Oral-History:James Bassingthwaighte
About James Bassingthwaighte
James B. Bassingthwaighte was born in Toronto, Ontario and grew up there until he finished his university years. Bassingthwaighte went to medical school and started working as a family physician in Ontario, Canada after graduation. Afterward, he received academic training in England at Hammersmith Hospital, the Postgraduate Medical School of London. Bassingthwaighte moved to the United States to join the residency program of the Mayo Clinic. He published his first paper on electrocardiography and has continued to pursue research on cardiac metabolism.
In the interview, Bassingthwaighte explains his ideas of research and teaching, recalling his experiences at various institutes. Bassingthwaighte pursued the Ph.D. in physiology where he developed mathematical models, on the transport through the circulation. He has combined physiology and biomedical engineering in his research and valued quantitative approaches, which is not common in physiology. Bassingthwaighte has paid a lot of attention to the interactions among physiology, biophysics and bioengineering.
The Mayo Clinic, despite its research-oriented program, was not an academic institution, so Bassingthwaighte accepted an offer from the University of Washington. He worked for five years as director of the Center for Bioengineering at the University.
In the interview, Dr. Bassingthwaighte noted that teaching can assist research; he put a lot of efforts in establishing educational agenda while he worked as the Center director. Bassingthwaighte has been working on cardiac metabolism and developing simulation models to understand cardiac cells. He is also engaged in the human Physiome Project, databases and developing thinking tools. The interview concludes with Bassingwaite discussing his belief in macroethical behavior.
About the Interview
JAMES B. BASSINGTHWAIGHTE: An Interview Conducted by Frederik Nebeker, IEEE History Center, 5 December 2000
Interview #279 for the IEEE History Center, The Institute of Electrical and Electronics Engineers, Inc.
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It is recommended that this oral history be cited as follows:
James Bassingthwaighte, an oral history conducted in 2000 by Frederik Nebeker, IEEE History Center, Piscataway, NJ, USA.
Interview
Interview: James Bassingthwaighte
Interviewer: Frederik Nebeker
Date: 5 December 2000
Place: Bassingthwaighte’s office at the University of Washington
Childhood, family, and education
Nebeker:
Let’s start with where and when you were born.
Bassingthwaighte:
I was born in Toronto, Ontario and lived there through my Kindergarten year. Then we moved to Belleville on the north shore of Lake Ontario, where I went to grade school. I spent my high school years in Ottawa and university years in Toronto.
Nebeker:
What did your parents do for a living?
Bassingthwaighte:
After my father came out of the First World War where he was first in the Canadian Army and then in the British Royal Navy on sub chasers, he became a lawyer. He decided he didn’t like that very much and went into the business world where he worked for DeForest-Crossley making the first radios and helped set up the company in Canada. (DeForest had developed the vacuum tube.) DeForest-Crossley Canada folded in the depression of the mid- thirties, resulting in the move to Belleville, where he ran Stewart-Warner’s radio division
He was manager rather than an engineer, but he learned a lot about the technology, though he was not trained in engineering. When war recurred in September 1939 he again joined the Navy, in the Antisubmarine Division. There he used his radio experience, and was involved in the whole sequence of events that led to the use of radar in submarine detection, working jointly with the U.S. and the British. His wartime duties involved quite a bit of travel. He wanted to be on a ship, but they weren’t about to let him on a ship with his age and the deafness he got from guns in the First World War.
Nebeker:
Did his work in those years influence you in making you interested in engineering?
Bassingthwaighte:
Yes, it did. I hadn’t thought of engineering in any serious way in my teenage years. I was enjoying skiing and track and a variety of other sports. My mother was interested in sports, but wasn’t particularly interested in engineering. She was a musician. Her father was a U.S. Consul and she grew up in France and Germany.
Nebeker:
Was she a U.S. citizen?
Bassingthwaighte:
Yes. Her mother was a Canadian from Peterborough, Ontario. Our family seems to cross the border every other generation. My sister and I both got involved in music because of my mother, so we had mixed influences. My youngest brother, George, was a successful pianist and composer in Toronto.
Nebeker:
When you were in grade school and middle school were you more interested in music than anything else?
Bassingthwaighte:
Not really. Though I played the piano fairly poorly in grade school, I was lucky to find an excellent teacher in Ottawa, Mrs. Taverner (the wife of the author of Birds of Canada, the Canadian version of Audubon.) She got me up to a good level of play, but my skills have been regressing ever since. I made crystal sets in grade school and communicated with a friend across the street in Morse code using a telegraph key my father had retrieved from a German submarine in Scapa Flow at the end of World War I. Actually I still have it.
Nebeker:
There are many engineers who built crystal radios, telegraphs and things like that when they were boys.
Bassingthwaighte:
I have to admit my Morse code has gotten pretty rusty. It was not too bad at one point. I could listen to the radio.
Nebeker:
Did you listen to coded transmissions during the war?
Bassingthwaighte:
Yes, that was a favorite pursuit. Some of this must have fused into my brain stem, because when I was trying to pick my way to university it was kind of a choice between going into electrical engineering or going into medicine. I made applications to both at the University of Toronto, and struggled with a decision when I was accepted by both.
Nebeker:
Did you go say you went to high school in Toronto?
Bassingthwaighte:
I was in Toronto for my last year of high school, Lawrence Park Collegiate. My earlier years were in Lisgar Collegiate in Ottawa. I was lucky, as these were my neighborhood high schools and they were then the two best in the Province. I got offered a scholarship that wasn’t for either electrical engineering or medicine but for an honors science program. That was the most economical choice, therefore I went into it. It was heavy on math, physics, chemistry and biology.
U. of Toronto
Bassingthwaighte:
Then I took the physiology and biochemistry path for my Bachelor’s degree.
Nebeker:
Were you thinking in terms of being premed in those years?
Bassingthwaighte:
I had been accepted into Premed but took Honors Science instead. At the University of Toronto the route to the M.D. was six years: two years premed and four medical years. One enters it right out of high school. I backed off to take the longer program because I liked the look of it. However when I finished the four year science program I went back into medicine, another four years to the M.D.
Nebeker:
You probably got a lot more physics and math than in straight premed.
Bassingthwaighte:
Yes, a lot more.
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Things happen by chance. It got me into research, because after my second year I started in research. The summer of 1949 and part time during the school years of ‘49 to ‘51 were in the lab of Reg Haist (Prof, Physiology) and Charles Best (Chair, Physiology and Nobel prize winner for the discovery of insulin with Banting and McLeod). In his lab I looked at the influence of insulin on muscle uptake of sugar to form glycogen in muscle cells. The technique was one from Otto Warburg, the discover of Vitamin B2, in the 1920s. The experiments were on rat diaphragm muscle, a thin muscle only several cells thick, so the diffusion of glucose into the muscle was rapid.
One experiment was to simply dip the muscle into an insulin-containing solution for 3 seconds, rinse it off thoroughly, then put the muscle into the Warburg apparatus and after 30 min. measure the glycogen content to determine the insulin effect on the incorporation of glucose. This was done in comparison with a muscle that wasn’t dipped into insulin solution. The brief dipping in insulin solution caused a remarkable increment in glucose uptake simply because the insulin binds to the surface of the cells (we now know that the binding site is the glucose transporter) and facilitates the glucose uptake. It was a very simple experiment with 1920s apparatus, yet it told us something about the rapidity of even a superficial introduction of insulin into the system. That was my introduction to the physiology of metabolism. something to which I am returning now in modeling cardiac metabolic systems.
Air Force training, Institute of Aviation and Medicine
Bassingthwaighte:
In 1950 I was in Air Force officer training at Crumlin Air Base, London Ontario. This led to summer research the next two summers at the Institute of Aviation and Medicine. In 1951 I worked with A.W. Farmer, Professor of Surgery at the Hospital for Sick Children, and Professor Wilbur Frank at the Banting Institute, both at the University of Toronto, and was asked to design and develop instrumentation to measure the spreading and disappearance of fluorescein injected along with hyaluronidase into the skin of the forearm. It involved having a source of ultraviolet light and a receiver that excluded the source light and looked at the fluorescence. In that way the fluorescence could be looked at as a function to time after injecting a tenth of a milliliter of fluorescein-containing material into the skin. I designed the instrument and the circuitry and contracted out to get the device built, a huge, heavy thing. We observed fluorescence intensity to determine whether the rate of disappearance of fluorescein was affected by the hormonal level of corticosteroids in the blood. At that time it was thought that this might become a useful clinical measure of the stress levels in children in the Burn Unit at the Hospital for Sick Children. The first summer was on the instrument development and the second, 1952, on using it in the Burn Unit. I didn’t think of it as biomedical engineering, but it was.
Nebeker:
Did that technique prove to be useful?
Bassingthwaighte:
It was all right scientifically, and high cortisol levels did retard the fluorescein disappearance. High corticosteroids inhibit hyaluronidase and so retard spreading of the wheal and the washout of fluorescein. However from the point of view of using it on patients it was not particularly valuable. It had to be done at night in a darkened room. It required an intradermal injection into children who were already hurting. It was only a little intradermal wheel, but it was questionable whether the information was worth it. Therefore it was never turned into a standard clinical test. Wilbur Frank was the man who first built a human centrifuge, and used it to obtain physiological information on the effects of gravitational stress on pilots diving airplanes. He developed the first antigravity leg cuffs for pilots during World War II. I was not involved in that effort of his.
Nebeker:
The flight medicine work in World War II was one of the first areas for biomedical engineering.
Bassingthwaighte:
Yes. By coincidence I ended up several years later working with the man who pioneered flight physiology in the USA, Earl Wood, at Mayo Clinic, Franks’ chief competitor. Earl Wood had developed a more effective antigravity flying suit, and was my advisor in research at Mayo.
Medical studies and practice
Nebeker:
You took the honor science program at Toronto and decided that you wanted to go into medical school after that.
Bassingthwaighte:
Yes, I obtained my M.D. from Toronto, and interned at the Toronto General Hospital. I met my wife Joan in the summer of 1954, and we were married the day after graduation in 1955. After finishing rotating internship in June of 1956 I went immediately into practice because I was totally broke. I had an “Arrowsmith” ideal. Arrowsmith (a novel by Sinclair Lewis, 1925) wanted a medical practice in which he was able to do both research and teaching. My ideal was a small community where I could do everything. However Lewis’ fiction was only a fairy-tale for me as a small town practice scarcely allows that.
Nebeker:
Had that book influenced you?
Bassingthwaighte:
Oh yes. It seemed so idyllic and conceptually desirable to have this mix of advancing the cause through research and while also putting it into practice. And I still hold to that ideal. I have to put it into effect in a different way than Arrowsmith did in the book.
Nebeker:
I have heard Arrowsmith named by other people who said that it inspired them. There are not many examples in literature where an engineer, scientist or doctor is the exciting main figure.
Bassingthwaighte:
There were other good books I read when I was young. There is a classic biography of Louis Pasteur by Valerie Radot. It was written in the early 20th century. That had something of the same elements. It’s a beautifully written book. I know there is a newer biography of Pasteur, but the ancient one was really good.
Nebeker:
How was medical school and internship?
Bassingthwaighte:
I don’t think the medical schooling was quite as bad as it is now. Medical schooling nowadays is not a high-level intellectual endeavor, but is a situation in which one memorizes a lot of material, and is much less of an intellectual exercise in how to solve problems. I think that is somewhat shameful, but people argue that they have to get all that material stuffed into them. It’s a debatable issue, but I believe that medicine should be taught on how to think and how to solve problems. Yes, one has to have the material, but that’s only the beginning. I survived medical school. I did all right, and actually enjoyed internal medicine because it was the one that included the most solving of problems. During medical school I continued some research, and my first paper was on plasma substitutes in burn shock.
Nebeker:
Was any of this research biomedical engineering?
Bassingthwaighte:
Not really. In the summer of 1954 I worked at the Defense Research Medical Labs on nerve gases. These incapacitating and killing gases that are potentially weapons of war. I worked on how to prevent or at least minimize their effects: they are acetylcholinesterase blockers; I worked on assessing the effects of adrenalectomy on the drug effects and on counteracting them with atropine. Nerve gas damage is only partially treatable, but atropine syringes were carried by personnel in the Gulf War.
Nebeker:
You had the ideal of practicing medicine and doing research and educating. Had you decided in what type of research you were most interested?
Bassingthwaighte:
No, not really. Internship had paid $25 a month, and financial survival precluded taking advanced training right then. I started internship a week and a half after graduation; nine months and a week later we had a baby, Anne, who is now the Commissioner of Health for the State of Virginia. My wife had been working as a geographer in the Ontario Department of Planning and Development to support us. With the new baby she had to give up that job, so I went into practice with International Nickel Company in Sudbury, Ontario after finishing internship, working as a general practitioner in the company clinic, delivering babies, treating patients in office or the hospital or at home.
Then my wife’s uncle, who worked as a family physician in Matheson, farther yet north in Ontario, pleaded with me to come and work with him. He was practicing by himself in a remote area with about a 50-mile radius that had 7,000 people in it and was very tired. He had not had an assistant in his practice for over three years. I succumbed to that and went up to work with him in his practice. He paid me about the same as the International Nickel Company had, $10,000 per year. I moved there New Year’s day, when it was 65 below zero Fahrenheit. Three days later it was 68 below; every day in January hit 50 below. The car, which we had to keep outside, would barely start, and bumped along for the first 5 miles as the tires gradually unthawed and rounded up.
Nebeker:
I suppose you didn’t have regular hours.
Bassingthwaighte:
Yes, we had regular hours. We started at 7:00 a.m. with hospital practice. I was the chief of surgery and he was the chief of anesthesia; I was the chief of obstetrics and he was the chief of medicine. We ran a 35-bed hospital, with an excellent nursing staff.
Nebeker:
Just the two of you?
Bassingthwaighte:
The two of us were by ourselves in this town 400 miles north of Toronto. His total practice income was $27,000 of which he paid me $10,000. We charged $1 for office calls; house calls were $3. We had afternoon hours and evening office hours. A month and a half after I got there he decided he’d waited long enough and was going to take a vacation. When he left for a month, I learned what he had suffered. I had the hospital hours plus the afternoon and evening office hours until 10 o’clock every day as he had been doing in the preceding years.
Nebeker:
My goodness.
Bassingthwaighte:
That included Saturdays. Of course I couldn’t get out of the hospital practice on Sundays, but the office was closed. It was very busy, but interesting, and I was close to the people. The population was about half French and half English.
Nebeker:
Did you speak French?
Bassingthwaighte:
I got better at it. I had taken French in high school and could read it OK, but wasn’t very good at hearing it, but people were patient with me.
Nebeker:
How long did you do that?
Bassingthwaighte:
I stayed only nine months, and then went to England for academic training at Hammersmith Hospital, the Postgraduate Medical School of London, which was the number one place as far as the British Empire was concerned.
Postgraduate Medical School of London, Hammersmith Hospital
Nebeker:
I could imagine that it would be difficult to get accepted there.
Bassingthwaighte:
They gave a course in which people could participate without charge. I was pretty good as a student, so I was accepted into this course, which was kind of an honor. It was a course people took toward their MRCP (Member of the Royal College of Physicians) and FRCP (Fellow of the Royal College of Physicians). People used it to top up their training. I came into it at the other end, having no advanced training in medicine. For the most part, my colleagues were a few years ahead of me. That was good fun for me, being very smart people selected from all over the world. It was just a wonderful environment.
When it finished the one-quarter course in December I applied for a house physician job in the hospital, which was very competitive. People from Australia, South Africa, New Zealand, Canada, Scotland, Ireland, and of course England, were competing for positions. It was the big deal. I suspect, but don’t know, that I got in because my Professor of Medicine, Ray Farquharson, at Toronto put in a good word for me to his friend Sir John McMichael, the Professor at Hammersmith. When they’ve got so many good people from whom to choose, I suspect that things like that tip the balance. I was the only Canadian in that system that year, and they needed to have a token Canadian on the Department of Medicine’s cricket team who might be able to throw a ball. They had to handicap surgeons’ cricket team and the medical team equally. This was ‘57 - ‘58.
Nebeker:
It must have been exciting to be living in London as well.
Bassingthwaighte:
Well, we didn’t do much fancy living. We were still pretty broke. We met wonderful friends, with whom we still keep in touch: Howard Duncan, Jenny and Peter Last, who brought lots of Jenny’s father’s wine to London, Peter Francis, John West, now at UCSD. London is a great city of course, and the theater and music were wonderful.
Hammersmith was a neat spot to be, and certainly from an educational point of view it was a highlight for my career. I remember explicitly the teachings on how to examine a patient’s heart, what lung disease did to a patient, how Sheila Sherlock’s liver patients could be helped, and many other things that were so important to my learning experience.
Nebeker:
Is the Canadian medical education system essentially the same as the English?
Bassingthwaighte:
It is somewhere in between American and English.
Nebeker:
Then it wasn’t a big shock for you to be in different system?
Bassingthwaighte:
No, not from the point of view of background training. In order to survive financially while there I also took on a weekend job as a Senior Registrar at the German Hospital in London. I had no trouble being a Senior Registrar teaching the juniors. The senior registrar is an assistant to the faculty. It’s like being the senior house staff at the top of the residency heap at a university hospital. The German Hospital was not a university hospital at that time or they wouldn’t have hired me. Queen Victoria set up that hospital before the turn of the century when the English royalty were so closely to the Germans, and it had a wonderful heritage of superb medicine. For example, Weber, the physician-in-chief around 1910 published two superb books, “Rare Diseases”, and “Further Rare Diseases” in which he described in careful detail a number of diseases that did not become identified or understood for another fifty years. He was a marvellous observer and described these in such clear precise detail that they paved the way for later discovery of their causes and chemical and pathological nature.
Nebeker:
Maybe with the extent of the British Empire he would encounter some rare diseases that other people would not have encountered.
Bassingthwaighte:
Definitely. People came from all over the world to the German Hospital, Queen Victoria having married into the Hapsburgs. It was the big hospital in London during her time. Weber was a German who took the post in London because of the prestige of that particular hospital early in the century.
Nebeker:
Were you also working as a house physician?
Bassingthwaighte:
The Registrar job was just for two weeks over Christmas, as a substitute “locum tenens” position while someone was away.
The house physician job starting January 1, 1958 was a full-time job, renewable every six months. This was a wonderful situation, giving me the run of the hospital and its abundance of patients who didn’t mind teaching me about their problems, and faculty who had to be about the best in the world, scientifically and socially, as patient-oriented physicians.
Mayo Clinic; cardiology research
Bassingthwaighte:
By early spring I was running out of money again, so I applied to five places in the U.S. that paid a salary. Toronto still paid a salary of $50/month in specialty training, so I didn’t apply there. I wrote to five places that paid $175 a month. That was the criterion. Life is just a chance, right? I selected them from the books on residency training on that basis. I didn’t really know where they were or really the quality of the work they were doing. I wrote to Columbia-Presbyterian, Mayo Clinic, the Woods VA Hospital in Milwaukee, and two other places. Two weeks later I got a telegram from the Mayo Clinic inviting me to join their residency program.
After another two weeks I still hadn’t heard from anyone else, and didn’t know what to do. “Should I go to the Mayo Clinic? Where is that? Rochester. That’s just across the lake from Toronto, isn’t it? No, it’s out in Minnesota.” I decided I couldn’t sit on it any longer. By lucky happenstance, Howard Burchell, an eminent scholar and cardiologist from the Mayo Clinic, came to Hammersmith and gave a lecture on congenital heart disease. It was a good lecture. I talked to him about the place and liked what he told me. So I telegraphed my acceptance to Mayo.
I didn’t know it at the time, but Dr. Burchell was also born in Toronto and worked at the Mayo Clinic for his career. Because of him and because Mayo was so efficient in sending their invitation, I ended up going to the Mayo Clinic for internal medicine and cardiology. I wrote my first paper, about electrocardiography, with Howard Burchell as one of the co-authors.
Nebeker:
Electrical engineering is back into it.
Bassingthwaighte:
I did vector analysis that looked to me to be the right way of approaching the problem of understanding the relationship between the electrical currents and the cardiac muscular contraction in pulmonary valve stenosis. My clinical colleagues, including Dr. Burchell, weren’t expert in vector approaches, so they thought it was a great paper. That was fun for me and for them. That became part of my cardiology training.
It was a Mayo Clinic policy and a requirement to train residents in research as part of their training. I hadn’t known this when I applied, but it was just what I wanted. This was the equivalent of a Master’s thesis. Therefore I embarked on six to nine months in cardiology research as a part of residency training.
The Mayo brothers, Charles and William, had established in 1915 the Mayo Foundation for Education and Research. The thesis was that the practice of medicine is one leg of a three-legged stool, and the other two legs being research and teaching. The Mayo Clinic puts substantial monies into the Foundation in order to allow that to happen.
Nebeker:
It sounds like it was a very good place for you. And I assume you were still interested in research.
Bassingthwaighte:
It was a good place to go. In going back into the research lab I chose to work with Earl Wood, the one who had developed the antigravity flying suit with Charlie Code and Ed Lambert in the 1940s and competed with my early mentor Wilbur Frank. He was interested in cardiac catheterization, so I went there to learn cardiovascular physiology and cardiac catheterization. He was a very good scientist and developed all manner of instrumentation for oximetry, for high fidelity blood pressure recording, and other things.
Nebeker:
What was his background?
Bassingthwaighte:
He was an M.D. with a Ph.D. in physiology from Minnesota under Maurice Visscher on the effects of potassium on cardiac contraction. He was a fastidious investigator, and still is. Whenever he needed a new type of physiological information he developed the instruments and techniques that would provide him with it. There was a man named Dave Clark who had manufactured the antigravity flying suits that were used in the latter part of the war. Clark was also interested in optics, so he had gotten onto some specialized photo detectors and Earl, from his collaboration with Clark, used this in part of his research. Earl Wood developed ways of recording with very long light beams. He used galvanometers with high sensitivity and in order to get amplification used light beams a couple of meters long. In order to record the signals accurately, he used photographic paper that was about two feet wide on which one could simultaneously record ten or fifteen signals from different galvanometers continuously. Our cardiac catheterization took advantage of those for recording pressures, indicator dilution curves from optically absorbing dyes, the electrocardiogram, respiration, syringe injections and so on. He developed indocyanine green densitometry for estimating cardiac output and for the diagnosis of congenital heart disease. His trainee I.J. Fox obtained this particular dye from Kodak. I wrote several papers on indocyanine green, on the kinetics of its binding to albumin and its shift in spectral absorption as it binds. Wood’s lab created an atmosphere not only with the equipment he already had there, but the ability to build new equipment and devise new schema for doing high quality research. That was a right place for my kind of thinking.
Physiology Ph.D. research, mathematical modeling and circulation
Nebeker:
And what exactly was the work you did there?
Bassingthwaighte:
What I did for my thesis work for the Ph.D. in Physiology, with Earl Wood as my advisor, was to determine the transfer function of a portion of the vascular tree, namely that of the artery in the leg going from the femoral artery in the groin to the dorsalis pedis artery on the top of the foot. To do this one makes an injection of indicator (we used indocyanine green) into the external iliac artery, records the resultant concentration-time curves at the entrance to the system under study, at the femoral artery, and the response at the other end of the system, the dorsalis pedis artery. We built a system to carefully characterize the shape of the input function at the upstream end and look at the output function at the downstream end.
Nebeker:
Is this a mathematical model?
Bassingthwaighte:
Then we developed a mathematical model to describe the system’s probability density function of transit times, its impulse response, h(t), which defines the relationship between the input dye curve, Cin. and the output dye curve, Cout. The relationship is a convolution: Cout(t) = Cin(t) * h(t), where the asterisk denotes a convolution integration. I worked with a former student of Earl Wood’s, Homer Warner, who was then in Physiology at Utah and ran the catheterization lab at the Latter Day Saints Hospital in Salt Lake City. I spent two summers with Homer working on some of the mathematical aspects of it, because he had a big analog computer. The model needed to account for the spread of indicator within the vessel as it travelled from the femoral artery to the foot. There are quite a few models that might do this: the spread is not random (Gaussian) but right skewed, because of the slow velocities near the wall of the vessel. We found that combination of a random process and a skewing process described the data best, the so-called lagged normal density curve.
Nebeker:
Was this also modeled on an analog computer?
Bassingthwaighte:
We began this as an analog computer model. A convolution integration is essentially a digital process, unless you can write the transfer function as a differential operator, something that one cannot do for a lagged normal density function. If you ever saw something strange, it was doing a convolution integration on an analog computer. You had to have a perfect gain of one through a system and then do repeated recordings onto a tape in order to do the integration. It was crazy, and very tedious, but worked. To make things simpler in the analysis, the two recording transducer systems at the femoral and dorsalis pedis arteries were made identical. Then when the deconvolution is done using the recorded signals as Cin(t) and Cout(t), a result is achieved which is the same as the deconvolution between the intra-arterial input and output of the system. That was the operational approach. The result was that the same model characterized the system over a wide range of flows.
Mathematical modeling applications
Nebeker:
What made this question of interest to you? Is this basic physiology to know what’s happening with circulation, or did it have an application at the time?
Bassingthwaighte:
This was an extension of what had been started by G. N. Stewart in 1893. Stewart looked at the transport through the circulation and how long it takes to get from point A to point B. In his time and in some earlier experiments, people had looked at transport time. For example they injected in the vein something that could be tasted in order to get arm-to-tongue transport times. This gives fairly precise information on how long a drug would take to travel through the circulation, and then one can infer how much longer other aspects of its transit to effector sites might take: permeation through cell walls, diffusion, time to inactivate an enzyme or such.
Nebeker:
Okay. What this just to better understand the circulatory system?
Bassingthwaighte:
One reason is to want to understand its hemodynamic characteristics. Another is to characterize the changes that occur when there are changes in flow through a limb. Third, potentially this same femoral-to-foot transfer function might be used diagnostically to assess limb flow in patients with ischemic arterial disease.
Nebeker:
If enough of it were characterized some circulatory problem might even be localized?
Bassingthwaighte:
Certainly it could be ascertained whether or not flow was below normal, and whether the characteristics of the flow were abnormal. Blood flows with the velocity profile across a vessel, with the highest velocities at the center and lowest at the walls. Characteristically, the flow of blood through an artery is not like water in a tube; it is less dispersive, and the bolus travels more compactly. A question was whether that would differ in people with atherosclerosis. The most important diagnostic test is what if the level of flow, rather than its dispersive characterisitics. People are now approaching this kind of characterization with ultrasound and magnetic resonance imaging (MRI) because these are noninvasive. The femoral artery can be pulse labeled with MR in order to look for the response function at downstream points. That’s what people do in carotids, femorals, and other major arteries where atherosclerosis is a concern. The actual mathematical technology that we developed is not really used diagnostically but is in research.
Nebeker:
Is that right? That’s quite a span of years from when you began working on it.
Bassingthwaighte:
Most of forty years.
Nebeker:
That must be gratifying for you that this mathematical modeling is still of interest.
Bassingthwaighte:
Indeed. And that kind of beginning expanded into other applications of mathematical modeling which we have used for image interpretation using positron emission tomography and MRI, particularly for the measurements of flows and metabolism within organs.
Mathematics and physiology education
Nebeker:
I have noticed that a lot of your papers seem to be mathematical. Did you take a lot of mathematics in college?
Bassingthwaighte:
Not nearly enough. I basically picked it up along the way. I didn’t give myself a very good start. In first year at Toronto I took math, physics, chemistry and biology in the honor science program. I didn’t go to the calculus classes all year.
Nebeker:
Was that because you already knew that?
Bassingthwaighte:
No, I didn’t know it, but it seemed boring. Three days before the exam I realized I had better do something. I learned enough to pass the exam, and get an A, but that isn’t a way to get an in-depth feeling for a subject. I really had to learn it later. Taking on problems in measurement and analysis of various signals and trying to measure transfer functions and do deconvolutions forces one back to learn some math. I took advanced calculus later. When I got into doing the experiments on the leg arteries I took the 1961-2 year to go to the University of Minnesota courses in differential equations, advanced calculus, and systems analysis as a part of my Ph.D. program. I actually took an EE course in network analysis, a very useful course. I was in over my head, taking a third year EE course when I was just starting differential equations, but I survived. I absolutely flunked the midterm in that course, but was third in the class by the end of the quarter. The reason it worked so well for me was that when the instructor was talking about RLC circuits and Kirchhoff’s laws and nodes and loops, I was hearing him while translating into one or other aspect of physiology. I knew a lot of physiology after all those years in Toronto and in medicine and in Earl Wood’s lab. Everything was physiology. That was great, and it allowed me to understand it readily. It also gave me a feeling for why it would be useful and made it so that it wasn’t just a trying to get through the course kind of game, but rather, “I need this stuff.”
Experimental studies, human subjects
Nebeker:
Earl Wood was your advisor?
Bassingthwaighte:
Yes, and he was a wonderful advisor, giving lots of freedom as to the direction of the research, guiding when desired, and allowing undertakings that were not supported by his grants. He explained to me carefully that characterizing arterial transport functions was not his game. “Your experiments, Jim.” Earl and John Shepherd, his colleague and later, after Charlie Code, the department chair, helped on many occasions. These were all human studies. The subjects for the studies were my friends who were all physicians-in-training at the Mayo Clinic. It was traditional at that time to serve as subject for experimental studies.
Nebeker:
And they put up with it for that reason.
Bassingthwaighte:
Yes. I was a subject for many other people’s experiments. It was all fair trade. We did what was reasonable and safe, and took lots of precautions, but there were no oversight committees in the early sixties.
Nebeker:
There’s a long tradition of medical researchers experimenting on themselves. It had always been done.
Bassingthwaighte:
Exactly. Some of the experiments were very strenuous. Earl Wood was still running the human centrifuge at that time, doing studies on responses to gravitational stress.
Nebeker:
Did you ever sit in the centrifuge?
Bassingthwaighte:
Many times. There is one particular day I remember most, when I had seven runs at 5 G lasting 5 minutes each.
Nebeker:
What do you experience on a roller coaster? Do you know?
Bassingthwaighte:
Roller coasters are usually less than 2 G. At 7 G one can’t lift one’s arm. I’m not that strong, but I couldn’t lift an arm and certainly not a leg.
Nebeker:
You don’t black out at that rate, do you?
Bassingthwaighte:
No, because I was in the Mercury position reclining back at such an angle that blood still gets to the head, but the chest is compressed and it is hard to breathe. One does deoxygenate a little bit, because the blood is under gravitational stress. Due to reclining on the back, the blood goes to the back of the lungs and the air goes to the front of the lungs so the blood is not fully oxygenated.
Nebeker:
How did you feel at the end of that day?
Bassingthwaighte:
When the centrifuge starts up I got a little dizziness, but when it ramped down I got serious vertigo. As it stops there is a short turn radius and there is this forward tum¬bling along with a side tumbling sensation. I am much more resistant to motion sickness than the average person and could tolerate that, but it’s stressful and tiring as well. At the end of a day with tubes in several orifices and arterial and venous catheters one is pretty tired out.
This wasn’t part of my thesis but was someone else’s thesis. Having a lot of interesting activities like that going on, plus other experiments in other faculty members’ labs made it a very interesting place to work.
Instrumentation Department
Nebeker:
Did Earl Wood have any electrical engineers working with him?
Bassingthwaighte:
Yes, he did. We had an instrumentation department that I guess had five engineers and seventy people. The early cardiovascular bypass surgery equipment was all designed there. I still have one of the pumps and still use it regularly. It is a pump that was used for bypass surgery since it doesn’t hemolyze blood very much because it’s got such good fitting of the rotors to the tubing. There were a lot of interesting developments achieved in the Instrumentation Department.
Ph.D. studies and colleagues
Nebeker:
Do you think your Ph.D. was well regarded?
Bassingthwaighte:
I think so. We had the Ph.D. exam in Minneapolis because Earl Wood’s chief, Maurice Visscher, had been my advisor during my year up there. Earl told me as we drove together back to Rochester that I was his best student; I assumed he meant among his current crop, for he had had some outstanding trainees in his program.
Nebeker:
I think I know that name, Visscher.
Bassingthwaighte:
He was a wonderful man. He took the Chairmanship of Physiology at the University of Minnesota in 1935 when he was thirty-five years old. His first two students were Earl Wood and Gordon Moe. Gordon Moe did wonderful work on arrhythmias at the Masonic Research Institute in Utica, New York. Out of that spun a whole area of arrhythmia work. Jose Jalife in Syracuse heads up the unit that is its successor. Gordon Moe and Earl Wood had done their Ph.D.s together looking at the effects of changes in potassium on heart muscle contraction.
Through Earl Wood to Morris Visscher, I figure that I am the scientific great grandson of Ernest Henry Starling. Morris Visscher was Starling’s last postdoctoral research assistant. Starling is the revered one who established the utility of the heart-lung preparation, the isolated heart preparation, and defined the balance of transcapillary water exchange. That’s where Visscher learned a lot. Then Wood used the isolated heart when with Visscher. I didn’t study isolated hearts while with Wood, but I use them extensively today, almost a century after Starling started.
Postdoctoral appointment and research, Mayo Clinic
Nebeker:
Did you stay on at Mayo Clinic after you completed your Ph.D.?
Bassingthwaighte:
Yes. I had completed Board requirements in Internal Medicine and done a lot of cardiology. and was given academic appointments in both Medicine and Physiology. I was actively doing clinical catheterizations as I completed the Ph.D. Then the catheterization lab was moved out to St. Mary’s Hospital, which was a more suitable place than in a physiology building. I decided I was not going to move with the cath lab but was going to stay in the more basic research. By the time I finished my thesis I wasn’t doing very much in terms of clinical care. I was trained in cardiology, but never took the cardiology specialty boards.
Nebeker:
If you weren’t going into practice then it probably wasn’t important to take those boards.
Bassingthwaighte:
Exactly. At that point I knew how to practice cardiology pretty well, partly from the English training and partly because of people like Howard Burchell and Tom Parkin and others on the faculty at Mayo Clinic. That was very good cardiology practice at Mayo and a first class group of people. I would have been a competent cardiologist, but I felt that they were many of my fellow trainees who were also, and I had something to offer on the research side.
Nebeker:
What was your next area of research?
Bassingthwaighte:
I did go into a new area of research, but I should tell you a story behind it first, because it is revealing in a way. I had a very good friend, Tony Edwards, who was working with Earl Wood in the lab when I started there. Earl assigned senior fellows to work with junior fellows. Tony Edwards had come from the University of New South Wales and was doing a postdoc. Tony and I worked together on the indocyanine green densitometry and became very good friends. In conversations over several months we asked ourselves what we were going to do with our research lives. What fields should we pursue. We decided that cardiac mechanics was passé. We thought that had been really well worked over and we didn’t need to spend time there since so many others were doing it. (We were totally wrong. There has been forty years of work done since then and there are very good things yet to be done.) Tony chose to go into respiratory physiology and gas exchange. He was exceptionally talented; he accepted a post in Physiology at the University of New South Wales, in Sidney, Australia, and embarked on a rapidly ascending career, tragically cut off by a lethal carcinoma of the bowel. I chose to look at cardiac metabolism, which was not being explored at that time, and to try to develop techniques for doing that. To start that off, I started doing multiple tracer indicator dilution experiments.
Cardiac metabolism research, multiple tracer indicator dilution experiments
Nebeker:
Dye tracer sorts of things?
Bassingthwaighte:
At that time it was with radioactive tracers, but it also works with dyes as long as one can separate them. I needed to use pairs or triples of substances simultaneously. The idea is to use reference tracers along with the tracer-labelled substrate of interest, e.g. D-glucose, the metabolized form. D-glucose (labeled with 14C) passes through the interendothelial clefts of the capillary endothelial barrier, and enters cells via a specialized transporter. Suitable reference tracers are albumin (labeled with 131I) which remains inside the blood stream and does not escape across the capillary wall, and L-glucose (labeled with 3H) which passes between the endothelial cells of the capillary wall in exactly the same way as does D-glucose but, being the wrong stereoisomer for the transmembrane transporter, does not enter cells. The three tracers are injected together in a short bolus injection into the coronary arterial inflow, and a sequence of samples is taken from the outflow at 1 or 2 second intervals. The outflow curves are normalized to the fraction of the injected dose so all three outflow dilution curves would be the same if there were no escape from the bloodstream. But both D- and L-glucose curves are initially lower than the albumin curve because they escape through the clefts into the interstitial fluid space, and return later to the outflow. The D-glucose curve is lower than the L-glucose curve by the amount that is taken up into the cells. Thus we can distinguish cellular uptake from transcapillary exchange through clefts. This was the kind of technology on which I was working. We extend it further by examining the chemical transformations undergone by the tracer before it returns to the outflow.
Nebeker:
You needed three tracers?
Bassingthwaighte:
Yes. This idea of using two had been expressed very nicely by Francis Chinard in 1954. He was using a similar technique as a means of measuring the water content of the tissue. Christian Crone in Copenhagen had measured glucose uptake in brain endothelial cells similarly in 1963. I thought, “We can look at cell uptake and cleft permeation together by using three in this way and also get measures of metabolism.” Crone and I became close friends through this work, and he spent two 3-month sabbaticals in my lab in 1970 and 1973.
Chinard is a wonderful man with whom I still correspond, including two weeks ago. Earl Wood and I are also still in correspondence. The third member of this triumvirate with Earl Wood and Francis Chinard was Kenneth Zierler, who is at Johns Hopkins. Francis Chinard was at Hopkins at that time also. Chinard invented this multiple tracer approach. Ken Zierler developed an approach to looking at input-output relationships that helped me a lot in my thesis work. Then Earl Wood was the down-to-earth practitioner of the single tracer indicator dilution techniques for looking at congenital heart disease. This triumvirate was intellectually in tune and put together an Indicator Dilution Symposium published in Circulation Research in 1962. My colleagues here organized a meeting for me on my seventieth birthday in September of ‘99 and the first three speakers were the three of them.
Nebeker:
That’s amazing.
Bassingthwaighte:
It was wonderful. Their reviews appeared in the Annals of Biomedical Engineering last August. Those three people were highly influential in terms of my thinking on different aspects of the field. My job was to take those different ways of looking at things and integrate them into approaches for looking at cellular metabolism. It has taken me the rest of my career trying to figure out how to do that.
Nebeker:
Your start concerned cardiac metabolism. Right?
Bassingthwaighte:
Yes, and that is still so. I haven’t graduated.
Nebeker:
Did you get the three-tracer system to work?
Bassingthwaighte:
Oh yes, that works. It gives specially accurate characterization of the capillary transport process. The time course of the tracer movement is strongly affected by the first barrier it runs into. It gives a less precise measurement of transport across barriers that are beyond the capillary wall, so the cell membrane permeabilities are not as well revealed by this technology as is permeability of the capillary membrane. Therefore one has to be very careful to get the capillary membrane measurement right in order to get the cell membrane measurement approximately right.
Nebeker:
I see. What were the technological challenges in getting this to work?
Bassingthwaighte:
One was multiple tracer techniques. We were the first people to use triple label beta counting. All my advisors told me it was impossible. It took us a little while.
Nebeker:
The impossible takes a little while.
Bassingthwaighte:
That’s the story of research grant applications. I’m sure that many people have told you that already. The reviewers send these things back saying it’s impossible. You have to do it before they’ll give you the money to do it.
Intersections of biomedical engineering and physiology; quantitative approaches
Nebeker:
Why is it that you are generally regarded as a biomedical engineer when a lot of this work seems like straight physiology?
Bassingthwaighte:
It is straight physiology. I think that is because of the style with which I approach the physiology. For instance the article (Circ. Res. 19, 332, 1966) I showed you is standard traditional engineering style, to look at black box operational analysis and try to parse the insides of the black box.
Nebeker:
The system description and then transfer function and so on.
Bassingthwaighte:
Yes. I approached it like an engineer would. I probed it with step responses, pulse responses, sinusoidal input functions and did the Fourier transform analysis. In those early years I learned a lot by going to the Annual Conference on Engineering in Medicine and Biology. That was a conference held jointly by IEEE/EMBS, BMES, and a consortium of over a dozen societies at its peak during the late sixties to early seventies. That had a lot of good analytical studies.
Nebeker:
You associated with the biomedical engineering community.
Bassingthwaighte:
I was at the founding meeting of the Biomedical Engineering Society. I felt that was part of what I did.
Nebeker:
Unlike many people in that field, you didn’t come from an engineering background but found that style to your liking and had enough training to do that?
Bassingthwaighte:
More than important than that, it’s the key to quantitation. This is not atomic theory where one does a lot of high-powered math to feel the intricacies of what particles are doing; rather, it’s a very practical analysis of experiments in quantitative terms. The name of the game is to get those data as accurately as possible and to interpret them through mathematical modeling.
Nebeker:
Isn’t that more of an engineering ideal? I can imagine that a traditional physiology ideal might have been more descriptive, such as, “Let’s understand how these flows and metabolic processes work” and not be so concerned with data.
Bassingthwaighte:
Not necessarily. There are many quantitative biologists. If you look at the papers of Hodgkin and Huxley in 1952, the classic papers on the nerve action potential, would you call that bioengineering? It’s in the style. It’s quantitative analysis using mathematical modeling. It took them years to figure out how to do the analysis and perform the computation. They had to develop the mathematics as well as the computation. And it was all done on desk calculators. That was horrible.
Nebeker:
Then there was an ideal of quantitative description within physiology already?
Bassingthwaighte:
Sure.
Nebeker:
In your case, and probably in many other cases, something like an engineering approach was taken because that was the way to deal with it quantitatively.
Bassingthwaighte:
There is historical precedent at the qualitative level as well. Luigi Galvani saw frogs’ leg muscles twitch when suspended between a copper hook and an iron rail and the field of electrophysiology emerged. From a biological experiment came important contributions to electrical engineering. Claude Bernard, the father of modern physiology in the 1860s and 70s, was quantitatively inclined when he did one of the first indicator dilution experiments. He injected goat red blood cells into the human circulation and then collected a timed sequence of samples, determined the relative concentrations of the goat blood cells in each sample in order to estimate transit times in the circulation. The goat blood cells are a different shape than human red cells, so he could identify them under the microscope.
Nebeker:
Could he count them?
Bassingthwaighte:
He could and did count them. This is in his Cahier Rouge, his little red notebook, which is kind of like Leonardo da Vinci’s notebook, only it wasn’t written backwards in Latin, but in normal French.
Nebeker:
Is it still the case that there are biomedical engineers dealing with physiology questions that are a recognizable subgroup of physiologists, or have all physiologists adopted many of these techniques?
Bassingthwaighte:
Biophysicists tend to be highly quantitative and use mathematical and engineering methods. Physiologists tend to be less so, perhaps because physiology training in this country has veered toward molecular biology, and is being taught at a degraded level. Let me explain. When I was taking physiology it was stock in trade to take courses in statistics, mathematics, calculus.
Nebeker:
To do control systems?
Bassingthwaighte:
Yes, even to do control systems, at a time when control systems analysis was the fiefdom of EE. Courses were given in physiological control systems at many universities in the sixties and seventies. Medical students at Yale University in the early seventies could take physiological control systems as an elective part of their medical school curriculum. These were expected as part of training in physiology. Physiology is an integrative discipline, historically speaking, so one is expected to integrate diverse observations into a self-consistent scheme and to look at the time courses of events to understand relationships. These cannot be very well understood without having some modicum of control systems analysis. Nowadays one may get a hint of statistical training in physiology, but no training in calculus, ordinary differential equations, advanced calculus or control systems. It’s gone. Across the continent. Gone.
Nebeker:
Then there is a further separation of straight physiologists, if I can use that term, and the ones taking a more biomedical perspective.
Bassingthwaighte:
The problem was that the physiology departments turned into departments of molecular biology. The exceptions have been departments that have strengths in biophysics and in the neurosciences. In our University of Washington Department of Physiology there is a strong neuroscience group that is quantitatively oriented. They are in the tradition of the Hodgkin and Huxley and can do all of that. On the other hand, the department offers no course for control systems, and there is no department requirement to take any math. There is a built-in contradiction in that the faculty members know all this and use it, but the students don’t. This seems to be true nationwide. We are at a crossroads in physiology. I personally believe that bioengineering will take over the domain of integrated physiology. We are certainly doing that now.
Nebeker:
You are helping me understand something that has troubled me since I started on this project of trying to do a little history of biomedical engineering. Many of the people within IEEE in this field, as in your case, seem to be fundamentally interested in physiology. They are trying to understand how the body functions in certain ways, and they have taken an engineering approach which often means quantitative models, systems kind of analysis, computer modeling these days and in the last forty to fifty years. However, I had imagined that all physiology would be that waynow, and I wonder why these people are biomedical engineers and not physiologists.
Bassingthwaighte:
I don’t think there’s a good answer to that. The trite answer is that people have turned their attention to what I think of as the romance of molecular biology and genomics. These are areas in which discoveries are frequent. There is something very satisfying about making a specific discovery: “I found that protein” or “I found that this enzyme is the expression of an identified gene.” These are money in the bank when it comes to one’s next grant application. On the other hand, “I have found that the transporter for adenosine on the luminal surface of the capillary endothelial cell is characterized in this way” does not create the same level of excitement. Right?
Nebeker:
Yes.
Bassingthwaighte:
I spend a lot of time looking at adenosine metabolism, its transporters and the enzymes that facilitate its reactions. What do I find out? Do I make “discoveries”? I certainly get a lot of quantitative information that wasn’t available before, and I can put the system together. Keith Kroll and I “discover” that xanthine oxidase has a peculiar behavior. This is a quantitative thing. Xanthine oxidase holds onto its substrate, hypoxanthine, for a very long time without reacting it. The first reaction product is xanthine. Xanthine is also held by the enzyme and barely released at all until a second oxidation reaction turns it into uric acid. These two oxidation steps are on one enzyme. Now I need to know more about the enzyme structure; those who are the experts on the enzyme structure I find are unaware of this behavior.
Is that a discovery? Or just a nuance. I found out something that was unknown about a particular enzyme. Such things keep turning up. For example we found a metabolic pathway that wasn’t on the biochemical charts. Was it the discovery of a new protein? Not really. It should have been on the charts, and was known in bacterial species.
McGill U.
Nebeker:
You came here in 1975 as director of the Center for Bioengineering. How did that come about?
Bassingthwaighte:
Like life in general, that was kind of accidental. That opportunity really came because of a close friend and colleague at McGill University, Carl Goresky. He and I worked in the same field and reviewed one another’s papers for the journals and so on. Maurice McGregor was the chairman of Cardiology and then Dean of McGill’s School of Medicine, had been able to benefit by some of my indicator dilution methods and has also become a friend. He and Carl tried to put together a position for me at McGill. I still felt that Canada was my homeland, and worked with them to build an appropriate situation there by gathering together a group of people to build the Department of Biomedical Engineering at McGill. The idea was that I would develop a big computational group to serve the medical school and university’s purposes, and build bioengineering around it.
We put in an application to MRC, the Medical Research Council of Canada, for the funding. It didn’t get funded, and two years of work went down the drain. Thus at McGill I wasn’t going to have the wherewithal to do the things that I needed to do scientifically and therefore decided not to go. Mayo Clinic is an excellent place to work, and I was quite content to stay there. Despite all the planning with McGill, Mayo was still a great spot. When one is being romanced by a university, even though it’s not really out in the public, people get to know about it. I wasn’t looking for a job. I was active in research and on the NIH scene during those years, and people at the University of Washington knew me. Bob Rushmer had founded the bioengineering program at the University of Washington in ‘68 and I had come to UW twice as a site visitor on behalf of NIH to see whether his program should be funded. I liked his program. Dr. Rushmer got to know that I had been in the market for the position at McGill, and when he decided to retire I was recruited here. Therefore instead of being in a physiology department I came to a bioengineering department as its director or chairman. I carried on the same lines of work in cardiac electrophysiology and in the mechanisms of transport in blood-tissue exchange processes.
U. of Washington, Center of Bioengineering
Nebeker:
How did you find the University of Washington?
Bassingthwaighte:
The reason I came here was because UW had one of Mayo Clinic’s prime attributes, namely, an atmosphere in which people would collaborate across departmental lines freely and openly in a noncompetitive way. This is in stark contrast to places like Harvard. I then regarded Harvard as a dog-eat-dog world, and I’m not sure that’s changed much. They have a lot of good people there so I shouldn’t put it down, but the atmosphere does not provide a large comfort zone. The University of Washington had another attribute similar to McGill: a medical school and engineering school on the same campus, right beside each other, and furthermore, the Center for Bioengineering was part of both schools. Also, the University of Washington had an outstanding Department of Physiology that was probably #1 in the world at the time.
Nebeker:
Yes.
Bassingthwaighte:
At Mayo Clinic I had been anxious to see a four-year college established in the city, because there is no university there at all. At that time the Mayo board of directors decided they were not going to support that kind of effort. They felt there were enough universities around Minnesota. Right after that the University of Minnesota established a new engineering school in Morris, a small town south of Minneapolis. It was a shame that it had not been put in Rochester. I think that was the biggest mistake Mayo ever made. They did most things right, but not that.
Nebeker:
Was the physiology department at the University of Washington already working with the Center for Bioengineering at that time?
Bassingthwaighte:
Not exactly. Bob Rushmer had established the Center for Bioengineering, but he carved it out to separate it from Physiology. He felt it had to be on its own feet. That separation came about with a lot of blood-letting. The university supported Rushmer’s group in establishing bioengineering and the remainder of the physiology department felt that it should have been done within the department. That antagonism and resentment was the downside to this particular situation. They didn’t want me, as the new Director for the Center for Bioengineering, to be also a member of the physiology department.
Nebeker:
Is that right?
Bassingthwaighte:
Despite the fact that I came with that expectation and the Dean had the same expectation. However the department head, Harry Patton, wouldn’t let that happen; he was still too upset about Bioengineering being formed in 1968, though this was 1975.
Nebeker:
Is that right?
Bassingthwaighte:
I work with the people in physiology and don’t give a damn about the history. They were my good friends.
Nebeker:
That may have been quite a good thing that someone who was in a sense a physiologist came into the Center for Bioengineering to kind of heal that.
Bassingthwaighte:
It took a long time to heal. It was very deep in the emotions.
Nebeker:
Then it was more your personal connection to the physiologists.
Bassingthwaighte:
Yes. I could keep the personal connection, but the connection at the teaching level was not really effective. That was too bad, because we should have been collaborating. The courses that they gave in instrumentation, we now teach. Originally they were taught by faculty in Physiology. Sandy (Francis Alexander) Spelman, who was jointly in the Center for Bioengineering and in the Primate Center, took them over. Sandy’s only academic appointment was Bioengineering, so the courses moved from Physiology to Bioengineering.
Nebeker:
How did your own research go here in Washington?
Bassingthwaighte:
Being a department head is a time sink, especially when one is trying to build a program. I brought in new faculty to try to develop things.
Educational program development; teaching
Nebeker:
Was that part of the deal, that there would be new positions created?
Bassingthwaighte:
Yes. That took time out of what I was doing. When I started the graduate teaching program at Mayo I found it immensely easy to do. One August I said, “Wouldn’t we like to have a teaching program?” and in September we had it. That didn’t happen here. I imagined it would be equally easy and that well-meaning folks would want to put their oars into the educational waters. Not so. The Center for Bioengineering was a research establishment, had heavy-duty research funding from NIH, and was determined to keep it that way. The faculty here didn’t want to lose their research time to educational efforts.
Nebeker:
I know from Lee Huntsman’s article on Rushmer and the beginning of program here that it was part of the original idea that teaching would not be part of the Center.
Bassingthwaighte:
The faculty let me know that. But the Deans of Medicine and Engineering had set forth goals in graduate education for me to help implement. We did eventually get a Master’s program off and running. I stayed as chairman for just five years. Lee Huntsman then became the next chairman.
Nebeker:
Were you pushing for an educational program during your five years as chairman?
Bassingthwaighte:
I was, but that was not a way to win friends within Bioengineering. It countered their personal incentives to make sure they got their research funding.
Nebeker:
Do you think that was a correct assessment on their part? Would it have hurt their chances for research grants?
Bassingthwaighte:
That’s a hard call to make. I find that teaching assists my research. However, people who have never done that do not have that same belief. And it obviously costs time. I’m teaching a new course next quarter. That’s going to cost me time that I won’t be able to spend in the lab or writing the next grant application. It is a real loss. On the other hand, when one joins a university faculty, teaching must be a part of what one does. It’s part of the game. The dean let me know in no uncertain terms that his expectation was that we would have an educational program, so I was sitting in between.
Nebeker:
Not an entirely comfortable position.
Bassingthwaighte:
I really didn’t understand the reluctance to teach. In any institution, there are always people who are reluctant to teach for one reason or another. Their reasons are not necessarily bad ones. However I felt I had to push, and did. There is another aspect to it. To put the face on the other side of the coin, this was a research group and that did not have state-tenured funding. I came with a state-tenured funded position and didn’t have to put my own salary into grant applications. Bob Rushmer and Allen Hoffman didn’t have to do that, but for the rest of them their salaries depended on research grant funding. I did bring in one person (Tom Hutchinson) who was tenured upon arrival and two others (Dale Johnson and Alan McKenzie) who were in tenure track positions. Dale became tenured because he did all the right things; Alan did not and remained as research faculty. Dale later became Associate Dean in the Graduate School and is now Dean of the Graduate School at University of Florida?
There were a group of others, including Lee Huntsman originally, who were entirely on soft-funded salary. He had arrived at the University of Washington in 1968 as a postdoc along with Gerry Pollack. I was able to provide these two with tenured positions in bioengineering, but that took until about three years after my arrival. Therefore in the first year there was a good reason for them to say, “Gee, I’ve got to get all my money, and I’m not being paid to teach.” (At Mayo Clinic there is no tenure or non-tenure. Everyone was tenured equally, and though anyone could be fired; they weren’t, but might be retrained for a different job. I guess that evoked a commitment to the community, and such a commitment may be less common here. I didn’t expect UW to be Mayo but was disappointed that investment in the communal educational effort wasn’t felt to be worthwhile.)
Cardiac metabolism research
Nebeker:
I can imagine that running the Center took a lot of your time in those five years.
Bassingthwaighte:
It reduced my research productivity, though not too badly, because I knew how to do it pretty efficiently. Looking back on it, it reduced my ability to be innovative. I simply did not have enough thinking time. Since getting out of the chairmanship I feel I have been much more “with it” in terms of developing new approaches.
Nebeker:
Would you give me an overview of the last couple of decades then of your work since you left the chairmanship? What have been the main areas in which you have worked, and what achievements have given you the most pride?
Bassingthwaighte:
The central theme is still cardiac metabolism, unraveling it in the normal state and to a lesser extent in cardiac ischemia. Ischemia has been a secondary mission. In the process of getting at these nuances of metabolism I started, in collaboration with Harvey Sparks at Michigan State University, a program to look at purine nucleoside transport and metabolism in cardiac capillary endothelial cells and myocytes. ATP is the prime energy source for cardiac con¬traction. Therefore looking at the ingredients that make up ATP and play a role in its regulation was important. Harvey Sparks was an expert in this; I had the technology for looking at the transport and metabolic rates. We applied tracer techniques to that. That was a step exactly in the direction I needed to take. Working with the group at Michigan State and with Ray Olsson at University of South Florida to develop some new tracer label compounds was a neat thing to do. That has evolved into more research in purine nucleosides, and I am still doing that. I also started looking at substrates for energy supply, glucose and fatty acids, characterizing their pathways from the blood through to the cell, an important part of cardiac metabolism.
Nebeker:
Is that different from other cellular metabolism?
Bassingthwaighte:
Cardiac cells are quantitatively different from other cells, since they must expend high amounts of energy on contraction continuously. But most of the mechanisms for cardiac cell metabolism are similar in other cell types.
Nebeker:
Does it makes sense to specialize your research in cardiac metabolism because there are enough differences that you have to be specific about the cells with which you are dealing?
Bassingthwaighte:
Yes.
Nebeker:
One might take a different approach and say, “We’re going to understand fatty acid uptake and metabolism in all cells,” but I suppose the techniques are specific to metabolism.
Bassingthwaighte:
Metabolic systems are parametrically different in different cell types. The kinetic rate constants for the same set of metabolic reactions is sure to be different in one cell type from another. For example, the same metabolic pathways probably exist in cardiac cells as in fat cells. But obviously a fat cell, an adipocyte, has got a different behavior than the cardiac muscle cell that does not store large amounts of fat but is using fat all the time. Also there are changes in how much of each substrate is metabolized. The shifts between fatty acid as a substrate and glucose as a substrate depend on the activity of the heart. Skeletal muscle does the same kind of thing, but the controls are different.
Nebeker:
As an outsider, I am trying to understand why one focuses on cardiac metabolism. You have explained it well.
Bassingthwaighte:
There is another reason, and that relates to clinical imaging. Regions that are damaged, infarcted or ischemic can be identified by injecting radio-iodinated fatty acids intravenously and then taking an image of the heart. That was done in the early sixties. Fatty acid accumulates in areas of injury, but it is not able to metabolize it. It accumulates because it is taken up, but not burned. That was clinically useful. Later on glucose came to be used as an imaging agent in the form of fluorodeoxyglucose, FDG. 18F is a positron-emitting isotope that can be attached to glucose. 18FDG is transported into the cell and then phosphorylated via hexokinase, the first reaction in the series of reactions for glucose metabolism, but then it cannot go through the next reactions and remains in the cell as FDG-6-phosphate. Thus the rate of the first step of glucose metabolism can be measured inside the myocyte by measuring the rate of the FDG uptake. Thus, as an imaging agent for positron emission tomography it gives higher resolution in identifying compromised regions than the gamma camera methods that had been used with the iodinated fatty acids. Then we get into receptor uptake in the heart. Of course this is also related to the metabolism. If the heart is stimulated with adrenalin or with an analog that binds to the adrenalin receptor on the surface of the myocardial cell, we may or may not learn something about regional receptor density but we do learn something about the ability of the cell’s response to the release of adrenalin from nerve endings. Regional receptor densities can be unveiled using PET methods, and are useful in examining the hearts of patients with heart failure.The clinical imaging fits my Arrowsmith ideal, because there I can apply the techniques that I have learned in cardiac metabolism to a patient study, analyze the data with the models that we have developed, and feel as if I have done something for clinical medicine. That’s not a discovery process, but the kind of effort that is a source of satisfaction for me as for any practising physician.
Nebeker:
Yes. I imagine that there is a real advantage to getting a fuller picture of the overall functioning of these cardiac cells. Looking at how they metabolize various substances one comes away with a better overall understanding of the heart.
Bassingthwaighte:
The heart is interesting from a structural as well as metabolic functional point of view. One of the intriguing things we discovered very early on was that the heart is very heterogeneous in its regional blood flows. Different regions had different flows, we had learned in the sixties. In the early seventies we learned that the different flows stay that way when examined at several later times. There are two problems here that I struggled with for years. One was how to measure heterogeneity. The other was how to ascertain its cause. With respect to its measurement, if one uses a different scales of measurement, one gets a different measure of heterogeneity. It is like being asked the question, “What’s the population density in the U.S.?” and then asking, “Do you mean the whole U.S. as a lump or east versus west of the Mississippi? Or state by state or county by county?”
Nebeker:
The smaller cells give a different picture of heterogeneity.
Vascular system as a fractal
Bassingthwaighte:
The measure of variance increases as one improves spatial resolution by making more refined observations in smaller pieces. It’s a mathematical truism that the higher the resolution used the greater the apparent variance. This is true in the heart. I tried to understand that in functional terms: Is its basis in the vascular system, which is a branching network, or are the different pieces of tissue really functioning differently? It’s the latter. Some parts of the heart have so little flow that if they had an average oxygen consumption they would die. Therefore we can safely infer that they are not doing as much work as other parts of the heart.
Nebeker:
Has the heart evolved to match the flow structure that’s there?
Bassingthwaighte:
More likely it is the other way around. The vascular system has probably adapted to supply the flow that is needed locally. An engineering concept which applies is impedance matching. The flow matches the ability of the transporters on the membranes to carry substrates into the cell, and this in turn matches the local metabolism of substrate. And that matches the local oxygen consumption within the cells. What we’re figuring out but haven’t yet proved is that oxygen consumption matches the contractile needs for ATP. I think all of the above processes are driven by the need for ATP for contractile force generation. That’s the hypothesis I’m working on right now. The intriguing thing that lies in between is this statistical appraisal of heterogeneity. It turns out that the heterogeneity is a spatial fractal. It took me years to figure this out. When I did finally figure it out, I tried Benoit Mandelbrot’s way of looking at it but I couldn’t get through his derivations and explanations. I finally worked it out and then saw that I should have been able to get it out of his publications. I just couldn’t understand his writing. He’s a very bright original man but not a clear enough writer for me. Anyway, the heart flow distribution is a fractal and so is its vascular system, so we are characterizing the network properties of the vascular system in terms of fractals. Fractal methods are good statistical tools.
Nebeker:
I think I understand how the vascular system is a fractal because rivers have been looked at in fractal terms.
Bassingthwaighte:
Exactly. The heart tissue itself is not fractal. The cells form a syncytium meaning that all the cells are connected electrically. There are groups of fiber bundles, cells linked end-to-end and side-to-side; groups of these form sheets. These arrangements are not fractal. The sheets are arranged in a spiral so that when the heart contracts it creates torque to empty the ven¬tricle, like wringing out a dishrag. It is only the flow distribution that is fractal. Statistically that means is that near neighbors are alike. There is correlation structure in the utilization of flow, and that means there is a correlation structure in the energy used for the contraction itself. Presumably the vascular system adapts to locals needs. Vascular remodeling occurs from birth onward and continues throughout life. If you change the work of your heart, you remodel your vascular system. People get hypertension, hypertrophy, and they change their capillary densities.
Nebeker:
Apparently fractal mathematics has proved useful in better understanding the heart.
Bassingthwaighte:
Yes. It has turned out to be useful for a lot of things in biology.
Nebeker:
I have encountered where in image analysis and image synthesis it has been useful.
Bassingthwaighte:
I was trying to teach myself about that, so in the usual academic tradition I wrote a book on it, choosing two smart collaborators to keep me in line. One of them, Larry Liebovitch, started out as an astronomical physicist and the other, Bruce West, is a particle physicist. Our fractal book was published in ‘94 and is already well outdated, the field has been moving so fast.
Nebeker:
This must have been one of the early efforts in bringing that new style of mathematics to physiology.
Bassingthwaighte:
Yes. It was the first book on fractals and chaos in physiology, but there is a lot of new work since ‘94. What’s in there is not wrong, but it’s not up-to-date. I need to spend some time next year revising it.
Nebeker:
Don’t you also have an appointment in biomathematics?
Bassingthwaighte:
Yes. Upon my arrival here, the bioengineering program was not anointed by the university as a graduate program. I had graduate students, so my Graduate School appointment was in the Biomathematics Program, which already had been approved. It was not that I am much of a mathematician, but it was a solution. The first student I had from the University of Washington under that auspice was a good mathematician and he did a thesis on flow heterogeneity in the heart.
National Simulation Resource Facility; SIMCON
Nebeker:
I want to ask you about the National Simulation Resource Facility. Would you give me a Reader’s Digest condensed version of that novel?
Bassingthwaighte:
That’s now in its twenty-first year. The Resource Facility is a vehicle for developing, implementing and making available for public use, which is mainly research use, mathematical models of biology as applied to circulatory transport and blood-tissue exchange processes. We are specialized in a fairly narrow area of applied biomathematics. The clinical applications are in the interpretation of dynamic three-dimensional images from PET (positron emission tomography), SPECT (single photon emission computed tomography), and MRI (magnetic resonance imaging). The research applications include these and a variety of other tracer and water and solute exchange studies, including the multiple indicator dilution technology we dis-cussed earlier, and in pharmacokinetics. Many of the same models apply to all of these fields. The kind of technology that we have there is much more broadly usable because it’s general. Investigators also download our simulation systems XSIM and JSIM and apply it modeling analysis in other organs, kidney, brain, liver, skeletal muscle and lung being the commonest, and to problems unrelated to biology. These systems provide an interface between the scientist and the computer, allowing him or her to fit data using built-in optimization routines, display results, and obtain confidence ranges and sensitivity analyses on parameters.
Nebeker:
Have you put this together as a single system?
Bassingthwaighte:
We have one system we developed over the years. Actually in 1967 I put together a simulation interface system called SIMCON, which was short for simulation control. It was the interface between man and machine that allowed him to use models to check data and thereby parse the transfer function of the black box. That turned into a very good modeling system with automatic ways of fitting equations and models to data, evaluating the accuracy of the param¬eters that came out, and displaying the solutions in real time so that one could see that the right result was being obtained. It allowed people to feel the data analysis; to see it as they do it. Our whole philosophy of the resource is centered on that, “You should be able to do your analysis and see it happen before your eyes and understand what you are doing as you are doing it.” The idea is for people to be able to look at the behavior of these models and understand the sensitivity of various parameters. This then enables the user to explore what the models can reveal about the system that wasn’t previously known. A model is always a mind expander, and so the simulation tool is an augmentation to one’s set of thinking tools.
Nebeker:
How has this been received?
Bassingthwaighte:
It’s gotten funding for five rounds.
Nebeker:
That’s a pretty good sign.
Bassingthwaighte:
Yes. My original grant starting in 1964, which is still running, supported the early SIMCON. The Simulation Resource Facility has supported the advanced efforts since 1978. The training grant, which is a cardiovascular bioengineering training grant for postdocs and some pre-docs is in its twenty-third year. These programs have had some endurance, which is nice. You asked me earlier what I’m proud of, and I’m proud of the endurance of these programs, because they are useful to people.
Nebeker:
If it weren’t of widespread value to the field you wouldn’t have continued to get funding.
Models, simulations, and computing
Bassingthwaighte:
We’re working hard to expand it further. My young colleague, Zheng Li, has developed a Java interface for the simulation system that we now call XSIM, and we will change the name to JSIM when it is more fully developed. It’s quite fun for a user to be able to develop models directly from the equations, and then to fit the model solutions to data, all without doing any computer coding. You can actually explore it yourself on the website when you go home.
Nebeker:
If I can figure out.
Bassingthwaighte:
You won’t have a problem. There are tutorials. On November 24th, the journal Circulation Research published a new model from Ray Winslow’s group at Johns Hopkins, simultaneously releasing the article in print form and on their website and the model on our website (Greenstein, J., R. Winslow. Action Potential Model for Canine Ventricular Cell (WRJ3) Circ. Res. November 2000). That model was made available on our website for anyone anywhere in the world to run, to change the parameters, and to explore its behavior. Ray Winslow and Joe Greenstein reveal all of their equations. This is exactly the way we’d like to see models and data released, publicly and with complete information. That is my philosophy on how to advance science most efficiently.
Nebeker:
That’s fantastic. That sounds like a wonderful advantage. Instead of reading some description and taking a long time to figure out what it’s doing.
Bassingthwaighte:
You can really do it yourself. This is a model of electrophysiology of the heart and it’s based fundamentally on things like the Hodgkin-Huxley action potential model of 1952. Such models incorporate time- and voltage dependent conductances for ionic currents carried by ions, particularly potassium, sodium and calcium. The models can be understood algorith-mically by an EE student taking network analysis.
Nebeker:
IEEE loves to hear things like that.
Bassingthwaighte:
Conductances, capacitances and charge transfer across a resistor all have biological equivalents. Right now we have moved to the next stages of these things. Our group is trying to put very comprehensive models of cellular metabolism and energetics together with muscle contraction. Then jointly with Hopkins, MIT, Harvard, San Diego and Connecticut we are putting together a large program project grant to do yet more comprehensive modeling of a myocardial cell. The aim is to compute the functions of the muscle cell.
Nebeker:
In a single model, all the aspects?
Bassingthwaighte:
Yes. But not with all the complexity of incorporating all the proteins down to the genome. We each have various modules for which we are responsible to create a functioning cell by working together: I’m in charge of metabolism; Ray Winslow is responsible for the electrophysiology; others are doing cell mechanics. others databasing and modeling systems.
Nebeker:
This really does sound like engineering. You are putting together a lot of things that have to function together.
Bassingthwaighte:
Looking at what’s coming out of the genome, one can’t just start at the genome and build a body; likewise, these models don’t start at the genome; they start wherever we have the information. Then the tentacles are sent down to the genome. My tentacles down to the genome are in the regulation of myofilament protein production. When a heart is paced at an abnormal site it actually remolds itself. The pacing site atrophies, the wall becoming thinner at this point, and changes its balance of substrates. It uses less glucose and relatively more fatty acid. At sites distant from the pacing site the heart hypertrophies, getting thicker walled as more myofilament protein is laid down and the metabolism is more glycolytic.
Nebeker:
Has all of this been modeled?
Bassingthwaighte:
No, but that’s why we want to put together the whole heart model.
Nebeker:
And then be able to simulate that process if you start pacing at this place.
Bassingthwaighte:
Yes. Ray Winslow has got a whole heart model for the spread of the electrical signal. That’s at Johns Hopkins. Andrew McCulloch at UC San Diego has a whole heart model for the contraction with all the fiber directions. I have whole heart models for the transport and metabolism. Now, can we get these together? That’s what we’re doing. It’s hard work, and it’s going to take a while to do it.
Physiome Project
Nebeker:
How does this resource center relate to the human Physiome Project?
Bassingthwaighte:
The integrated cell modeling is part of the Physiome. The Resource is the base from which I started the physiome. The Physiome idea represents the belief that we need to find a way to integrate the information we have and to identify the information we don’t have. We are in the stage of the “ignorance explosion.” For each thing we learn, we find that we need to learn three more things that we can’t yet find. It’s an interplay between the experimental world and the analytical world: back and forth, back and forth. We use the models to design the best experiment to explore the parameter space that we most acutely need to learn more about. We try to do the critical experiments, analyze them, find out what’s wrong, and go the next step. This multi-university program that we put together at the year’s end is designed to do just that. We’ve got experimental data and analytical models and they will be brought together. Some of the effort is at the genomic level, some is at the level of what’s happening with the enzymes and proteins, some at the membrane excitation level, some will be at the level of the spread of excitation across many cells, and so on. Another program we’re putting together is with a group in computer science at Utah and Indiana is on computational methods for the very large-scale systems. We’re trying to develop new methods of computing that we don’t yet know how to do.
Nebeker:
Is that because it would be helpful in modeling to be able to handle those difficult computations?
Bassingthwaighte:
Yes. Computers are too slow. There are people who will tell you, including people on our own faculty, that the computers are fast enough and the models just need to be better. In fact there are no computers on earth, and probably never will be, that are fast enough to compute from the genome up to the whole organism on first principle basis and provide the results to an investigator quickly enough to allow him to speed up his thinking. Approximations have to be made all the way, and to bring more and more information into a self consistent scheme. I’ve been puzzling about this for eons and couldn’t get it through my skull what to do. When mathematical models are put together from a biophysical-biochemical basis, they get very complex very quickly so that one ends up saying, “It doesn’t make sense to do it that way.” All the computers in the world won’t suffice especially if you go to a whole tissues composed of many cell types and to functioning humans instead of just modeling one cell. For example, we really want to be able to control blood pressure. If we examine the Guyton model of the control system for blood pressure regulation, and focus on the vasoconstrictor part of the system, we see that there are blood pressure responses in the heart, kidney, lung, muscles, and so on. There is a pattern of responses that are well organized and reproducible. A description at the cellular biophysical level is not necessary in order to have an understanding and an appreciation of the details of this pattern.
Nebeker:
It can be effectively modeled at a higher level.
Bassingthwaighte:
Right. The models would be at a single hierarchical level to be at their simplest, but realistic models with some adaptability to changing conditions need to encompass at least two levels but hopefully not more than three. Otherwise the complexity is too formidable and computation becomes too slow for practicality. Even so, it is necessary to retain the fuller, more complex system description as a reference model. If one wishes to model cardiac contraction at a level that allows adaptation to a change in the site of electrical excitation, responding by gradually changing the heart structure through local atrophy or hypertrophy of the muscle, then one has to account for the changes in activity in many different subcellular units, the tricarboxylic acid cycle within the mitochondria, the glucose utilization, the strength of contraction, etc., are all changed. I have to allow each subcellular unit, way down in the scale of detail and different from myocardial region to region, to change and to have that change reflected in changes in the global model of the contracting heart. Therefore when one starts pacing the model heart at an abnormal site, the adaptation requires recasting the kinetics of the metabolic events as well as of the contractile and signaling events.
Nebeker:
What you’re saying then is that it’s not feasible to model everything from the very smallest level.
Bassingthwaighte:
Not feasible to keep it both an atomic level and at the level of a whole human.
Nebeker:
You have to be able to adjust your model at each higher level to reflect the changes that have occurred in a more detailed modeling at a lower level.
Bassingthwaighte:
Yes. I think that is the way to go. But I have no idea how to do this efficiently. One way is possibly to use what I’ll call pattern computing. Patterns of gene expression, patterns of metabolic flow through different pathways, are all reproducible in given settings. If we can use those patterns as part of the building block to understand patterns at higher level in the hierarchy we can start to understand the system. A clear example is the response to giving a peripheral vasoconstrictor that raises the blood pressure. The heart works harder to pump against the increased resistance. The cardiac ejection must be more forceful and muscle tension higher. That takes at least a two-level model. a part of the hierarchy. Then if one wishes to explain the higher muscle tension one must go down to level of ATP utilization. That’s down another couple of levels to biochemical kinetics. Those levels need to be made available, but they don’t need to be there in the first instance. With the computer scientists we are trying to figure out what patterning means and how to compute on it.
Neural nets, genetic algorithms, and fuzzy logic systems are analysis tools that have a lot of probabilism built into them. Then there is simulated annealing, which is another approach to get things to converge to being just right as a way of optimizing the models to data. But these are analysis techniques rather than techniques for automating how much of a huge model needs to be computed at a particular time to maintain fidelity to the biology in the simulation.
Nebeker:
Is simulated annealing a general technique?
Bassingthwaighte:
Yes. I have not used it so I don’t know its details. These analysis techiques use global, relatively crude statistical approaches that by multiple iterations end up providing a correct fit, but the resultant statistical measures have no specific relationship to the biology and are therefore unlikely to provide insight. The mechanisms that you use to jump up to answer the phone are not iterative. You do it correctly the first time through a refined predictive control.
Nebeker:
Right, but maybe our computers are not going to allow modeling of that.
Bassingthwaighte:
One can imagine that body mechanics could be structured algorithmically to have the virtual human get up to answer the phone. Going down to the cellular level would not be necessary to make that happen.
Nebeker:
Sure. Fluid mechanics at the molecular level is a probabilistic set of events producing average pressures and so on, but of course you could function at a higher level and get perfectly accurate answers.
Bassingthwaighte:
Absolutely. Hodgkin and Huxley didn’t know what the patch clamp would reveal years later, and they got a very good description of the nerve action potential. Are they now out of business because someone came along with a high-resolution patch clamp technique to look for the single channel? Not at all. The data from the patch clamp experiments can be integrated to give the Hodgkin-Huxley action potential. It takes a lot of hard work to gather enough data from many channels to perform that integration.
Nebeker:
Is that right?
Bassingthwaighte:
Yet nature does it all the time, because there are thousands of channels per cell. They are all governed by the transmembrane potential and the events at the protein level sum to give the action potential in a single cell. Hodgkin and Huxley had it right. The patch clampers, starting with Neher and Sakmann, have it right too, but it’s a different level of the hierarchy.
Nebeker:
Yes. That’s fascinating. You’ve made me understand better how the heart needs to be understood at a whole series of levels. It’s remarkable to try to integrate all of that.
Bassingthwaighte:
It’s a remarkable challenge that we have in front of us, and yet it’s going to happen. As I mentioned with pattern computing, I don’t know exactly how that will be accomplished. I can think of some primitive ways that ought to work. For example, given that there are known concentrations of potassium, calcium and sodium concentrations inside and outside a cell, and if some other assumptions are made about the inside of the cell, the form of the action poten¬tial can be extracted from a data bank containing previously computed waveforms. If the external ion concentration is changed, the change in the action potential can again be retrieved. Such strategies can be built into relatively simple models that represent the functional behavioral relationships without taking it back to the patch clamp level or even the Hodgkin-Huxley action potential model level. They use stored patterns, chosen automatically in accord with identified conditions, to evoke representative responses, and do it without massive computation, and without having to compute at the underlying hierarchical levels.
Nebeker:
I see.
Bassingthwaighte:
That is one possibility to obtain fast computing. We’re looking at huge needs in computational speed. We need to simplify the models a lot, and we’re working on that.
Nebeker:
I should give you an opportunity now if there is any large area we have not touched on that you want to mention.
Bassingthwaighte:
Maybe two things related to the Physiome Project, which you have mentioned. Databasing and developing thinking tools. It’s important, at the national level, to support the databasing in order to allow the Physiome Project to go forward, because having the data is essential to progress, and having it readily retrievable is going to save money. While we have genomic databases, and rapidly expanding protein data banks, we seriously lack mechanisms for the databasing of physiological and pathophysiological information. The ability to predict is what is needed in health care delivery systems, diagnostic procedures, the pharmaceutical drug development and therapeutics, and in genomic intervention. The only vehicle for prediction is the knowledge of the behavior of the integrated human organism and prediction of what an intervention can do. I don’t pretend that the quantitative description of the human physiome is anywhere close on the horizon, but we must strive toward that.
Macroethical behavior
Bassingthwaighte:
There’s more than one reason for doing that. William Wulf, the president of the National Academy of Sciences, stimulated the engineers of the Academy with an address concerning the development of macroethical behavior in societies and groups. This is quite distinct from personal ethical behavior, which is fairly readily characterized. It goes something like, “If you don’t know what you’re doing, you had better figure out how to do it while minimizing mistakes.” If doctors are going treat humans, whether with new drugs or to intervene on the genomic level, or our industries create environmental pollution, noxious gases and greenhouse effects, or develop atomic energy or create world wide communication, we must try to anticipate the consequences to minimize risk. These are all in the same class: they are big issues that need to be dealt with carefully. And if we are going to develop bioengineered corn, bioengineered people, or anything in between, we had better know what we’re doing.
What’s macroethical behavior? One wants to do no harm. Yet anything we do carries some risk of doing harm. The ethical requirement, put on a personal level, is to think as hard as one possibly can in order to prevent errors that cause harm. How hard can one think in terms of multidimensional systems, with multiple levels of hierarchical control? The answer is, “Only about one or two levels.” I’m told that anyone who tried to drive a Trident submarine without a built-in control system would porpoise the sub out of the water or send it into bottom. The system is too high order, about fifth order, for people to handle. It takes a computer. Likewise, biological systems are so high order that a computer is needed to help think about it. Macroethical behavior therefore requires us to arm ourselves as well as we possibly can with the thinking tools that aid us in making the right interventions. To refrain from intervention is not a viable option. We have to treat patients and we have to try to improve patient care. It isn’t a question stopping in our tracks; it’s a question of how it should be done. Therefore, I think the undertaking of the Physiome Project falls into the class of what has to become a macroethical societal investment, and not to proceed with that would be unethical.
Which groups advocate studying biology on a large integrated scale. Very few. It’s too early. However that’s what I am going to present at this meeting this coming weekend at the Biomedical Engineering Educational Summit, a gathering of bioengineering educational program leaders from around the world, sponsored by the Whitaker Foundation in the USA. I think it’s really important for us to appreciate that we can do something by thinking hard and developing the technologies so we can think harder than we could ever think before. Theoretical physicists showed how to do this long ago, but in biology we are lagging behind, even the leadership at NIH. There are leaders there, however, for example within the National Institute for General Medical Sci-ences. Marvin Cassman, the Director, and his staff invited proposals to undertake such work as early as June 1998. NSF too has been inviting applications to fund programs in biological complexity.
Nebeker:
Yes. New intellectual tools being brought to the problem.
Bassingthwaighte:
Yes. We need to consider macroethical behavior. For example, what’s the behavior of the Biomedical Engineering Society or IEEE with regard to tissue engineering? The Physiome is needed for pharmaceutics, for genomic intervention and for tissue engineering, but there is no BMES or IEEE policy defined with respect to the major issue of planning for it. William Wulf did wonderful service by painting the picture of macroethical behavior.
Nebeker:
Yes. It reminds me of “The Tragedy of the Commons” an article by Barry Commoner article a couple of decades ago showing how individuals, thinking they are acting in their own best interests, can create a catastrophe for everyone. An example is each farmer putting more than his share of goats on the village common so that there is before long nothing left to graze.
Bassingthwaighte:
I think it was even earlier, in 1961. But I’m wrong: it was by Garrett Hardin, and appeared in 1968 (Science 162: 1243-1248)
Nebeker:
Is that right? It seems like yesterday. The ecology movement was more prevalent in the seventies.
Bassingthwaighte:
The ecology movement, prevention of environmental and atmospheric pollution, universal health care and education, population control, all stand out as fundamental issues requiring a macroethical view.
Nebeker:
Thank you very much. This has been very helpful.
