Oral-History:Shu Chien

About Shu Chien

Dr. Chien attended pre-med school at Peking University. He moved to Taiwan in 1949 where he received his M.D. from the National Taiwan University in 1953. He earned his Ph.D. in physiology from Columbia University in 1957. He founded and directed the Institute of Biomedical Science in Taiwan. He was the founding chair of the Department of Biological Engineering at the University of California, San Diego (UCSD). He became president of the American Institute of Medical and Biological Engineering.

This interview begins with Chien’s family background in China and Taiwan and his early interest in medicine and mathematics. Chien explains why he wanted to pursue biomedical research in the US. He goes on to describe his research at Columbia University and his long collaboration with Dick Skalak. He discusses in detail how he acquired his training in engineering, making the transition from physiology to biophysics. He comments on his interest on simulation and modeling for his research on blood cells. He describes his decision to move to UCSD in 1988 and his work at the Institute of Biomedical Sciences in Taiwan. He concludes with the description of the founding of the Biological Engineering department at UCSD.

About the Interview

SHU CHIEN: An Interview Conducted by Frederik Nebeker, IEEE History Center, 11 December 2000

Interview #280 for the IEEE History Center, The Institute of Electrical and Electronics Engineers, Inc.

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Shu Chien, an oral history conducted in 2000 by Frederik Nebeker, IEEE History Center, New Brunswick, NJ, USA.

Interview

Interview: Shu Chien

Interviewer: Frederik Nebeker

Date: 11 December 2000

Place: Shu Chien’s office at the University of California, San Diego, La Jolla, California

Childhood, family, and education; Pearl Harbor and World War II

Nebeker:

You were born June 23rd, 1931, in Beijing.

Chien:

That’s correct.

Nebeker:

Tell me a little about your family.

Chien:

My father was a professor of chemistry. He studied chemistry at the National Chinghua [now spelled Tsinghua] University in Beijing. I was born as his second son just after his graduation. Two weeks after my birth, he came to the United States to study for his Ph.D. in chemistry, especially organic chemistry, at the University of Illinois at Urbana-Champagne. His advisor was Dr. Roger Adams. He got his Ph.D. in less than three years and went back to Beijing in 1934 to become a full professor at Peking University when he was twenty-five years old. He taught there for three years. When the war with Japan broke out in 1937 he went to Kun-ming, where Peking University was combined with two other universities – Chinghua and Nankai– to become the Southwestern Union University. My mother and the three sons (Robert Chun was born in 1928 and Frederick Foo in 1935) moved to Shanghai to stay with my grandfather. My father taught chemistry in Kun-ming until the time of Pearl Harbor, traveling back to Shanghai during summer and winter vacations. In December 1941 he was not able to get back to Kun-ming and worked for a pharmaceutical company in Shanghai until the end of the war. After the war, he went back to Peking University to become professor and chairman of the department of chemistry.

Nebeker:

What did you grandfather do?

Chien:

My grandfather was a judge. He attended a law school.

Nebeker:

Was that at a university?

Chien:

It was probably a freestanding college specializing only in law. He went into the judicial system in China and later became a criminal court judge in Shanghai.

Nebeker:

Did he leave Shanghai?

Chien:

He stayed in Shanghai because the international settlements were not under Japanese occupation. During the war, when the Chinese government led by Generalissimo Chiang Kai-shek moved to the Chung Ching [now called Chungqing], the courts continued to carry out the judicial processes for the Chinese government in the international settlements – French, British and so forth.

Nebeker:

Were the settlements controlled by the Japanese military?

Chien:

Although Japanese surrounded the area, the settlements were still under the control of the various western countries, and my grandfather continued to report to the Chinese government that had moved to Chung Ching.

Nebeker:

At least until December 1941.

Chien:

Yes, but my grandfather was assassinated before that. We never learned exactly who killed him, but it was most likely the Chinese puppet government under Japanese control.

Nebeker:

Was this in 1942?

Chien:

It was shortly before Pearl Harbor.

Nebeker:

Was he still there and practicing as a judge until just before Pearl Harbor?

Chien:

Yes.

Nebeker:

You told me earlier that you moved to Shanghai to live with your grandfather when you were five years old.

Chien:

Yes. My grandfather lived in an apartment in an alley in the French settlement off a street called Avenue Foch, which was named in honor of a French Marshall in the First World War. The Chinese translation of Avenue Foch was Foo Shu Road. I believe I was named Shu because of this.

Nebeker:

Were those the characters for that street?

Chien:

Yes. Foo Shu Road. Foo means fortune, and shu means warmth. So my grandfather thought that was a good word, and that is how I came to be named Shu.

Nebeker:

You have a French name?

Chien:

It may not be a French name, but my name has a French origin. When we went to Paris for a tour in 1971 with our two daughters, my wife took a picture of me in front of Marshall Foch’s statue.

Nebeker:

Did you go to elementary school there?

Chien:

Yes. I went to an elementary school in Shanghai called the Copper School.

Nebeker:

Do you remember when you first heard about Pearl Harbor as a child?

Chien:

Oh yes. I was ten years old. It was quite a big change for us. Shanghai changed. The international settlement, an area that had been fairly independent of Japanese control, was suddenly turned over to the Japanese.

Nebeker:

Did your living conditions change?

Chien:

We were fortunate in that they did not change that much. It was not as bad as we might have anticipated. The economy, however, got tighter and tighter as time went on because of the war conditions. The situation in Shanghai had gotten very bad, because it was under bombardment toward the end of the war. In addition, the supply lines between rural farming areas and cities were cut, which made living very tough. We were not able to get three meals a day.

Nebeker:

After a war it sometimes takes quite a while for an economy to get functioning again.

Chien:

Right after the end of the war the Chinese Government led by Chiang Kai-shek back to the part of China occupied by Japan. There was a Chinese puppet government set up under Japanese control, and that facilitated made the transition period during which the Japanese were turning over all the controls. People were very, very happy when the war was over, almost euphoric.

Nebeker:

Do you remember that announcement?

Chien:

Oh yes. It was August of 1945. There was tremendous celebration everywhere in the streets and in the houses. Everybody said, “From now on everything will be wonderful, with peace and prosperity.” However, it was not long before the civil war broke out. Then things got worse and worse over time.

Nebeker:

Did your family move back to Beijing after the war?

Chien:

Yes. My father was offered the position of Professor and Chairman of the Department of Chemistry at Peking University, as I mentioned already. He went back first, and gradually we all returned to Beijing.

Medical and bioengineering education; mathematics

Nebeker:

Were you in high school in those years?

Chien:

I transferred from Yu-Tsai High School in Shanghai to Yu-Ying High School in Beijing during my junior year. One thing I should mention is how I got into medicine and how I eventually came to bioengineering even though I studied medicine. In high school I was very interested in mathematics. I was planning to major in math when I enter college. When I was in my junior year of high school in Beijing, there was a joint entrance examination offered by the major universities in China, including Peking University, Chinghua and others. For some reason that year and the year before, the government rules allowed junior-year students to take the examination even though they still had one more year of high school to finish. I decided to take the examination. I wasn’t expecting to pass it, but I thought it would be a good idea to take the exam in order to get experience that would help me the next year. When I registered for the exam I wanted to select math as my first choice for a major. Then I realized that the entrance examination for math majors included analytical geometry, which was a course I wouldn’t be taking until my senior year.

Nebeker:

I see.

Chien:

I looked at all the other subject areas I was interested in and did not require analytical geometry, and found premedical studies to be the one. That’s how I picked pre-med as my first choice. Even then, I still had deficiency in several subjects, especially physics. My elder brother Robert helped me in studying for that and I got a fairly good mark on that subject. To my great surprise, I passed the exam and was admitted. I decided that if I got admitted I would do it, so I entered the premed program. In Peking University the premed and medical schools are continuous, as a seven-year program. Following acceptance into the premed program and passing the courses satisfactorily, the student would move on to medical school automatically. I studied at Peking University for a year and half. Before, I could move on to the medical school, however, the civil war evolved to a state that Beijing was under siege by the Communist Army and they were shelling the city. At that time the Nationalist Government sent two airplanes to evacuate the professors from the universities in Beijing.

Nebeker:

And their families?

Chien:

Yes. In retrospect, it is truly remarkable that my parents were able to decide to leave. They did not know exactly where we would end up. First it was to go to Nanjing, which is west of Shanghai and was the capital at that time and. Shortly after we arrived in Nanjing, the government was moving to Shanghai, and our family did too. But soon it was obvious that it was not safe there either. The university known as Taihoku Imperial University of Japan while under Japanese control was renamed the National Taiwan University in 1945. Mr. Sze-Nien Fu, a historian who was going to be president of the university, invited my father to become dean of studies, which is equivalent to a provost in the U.S. My father accepted that position, and the whole family moved to Taiwan.

Nebeker:

Was that in 1949?

Chien:

Yes, the beginning of 1949. I transferred to the College of Medicine of National Taiwan University as a second-year student. The medical program at the National Taiwan University at that time consisted of only six –years, with one year of premedical study, four years of medical school and one year of internship. In this transfer, I skipped another year.

Nebeker:

You saved another year. You had already skipped a year of high school.

Chien:

Yes. I skipped three years altogether, because I went from kindergarten straight to the second grade of elementary school. I was two years younger than the great majority of my medical school classmates. Many of many classmates had worked for several years during the war, and then came back to study. For this reason many were more than two years older than I.

Nebeker:

You must have felt very young.

Chien:

Yes indeed.

Nebeker:

Was mathematics always your principal interest?

Chien:

Yes. Numbers, geometry, and the way things work have always fascinated me. I can readily see the relationships in terms of quantity, space and time. It seems second nature to me and I like that.

Radio during World War II

Nebeker:

Were you also interested in gadgets?

Chien:

Not that much. I was interested in gadgets, especially how they work, i.e., the functional aspects, rather the structural construction. I didn’t have much opportunity to play with gadgets. During the war, most of the courses in middle school and high school that were the essential ones – such as Chinese, English, math, chemistry, physics, geography, history, etc. Subjects such as art and music, labs, and things that require manual work were nearly absent. I never had any music course throughout my years of study, for example. I knew very little about music until rather late in life. Opportunities to play with radios barely existed due to economical difficulties during the war.

Nebeker:

Did your family have a radio during the war?

Chien:

Yes, we did.

Nebeker:

Were you able to listen to the BBC?

Chien:

Before the attack on Pearl Harbor it was okay to listen to anything, but then it became forbidden to listen to the free voices such as the Voice of America.

Nebeker:

Did your family do it nevertheless?

Chien:

Not very much.

Nebeker:

Did you listen to Japanese sanctioned stations?

Chien:

We didn’t listen to those much either. We listened to amusement programs.

Medical degree; military service

Nebeker:

You must have found the premed program to your liking since you decided to continue with that.

Chien:

Yes, I liked it. My mother was having various medical problems, and I felt that it would be good to be able to help sick people. I liked medicine particularly from that point of view. However, all the time I liked this quantitative approach. I think that is how I eventually got back into bioengineering. Not everyone trained in medicine and physiology would have this kind of interest, i.e., the quantitative approach. I think that is what is needed in order to merge biology and engineering.

Nebeker:

Yes. Did you anticipate becoming a practicing doctor?

Chien:

I was considering that. I felt that as a practicing doctor I could help people directly, and it would be very rewarding. I went with my mother to see the physicians when she was having illnesses, and I had minor health problems myself. In those days only a very small portion of the student population was able to avoid at least mild forms of tuberculosis and hepatitis. I missed more than a month of school due to each of these. When I went to see my doctor in those days, I always felt comforted. I felt it would be nice to be able to give people that kind of feeling. Therefore it was a very difficult decision for me when I graduated from medical school.

Nebeker:

You received your M.D. in 1953.

Chien:

That’s right. Then I went in for the ROTC military training, which was a one-year mandatory training for college graduates in Taiwan at that time. After the completion of the ROTC in 1954, I was able to pursue further studies and debated between clinical medicine and basic science.

Decisions about graduate studies; father's career as University President

Nebeker:

Medical research?

Chien:

I was deciding between graduate study and medical internship. It was a very difficult decision because I liked both. On the research side, one is able to find interesting problems in which to be innovative and create new knowledge that will eventually help people in terms of health problems. On the other hand, clinical medicine would give me the opportunity to treat patients, and I very much like working with people. It was indeed a very difficult choice. In either case, I wanted to pursue my further education or training in the United States.

Nebeker:

Why is that?

Chien:

The United States had the best education and training opportunities – and still does.

Nebeker:

Was it felt that one should get training in the United States if a person wanted to do as much as possible in research?

Chien:

Yes, especially in those days. Although there were people doing good work in Taiwan, overall it was not at the same level. Today Taiwan is much better in its academic and intellectual environment for biomedical research.

Nebeker:

Was it sort of general consensus that one should study in the United States? Your father also studied in the United States.

Chien:

That’s right. Even in my father’s time. I knew that in order to get the best training possible I would have to study abroad. The United States was almost without doubt the best place for graduate study or training in clinical medicine. I applied for both kinds of opportunities. I applied for medical internship at a few hospitals and also applied for graduate studies with research assistantship and other kinds of support at a few places. My father, though the president of a university, really did not make a lot of money.

Nebeker:

Wasn’t he provost?

Chien:

He was provost for about a year and a half. One day in 1950 the then president Fu of the university appeared before the legislative body of the Taiwan Province. One of the legislators was questioning him very hard and I think he got a little angry. Having a history of high blood pressure, he suffered a stroke during the session, and died suddenly. At that time, my father was traveling in the United States on behalf of the university. Shortly after my father returned he was appointed president. He was only forty two years old. The Chinese like to go to senior people, so this was very unusual. Even today when people are appointed in their forties for presidency there would be questions, “Isn’t he a little on the young side?” That was 1951 when he was appointed president.

Nebeker:

Even though your father was president of the university you still had to apply for research assistantships or some means of supporting yourself?

Chien:

That’s right. The salary for the president was only slightly better than the average professor, which was not very good in those days. It is getting better now. However a president did have housing and a car with chauffeur, but in terms of directory monetary income, it was very low. The family was not in a position to support me financially to study abroad and I needed external support for my advanced studies. I was going to go with whatever place accepted my application and let that make my decision for me, but I got offers from just about every place I applied. The hospitals were asking for my measurements for my internship uniform and so forth in anticipation of my accepting their offers.

Nebeker:

It must have been exciting for you to have all these choices.

Chien:

It was very exciting but very difficult. I finally decided to go into graduate study for a Ph.D. degree in physiology. Then there were several places from which to choose. Dr. Magnus Gregersen, who was my advisor at Columbia later on, was visiting Taiwan when I was in medical school. He told me, “There is no doubt you should come to Columbia University.” That was a sort of a direct recruitment. Everything happened by chance.

Nebeker:

There is a lot of chance involved.

Chien:

Yes. I could have gone into math and had a totally different life from today, but that is how I wound up in medicine and how I wound up studying at Columbia. Gregersen was doing cardiovascular physiology research, so I went into that. The other places to which I applied were doing neurophysiology. I was fascinated by the brain and the cardiovascular system, so I applied for all those opportunities. Things could have turned out totally differently.

Nebeker:

And you finally decided on the Columbia offer, and you had applied for a Ph.D. program there?

Chien:

That’s right. Exactly.

Nebeker:

Did you know about Gregersen at the time you applied?

Chien:

I knew that he was the chair, but did not meet him until he came to Taiwan. He was on the board of an organization that was formed during the war called American Bureau for Medical Aid for (later changed to Advancement in) China (ABMAC). Its original purpose was to help the Chinese army with their medical supplies and other needs during the war. After the war the organization’s purpose changed to fostering medical education and training in China. When the Nationalist government moved to Taiwan they fostered the work there, and Dr. Gregersen was on the board so he came with another professor from Columbia, a surgeon named Dr. George Humphries. I was a medical student and had a chance to meet with them.

Columbia University Ph.D. studies

Nebeker:

Tell me about when you started the program at Columbia.

Chien:

I arrived in 1954. Today Taiwan is industrialized and cities like Taipei look very similar to big cities in this country. However, in those days Taipei was still somewhat rural. I was very impressed by New York. Uncle L.T. Yip met me at the airport and drove me to the International House near Columbia University, where I lived for the first three weeks. I was amazed by the multi-lane highways and the cloverleaf arrangements of the approaches.

Nebeker:

That International House is famous, isn’t it?

Chien:

Yes. I stayed there before I found an apartment, which was cheaper. I found Columbia to be a wonderful place to study. I was at the medical center (College of Physicians and Surgeons, or P&S). Shortly after I got there Dr. Gregersen said, “You already have a medical degree. You have taken physiology. Help us teach in the physiology course.” He put me into a lab teaching physiology to dental students. I had no teaching experience at all prior to that. I learned a great deal from teaching and found that to be a great experience.

Nebeker:

Is there some explanation of how your English was good enough to be able to do that immediately? Chien:

I think I did have to improve upon my English, but my ability to speak and comprehend English was probably better than the average among my classmates. I spent a lot of time working on improving my English vocabulary and my reading and writing abilities. However, I found it was more difficult to speak and to understand others, especially people with different kinds of accents. The ways they used the words and expressions were not the same. And sometimes I would use words that were not really part of the spoken language. I cannot think of a good example right now, but I remember saying words that were out of Shakespeare or something like that. Nobody really speaks that way. My friends, fellow graduate students and faculty members were very nice and told me how to say things in a way that was very friendly and helpful. The Columbia physiology graduate group is very small. At any given time it is always less then ten students. There were seven or eight of us during my three years of study. We knew each other very well and worked very nicely together.

Nebeker:

Tell me a little about your research there.

Chien:

Magnus Gregersen was interested in the volume of blood in the circulation and how that is regulated – particularly when there is a loss of blood as in hemorrhage and circulatory shock and how the body compensates for that. My Ph.D. thesis was entitled “The Role of the Sympathetic Nervous System in Hemorrhage.” When we lose blood our sympathetic nervous system gets activated. Adrenalin flows and other regulatory mechanisms operate to compensate for the loss of blood to maintain the blood circulation in the face of this stress. The choice of this topic reflected my interest on neurophysiology in addition to cardiovascular physiology and represented an attempt to combine the two.

My thesis involved quite a lot of surgery on animals. In order to study the role of the sympathetic nervous system, I removed all the sympathetic nerves surgically (total sympathectomy). That was difficult because the system consists of a whole series of nerve cell bodies called ganglia, which are located along the two sides of the spinal cord and connected by fibers running parallel to the cord. In total sympathectomy these two strings of ganglia need to be removed as intact strands from top to bottom. The surgical operation, which was performed under general anesthesia, involved two stages of sterile operations performed one week apart, with four chest incisions and one abdominal incision. The sympathetic ganglia chains had to be removed cleanly and the health of the animal had to be maintained, without infections or other complications. I remember that I cared these animals just as I cared patients when I was an intern. As a result, the sympathectomized animals were living normally and happily, but they had a reduced tolerance to stressful situations such as hemorrhage. I compared the cardiovascular responses to various levels of hemorrhage between this group of animals to normal controls that had an intact sympathetic system This approach allowed me to deduce the role of the sympathetic nervous system in quantitative terms. For example, I was able to determine that one quarter of the lost blood can be replaced by the influx of fluid from the tissue space surrounding the blood capillaries and how much does the sympathetic system contribute to this fluid influx following various levels of blood loss. Other examples are the quantitative assessment of the relative contributions of the excitation of the sympathetic nerves and the withdrawal of vagus nerve activities in causing the heart rate acceleration following various degrees of hemorrhage and the shift of the arterial pressure-blood volume relationship as a result of sympathectomy. My fellow students in neurophysiology, which was generally more quantitative than cardiovascular physiology in those days, at least in Columbia, were quite impressed by the possibility of treating cardiovascular physiology in such quantitative manners. I suppose my interest in math influenced my thinking and working even in this very early stage of my career in physiology.

Nebeker:

That sympathectomy sounds like a very difficult experimental situation.

Chien:

That’s right. I learned that operation from a professor in the Department Dr. S. C. Wang. His first name is Shih Chun, but he was known as S. C. because his full first name is not easy to pronounce. I later learned that he had been a classmate of my father’s in elementary school in Tien-tsin, China. What a coincidence! As a graduate student I took a course on “techniques in physiology”, which involved rotation among different labs to learn different things from the various professors. It was a very good education in the sense that the students, while having one professor as his/her thesis advisor, were not tied to only one professor.

Nebeker:

This sounds like experimental physiology as it was often practiced. Was there anything that looked like biomedical engineering at Columbia at the time?

Chien:

Not much. The Engineering School at Columbia was on West 120th Street and the medical school was on West 168th Street, so by subway it was about four stops. It was not that far, but somehow there was not a lot of connection between the two campuses. By the late 1960s, there began a few excellent co-operations, e.g., that between Dr. John Kinney in Surgery and Drs. Edward Leonard and Jordan Spencer in Chemical Engineering.

Nebeker:

Cooperation between medicine and engineering would have been unusual in those days.

Chien:

That’s right.

Nebeker:

I was wondering if there was something there that got you aimed more toward the engineering approach.

Chien:

In analyzing the different factors affecting the cardiovascular responses to hemorrhage, my initial focus was on the sympathetic nervous system. However, the results made me realize that there were other factors, even when the sympathetic nervous system had been removed. There are humoral and endocrine factors; and there are physical factors. More than one hundred years ago the French physician Poiseuille formulated the physical flow governing the flow of fluids, including blood. In Poiseuille law, the resistance to blood flow is clearly attributable to blood viscosity, as well as the size and number of resistance vessels. Thus, blood viscosity can play a role in cardiovascular regulation in health and disease, besides the nerves and hormones. The flow properties of the blood can change after hemorrhage due to the dilution of the blood cellular elements and proteins and the alterations in the adhesion and aggregation behaviors of the cellular elements, as well as other factors. Therefore I got interested in the factors that regulate blood viscosity.

Nebeker:

Had you taken much physics?

Chien:

No. My physics in college was rather weak due to my skipping of my high school senior year, as mentioned above. Because physics was not my strong suit, I decided to study more in order to be able to investigate the physical properties of blood or blood rheology. In the late fifties Magnus Gregersen attended a meeting in Europe and he was greatly impressed by a paper given there by Dr. Lars Erik (Charlie) Gelin, who was a Professor of Surgery in the University of Gothenburg. Gelin showed evidence that blood rheology could affect the response of animals – and hence people – to shock. Gregersen and I felt that was an important subject, so we switched our program to investigate the flow properties of blood, though we had previously known very little of this subject.

Nebeker:

Was this after your Ph.D.?

Chien:

It was about two years after my Ph.D.

Instructorship and assistant professorship at Columbia

Nebeker:

You stayed on at Columbia?

Chien:

That’s right. I got my degree in 1957. I was an instructor during my last year of study and the first year after I finished. Then I became an assistant professor in ’58. Shortly after that we got interested in viscosity and began to work on that in collaboration with Shunichi Usami from Kyoto, Japan. Shunichi and I are still working together at UCSD; this collaboration is over forty years. There are other colleagues who worked on this subject, including Dr. Robert Dellenback. None of us had worked on this subject before, so we got some of the experts to come in and give us seminars, e.g., Edward Merrill from M.I.T.

Nebeker:

This is an interesting case where really you were approaching it from the biological side.

Chien:

Purely from the biological side, yes.

Nebeker:

Your attention had been directed to the flow properties of blood, so you needed to learn the physics.

Chien:

Yes. We did experiments in the mid-sixties and published a series of papers. Our greatest success was the publication of a series of three back-to-back papers in Science on this subject in 1967. These papers are extremely important not only because they put our lab (a group of novices) on the map in this area of investigation, but also they triggered my thirty years of collaboration with Richard Skalak in the Department of Civil Engineering and Engineering Mechanics at the Columbia Engineering School. Dr. Skalak was on sabbatical leave in Gothenburg (Göteborg), Sweden in 1968-1969, working there with Professor Per Ingvar Brånemark (P.I. later developed a titanium dental implant called the Brånemark, which. grew out of his work on bone microcirculation using a titanium window implant. Although Dick and I were both faculty at Columbia, we had never met prior to 1968. Dick read the three articles in Science when he was in Gothenburg and wrote to Dr. Gregersen. He later became very expressing his great interest in them, especially the paper on the flow of red blood cells through narrow filter pores, which is very similar to capillary flow.

In 1968 I went to Gothenburg to attend the European Conference on Microcirculation (small vessels), when Skalak was still there. That was my first trip to Europe, and the first city I visited was Gothenburg. It was there that I met Dick Skalak.

Nebeker:

You met a Columbia person during your visit to Sweden?

Chien:

Yes, thousands of miles away. Dick said we should work together when he returned to Columbia. He had a student Tio Chen who was going to work on a thesis computing the flow of small particles through a narrow tube, a situation analogous to blood cells flowing through a capillary. Dick put me on Tio’s thesis committee, and through that we began to collaborate. We continued to collaborate for thirty years and published together many full-length papers. That’s where I got a lot of my engineering training.

Flow properties of blood; simulation and modeling

Chien:

So I was able to go from physiology to the biophysics of flow properties of blood, and to engineering simulation and modeling. Then I began to appreciate the power of simulation and modeling. That really put my math interests into practice.

Nebeker:

Tell me about how that simulation was done.

Chien:

Simulation was done by a number of methods, one of which was the finite element method.

Nebeker:

Were all of these numerical methods?

Chien:

Yes.

Nebeker:

Did you use a computer?

Chien:

Yes, I began to learn computers. In those days it was all FORTRAN and punch cards.

Nebeker:

There was probably just the main campus computer?

Chien:

That’s right. I think it was the 3060 IBM mainframe. It was bigger than this room we are sitting in. Today a tiny hand-held device would be much more powerful. We had no computation facility at the Medical School, so we had to punch cards. We would punch a program and put them into a box. These boxes were picked up at 4:00 p.m. every day. The results were delivered back to the Medical School the next morning at 10:00 a.m. Often the printout came back saying that there was a syntax error and I had then to do it all over again and wait for another day. Now we complain about the speed of the computer if the response is not instantaneous. The changes in size, speed and time in computation are truly remarkable!

I had no prior training in computers, and I learned how to program. I learned viscoelasticity and rheology partially from Dick Skalak and partially by reading. However, even before that I was taking courses in engineering topics. For example, in the City College of New York there was a famous Professor of Electrical Engineering named Taub.

Nebeker:

Oh yes.

Chien:

He wrote a book with Millman on network analysis that is a classic and was the best book in the field. It’s like Dr. Y.C. Fung’s book on biomechanics or Cecil and Loeb’s book on internal medicine. Because of that book I decided to take that evening course at City College while I was a Ph.D. student at Columbia.

Network analysis, engineering systems analysis

Nebeker:

How did you get interested in network analysis?

Chien:

I felt this was a way to apply math to something tangible. Also, I was beginning to use some equipment that had electronic circuits, and I wanted to understand them. For example, in physiological recording of pressure, there is the need to balance the resistors and capacitors in calibrating them. I was tweaking these knobs, and I wanted to understand what was behind them, instead of just doing it.

Nebeker:

Did you also think about working in instrumentation yourself and improving such devices in physiology?

Chien:

Not so much. I was really interested in the application and wanted to understand the principles so I could apply it properly. I wasn’t going to shift totally away from the physiological problems I was trying to solve, but I would like to solve them with instrumentation that I understand. That’s why I took the course. Later on I realized that using the network theory and related areas one can begin to understand how the physiological systems work. There were several papers out during those years about how to simulate the physiological systems using the engineering control theory. Therefore, I took a course in control theory.

Nebeker:

Did you take that course in the engineering department?

Chien:

Yes, in the electrical engineering department at Columbia. The course was given by Dr. Bernstein. I sat through the whole course, did all the homework, and took the exams. The network basis I had from taking the course with Dr. Taub was very useful. I was able to use the electronic circuitry base to understand the transfer function, feedback control, and so on.

Nebeker:

Was this kind of engineering systems analysis something that a number of people were beginning to explore at that time?

Chien:

That’s right. Dr. Arthur Guyton of the University of Mississippi was one of those people, but there are not too many. Dr. Guyton is retired but still working there.

Quantitative physiology; hemodynamic regulation and viscoelasticity

Chien:

I got interested in this and gave a course on “The Application of Control Theory in Physiological Systems” in the physiology department at Columbia.

Nebeker:

When did that start?

Chien:

That course was given from the late seventies to mid-eighties. The students liked it. That was introducing the quantitative approach to physiology. In physiology we generally tend not be so quantitative. For example, we teach that the carotid artery has baroreceptor to sense the arterial pressure and modulate the neural signals to return the pressure toward the control level – but usually not about the quantitative nature, dynamics or time dependence of the process. Such quantitative and dynamic information is what the control theory in the engineering approach would give us.

Nebeker:

Was it your predisposition to mathematics to a quantitative approach that led you in that direction?

Chien:

I think that helped a great deal, because it was easy for me to pick up this kind of thing. I can appreciate, understand and assimilate this kind of knowledge. The same is true on the mechanics side. Electrical and mechanical systems are analogous, for instance the use of resistors and capacitors.

Nebeker:

Right. Often the mathematics is the same.

Chien:

Yes. Ohm’s law and Poiseuille’s law are parallel to each other. The former is for voltage and current flow in the electrical system and the latter is for pressure and fluid flow in the mechanical system of flow. In the late seventies and early eighties, I instituted a series of talks on viscoelasticity at our lab meetings. We would have Skalak or one of his students, Dr. Aydin Tözeren and sometimes myself taking turns to give talks for the people in the lab. Although there were people who had received training in bioengineering (e.g., Herb Lipowsky, Geert Schmid-Schönbein, George Schuessler, and Kung-ming Jan), most of our people were biologically and medically.

Nebeker:

Right.

Chien:

We would explain it in such a way so that we did not give all the details of the mathematical formulation and derivation. The purpose was to let people have the feel for it and be conversant about it.

Nebeker:

I take it that in the years immediately after you got your Ph.D. that the flow properties of blood became your main interest.

Chien:

I think my interest in flow properties started in the early sixties. I got my degree in 1957.

Nebeker:

It took some time before that became your main interest.

Chien:

Right. In that time I continue my work on hemorrhage, shock and the control or flow and volume in health and disease.

Nebeker:

The same sort of thing as the subject of your dissertation.

Chien:

That’s right, but these studies were amplified to study how the body copes with other kinds of shock such as bacteria endotoxin shock, and cardiac tamponade. I also applied this approach to elucidate the mechanisms of hemodynamic regulation.

Nebeker:

That is getting close to engineering again.

Chien:

Yes. It is engineering on one hand and biomedical problem on the other. I am always interested in merging the two. Hemorrhagic shock is a major medical problem in intensive care surgery, which in turn is closely related to engineering. At the same time, we also moved from studies on the blood as a suspension to investigations on individual cells.

Nebeker:

Do you mean in the sense of modeling of the processes?

Chien:

Both in experiments and modeling. We isolated the individual cells, determined their viscoelastic properties, and modeled those properties. Dick Skalak, two of his students (Tözeren and Richard Zarda) and myself published a paper about the mechanical properties of the red blood cell (RBC) membrane. It is different from an elastic material like rubber in that this membrane has very different properties depending on the mode of deformation. The normal RBC at rest is like a disc with a depression in the middle, i.e., it has a biconcave discoid shape with a certain area and a certain volume. If that volume is enclosed in the sphere, a much smaller area than the discoid shape is needed. Thus, there is a large excess surface area in the normal RBC. As long as the surface area is not changed this excess are allows the cell to can into a variety of shapes, including like a sausage, and will fit into a cylindrical channel with a diameter of about 2.7 microns. We computed that from the geometry. We also conducted experiments to prove that rhia is indeed the case.

In contrast, if the cell deformation involves an increase in surface area, e.g., during cell swelling in a low salt solution, water will go in and expand the area. An expansion of surface area by three percent would cause a dramatically increase in membrane stiffness by 10,000 times or four orders of magnitude. Thus, a material can have two kinds of properties: one is when the area is preserved and the other is when the area is changing. That’s a new concept in the material properties of the cell membrane.

Nebeker:

Is this medically important because of certain situations?

Chien:

That’s right. As you and I talk, the blood is flowing through our tiny capillary vessels 5 microns or less in diameter. The RBCs zip through these narrow channels with ease, because deformation under these circumstances does not involve area change and can occur very readily. However, when area change is needed the membrane becomes very, very stiff. The ability of normal RBCs to deform readily with a constant area has a lot of implications in health and disease. When the membrane is stiffened in disease states, the RBC cannot traverse through the narrow channels as easily and it becomes trapped in organs, especially the spleen. This is why in several blood diseases the spleen is engorged with RBCs; because they cannot negotiate the fine channels.

Dick Skalak and I also worked together on the mechanism of RBC adhering to each other in a reversible way. This is due to the presence in the blood plasma of proteins that bridge the surface, e.g., fibrinogen. These long proteins can bring the cells together like a stack of coins, which is called rouleaux from French in the absence of flow forces, a drop of blood left standing would form long strings of RBCs, which can be seen under the microscope. During flow, however, the rouleaux are broken up by the shearing forces due to flow. We modeled the forced balance between the adjacent RBCs in terms of the aggregating force due to macromolecular bridging by the plasma proteins versus the disaggregating forces due to electrostatic repulsion between the negatively charged surface and the mechanical dispersion by flow. When the aggregation force exceeds the disaggregation forces, the RBCs will form rouleaux, and the net energy of aggregation will be stored in the cell membrane as an increase strain energy, which cause RBC deformation, i.e., a change in cell shape. As the cells are bridged together, we can look at the shape of the end cell and deduce what is the membrane strain energy stored in the cells When the aggregation force between the adjacent cells is strong, the membranes are pulled toward the aggregation plane and the last cell would bulge out. If the aggregation force is weak, the end cell will remain concave in shape similar to that of a resting single cell. We worked out a way of computing what energies are inside the aggregate, i.e., between the cells, by measuring the curvature of the end cell on the outside.

Nebeker:

Were you able to do this with a regular microscope?

Chien:

It can be seen very easily with a light microscope, but we confirmed it with transmission and scanning electron microscopes.

Nebeker:

You get some measure of that curvature and then relate it to the force.

Chien:

Yes, the force between the cells inside the rouleaux. Because we know the material properties of the RBC membrane, so the cell curvature reflects a certain degree of energy change in the cell.

Dick Skalak

Nebeker:

Can you tell me a little bit about Dick Skalak’s background?

Chien:

He was trained in civil engineering. He was a New Yorker born and raised in New York’s east side, the German town area. His family is Czech in origin. His father came over from Czechoslovakia. He went to Columbia as an undergraduate and received his Ph.D. degree from Columbia in civil engineering. He stayed at Columbia as a faculty membrane, a chair professor, department chair, and director of the Bioengineering Institute until 1988 when we moved together to UCSD. Prior to that, he had spent all his time in New York City and in Columbia.

Nebeker:

How does a civil engineer get interested in such things?

Chien:

I was not the first biomedical person to work with him. He got interested in biomedical problems a few years before that. Dick worked with colleagues in the Pulmonary Division of the Department of Medicine at Columbia, headed by Alfred Fishman. Dick Skalak was interested in the propagation of waves in relation to fluid flow or other kinds of propagation such as shock waves in non-biological system. In the blood circulation in the lung and elsewhere, there is wave propagation. The heart ejects a pulse and the wave propagates. That’s how we feel the pulse in the wrist. The pulse gets to the artery there ahead of the blood, because it is propagated through the vessel wall.

Nebeker:

Right.

Chien:

Dick did a very comprehensive study on pulmonary wave propagation with Al Fishman and his colleagues, including Eugene Morkin and Fred Wiener. They made the pressure and flow measurements as a function of time, and Dick Skalak did the computation and modeling. He was able to match the experimental results with theory to derive the material properties of the pulmonary vessels.

Nebeker:

It was a mathematical or physical explanation of the observed pulse or wave movement.

Chien:

That’s right. It explained how the wave propagated and hence how it affected the dynamics of flow.

Nebeker:

I’m still wondering how someone trained in civil engineering ever got hooked up with pulmonary people.

Chien:

I don’t know exactly how that came about. I think Dick was probably interested in seeing how what he was doing could be applied to biology and medicine. He may have been the one who initiated the collaboration. Maybe Fishman and his colleagues were also looking for someone to help them find an explanation. I think it probably worked both ways. Perhaps Fred Wiener was the one who got Dick interested.

Dick Skalak also worked with Werner Loewenstein in Columbia Physiology on the mechanisms of mechano-sensing and the transduction of mechanical deformation into electrical signals. Werner Loewenstein was interested in how pressure can trigger sensory nerve impulses to originate from these receptors. In the abdomen there is a kind of mechano-sensor called Pacinian corpuscles, which are small elliptical bodies that have nerve endings that can transmit information form the corpuscle toward the central nervous system. Loewenstein did a lot of work on how the applied mechanical forces can lead to the activation of the nerve endings. These corpuscles have many layers, like an onion. He wondered why this layering was there and how did it affect impulse transmission. Dick did the modeling with Werner. They published a couple of papers dissecting how the mechanical forces are transmitted through the layers and to the nerve endings embedded inside these onion layers to trigger the sensory nerve impulses. It was an excellent study on mechano-electrical and mechano-chemical conversion. Research on the pulmonary circulation and on the Pacinian corpuscles were Dick’s first two studies involving the biomedical sciences.

P.I. Brånemark gave a talk in Philadelphia in the mid-sixties on the dynamics of blood cells in the microcirculation that Dick attended. Brånemark developed a technique of making a little skin fold in the human forearm in which a titanium chamber was implanted to make possible microscopic observations on blood flow in living capillaries. Human investigation like this could be done more readily in Sweden in those days. The students volunteering to be the subjects would carry this little chamber on their forearms for months for periodic studies. By placing the skin fold with the titanium chamber under the microscope, one could see the microcirculatory blood flow in a living human. The skin fold could be subjected to various types of manipulation, for example clamping to stop the flow for a short period and observing what happens and then opening it again. Microscopic observation on the living circulation can be made only in a few other places, e.g., the eye and the finger nail fold.

Brånemark told me, “After my talk in Philadelphia, this young man (Skalak) walked up to me and asked if it would be possible for him to spend time in my lab.” He asked Dick, “What’s your background?” After Dick told him, Brånemark said, “Great!” That’s how he came to spend that sabbatical in Gothenburg in 1968-69 that I mentioned earlier.

Modeling in physiology; computer modeling

Nebeker:

One of the characteristics of the engineering approach to physiology is the modeling, particularly computer modeling.

Chien:

Yes, that’s right.

Nebeker:

At some point that came to be highly regarded and I imagine that more and more physiologists would want to do that kind of thing. Whatever they are studying, it seems they would want to have a computer model. Is that something you observed in the ‘60s?

Chien:

Yes, more and more. I think the problem with engineering modeling in the early days is that a lot of the modeling studies were not done in relation to the biological reality.

Nebeker:

More abstract mathematical models?

Chien:

More abstract and very elegant solutions to a problem, but not necessarily applicable to biological systems. Therefore, it is very important that biology and engineering be brought together. What is required is that the engineers have an appreciation for the biology, and the biologists have an understanding of engineering. Both must be conversant with the other so that they can talk to each other. I would never be able to do the modeling as precisely or directly as what Dick did, but I could understand what he was doing and make comments and suggestions.

Collaborations

Nebeker:

Could you understand all of the equations?

Chien:

I understand the ones we worked on – but I would not be able to formulate all of them. Once Dick formulated the equations, I would be able to judge which one is more applicable and which way we should go with it. That is the kind of collaboration that is needed.

Nebeker:

It’s remarkable that you and Skalak worked together for so many years.

Chien:

Yes. I am very, very grateful of that. The other groups (Fishman and Lowenstein) did not keep up their collaborations. In his later years at Columbia, Dick also worked closely with Melvin Moss of the Dental School (on bone growth) and Gerard Turino of Pulmonary Medicine (on lung mechanics). Brånemark continued to work with Dick for all these years, and in fact a year or so longer than me. Dick went to Gothenburg two or three times a year in the ‘80s to work with P.I. on osseointegration and implants, and I also go there periodically. Because Dick and I were together first at Columbia and then at UCSD, we had more opportunities to interact, and we were able to communicate extremely well. Dick and I really understood each other, not only in science but as individuals. I was blessed to have him as a friend and colleagues for nearly thirty years.

I am very fortunate in that, besides Dick Skalak, I have worked with several other outstanding engineers. I would like to mention particularly Shelly – Sheldon Weinbaum – from City College of New York (CCNY) and I have been working on the endothelial cells lining the blood vessels.

Nebeker:

How did this collaboration come about?

Chien:

Colin Caro, who is in the Imperial College of London, has done a lot of fundamental work on blood vessels in relation to fluid mechanics. He wrote an outstanding book on fluid mechanics in relation to blood flow, Blood Flow in the Arteries, in the early seventies. He is medically trained, but has a great appreciation for fluid mechanics. He has made a number of important observations, particularly in relation to how the flow condition in arteries affects the prevalence of atherosclerosis. Several well-known people from this country worked in his lab on sabbaticals, including Bob Nerem now at Georgia Tech.

Shelly Weinbaum and Bob Pfeffer (Professor and Chairman of Chemical Engineering at the City College at that time) each spent a sabbatical year with Colin working on atherosclerosis problems in the early seventies, and they talked about continuing that work after Shelly returned to New York. Shelly told me that Colin said, “The person in New York you should collaborate with is Shu Chien.” I already knew Shelly and Bob from other contacts in New York. In 1969, Dr. Y.C. Fung traveled from San Diego to give a number of special lectures at CCNY, and he made sure that Shelly met Dick Skalak and me during his visit. In 1970 Shelly and Bob took a summer physiology course I gave with other colleagues in the Department, just as I did in taking the engineering courses

Nebeker:

Can you describe their interests?

Chien:

By training Weinbaum was a mechanical engineer and Pfeffer was a chemical engineer, so they were primarily interested in engineering modeling. Both of them were interested in transport phenomena; how molecules move. And in atherosclerosis the important thing is how cholesterol or low-density lipoproteins, which are the large molecules that carry the cholesterol, move into and through the artery wall; how do they get accumulated and removed. That was the central problem in which they were interested. They did not have much contact with biology until they took the summer physiology course and then went to work in Caro’s lab. As mentioned above, they wanted to continue in this line of research after returning to New York, so they came to me and said they wanted me to collaborate on this project. At that time I was working very heavily with Dick Skalak, so I got Skalak involved in it too. This is a problem related to my interests because of the blood vessels and fluid mechanics. I was focusing more on the blood cells for quite a while, and here was an opportunity to look at the blood vessels and the cell-vessel interface as well. I was interested in initiating new approaches, and we began to work together.

Nebeker:

When was this?

Chien:

This was in 1974. We submitted a proposal entitled “Studies on Endothelium in Atherogenesis.” to the NIH, and this grant application was funded in 1976; it is still active now after twenty-four years.

Nebeker:

Have you continued to work on this?

Chien:

I have continued to work on this, and if fact almost all the work that we are doing now is related to this theme. We are getting to be more molecular in our approach. Looking back, I first started with the organ-system; got down to blood as a tissue; and then blood cells and endothelial cells. I realized that the rapid advancement of molecular biology should be introduced to physiology and engineering. At that time, in the early eighties, molecular biology was not commonly recognized. It had advanced tremendously and become an extremely powerful tool for biological research since Watson and Crick discovered the double helix in the ‘50s.

Molecular biology; evolution of instrumentation

Nebeker:

I think it may have been in the seventies and eighties that the instrumentation advanced to the point that this approach to biology became more and more possible.

Chien:

Exactly. I was primarily a physiologist and was elected to the Council of the American Physiological Society in the mid-eighties. I proposed that we incorporate molecular biology into physiology. I went to a few workshops trying to understand how to do molecular biology, but came away learning very little. This is because the experts in molecular biology started so rapidly at such a high level that I, as well as all the non-experts in the audience, could not follow. The people who gave these workshops probably thought everybody was like them and that they shouldn’t talk about the fundamental and mundane things. Little did they know, the audience had virtually no background in that area.

I decided that I had to learn more about molecular biology and took some courses, but more importantly I did a lot of reading on my own. The ability to learn continuously is the key. A lot of what I am doing today was not learned by me as a student in the classroom. Rather, it depends a great deal on what I learned later both on my own and with the help of others. What I learned as a student is the way to learn, i.e., how to continuously educate oneself. As mentioned above, I first learned viscoelasticity, and then cell biology and molecular biology. There is a very well written book on Molecular Biology of the Cell by Bruce Alberts, the president of the National Academy of Science, and five other co-authors. I chose this book and assigned chapters to different people in the lab to read and report to the group and everybody can ask questions. If we could not solve a problem, we’d ask other people later on. None of us were very familiar with the subject except for Amy Sung, who was a Ph.D. student at that time with Dr. Elvin Kabat of the human genetics department and myself as co-advisors. We finished this book in about one year and learned a lot that way.

Nebeker:

What year was this roughly?

Chien:

It was around 1985.

Nebeker:

Your self-study in molecular biology.

Molecular biology symposia and workshops

Chien:

Yes. In 1986 I proposed to the American Physiological Society that we have a symposium and workshop on the topic of Molecular Biology and Physiology and that I would give the introductory talk – where I would spend forty minutes to say what it is all about and go over all the terms and fundamentals so that the later speakers could take off from there. We got several people, including Eric Kandell in Columbia Physiology, who won the Nobel Prize in 2000. Eric was just getting into molecular biology at that time and he foresaw the importance of this approach. He won the prize because of his molecular approaches to neuroscience research. Another speaker was Dr. Numa from Japan. He was terrific, but unfortunately he died a couple of years ago. I was amazed that these top people were willing to help me with this initiative to introduce molecular biology to my physiology colleagues. This symposium was published as a book: “Molecular Biology in Physiology,” Raven Press, N.Y., 1989.

Nebeker:

Do you think that was an influential symposium?

Chien:

There was not only a symposium. I also conducted a workshop. I got several companies to agree to give hands-on workshops. We set up four different rooms – for hands-on experience on western blotting, gel electrophoresis DNA purification, DNA sequencing, etc. Four different companies picked up these four different topics, and we got very good attendance. We had it throughout the four days during the American Physiological Society meeting. People could sign up for each day and rotate through. Dr. Dale Benos, a recent chief editor of the American Journal of Physiology Cell, which is a premiere cellular and molecular oriented physiology journal, told me a few years ago, “You know how I got into molecular biology? It was that workshop that you held.” I felt very gratified by that, because what I did then really made a difference. Several other people also have told me that they got into the field through that workshop and symposium. I think it’s important for somebody who is part of a group to try to learn and understand a frontier area and then give it back to the colleagues for the advancement of the field.

When I give an introduction to the topic of molecular biology, I started it from ground zero – with no assumptions whatsoever. I moved at such a pace that by the end of forty minutes the audience would have a sufficient background to listen to the experts speaking on specific topics. I believe that anything can be gotten across in any given amount of time, but the amount of information transmitted will depend on the time available. The fundamentals can be gotten across in a very short amount of time when there is sufficient preparation. One has to think about what is absolutely necessary and essential in order for the audience to be able to follow the rest of the symposium. The results were very, very gratifying.

I organized a second symposium and workshop for the American Physiological Society that was focused on the cardiovascular system. That symposium was published as a book: Molecular Biology of Cardiovascular System, Lea and Febiger, Philadelphia, 1990. Later I talked to other groups like the biorheologists, the microcirculation group, and the bioengineers. I tried to preach the same thing to them, and I think it was helpful.

Biorheology group and research

Nebeker:

This biorheology group sounds a little bit like engineering.

Chien:

Yes, it is.

Nebeker:

Can you tell me about that research community?

Chien:

Rheology is the study of flow and deformation of matter. There is a Society of Rheology, which is part of the American Institute of Physics. Deformation and flow can be those of materials in a chemical plant, but in blood it is particularly deformation of the cardiovascular system and the blood cells and how the blood flows. It is really an interface between physiology and engineering.

Nebeker:

Do you know the history of the physiology interests of rheologists and when it developed as a field?

Chien:

Biorheology probably developed in the ‘40s and ‘50s. The late Dr. Alfred Copley was a strong proponent of the field. He formed the International Society of Biorheology and organized many congresses. He also started the journal Biorheology, which has Dr. Harry Goldsmith of McGill University and Montreal General Hospital as the Editor-in-Chief. The Congresses were usually attended by several hundred people and they provided a forum for the exchange of scientific information on a lot of interesting work in the field.

Nebeker:

It strikes me as a bridging field.

Chien:

It’s a bridging field. That’s right. It overlaps a lot with bioengineering and physiology, but it’s a very specialized area of bioengineering. However, when one talks about biomechanics and biorheologists, it is very hard to distinguish these two. For example Dr. Fung’s work is also recognized by the field of biorheology. He received the Poiseuille Medal, which is given by the biorheology community once every three or four years to the one scientist that has made the most outstanding contribution to the field..

Nebeker:

Did you regard yourself as part of the biorheology community?

Chien:

Yes. People working in the biorheology field regard me as a part of it. I was surprised at first when people referred to me as a biorheologist, because I still regard myself as a physiologist. In the seventies and eighties when I was working on biorheology as a major emphasis in my lab, and people thought of me as a biorheologist and I was accepted by the community – just like today I am thought of as a bioengineer.

Interdisciplinarity; bioengineering field, quantitative engineering

Chien:

I am currently president of the American Institute of Medical and Biological Engineering.

Nebeker:

Then you must be a biomedical engineer.

Chien:

Yes. I am a professor of bioengineering and was the founding chair of the Department of Bioengineering at UCSD. I appreciate that people accept me as an engineer.

Nebeker:

Did you also belong to the Physiology and Biorheology Societies, receive their publications and publish in their journals?

Chien:

Yes. I have been a member of the American Physiological Society for forty years. I was the president of that society 1990-1991. Subsequently I was the president of the Federation of American Societies of Experimental Biology, which includes physiology, biochemistry, pharmacology, immunology, pathology, nutrition, cell biology, and biophysics at that time. The Federation later added ten other socieities and now it is a very large federation.

Nebeker:

It’s remarkable that your work has somehow stretched from physiology to engineering to biophysics.

Chien:

I think this kind of cross-discipline interactions is very much needed. I keep fostering this idea that, whether it is bioengineering or physiology, we need to have an integrative approach, going from genes and molecules to cells and tissues, and to organs and systems. We have to use both experiments and theories to integrate them together, bridging biomedical and engineering sciences. That’s the theme I have used in the last two decades. The diagram I designed to represent this integrative concept is still used by the American Physiological Society for the brochures on its publications and by the UCSD Department of Bioengineering for the cover of its departmental brochure.

Nebeker:

There seem to be certain skills and theoretical tools that have traditionally come out of the engineering community that prove very useful in this. I know that biologists had looked at life in a hierarchical way.

Chien:

That’s right.

Nebeker:

I think what’s new in the last fifty years – and please correct me if I’m wrong – is this large input from the quantitative engineering ideas that are applied to the systems.

Chien:

Oh yes. It’s having an impact on the biologists’ side. I think it was the physiologists that sensed this first, but now the general biology community, including the cellular and molecular biologists, is seeing this impact. I mentioned the book by Bruce Alberts.

Nebeker:

Yes.

Chien:

In the most recent edition of this excellent book, Molecular Biology of the Cell, there is a chapter on the mechanics of cells, which is a new chapter not present in previous editions. This is a clear indication that cell and molecular biologists are now seeing the importance of quantitative engineering in the study of biology. There is still not sufficient quantitative treatment in biological research, but I think the next generation of biologists will be educated with the quantitative capability. Quantitative treatments are already being used in some of the biological fields. For example, signal processing is being used in the study of ion channels in excitable cell membranes. The opening and closing of these channels in a particular pattern of frequency distribution modulate the function of cells such as the neurons. The analysis of such data requires the application of quantitative methodology. I believe such quantitative analysis and engineering modeling will be increasingly applied to biological research. In my current research, we study how cells modulate their signal transduction and gene expression in response to flow or deformation of the cell. The time course and the extent of the responses need to be analyzed by treating these molecules as a circuit or network, because of their interrelations and interactions.

Nebeker:

Have those physical events changed gene expression for example?

Chien:

That’s right. The cells can concert (or transduce) the physical stimuli of flow or pressure into chemical molecular events inside the cell. It’s mechanochemical transduction. We are only working at a qualitative level to identify which aignaling molecule activates which one, i.e., which one is upstream to what and which one is parallel to what. That’s only qualitative. Eventually it has to be quantitative. We need to know the dynamics of the interplay between one set of molecules to the next, to understand the transfer function, i.e., the input-output relationship, and to identify the kinetics and the rate-limiting step. We are far from that. We need to use an engineering approach to solve these kinds of problems. However, the qualitative framework needs first be established in order for us to address the problem quantitatively.

Nebeker:

Absolutely.

Chien:

Down the line we must be able to use the quantitative approach to determine how these molecules crosstalk and interact with each other to accomplish the coordinated action of control and integration. That’s what a biological system does. It integrates all the signals and modifies its behavior appropriately to optimize the function of the system. However we are not yet able to understand all of that. That’s why we keep on studying.

Nebeker:

Plenty of work to do.

Chien:

Yes. The control theory that I mentioned before was mostly applied at the higher level, such as the organ system level, e.g., in blood pressure control.

Nebeker:

And like temperature control.

Chien:

Yes, indeed. These are the physicochemical parameters at the whole body or organ-system level. We will be able to get down to the cellular-molecular level eventually. The control mechanisms at the cellular-molecular level, or even gene regulation, utilize some of the same principles as in the higher levels of biological hierarchy. The mechanisms that control DNA replication and transcription involve feedback control and they are exceedingly well controlled. This needs to be studied in detail. I wish to emphasize that of the fundamental principles transcend all levels of the biological hierarchy and that what we learn at the genetic-molecular level needs to be integrated with what we know at the organ-system-whole body level.

Biomechanics

Nebeker:

While we are on this more general level, comment on the emergence of the biomechanics community?

Chien:

One of the emerging areas among biomechanics activities is molecular biomechanics. We have begun to have the instrumentation and capability to study the biomechanical properties and behaviors of individual molecules. For example, in the cytoskeleton network composed of structural proteins including actin. What are the mechanical properties of the actin filaments? The answers to this are important in understanding the mechanisms controlling the motion, mechanical stability and shape of the cell. How do the cytoskeletal elements change to deform the cell during adaptation to the environment? For instance, in the endothelial cells subjected to sustained flow, the cells and actin fibers become oriented and aligned with flow. What are the mechanics involved in such reorganization? When one molecule interacts with another, what are the mechanics involved and how are they controlled? For example, muscle contraction is due to actin-myosin cross-linkage. What kind of force at the molecular level is involved in the actin-myosin linking and the resulting power stroke? In DNA transcription, the RNA polymerase would use one of the DNA double strands as a template to make a complementary copy of RNA. During the transcription process, DNA is subjected to stress and undergoes deformation. There are now methods such as the laser traps that can be used to determine the stress-strain relationship during DNA transcription and RNA elongation, i.e., the molecular mechanics of these nucleic acids.

Nebeker:

On a single molecule?

Chien:

Yes. The question is “What are the molecular dynamics during transcription?”

Nebeker:

That’s remarkable.

Chien:

Yes. We are actually on the verge of understanding the mechanical basis of molecular events. I think this type of study will flourish in the next few years.

Nebeker:

Historians are always looking for large patterns that can describe decades of work. Maybe biomechanics starts at this very largest level – the arm is a lever and all this sort of thing – and with improved instrumentation and understanding especially on the molecular level, there is an understanding that just didn’t exist thirty years ago. Now what’s going on with muscle contraction and so on is being understood for the first time, the scale is becoming finer and finer and giving a mechanical explanation of things.

Chien:

Right. However this must eventually be incorporated back into the integrative system level of understanding. On the one hand we have the reductionist approach to get it down to smaller and smaller levels, yet on the other hand we must be able to synthesize it back to the systems level. Whatever we see at the individual molecular level, we need to put it inside the cell, tissue, organ and whole system. After all, we are ultimately interested in the overall ensemble behavior.

Nebeker:

Right.

Chien:

We do want to understand the finest details so that we can synthesize the knowledge to provide understanding of the whole.

Nebeker:

This is done both in simulation and computer modeling. A description is taken at one level and then that generates the observed behavior at a higher level.

Chien:

That’s right. In order to do that, the understanding of just one kind of molecule is not enough. We must be able to put together the information together with that on all the other molecules. It’s a very demanding task to do that on different kinds of cells, tissues and eventually whole organs and the body. We can use theoretical modeling to match some of the experimental findings, and modeling can also help us to predict new findings and design new experiments. This is the power of modeling and simulation. If we can explain all the existing experimental data using a given model, then we study some additional perturbations and predict how a system should behave. If we do the experiment and the results bear out the prediction, it reinforces the theory. If the results do not agree with the prediction, then we need to modify the theory to match the experiments. This can be done at the systems level as well as the molecular level. At the molecular level we need more experimental data designed with the aid of theoretical modeling in order to initiate this kind of approach. Ultimately this is the goal, but it will take a tremendous amount of effort to pull it all together.

Microcirculation, cellular-level research

Nebeker:

Let’s talk about the areas in which you worked in the ‘80s.

Chien:

I would like to step back a little more to the late seventies first. Besides this movement into the cellular level, at the same time my lab at Columbia was beginning to work on the microcirculation. We recruited two young bioengineering graduates, Herbert Lipowsky and Geert Schmid-Schönbein. Both were recent graduates from the University of California, San Diego.

Nebeker:

With whom had they studied?

Chien:

Geert Schmid-Schönbein studied with Dr. Fung and Herbert Lipowsky with Benjamin Zweifach. Fung and Zweifach were the founders of the Bioengineering program at UCSD, and both of them were outstanding scientists. Y.C. Fung came from an aeronautical engineering background and he is widely regarded as father of biomechanics. Ben Zweifach came from a biology background, and was widely regarded as father of microcirculation; he passed away in 1997. Fung and Zweifach came together to San Diego in 1966 to initiate the bioengineering program. Both Herb and Geert came to my lab in 1976 to receive postdoctoral training and they contributed a lot to the engineering environment in my lab at Columbia in bridging engineering and biology in our research.

Nebeker:

Was this in the late ‘70s?

Chien:

Yes. Geert Schmid-Schönbein returned to UCSD three years later, in 1979, to become an assistant professor. Now he is a full professor. Herb Lipowsky went to Penn State University in 1990 to become the chairman of their bioengineering program. We also had other bioengineers in the lab. Some worked on the computers. George Schuessler, who received his Ph.D. in Carnegie-Melon in Pittsburgh, was in charge of the computer system in my lab. From Dick Skalak’s group, Aydin Tözeren, Si-shen Feng, Cheng Dong, Cheng Zhu, and others often came to my lab in P&S. We needed the cooperation all of these people to form the team. We also had basic bioscientists (including molecular biologists, electron microscopists, and physiologists) and clinical investigators (cardiologists, hematologists, anethesiologists, and neurosurgeons). I was also fortunate in having a terrific group of technical and administrative staff. It really was a marvelous multidisciplinary team. While I cannot be an expert in every field, I need to be able to understand the disciplines involved in order to synergize their activities.

Nebeker:

How large was your group?

Chien:

We had about thirty people in Columbia. One of the reasons I was in favor of moving to La Jolla, besides the wonderful academic environment and the new opportunities to collaborate, was that I felt that the group was too large. I wanted to reduce the size of the group, but that was very hard to do while staying in the same place. When I first came to San Diego, I had only six people, but now it’s grown to again twenty. This is a sufficiently large team for us to cover the different areas in our interdisciplinary research.

Nebeker:

Yes.

Bioinformatics

Chien:

For example there are now in my group several people in bio-informatics because we are doing DNA microarray studies to systematically assess gene expression in response to mechanical stimuli. With this novel technology, we can simultaneously search for the expression of 10,000 or more genes, whereas the previous techniques only allowed us to study one gene at a time. Bioinformatics is needed in order to sort out the meaning of the response pattern of a large number of genes. We need people from all of these different disciplines, and we also work with colleagues in the department and in other departments and institutions.

Nebeker:

If the group gets too large the management or administration of it is too time-consuming.

Chien:

Yes, it takes a lot of time. Also, the group tends not be as cohesive. The reason I was able to do that at Columbia was because there were several relatively senior colleagues, e.g., Shunichi Usami, Kung-ming Jan, and Herb Lipowsky, who were functioning almost independently and help guiding the younger associates and students.

Research and clinical applications

Nebeker:

Are there other areas of research you got into at Columbia that we haven’t talked about?

Chien:

I think we’ve covered it pretty well. One thing I would like to mention is that in all our studies we were always looking for applications to clinical medicine, i.e., disease states. For example, we applied our expertise on blood cell rheology to the study of sickle cell disease, which involves a reduced RBC deformability due to the crosslinking of sickle cell hemoglobin during deoxygenation. We study with our clinical colleagues the roles of blood rheology in clinical conditions such as myocardial infarction, hypertension, carotid occlusion, malaria, muscular dystrophy, hypothermia surgery, etc. We were doing that kind of study in parallel to our fundamental research. In the eighties we conducted these types of research, and also the mechanisms controlling white blood cell rheology and cell adhesions (primarily done with Paul Sung). With Amy Sung, we also began our research on molecular biology of RBC membrane proteins, i.e., the molecular basis of RBC rheology, which was continued in UCSD.

Nebeker:

Were you able to model that deformation in sickle cell disease?

Chien:

There was some modeling, but that study was more experimental in nature. It did shed new lights on why the sickle cells behave the way they do. Studies on sickle cells became very popular when the U.S. Congress placed an emphasis on this field in the mid seventies. We started our work on sickle cells earlier in the late 1969s with a hematologist colleague at the St. Lukes’ Hospital Center in New York, Jack Bertles. I gave a seminar at St. Lukes’ Hospital on RBC deformability and he said, “We should do this type of study on sickle cell disease.” We started our collaborative study in the early sixties and published our first paper in 1970. It was the first papers that dissected out the mechanisms underlying the rheological abnormalities in sickle cell disease. It is interesting that you never know when these kinds of fruitful interaction would get started. I met Dick Skalak at a meeting in Gothenburg, and I met Jack Bertles at a seminar in New York. There were many similar encounters with other scientists, but they did not lead to the same kind of developments.

Nebeker:

Whatever physiological system you were looking at, you’d try to look at disease states and pathological states.

Chien:

Right. I am always interested in knowing potential applications of our scientific research to disease states, right. I collaborated with Dr. John Laragh, a leading expert in hypertension, in our studies on blood rheology in hypertension. John was at Columbia when we started and later moved to Cornell; we continued to collaborate after his move until I left New York.

As mentioned above, I also worked on problems related to atherosclerosis and other diseases. For example, we studied plasma protein abnormality and how it affects the flow properties of blood, and polycythemia when there are too many RBCs. We studied how these pathological states affect the rheology of flow and the transport of oxygen.

Nebeker:

You mentioned that the sickle cell work was valuable. Were there other of these where you felt that someone interested specifically in the disease state gained something from your biomechanical approach?

Chien:

Yes. We identified that blood rheology is a potential factor in hypertension. Our results indicate that, in addition to the constriction of blood vessels and/or a high cardiac output, there is a third possibility, namely an elevated blood viscosity. We worked with John Laragh’s group to show that the increase in left ventricle mass, i.e., cardiac hypertrophy, in hypertension is correlated best with the blood viscosity, rather than other circulatory parameters such as blood pressure, cardiac work, etc. While cardiac hypertrophy is adaptive to allow a greater cardiac output against an elevated peripheral resistance; it can be also deleterious when persisting. Our finding that blood viscosity is the parameter that correlates best with the left ventricular mass indicates that blood viscosity probably is a major resistance factor that the heart has to work against and hence causing the increase its mass. That is to say, blood viscosity can play an important role in the pathogenesis in hypertension and the associated cardiac hypertrophy.

Nebeker:

It’s actually the rheological property really determining that.

Chien:

Yes. Another kind of hyperviscosity condition is polycythemia. We have analyzed how the hematocrit, i.e., the RBC concentration, impacts on blood viscosity and oxygen transport, as well as how the cell concentration should be titrated in treating this kind of hyperviscosity.

UC San Diego

Nebeker:

How did the move to UCSD come about?

Chien:

At around 1984 UC San Diego wanted to recruit a senior faculty in bioengineering in anticipation of Dr. Fung’s retirement in 1989. Dr. Zweifach had retired shortly before that, so UCSD wanted to bring in somebody to continue what they had been doing. I was surprised that Drs. Fung and Zweifach called me in late 1984 and told me that I was being considered. The first thing I said was, “I am not a bioengineer.” They said, “You are a bioengineer.” I was flattered that they asked me to consider this possibility. Judging from what we are doing now in recruiting new faculty to UCSD, I’m sure that the bioengineering faculty went through a lot of soul-searching in deciding whom did they want.

At that time, I was deeply entrenched and involved at Columbia with my large group and a lot of activities related to my NIH program project grant and training grant, so my first reaction was that I really could not move. It seemed too difficult. But UCSD persisted for two years. Another important factor was that my wife K.C. was not prepared to leave New York. Our children were in New York, and we had a lot of friends there. K.C. had a full-time job in New York as a pediatrician; to practice in California she would have to take the medical license exam again because the State of California does not have reciprocity with the States of New York or New Jersey, where K.C. is licensed to practice. It was a tough situation for her. For those reasons I wasn’t ready for the move. UCSD kept inviting us to visits, and after several visits my wife said, “Maybe we’ll give it a try.”

Nebeker:

Did you move in 1988?

Chien:

Yes. In 1987 and the early part of ’88 I was in Taiwan, where I was committed to start the Institute of Biomedical Sciences, and couldn’t move at that time. Normally one cannot take a terminal sabbatical leave from Columbia. I took a leave to Taiwan, came back to Columbia in June 1988, and left again in September 1988 to come to UCSD. Columbia was very accommodating in giving me the terminal sabbatical. Partially it was because during the eighteen-month period I was in Taiwan, I made seven trips back to Columbia to teach and carried out my full teaching responsibility. I was not only allowed the terminal sabbatical, but also given a two-year leave of absence. I was told by Columbia that “Maybe you will come back, so we’ll let you try it out.” We moved in fall 1988 and a few months later decided to stay in San Diego.

One of the other things I was concerned about was leaving my colleagues with whom I had worked for so long – particularly Dick Skalak. In response to my concern, UCSD asked Dick to also come to San Diego. UCSD got a wonderful deal with two people at the same time. Dick was in his early sixties at that time and did not want a full job. He would like to have the freedom to do research and some teaching when he wanted. Accordingly, UCSD gave him an appointment of Professor-in-Residence, which is in every way the same as the other professors except that there is no obligation to teach.

Nebeker:

I see.

Chien:

Dick liked that, and we collectively made the decision to come to UCSD.

Nebeker:

Did he also come to UCSD in 1988?

Chien:

He actually came a couple of months before I did, because when I returned from Taiwan in July I had to stay in New York/New Jersey long enough to get my lab prepared and my house packed for moving. Those two months were very hectic. As for the lab, it was fortunate that my long-time colleague Shunichi Usami was able to stay for two additional years to close it.

Institute of Biomedical Sciences

Nebeker:

Let’s talk about the Institute of Biomedical Sciences in Taiwan that you founded and directed.

Chien:

The process started in 1980 during the biennial meeting of Academia Sinica, of which I am a member.

Nebeker:

When were you named a member?

Chien:

I was elected as a member in 1976. Election to membership in Academia Sinica was done every two years. Several members tried to nominate me for membership in 1972 and again in 1974. My father, who was president of Academia Sinica from 1969 to 1983, was a wonderful man. He tried to do everything possible to avoid any sense of impropriety or conflict of interest, and hence talked these members out of nominating me both times. I admire him very much and am fully in agreement with him. In 1976, however, father was not able to stop my nomination, and I was elected there year with the highest number of votes. Father abstained and did not vote.

During the Academia Sinica membership meeting in 1980, Dr. Paul Yu, who was the president of the American Heart Association and chief of cardiology at the University of Rochester, proposed with some thirty members, including myself, the establishment of the Institute of Biomedical Sciences (IBMS). The Academy had several institutes in the life science fields:, including zoology, botany, and biochemistry– and then there were institutes in the humanities and natural sciences. I remember that the meeting was almost over, and Dr. Yu made the proposal at the last minute. We were told that we needed a written proposal, so the two of us went to a little room to write it in about fifteen minutes. I dictated the draft proposal (in Chinese), and Dr. C.Y. Chai wrote it by hand. This proposal was officially passed as the last item of business of the members’ meeting and sent to the Executive Council and President of the Academy for approval and submission to the government for final approval and implementation.

Dr. Yu had tremendous government connections because he was the physician for President Chiang Kai-shek, his son Chiang Ching-kuo, Premier Y.H. Sun, and people in charge of science and technology such as K.T. Li. Many of them had heart conditions and other problems, and Paul was a marvelous, trusted physician to all of them. Paul was an excellent physician-scientist, but particularly a physician with a wonderful bedside manner and patient rapport.

Nebeker:

Some of the great scientists in the past who were also court physicians.

Chien:

Court physician. You said it. He was at Rochester, but President Chiang Kai-shek got him to come back several times a year. Once Paul had to turn around as soon as he arrived back at the Rochester airport because the President’s condition turned worse.

The proposal had its strong merit. Without the merit, the connections would not have helped. Taiwan was improving in the biomedical fields, but there was no organizational structure to coordinate the activities and help everyone to work together. There was a tendency for people to work in isolation. This proposed institute (IBMS) would not only pursue frontier biomedical research in Academia Sinica, but would also take the leadership to promote cooperation. The Academy, which belongs directly to the Office of the President in R.O.C., is in a position to carry out this mission. While the proposal was intrinsically meritorious, Dr. Yu’s connections helped things to move very smoothly – and remarkably fast. It went through the legislature and executive government branches in less than one year. An advisory committee was formed, Dr. Yu chaired it, and I was one of the members. In the States we had five members, and in Taiwan there were eight more members. Paul was in the United States, so most of the decisions were made by the overseas members and subject to the approval of the members in Taiwan, who were very supportive.

The government appropriated the money to build the institute, and the building was completed in 1986. The Advisory Committee made careful planning and had been recruiting scientists, especially from the U.S.; I was in charge of recruitment, and we had succeeded in recruiting more than twenty scientists. In November 1986, we held an Advisory Committee meeting in New York and decided that the Institute will start functioning in January 1987. Everyone had thought that Paul Yu would be the director; it had never been officially decided but just assumed to be the case. At the meeting, however, Paul said that he was not able to leave Rochester in 1987. Everyone on the Committee pointed to me and said, “You are the one that will have to go to start the Institute.” I had to ask for a sabbatical leave from Columbia with only a two-month lead-time. I had to arrange my lab, my home and everything. My wife was unprepared for that, and she had to take a leave from her job also. It was really hard, but I did go to Taiwan, arriving there on January 6, 1987.

The Institute had a big six-story building, very nicely constructed under the able supervision of Dr. Chai. When I got there, it was almost totally empty. We had a few investigators that were already there (including Dr. Chai and Dr. Eminy Lee), and then the recruited scientists began to arrive. Recruiting people from the U.S. to do long-term work in Taiwan was very difficult. Senior people have a lot of commitments, younger people have young children and hence concerns about schooling in English, and there are many other problems. A major problem is that, although the scientist would be interested in going, the spouse could not or would not. We did finally recruit quite a few permanent members, but we compromised by recruiting some scientists who would work there for a short –term e.g., a year or several months. With the help of Dr. Chien Ho at Carnegie-Mellon University, we assembled a team of twelve cell biologists who committed to go to IBMS for three months each, with two at a time and with overlaps like a relay team. The group met in New York several times to plan the team research on cell biology of esophageal epithelium, based on (1) the expertise of the participants, (2) a problem of interest to Taiwan (esophageal cancer is a prevalent disease), and (3) the lack of duplication with the scientists’ research in their home labs in the U.S. (so that something unique can be established in IBMS).

This team research plan worked out very well, and eventually two papers got published from that. It was a very exciting time.

Shortly after I arrived in Taiwan, I requested permission to go to every medical school in Taiwan to talk about this new Institute. I made a number of transparencies and slides for presentation. I told the faculty and students in these institutions about what we were trying to do and the opportunities available for research and training. We wanted to find people that would like to come, but we didn’t want to raid the local institutions, because that would not help to enhance biomedical research in Taiwan. Rather, we asked their students and fellows to come to do research and receive training at IBMS. We got many medical students coming to the institute, especially in the summer time, and it was very exciting. Some of them are now faculty members in the United States or Taiwan. The training was very, very fruitful.

We also held a series of workshops, particularly with the team of prominent cell biologists from the United States who could go there for only three months. We asked each one of them to give a seminar and/or workshop on their expertise. These workshops attracted people from all over the island, including southern, central and eastern Taiwan. I remember clearly the first workshop was given by Drs. Jim Lin (University of Iowa) and Yu-li Wang (now at the University of Massachusetts) on monoclonal antibodies and video microscopy imaging; these were frontier areas in biology and medicine that arose a great deal of interest. The IBMS auditorium, which can hold 200 people, was not large enough.

Nebeker:

Is that right?

Chien:

We had to set up a closed circuit TV in an adjacent room for another 200 people. It was just fantastically exciting. In addition, we held several international symposia. For example, in August 1987 I organized a satellite symposium after the Microcirculation World Congress in Tokyo. I invited some forty internationally know scientists in the field to come to Taiwan to speak at the satellite meeting. I was most gratified that they all came. That satellite symposium stirred up a lot of interest and activity.

In the summer of 1987, nearly everyone from my lab at Columbia went to IBMS to help me build up the Institute, whether they were Chinese in origin or not – and most of them were not. I didn’t make them go, but let them know that they were most welcome and needed. Because of our friendship and their desire to help in building this new Institute in a land far away, most of my colleagues in the lab went to IBMS that summer.

Nebeker:

That’s great.

Chien:

During that summer, we gave a course on Microcirculation and Cell Biophysics. Eight students from four schools registered for credit, but the course was regularly attended by about seventy people, including some of my teachers. This kind of short-term activity – as well as its newness – made it really intense. I worked day and night, and did not have time to sleep. IBMS is somewhat out of the way from the heart of Taipei. It was an hour of cab ride to go out, and an hour to come back. I slept a lot in taxicabs, because I often needed to go into the city to meet with people in the universities, medical schools and hospitals, as well as government agencies, and also to attend dinners, which I needed to attend in order to connect with people with these institutions.

Nebeker:

That’s when you could sleep.

Chien:

Yes. By napping in the taxicabs I was able to get enough sleep.

When I came to IBMS in January 1987 the building was empty, but by the time I left it was almost full.

Nebeker:

When did you leave?

Chien:

I left in July 1988.

Nebeker:

It was a year and a half that you directed there.

Chien:

Yes. As I mentioned, I came back to Columbia seven times to give lectures and to made sure all my research activities were going well. We had faxes going back and forth between Columbia and IBMS. In those days faxes had just become available for relatively common use. Nowadays they are made almost obsolete by the e-mail. We had the very first fax machine at Columbia Medical Center. Everybody who needed to send or receive a fax came to my lab to use it. That was only thirteen years ago.

Nebeker:

Yes. I was studying high-energy physicists around 1989 and 1990. They had begun using fax machines, and it was very important. I think they were one of the early communities to use it.

Chien:

Yes. While we got the first fax machine at Columbia Medical Center in 1987, they actually had it a little earlier in Taiwan, because of proximity to Japan, where FAX was first used.

Nebeker:

Yes, the Japanese were the first.

Chien:

The fax kept me going, because it enabled me to keep track of both sides. When I was in Taiwan I kept in contact with my lab, and when I was at Columbia I kept in contact with the Institute. People were working day and night, even the office staff. The diligence and dedication was just fantastic.

Nebeker:

That must have been very gratifying to get an institution like that off the ground.

Chien:

Yes, it was very gratifying. Now it’s thirteen years old and going well. When I left in July 1988, Dr. Cheng-wen (Ken) Wu, who has also been a member of the IBMS Advisory Committee and was a Chair Professor of Pharmacology at The State University of New York at Stony Brook, came to Taipei to succeed me as IBMS Director. His wife, Felicia, who was also an outstanding cancer researcher, came with Cheng-wen (unfortunately she just passed away this year because of breast cancer). After one year of service at IBMS, Cheng-wen decided to stay in Taiwan and became its full-time, long-term Director, and his outstanding, sustained leadership from 1988 to 1996 was very important for the development of the Institute. In the early 1990s I helped establish the National Health Research Institute (NHRI), which is like the NIH in the U.S. Following its establishment, Cheng-wen was appointed as its first Director. From 1996 to 1999, Kenneth K. Wu, Chair Professor in the Division of Hematology and Oncology at the University of Texas, Houston, served as the Director at IBMS. Kenneth was not able to stay beyond the excellent service for three years. Dr. Yuan-Tsong Chen, Professor of Pediatrics and an expert of human genetics at Duke University will succeed Kenneth. It is comforting to see the willingness of these outstanding scientists to work for the advancement of IBMS and biomedical research in Taiwan.

Nebeker:

Is NHRI a government-funded research establishment?

Chien:

NHRI is organized as a foundation, but a large proportion of its funding comes from the government, which puts money into the foundation. The original idea was that a foundation would have less restriction in matters such as personnel appointment, salary range, etc., but in reality it still operates in a manner rather similar to a government agency because the bulk of funding is derived from the government. Thus the annual budget must be approved by the legislative bodies.

Nebeker:

If you put the foundation between the projects and the legislature you get less control by the legislature.

Chien:

That’s right, a little less. It would be ideal if later money will be raised from the private sector. That would be great. However it’s going very well. The person who succeeded me at the Institute of Biomedical Sciences was a professor at SUNY Stony Brook. He is a pharmacology professor named Kenneth Wu. He succeeded me as permanent director at the Institute and stayed for seven or eight years. When the National Health Research Institute was formed he moved over there. He did a great job. He set up several sections in the institute including medical engineering, infectious disease, cancer, public health policy, biotechnology and diseases related to aging. There were ten of these. He recruited eight heads and only two or three more are needed. These are all excellent people. I was out there a month ago to serve on a seven-person review committee. Dr. Fung was there too. It is very gratifying to see these kinds of things happening.

The National Health Research Institute is a granting agency, so I helped them to form a review system modeled after the NIH. I had worked for the review process at NIH. At first I got together about fifteen or twenty people, and they have over fifty people – mostly scientists educated in this country but are from Taiwan and know the situation. First we conducted review in the U.S., and then we moved the review to Taiwan. It’s very rigorous and efficient. We took the strengths of the NIH review system and added a few more so that we can do all the reviews within one week – both layers. The NIH would take four months to do the same thing. It is generally recognized in Taiwan as the best review system on the island. Hopefully this system will also be used in other countries, but Taiwan has a special advantage in that it has a large number of people who received their early education in Taiwan and now are in the States. These people can be called upon to serve.

Nebeker:

It can make a very strong research community in a relatively small country.

Chien:

That’s right. I would think a place like Israel would be able to do something like that. There are many people who have close ties to Israel. However people from the Weisman Institute told me that they have not been able to do this.

Nebeker:

This is a very interesting situation and has a long history. For instance your own father trained briefly in the United States.

Chien:

Yes I have several jobs in a way. All of these things are things that I do on the side. My primary job is here at UCSD.

Nebeker:

Yes.

UCSD Department of Biological Engineering, Institute of Biomedical Engineering

Chien:

It has also been very gratifying that we have been able to establish the program here.

Nebeker:

A department was established after you came.

Chien:

That’s right. People like Dr. Fung and Dr. Zweifach made a tremendous foundation to allow us to do these things. What I’ve done using that tremendous foundation is first to get a program project grant from the National Institute of Health. This program project grant is a group effort that requires that four or five projects be tied together by a common theme. I got that funded in 1990. Dr. Fung, Schmid-Schönbein, Dr. Ami Sun and myself all have projects in that. The common theme is the biomechanics of blood cells, blood vessels and the circulation. There is leverage on our strength, but we have a common theme. Up until that point the department’s program was very strong, but we never had a group or team effort like this. That was a big breakthrough. It’s because of the foundation we have here and because of the experience I gained at Columbia doing the same thing. We had a program project grant running for fifteen years at Columbia. That has been a major help.

Then we began to talk about an identity for our program. From the outset we had been a part of the applied mechanics and engineering science (AMES) department. The program was started in 1966 by Drs. Fung and Zweifach, but was always under the department of AMES. The department was very good to us and always fostered things we needed to do. However as one group of a large department, we always had to wait our turn for resources. And to the outside you we were not an entity by ourselves and always had to go through AMES department. Therefore despite their support it was not ideal. Most of my colleagues were used to the situation and comfortable with the way it worked. Dick Skalak agreed with me, and the two of us were finally able to convince our colleagues of this. In the end everyone agreed and some of the people who at first had the most reservations became the strongest proponents for this.

Nebeker:

How difficult was it to get the university to agree?

Chien:

The most difficult thing was to get the department of AMES to allow us to leave.

Nebeker:

Is that right?

Chien:

This is because we were contributing more and getting less from the department. I hope you don’t write this down. If I had been a member of AMES who was not in bioengineering, I would have hated to see the bioengineers leave. They were very reluctant to let us leave. I had to work with people individually and appear before the faculty as a group many times. Finally they agreed to let us leave. Once that was accomplished the rest was not so difficult. The university administration was very supportive. Actually it was more difficult in the Academic Senate, which is the faculty group. There are several committees that review educational policy and budget, and that was a tough time for budget at the University of California.

Nebeker:

I can imagine there was skepticism about a new department of any sort.

Chien:

That is exactly right. Every committee always came back after their meetings with a series of questions and for which we’d have to draft a response. Then they wouldn’t meet for another two or three months and then there is the summer in between. Then several months later we could get back another series of questions and we’d respond again. They were doing their job, but it took time. It got approved in the end.

Nebeker:

Was it in 1994 that it finally got approved?

Chien:

Yes. Before that we got a Whitaker Foundation Development Award. Actually we first formed this Institute of Biomedical Engineering in 1991. Knowing how difficult it is to form a department, we first formed a regular organization for research – not for teaching but for research. We could not appoint faculty and we didn’t have students, but we coordinated and fostered research activities. I did that by asking many faculty from other schools – such as medicine, biology, other departments in bioengineering, and even people from Scripps – to come together. We got about thirty people and all agreed that we should get this institute going. We talked about what theme should be emphasized and agreed on tissue engineering. This was something that was able to tie all of us together – working on different kinds of tissues.

Getting this institute approved by the local campus and the UC System took some doing, but it was easier than convincing the department. We had this theme identified in which we could work together, and shortly after that the Whitaker Foundation came out with this request for a proposal for the development award – which is $5 million for six years – to develop biomedical engineering. We were in the right place at the right time. We had just gotten people together to form the institute and define then objectives, and very soon we were submitting that proposal. I spent a lot of time getting the material from everyone, but I had to write the whole thing again.

That was very successful. First the pre-proposal was approved, then we submitted a full proposal, and then there was a site visit. I think there were over sixty pre-proposals. Out of those something like fourteen were selected for complete proposals, and then out of those five or six were selected for site visits. Only three were funded, and we were one of the three. That was very helpful. The reason we were able to finally form a department was because we got this award in 1993. The award allowed us to recruit faculty and so forth for a three-year time period. We were given four slots. Therefore we were able to say to the university, “We have these four slots and don’t need any money for three years and the university will pick up later.”

That’s what the Whitaker Foundation wants to do. They want to leverage the university to do that. So they were very, very wise.

Nebeker:

Yes. That’s smart.

Chien:

Very smart. They really know how to foster the field, and they are very successful. They are extremely wonderful. It’s a win-win-win situation. The university wins because they save the first three years; the department wins because we have got this tremendous support from the outside and from the university; and the Whitaker Foundation wins because fostering the field is their goal. It’s a tremendous cooperation. Getting that made it easier for us to become a department. Our new dean, Dr. Khan, was not in bioengineering at all, but very quickly identified that this was the field he wanted to foster. He was extremely supportive. He came in January of 1994. The grant came several months earlier in September 1993. The department was already in the process of forming when he came, but he facilitated that. It was formed in August of 1994. I was appointed to be the chair starting July 1st, but I didn’t get the letter informing me of this until around August 20th. I didn’t know I was the chairman before that. It all happened very quickly.

Nebeker:

That’s remarkable. Did you remain chair?

Chien:

Yes. We formed a rule that the chair serves for three years and can be renewed for and additional two years – and therefore may serve up to five years. That was our agreement.

Nebeker:

That was decided from the beginning.

Chien:

Yes. The way we govern this department is by consensus, and it’s good to have different people participate in this. By 1999 my term was up, and I was very happy to relinquish that position. We had to get a consensus for the next chair, and we were very happy to get David Golf to do that. Time goes by so quickly. Already a year and a half has passed. Soon he will need to consider whether he wants to continue beyond three years. In my case I felt that since it was just starting out that I needed to stay with it for the five-year duration. In 1997-98 we went in for the Leadership Award, which is the next level award by the Whitaker Foundation. We were able to get $18.2 million for the Leadership Award. Most of the money is for the construction of a new building. To the right of the blue-tinted glass building there is a field, and that is where our new building be constructed. The building will cost $34 million. Half of that will be from the Whitaker Foundation, and we will raise matching funds.

Our dean has been very supportive. He got money from the Apollo Foundation. At first it was going to be $3 million, but when the Apollo Foundation saw our survey rating and so forth they decided to give us more money than they earlier identified. Without being asked, they called and told our dean that they were upping the amount to $8 million. We did so well as a group during the site visit that I couldn’t believe it. It was unbelievable. I have been at many site visits and have usually thought we did very well, but that day just clicked. The Whitaker Foundation’s site visitor was very impressed. We asked for $14 million to build a building that would accommodate two-thirds of our people. The remaining one-third was to be left in the old building.

Whitaker Foundation

Chien:

Then the Whitaker Foundation kept questioning me, “Why do you want to leave one-third of the people in the old building? Why don’t you include everyone?” Finally I said, “I would like to propose a larger building, but we didn’t think we could justify the amount of money that we would have to ask.” They asked me to put in a supplemental proposal as to how much money we would need for that. Now remember, whatever we proposed would have to be matched. The university is also given a responsibility. When we ask for another $4 million, the university has to be able to come up with another $4 million. We asked for $4 million more, so that the total moved up to $18.2 million.

Nebeker:

Have you received that?

Chien:

Yes, we received it just like that. I have never before been in a situation where the initial proposal was increased.

Nebeker:

And not cut back.

Chien:

Being cut back is usually the case. We are very grateful to the Whitaker Foundation, both as an institution and as a member of the community. They have done much for biomedical engineering nationwide. It’s unbelievable. In the last couple of days I was in an education meeting that they sponsor. Jim Bassingthwaighte and many other people were there. It was a terrific meeting to talk about education for biomedical engineering. Mr. Whitaker, his daughter and her husband Mr. and Mrs. Shumaker, Dr. Ruth Holmes and Dr. Bertle Holmes, and the president, Dr. Katuna, have tremendous vision following Mr. Whitaker’s foresight. Whitaker’s daughter lives near here in Bonzai. They strategize in a most remarkable manner.

Nebeker:

When I talk to people, the Whitaker Foundation is named again and again.

Chien:

They should be awarded for outstanding achievement as a foundation. Maybe one day you will write something.

Nebeker:

I will certainly give them recognition in whatever I write.

Chien:

One day their history should be written up.

Nebeker:

It is very interesting also that they are a foundation with a definite life span.

Chien:

Their life span ends in 2006. They are determined to stick to that. This maximizes their impact and ability to make sure every dollar is going where they have intended. Some foundations have kept on going but have changed.

Nebeker:

Yes, that’s the usual way. Thank you very much for your time.

Chien:

It’s a pleasure.