molecular imaging and diagnostics. These are far-reaching new technologies with implications that we have yet to see. This venture is more an extended journey than a trip.” Through its research laboratories in the Netherlands and Germany, and in clinical partnerships and alliances, Philips began studies in mole cular imaging in the late nineties and expanded into molecular diagnostics at the end of 2001. Areas include biosensors, focused ultrasound and signal and image processing, aspects of PET and SPECT imaging, multi-nuclei MR imaging and spectroscopy, quantitative imaging techniques and local drug delivery. Other projects have been defined for the coming years that will cover all aspects of MID that the company considers necessary and feasible for its mid - to long-term future. Dr. Dye Jensen, Department Head, Tomographic Imaging Systems at Philips Research in Hamburg, Germany, said: “An additional aim of Philips’ research program is to build MID

Philips’ progress and achievements in MID

• Co-operation in several clinical trials for development of new imaging agents and treatment methods in cardiology and oncology

• Leadership position in nuclear medicine, MR, ultrasound and CT imaging • Unique imaging equipment features that accelerate development of new imaging agents

and determine efficacy of treatment • Industrial collaboration agreements with Theseus and Kereos to develop molecularly

targeted contrast agents for ultrasound, MR and nuclear imaging and related imaging hardware, software and techniques

• Formation of an MID Project Office • A significant investment in US Academic/Medical Cooperations • Expansion of number of clinical co -operation sites and their work • Increased investment and effort in R&D • Commencement of building and international MID network

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networks in Europe and the USA that will work with and co-operate in programs at key clinical research sites.” CONCLUSIONS Without doubt, MID has enormous potential, with far-reaching financial, social and industrial consequences for patient welfare, healthcare, and numerous commercial enterprises. Above all, the ultimate effect should be to improve the quality of life through true predictive and preventive medicine. MID is only at the threshold of implementation, but, with concurrent developments in molecular biology, genomics and gene therapy, and with the right investments and for the right reasons, there is every chance that the real benefits will begin to be enjoyed over the next 5 to 10 years. Philips is one of the companies dedicated to fulfilling the promise of MID. It is well equipped, in terms of resources, experience, expertise and clinical and marketing channels, to take a leading position in this exciting new field. Doing so gives new and broader meaning to the expression ‘Clinical excellence without compromise’.

oooOooo Glossary of terms relevant to MID Allele – The gene regarded as the carrier of either of a pair of alternative hereditary characters.

Angiogenesis – the formation of the body's network of blood vessels. May also be triggered by certain pathological conditions - such as cancer - where the continuing growth of solid tumours requires nourishment from new blood vessels.

Antio-angiogenesis – The inhibition and destruction of new blood vessel growth.

Apoptosis – programmed cell death, the body’s natural method of disposing of damaged, unwantd or unneeded cells.

Bioinformatics - The science of managing and analyzing biological data using advanced computing techniques. Especially important in analyzing genomic research data.

Biotechnology - A set of biological techniques developed through basic research and now applied to research and product development. In particular, biotechnology refers to the use by industry of recombinant DNA, cell fusion, and new bioprocessing techniques.

Cancer - Diseases in which abnormal cells divide and grow unchecked. Cancer can spread from its original site to other parts of the body and can be fatal.

Carrier - An individual who carries the abnormal gene for a specific condition without symptoms (also referred to as heterozygote).

cDNA -- complementary DNA produced from a RNA template by the action of RNA- dependent DNA polymerase.

Cell - The basic structural unit of all living organisms and the smallest structural unit of living tissue capable of functioning as an independent entity. It is surrounded by a membrane and contains a nucleus which carries genetic material.

Chromosome - A rod-like structure present in the nucleus of all body cells (with the exception of the red blood cells) which stores genetic information. Normally, humans have 23 pairs, the

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unfertilised ova and each sperm carrying a set of 23 chromosomes. On fertilisation the chromosomes combine to give a total of 46 (23 pairs).

Complementary DNA (cDNA) - DNA that is synthesized in the laboratory from a messenger RNA template.

Cytogenetics – The study of the physical appearance of chromosomes.

DNA (Deoxyriboneclic acid) – The molecule or ‘building block’ that encodes genetic information.

DNA repair genes – Genes encoding proteins that correct errors in DNA sequencing.

Enzyme - A protein substance that acts as a catalyst to speed the rate at which a biochemical reaction proceeds.

Epistasis – A gene that interferes with or prevents the expression of another gene located at a different locus.

Fingerprinting - In genetics, the identification of multiple specific alleles on a person's DNA to produce a unique identifier for that person.

Gene – The fundamental physical and functional unit of heredity. A gene is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product (i.e., a protein or RNA molecule). The collection of genes in an organism determines its characteristics.

Full gene sequence - The complete order of bases in a gene. This order determines which protein a gene will produce.

Gene expression - The process by which a gene's coded information is converted into the structures present and operating in the cell. Expressed genes include those that are transcribed into mRNA and then translated into protein and those that are transcribed into RNA but not translated into protein (e.g., transfer and ribosomal RNAs).

Gene mapping - Determination of the relative positions of genes on a DNA molecule (chromosome or plasmid) and of the distance, in linkage units or physical units, between them.

Gene prediction - Predictions of possible genes made by a computer program based on how well a stretch of DNA sequence matches known gene sequences.

Gene therapy - An experimental procedure aimed at replacing, manipulating, or supplementing nonfunctional or misfunctioning genes with healthy genes.

Genetic code - The sequence of nucleotides, coded in triplets (codons) along the mRNA, that determines the sequence of amino acids in protein synthesis. A gene's DNA sequence can be used to predict the mRNA sequence, and the genetic code can, in turn, be used to predict the amino acid sequence.

Genetic marker - A gene or other identifiable portion of DNA whose inheritance can be followed.

Genetic predisposition - Susceptibility to a genetic disease. May or may not result in actual development of the disease.

Genome - All the genetic material in the chromosomes of a particular organism; its size is generally given as its total number of base pairs.

Genomics - The study of genes and their function.

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Genotype - The genetic constitution of an organism, as distinguished from its physical appearance (its phenotype).

In-vitro - Studies performed outside a living organism such as in a laboratory.

In-vivo - Studies carried out in living organisms.

Messenger RNA (mRNA) - RNA that serves as a template for protein synthesis.

Microarray - Sets of miniaturized chemical reaction areas that may also be used to test DNA fragments, antibodies, or proteins.

Micronuclei - Chromosome fragments that are not incorporated into the nucleus at cell division.

Molecular biology - The study of the structure, function, and makeup of biologically important molecules.

Molecular genetics - The study of macromolecules important in biological inheritance.

Molecular medicine - The treatment of injury or disease at the molecular level. Examples include the use of DNA-based diagnostic tests or medicine derived from DNA sequence.

Nucleotide - A sub-unit of DNA or RNA consisting of a nitrogenous, a phosphate molecule, and a sugar molecule. Thousands of nucleotides are linked to form a DNA or RNA molecule.

Oncogene - A gene, one or more forms of which is associated with cancer. Many oncogenes are involved, directly or indirectly, in controlling the rate of cell growth.

Ligand – The atoms or groups bound to a central atom in a polyatomic molecular entity.

Locus – The relative position of a gene on a chromosome.

Phage - A virus for which the natural host is a bacterial cell.

Pharmacokinetics - The study of what the body does to a drug.

Pharmacodynamics - The study of what a drug does to the body.

Pharmacogenomics – The study of the particular gene codes of proteins that allow development of specific molecules to block a gene or protein or stimulate gene expression.

Pharmagenomics – The study and therapeutic treatment of defective genes or proteins.

Phenotype - The physical characteristics of an organism or the presence of a disease that may or may not be genetic.

Plasmid - Autonomously replicating extra-chromosomal circular DNA molecules.

Probe - Single-stranded DNA or RNA molecules of specific base sequence, labeled either radioactively or immunologically, that are used to detect the complementary base sequence by hybridization.

Protein - A large molecule comprising one or more chains of amino acids in a specific order that is determined by the base sequence of nucleotides in the gene that codes for the protein. Proteins are required for the structure, function, and regulation of the body's cells, tissues, and organs. Each protein has unique functions. Examples are hormones, enzymes, and antibodies.

Proteomics - The study of the full set of proteins encoded by a genome.

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Ribosomal RNA (rRNA) - A class of RNA found in the ribosomes of cells.

RNA (Ribonucleic acid) - A chemical found in the nucleus and cytoplasm of cells; it plays an important role in protein synthesis and other chemical activities of the cell. The structure of RNA is similar to that of DNA. There are several classes of RNA molecules, including messenger RNA, transfer RNA, ribosomal RNA, and other small RNAs, each serving a different purpose.

Sequencing - Determination of the order of nucleotides (base sequences) in a DNA or RNA molecule or the order of amino acids in a protein.

Stem cell - Undifferentiated, primitive cells in the bone marrow that have the ability both to multiply and to differentiate into specific blood cells.

Structural genomics - The study to determine the 3D structures of large numbers of proteins using both experimental techniques and computer simulation.

Theranostics – The application of MID for therapy guidance that applies to pharmacogenomics for predicting and assessing drug response.

Virus - A non-cellular biological entity that can reproduce only within a host cell. Viruses consist of nucleic acid covered by protein; some animal viruses are also surrounded by membrane. Inside the infected cell, the virus uses the synthetic capability of the host to produce progeny virus.

References: (1) Watson, J. and Crick F. - A Structure for Deoxyribose Nucleic Acid. Nature, Vol. 171,

page 737, 1953 (2) Nature 409, Feb 2001 (3) Weissleder, R. – Molecular imaging: explaining the next frontier. Radiology 212: 609 -

614, 1999