Lessons in Excellence

Transcription

1 Lessons in Excellence Expanding Curricula in Pharmaceutical Education and Training UNIVERSITY OF THE SCIENCES IN PHILADELPHIA Maribel Rios To prepare the next generation of pharmaceutical scientists, colleges and schools of pharmacy are implementing the latest technical innovations in drug discovery, design, development, and manufacturing. Maribel Rios is the managing editor of Pharmaceutical Technology, 32 Pharmaceutical Technology August 2002 T he vitality of any industry relies on the talent of its researchers, educators, managers, and manufacturers. The success of each employee s job begins with proper education and training. A review of the curricula offered at several schools of pharmacy reveals the extent to which advanced areas such as genomics and information technology have revolutionized the tools used to teach pharmaceutical science today. Those who thought mastering a graphing calculator in school was a triumph would be quite impressed at the computational horsepower that is giving a big boost to current drug discovery and development efforts. Clearly, at every stage of their education students of pharmaceutical science are getting a lot more bang for their tuition buck. Those who are either new to the job market or established employees looking for advancement will have to meet the demands of an industry known for its innovation, fast-paced ingenuity, and competition as well as its highly regulated environment. To this end, several colleges and universities have added new areas of study to their curriculum while continuing to emphasize fundamental skills. Informatics Perhaps the most apparent change in research is the implementation of informatics. Informatics is a means of acquiring, storing, processing, analyzing, and presenting vast amounts of data using computer and statistical techniques. In genomics research, scientists use informat- ics to quickly search databases, analyze DNA sequence information, and predict protein sequence and structure from DNA sequence data. Because informatics is applicable to various disciplines, several academic and industry pundits have predicted it to be the next fundamental discipline. Most familiar to those conducting pharmaceutical and biopharmaceutical research is bioinformatics, a broad field that integrates molecular biology, genomics, highend computer analysis and programming, computation science, and statistics to determine how genetic information affects biological functions. Applications include problems in computational chemistry, functional genomics, pharmacogenetics, pharmacogenomics, pharmacometrics, proteomics, and structural biology. Bioinformatics can, for example, be used to analyze the gene patterns in tissues from various species and to study the gene patterns in diseased organs. High-powered algorithms are developed to manipulate immense amounts of data stored and processed on high-performance computers to quickly access genomic or protein sequence data. Several bioinformatics research institutes have been established worldwide. Plans are under way for construction of The Buffalo Center of Excellence in Bioinformatics facility in the downtown Buffalo Niagra Medical Campus (Buffalo, NY). The 150,000-ft2 multifunctional, high-tech facility will house drug design and research laboratories, high-performance computational facilities, three-dimensional visualization capabilities, product commercialization space, and workforce training facilities. The University of Buffalo (New York) is the lead research partner in the center, which will be led by Jeffrey Skolnick, PhD, a scientist in the field of computational biology. The University of the Sciences in Philadelphia (USP) has established a bioinformatics program at both the undergraduate (bachelor of science) and graduate (master of science) levels. The program, the first to be approved by the Board of Education in Pennsylvania, was initiated by

2 E D U C AT I O N members of the school s faculty, including James C. Pierce, current director of USP s undergraduate program, whose specialty lies in genomics. It s clear to me that the field of biological sciences in general is moving into a very data-intensive type of discipline, says Pierce. Biology has become an information science. The demand for bioinformatics expertise also has intensified the recruitment efforts of several pharmaceutical and biotechnology companies, long-established companies such as IBM and Compaq Computer Corporation, and academic and government research centers. Those who are valuable to the industry are those who are able to use computers to manipulate biological information. Computer scientists often don t understand the biology, what type of questions to ask, or what the information means, says Pierce, and the average molecular biologist doesn t really know how to build databases, write the algorithms, or use the tools in a productive manner. A bioinformatics specialist can blend those two areas together. In fact, the majority of the students who have enrolled in USP s graduate program are professional molecular biologists who already are working in the pharmaceutical and biotechnology industries and wish to retrain themselves in current computer technology methods. At the heart of bioinformatics is the creation, manipulation, and maintenance of large databases of biological information. It doesn t really matter what field you are studying it could be molecular biology or biochemistry. You re going to have to be skilled in your ability to manipulate databases, to use computers to study problems, and to analyze data, says Pierce. Experiments in genomic science generate vast amounts of data, but not all of it is useful. Traditional methods of setting up an experiments and recording and analyzing results are inadequate in today s life sciences community. The approach now is to set up a system, collect the data, and then try to UNIVERSITY OF THE SCIENCES IN PHILADELPHIA interpret and understand the tens of thousands of data points that are generated. We ve gone from the first case in which we hope to get an answer to the second case in which we always have too much information coming in faster than we can handle it, Pierce points out. There s a tremendous amount of information out there, but if you don t know how to access it and use it, it s useless to you. Pierce perceives the information to have three levels: genomics, which involves obtaining all the genetic information of an organism at the DNA level, organizing it, and analyzing it; functional genomics, which entails taking the information to the RNA and protein level and trying to determine what it means; and systems biology, which involves looking at the entire package together and attempting to build a model of living cells, for example, on a computer and to manipulate the model. Progress in functional genomics already has been made in the study of cancer cells. By analyzing the differences in the global patterns of gene expression between a nor- Bioinformatics in microarray technology The University of the Sciences in Philadelphia is implementing a National Science Foundation grant for incorporating microarray technology into the bioinformatics and biology undergraduate curriculum. Two projects are planned to introduce this technology to their students. These projects will be used in formal courses and are designed to provide a foundation for data sets and class projects as they relate to microarray technology. The first project concerns the design, construction, and analysis of a DNA microarray. Students will design a chip that can be used to identify bacteria that are commonly used in the microbiology teaching laboratory. Dr. Pierce will have students use polymerase chain reaction equipment to amplify various portions of the ribosomal RNA 16S gene and use it as the substrate for the microarray chips. The students will make the chips and then perform a microarray experiment to identify an unknown bacterial isolate. Using various bioinformatic tools, the students should be able to determine not only the identity of the sample but its relationship to other bacteria using a phylogenetic approach. The second project will use the yeast Saccharomyces cerevisiae as a model system to study gene expression. Microarray chips containing all of the yeast gene ( 6200) will be used to study how yeast responds to various types of environmental changes (e.g., a blast of UV light) or genetic changes (a specific mutant) and how these changes affect global gene expression in this single-celled eukaryote. Students will use bioinformatic tools to study the microarray data, analyze the gene expression clusters, and determine the roles the various genes may have in the life cycle or metabolism of yeast. mal cell and a cancer cell, researchers may be able to determine potential targets such as the proteins, enzymes, receptors, or other biomolecules that one would want to interact with a drug or have a drug bind to for a therapeutic result. USP s undergraduate bioinformatics curriculum comprises a four-year study that includes molecular biology, chemistry, computer and database programming, biochemistry, biostatistics, genetics, two semesters of bioinformatics, and a bioinformatics project (see sidebar, Bioinformatics in microarray technology ). The master of science track requires an additional year of biotechnology, statistics, computer algorithms, and programming as well as an independent masters project. The first undergraduate class began in fall 2001 with seven students, and approximately 30 students applied for the second undergraduate class. The first graduate program began in fall 2000 with classes completely filled, and more than 20 graduate students enrolled. The USP undergraduate degree was designed to provide a foundation in bioinformatics that prepares students for entry level positions in pharmaceutical or biotech companies or in academic laboratories. The program itself provides a lot of flexibility; students can choose whether to emphasize programming, data analysis, or Web-based interactive programs. These projects may involve various types of programming languages, including PERL, a very popular computer programming language used in bioinformatics. The projects also may involve molecular modeling, in which students are asked to analyze various types of compounds and determine their three-dimensional structures and whether they might be good drug candidates. Several students in the program also work off campus, full time, as research scientists in pharmaceutical and biotechnology companies. Students who have earned a bachelor s degree have some laboratory skills and have used bioinformatics tools, but they are not prepared to use them at a high level, notes Pierce. For example, the final exam in his course is a three-week practical exam. Students are given raw DNA sequence data, and they must manipulate that data from beginning to end and be able to turn it into a protein, understand the various aspects of the gene, go into the databases to find out who it is related to, and other information that may be embedded. To complete the master s project successfully, students must demonstrate that they can work independently and creatively on a bioinformatics problem. Admittedly, teaching such a rapidly changing field can be challenging. It makes little sense to train a student in the use of one platform such as a particular computer language. But knowledge of DNA is not going away, and gene expression patterns are not going away, says Pierce. The real goal is to get students to be skilled in a certain subset of skills, including algorithms, computational biology, computer programming, database analysis, and, because this is bioinformatics, to understand how life works at the molecular level. Recruiting students to study a new field also can be a problem. Many high school students and teachers do not know what bioinformatics is nor are they aware of its role in the industry, so students may be reluctant to apply to a bioinformatics program. Although the Human Genome Project accelerated bioinformatic activity, the field itself is still very new, and getting pharmaceutical scientists up to speed will take some work. In addition, the tools used in bioinformatics research often become obsolete before the student graduates. The program that I used five years ago is completely out of date, says Pierce. Our bioinformatics program is only two years old and we 34 Pharmaceutical Technology August 2002

3 Vital signs are already updating the software throughout the entire internal network, which means all of the other programs must be updated too. The bioinformatics laboratory includes 15 workstations of imacs running OS X, a new Unix system that interfaces with the school s high-end machines. The goal is to provide students with a workstation where they can interact with all the main types of tools that they will be using in a bioinformatics environment, including DNA sequence analysis programs. Students also must be able to access databases, mainly through the Web, and perform Web-based data analysis as well as present the data using modeling programs and HTML. In comparison with traditional methods, however, the efficiency, speed, and power of an effective bioinformatics system far outweigh the cost of maintenance and upkeep. The amount of information coming from genomics, genetics, and proteomics requires more than the use of simple algorithms or any other comparable methods of analyzing, warehousing, and manipulating data. In fact, says Pierce, bioinformatics may well be the tool that pharmaceutical companies of the genomic era can t afford not to have. If you re going to be in the business of life sciences in the twenty-first century, you have to do bioinformatics. It s not going away. Pharmacometrics Pharmacometrics is a branch of informatics that involves the development of mathematical models of pharmacokinetic and pharmacodynamic (PK/PD) data through theoretical and practical knowledge in statistics, computer programming, and numerical analysis. Companies such as Quintiles, a contract research organization specializing in drug and biologic development, have recruited scientists experienced in pharmacometric techniques for analyzing and reporting PK/PD data from clinical trials. The University at Buffalo School of Pharmacy and Pharmaceutical Sciences (UB, Buffalo, NY), which is scheduled to enroll approximately 28 students at the undergraduate level of pharmaceutics and nearly twice that many at the graduate level in pharmaceutics, recently formed an intensive masters degree program in pharmaceutics that focuses on pharmacometrics. The program integrates pharmacology with computational and statistical analysis. According to Wayne Anderson, dean of the school, students skilled in pharmacometric techniques are heavily recruited in the pharmaceutical industry, and many have offers before they graduate because all pharmaceutical companies must conduct clinical and preclinical trials and are looking for efficient methods of analyzing the data from these trials. Pharmacometrics allows one to mathematically relate the properties and characteristics of a drug as a chemical entity to PK and PD data. These relationships are then used to determine how the drug must be modified to decrease toxicity, increase efficacy, and avoid metabolic pitfalls, says Anderson. Pharmacometrics has various applications in genomics as well. Humans can be categorized in subpopulations according to how individuals respond to specific drugs, he says. Two individuals may respond differently to the same drug not because the drug is faulty, but because people are genetically different. Students skilled in pharmacometrics can relate genetic and proteomics information to predict toxicology and efficacy. The UB program has been successful in recruiting students who already hold a doctorate degree but who go back to school to obtain a masters degree in pharmacometrics. In fact, the first graduate from the pharmacometrics program had a PhD in biochemistry, says Anderson. Combinatorial chemistry Having been a part of drug discovery research for the past decade or so, combinatorial chemistry is an established yet still relatively new technique. Taking into account the use of computer-aided modeling and high-throughput synthesis, however, one could argue that new drug entities are more often designed than discovered. David Hangauer, professor of medicinal chemistry in the UB department of chemistry, teaches a course about the combinatorial synthesis of molecules as well as a graduate course about the computer aided design of combinatorial libraries. His research focuses on molecules with molecular weights below 500 because they are more likely to be active as a solid dosage form. Hangauer s work is a broad approach to the study of many types of cancer. A combinatorial library is a large collection of related molecules. Depending on how these molecules are prepared, the library could consist of anywhere from a hundred to a billion molecules that are similar yet slightly different in their configuration. The combinatorial part means that the library was constructed by appending combinations of various side chains to a core molecule. For example, if the core molecule has three positions at which a structure might bind and each of these positions has 10 possibilities, a total of 1000 ( ) compounds are likely candidates for a new drug entity. One can then use the computer to design a library of 1000 molecules or more that are the type that could bind to the target, says Hangauer. Computer programs can rank these molecules from most likely to work to least likely to work. From this library, the chemist chooses a subset (typically 100) most likely to work, and they are synthesized simultaneously. Highthroughput tests must be conducted to determine which ones would be the most The American Association of Colleges of Pharmacy, which conducts annual studies of the status of colleges and universities in the United States that offer accredited professional degree programs in the pharmaceutical sciences, has released its report, Academic Pharmacy s Vital Statistics. The report is based on the association s Profile of Pharmacy Faculty, Pharmacy School Admission Requirements, and Profile of Pharmacy Students. According to this report: There are 83 colleges and schools of pharmacy with accredited professional degree programs as of fall Of these 83 institutions, 64 offer graduate programs in the pharmaceutical sciences at the MS level and/or PhD level. There were 3777 full-time and 776 part-time pharmacy faculty members at 83 colleges and schools of pharmacy in fall The total fall 2001 full-time graduate student enrollment was Of these, 2264 students were enrolled in PhD programs and 820 in MS programs. successful because nature seems to be not as predictable as we think she should be, says Anderson, so rather than spending a decade on the computer and going to make that drug only to find that drug doesn t work, one designs a family of drugs using combinatorial chemistry around the fundamental concept of what the receptor looks like. Robotics and special reactors are used to quickly make the 100 or 1000 compounds that have been designed. Those compounds are then tested against the biological target in a real assay. All compounds that are synthesized in Hangauer s laboratory are tested because it costs more money to synthesize the compounds than it does to test them. The test process can quickly narrow the list of potential new drug entities. For example, from a possible 1000 compounds tested in vitro against the isolated protein, perhaps five would look promising. These would be tested in vivo, in an animal system. Of these, perhaps two would still look promising. These two compounds would advance to the development phase in which they are tested for stability, solubility, formulation, and so forth before proceeding to clinical trials. The process from designing the library to synthesizing the library to testing the library typically occurs in a period of 6 months, says Hangauer. Genomics has vastly increased the number of potential drug targets (enzymes, receptors, or other biomolecules). That hasn t directly translated into an increased number of drugs so far, says Hangauer, but that s the hope. For medicinal chemists, our job just got bigger. Pharmaceutical engineering Pharmaceutical engineering approaches pharmaceutical manufacturing problems with engineering concepts. In 1995, Rutgers (Piscataway, NJ) implemented the first program that combined pharmaceutics and engineering as its Pharmaceutical Engineering Training Program (PETP) (1). Fernando Muzzio, professor and director of PETP, believes that pharmaceutical manufacturing should always In , 375 PhD degrees were awarded, which was a 16.1% increase from the number awarded in the academic year. The number of MS degrees that were awarded also increased from 354 in to 461 in The majority of MS degrees conferred in was in pharmaceutics (31.7%), followed by pharmacology (19.3%), and social administrative sciences (18.9%). Slightly more than 17% were in disciplines such as quality assurance and regulatory affairs. Pharmaceutics also was the leading discipline of PhD degrees awarded in (36.5%), followed by pharmacology (26.4%), and medicinal chemistry (24.5%). However, of the total number of PhD degrees conferred, only 1.9% were given in the field of pharmaceutical and biomedical science. have been primarily an engineering effort. Because engineers were hired mostly by oil and chemical industries, engineering education focused on those processes, whereas the pharmaceutical industry remained a concern of pharmacy practice, and schools of pharmacy deemphasized education in manufacturing processes. A lot of this has to do with funding, Muzzio says. Pharmacy faculty can get government funding to do drug discovery and drug delivery research, but they have a hard time attracting funding in manufacturing. To optimize manufacturing processes, he says, engineering students must have a strong mathematical background, more so than what the pharmaceutical discipline requires. Engineers apply math to design, optimize, and control processes in many industries, Muzzio explains. But the pharmaceutical industry has been slow to incorporate engineering tools. Muzzio points to the use of computer simulation as an example. Computer simulation to design fluid-mixing processes in the chemical industry is nearly standard. The aviation industry and the automotive industry also use computer simulation before testing in a lab. In the pharmaceutical industry, he says, almost nobody does any type of computer simulation. You can find isolated examples, but it s not standard, and it reflects the background of the people doing it. Computer simulation would not only be less expensive, but it would provide an in-depth understanding of the manufacturing process. Because engineering has a stronger mathematical foundation, engineers can bring to the table process design, process analysis, and process optimization tools that allow the industry to do a more systematic selection of materials and methods, says Muzzio. Students in the Rutgers pharmaceutical engineering training program are exposed to various pharmaceutical manufacturing applications such as blending, drying, sampling, compression, dissolution, and crystallization. These are much of the same applications used in the industry. Research is conducted at both the graduate and undergraduate levels. Most undergraduates 36 Pharmaceutical Technology August

4 Covering the basics perform at least two semesters of research related to unit operations used to make pharmaceutical products. The biggest changes in pharmaceutical manufacturing most likely will be in the materials companies will have to handle, says Muzzio. For example, manufacturing equipment and processes will have to be updated to accommodate nanotechnology. The existing technology was developed and incorporated when most of the products were granulated, says Muzzio. Already, direct compression products are challenging the abilities of older, standard-style equipment. The nature of pharmaceutical materials has changed significantly and, given the regulatory framework, current methodologies are antiquated. Drugs are becoming more potent and also more insoluble. For them to be effective [the industry] will need to make smaller and smaller particles that must be handled accurately, he says. Low-temperature nanotechnologies will need to be implemented to effectively manufacture and process products that contain small amounts of these highly potent molecules. Even the basic aspect of personnel protection will need to change because nanoparticles are smaller than the smallest tolerances of current equipment. Much is still unknown about these materials, including how to assay them, how to compress them, how to blend them with particles that are much larger, how to determine particle-size distribution all of the current methodologies don t work for nanoparticles. Pharmaceutical manufacturing methods will have to change dramatically to accommodate these major changes in the materials that we re working with, and that s a major scientific effort that must be put in place, says Muzzio. Engineers, physicists, chemists, mathematicians, and pharmacists will be needed. Students who have the right engineering background and who have been exposed to these experiences will be needed. Muzzio et al. have outlined other areas of manufacturing that are in need of change, including controlling crystal size distribution and developing methods for making increasingly smaller crystals of increased purity drying very small particles, which tend to agglomerate upon drying improved scale-up and control of granulation processes methods for mixing or dispersing tiny Academic leaders agree that there are fundamental skills that no student, regardless of the discipline of study, should be without. To be successful in the industry, students should be proficient in independent thinking and problem solving written and verbal communication mathematics computer science/computational techniques. Beyond knowing how to use state-of-the art technology and current tools of science, says Wayne Anderson, dean of The University at Buffalo School of Pharmacy and Pharmaceutical Science, it is important that a student be able to think. In five years, these portions of mostly minute particles within a matrix of much larger ingredients better testing methods and blending performance assessment strategies more reliable and physiologically meaningful dissolution tests (2). Drug delivery systems also may change as a result of advances being made in the micro- and nanoscale delivery of controlled-release drugs. Robert Langer, writing in Science, has predicted that in the future, the intersection between nanotechnology and drug delivery may see exciting developments. Approaches involving microelectrical mechanical systems (MEMS) or microchips are being studied. An implantable system consisting of nanoliter-capacity reservoirs containing various drugs or different doses of the same drug may someday be realized (3). tools will have evolved and the knowledge base will have grown immensely. Students benefit the most with small classes, hands-on laboratory skills, discussion learning, and educators who are also on the cutting edge of research. One cannot overstress the importance of a program that allows a student to see how to analyze a problem and use problemsolving skills. Those who will succeed are the ones who are able to solve problems, says Anderson. If they don t have thinking and problem-solving skills, they re only as good as the first few weeks after they graduate or until the technology changes. Muzzio recommends that pharmacy students interested in careers in industry take some engineering courses. Courses from industrial engineering to general systems design to particle technology classes that typically are offered by material science departments could be beneficial. I expect that for the foreseeable 10 to 20 years, the actual design of pharmaceutical products as well as the manufacturing of products will increasingly rely on engineering skills. A growing number of companies are hiring engineers for jobs that 10 years ago would only be filled by pharmacists. The interdisciplinary approach Academic research at both the graduate and undergraduate levels has traditionally been conducted by one student or a small team of students and one faculty advisor, Circle/eINFO Pharmaceutical Technology August

5 all from the same department or research area. Students would work within their field and have little or only introductory knowledge of other disciplines. However, research has become much more complex, requiring an interdisciplinary or multidisciplinary approach. Combining concepts of several disciplines such as chemistry and computer technology or engineering and pharmaceutics has become more than a trend in education, it has become a necessity for solving real-world problems. That s just reality, says Pierce. The only way that you can tap these problems is from many different angles. You need somebody that understands the biological system to get the molecules, isolate the DNA or isolate the RNA from the tumors. You need someone who can do the biochemistry in the lab. You need someone who can get that information into a digital format. You need a computer scientist who can then develop algorithms or the programs that are used to understand it and then have to flow back to the biologist so that he or she can interpret it. And you should be able to take all of those different skills and wrap them up into one individual or group of individuals, each with their subspecialty. Collaboration among individuals of various areas of expertise is part of Dr. Hangauer s work. His research team consists of cancer biologists who conduct in vivo testing, a scientist who conducts enzymology studies, and another who conducts PK studies. Cross-functional team environments are an integral part of solving problems in an industrial setting as well. Cooperation between team members of a multitude of specialties is necessary to successfully carry a drug or delivery system through development and approval. Team members should at the very least know how the data that they are given have been generated. Those who discover or design the drug know information about the molecule s specific characteristics that could be useful to drug developers, who in turn have information useful for drug manufacturers. According to Muzzio, We need a multidisciplinary approach in which pharmacists contribute a lot of the understanding of the pharmacokinetics and the medicinal chemistry, the chemists know a lot about the basic material, and the engineer can conduct detailed modeling that allows for optimal design of the delivery pathway and the systematic manufacturing method to make it quickly, reliably, accurately, and stable. Conclusion Several reports have been written about trends in pharmaceutical science education. However, trends come and go, and their long-term staying power is questionable at best. Of the more than 3000 graduate-level students preparing themselves for an industry that requires leading-edge technologies and a highly skilled workforce (see sidebar Vital signs ), those who will succeed are those best prepared to combine their technical skills with the fundamental skills for professional growth and longevity (see sidebar Covering the basics ). Bioinformatics, pharmacometrics, combinatorial chemistry, and pharmaceutical engineering are some of the disciplines very likely to play vital roles in how pharmaceutical science is taught, how information is communicated, and ultimately the pace at which the industry progresses as a whole. Acknowledgment The author thanks James Pierce, Wayne Anderson, David Hangauer, Fernando Muzzio, Ellen Goldbaum, and Lynsey Grady for their time and expertise. More information about the programs discussed in this article can be obtained from University of the Sciences in Philadelphia: Buffalo Center of Excellence in Bioinformatics: edu Rutgers University, Pharmaceutical Engineering and Training Program: Department of Chemical and Biochemical Engineering, 98 Brett Rd., Piscataway, NJ American Association of Colleges of Pharmacy: References 1. B.J. Glasser, J. Cole, and F.J. Muzzio, A Comprehensive Approach to Pharmaceutical Engineering Training, Pharm. Technol. 25 (12), F.J. Muzzio, T. Shinbrot, B.J. Glasser, Powder Technology in the Pharmaceutical Industry: The Need to Catch Up Fast, Powder Technol. 124, 1 7 (2002). 3. R. Langer, Drugs on Target, Science 293, (6 July 2001). 4. M. Rios, Pharmaceutical Technology Pharmaceutical Technology Europe Employment Survey 2001, Pharm. Technol. 25 (12), PT Circle/eINFO Pharmaceutical Technology August