A. Introductory Remarks

This essay highlights some of the critical stages of my scientific apprenticeship and intellectual development. It is dedicated to Professor David E. Hughes on the occasion of his 80th birthday and is also written to commemorate the 30th anniversary of the Microbiology Department at Cardiff.

​

Because of my interests in cultural and intellectual history and my belief in their importance, certain personal historical landmarks and remarks are included both in the beginning of and throughout this essay to set the scenes.
    

I was very fortunate to have a head-start in my scientific career: in the autumn of 1964,1 joined Professor Hughes' group as a junior research technician while his group was still located in the Medical Research Council Cell Metabolism Research Unit (headed by the late Sir Hans Krebs) in the Biochemistry Department, University of Oxford, United Kingdom. That was an unforgettable beginning of my research experience. I can distinctly remember being in an atmosphere in which the intellectual excitement and stimulation were seemingly endless and provided me with the motivation for hard work and for facing the challenges. Moreover,1 can still recall meeting some of the then junior scientists in Sir Hans' group within the Unit (e.g. D.H. Williams, A. Page, R. Hawkins, just to name a few) whose research areas parallelled mine In the late 1970's and 1980's. (For some of the references to their work, see my reviews (1,2)).

​

As will be evident in the discussions below, my early exposures to and

apprenticeship in scientific research have had lasting and important influences on my subsequent research directions and career. Because of space limitation, I will only highlight some of the key issues.

​

B. Impact of My Early Research and Undergraduate Experiences on the Development of My Research Directions and Career

I. Structure and Function of Brain Mitochondria; Development of New Isolation Methodology.

For about a year (1964-1965) I worked in the M.R.C.Unit at Oxford under the able tutelage of Julian Wimpenny and Jeff and Heather Cole. During that penod, I was taught cell breakage, subcellular fractionation, and enzymatic techniques that - were - and still are - critical in studies of structure and function of microbial and other cells. Under the expert guidance of my tutors, I invesigated the functional expression of tricarboxylic acid (TCA) cycle and respiratory chain enzymes in membrane-and-soluble fractions Isolated from E. coli own under a variety of growth and environmental conditions.

​

In the summer of 1965, Professor Hughes finally moved his laboratory from Oxford to Cardiff. Thus, I moved there with the other members of his group from Oxford: we became members of the then newly formed Medical Research Council Microbial Structure and Function Group. Other Group members, who were already in Cardiff, included David Lloyd and David Evans.

In my first year (1965-1966) at Cardiff, I continued to work closely with Julian Wimpenny and the Coles. The new excitement (and challenge) for me was to assist Julian in setting up the first continuous culture fermentor/vessel in the Department. Once the equipment was set up, I was put in charge of running it on a day-to-day basis. I recall having to learn to be technically competent in a variety of ways to cope with the diverse experiments in studying structure and function of E. coli and Yeast cells grown in continuous culture under different environmental conditions. During those "new Waves" of activities and learning, I was increasingly aware that I immensely enjoyed scientific research but also realized that I could not progress much further without additional formal training. Thus, with the advice, encouragement, and support of Professor Hughes and other members of the M.R.C. Group, I became a full-time undergraduate student (1966-1970) majoring in microbiology.

​

For my BSc Honours thesis research project, I chose to work on the effects of ultrasound on the structure and function of mitochondria isolated from
Tetrahymena under the joint supervision of Professor Hughes, David Lloyd and Terry Coakley. At the time, what attracted me to undertake the project was the multidisciplinary approach needed to frame the critical questions to be addressed both theoretically and experimentally. From the trio, I learned a lot about how to think scientifically from the viewpoints of a microbiologist, a chemist, and a biophysicist.

​

Just prior to undertaking my Honours project, I was fascinated by some of elements of the then new and emerging field of Neurobiology/Neuroscience. There were some novel but controversial observations concerning the process of learning and memory based on the applications of biochemistry and molecular techniques. I was particularly attracted to the possibility of furthering a better understanding of the functions of a complex organ such as the brain in through multidisciplinary research in which Cell Biology and Blochemical approaches play significant roles. Consequently, I thought deeply and extensively about how my training in Microbiology could be utilized in helping to pursue a research career in Neuroscience.

​

I was also convinced that any significant experience in multidisciplinary research could "open new doors". With this conviction I chose and began my Honours project. Being keenly Interested in the philosophy and creativity of science, I tried, through the many interactions with my three supervisors to determine how a multidisciplinary approach in defining and executing my project could be "engineered" from the perspectives of a microbiologist, a biochemist, and a biophyscist. In so doing I later appreciated - although I was not fully aware of the implications at the time - that I had to have learned a lot about how to define and execute a multidisciplinary project and, more importantly, about the various critical thinking processes involved.

​

While I was doing my Honours project, I recognized that I would need a broader and yet comprehensive introduction to brain function before initiating any research projects in Neuroscience. Consequently, I applied to the Neurocommunications (1970-1971), which was the only course of its kind in the UK in the early 1970's and involved a multidisciplinary study of information processing in the nervous system. During the Course work and discussions therein, I could apply - and did - many of the approaches (e.g Cellular, Subcellular, Biochemical, Applied Biology, and Bioengineering approaches) that I had learned as an undergraduate in Microbiology.

​

In the autumn of 1971, after graduating from Birmingham University with an MSc in Neurocommunications, I began my research project in Brain Biochemistry in John Clark's laboratory in the Biochemistry Department at St. Bartholomew's Hospital Medical College, University of London in preparation for a PhD degree. The major focus of my research was to elucidate the relations between the heterogeneity of brain mitochondria and metabolic compartmentation.

​

After a very critical review of the literature on brain mitochondria from the 1950's to the late 1960's, 1 came to the conclusion that the methodology then available was grossly inadequate to address the theoretical and practical issues and questions that I was framing. Thus, new techniques for the isolation of metabolically competent and relatively pure populations of brain mitochondria had to be devised. My solid background in Microbial Structure and Function greatly facilitated the critical thinking that ultimately led to my designing such methods. Furthermore, I recalled that I was able to bounce ideas off David Lloyd and Terry Coakley in the early stages, particularly in regard to the pros and cons of various cell disruption methods that could be applied to brain tissue. Thus, it was particularly rewarding and satisfying to me that some years late, my chapter on the isolation of brain mitochondria (co-authored with John Clark) also appeared in the same volume of Methods in Enzymology (3) in which David Lloyd's chapter on the general methodology for isolation and characterization of mitochondria from microorganisms was featured.

 

2. Metal Ions and Brain Function; Neurotoxicology of Metals                          

During my undergraduate studies, discussions, often cropped up regarding the division of research into the "pure" and "applied" varieties. One "camp" maintained that "pure" research is intellectually more challenging than and superior to "applied' research. On the other hand, some people - the stories of Ted Hill and Professor Hughes came to mind - argued that "applied" research could often yield results that can unexpectedly illuminate "pure" research. This contrast in research preference made me think, then and subsequently, about how the fruits of "pure" research can benefit "applied" research and vice versa. Consequently, even quite early on in my research career, I recognized the need to develop a dual-purpose approach in research orientation.

​

The dual-purpose approach in a particular area is usually developed so that the more "applied" aspects of my research will feed back positively to the more "basic" aspects of the same research area. This is best illustrated by my years of sustained interests in elucidating the neurotoxic mechanisms of manganese led to the emergence of discrete questions as to what the normal neurobiological roles of this metal may be (see 4 and references cited therein for further discussion). Additionally, I owed Sir Hans Krebs and his followers an intellectual debt for my formulation, in the 1980's (4), of the "Neurotransmitter Metabolic Cycle" (which was synthesized as a framework for the systematic investigation of the mechanisms underlying the neurotoxicity of metals).

 

3. Regulation of Intermediary Metabolism in Brain: Subcellular, Cellular, and Whole Organ Approaches ultimately become Integrated Approaches

Although space limitation precludes a more extensive discussion, my early research and other experiences in the Microbiology Department at Cardiff - not forgetting those at Oxford - have exerted distinct influences on and in part led to my sustained interests in the elucidation of control mechanisms in brain intermediary metabolism, ultimately culminating in my recent formulation of an integrated approach in studying metabolic control involving the merging of subccllular, cellular, and whole organ considerations (see 5 & 6 for a more detailed discussion).

 

C. Impact of My Early Research and Undergraduate Experiences on the Development of My Teaching Career and Directions

Besides the influences on my research career, my early research and undergraduate experiences have also had some remarkable effects on my teaching philosophies. I will just mention two of the many areas in which I have been aware of such effects.

 

1. Applications of Biotechnology to Pharmacology and Toxicology

Towards the end of my undergraduate days, the publications on the discovery of reverse transcriptase appeared. I was able to emphasize the significance of such a discovery in my teaching of the applications of Biotechnology to Molecular Pharmacology and Toxicology.

 

2. Cellular and Subcellular Approaches within the Interdisciplinary Context as
Applied to Problem Solving

My early exposures to the cellular and subcellular viewpoints in biomedical research undoubtedly left a deep and lasting impression on me in more ways than I can name. Thus, it is no surprise that I have been an avid advocate of showing the importance and versatility of such approaches in problem-solving in the various branches of Biology and Biomedical Sciences.

 

D. Conclusion

As I write these paragraphs, many fond memories of exiting and stimulating times - times often proved to be very taxing intellectually - "flash by in the front of my mind". Indeed, the vicissitudes of my journey from Microbiology to Neuroscience are not without rewards. I just hope that the inspirations and insights that originated from "the Hughes period" will continue to sustain me and my creative efforts for the rest of my scientific and teaching career.

 

References

1. LAI, J.C.K. & A CLARK, J.B. (1989). Isolation and Characterization of Synaptic and Non-synaptic Mitochondria from Mammalian Brain. In NeuroMethods Vol II (Boulton, A.A., Baker, G.B. & Butterworth, R.F., eds). pp. 43-98. Humana, Clifton, NJ.

2. CLARK, J.B. & LAI, J.C.K. (1989). Glycolytic, Tricarboxylic Acid Cycle, and Related Enzymes in Brain. In NeuroMethods Vol II (Boulton A.A., Baker G.B. & Butterworth R.D., eds), pp. 233-281. Humana, Clifton, NJ.

3. LAI, J.C.K. & CLARK, J.B. (1979). Preparation of Synaptic and Non-synaptic Mitochondria from Mammalian Brain. In Methods in Enzymology (Fleischer. S. & Packer, L, eds) Vol 55, Part F, pp. 51-60. Academic, New York.

4. LAI, J.C.K. & CLARK, J.B. (1985). Effects of Metal lons on Neurotransmitter Function and Metabolism. In Metal Ions in Neurology and Psychiatry (Neurology and Neurobiology) Vol 15 (Gabay, S, Harris, J, & Ho, B.T., eds), pp. 177-197. Alan Liss, New York.

5. LAI, J.C.K. (1992). Oxidative Metabolism in Neuronal and Non-Neuronal Mitochondria. Can. Pharmacol 70.S130.S137.

6. LAI, J.C.K. &  BEHAR, K.L. (1994). Glycolysis-Citric Acid Cycle Interrelation; A New Approach and Some Insights in Cellular and Subcellular Compartmentation. Developments in Neuroscience (in press).