Acupuncture Today article #10

Molecular Motors: Tiny Machines Behind the Rhythm of Life

In the clinic, we aim to restore healthy patterns of movement for qi that has gotten trapped or misdirected, or may have even collapsed. We may be focused on freeing stagnation, releasing heat or redirecting counterflow qi, but it often comes down to helping re-establish a flow of sorts. Acupuncture is really about this movement, this flow, and shifting whatever might block it.

It may have been my acupuncture background that made the molecular motors of intracellular movement stand out to me when I began to study biology in earnest. Learning about the physical ferrying of information within cells actually took my breath away. Now there are YouTube videos in which artists have rendered approximations of what it would look like to encounter these parts of ourselves at our own perceptual scale.1

At the time I first encountered them, information about molecular motors existed in paragraph form in textbooks and in the minds of those researching them. A student could still get a vivid mental picture of innumerable tiny machines, purposefully marching and working at the cellular scale. It was more than enough to astonish, and capture the imagination of someone who’d been thinking about the equally mysterious movements of qi.

One of the most important things motor proteins do is move information. Much of the information within cells is written in the language of chemistry. Proteins, lipids, and carbohydrates are tagged and toted, carrying coded designators of what was happening in their immediate vicinity to the next location. These dispatches are read and responded to like letters from a far off family member: with care and precision.

molecule - Copyright – Stock Photo / Register MarkMotor proteins do the physical work of transporting the messages by traveling on a set of dedicated rails, shepherding materials and information in a complex dance. Even the rails, the basic infrastructure for messaging, are completely dynamic in cells. They assemble and disassemble as needed, sprouting new lines on which these little motors can whir and ride to where ever their cargo could help.

One of my favorite motor proteins to think about is named kinesin. This little machine specializes in moving material from the interior of the cell out to the periphery. For example, receptors bound for the cell surface are made in the depths of an organelle called the Golgi body. During the manufacturing process, new receptors are embedded into a patch of membrane.

When this section of membrane is fully loaded and ready to move to the surface of the cell, it pinches off and curls into a hollow ball called a vesicle, studded with newly made components. Kinesin then captures the vesicle and walks it to the cell’s outer membrane, which absorbs and integrates the new parts.

So, if a cell wants to become more sensitive to a certain kind of signal, additional receptors which recognize the signal are generated and kinesin moves them to their functional destination, facing the extracellular environment.

Likewise, if the cell has produced a communication signal, such as a neuropeptide, to be secreted into a synaptic space, kinesin will guide a vesicle full of the neurotransmitter to the correct port from which to release the contents.

By moving both the machinery of “cellular listening” (receptors) and the chemistry of “cellular speaking” (secreted signals), kinesin allows cells to be in conversation with one another.

In this era of smartphones and intense connectivity, we can forget that communication often requires moving material and information from one physical location to another. Our cells remember this, though, and do not forget to do the daily work it takes to keep information flowing.

Molecular motors also do much more than communication. Some types do the physical work of moving muscle fibers so that we can move as we choose. Some crawl along DNA so that it can be read or replicated by other specialized proteins. Some restock every conceivable kind of cellular building material, and others haul back any waste products for recycling. Some organize the complex process of cell division.

Within their world, molecular motors are the postal system, Amazon.com and the burly furniture movers.

For me, it adds something when I learn about the elegance, the faithfulness, the complexity, and the diversity of the players who ensure that movement is possible within any living cell. It adds a bit of appreciation, of more specific gratitude for the opportunity to help guide movement with carefully placed needles.

To lean over a patient’s body on the treatment table is to lean over a field of inconceivable motion, each body a thrumming, bustling, working world unto itself. Studying particular cellular components turned out to be one of the ways I could directly appreciate the subtle and robust beauty of life energy.

Reference

  1. https://www.youtube.com/watch?v=y-uuk4Pr2i8

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33272

Acupuncture Today article #9

Discovery: Finding Insights and Each Other in Different Disciplines

Recently I’ve been thinking about all sorts of things which are hidden from our daily direct experience. That general category is what links nearly everything that catches my attention and then demands some kind of investigation.

I’ve mostly written about the ways in which the mysterious worlds of acupuncture and molecular biology have informed one another in my life, but they are hardly the only topics that occupy the realm of the hidden. Everything from statistics to mysticism probably has a presence there.

A day in the life of a human is rich with experience, but also rather shockingly limited. We can only see and hear a small subset of the wavelengths which are passing by and through us. We tend to think in patterns of association that make it hard to absorb and integrate new ideas, even if we encounter them pretty directly. We suspect that there are structures underlying the realities we encounter, and pinwheel wildly trying to make mental models which will allow us to make predictions, to feel more informed and ready for life. At some level, we must know that we are operating at least partially in the dark. The beauty of this recognition is the capacity for deep curiosity, about the big questions of why and how, applied to everything.

When curiosity gets connected to rigorous observation, astonishing things can happen. In the case of acupuncture, a network of otherwise invisible interactions was meticulously mapped. That allowed the knowledge to be organized and passed from person to person through the practice of study. It made the previously uncharted pathways, now known to us as meridians, available to direct experience where they were once concealed. A skilled acupuncturist can even introduce a reluctant patient to their own direct experience of these pathways, so that needling creates sensations of heat, or flow, or release. This is a phase shift, where a once-hidden structure is made part of direct human experience through the process of curiosity, then observation, then learning, then skill.

I have a very clear memory of the first time I reproduced the correct needing sensation in a patient after my teacher had demonstrated a certain technique. There was a delighted sense of being very close to the divide between the hidden and the known. I was bringing an underlying structure up to the surface in order to interact with it, on purpose and with intent. Next to this moment I hold a memory of looking at a computer screen. I was now a decade older, hundreds of miles away, and had a few extra degrees under my belt. I’d placed a fluorescent signal in living cells and a microscope watched them, sending the picture to the screen where I watched in turn. I could actually see the light of my signal as it was moved through the inner workings of a cell, answering a question I’d had about intracellular traffic. It was another previously invisible structure made part of my direct experience. It can make a person woozy, to be this close to encountering something that was hidden until that moment, perhaps just hidden for you or perhaps heretofore hidden from everyone.

These are just a couple of my specific experiences with encountering something mysterious in the midst of what I was doing in my chosen fields. I mention this parallel in my life to make this point: engaging with the unknown is part of the human endeavor.  This impulse to inquire into what forms, defines, and invisibly undergirds our daily reality shows up in every possible setting.

It can give a scientist the drive to set up one more experiment, an acupuncturist the motivation to learn the best needling techniques, a farmer the faith to see a crop in a bag of seed, a mathematician the focus to pull meaning out of a jumbled data set, a meditator the patience to outwait mental noise and see something deeper and quieter. While different people are most attracted to different leading edges of inquiry, many kinds of seekers are in this together.

The subcultures that divide such explorers continue to be a problematic. I have only encountered one scientist who outright laughed out loud at the mention of acupuncture, but I also haven’t gone out of my way to bring it up. I’ve known my share of holistic-minded people who are similarly strident in their dislike of Western medicine. Even within the Western tradition, basic scientists and clinicians can struggle to communicate across the divide between their worlds. Whole groups of people can be effectively hidden one from another, separated by foundational beliefs, priorities, and jargon. It’s another instance of something of value being hard to perceive without the right tools or knowledge base.

So, the first challenge may be to encounter something hidden and savor the discovery. The second challenge is to find a way to share it, and a critical step is organizing the information and insights to facilitate their transmission. As acupuncturists, we reaped the rewards of others meeting this challenge when we went through our training programs, when we absorbed an entire conceptual universe and learned to navigate inside of its rules, defined by polarities of excess and deficiency, yin and yang, flow and counter-flow. These lessons were available and coherent because people made discoveries and then organized them into systems over centuries.

The third challenge is one that invites all trained practitioners of any tradition. It is the work of translation. Translation between cultures happens any time there is dialogue between a practitioner and a patient, a popular press outlet, a clinician with a different training background, a researcher. (The current effort to translate acupuncture practice into the billing code language of hospitals is also an example.) Translation between cultures is one way to make sure that working knowledge doesn’t get functionally re-hidden, buried in esoteric practice or specialty journals. The emerging models of integrative medicine are an especially encouraging development on this front. Hopefully, they will support a robust system to value, synthesize, and use discoveries currently held by disparate professional cultures.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33237

Acupuncture Today article #8

Immunotherapy: Where Molecular Medicine Crosses Into Holistic Thinking

Immunotherapy, and its promise as a cancer treatment, has been in the news a lot in the last few years, and for good reason. Real shifts are happening in oncology and exciting researchers, clinicians, and patients.

It can be challenging for the casual reader to get a clear picture of immunotherapy because the term can be found in reference to different treatment paradigms. Occasionally, this will just mean a treatment given with intent to activate the immune system. In that regard, anything that is immune supportive is immunotherapy.

Recently, immunotherapy has come to refer to one of two distinct treatment approaches. One is a refinement of the long-standing practice of targeting cancer cells, but using tools cribbed from the immune system. Another idea referred to as “immunotherapy” does not target the cancer but rather impacts the patient immune system quite directly, a radical departure from historical treatments. Both offer new opportunities to move oncology toward personalized medicine, a foundational value of TCM.

Immunotherapy: Where Molecular Medicine Crosses Into Holistic Thinking - Copyright – Stock Photo / Register MarkBackground

The usual treatments for cancer are fairly blunt instruments directed against renegade cells. Surgical excision and radiation are obviously aimed directly at the malignant mass. Chemotherapy typically does the most damage to rapidly dividing cells which have lost some of their quality-control mechanisms, and this winds up affecting cancerous cells more than healthy cells overall. Still, the goal is to attack the cancer with as much ferocity as the rest of the body can withstand. The organizing philosophy has been to name the enemy “cancer” and declare war. This approach has rallied policy makers, researchers, and funding bodies to focus resources on a very difficult problem, and in that way it has been effective. However, the word “cancer” has some limitations as a clinical term.

“Cancer” only means that some cells are multiplying out of control and have acquired the ability to invade other tissues. That is the observable behavior arising from an underlying dysfunction. The word cancer is often used as if it describes a disease, but it really only describes the basic sign/symptom of uncontrolled cell replication. As is true for any sign or symptom, cancer can arise from very different underlying problems. Like an emergency room doctor must determine if a patient’s shortness of breath is from anxiety or from a heart attack, and like an acupuncturist must determine if insomnia is rooted in a deficiency or excess pattern, practicing oncologists are beginning to ask questions about what is behind the presentation of cancer.

The science of biomarkers charted the first steps toward making this question a real part of clinical practice. We now know of many different pathways to the state we call cancer and can test for them. Did the cell start producing too many receptors for growth signals, effectively locking itself into an eternal state of growth? Did a mutation cause a receptor to be locked into the “on” position, whether it was being signaled or not? Did the cell lose one of its DNA proofreading proteins? The more we can diagnose the specific underpinning of each person’s disease, the more targeted treatment can be. Immunotherapy has played an important part in this shift. Its contribution has been to harness an aspect of the immune system to target the disease drivers, which may vary from person to person, from cancer to cancer.

Immunotherapy Basics

Immunotherapy simply refers to using antibodies as the active agent in treatment, rather than a chemical or knife or radiation. Antibodies are proteins which each have a specialized binding surface which will adhere to a specific target. Normally, they are made by a subset of immune cells (B cells) and attach themselves to materials which have been identified as foreign or abnormal in some way. They can also be generated in laboratories, however, and this is the heart of immunotherapy. A typical scenario is: a tumor is found to have overexpressed a growth receptor, so that all its cells are absorbing too many growth signals, fueling the problem. These receptors are a normal constituent part of the body, so the immune system would not see them as anything to attack. Lab-grown antibodies can be infused, which will find the problematic receptor and effectively coat it. The antibodies will “jam” the receptor’s ability to receive signal and also alert the patient immune system to focus on the tagged material. This is the exact clinical picture for a breast cancer patient with HER2 positive disease. HER2 is a growth factor receptor and Herceptin is the name of the most common immunotherapy used to address its overexpression.

Each tumor has its own fingerprint of aberrant genes and this fingerprint changes over time as additional mutations accumulate. Not only does every person have an individual pattern driving their disease, but that pattern is a moving target. This perspective is a given in acupuncture, where each patient’s symptoms are seen as arising from an underlying dynamic pattern. Immunotherapy is helping Western medicine to see and address the personal and evolving nature of disease.

Immunotherapy Revolution

Immunotherapy has recently made a leap that is qualitatively different from the treatment model of targeting cancer cells. It still makes use of antibodies, but instead of homing to targets on cancer cells, the antibodies coat a key portion of immune cells. This treatment coats receptors on T cells, the attack cells of the immune system. The twist is that these antibodies coat a receptor which accepts inhibition signals. When inhibition signals can’t reach the receptor due to this coating, the cell is locked “on” and is free to attack at will. It is actually an end-run around cancer cells who, craftily, often churn out signals just for such inhibition receptors on T cells. This may also be a treatment strategy that acupuncturists can relate to. It can be thought of as a tonification approach, where bolstering a patient’s native healing system is a key component of therapy.

Where antibody-based therapies are concerned, cancer researchers are just getting started. Most treatments are still in trials, with only a few in standard, first-line use. The recent explosion of interest does suggest that there may be a new era coming in cancer treatments, one whose philosophy includes some very old wisdom.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33212

Acupuncture Today article #7

Energy: For Life and For Death

Energy is a deep topic in Traditional Chinese Medicine. Qi is understood to underlie all of existence, animated or not, and the qi of the living is studied with special attention. Our bodily qi is most often named according to either its originating location or its function: liver qi, defense qi, grain qi, kidney qi… the list is nearly endless. This background prepared me for the bewildering variety and complexity of cellular biology when that became my focus.  One thing it did not conceptually prepare me for is a phenomenon called apoptosis. Yet, it is a physiological imperative and an important part of balance and health. Apoptosis is a form of cell death, one that is executed with care and organization in order to serve the whole body. A cell dying via apoptosis requires energy to do it properly; it is an investment of something we might call death qi.

Cells undergo apoptosis for many reasons. For some, it is the natural end of their cellular life span and was programmed in from the beginning. One example from developmental biology is the loss of webbing that we had between our forming digits. That most people are not born with webbed fingers or toes is because those structures were pruned away through apoptosis. In other cases, a cell gets damaged and senses that it is no longer running correctly. That cell may take the last energy that it has and implement this self-destruct program. Then, the DNA of that cell is compacted down to tiny packets. The structures within the cell start dissolving and leaking. The cell membrane starts to stretch and pucker with the eventual result being that a small colony of small, round, sealed bubbles of slurry take the place of the former cell. These bubbles of debris can then be easily cleaned up by circulating immune cells called macrophages without compromising neighboring cells.

Energy: For Life and For Death - Copyright – Stock Photo / Register MarkWhen the apoptotic response fails, it can throw the entire body into danger. The quintessential example of this is cancer. Cancer cells are clearly operating outside of normal parameters and their internal surveillance should trigger an apoptotic response. Failing that, some immune cells are able to recognize faulty or mutated cells and to send those cells clear directives to apoptose. If either system catches the problem, if the self-destruct impulse or the direct command to apoptose from the immune surveillance squad gets a dangerous cell to trigger the program for cell death, the person whose body is doing this quality control will never be aware of the problem or its solution. In point of fact, this is standard operating procedure and every reader of this column has benefitted from this system many, many times over. For every person, some portion of qi has been diverted to actively manage cellular deaths.

Naturally, it will not surprise holistic health professionals to learn that there is a balance between life and death, down to the cellular level. I have to confess that I was surprised to learn just how integrated the molecular machineries of life and death are. The apoptotic process is executed by a group of proteins that perform the specific tasks required to re-package a cell into contained, digestible bites. The most commonly discussed group of apoptotic proteins are called caspases; there are several varieties which are stationed at specific positions within the cell. For example, caspase 8 resides near the inner surface of the cell membrane, while caspase 3 acts in the nucleus. It would be reasonable to assume that apoptotic proteins are generated when needed, as part of an injured cell’s last efforts, but this is not the case. The proteins required to perform cell death are present all the time and are held in check by another group of proteins, collectively known as anti-apoptotic proteins. Further, these anti-apoptotic proteins have rather short half-lives, meaning that they are degraded and replaced quite quickly as part of normal cellular metabolism. Caspases, on the other hand, are longer-lived proteins. The practical effect of this system is that the death program is in place and ready to go if there is an interruption in the production of anti-apoptotic proteins.

The integrated nature of programmed cell death does have a certain logic. This is one built-in method to make sure that a sick cell will “take itself out” if it is too impaired — when things start to fall apart, the apoptotic proteins will emerge from behind their inhibiting partners and do their work. The embedded death program is also beneficial when a cell is identified as dangerous by the circulating immune surveillance system. The apoptotic program is already installed in the problematic cell and just needs to be activated by an alert immune cell.

The apoptotic program has been conserved across evolution and this suggests that there is a practical advantage to maintaining the capacity for cellular suicide. The example of cancer is a stark example of how this capacity can be life-saving for us. Strangely, though, it isn’t only multi-cellular organisms who harbor this machinery. Even bacteria have a version of programmed cell death. It’s a little counter-intuitive to consider a single cell organism’s interest in managing its own death. However, once bacteria have multiplied into a colony, they acquire some habits which protect the colony’s well-being over the individual. Even at this scale, the machinery for death is part of life. It may be that a fundamental part of healthy continuity includes an investment in needed deaths, in the responsible winding down of what is no longer working. The cellular wisdom is that the application of “death qi,” when mustered to cull unhealthy components of a system, serves living qi in all its myriad forms.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33193

Acupuncture Today article #6

Models: The Value of Using Conceptual Maps

When I was first learning about five phase theory, during an independent study class in college, I was also taking a microbiology course. Over the course of the semester, I was increasingly mesmerized by the elegance of each approach to understanding health and disease.

It also seemed that these two ways of understanding were based on such divergent principles that it would be hard to really get them to “talk” to one another. Frankly, it seemed like an irresistible challenge. Fast forward twenty years, and this column is my small way of contributing the dialogue. I’ve been both an acupuncturist and a scientist and continue to value both worlds. Some themes cross over naturally and some are harder to translate, but I hope to share some of the moments of connection I’ve seen.

Traditional Chinese Medicine practice is a science of homeostasis. Thousands of years of empirical observation have charted the physical pathways and energetic currents that undergird a state of balance or of disease. A similar undertaking is happening right now in laboratories all over the world. Researchers are trying to see, understand, and communicate the interior map of the cells which make up the larger bodily context already described in TCM.  The relational diagrams that these researchers produce are thematically quite different from the ones used in TCM. As a general rule, new cellular information is presented in graphics which look rather like wiring diagrams, zoomed in to detail the specific relationships being discussed in each paper or presentation. That may reflect something about the culture doing the investigation — this is a science of mechanism. As a result, it leans toward linear graphics rather than the circular, sweeping graphics of five phase theory. As is often the case, being able to look at the same information represented in different ways can be a wonderful tool to see new angles, new possibilities. As an example, I’ll discuss my personal favorite protein in the body: a little gem called elongation factor 2 (EF2).

Models: The Value of Using Conceptual Maps - Copyright – Stock Photo / Register MarkFigure 1: Representative Biomedical ModelOne of the fundamental processes of life is the translation of information stored in DNA into material form. The DNA must first be transcribed into a portable copy made of RNA. The RNA is then fed through a ribosome, which links amino acids together to create a protein version of the RNA strand. There is a single protein which does the work of moving each amino acid along once joined, clearing space for the next to be recruited. Without this protein (EF2) no other protein can be manufactured. Its regulation is a complex web, requiring many kinds of information about the state of the cell to be integrated. One way to describe this is shown in Figure 1. It is a typical mechanism graphic, such as might be found in current scientific literature, showing activating forces as arrows going in the direction of action. Inhibiting forces are shown as lines ending with a perpendicular line segment. This is a fairly clear way for researchers to summarize a set of relationships, isolated away from larger context.

Models: The Value of Using Conceptual Maps - Copyright – Stock Photo / Register MarkFigure 2: Five Phase VersionAs someone interested in the sciences of both mechanism and homeostasis, I find myself playing with this form. Because it facilitates making the material version of information, EF2 strikes me as playing the role of spleen/earth inside of the cell. That places its inhibitor, a protein called EF2k, in the role of liver/wood and its activator, the protein PP2A, in the role of heart/fire. The other types of cellular information graphed in Figure 1 can slot into the rest of the five phase positions with surprising ease. DNA replication occurs during the S phase of the cell cycle this duplication of inherited material would easily sit in the position of kidney/water. Influx of external calcium and oxygen would both fall into the role of lung/metal as it is the guardian between inner and outer worlds. Diptheria would certainly qualify as an exogenous evil. If the same players are mapped to the five phase model as shown in Figure 2, many additional connections are hinted at which Figure 1 does not suggest. The arrows shown as solid in Figure 2 are those which have a correlate in Figure 1. More intriguingly, arrows in Figure 2 with a dotted motif, either in the outer sheng cycle or the inner ke cycle, are simply shown to complete the relationships that five phase theory would suggest would have to be in place for homeostasis to work.

Whereas Figure 1 does not suggest where additional interactions may be happening, or may even be needed, Figure 2 has a number of those dotted lines, which suggest that certain players may have some relationship that is as yet unknown but may be needed to stabilize the system. As it happens, when I was working with EF2, I came to study it in a slightly unusual way. I was working with several other proteins and noticed that there must be something, some X factor I didn’t know about, that was acting my system. I could define exactly what it must be like in order to explain my observations, and went looking for something that matched the description of my X factor. This is the kind of thinking that alternate models can really help with; their structure can hold a place for where some unknown entity or relationship might need to be.

Of course, there may sometimes be no one-to-one matching of a particular biological mechanism to five phase theory, but this example demonstrates that keeping multiple models in mind can help keep us open to the cross-pollination of ideas and resulting insights. Figure 2 as presented here would suggest some potential areas for research and, in fact, many of the dotted lines represent relationships under investigation. Despite differences in training, philosophy, and methodology, practitioners of traditional medicine and current day researchers do share fundamental interests and do have opportunities to share their knowledge across conceptual divides.

Reference:

  1. White-Gilbertson S, Kurtz DT, Voelkel-Johnson C. The role of protein synthesis in cell cycling and cancer. Mol Oncol. 2009 Dec;3(5-6):402-8. Review.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33179

Acupuncture Today article #5

Mechanism: Experimental Approaches to Understanding Acupuncture, Part 2

Biomedical research takes for granted that the best way to cleanly and rigorously study any phenomenon is to experimentally isolate it, something which has proven to be difficult in clinical acupuncture studies.

For example, the problem of how to create a sham acupuncture treatment has troubled researchers for decades, on both sides of the acupuncture/allopathic divide. The complex experimental system embodied by any patient synthesizes responses to a wide array of experiences; definitively creating a control acupuncture experience for such a complex system has been challenging. However, thanks to the flexibility and sensitivity of available tools, today we can study a simple cellular response to acupuncture. Reducing an experimental framework to simple cells could certainly strike holistic healers as absurdly disconnected from the energetic nuances of human health, and this is a valid concern. I’ll describe representative possible experiments here, and the information that could be obtained may appeal to the imaginations of people from diverse training and backgrounds.

One recent hypothesis about cellular response to acupuncture is the micro-damage hypothesis. This suggests that the mechanical stress of needle insertion and manipulation causes a signaling cascade inside the body.1,2 The micro-damage hypothesis indirectly references a fascinating aspect of cellular biology called “lysosomal exocytosis”. Lysosomal exocytosis is a cellular behavior I studied for a few years under the direction of Dr. Alessandra d’Azzo and I learned that this phenomenon is linked in some way to much of cellular physiology.3

Lysosomes are constituent parts of our cells, like nuclei and mitochondria. They are multi-functional but most commonly known for being the recycling center of the cell, where old or faulty components are sent to be stripped for parts. Thus, the interior of a lysosome contains a snapshot of how things are going for that cell. Is a certain class of protein being turned over at an increased rate? Has a certain protein failed quality control over and over? Lysosomes are charged with processing such proteins. This normal duty is interesting enough but under micro-damaging circumstances, the lysosomal population can do a really amazing trick. Lysosomes rush to the site of injury, where a tear in the cell membrane has occurred, and they fuse their membranes to the greater cell membrane to create a patch.4 When their normal spherical shape is pulled apart to create a flat patch, the contents of the lysosomes get released into the extracellular space, spilling the most intimate information about that cell’s status. This capacity may mediate some of the body’s response to acupuncture, and some investigation could be done very directly.

It is fairly trivial to maintain a population of skin cells or connective tissue cells — or a blend — in a dish. Cells grown in the lab are bathed in a type of nutritious fluid called “media.” A population of cells that undergo micro-damage will likely, subsequently experience lysosomal exocytosis and information about the cells’ interior life will escape into the media. We now live in an age when this media can be collected and analyzed with incredible precision, helping us to understand the type of information released from cells. Additionally, it is possible to grow cells in stressed environments. They can be under-fed by using less nutritious media. They can be kept in a low-oxygen environment. Their media can be spiked with a wide assortment of drugs, both therapeutic and harmful. Any of these cell populations could be micro-damaged, even using a grid of actual acupuncture needles. If differently stressed populations release measurably different signals into the media, it would validate the idea that minimally damaging techniques can foster communication that describes cellular health.

The second step which would interest me would require an additional piece of equipment and one more ingredient, both easy to come by and work with in the lab. The equipment is a fine mesh. It supports an experimental design called a transwell experiment, and meshes of many varieties exist, allowing researchers to choose exact specifications for the mesh permeability. The needed ingredient is a panel of normal healthy blood cells, which can also be maintained in dishes in the lab. To assemble the experiment, simply micro-damage a group of test cells and then overlay the mesh. On top of the mesh, place the blood cells. Blood cells are able to squeeze through small openings when motivated; this is how an immune cell traveling through the blood stream gets past the lining of a blood vessel and finds its target in tissue. If micro-damaged cells are releasing interpretable information, blood cells above the mesh will respond and migrate toward the damage. A different variety of blood cells might even respond, depending on what sort of stress situation the cells are reporting, whether the cells are cold, or hungry, or drugged.

If we can study response from one bodily intelligence, in this instance the blood cell population, to a simple release of status information from cells in a dish, we could establish something basic, something measurable, on which to build further discussion and exploration. It could provide an empirical analysis of the information released by acupuncture and fuel desire to ask more integrated questions. What about anatomical and chemical networks make certain information releasable from particular point locations? For example, HT7 and PC7 are very close to one another on the inner wrist surface — does something about their position make them particularly relevant to emotional stability, a common application of both? Could cells at these positions store specialized information, or might they release their information into a local environment that has special sensitivity, or could a combination of these possibilities be in play? And how do different meridians link up into a larger network? Researchers who study acupuncture are in an exciting time. Work continues on understanding the whole organism response to treatment, even as approaches using cultured cells are becoming more productive and targeted. Along this experimental continuum, I hope that partnerships between researchers and practitioners will be naturally enriched, for the benefit of us all.

References:

  1. Langevin HM, Churchill DL, Cipolla MJ. Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture. FASEB J. 2001 Oct;15(12):2275-82.
  2. Langevin HM, Bouffard NA, Churchill DL, Badger GJ. Connective tissue fibroblast response to acupuncture acupuncture: dose-dependent effect of bidirectional needle rotation. J Altern Complement Med. 2007 Apr;13(3):355-60.
  3. Bonten EJ, Annunziata I, d’Azzo A. Lysosomal multienzyme complex: pros and cons of working together. Cell Mol Life Sci. 2014 Jun;71(11):2017-32.
  4. Jaiswal JK, Andrews NW, Simon SM. Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J Cell Biol. 2002 Nov 25;159(4):625-35.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33131

Acupuncture Today article #4

Mechanism: Experimental Approaches to Understanding Acupuncture, Part 1

The clinical benefits of acupuncture are difficult to ignore, but also can be difficult to explain to a Western audience. For nearly 50 years, relentlessly inquisitive scientists and physicians have been working toward a conceptual model to explain acupuncture.

This two-part article will offer an extremely abbreviated review of where research has been and where it may be going, offered as a possible starting point for conversations with interested patients.

In the interest of simplicity and focus, this overview will cover work addressing the question of how acupuncture works, not whether acupuncture works, an important separate area of research which often includes clinical trials. Here I will simply review the progress made toward understanding what happens during acupuncture. Work in this area typically begins by assuming that there is some measurable physiologic response to the treatment and designing methods to capture or modify that response.

Broadly speaking, a class of experiments was established in the 1970s and has been iteratively employed ever since. In this basic design, a specific acupuncture protocol and its measurable effect are the starting point. These systems often revolve around analgesia, as it is an established effect of acupuncture and easy to measure in animal models. The standard pain relief offered by acupuncture to some noxious stimulus is quantified and then experimental variables are tweaked to find out what can eliminate the analgesic effect. For example, endogenous opioids, those chemicals made by our own bodies which dull pain, were a natural target for such analgesic research. Investigators have created multiple experimental systems in which animals have a specific pain response and a predictable amount of relief from acupuncture. Then, researchers try different delivery methods and concentrations of a drug – such as naloxone – that blocks endogenous opioids. Some groups have observed that in the presence of naloxone, acupuncture loses its analgesic property, and they therefore conclude that endogenous opioids are part of the mechanism that mediates acupuncture’s effects.

acupunctre - Copyright – Stock Photo / Register MarkThis same basic design has been used to test the role of other signaling molecules (such as hormones) and the role of specific anatomical structures which can be selectively damaged in experimental settings to test whether acupuncture effects require those structures. As early as 1978, an excellent review by Sung Liao of the then-current research concluded that, “acupuncture involves both the nervous system and certain humoral factors,” meaning that both physical and chemical signaling networks were involved.1 This early research has been foundational to the field and consists of asking simple questions in complex systems.

As technology has evolved, new ideas have been applied to the question of acupuncture’s mechanism. These new approaches can be characterized as asking complex questions in complex systems. Instead of trying to experimentally isolate a single cause and its effect, these newer approaches take advantage of our increased ability to collect and analyze huge amounts of data. As a result, experimental questions have moved away from the form: “Does acupuncture require X to work?” And toward questions like: “What effect does acupuncture have on X?”

For example, a group might ask, “What effect does acupuncture have on brain activity?” and perform MRIs on patients during treatment. More open-ended questions are possible because we are now better positioned to analyze large amounts of information, look for trends, and put any findings into biological context. Brain activity is better mapped than ever before, as is the chemistry of intra- and extra-cellular signaling, and immunological cross talk with endocrine and neurological systems.

This new reality is referred to as the age of “–omics” in the biologic sciences. Proteomics, genomics, lipidomics, transcriptomics, and metabolomics are just a few of the words which have begun to make their way into the popular press from the expanding world of biology research. Each refers to a research method that captures a large set of proteins, genes, etc. and creates a profile or fingerprint. When a set taken from one condition is compared to a set taken under a different condition, we can begin to see how a whole population of biologic components shift and adapt to circumstance.

An example of this newer approach was undertaken within an established system of pain relief. In this investigation, the experimental groups consisted of normal rats, rats with a particular pain condition, and rats with the pain condition treated with an electroacupuncture protocol shown to reduce pain from that condition. Tissue samples from each group were analyzed for the expression of 8,400 genes, and a sub-set of genes was identified which was altered between normal rats and rats in pain, but which returned to normal expression levels post-acupuncture. Confirming earlier findings, the researchers found that expression of an opioid receptor dropped in the rats with pain but returned to normal levels after acupuncture treatment. In addition, 67 other genes were found to follow such a pattern of disruption in pain and restoration to normal with acupuncture treatment, suggesting a multi-factorial response to acupuncture.2

More complex questions have been running concurrently with the older model of research for the last 15 years or so, and today we have a staggering list of possible players in acupuncture’s mechanism. A recent review cites bioactive molecules in cerebrospinal fluid, blood serum, organs, and the acupoints themselves.3 Meanwhile, the acupoints and meridians have been studied as anatomical structures distinct from the nervous system. They are now sometimes thought of as being primarily composed of connective tissue, with the winding of this connective tissue around needles creating mechanical stress which activates surrounding cells to mobilize or signal more widely.4 As an example of the level of complexity emerging from this type of research, a recent paper utilizing this model of mechanical stress and subsequent chemical signaling was entitled, “Acupuncture modulates the neuro-endocrine-immune network.”5 In Part 2 of this article, I will explore some ways in which we could leverage our current knowledge and methods to ask complex questions in simple systems, a relatively unexplored possibility for acupuncture research, but one that holds a particular interest for me since I was trained to do research at the level of cells rather than on whole organisms.

References:

  1. Liao SJ. Recent advances in the understanding of acupuncture. Yale J Biol Med. 1978 Jan-Feb;51(1):55-65.
  2. Ko J, Na DS, Lee YH, Shin SY, Kim JH, Hwang BG, Min BI, Park DS. cDNA microarray analysis of the differential gene expression in the neuropathic pain and electroacupuncture treatment models. J Biochem Mol Biol. 2002 Jul 31;35(4):420-7.
  3. Wang Y, Yin LM, Xu YD, Lui YY, Ran J, Yang YQ. The research of acupuncture effective biomolecules: retrospect and prospect. Evid Based Complement Alternat Med. 2013;2013:608026.
  4. Langevin HM, Churchill DL, Cipolla MJ. Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture. FASEB J. 2001 Oct;15(12):2275-82.
  5. Ding SS, Hong SH, Wang C, Guo Y, Wang ZK, Xu Y.Acupuncture modulates the neuro-endocrine-immune network. QJM. 2014 May;107(5):341-5.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33109

Acupuncture Today article #3

Help: A Need at Every Level

One of the great gifts of training in acupuncture is the ability to take good care of oneself. I recently had a bout of frozen shoulder — an inflammatory syndrome which can be debilitatingly painful and take years to resolve.

Luckily, I figured out what was happening quickly and started needling nearly every day. Sometimes the needles were placed locally, but often distal points were needled to help pull heat away from the painful site. Some mornings, as soon as I woke up, I could feel the overwhelmed LI 11 points, asking for attention. I’m convinced that acupuncture played a key role in allowing me to fly through the acute stage in about a month and arrive on the other side of frozen shoulder in about six months.

When a patient has become knotted in some unhealthy way, be it frozen shoulder or any other pathology, the work of the acupuncturist may be much more subtle than pounding out the knot. The patient’s whole system may need adjusting, perhaps with a push or pull at quite a distance upstream or downstream from the presenting complaint. It’s not uncommon for a patient to ask why needles would be inserted close to their knees for a digestive symptom. But, when ST36 is employed correctly it helps to un-knot the whole person and improved digestion proceeds naturally from there. This healing art of re-shaping a system so that a healthy conformation can emerge is a marvelous gift, and it is a dynamic we depend on both for healing our diseases and for our foundational health at the cellular level.

back acupuncture - Copyright – Stock Photo / Register MarkThere is a whole family of proteins who populate our cells and whose explicit job is to shepherd other proteins through the process of attaining their healthy shape. These helpers are called chaperone proteins, and the proteins they help are referred to as their client proteins. Like patients in an acupuncturist’s office, client proteins may face a number of challenges in their quest to achieve a healthy and functional state.

When proteins are initially assembled, individual amino acids are linked together in a long chain which must fold into a very specific final shape in order to function. Depending on which amino acids are present at any given point in the chain, different properties arise locally. For instance, some amino acids carry a positive charge. A long stretch of these amino acids will make that section of the original string strongly positive, and it will tend to lean toward any negative charge it encounters. There can certainly be a stretch of negative charge elsewhere in the same string, making the protein inclined to bend and hold its negative and positive parts together. What if this would destroy the proper conformation? Imagine another scenario: two distant sections of the chain have to be linked together in order to form a little pocket which is critical to the protein’s eventual function. What will guide those two sections toward one another in a targeted way? The plain fact is that without chaperone proteins, there are client proteins which would never fold correctly — there are too many other, easier conformations to fall into left to chance. Left to themselves, the client proteins would become knotted, dysfunctional, or even pathogenic. Only the targeted care of a chaperone protein allows them to achieve an ordered state.

One chaperone protein with which I have some personal experience is called gp96/GRP94. The name is not inspiring, but its performance truly is. Its clientele includes proteins needed for a wide array of basic cellular function and immunological response. Quite simply, without gp96 none of us would be here; the lack of gp96 is incompatible with even embryonic life. I studied this protein under the direction of Dr. Bei Liu, and recently the two of us were in conversation about some of the mysteries which are still left to solve about this important protein.

At an exacting molecular level, work continues on trying to see the exact way in which the chaperone binds to its client protein, how it guides the client into the correct shape, and how it powers the whole interaction.1,2 Some of these questions have been answered in general for chaperone proteins, and there may be wisdom to be found in how they operate. Chaperone proteins themselves have multiple conformations, and for the purposes of this brief introduction we will look at two. In addition to the chaperone and the client, there is one additional critical component for the work which needs to be done: an energy source. Like most cellular functions which require work, chaperones are powered by the internal currency of the cell, a little energy “pellet” called ATP. When chaperones are ready for a client, they assume conformation 1, opening a slot to take up both an ATP and a client. Once the power supply and client are in place, conformation 2 clicks in and the client is bent as needed. Doing the work of caring for a client burns the ATP and the chaperone then releases both the spent ATP and the newly folded client. The chaperone resets to conformation 1. This is true every single time. The chaperone meets each client fully powered because it re-charges for each interaction. In this way, the chaperone does its critical work without being exhausted.

The chaperone proteins don’t have a choice; they physically can’t engage with their clients without re-powering. On the other hand, health care professionals attempting to guide patients into healthier states can easily out-work power supplies and neglect to re-charge adequately. The built-in sustainability of chaperone proteins is a comfort, considering the degree to which life depends on their function. It may also be a kind of allegory, a molecular meditation on the importance of being a helper and the importance of caring for oneself in order to help others.

References:

  1. Dollins DE1, Immormino RM, Gewirth DT. Structure of unliganded GRP94, the endoplasmic reticulum Hsp90. Basis for nucleotide-induced conformational change. J Biol Chem. 2005 Aug 26;280(34):30438-47. Epub 2005 Jun 11.
  2. Marzec M1, Eletto D, Argon Y. GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta. 2012 Mar;1823(3):774-87. doi: 10.1016/j.bbamcr.2011.10.013. Epub 2011 Nov 3.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33086

Acupuncture Today article #2

Desert: A Metaphor from the Study of Genetics

In most of the human lives I know about, there are stretches of time which feel stagnant, or worse. We can feel adrift, or wounded and sidelined, and these times don’t seem to carry much usefulness while they are unfolding.

These same passages through difficult days often wind up being pivotal in some way for our development, although it is only retrospection that allows us to appreciate that a depression or heartache has influenced the more engaged and lively periods afterward.

How many of us can trace some impulse of compassion to a remembered time when we were suffering? How many of us needed some event to slow us down so we could hear something important from within our own hearts? Recently, I’ve been thinking about how many times I’ve undervalued an experience, or idea, or piece of advice along the way. The musing was triggered by a seminar I attended recently which included a presentation on breast cancer genetics. During the talk, I noticed that something has changed in the terminology used by geneticists in recent years.

DNA is often referred to as the instruction book for how to make an organism. It contains the codes for how to assemble proteins, information which is held in genes. There are also long stretches of DNA that do not code for protein. As these sections did not do the job that had been established for DNA, such regions were referred to as “junk DNA” for many years. It slowly began to emerge that these regions did perform functions, often having to do with providing a physical scaffold on which to assemble machinery to copy the DNA instructions.

Over time, DNA that did not contain genes became known as, “non-coding DNA.” This is an improvement over “junk DNA,” although it still defines the region by something it is not. As research progresses, more information and significance accrues to these areas. It turns out that important regulatory functions reside in non-coding DNA, with real consequences for health. Even genes which are coded perfectly will fail us if the regulation of their expression is faulty, and such vulnerability would be found in DNA which surrounds a gene rather than in the gene itself.

Most recently and rather evocatively, I’ve begun to see the term “gene deserts” applied to particularly extensive stretches of non-coding DNA. While still defining the areas by their lack of genes, the “desert” term appeals to my imagination. Long stretches without obvious meaning which nonetheless shape the outcome of the whole … this image brings back memories of times in my life which have felt meaningless and turned out to be vital, even foundational. The term “desert” captures that sense of wilderness, of not knowing how to find one’s bearings but sensing that there is something there to know, something that does not give up its secret meaning immediately.

The shift in the language of genetics made me smile. It is so predictably, fallibly human to discount the value of anything we don’t have a name for, a schematic for. Again, my training in acupuncture prior to molecular biology came to rescue my perspective as this basic error is not as built into holistic thinking. In acupuncture, we look at meridians, which have long stretches unpopulated by the named points that we memorize and work with. Yet, there is no tradition of calling the space between Large Intestine 11 and Large Intestine 10 “junk meridian.”

Someday, there will probably be no place for the term “junk DNA” in biology. In the last year, research from a genetics group in London demonstrated that gene desert DNA physically influenced genes residing millions of base pairs away. The contorting of a DNA strand to make these connections is perhaps counterintuitive, but a reminder that even those parts of ourselves that we believe to be linear are actually much more complex and more interconnected than that. Even if two pieces with functional linkage are separated by apparently meaningless material, they may actually require enough separation that one piece can make the curve, double back, and connect to the other at just the right times. It’s built into this model that even if the significance of non-coding DNA is fully described, some of it may exist to facilitate the function of other sections, the flashier parts which seem at first glance to be where the meaning resides.  But in DNA, as in life, there is meaning to be everywhere. The holistic approach to health and disease does not find this surprising.

Reference:

  • Dryden NH1, Broome LR1, Dudbridge F2, et al. Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C. Genome Res. 2014 Nov;24(11):1854-68. doi: 10.1101/gr.175034.114. Epub 2014 Aug 13.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33051

Acupuncture Today Article #1

Breath: The Movement of Oxygen and Energy

I remember with surprising clarity the first time a patient started crying during an acupuncture treatment I was giving. This is now quite a long time ago, back in 1999, when I was a student.

I had just needled Lung 7 on her right wrist and looked up to see that her eyes were full of tears and, it seemed to me, a question: why is this happening? I thought for a moment and then said, “The needle I just placed is in the lung meridian. That particular meridian has the special job of processing grief. Is there any chance it might be especially sensitive or might need extra support today?” No acupuncturist will be surprised to learn that there had been significant sadness in my patient’s life recently, a troubling family matter that weighed on her. She would, indeed, be appreciative of any directed support I could work into her treatment.

I no longer remember the rest of the appointment, and the countless number of times I’ve had a variation on that conversation have blended together to such a degree that I don’t think I could recount any others with such specificity. That first, right wrist, though? It has stayed with me. My guess is that, as was my habit in those days, I probably offered this patient an image to consider during needling and that image probably involved breathing in a color or temperature that would support her overall treatment, intending to gently blow some of the lung’s resonant energy into her rough and hurting places. Lung, air, grief, breath: these are deeply connected concepts in acupuncture practice.

Molecules and Meridians

Since I left practice to become a molecular biologist, I’ve learned many strange and wonderful things about cells. When I am navigating my own times of grief, of held breath, the imagery that rises is now informed by both my acupuncture background and the knowledge acquired over many years of biomedical classes and research. The journey of air through the lungs, into the bloodstream, and finally into every cell is an especially rich story.

A little background is in order, but anyone who has built a sandcastle or saved for a vacation will quickly understand the principle at work: small, low energy efforts can build something quite amazing if those small efforts are allowed to accumulate. In the case of the cell, a series of proteins embedded in the inner membrane of mitochondria patiently and cleverly execute a single difficult task. The proteins each use a tiny amount of energy to move protons to a designated holding area. Energy has to be invested in order to continuously pump protons to an area that is already teeming with them. As the protons accumulate, the natural tendency is for the protons to flow away from this area of overpopulation and the cell provides one doorway in order to create a river of protons, not unlike the flow you would see if the Hoover Dam sprouted a single culvert in its vertical surface. This flow is the sandcastle, the savings account that the cell has meticulously created with relatively small efforts: move one proton, move two protons, don’t stop. The result is a mechanical force that can run a tiny molecular turbine. It’s worth taking a moment to let that settle: the proton “river” does not metaphorically turn an axle; rather, it quite literally does this in every cell, every minute. This mechanical power source is critical for making the chemical energy that allows us life, and oxygen plays a key role in maintaining the power source.

Much of the oxygen we breathe finds its way to this workstation of the mitochondria. There is a specially carved place for the oxygen molecule to land in a protein called cytochrome C oxidase. This protein is the anchor in the relay team that creates the proton storehouse. As the final player, it falls to cytochrome C oxidase to make sure that the important process leaves no harmful by-products. The cell offers an excellent example for us here, as it strives to ensure that no industrial waste is associated with generating its power supply. The possibility of such contamination is real; the energy that moves the protons involves a complicated dance of passing electrons from one pumping protein to another and these electrons can hardly be left to wander unsupervised after passing through the gauntlet. Instead, the electrons are combined with protons which are allocated to cleaning up rather than being pumped into the proton warehouse. In cytochrome C oxidase, the protons, electrons, and molecular oxygen are combined.

Elegantly, safely, and neatly, the final product released by cytochrome C oxidase is two molecules of water for every molecule of O2. Should this reaction be stalled, the entire relay team of proton-pumping proteins will back up and eventually grind to a halt, and the river of protons will dry up. It is at this deep, cellular location that oxygen does its magic and it is to this level that breath is drawn.

Breath turning to water is already a respected concept in Chinese Medicine, particularly in the Five Phase school of thought where lung energy nourishes the kidney element of water. As the kidney meridian is charged with processing the emotion of fear, any activity that nourishes both lung and kidney has wonderful potential for our lives. The deep and steadying breath we have all taken in some difficult moment unlocks energy and buffers fear energetically, chemically, physiologically.

Oxygen allows the energy-making machinery of our cells to whir along, and part of that process is actually making pure water appear from a protein that would otherwise be stuck. It is the exact opposite of rust, that combination of moisture and machinery that results in any bike left outside for too long fusing its chain and gearing. In the body, instead of water turning a mechanism stiff and brittle, water flows out, leaving behind a sparkling flexibility. This is a very different image than the one I might have considered in 1999, but one I appreciate carrying with me now.

http://www.acupuncturetoday.com/mpacms/at/article.php?id=33036