voices of experience [biomedical engineering]

42
Those Who Have Played Pioneering Roles in Biomedical Engineering Come from Many Fields. In These Excerpts from the Oral-History Project, Some of the Pioneers Tell of Their Involvement in Shaping the Discipline. The oral-history project, initially funded as part of the EMBS anniversary project, was substantially expanded through a grant from the United Engineering Foun- dation, which made possible the inter- viewing of an additional dozen pioneers of biomedical engineering from other engineering fields, mainly chemical and mechanical engineering. This article in- cludes a large collection of excerpts from all of the oral histories, hence providing some indication of the full range of bio- medical engineering. Frederik Nebeker and Michael Geselowitz IEEE History Center, Piscataway, New Jersey 0739-5175/02/$17.00©2002IEEE ©PHOTODISC

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  • Those Who Have Played Pioneering Roles in Biomedical Engineering Come fromMany Fields. In These Excerpts from the Oral-History Project, Some of the PioneersTell of Their Involvement in Shaping the Discipline.

    The oral-history project, initially funded

    as part of the EMBS anniversary project,

    was substantially expanded through a

    grant from the United Engineering Foun-

    dation, which made possible the inter-

    viewing of an additional dozen pioneers

    of biomedical engineering from other

    engineering fields, mainly chemical and

    mechanical engineering. This article in-

    cludes a large collection of excerpts from

    all of the oral histories, hence providing

    some indication of the full range of bio-

    medical engineering.

    Frederik Nebeker and Michael GeselowitzIEEE History Center, Piscataway, New Jersey

    0739-5175/02/$17.002002IEEE

    PHO

    TODI

    SC

  • Robert ArzbaecherDirector, PritzkerInstitute of MedicalEngineering IllinoisInstitute of Technology(interview byFrederik Nebeker on14 October 1999)

    Nebeker: Your work was on control systems.

    Arzbaecher: Yes, I focused my graduatework on that. When I finished my degree in 1960and left [the University of Illinois at] Urbana Itook a teaching position at the ChristianBrothers College in Memphis, Tennessee.Christian Brothers College had a good under-graduate engineering school, particularly in theelectrical area. It was not a small school, butnot much was going in on the area of control.Certainly not much in my area of reactor controlwas going on in Memphis. I taught electrical en-gineering but was not able to continue my re-search. It was in that context that my conversionfrom electrical to biomedical engineering be-gan.

    For a year I looked for a challenging re-search opportunity in Memphis to go with myteaching. Then I met Daniel Brody at a cocktailparty. He was a cardiologist from the Univer-sity of Tennessee College of Medicine in Mem-phis. Unknown to me at the time, he was a verywell-known cardiac theoretician. Brodys un-dergraduate training was in physics. When Ifound out more about his background, it wasthe beginning of a wonderful relationship. Ispent the next seven years working with Brodyin his laboratory every chance I could get, onSaturday, Tuesday, and Thursday afternoons tothe extent I could arrange my teaching sched-ule. We worked in what is now called theoreti-cal electrocardiography, which is the physicaland mathematical basis for interpretation of thehuman electrocardiogram in health and dis-ease. Brody and I wrote a lot of papers together.Thats how I became a biomedical engineer.

    * * * * *

    Arzbaecher: After six years of theoreticalmathematical modeling work I had an urge toget closer to clinical electrocardiography. I hadan opportunity to go to Europe for a year on aNational Science Foundation fellowship, andDan Brody set up an opportunity for me to workin the laboratory of Dirk Durrer at the Universityof Amsterdam. That experience was of majorsignificance in my career. Durrer had a conceptfor removing the human heart soon after clinicaldeath and keeping the heart alive long enough tomap its electrical activation. This had been donewith the hearts of animals, and Durrer waspoised to do the same thing with the humanheart. The instrumentation requirements of thattask were significant. With the isolated heart ona perfusion stand, needle electrodes were placedall over the heart to record on a multichannel ba-sis. This was in the mid-60s, when that was notan easy thing to do. My time in Amsterdam wasfortuitous for him and for me. I became involved

    at the highest level of experimental cardiology,and he found a trained electrical engineer to helphim with instrumentation problems. During thatyear we did the first isolated human heart map-ping experiment and published in Circulation.

    * * * * *

    Nebeker: What was the impact of the mini-computer on electrocardiography and similarareas?

    Arzbaecher: There were two impacts. First,it made it possible for many laboratories withoutmajor computer resources to acquire significantcomputing resources. Secondly, it led to digitalsignal processing, which is now standard, andalso to on-line real-time signal processing.Without the smaller computer and its capabili-ties for on-line acquisition, analog-to-digitalconversion, and processing in the digital do-main, that wouldnt have happened so quickly.My experience before then had been with punchcard machines, batch processing, and numbercrunching.

    * * * * *

    Nebeker: Was delivering the drug automati-cally your objective?

    Arzbaecher: Yes. That was my dream. It hasbeen a long time in bearing fruit.

    Nebeker: It sounds very ambitious for the1970s.

    Arzbaecher: Yes, it was. Support camefrom the pharmaceutical company G.D. Searle.They were particularly interested in finding outwhether their drug Norpace was effective intreating atrial arrhythmias. Necessity being themother of invention, I invented the esophagealelectrode for recording the electrocardiogramfrom the esophagus.

    * * * * *

    Arzbaecher: It is interesting how I discov-ered the pill electrode. In the lab, I had a grad-uate student of mine push a catheter electrodedown my nose and into my throat and esopha-gus. I was able to measure a beautiful p-wave,which was an atrial recording in the electrocar-diogram.

    Nebeker: Did you get a much clearer signalthat way?

    Arzbaecher: The p-wave obtained is threeto four times bigger than QRS. Compared toroutine electrocardiography on the body sur-face, the esophagus gives a beautiful p-wavefrom the atrium. The recording we made wasclear, but it hurt. That night I could still feel the

  • irritation in my throat that had been caused bythe catheter.

    Nebeker: Youre in the class of people whoexperiment on themselves.

    Arzbaecher: That was in the days before wewere so careful about human investigation. Mythroat and sinuses hurt, I realized that the problemwas that big old stiff catheter. All I really wantedwere the two rings at the end of the catheter. Thenext morning I went into the lab, took a pair of di-agonal cutters, and stripped away the polyethyl-ene coating until I was left with the tip of thecatheter and the pair of wires. Then I buried thecatheter tip in a spoonful of ice cream and swal-lowed it. My students laugh about this. One does-nt chew ice cream, so the bipolar pair ofelectrodes caused no problem. I just swallowed it,and down went the pill. That was the first pillelectrode. That was the business end of a catheterelectrode with a bipolar pair and a pair of wiresholding it up. Within a week or two I discovered asource of very thin and flexible stranded stainlesssteel wire with Teflon insulation.

    * * * * *

    Arzbaecher: The esophageal electrode gaveus the signal with which atrial arrhythmias couldbe instantly recognized. Atrial arrhythmias arenot easy to recognize on the bodys surface.

    Nebeker: Is this a recognition that comesthrough visual analysis by a cardiologist?

    Arzbaecher: Its computer recognition. Thealgorithm looks at the esophageal signal, ana-lyzes it, and comes up with a rhythm diagnosis inreal time. The whole spectrum of cardiac arrhyth-mia can be detected, including atrial fibrillation,atrial flutter, atrial tachycardia, premature atrialbeats, and ventricular arrhythmias.

    Our interest was in treating atrial arrhythmiaswith a Searle drug. I had the first half of thatproblem solved, which was how to automati-cally recognize the onset of an atrial arrhythmiain a coronary care patient.

    Nebeker: Did you write programs to analyzethe p-wave?

    Arzbaecher: Yes, my students and I wrotethem. A student who helped with that was JaniceJenkins. She is now a professor at the Universityof Michigan and on leave from Michigan serv-ing as the program director of bioengineering atNSF. She took the esophageal signal and wrotethe program to analyze the arrhythmia. It was thefirst dual chamber arrhythmia analysis programever written.

    * * * * *

    Arzbaecher: One day in my laboratory inIowa City I disconnected the pill electrode fromthe electrocardiograph, connected it to an exter-nal stimulator, and discovered I could pace myheart.

    Nebeker: More experiments on yourself.Arzbaecher: By connecting the electrode lo-

    cated immediately behind the left atrium to anexternal pacemaker I was able to capture theheart and run it at any rate I wanted.

    We proved that esophageal pacing was bothsafe and effective and received premarket ap-proval. No longer a substantial equivalencething, this required the full FDA premarketroute. It was necessary to perform experimentsand prove there would be no damage to theesophagus. It also had to be proved that this de-vice was effective in pacing the heart. Followingall those studies we appeared before the FDACardiology Advisory Board at the end of 1986and got the PMA approved. I developed a smallbattery-operated electronic external pacemakerto which the pill electrode could be connected.That was it. It could pace the heart.

    This created an opportunity to do a number ofthings that couldnt be done before. For exam-ple, a lot of patients cant exercise due to age, in-firmity, obesity, and other reasons. Cardiacstress testing can be done by pacing the heartrather than by exercising the patient. That was animportant development. Imaging studies such asechocardiograms could also be done. Tempo-rary esophageal pacing could be used to convertarrhythmias. Atrial flutter, especially in chil-dren, is easily converted by over-drive pacing. Ashort ten-second burst of temporary pacing fromthe esophagus could convert the arrhythmia tonormal rhythm.

    * * * * *

    Arzbaecher: The dream of the drug pumppeople is the treatment of diabetes. A drug pumpwith insulin to automatically treat the diabeticpatient would be a marvelous technology. Bil-

    Dr. Robert Arzbaecher swallowing the PillElectrode, which he invented, for recordingthe electrocardiogram from the esophagus.

  • lions of dollars have been spent to develop thattechnology, and several companies are in-volved. They have been stymied largely by theabsence of a good glucose sensor. The pump candeliver insulin, but no way has been found toclose the loop. Insulin is not an easy drug to storeand deliver in an implanted pump, but the big-gest problem is the measuring of glucose levelsto trigger the pump. That technology is still be-ing developed. I believe implantable pumps willbecome more commonplace, and maybe withtime the particular notion of an implantablepump for the treatment of atrial fibrillation willbecome more attractive.

    Nebeker: Is the control system developed?Arzbaecher: Yes. For my own lab I have

    published protocols for running a pump. Theimplantable pumps that are available do nothave motors in them. They have valves. There is

    a pressurized reservoir of drug with a valve.When you open the valve, drug squirts into acatheter and then moves into a central vein. Thatdevice is pretty reliable. There are not manymoving parts, and it is easy to control. All thathas to be controlled is the rate at which the valveis operating.

    Nebeker: Are these valves controlled elec-tromagnetically?

    Arzbaecher: Yes. I have a concept I havetested on animals in which I programmed animplantable drug pump with a valve to deliverpharmacokinetically designed exponentiallytapered infusions, which are known to giveand maintain a good therapeutic response.Control of the pump is not difficult, and theproblem of recognition of atrial fibrillation iswell in hand in my laboratory as well as inother places.

    Babb: [Babb, in charge of the nuclear engi-neering program at University of Washington,had just begun using a teaching reactor for neu-tron activated spectroscopy] a secretary said, My daughter has cystic fibrosis, and oneof the manifestations of it is the abundance of so-dium chloride in the sweat, fingernails, and toe-nails. Maybe you should get together with thepeople at Childrens Hospital and see if you mayhave a way of screening newborns for the pres-ence of cystic fibrosis so that they can get intoearly treatment. Dr. Stanley Stamm camedown, and we talked about it. The result was thatwe set up a protocol whereby he advertisedaround the country and overseas that we wereaccepting toenails which would be irradiatedwith neutrons.

    We accepted maybe a thousand samplesfrom all over the world to irradiate. Here is a pic-ture of a resident clipping the toenails of a babyat the University Hospital. There was a writer forLife magazine who lived in Belleview, justacross Lake Washington, who did a story on thisnovel use of a nuclear reactor. Thats what gotme associated with some clinical people.

    * * * * *

    Babb: Early in 1963 Dr. Moulton called meinto his office and said, I just had a telephonecall from Belding Scribner, M.D. He wanted toknow if theres a young faculty member herethat could work with him in reducing the cost ofhemodialysis. I had never heard of this proce-dure. The reason Scribner called him was be-cause he took care of Moulton when he was sick

    the year before I came. Suddenly Moulton saidto me, Youve always been interested in medi-cine. Why dont you go and see him? Thus wemade an arrangement. I went down to the Uni-versity Hospital to a little room off the cafeteria.It was a daunting situation. There were about sixphysicians in white coats sitting there. They ex-plained to me how they had just developed a wayof permanently implanting plastic tubes in theartery and vein of patients, bringing them outthrough the skin and connecting them with aU-tube so that when they were not on dialysis theblood flowed at a high enough velocity to pre-vent clotting. Then they were clamped off andconnected to the dialyzer with the artery going tothe inlet port and the vein to the outlet port tostart a dialysis episode.

    Nebeker: How long had that kind ofextracorporeal dialysis been possible?

    Babb: It was first used during World War II.A physician named Willem Kolff treated pa-tients in Kampen in the south of Holland. butthey could not treat patients whose kidneyswould never return to normal function. Theywere only able to keep the patency of the bloodaccess to the cardiovascular system for a fewweeks or a month at the most. If their functionwere not restored they would die. After the wareveryone was trying to develop permanent ac-cess.

    * * * * *

    Babb: I assimilated all this information,looked at the tanks in use, made some mentalnotes, and came back to my office in the nuclear

    Albert Les BabbProfessor Emeritus ofChemical and NuclearEngineering,University of Washington(interview byFrederik Nebeker on6 December 2000)

  • reactor building. I had barely arrived when therewas a phone call from Dr. Scribner, who had toldme it cost about $20,000 per patient per year fortwo 12-hour dialysis sessions per week.

    I said to Scribner, I take it your are inter-ested in reducing the cost, he said, Yes, wedlike to get the cost down. Do you think you canhelp us? And I said, I need more information. Ineed to be walked through the whole proce-dure.

    From this idea we said to ourselves, Whydont we premix those chemicals in a concen-trate and dilute it in the right proportion continu-ously. In this way well remove the tank fromeach bedside and pipe the dialysate around thewalls to maybe five stations where they can beconnected to the dialyzers. The dialysate wouldflow through and then come back into a wasteline. it was dubbed the monster! Then allhell broke loose because manufacturers of com-mercial machinery besieged us, each wanting tobe a supplier.

    [The Milton Roy Company of St. Petersburg,Florida] flew me down as a consultant. I wasthere at the startup at the old VA Hospital in CoralGables, Florida. From that beginning these cen-tral systems appeared all over the world.

    Nebeker: Were these multipatient dialysissystems?

    Babb: Yes. Here we could handle five pa-tients at once. it was working and at half thecost; i.e., the annual patient cost was now about$10,000. A lot of the work we did after that wasmathematical, and we tried to model this processto see if it could be optimized. We suggested

    three 8-hour treatments per week rather than two12-hour treatments were more optimal and con-vinced the medical staff to switch to this prac-tice.

    * * * * *

    Babb: Then I received a call early one Satur-day morning [in 1964]. [Dr. Scribner] explainedto me that a 15-year-old girl hed seen manytimes had been turned down for treatment by thedeciding committee I mentioned earlier. He toldme she was going to die if she didnt get treat-ment within four months, and the university hadprohibited him from taking any more patients.He said, Could you take this monster and min-iaturize it? He said, It would be the sameprinciple, diluting concentrate, but for one pa-tient and portable so it could be taken to a pa-tients home. I said, I dont know. Ill have totalk to my engineers and technicians. I calledthem together and put the problem before them.And I said, Wed have to make most of the stuffourselves. We couldnt buy heat exchangers,for instance, that were this small, and the instru-ments werent readily available and wed haveto modify them. I said, It really has to be almostautomatic. The patient could not be expected todo too much. We went for an automated systemwherein at the push of a button the machinewould pasteurize itself using hot water then.Then it needed to produce dialysate at the righttemperature and composition and give an indi-cation when one could hook up the blood lines.My staff said theyd like to do it, and I toldScribner wed take a shot at it.

    Nebeker: This was a bootleg development.Babb: Yes. And I couldnt have done it if I

    hadnt had control of it. I could not do that herenow. And at that time we happened to haveprobably the best cadre of electronics techni-cians on campus, and they were all under mysupervision. We had a lot of ex-Navy peoplewho had been in the nuclear propulsion pro-gram. We couldnt have done it without them.If I had gone to this current chairman and said Iwanted to do this, there would be no way. It wasjust the right time.

    Nebeker: How many people did you haveworking on this project?

    Babb: I would say about eight at the peak ofit. [The machine was a success.] People camefrom literally all over the worldSweden, Den-mark and so onto photograph the machine andtake away drawings.

    Albert Les Babb describes an extracorporealsystem for the continuous treatment of patientswith sickle cell anemia in 1981. The design ofthe machine was based on the pioneering proto-type designed and built by Babb and his teamat the University of Washington for over-night-unattended home dialysis.

  • Nebeker: What was Norman Jeff Holtersmotivation for using this ambulatory ECG?

    Bailey: His idea was that taking a singleresting ECG was too narrow a slice in time.The idea was to capture a much larger block ofcardiac activitythroughout the day andnightto get a better picture of what was hap-pening with the patient during his normaldaily routine.

    Nebeker: Whereas a stress-test ECG couldbe connected and done in a single location?

    Bailey: Right.Dunn: There was a classic study, from the

    1960s perhaps, monitoring workmenI cantrecall the industry involved, perhaps stevedoresor electricianswho were wearing theseHolters for at least one day, if not more. Thesestrapping, healthy men were throwing spuriousarrhythmias like PVCs and PACs. This mayhave been the first study documenting signifi-cant normal variation. What did this meanprognostically? They didnt know.

    Nebeker: Was this the first time somebodyhad done ambulatory ECGs?

    Bailey: Holters was the first, yes. And it wasall analog when he started. Avionics was still an-alog even in the late sixties.

    Dunn: This capability for monitoring wouldnot have been available from the average cardi-ologist, but it was used in some hospitals.

    Bailey: Yes. Where I did my residency, thecardiology department used one. That was in1966-1969.

    Nebeker: Was the Holter Monitor some-thing that was manufactured?

    Bailey: Yes. Avionics was the company thatmade it. For patients that were having palpita-tions or seizures or fainting spells, it was appro-priate when the cause was not otherwise clear. Italso probably unmasked coronary disease forsome patients.

    Nebeker: Has this kind of diagnosis contin-ued to the present?

    Bailey: Oh yes. Its big business.Nebeker: I suppose these Holter Monitors

    have become transistorized and miniaturized.Dunn: Hardware has been miniaturized, in-

    cluding compressed software and more sophisti-

    cated analytic programs for diagnosis uponplayback, or even better, immediately.

    * * * * *

    Dunn: Hubert Pipberger was interested in de-termining the physiological phenomena behindthe production of the ECG signals, developingthe model that could accurately reproduce suchsignals, establishing the external electronic sys-tem, which could detect these signals, and, by useof a validated model, properly interpret them witha high level of sensitivity and specificity.

    Nebeker: His way of creating that modelwas going to be on a digital computer?

    Dunn: He saw the computer as his basic tool,capable of reading tracings with higher resolu-tion, consistent accuracy, and greater speed.

    Nebeker: There were quite a number of peo-ple in various areas of science, with, for exam-ple, analog harmonic analyzers, looking forperiodicities in data.

    Bailey: Every ten years someone comes upwith the idea of applying harmonic analysis tothe ECGs. The problem is that harmonic analy-sis doesnt tell whether the T-wave is before orafter the QRS. That is critically important loss ofinformation.

    Nebeker: Was the use of harmonic analysisever fruitful with cardiographs?

    Bailey: I dont think it has been helpful, ex-cept for the fact that in the early sixties peoplebelieved that all the information was containedbelow 60 Hz.

    Bailey: Later people found important infor-mation at the 100 Hz level. Some investigatorshave found important information at evenhigher levels than that.

    Nebeker: How did they learn that thesehigher frequencies were important?

    Bailey: They learned that by studying pa-tients with cardiac pathology.

    Nebeker: Earlier they might have filteredout that part of the signal?

    Bailey: Thats right. In the old PHS-D pro-gram of 1964 was based on the idea that the sig-nal would have been passed under a 50 Hz filter.It really distorted the QRS.

    Dunn: When I began to work in this field inthe seventies, a large percentage of papers pre-sented at conferences dealt with filtering andmassaging the signal.

    * * * * *

    Bailey: I am skeptical of cardiologists uncrit-ically taking interpretation from a computer pro-gram.

    Dunn: This became a serious issue.Pipberger himself always warned against heartdisease of computerized ECG origin.

    James Bailey andRosalie DunnBailey: Center forInformation Technology,NIHDunn: National Heart,Lung, and BloodInstitute, NIH(interview byFrederik Nebeker on25 April 2000)

    Every ten years someone comesup with the idea of applyingharmonic analysis to the ECGs.The problem is that harmonicanalysis doesnt tell whether theT-wave is before or after the QRS.That is critically important loss ofinformation.

  • Nebeker: If the computer said it, it mustright.

    Bailey: A lot of them had that kind of naivet.Dunn: Some preferred a system whereby

    everything that came out of the computershould be over-readthat some cardiologistshould at least take a look at it and sign off onit.

    * * * * *

    Bailey: What evolved in the seventies was si-multaneous collection of multiple leads. In thebeginning, in the late sixties and early seventies,there were carts that collected three channels ofleads simultaneously. In the eighties there werecarts that could collect 12 or 15 leads simulta-neously; i.e., the standard 12 and the XYZ. Ei-ther analytic approach could be taken.Controversy between the 12-lead and theXYZ-lead adherents could be studied more ef-fectively when data was collected by a 15-leadcart. The logical question was, why not use thehighly powerful multivariate techniques that theXYZ-lead people were using on 12-lead data? Ithink thats where Jos Willems came into thepicture.

    Dunn: Jos Willems had been a fellow inHuberts lab when I was there. He was the bridgebetween the two camps. And he showed that

    comparable results could be obtained, for themost part.

    * * * * *

    Nebeker: The way it was actually imple-mented was that a cardiologist would run thisprogram, over-read it, and then feel free to dis-agree if his interpretation was different?

    Dunn: And the cardiologist would notate thetracing for differences. Computerized rhythmdetermination was probably the first aspectabout which the cardiologist became comfort-able.

    Nebeker: Maybe it was something the com-puter could do a more accurate job of measur-ing.

    Dunn: With proper wave recognitionthepoints of the QRST, the ST-T segment and thebaselinethe computer could make better mea-surements than the cardiologists and save time.The computer could merely print out the ECGmeasurements, and the cardiologist was alreadyprovided some assistance.

    Bailey: When I first had to read ECGs in myresidency, we had little calipers where we had tomanually make measurements on magnitudesand intervals and so forth. Then we had to recordthem before offering an interpretation. The mea-surements are what the computer produces auto-matically.

    Bassingthwaighte: In 1950 I was in AirForce officer training at Crumlin Air Base, Lon-don, Ontario. This led to summer research thenext two summers at the Institute of Aviationand Medicine. In 1951 I worked with A.W.Farmer, professor of surgery at the Hospital forSick Children, and Prof. Wilbur Frank at theBanting Institute, both at the University of To-ronto. I was asked to design and develop instru-mentation to measure the spreading anddisappearance of fluorescein injected along withhyaluronidase into the skin of the forearm. It in-volved having a source of ultraviolet light and areceiver that excluded the source light andlooked at the fluorescence. In that way the fluo-rescence could be looked at as a function to timeafter injecting a tenth of a milliliter offluorescein-containing material into the skin. Idesigned the instrument and the circuitry andcontracted out to get the device built, a huge,heavy thing. We observed fluorescence inten-sity to determine whether the rate of disappear-ance of fluorescein was affected by thehormonal level of corticosteroids in the blood.At that time it was thought that this might be-come a useful clinical measure of the stress lev-els in children in the Burn Unit at the Hospital

    for Sick Children. The first summer was on theinstrument development and the second, 1952,on using it in the Burn Unit.

    * * * * *

    Bassingthwaighte: We began this [in about1960] as an analog computer model [to deter-mine the transfer function of a portion of the vas-cular tree, namely that of the artery in the leggoing from the femoral artery in the groin to thedorsalis pedis artery on the top of the foot]. Aconvolution integration is essentially a digitalprocess, unless you can write the transfer func-tion as a differential operator, something thatone cannot do for a lagged normal density func-tion. If you ever saw something strange, it wasdoing a convolution integration on an analogcomputer. You had to have a perfect gain of onethrough a system and then do repeated record-ings onto a tape in order to do the integration. Itwas crazy, and very tedious, but worked.

    Nebeker: The purpose of this work was tounderstand the circulatory system better?

    Bassingthwaighte: One reason is to want tounderstand its hemodynamic characteristics.Another is to characterize the changes that occur

    James BassingthwaighteProfessor, Departmentof Bioengineering,University of Washington(interview byFrederik Nebeker on5 December 2000)

  • when there are changes in flow through a limb.Third, potentially this same femoral-to-foottransfer function might be used diagnostically toassess limb flow in patients with ischemic arte-rial disease.

    The actual mathematical technology that wedeveloped is not used diagnostically but is usedin research.

    Nebeker: Thats quite a span of years fromwhen you began working on it.

    Bassingthwaighte: Most of 40 years. Andthat kind of beginning expanded into other ap-plications of mathematical modeling that wehave used for image interpretation using posi-tron emission tomography and MRI, particu-larly for the measurements of flows andmetabolism within organs.

    * * * * *

    Bassingthwaighte: I chose to look at cardiacmetabolism, which was not being exploredmuch at that time, and to try to develop tech-niques for doing that. To start that off, I starteddoing multiple tracer indicator dilution experi-ments. I needed to use pairs or triples of sub-stances simultaneously. The idea is to usereference tracers along with the tracer-labeledsubstrate of interest. The three tracers are in-jected together in a short bolus injection into thecoronary arterial inflow, and a sequence of sam-ples is taken from the outflow at 1 or 2 second in-tervals.

    Nebeker: What were the technological chal-lenges in getting this to work?

    Bassingthwaighte: One was multipletracer techniques. We were the first people touse triple label beta counting. All my advi-sors told me it was impossible. It took us a lit-tle while. The reviewers send these [grantproposals] back saying its impossible. Youhave to do it before theyll give you themoney to do it.

    * * * * *

    Bassingthwaighte: Physiology is an integra-tive discipline, historically speaking, so one is ex-pected to integrate diverse observations into aself-consistent scheme and to look at the timecourses of events to understand relationships. Thesecannot be very well understood without havingsome modicum of control systems analysis.

    * * * * *

    Bassingthwaighte: Bob Rushmer hadfounded the bioengineering program at the Uni-versity of Washington in 1968, and I had come toUW twice as a site visitor on behalf of NIH to seewhether his program should be funded. I likedhis program. Dr. Rushmer got to know that I hadbeen in the market for the position at McGill, andwhen he decided to retire I was recruited here.

    The reason I came here was because UW hadone of the Mayo Clinics prime attributes,namely, an atmosphere in which people wouldcollaborate across departmental lines freely andopenly in a noncompetitive way. The Universityof Washington had another attribute similar toMcGill: a medical school and engineeringschool on the same campus, right beside eachother, and furthermore, the Center for Bioengi-neering was part of both schools.

    * * * * *

    Bassingthwaighte: The central theme is stillcardiac metabolism, unraveling it in the normalstate and to a lesser extent in cardiac ischemia.Ischemia has been a secondary mission. In theprocess of getting at these nuances of metabo-lism, I started, in collaboration with HarveySparks at Michigan State University, a programto look at purine nucleoside transport and me-tabolism in cardiac capillary endothelial cellsand myocytes. ATP is the prime energy sourcefor cardiac contraction. Therefore looking at theingredients that make up ATP and play a role inits regulation was important. Harvey Sparks wasan expert in this; I had the technology for look-ing at the transport and metabolic rates. We ap-plied tracer techniques to that. That was a stepexactly in the direction I needed to take.Working with the group at Michigan State andwith Ray Olsson at University of South Floridato develop some new tracer labeled compoundswas a neat thing to do. That has evolved intomore research in purine nucleosides, and I amstill doing that. I also started looking at sub-strates for energy supply, glucose and fatty ac-ids, characterizing their pathways from theblood through to the cell, an important part ofcardiac metabolism.

    * * * * *

    One of the intriguing things wediscovered very early on was thatthe heart is very heterogeneous inits regional blood flows. In thesixties we had learned thatdifferent regions had differentflows. In the early seventies welearned that the different flowsstay that way when examined atseveral later times.

  • Bassingthwaighte: The heart is interestingfrom a structural as well as metabolic functionalpoint of view. One of the intriguing things wediscovered very early on was that the heart isvery heterogeneous in its regional blood flows.In the sixties we had learned that different re-gions had different flows. In the early seventieswe learned that the different flows stay that waywhen examined at several later times. There aretwo problems here that I struggled with foryears. One was how to measure heterogeneity.The other was how to ascertain its cause. Withrespect to its measurement, if one uses differentscales of measurement, one gets a different mea-sure of heterogeneity.

    Anyway, the blood flow distributionthroughout the heart tissue is a fractal and so isits vascular system, so we are characterizing thenetwork properties of the vascular system interms of fractals. Fractal methods are good sta-tistical tools.

    *****

    Bassingthwaighte: We have one system wedeveloped over the years. Actually in 1967 I puttogether a simulation interface system calledSIMCON, which was short for simulation con-trol. It was the interface between man and ma-

    chine that allowed one to use models to checkdata and thereby parse the transfer function ofthe black box. That turned into a very good mod-eling system with automated ways of fittingequations and models to data, evaluating the ac-curacy of the parameters that came out, and dis-playing the solutions in real time so that onecould see that the right result was being ob-tained. It allowed people to get a feeling for thedata analysis; to see it as they do it. Our wholephilosophy of the resource is centered on that,You should be able to do your analysis and seeit happen before your eyes and understand whatyou are doing as you are doing it. The idea is forpeople to be able to look at the behavior of thesemodels and understand the sensitivity of variousparameters. This then enables the user to explorewhat the models can reveal about the system thatwasnt previously known. A model is always amind expander, and so the simulation tool is anaugmentation to ones set of thinking tools.

    Nebeker: How has this been received?Bassingthwaighte: The grant has received

    funding for over 20 years. My original experi-mental grant, starting in 1964 and still running,supported the early SIMCON. The SimulationResource Facility has supported the advancedefforts since 1978.

    John ChatoProfessor Emeritus,Mechanical EngineeringDepartment,University of Illinois(interview byFrederik Nebeker on11 October 2000)

    Chato: Ive worked in heat transfer pretty muchall my life although its what Id call oddballheat transfersuch as biological heat transfer andelectrohydrodynamics with heat transfer.

    Oddball heat transfer is where you reallyhave to work with another field, such as biology,physiology, or electrical engineering, as withelectrohydrodynamics, so that another disci-pline must be combined with heat transfer in or-der to do the work well.

    * * * * *Chato: I always tell my students that when I

    did my initial work I never had any problem withdata acquisition. I had a potentiometer and wrotedown the numbers by hand. However now weconsistently have trouble with computerizedsystems. Occasionally a computer will screw updue to a glitch in the software or an electronicdisturbance. We have to be very careful check-ing over our numbers to make sure that the num-bers we get from the computer are correct.

    * * * * *

    Chato: In 1960 I took a phone call that camein from a doctor at Massachusetts General Hos-pital who was looking for a heat transfer expert.

    He wanted to have a brain probeused for sur-geryinsulated so that he could cool only thetip. The probes were typically about 20-30 cmlong and 2 mm in diameter.

    Nebeker: Why did he want to cool the tip?Chato: He was working with cerebral palsy,

    which is somewhat similar to Parkinsons dis-ease. The hypothalamus is deep in the brain, andit has been found that if a small part of it is de-stroyed, the uncontrollable shaking of the pa-tient ceases. It doesnt cure the disease but stopsthe shaking typical of both cerebral palsy andParkinsons disease. He was trying to get to thatlittle spot in the brain. When the temperature ofthe nerves is reduced to below 27 C, they essen-tially stop functioningas when fingers ex-posed to cold get numb. He wanted to insert theprobe, turn on the cooling, and see whether ornot this would stop the shaking. If it did stop thenhe could apply rf (radio frequency) current topermanently destroy the tissue.

    The doctor explained that he wanted to insu-late a long tube, not to exceed 2 mm in diameter,so that only the tip would be cold. I didnt think itcould be done. When he explained to me why hewanted this, I said, I think what you really needis a new refrigeration system. I went on to de-velop for him what I call the smallest refrigera-

  • tor ever built, and it worked out very well. Thecooling tip was 2 mm in diameter and 5 mm inlength. That was the evaporator. Thats how Igot started in bioengineering.

    * * * * *

    Chato: Probably the most commonly usedcryosurgical protocol is in cancer surgery. Forinstance, the liver cannot be cut but can befrozen. Therefore when there is cancer in theliver, if its in one area the tumor can be frozenwith some rather clever techniques. The frozenvolume is followed using an acoustic radar tech-nique, on-line, and when the frozen ball is bigenough one can be sure that the cancerous tissueinside has been destroyed.

    * * * * *

    Chato: The next question the doctor askedme was, If I make the tip 0 C so that it is as coldas it can be without freezing the tissuebe-cause he wanted to use rf current to create the le-sion, not freezingwhere is the 27 C surfacegoing to be? My first reaction was to ask my-self, What is the thermal conductivity ofbrain?and of course there was no answer tothat. That led me to measuring thermal proper-ties of biological tissues.

    * * * * *

    Chato: A good example of obtaining impor-tant information with simple but effective analysisoccurred when I started looking at the heat transfereffectiveness of various blood vessels. The earlybioheat transfer models assumed that the most sig-nificant heat transfer occurred in the capillaries. Iapplied well-known heat exchanger analysis to thevarious kinds of blood vessels in the human bodyand found that virtually all the heat transfer shouldoccur in the small arterioles and venules; the capil-laries should be essentially at the surrounding tis-sue temperature with no significant heat transfer.That was an important discovery.

    * * * * *

    Chato: Then later, through one of the NASAfaculty grants, I spent a couple of summers out atNASA Ames in California and got into the ther-mal regulation and thermal control of space suitsfor astronautsthe cooling of astronauts in theApollo spacesuits. One thing led to another and Idid more bioheat transfer work.

    * * * * *

    Chato: Cancer treatment withheathyperthermiawas particularly a bigstimulus of research efforts in bioheat transfer.Researchers were trying to estimate how muchheat must be applied to the various parts of thetumor and worked on the associated problem ofdeciding how best to aim the heat source, such asan ultrasonic beam. For instance, in using an ul-trasonic generator, the question was how to aimproperly and how to move it so that it would heatthe tissue properly.

    * * * * *

    Chato: Another field I worked in that wasoddball, as I told you, was electrohydrody-namics.

    Nebeker: How did you get into that?Chato: The Electric Power Research Insti-

    tute (EPRI) was formed while we worked withits predecessor the Edison Electric Institute. Theproject on which I worked had to do with under-ground electric cables using oil as a cooling me-dium. We were looking at the heat transfer andflow characteristics. I took some courses in elec-trical fields and magneto- and electro-hydrody-namics at MIT. I had some time for extracourses, and even then I was willing to go up tostrangers like electrical engineers and ask ques-tions. What happened was that I looked at thatproject and said, Here is oil, which is a dielec-tric fluid. Pumping is not possible with mag-neto-hydrodynamics, but maybe we could pumpwith electro-hydrodynamics. Dielectric fluidswould be ideal for that.

    * * * * *

    Chato: Bioheat transfer is still a relativelysmall arena. Even in bioengineering, the bioheattransfer area is relatively small compared tobio-fluid-dynamics for instance or biomech-anics in general. However, I think it is a very im-portant field.

    * * * * *

    Bioheat transfer is still arelatively small arena. Even inbioengineering, the bioheattransfer area is relatively smallcompared to bio-fluid-dynamicsfor instance or biomechanics ingeneral.

  • Nebeker: Have you been involved with theheat destruction of tissue for surgical purposes?

    Chato: Not as such. I was involved in burndamage, but mostly in terms of legal problems.

    Nebeker: What was that work?Chato: There were things like, for instance,

    someone worrying if a certain piece of equip-ment that has hot air going through it may actu-ally cause a burn on a human body in the case ofa patient who is exposed to it.

    * * * * *

    Chato: I remember looking at an electricalengineering paper that had to do with a questionof the electric field distribution around buriedcables. It was the same problem as the tempera-ture distribution around the buried pipesamegeometry, same controlling equation. For in-stance, in conjunction with this cooling of un-derground electric cables, I used the solutionsfrom an electrical engineering paper that wasfrom the twenties. As a matter of fact I modifiedthe same solution to estimate the heat transferfrom a blood vessel near the skin surface.

    Shu ChienProfessor, WhitakerInstitute of BiomedicalEngineering, Universityof California San Diego(interview by FrederikNebeker on 11 December2000)

    Chien: [We published] a series of threeback-to-back papers in Science on [the flowproperties of blood] in 1967. they triggeredmy 30 years of collaboration with RichardSkalak in the Department of Civil Engineeringand Engineering Mechanics at the ColumbiaEngineering School. He expressed his great in-terest in them, especially the paper on the flow ofred blood cells through narrow filter pores,which is very similar to capillary flow.

    Dick had a student, Tio Chen, who was start-ing to work on a thesis computing the flow ofsmall particles through a narrow tube, a situationanalogous to blood cells flowing through a capil-lary. Dick put me on Tios thesis committee, andthrough that we began to collaborate. We contin-ued to collaborate for 30 years and published to-gether many full-length papers. Thats where Ireceived a lot of my engineering training. So Iwas able to go from physiology to the biophysicsof flow properties of blood and to engineeringsimulation and modeling. Then I began to appre-ciate the power of simulation and modeling. Thatreally put my math interests into practice.

    * * * * *

    Chien: Later on I realized that using the net-work theory and related areas one can begin tounderstand how the physiological systemswork. There were several papers out duringthose years [the early 1970s] about how to simu-late the physiological systems using the engi-neering control theory. Therefore, I took acourse in control theory.

    Nebeker: Was this kind of engineering sys-tems analysis something that a number of peoplewere beginning to explore at that time?

    Chien: Thats right. Dr. Arthur Guyton ofthe University of Mississippi was one of thosepeople, but there were not too many.

    I became interested in this and gave a courseon The Application of Control Theory in Physi-ological Systems in the physiology departmentat Columbia.

    * * * * *

    Chien: I am always interested in merging[engineering and biomedicine]. Hemorrhagicshock is a major medical problem in inten-sive-care surgery, which in turn is closely re-lated to engineering. At the same time, we alsomoved from studies on the blood as a suspensionto investigations on individual cells.

    Nebeker: Do you mean in the sense of mod-eling of the processes?

    Chien: Both in experiments and modeling.We isolated the individual cells, determinedtheir viscoelastic properties, and modeled thoseproperties. Dick Skalak, two of his students(Aydin Tzeren and Richard Zarda), and myselfpublished a paper about the mechanical proper-ties of the red blood cell (RBC) membrane.

    * * * * *

    Chien: I think the problem with engineeringmodeling in the early days [the 1960s and1970s] is that many of the modeling studies werenot done in relation to the biological reality.

    Nebeker: More abstract mathematical mod-els?

    Chien: More abstract and very elegant solu-tions to a problem, but not necessarily applica-ble to biological systems. Therefore, it is veryimportant that biology and engineering bebrought together.

    * * * * *

    Chien: Shelly Weinbaum and Bob Pfeffer(Professor and chairman of chemical engi-neering at the City College at that time) eachspent a sabbatical year with Colin Caro [at Impe-rial College] working on atherosclerosis prob-lems in the early seventies, and they talked aboutcontinuing that work after Shelly returned toNew York. Shelly told me that Colin said, Theperson in New York you should collaborate with

  • is Shu Chien. I already knew Shelly and Bobfrom other contacts in New York. In 1969, Dr.Y.C. Fung traveled from San Diego to give anumber of special lectures at CCNY, and hemade sure that Shelly met Dick Skalak and meduring his visit.

    Nebeker: Can you describe their interests?Chien: By training Weinbaum was a mechani-

    cal engineer and Pfeffer was a chemical engineer,so they were primarily interested in engineeringmodeling. Both of them were interested in trans-port phenomena; how molecules move.

    They had not had much contact with biologyuntil they took the summer physiology course atColumbia and then went to work in Caros lab.As mentioned above, they wanted to continue inthis line of research after returning to New York,so they came to me and said they wanted me tocollaborate on this project. At that time I wasworking very heavily with Dick Skalak, so I gotSkalak involved in it too. This is a problem re-lated to my interests because of the blood vesselsand fluid mechanics. I was focusing more on theblood cells for quite a while, and here was an op-portunity to look at the blood vessels and thecell-vessel interface as well. I was interested ininitiating new approaches, and we began to worktogether.

    Nebeker: When was this?Chien: This was in 1974. We later submitted

    a proposal titled Studies on Endothelium inAtherogenesis to the NIH, and this grant appli-cation was funded in 1976; it is still active nowafter 24 years.

    * * * * *

    Chien: Rheology is the study of flow and de-formation of matter. There is a Society of Rheol-ogy, which is part of the American Institute ofPhysics.

    Nebeker: Do you know the history of thephysiology interests of rheologists and when itdeveloped as a field?

    Chien: Biorheology probably developed inthe forties and fifties. The late Dr. Alfred Copleywas a strong proponent of the field. He formedthe International Society of Biorheology and or-ganized many congresses. He also started thejournal Biorheology, which has Dr. Harry Gold-smith of McGill University and Montreal Gen-eral Hospital as the Editor-in-Chief. TheCongresses were usually attended by severalhundred people and they provided a forum forthe exchange of scientific information on a lot ofinteresting work in the field.

    Nebeker: It strikes me as a bridging field.Chien: Its a bridging field. Thats right. It

    overlaps a lot with bioengineering and physiol-

    ogy, but its a very specialized area of bioengi-neering. However, when one talks aboutbiomechanics and biorheologists, it is very hardto distinguish these two. For example, Dr.Fungs pioneering work in biomechanics is alsopacesetting in the field of biorheology.

    * * * * *

    Chien: In the most recent edition of this ex-cellent book Molecular Biology of the Cell byAlberts et al., there is a chapter on the mechan-ics of cells, which is a new chapter not presentin previous editions. This is a clear indicationthat cell and molecular biologists are now see-ing the importance of engineering in the studyof biology. There is still not sufficient quantita-tive treatment in biological research, but I thinkthe next generation of biologists will be edu-cated with the quantitative capability. Quanti-tative treatments are already being used insome of the biological fields. For example, sig-nal processing is being used in the study of ionchannels in excitable cell membranes. Theopening and closing of these channels in a par-ticular pattern of frequency distribution modu-late the function of cells such as the neurons.The analysis of such data requires the applica-tion of quantitative methodology. I believesuch quantitative analysis and engineeringmodeling will be increasingly applied to bio-logical research. In my current research, westudy how cells modulate their signaltransduction and gene expression in response toflow or deformation of the cell. The time courseand the extent of the responses need to be ana-lyzed by treating these molecules as a circuit ornetwork, because of their interrelations and in-teractions.

    * * * * *

    Chien: One of the emerging areas inbiomechanics is molecular biomechanics. Wehave begun to have the instrumentation and ca-pability to study the biomechanical propertiesand behaviors of individual molecules. For ex-ample, the cytoskeleton network is composed of

    I think the problem withengineering modeling in the earlydays [the 1960s and 1970s] isthat many of the modeling studieswere not done in relation to thebiological reality.

  • Clark ColtonProfessor of ChemicalEngineering,Massachusetts Instituteof Technology(interview byMichael Geselowitzon 20 February 2001)

    structural proteins including actin. What are themechanical properties of the actin filaments andthe network during cell movement and in otherfunctional states? The answers to this are impor-tant in understanding the mechanisms control-ling the motion, mechanical stability, and shapeof the cell. How do the cytoskeletal elementschange to deform the cell during adaptation tothe environment? For instance, in the endothe-lial cells subjected to sustained flow, the cellsand actin fibers become oriented and alignedwith flow. What are the mechanics involved insuch reorganization?

    * * * * *

    Chien: For example, there are now severalpeople working in my group on bioinformaticsbecause we are doing DNA microarray studiesto systematically assess gene expression in re-sponse to mechanical stimuli. With this noveltechnology, we can simultaneously search forthe expression of 10,000 or more genes,whereas the previous techniques only allowedus to study one gene at a time. Bioinformatics isneeded in order to sort out the meaning of theresponse pattern of a large number of genes.We need people from all of these different dis-ciplines, and we also work with colleagues inour department and in other departments andinstitutions.

    Colton: [For my Ph.D. thesis] I chose to fo-cus on understanding the process of hemo-dialysis. That involved a multiplicity of things:diffusion in blood, diffusion through dialysismembranes (particularly cellulosic mem-branes), convective transport in well-definedgeometries (I picked the flat plate, which was themost common at that time), and overall analysisof performance. In the course of doing that I be-gan measuring membrane properties in a batchdialysis device I designed. I did the drawings,the whole works. It was modeled after some-thing Ed Leonard had published, and he waswilling to sell me one of his devices, but Prof. EdMerrill felt that I should design and build it my-self, so I did.

    Building something mechanical with pipethreads and screw threads was something newfor me. In any event, I got into how the fluid me-chanics and mass transfer worked in the device.That was a kind of side study. I wound up withpublications on that. We did a numerical analy-sis finite difference solution of the convectivetransport equation. Its a very complicated sys-tem that had never been looked at intellectually.That turned out to be a lot of fun. Then I mademeasurements with it and had an undergraduatedoing measurements of diffusion in blood. I thenput it all together in a dialyzer in a very well-de-fined geometry.

    * * * * *

    Colton: At that time MIT had a grant fromthe Ford Foundation. They hired a lot of theirown students and made them assistant profes-sors and Ford Foundation Fellows. I got that andI had it for one year, but when the program endedI was allowed to stay. Thing were very tense atthat time, Ive got to tell you, because the per-centages were poor. When I joined the faculty I

    had a debate within myself. Well what am I go-ing to do? I want to do biomedical work, but is itreally legit and will it be viewed as legit? Iknew that Professor Merrill was not universallyviewed as doing solid work because of his workwith blood. There seemed to be an attitude ofWhat kind of nonsense is this? I wanted tocontinue in this direction but I also had to dogood engineering. I wanted to pick problemswhere I could see an engineering component.

    Geselowitz: Did you want it to have an engi-neering component so that you could explain toother chemical engineers who had no interest inbiomedical work the problem in terms theywould understand and think of as relevant?

    Colton: Exactly. We would make use of theskills we learned as chemical engineers and ap-ply them to a new system. That characterizedsome of my early work, although I rapidly be-came a lot more biological or physiological thanI had anticipated in some ways. And at that timeI was in touch with a small number of studentsaround the country who had obtained theirPh.D.s working on biomedical problems. WhenI graduated I knew everybody in the countrywho was working on a biomedical problem.That was only about three or four people, al-though it started to grow rapidly. At meetings ortalks we gravitated toward one another becausewe were not part of the mainstream.

    * * * * *

    Colton: I continued to be interested in mem-brane processes. My interests bifurcated andtrifurcated over the next couple years. Right af-ter my thesis I had a summer job at Amacon Cor-poration. That was an incredibly stimulatingenvironment. I was out there when fiberultrafiltration membranes were first developed.They were looking for applications and trying to

  • Murray EdenProfessor Emeritus ofElectrical Engineering,Massachusetts Instituteof Technology(interview byFrederik Nebekeron 10 November 1999)

    understand how they worked, and I became in-volved in some basic work in an application thatled to a new process called hemofiltration. Thatwas really very exciting.

    When I was a student, I was involved in workon membrane oxygenation through some con-sulting. I had sat next to a student, RichardBuckles, who had worked on oxygen transportin blood. There was a request for a consultantthat came while I was a doctoral student workingon a device to take oxygen out of blood to powera fuel cell for an artificial heart. I made use of thework in his thesis in my consulting. That got meinterested in oxygen transport in blood.

    * * * * *

    Colton: Then there was yet another area inwhich I became involved, and that was throughour department chairman at MIT, who was push-ing enzyme engineering. It was part of a largerprogram aimed at using enzymes to carry out achemical process to synthesize chemicals. Wewere looking at antibiotics with enzymes usingATP as an energy source to push the synthesis.That was very exciting, and I had a very big labon that.

    * * * * *

    Colton: Right now I am focused on diabetesand the area of artificial organs that I got startedin about 1973. Ive expanded that work. A lot isgoing on with islets of Langerhans per se. Itmight be called cell biology or biochemistry orbiochemical engineering, but the obvious appli-cation is biomedical. Its for transplantation. Itsreally a blending of everything. It does have atransport flavor. A lot of what Im doing dealswith oxygen consumption and uptake. Someonein the lab introduced me to NMR, and now wereusing NMR to study islet properties in vitro andpossibly in vivo. Im still getting into newthings that doesnt endbut its all now morefocused in the diabetes area.

    * * * * *

    Colton: The point is, this stuff [engineering]is hard to learn. If you give students just a bit ofengineering and get into the applications tooearly, you have stolen from them the opportunityto develop some competence. For that reasonbioengineering is a really tough thing. I thinkthat in most cases its been a mistake to developlarge numbers of engineering programs. Gradu-ate programs? Yes. Those are appropriate. Andthere you focus in certain areas and develop con-fidence in certain areas. The students can choosewhen they decide where they want to go in whatsubareas a department should be active, becauseevery subarea is a bit different. Thats dangerousat the undergraduate level, because you run theriskwhich I think has played outof trainingpeople who are only modestly competent, if atall, in fundamental areas.

    Eden: My uncle was not much older than 12or 13 or 14 when he came to the U.S. He musthave been a remarkable man because he was ul-timately admitted to Harvard and received hisundergraduate degree, and he then obtained aHarvard M.D. about 1924 or 1925. He was avery important influence on my life and the livesof some of my cousins. We used to pal around;he would take us with him and try to teach ussomething. He was a pediatric cardiologist andwas director of a hospital for rheumatic feverkids in Roslyn, Long Island [New York]. He hadone of the earliest of the electrocardiogram ma-chines. He was interested in observing what hap-pens if you put the old-fashioned three-positionconnections (electrodes) anywhere other thanthe two arms and the left leg. He and I designed acorset. It had buttons on the side so that youcould open it and put it on, and it was full of but-tonholes. There were buttonholes all over this

    corset, and we had little brass buttons to putthrough the buttonhole, then you could put itanywhere you wanted on the chest.

    Nebeker: Just to have controlled positions?Eden: Thats right. I dont know whether he

    ever used it on patients or not.Nebeker: So that was biomedical engineer-

    ing at an early age.

    * * * * *

    Eden: I worked on two important pieces ofwork at that time [the mid 1950s]. We developeda special-purpose analog computer to analyzethe kinds of spectra that you might get in electro-phoresis, or anywhere the curves of the experi-mental data had peaks, under circumstanceswhere you know that these peaks and valleysrepresent concentrations of some entity, mole-cules or ions usually, but with a lot of overlap of

    If you give students just a bit ofengineering and get into theapplications too early, you havestolen from them the opportunityto develop some competence. Forthat reason bioengineering is areally tough thing.

  • the peaks. This is the kind of problem that isamenable to mathematical description, usually,and its surprising what you can do. We couldtake the circumstance where you had a peak andjust a little teeny bit of shoulder on one side andyou could estimate the concentrations of the twocomponents that are overlapping with remark-able sensitivity, so long as you knew the distri-bution function that the peaks followed. So itcould be used in a variety of applications, in-cluding optical spectra where there is pressurebroadening. We built this device, and it workedfairly well. It was ultimately manufactured byDupont for a period of ten or 15 or 20 years.

    * * * * *

    Eden: Another instrumental development Iworked on [in the mid 1950s] had to do with sep-arating out groups of red blood cells based ontheir density. Human red blood cells reach amaximal age of about 60 days. The young arelighter in terms of density than the old ones, soyou want to separate them out by tagging thenewly formed cells with some radioactive mate-rial to identify a particular fraction. I also contin-ued to work on what I had done at Princeton,basically a growth model. As far as I can tell itis the first algorithmic, computer-worked-outmodel of two-dimensional growth. The originalmodel is very easy to describe.

    Nebeker: Microbial growth, for example?Eden: Thats precisely what I was trying to

    model. A cell divides in two. They remain sittingnext to each other. Then one or another or bothof them divide. There are all kinds of algorithmsyou can invent. My algorithm was very straight-forward. I said, One of these two cells shapedas squares will divide, and as theyre still con-nected each has only three sides that are not cov-ered. It can divide right, left, or down. You buildmore and more. The work on this model and,later, on others reflects the development of com-puters, because the first use of this model back inPrinceton was on what was a computer calledthe Johnniac. There were three names: John vonNeumann, Herman Goldstine, and JulianBigelow associated with this computer. Bigelowwas the engineer. We made pictures. The waywe made pictures prevented us from addingmany cells. The most we could do was on the or-der of 20 or 30 cellsthe computer was too slowand the only output was a Hollerith punch card.We would produce a picture on a punch card.The holes on the punch card are rectangular, notsquare, in columns. But if you look imagina-tively you can see a picture.

    Nebeker: An early graphical output.

    * * * * *

    Eden: By that time or shortly thereafter I leftRosenbliths group and set up a group with Wil-liam Schreiber and Samuel Mason. Masonsclaim to fame was that he invented flow graphs.He was an ingenious engineer with a wry senseof humor. His research was on sensory aids forthe blind. One such, with Schreiber and DonTroxel, was a machine that read printed books.Bill Schreiber came to MIT from Technicolor.He has worked mostly on picture processing. Inrecent years he has been one of the leading ex-perts on high-definition TV.

    So we set up this lab. We had a number of grad-uate students who later became faculty includingTroxel, Tom Huang, Oleh Tretiak, Jon Allen, TedYoung, and Barry Blesser. After a while we werejoined by Paul Kolers, a psychologist who hadbeen at Harvard. We couldnt get him an appoint-ment at the MIT Psychology Department, but hestayed with us a while and he chose our name. Webecame the Cognitive Information ProcessingGroup, and it was that from about the early 1960suntil long after I left in 1976. We had hired somestrange people. We had a psychiatrist for a whilewho tried to model the very different world per-ceived by very disturbed children.

    Nebeker: Can you give some examples ofthings you and the others in this group workedon in those years?

    Eden: Yes. Most of the things that I workedon had to do with biology. Thats how I cameback to biology; I had sort of drifted away. Mostof the pattern recognition problems that we pro-posed for students to work on came from medi-cal applications, diagnostic applications, and wereally worked on a whole range of problems. Welook at patterns.

    Chromosome karyotyping is a very good ex-ample. When we started, it was very difficult.We knew very little other than each chromo-somes size and shape. Then a biologist by thename of Caspersson, if I remember correctly,discovered that you could differentially stain thegenes in the chromosome so youve got a bunchof transverse stripes of different widths and graylevels. Suddenly the problem changed becausewe now had additional information related tostructure. We looked at debris in urine. Welooked at cancer cells in Papanicolau stains. Welooked at X rays to tell the difference betweenthe presence of tubercular lesions or not.

    * * * * *

    Eden: We independently invented comput-erized tomography. I think its fair to say we didit independently, although Hounsfield at EMImay have begun a year or two earlier. We pub-lished the first section of a human tissue in the1969 International Conference on Engineeringin Medicine and Biology.

  • Yuan-Cheng Bert FungProfessor Emeritus ofBioengineering,University of California,San Diego(interview byFrederik Nebekeron 12 December 2000)

    * * * * *

    Eden: We went over to the Brigham andtalked to Herb Abrams, chief of radiology, andhis staff. They were mostly interested inangiography. They wanted to look at skinny lit-tle blood vessels in the hand or the heart ormaybe elsewhere. Our pictures were very crude.

    They looked like a patchwork of different col-ored squares. We could only digitize in a matrixof 32 32 or 16 16very small numbers. Wecould have done better, but it would have re-quired more computer power than we hadreadily available to us. They looked at our pic-tures, which were full of quantizing noise, andsaid, Well, we have no interest.

    Fung: Dr. Sechler, my mentor [at Cal Tech],asked, What would you like to work on?Well, I said, I would like to work onaeroelasticity. Ah, he said, just right. In1942 the Tacoma Bridge on Puget Sound inWashington State was blown down by wind.Von Krmn said that the oscillation was causedby vortex shedding from induced aerodynamicforces. The State of Washington Public Workssponsored a research project here. When vonKrmn retired, that job was given to Dr. LouisDunn. When Dr. Dunn became the director ofthe Jet Propulsion Laboratory a few monthslater, he handed the job to Maurice Biot. Biotsoon left. They left a filing cabinet here whichyou may take a look at.

    I inherited a wind tunnel designed particu-larly for this project. I used it to study the bridge.I found bridge aerodynamics very difficult, veryawkward. Airfoils are simpler and cleaner. So Ibegan working on aeroelasticity of the wings. Iformulated the general aeroelastic problem andthen designed ways to systematically study itstep by step.

    Nebeker: You were interested in a generaltheory of aeroelasticity rather than in how a par-ticular structure responds?

    Fung: Yes. I wrote one of the first books onaeroelasticity.

    * * * * *

    Nebeker: Can you tell me how you first be-came interested in biomedical problems?

    Fung: I became interested in biomedical prob-lems for a personal reason. In 1957 I took a sabbat-ical leave with a Guggenheim Fellowship andwent to Germany. My mother had acute glaucoma,a very painful disease, and I could do nothing forher. In frustration, I read American literature onglaucoma and sent her a weekly translation orsummary. I told her, If you cannot use it, give it toyour surgeon. Many years later, in 1973, I finallywent back to China. My mothers operation was asuccess. Her surgeon thanked me.

    In Germany, right across the street from theAerodynamics Research Institute was the Physi-ology Institute of the University.

    Nebeker: This is in Gttingen?Fung: Yes. It was the Gttingen Physiology

    Institute. I enjoyed their library and their facili-ties. Thats the beginning of my interest in thatfield. Gradually one thing became quite clear tome: the biologists do not think about what weengineers always think aboutnamely, theforce, motion, and transport phenomena. Fur-thermore, biology is full of interesting nonlinearproblems. The field seems to ignore the kind ofthings which you can do. I found the field veryattractive.

    After returning to Caltech I began to work onphysiology. A few years later my feeling wasthat I wanted to work on it full time; I didnt wantto dilute it with other work. Thats how I endedup at UCSD.

    * * * * *

    Fung: Now, the mechanical properties of bio-logical tissues were virtually unknown in the1940s. The question was how to describe the me-chanical properties and what to measure. Todayyou would consider successively the hierarchiesof organelles, cells, interstitial materials, tissues,organs, and the individual. Historically, the studywas done in downward order of hierarchies.

    Every step is difficult. For example, it wasvery difficult to quantify the mechanical prop-erty of tissues, but without that you cannot be-gin. With testing, theorizing, and hypothesizing,you hope that youll eventually understand thematerials that you are dealing with.

    * * * * *

    Bert Fung working on tissue remodeling withWei Huang, Ghasan Kassab, and a student atthe University of California, San Diego.

  • Fung: Capillaries have a diameter of aboutten microns (about one-third the thickness of ourhair) and a wall thickness of one or two microns.Dr. Zweifach and his associates could not detectthe change of the capillary diameter when theblood pressure was changed by as much as 100millimeters of mercury. Since they used an opti-cal microscope for the measurement, this meansthat the change of diameter is much less than onewavelength of light, or 0.5 micrometer.

    Nebeker: Isnt it surprising, because such athin structure should respond to that change inpressure.

    Fung: Yes. Very surprising if we think of thecapillaries as small cylindrical tubes. Collagenor steel tubes can do it, but not a single layer ofendothelial cells with a thickness of one to twomicrons.

    Where did this rigidity come from? I lookedat the problem and my suggestion was that the ri-gidity came from the surrounding media. Inother words, the capillary blood vessels we haveare not a tube, but a tunnel lining.

    To verify that the rigidity comes from thetunnel material outside, I measured the mate-rial properties of the stuff outside the capillary,then computed the expected deformation of thecapillary. I found agreement. That kind of thingmakes engineering thinking suddenly relevant.

    * * * * *

    Fung: The next thing I wanted was to deter-mine the elasticity of the capillaries of the lung.Then work out the implications of the newunderstanding on the physiology, pathology,diseases, and injury of the lung. In this endeavor,I was fortunate to have the collaboration of a fa-mous physiologist, Dr. Sidney Sobin, and myformer student and colleague, Michael Yen, andmany graduate students of ours.

    This was where the payoff from an engineer-ing point of view of physiology came in. If youlook at the lung, you see that it is an organ of cap-illaries. These capillaries, however, are not sin-gle long tubes; they are organized intotwo-dimensional sheets. The geometry isunique. We had to measure the dispensability ofthe sheet, analyze the flow, and understand thephysiology.

    Nebeker: Even the microanatomy wasntfully known at that time?

    Fung: The Sobin-Fung sheet-flow model ofpulmonary capillary was novel. It changed thelanguage of pulmonary microanatomy. Itshowed that the classical Poiseuille formula of

    blood flow does not apply to the lung. It showedthat it is simpler to think of a continuous sheetwith a pattern of obstructions.

    * * * * *

    Fung: [At UCSD] we had tremendous rela-tionships with the surgeons.

    Nebeker: More so than with other doctors?Fung: I think so. Surgeons really see imme-

    diately that engineering is what they need. Wehad very good collaborations with the surgeons.The barrier was broken down almost without ef-fort. I think we were extremely lucky on that.

    * * * * *

    Fung: Microcirculation is a big field, butreally the organs they study are not many: themesentery, the cheek pouch, the skin flap, anda few others. Everybody is interested in mus-cle, but there arent many muscles tested. Firstthe frog.

    Nebeker: That goes way back.Fung: When A.V. Hill worked on muscle

    mechanics he used British frogs and got poor re-sults. One day he visited Italy and got the Italianfrog; then [his experiments] worked.

    Nebeker: So that was the advantage Galvanihad.

    Fung: There are really not many models thatpeople make observations on.

    * * * * *

    Fung: I think biomechanics will be there al-ways. No understanding can be reached if forceand motion are ignored. I dont ever think thatapplication can be minimized. Applications al-ways have surprises of some real good importantdiscovery.

    Nebeker: From the purely scientific view-point.

    Fung: Even from the scientific point of view.Biomechanics is the middle name betweenstructure and function.

  • Leslie GeddesShowalter DistinguishedProfessor, Emeritus,Department ofBiomedical Engineering,Purdue University(interview by FrederikNebeker on13 October 2000)

    Geddes: My first paper described the RCAMC electromyograph. It was published inApril 1945. I was working on it in 1944. It wasquite an elegant device with a differential ampli-fier, a loudspeaker, and oscilloscope. Therewere a lot of soldiers returning home with nerveinjuries. You could diagnose nerve injury withthe electromyographjust place some elec-trodes in a muscle and one could detect a charac-teristic electrical activity. That was what I wasdoing during the last year of the war at McGill.

    I then joined the Montreal Neurological In-stitute in 1945 as a research assistant and stayedthere until 1952. I was an instructor in the Elec-trical Engineering Department at McGill from1945 to 1946. I was one of the early biomedicalengineers. They didnt know what that was at thetime. It was all medical physics at that time. Iwas responsible for the operating room equip-ment and for the electroencephalography labo-ratory.

    * * * * *

    Geddes: At Baylor I built the physiograph.The teaching of physiology was in the dark agesthen. Everybody used a smoked drum (the Lud-wig kymograph) to record only mechanicalevents. So, I built the physiograph as a modularelectronic system that permitted recording manydifferent types of physiological events. This iswhere my Northern Electric experience andham-radio experience paid off. The Bell Tele-phone System has a philosophy that any new de-vice that is made must fit with the old systemitmust be compatible. So a modular concept wasthe keynote for the physiograph, which had atransducer, an amplifier, and a display device.One could connect a variety of different compat-ible transducers to the amplifier, which ener-gized the transducer and amplified its signal.One could then have the event written out on agraphic recorder, or displayed on an oscillo-scope, or heard by a loud speaker. We displacedthe smoke drum kymograph around 1954 or so.

    * * * * *

    Geddes: This system created so much atten-tion that the NIH funded us for a training pro-gram which originated in the following way.

    My mentor (Hoff) and I were sitting in theWashington National airport about 1955 or so.We had three hours to kill. We sketched ourideas for a summer course on physiology on therestaurant menu.

    On arriving home, we applied to NIH for sup-port to teach modern physiology. The programwas titled, Classical Physiology with ModernInstrumentation. The concept was like Shake-speare in Modern Dress. We received the funds

    for a six-week summer course with stipends fortuition and expenses. We had people from allover the world as well as the United States. ThisNational Heart Institute training program wasthe longest single managed training grant thatNIH had ever funded up to that time. It ran from1956 to 197418 years. We trained about 1,000people.

    * * * * *

    Geddes: Let me tell you something about theearly days of ventricular defibrillation. The firsthuman transchest defibrillation was in 1947. Byabout 1954 our students had all done ventriculardefibrillation with a physiograph. We had sev-eral calls in 1957 and 1958 from the local hospi-tals where we had former students. They wouldcall and say, Send us over the physiographdefibrillator and the paddles. We have a patientin fibrillation. Were doing cardiac compres-sion. Hurry up. Send us the defibrillator. So wesent the defibrillator over and they put the pad-dles on the heart and defibrillated.

    Nebeker: There were few companies outthere producing any kind of defibrillator at thattime.

    Geddes: As a matter of fact, it didnt reallystart until 1952 with transchest defibrillationwith a 700-volt, 60-cycle alternating currentdefibrillator. Then Lown did it in 1962, ten yearslater, with a damped sine wave. And so, humandefibrillation didnt start until the early 1960s.

    * * * * *

    Nebeker: What was the response of the med-ical community [to your publication of thedefibrillation dose concept]?

    Geddes: You see, cardiologists only sawadults. They knew they had difficultydefibrillating 200-pound subjects. But theycould defibrillate most of the subjects with thedefibrillators they had. Turn it up to the top andwe defibrillate all. So, who is interested in thedose concept? That fight went on from 1974 forabout the next eight or so years. It was only whenthey decided to make defibrillation efficient be-cause they had to implant them that they beganto know that big hearts are difficult todefibrillate. Small hearts are easy to defibrillate.

    * * * * *

    Geddes: I was a consultant for the VSAF atBrooks AFB in San Antonio, Texas, for manyyears. In the early 1960s, when I was at BaylorMedical College in Houston, NASA contactedme and invited me to be a consultant on physio-logical monitoring of astronauts before therewas a suborbital flight. I, along with other scien-

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  • tists (Pat Meehan and Col. Jim Henry), met witha few NASA people in a garage rented fromHomco Oil Co. located at the intersection of OldSpansh Trail and Wayside streets in Houston.Then there was no Manned Spacecraft Center.We all discussed the important physiologicalevents that we should measure and telemeter toearth from the astronauts.

    From the outset it was obvious that it was de-sirable to telemeter the four vital signs: tempera-ture, pulse rate, respiration rate, and bloodpressure (T, P, R, and BP). It turned out that thechimps on the sleds at Holloman AFB would nottolerate a rectal thermometer; they unceremoni-ously ejected it. The heart rate could be detectedfrom the ECG. Respiration was detected by thecooling of a heated thermistor on the micro-phone in the helmet when the astronaut exhaled.In the first flights, indirect blood pressure wasnot obtained due to the cramped space. Accord-ingly, only ECG heart rate and respiratory ratewere telemetered to the earth-bound monitoringstations. But there was a problem because therespiration signal was lost when the astronautturned his head away from the microphone. Atthis point NASA contacted me and asked if Icould devise a more reliable method of detectingrespiration. On a Saturday afternoon at Baylor, Iwent into the lab, placed two electrodes acrossmy chest at the xiphoid level, and measured the20-kHz impedance changes that occurred withrespiration. The method was described later inAerospace Medicine in 1962, and we used it inthe medical student physiology laboratory; themethod became known as impedancepneumography.

    * * * * *

    Geddes: During my time at Baylor, I had al-ways been interested in the measurement of di-rect and indirect blood pressure. I published twobooks on the direct and indirect measurement ofblood pressure. We actually developed theoscillometric method, which is the standardmethod used now. We did the study that showedthat when cuff pressure is decreased, the ampli-tude of cuff-pressure oscillations increased,reached a maximum, and then decreased. Themaximum oscillation point signals mean pres-sure.

    * * * * *

    Nebeker: Was it in 1968 that the first editionof your book with L.E. Baker on medical instru-mentation was published?

    Geddes: Here is the first edition, 1968.

    Nebeker: Would you tell me a little abouthow that book came to be?

    Geddes: That book came as a result of teach-ing medical students, residents, and interns, andthe need to make devices for research. It alsocame as a result of the summer course ClassicalPhysiology with Modern Instrumentation.There was just no way you could buy devices tomake the measurements. Lee Baker was mygraduate student. We decided that we would putthis all down so people could learn how to maketheir own devices from a book. Its really a mea-surement handbook.

    Nebeker: Its become a real classic withthree editions.

    * * * * *

    Nebeker: You were saying that it is very im-portant as a teacher to provide historical back-ground.

    Geddes: Yes. I think it is important becauseby knowing that, down the road the student willperhaps be able to make the next leap from theknowledge that he or she has now. It gives themthe thought that discovery is an evolutionaryprocess. For every discovery, there is a littlebackground and there is going to be a future. Weare not at the end of the discovery road now.

    Nebeker: Occasionally, an earlier approachthat didnt result in anything useful might be-come feasible when new technology arrives.

    Geddes: Thats exactly the point. New tech-nology is around, and one can do things now thatwere very difficult to do previously. The knowl-edge was around, but the execution was very dif-ficult.

    So, I always start my lectures with the historyand what was done and why it was done. To justsay what was done is not enough. One has to getinto the mind of the person who did it to find outwhy he did it.

    * * * * *

    Geddes: I dont know that biological engi-neering it is getting fragmented. It has changed.The transactions on biomedical engineering arebecoming a little more theoretical and more con-cerned with modeling than they used to be. Thetrouble is that doing experiments is expensive. Itis easier to sit at the computer and put data in andmodel. It is expensive to take those data and sub-ject them to the real-world animal or human test.So that is a change that I am not particularlyhappy to see because I like to see theory andpractice joined.

  • Nebeker: I understand that while you wereat Cornell you started working with some instru-mentation for animals for the Psychology De-partment.

    Greatbatch: Yes. At that time CornellsPsychology Department was one of the coun-trys foremost centers of Pavlovian psychology,which is a physiological psychology. I got a jobbuilding amplifiers for a hundred sheep andgoats, measuring their heart rate and blood pres-sure and so on. I also participated in conditionedreflex experiments. My experience there turnedout to be quite useful. Because I knew what con-ditioned reflex was, a few years later I had theopportunity to build all the amplifiers for one ofthe first monkeys shot up into space. That waswhat really got me into the field of medical elec-tronics.

    * * * * *

    Nebeker: Id like to hear more about yourinstrumentation for these animals. Were youfirst building amplifiers for the EKG?

    Greatbatch: Yes. The heart generates a sig-nal which is about a millivolt in amplitude, sothis has to be amplified by a factor of somethinglike a thousand before it can get up to the pointwhere it will record. At that time we didnt havetransistors yet, so all our work was done withvacuum tubeswhich is not the right way to dothis sort of thing.

    * * * * *

    Greatbatch: A friend of mine in Minneapo-lis, Earl Bakken, was building battery-operatedpacemakers that could be worn on a belt. Theyhad wires going right through the skin. That wasonly marginally satisfactory, though some peo-ple lived a long time with them. We engineershave not to this day learned how to run a wirethrough the skin and have it seal. Its always anopen wound. Therefore the people have to putantibiotic jelly around it every morning and ev-ery night. They cant bathe, go swimming ortake showers. They can take a sponge bath, but

    that box is always there. They roll it over at nightand they can never forget that its there.

    * * * * *

    Greatbatch: Five years later when transis-tors had been invented and had become readilyavailable I thought, Now I can make a pace-maker.

    Nebeker: Can you recall dates?Greatbatch: It was somewhere between

    1949 and 1951 when I learned about the disease.We built our first pacemaker with transistors forimplantation into an animal in 1958. Much tomy wifes consternation, when I realized I couldactually make pacemakers I quit all my jobs. Ihad two thousand dollars in cash, which wasenough to keep my family going for two years[1958 to 1960]. I gave the family money to mywife and went up in the barn behind my house. Intwo years I made 50 pacemakers.

    Nebeker: You made them by yourself?Greatbatch: Yes.Nebeker: Did you make any attempts to in-

    terest a medical equipment manufacturer? Iwould think a young engineer might go thatroute with a good idea like that.

    Greatbatch: I considered that and I did talkto some people, but no one was really interestedin it. Of course we hadnt implanted devices inour first patients yet. Once we had our first pa-tients with the device successfully implanted,there was a great deal of interest. We workedfairly closely with Earl Bakken and hisMedtronic Company at that time.

    * * * * *

    Nebeker: How did the connections withDoctors Chardack and Gage come about?

    Greatbatch: Our local chapter of the PGME[Professional Group on Medical Electronics ofthe Institute of Radio Engineers] in Buffalo hada meeting every month. Ours was the first chap-ter in the country. We tried very hard to get anequal number of doctors and engineers to attendthe meetings, and sometimes we had as many as50 people at a meeting. The engineers offered tosend a team of engineers to help any doctor thathad a research problemfor free. Quite a fewdoctors took advantage of that offer. In fact,about five different medical doctor-engineerteams that resulted from that stayed together forquite some time. I went up with one of thosegroups to see Dr. Chardack.

    * * * * *

    Nebeker: It sounds like you became very in-terested in battery design.

    Greatbatch: Yes. Once we realized that the

    Wilson GreatbatchPresident and CEO ofGreatbach Enterprises(interview byFrederik Nebekeron 4 April 2000)

    One of the first pacemakers thatran on a lithium battery wasimplanted in a patient inAustralia. That patient went outinto the outback and became sortof lost from civilization. Theyfinally caught up with him anddiscovered that his pacemakerhad been running for 22 years.

  • battery was the limiting factor, we started look-ing at all sorts of power supplies. We evenlooked at rechargeable batteries. However, wefound out that the life of a rechargeable batterywith recharging was not as long as the life of ourprimary cells without recharging. That knockedout that idea.

    Nebeker: Would this have been a kind of re-charging that could be done through the chest?

    Greatbatch: Yes, inductively through theskin. That would have been no problem.

    * * * * *

    Greatbatch: We came up with the lithiumbattery in 1970. The lithium battery had a muchlonger life than mercury. And it didnt generategas, so it could be hermetically sealed. The factthat it didnt have gas was a big deciding factor.The fact that it could be hermetically sealed wasan even bigger factor, because that meant wewere no longer running under water. One of thefirst pacemakers that ran on a lithium batterywas implanted in a patient in Australia. That pa-tient went out into the outback and became sortof lost from civilization. Last year they finallycaught up with him and discovered that his pace-maker had been running for 22 years.

    * * * * *

    Nebeker: Did the paper published in Sur-gery and other publications create an immediatedemand?

    Greatbatch: Yes. Of course we also went toall of the shows. Medtronic had a booth at everyshow. I published in the IEEE/PGME journal,and I published any new battery developments.Dr. William Chardack and I published jointly inthe medical journals. I used to accompany aMedtronic salesman and visited a lot of hospi-tals, and I gave talks at their research seminars.We gave a very strong educational push in thosefirst five years. It is interesting to me that it tookonly five years for the pacemaker to bec