Lectures

Research In Molecular Endocrinology-Validation Of Reductionist Biology And A Case For Teaching Integrated Biology

by Kambadur Muralidhar

What should I speak on and about the great man whose memory we are cherishing and honouring?

Dr. Yellapragada SubbaRow is deservedly considered as the greatest medical researcher of all times but unofficially. He was not a Nobel Laureate or a Fellow of any national academy either of US or of India. Peer reviewed journal publications in which he figures do not tell the complete story of his efforts, his contributions and of the man himself. The story of his personality is in the league of all time classics or even epics of human civilization studied at a global level. His contributions to biomedical science should be judged not just from technical point of view but also from the point of view of value addition in terms of turnover of business in dollars, in terms of impact on human health and in terms of global reach of his discoveries. From these perspectives he would be in the league of Newton, Einstein, Socrates, Shakespeare, Vedavyasa, Edison, Graham Bell, Linus Pauling, Crick, Charles Darwin, Louis Pasteur, Ramanujan, Faraday and such others. These are not ordinary technical experts. They are the signposts of human civilizational growth. Truly, Yellapragada SubbaRow is a giant. Many Nobel Laureates look like pygmies in front of him.

Yet his personal and professional life is a life of contradictions. His life raises many questions deeply troubling humanity. What is the role of religion in human affairs? Are religion and science of the purest kind different from each other? Aldous Huxley said ends do not justify means. But SubbaRow's life disproves it. He did not demand any honour or recognition in order to realize the goals of his research. He loved Ayurveda but did remarkable work in modern molecular medicine and medicinal chemistry! He made contribution in the basic biology of muscle contraction. Each of his half a dozen contributions like Aureomycin, Diethylcarbamazine (DEC), Methotrexate, a derivative of aminopterin, Folic acid, ATP, deserve a Nobel Prize but he did not get even a professorship leave alone honours and awards! His life raises another important question. What is the purpose of scientific research-personal ego satisfaction, social status, monetary gain, diabolical goal of causing human suffering or simply making a career or realization of TRUTH? Is ethics part of scientific enterprise or not? I can add a newer dimension to this: Is research necessary to do good teaching?

I believe that all teachers should indulge in appropriate research to consolidate the knowledge, to keep motivation for learning and to become better teachers. I wish to relate our research in our laboratory and how it enabled me to become a better teacher of biology in spite of much inherent contradiction in my career, in the system and in our society in general. I wish to make two summary statements of this lecture.

One, molecular endocrinology is a powerful validation of reductionistic philosophy of biology. Two, my experience of this research cutting across disciplinary barriers enable me to propose teaching of integrated biology at school and undergraduate level.

I will make a written version about the second statement and the audiovisual version of the first statement.

A CASE FOR TEACHING INTEGRATED BIOLOGY AT UNDERGRADUATE LEVEL OF EDUCATION

Nature of Biology

Biology is the science of life. Biology is a historical science. It gives us the history of life on earth. Biology is the science of living state and living process. The living state is best understood from physical perspective. It is a non-equilibrium state as systems in equilibrium do not and cannot perform work. The laws of thermodynamics make us believe that every system moves towards equilibrium spontaneously. Hence, living is a metaphor for preventing one self from reaching equilibrium. This is made possible by constant input of energy into system. Energy is obtained by breakdown of dietary components. Energy is stored as chemical bond energy. Energy is utilized and transformed as osmotic, metabolic and mechanical work. Energy is partitioned between growth and reproduction. Environmental factors (physical like O2 tension, temperature etc; chemicals like pollutants, dietary toxins etc; biologicals like other organisms) constantly disturb the steady state. Organisms sense and respond to environmental factors to get back to steady state. Sensitivity and response to environment, and growth and reproduction are the cardinal features of living organisms.

Biology addresses three questions. One, origin of life and evolution of biodiversity in different ecological niches. Two, can we understand internal (physiology) and external (behavior) living processes through physics and chemistry? Three, what has biology contributed to human welfare? There are various theories of origin of life- some untestable and others testable. We are far from creating, in a test-tube, the simplest of life forms de novo from non-living material. However, man has learnt to manipulate and engineer existing life forms to newer forms.

Evolution from Darwinian point of view is more or less an accepted idea by all biologists. All the currently living organisms are related, to varying degrees, to all the organisms that ever lived in the past and to those that ever will live in future. The relatedness in structure and function is because of shared genetic material that directs all living processes. The functioning of genetic material (genes and non- genes) results in the entire physiological, developmental, behavioral and evolutionary phenomena. While some details of this translation of genotype to phenotype are known some other aspects are not yet understood. What is known of the translation as well as of the processes (physiological, developmental, behavioral and evolutionary) is the bulk of biochemistry and biophysics. Among many things not known is the mechanism that incorporates the concepts of time and space in these processes. Whether it is gene expression or growth or behavior, both intensify and duration appears to be involved. How do biological systems sense among other things time and space?

From the days of Rene Descartes, anthropocentrism has been the key approach for both generation of knowledge and utilization of knowledge. Man is the only animal who knows that he knows. When we add humans as study material to biology, an entirely new dimension to biology appears. Human biology and human evolution is of utmost importance to human race. Three aspects are worth noticing and discussion. One, like in plant, animal and microbial science, there has been considerable progress in human biology. Two, there are problems to be answered from epistemological, ethical and philosophical perspectives and three, evolution of human brain and its higher cognitive functions is the most challenging aspect of understanding biology. It is important to note that the observer and observed become one and the same here. The highest form of knowledge becomes self-knowledge. Biology, metaphysics culture and philosophy merge at this level.

Growth of biological knowledge

The history of biology as a branch of human knowledge is hardly 3000 years old at the most. Progress in any branch of knowledge much more so in science, depends upon the availability of tools and techniques. When observation (through eyes) was the only tool, branches that could grow were taxonomy, behavior and natural history. For centuries, this was the biology. For convenience of handling data, Zoology and Botany were the biological disciplines. When microscope became available other disciplines came (e.g.: anatomy, histology). Experimental biology brought in physiology and microbiology where abstract phenomena were related to structure. Being anthropocentric, the application part was medicine, surgery, pathology, epidemiology etc.

When reductionist biology took roots, biochemistry, cell biology, molecular biology, biophysics, genetics, physiology grew and flourished. Phenomenal progress in the advent of tools and techniques, not to speak of instrumentation made this possible. In the 20`h century while physics and chemistry continued to flourish as natural sciences laboratory science got delinked from natural history and phenomenological biology in general. Funding agencies contributed to this misery also. How did this affect university departmental structure with regard to teaching of biology? More than a dozen departments exist teaching some fragment of biology (e.g. Zoology, Botany, Microbiology, Genetics, Life Sciences, Medicine, Biomedical Science, Biochemistry, Biophysics, Physiology, Anatomy, Pharmacology etc). This is academically an unsound and unhealthy development. While research can be and can only be done in a small focused area, teaching has to be at a discipline level. What is a discipline? A set of self-sustaining concepts and techniques and questions constitute a discipline. Physics, Mathematics, Chemistry are discipline. Fragments of biology are not disciplines. Precisely for this reason in the last 3-4 decades these has been talk of interdisciplinary sciences and areas of research and training! The fact is, people created disciplinary boundaries for fragments of biology, created departments in their names and perpetuated a tunnel vision of biology. I am reminded of the elephant and four blindfolded men describing it! It is time we dismantle all these departmental structures and create and teach a single discipline of Biology in singular. Not even `life sciences' which is plural and means mixture and not a compound. We must integrate both vertically (Physics, Chemistry, Mathematics and Biology) and horizontally (Zoology, Botany, Genetics, Biochemistry, Microbiology etc.). Information transfer cannot replace understanding and concept driven teaching. This is more so at the undergraduate level.

Undergraduate teaching in biology

Because of historical accidents, we are faced with at least a dozen biology related undergraduate degree courses (e.g. Zoology, Botany, BZC, Microbiology, Biotechnology, Bioinformatics, Sericulture, Life sciences, genetics etc). A fundamental flaw in these courses is misunderstanding of what is an undergraduate level education. Put in simple words, it is a transition from 4-5 discipline study stage (high school) to one discipline study. At the undergraduate level, the student gets exposed to a set of courses leading to conceptual and broad understanding of a single core discipline with all its ramifications. (e.g. Philosophy, Social Science, Literature, Physics, Mathematics, Biology, Chemistry, Geology, Economics etc.) If one were clear about the aims of undergraduate education it would be fairly simple to see sense in what has been said just now. Undergraduate education (between 18-21 years of age) should help in developing an integrated personality through combination of self-learning, formal teaching and extra-curricular activities. It is a period of formal education where physical, mental (technical), cultural (emotional) and spiritual development should be realized to its maximum potential in each student. The experience should enable the students to either go further for employable training leading to jobs or for higher education, teaching and research. The ratio should be 10: 1. Truly motivated and talented students should pursue research and higher teaching. Postgraduate education should be integrated with research. Limited intake and quality output should be mandatory for research departments.

Today biology can be and should be presented as a conceptualized discipline. It is no more an information-oriented subject. In the last 5-7 decades primary data collection and description was the main research. There are over 13000 colleges, 300 universities, 500 medical, veterinary, dental, agricultural, biomedical teaching and research institutes in our country. In the last 10 years working with almost all funding agencies, a large sample of over 1000 research proposals and over 500 biology related departments (Zoology, Botany, Agricultural, Medical, Biochemistry, etc) have been analyzed and evaluated. India publishes over 12,000 papers in a year. Majority of publications, at least in biology related areas is repetitive and confirmative (Type III). A good proportion is innovative but consolidative (Type II). An insignificant percent is original and stimulating (Type I). If the figure of over 12,000 crores of rupees spent on research development and education is taken as true, this would simply mean that most of the expenditure has gone in building infrastructure and providing salaries. The returns in terms of value added knowledge based marketable products are negligible. In a list of one thousand benchmark papers in all branches of biology, both basic and applied, less than 10 may be coming out of Indian science. My conclusions are based, in addition, on examination of over 150 Ph.D. theses from more than 30 Universities and institutions. The solution for increasing the proportion of type II research lies in appointment of quality teachers, on one hand, and strengthening undergraduate education on the other hand. Optimization of resources, broad based training, and conceptual understanding of subject dynamics should be the aim of undergraduate science education in Biology.

Buffalo pituitary protein hormones

I will briefly present the nature of our research work on buffalo pituitary protein hormones and show that reductionistic approach to biology is nowhere more powerfully stated and proven than in molecular endocrinology. We have purified and characterized five hormones from water buffaloes i.e. Follicle stimulating hormone (FSH), Luteinizing hormone (LH), Prolactin(PRL), Thyroid Stimulating hormone(TSH) and Growth hormone(GH). We have modified the protocols to increase the yields enormously in the case of GH and PRL. We have isolated both of these from discarded side fractions which were going waste for years. We have characterized these proteins well especially with respect to microgeneity. We discovered an unusual post-translational modification in buffalo and sheep PRL i.e. Tyrosine-o-sulfation. We have isolated in bulk for the first time in the world isoforms of LH. We have produced and characterized polyclonal antibodies to these hormones. We have developed sensitive RIAs and ELISAS for measuring these hormones in circulation. We developed monoclonal antibodies to buPRL and used it judiciously to establish sandwich ELISA for PRL. This assay is more sensitive than the earlier polyclonal antibody based ELISAS. Ours is the only laboratory in the world which has reference preparations of all these hormones. Our work has relevance to the ongoing Embryo Transfer Technology programme of our country for herd improvement in water buffalo. Even though India is number one in total milk production in the world, the per capita milk yield is below the US average. Hence this programme. We are presently attempting to understand their molecular actions in the regulation of buffalo reproduction as well as to obtain these hormones by recombinant DNA technology to avoid using abattoir material.

Professor K. MURALIDHAR (b. 25 December 1948, Coimbatore, Tamil Nadu, India) is Professor of Biochemistry & Endocrinology at the Hormone Research Laboratory, Department of Zoology, University of Delhi. He is an outstanding teacher and is well known for his research in the area of protein hormone chemistry.

(E-mail: kambadurmurali2001@rediffmail.com)