INTRODUCTION

     In 2005, I had a highly impactful conversation with a Chief of General Medicine while taking a car ride to an interview.  I had just completed Fellowship in General Medicine/Complementary Alternative Medicine at Harvard Medical School and had recently submitted an NIH K23 Career Development Award.   My wife had completed pulmonary fellowship a few years earlier, was serving as the ICU director for Boston VA Medical Center, and was looking for a more family friendly schedule with the arrival of our second child.  She was looking to transition from Critical Care to Sleep Medicine, and she was being courted heavily by this academic institution (in another city few hours away).  I was simply the “Partner” – the additional piece that could potentially serve as a lure for her if an appropriate position was identified for me.    

     The day started with lunch with both the Pulmonary and General Medicine leaders who were kind enough to set aside time to meet us at an Italian restaurant in town.  The conversation started with my wife who said all the right things.  She even dropped a few names which drew common connections between her and the pulmonary group there.  Apparently, they had already been told of her impeccable qualifications, and they were genuinely enthusiastic to have someone like her.  She fit right in. 

     When the conversation turned over to me, I began to explain my interests in integrative medicine; how I was credentialed in acupuncture; how I believed that alternative traditions had concepts of systems and holism that could contribute important lessons for conventional medicine; and how my interest evolved into the biophysical aspects of acupuncture for which I sent an application for a NIH Career Development K-23 award studying the electrical properties of connective tissue as a potential mechanism. 

     As I continued to talk, I could palpably feel the air at the table steadily transition from a light-feeling of joviality to one of awkward discomfort and blank stares.  They had no idea what I was talking about and were struggling to kindly maintain a thread of communication: “Why not do clinical trials of acupuncture for osteoarthritis?”; “Where did you apply for your K-grant?”; ” Do they usually receive applications like this?”.   I clearly was not helping out my partner’s case, and so I decided to just shut up and keep my even more eccentric notions hidden from plain view.  Evidently, I was the 60’s-retro, off-green corduroy seats that came with the otherwise perfect car with sunroof and shiny chrome wheels.  The people here would probably take the car but only because the sunroof was so cool – they could do without the seats if given the choice.   

     My perception of the reproachful sentiments was confirmed on the ride towards to my subsequent interviewers.   The Chief was driving me to a specific campus; while Anjali was being driven to another campus.  Somewhere half-way there, the Chief said, “You know, Andrew, to succeed in medical research, it is really important to find a specific topic and truly focus on it.  Become the world’s expert on it.  All the well-established, successful researcher has taken this track.  You should really think about which topic to focus on and make that your career.”    I thanked him for the advice and told him I would think about it…   

EARLY RESEARCH – ACUPUNCTURE

     And frankly, I did.  His words weighed heavily on me for much of my early career: Here was this prominent researcher who was clearly successful in his field – a highly respected, academic leader who mentored many junior researchers in his tenure.  He knew what he was talking about.  I, on the other hand, was a new investigator starting a new research career who had absolutely no concept of whether my proposed research venture would have any traction or whether I had the constitution to even sell the importance of this research.  Moreover, I had a growing family to think about.  Selfish pursuit of undisciplined passions would have to wait for another time.    

     Ultimately, I ended up getting funded on my K23-award; my wife found the perfect job locally; and we stayed in Boston to pursue our respective career interests.   However, his advice reverberated like an echo in my mind and reminded me at every turn in my early career to reel in that curious, wandering mind and to focus, focus, focus.   I focused on the projects proposed in the K-23 as best as I could.  But, even so, the topic I chose for my K-23 was already interdisciplinary, unexplored, and seemingly nebulous. 

     The hypothesis was this: because (1) loose connective tissue (i.e., intermuscular fascia) was identified as a viable anatomical correlate for acupuncture meridians and (2) acupuncture points and meridians were ascribed with distinctive electrical properties (e.g., increased electrical conductivity), loose connective tissue may have physiologically-relevant electrical characteristic that can account for acupuncture’s therapeutic effect.  At its core, this K-23 proposal was expansive and multidisciplinary requiring some expertise in electrical engineering, signal analyses (dielectrics), acupuncture, ultrasound imaging, and connective tissue physiology.    

     The struggles in pursuing this work was profound: I was charting a research trajectory that no-one had explored before and I had to do it in a way that seemed contextually relevant.  It’s one thing to evaluate an obscure protein in a cAMP signaling pathway, and it’s another thing to study whether electrical impedance at 1 kHz frequency was significantly lower in loose connective tissue compared to an adjacent muscle control.  The former was buttressed by decades of molecular and pharmacological research, while the latter had no fundamental physiological basis (at least from a conventional view) upon which to justify its evaluation. 

     Furthermore, the tools and methods for conducting these studies were far from established: “Should I use a Solartron Gain-Phase Analyzer and if so, what frequencies should I focus on?”; “How does electrical impedance relate to physiological function?”; “Are needle electrodes with insulated shafts better than uninsulated needles?”, and “How do you confirm whether a needle is embedded in connective tissue and not a blood vessel?”   Nothing came pre-packaged.  Every detail had to be evaluated and justified, and I confronted doubts and uncertainty at every step.  I had mentors who were extremely helpful in imparting specific topical advice, but when it came to executing the specific K-23 projects, I was largely on my own.    

      Although I may have floundered in the beginning, I became adept at navigating strange waters, speaking different discipline-related lingo, identifying the gaps in knowledge, and establishing realistic targets that would help advance a scientific question in some meaningful way.  I took ~ 7 graduate level courses at MIT paid by my K-award and found collaborators who were experts in their respective fields.  When I needed an expert in the biochemical and bioelectrical properties of connective tissue, I linked up with Professor Alan Grodzinsky (Chair, MIT Center for Biomedical Engineering), became a Visiting Scientist in his lab, and published several papers in collaboration with him.  When I needed to figure out how to attain bioimpedance measurements, I contacted the world’s bioimpedance expert Ørjan Martinsen (University of Oslo) and similarly co-authored several articles together. 

     When I realized that contact impedance was a profound confounder for bioelectrical measurements, I identified a contact-less electrical potentiometer called the Scanning Kelvin Probe, worked with its eccentric innovator – Iain Baikie in Scotland – and procured a NIH R-21 grant to investigate it.  In fact, our study was one of the first to evaluate its use in live human skin.  Furthermore, the theoretical basis for applying the Kelvin Probe in biological systems had never been established.  It was primarily used for deriving surface Work Function of metals and semiconductors.  In response, I established the physical equations relevant to biological tissues, performed symbolic and computational calculations for different tissue types, and validated the Kelvin Probe’s applicability in biological systems.  This was published in Physical Review Letters E.   When I recognized that there were interesting physical features of the subcutaneous fascia, I learned Image J, utilized Matlab image processing tools, and devised a spatial autocorrelation measure that could be used as a surrogate for biomechanical strain.  Finally, when I wanted to advance my ultrasound research, I got a position as a radiology researcher at Martinos Center of Biomedical Imaging at MGH.    

     Believe it or not, this was my idea of ‘focus’.  After all. it all pertained to figuring out the electrical impedance of connective tissue as it related to acupuncture points and meridians.  However, no matter how hard you try to map out your career trajectory, the Universe will put a wrench in the works and have other ideas in mind.  At that time, NCCAM (now National Center for Complementary Integrative Health) was a relatively young NIH Institute and was intent on proving its worth to the medical establishment by producing powerful (and ideally positive) clinical trials.  A good, safe bet was acupuncture because it was considered an easy-win.  Unexpectedly, large randomized-controlled trials after large trials revealed that there were no substantial differences between verum acupuncture and sham acupuncture across multiple chronic conditions. 

     Suddenly all the luster for acupuncture had faded away, and I could see the writing on the wall: there would be no safe future in acupuncture research.   Even though I was evaluating mechanisms and not clinical efficacy, the thinking adopted by the Project Officers at the time was – “why invest in identifying mechanisms of a therapy that doesn’t work in the first place?”.   Seeing this career in research steadily disintegrate in front of me, in the remaining 1-2 years of my grant, I transitioned to the study of novel, unexplored bioelectrical phenomena – specifically, streaming currents in the vasculature and collagen piezoelectricity in fascia.   These were important concepts which I believed would have enormous physiological and clinical implications – even transformative ones.   But it was too little too late. Without sufficient preliminary data, I was unsuccessful in procuring funding despite applying to multiple NIH, NSF, and foundation grants – even those that were self-ascribed “innovative, high-risk” ones.          

SYSTEMS MEDICINE & BIOELECTRICITY

     The truth was that, by this time, I was already becoming disenchanted with the standard academic path and frustrated with the pace of discovery and dissemination.  I could spend years and years applying for grants, proposing ideas, conducting studies, submitting manuscripts, and yet the final product was a paper with little clinical or medical impact.  Also, I was feeling that I was constantly confronting a wall of resistance – I was incessantly battling the momentum of tradition and struggling against the currents of skepticism around every turn.  From one point of view, this experience was extremely helpful, because I learned to apply scientifically rigorous standards to my work and to produce studies and manuscripts that could withstand even the most discerning of scrutiny from topic experts.  Yet, on the other side, it became frustrating and energetically draining because the rewards – if any – were not fully commensurate to the amount of effort being invested into it.  The results were subjected to the random roulette of reviewers and institutional biases.    

     Ironically, the times where I felt my work sustained its greatest impact was when I had followed my heart and let go of this notion of ‘focus’.  In 2006, at end of my fellowship, I published a two-part series on the importance of applying systems principles to clinical medicine.  At that time, systems biology was becoming a hot topic.  However, I was disappointed to see the emphasis being placed solely on genomic and molecular sciences.  In my mind, systems principles and non-linear dynamics can and should similarly be applied to physiology and clinical medicine.  These papers outlined potential areas of exploration and were both highly cited and well-received. 

     One other example was my critical review of collagen piezoelectricity published in 2009.  Collagen is the most abundant protein in the animal kingdom.  Due to its liquid crystalline properties, it possesses several underappreciated electrical properties such as piezoelectricity, pyroelectricity, and second harmonic generation under coherent, optical light.  These physical attributes were known as early as the 1960s and for a while was all the rage in certain orthopedic circles.  But without evidence for a viable physiological role, collagen piezoelectricity steadily fell out of the limelight and was largely forgotten.  When taking the Molecular, Cellular and Tissues Biomechanics course at MIT, I decided to write my final paper on the relevance of collagen piezoelectricity in bone deposition.  I ended up getting an “A+” and suggested to the course teacher, Dr. Grodzinsky, that we publish this paper because of its potential usefulness in bone research. 

     It got readily accepted to Medical Engineering & Physics and may have single-handedly revived a lost topic.  Since then, over 200 studies have cited our paper and collagen piezoelectricity has returned as subject of interest in the bone, biomechanics literature.  In fact, within the year the paper was published, the original discoverer of collagen piezoelectricity, Eiichi Fukada, had emailed me excitedly thanking me for putting these ideas together.  Apparently, he had been searching in vain for a physiological function for collagen piezoelectricity for the past 40-50 years and was exhilarated to read our paper.  He thought we had the answer and asked permission to use my figures for an upcoming talk.  Of course, I said yes.   

WEARABLE TECHNOLOGY, PHYSIOLOGY, & BEING A CATALYST

     After my disenchantment with traditional academic tracks and after placing priorities on ‘impact’, I made a conscientious decision around 2012-2013 to not play the academic game any longer.  I stopped writing papers, applying for grants, and giving talks at conferences; and instead began applying my knowledge to where I felt most impact could be made.  I placed more emphasis on implementation and less so on basic science with the hopes of effectuating meaningful change in clinical care.  Furthermore, I decided to redefine myself: I was not an “expert”, but a “catalyst” – one who would help certain topics get advanced and provide momentum where there was none.  I would not receive the glory nor the prestige that came with a higher academic title, but I didn’t really care: this role best fit my character and would enable me to make the most impact with the skill sets I possessed. 

     I committed one-half to three-fourth of my time to clinical work (to support family) and left the remainder of my time unpaid allowing for free time for research work in meaningful endeavors.  To me, the most promising area of research was portable technologies and the wearable space.   While little doubt exists about whether wearable devices are here to stay, the unfortunate truth is that we are not scientifically ready for it.   Our scientific methodologies are largely adapted and designed according to the type of data made available, and for the past 5 to 6 decades that data had been predominantly sporadic and intermittent in nature.   Clinical data were obtained from infrequent blood or functional tests, all of which were acquired only when the patient had made the extra effort to come to the clinic or hospital. 

     Now, with wearable technologies, the data format is altogether different: it is continuous, noisy, and multimodal in nature and has the potential to be more ecologically consistent (i.e., aligned with day-to-day living).  The capacity to deal with this kind of data will require a complete shift in how we conceptualize the problem.  The human being is not static nor isolated, but rather dynamic, interactive, and complex.  To address these imminent challenges, I joined forces with Professor CK Peng and became the Associate Director of the Center for Dynamical Markers at Beth Israel Deaconess Medical Center.  Here, we utilize non-linear mathematical methods such as multiscale entropy, detrended fluctuation analysis, and Hilbert Huang transform to help identify the hidden signatures within physiological data.  We apply these tools to different states (sleep, exercise, and physical activity) and medical conditions.  In this role, I also mentor graduate students and post-doctorates from multiple disciplines: computer science, signal processing, engineering, and various medical specialties.      

     In 2013 and from this lab, we launched our entry into the XPRIZE Qualcomm Tricorder Challenge in collaboration with HTC in Taiwan.  CK Peng was the Team Leader and I was the Lead Medical Adviser for the group.  This experience was a highly enlightening one and was an important induction into the world of wearables.  It highlighted the supreme importance of “UX” (User-Experience) and also opened my eyes to the strengths and weaknesses of machine learning.   In my role, I guided the engineers and programmers on content-specific diagnostics and strategies.  Furthermore, I designed the AI diagnostic algorithm which provided the basic structure for the device’s approach to the User’s complaints.  Using a Bayesian approach, this algorithm prioritized which information was needed, determined what question should or should not be asked (and in what order), decided when to prompt the user to use a specific, confirmatory medical test(s), and calculated the final risks based on vital signs, demographics, symptom answers and confirmatory test data.   

     Ultimately, our team entered the finals for the competition, and we were the runner-up winners.  Our Tricorder activities continue till this day – some of which is being conducted at the UCSD Altman Clinical & Translational Research Institute as part of the Post-Prize activities.  Furthermore, realizing that the barriers to optimal utilization of wearable devices arise from insufficient data capturing/storage tools and from the unfortunate trend of larger corporations owning most of the data, we started a non-profit called PhysioQ - aimed to empower citizens to own their own wearable data and to ultimately enable individuals to lead and conduct their own scientific research.  This is an ongoing endeavor and one which, I suspect, may be a profound catalyst for scientific literacy and patient engagement in the future.

NATURE-INSPIRED DESIGN SCIENCES

     At this stage of my career, I have experienced enough mistakes and successes and have done enough soul-searching to recognize where my passions lie.  I know that I enjoy working across disciplines, studying the less explored, and making impact where possible.  And even though my research activity may seem disjointed and fragmented, there is in fact a unifying theme that forms a common thread through it all: and that is the deep-seeded conviction that at the root of natural dynamics and processes lie fundamental design-principles – blueprints, if you will – which form the backbone of what transpires in human and societal health.   

     This was (and is) the reason for my strong interests in ancient Chinese medicine/philosophy.  These ancient systems were predicated on the firm belief that certain design principles (e.g., yin/yang, five elements, and eight trigrams) pervade all of nature.  According to these principles, “microcosm reflects the macrocosm” and, as a result, generations of healers and masters focused on identifying the connections between patterns in nature and the patterns in the human body.  (Note, many other traditional systems have similar concepts: the Chinese did not have a monopoly on this).   

     The reason for my interests in bioelectrical mechanisms in living systems is because, from a design point of view, it is fundamentally logical.  The human body necessarily requires an information transmission system that operates at multiple temporal and spatial scales.  The chemical mechanisms (e.g. diffusion) operate at small spatial scales but larger temporal scales; electrical mechanisms operate at extremely rapid time scales (e.g., nanoseconds) and larger spatial scales; while mechanical mechanisms operate somewhere in between.  Each of these forces serve their specific roles and often operate in coordination with each other.  Importantly, each is best suited for a specific range of dynamics.   

     In my mind, it is no coincidence that electrical processes such as vascular streaming currents, Donnan potential forces across tissue compartments, or collagen piezoelectricity exist.  The reason these processes have been ignored thus far is because our medical science has traditionally emphasized mostly chemical ones.  But a design perspective reveals that chemical processes cannot single-handedly accomplish all the needed information/energy processing and that our understanding is thereby incomplete.    

     Finally, my interest in physiological signal analyses is based on the recognition that intrinsic patterns within the dynamics of biological systems exist: there are fractal dynamics across temporal scales; health is balanced between regularity/stability and flexibility/adaptability; and control mechanisms can be mediated via different resonant frequencies.  Basically, nature is eminently logical and certain design principles exist because they confer fundamental functions.     

     When I view my work from the perspective of “natural design sciences”, I realized that maybe I didn’t lack ‘focus’ all along.  Rather, maybe the research discipline which defined my ‘focus’ had not yet been established.  My research goal is to identify these design principles in physiology and nature, further characterize their dynamics, understand their functional role, and apply them in real life scenarios across medicine, organizations and social structures.  I have learned and continue to discover many things along the way, and this website is a medium through which I hope to effectively disseminate these learned lessons and insights.  I truly love what I do and look forward to joining many others in exploring the uncharted territories of health.