Being of a curious mind, I am occasionally fascinated by simple things such as the phenomenon of cracking knuckles. In this respect, I have done some very basic research regarding this phenomenon and have been repeatedly disappointed by the explanations presented on nearly every web site I have seen that attempts to describe the process in question. There are many physiological reasons that our joints make noise, but the description of at least one of these processes is always, well…not what it is cracked up to be.

Specifically, virtually every web article mentions “cavitation” as the primary cause of the sound that accompanies knuckle cracking in our finger joints, but in almost every case they go on to describe cavitation incorrectly, or propose a scenario that has little, if nothing, to do with cavitation. Here, for example, is an excerpt from the article on knuckle cracking at HowStuffWorks.com (italics added):

“If you’ve ever laced your fingers together, turned your palms away from you and bent your fingers back, you know what knuckle popping sounds like. Joints produce that CRACK when bubbles burst in the fluid surrounding the joint.

Joints are the meeting points of two separate bones, held together and in place by connective tissues and ligaments. All of the joints in our bodies are surrounded by synovial fluid, a thick, clear liquid. When you stretch or bend your finger to pop the knuckle, you are causing the bones of the joint to pull apart. As they do, the connective tissue capsule that surrounds the joint is stretched. By stretching this capsule, you increase its volume. And as we know from chemistry class, with an increase in volume comes a decrease in pressure.

So as the pressure of the synovial fluid drops, gases dissolved in the fluid become less soluble, forming bubbles through a process called cavitation. When the joint is stretched far enough, the pressure in the capsule drops so low that these bubbles burst, producing the pop that we associate with knuckle cracking.”

(http://health.howstuffworks.com/question437.htm)

The above excerpt is typical of the hundreds of articles about knuckle cracking, and the fact that no one questions this description of the cavitation process is tragic. In a closed system such as the synovial capsule of a joint, this description makes absolutely no sense. Why? Because these gas bubbles simply cannot burst! Gas bubbles created in a liquid under negative pressure do not pop like balloons, or soap bubbles in the air, no matter how low the fluids pressure becomes. To say they “burst” is to say that they somehow cease to be bubbles and become re-dissolved in the surrounding liquid. This defies the laws of physics, at least as I understand them. Balloons and soap bubbles burst because the material of the bubble/balloon eventually ruptures and fails. Gas bubbles in a liquid have no such container. They simply cannot “fail “ to be bubbles.

In such a system, the only things that individual gas bubbles can do is:

1.) Get bigger (take up more volume) when pressure is further reduced. (Note: This produces no sound whatsoever.)

2.) Combine with each other. (Ahh, now it can be argued that small bubbles “burst” in a fashion as they combine with larger bubbles, but this does not accurately describe the knuckle-cracking phenomenon. Think of opening a can of soda. As the small CO₂ bubbles reach the surface, they “pop” as the surface tension of the liquid soda weakens and fails. But in this example we do not hear a single “pop.” Instead, we hear hundreds of “pops,” producing the typical fizzing sound.) By the way, this soda pop analogy is also often used incorrectly to describe cavitation in many knuckle-cracking articles. It is wrong for the same reason.

3.) Get smaller / collapse when the pressure is increased. (Aha! Now we are getting somewhere. The only thing that produces loud sound in such a system is the collapse of a gas bubble as a direct result of the sudden introduction of pressure. This is the very definition of cavitation!)

Cavitation is the sound that occurs when gas bubbles are partially or totally collapsed as result of a sudden and dramatic increase in surrounding pressure. The sides of the bubble clap together violently as it collapses, producing a surprisingly loud sound. Submariners hate cavitation because it occurs when the submarine’s propellers, or more properly “screws,” turn too quickly for the surrounding water conditions. The friction of the blade against the water produces a partial vacuum along its surface. Gas bubbles form as a result of this partial vacuum, and move to the edge of the blade. As these bubbles are pushed off of the blade, they are immediately no longer under the partial vacuum created by the blade friction and they collapse instantly, producing the telltale sound. This sound makes the submarine easily detectable at great distances, and hence, is extremely undesirable.

In a sealed system, like the synovial capsule of a finger joint, cavitation of a gas bubble formed under negative pressure can only occur if pressure is suddenly and quickly re-introduced. This is not discussed, described, or mentioned in any knuckle-cracking article I have ever read. This is not to say that cavitation is not at the heart of the sound that we hear, but rather that the common description of the knuckle cracking process is likely faulty.

Here, instead, I propose my own theory and description as to what happens when you crack your knuckles:

When you flex your knuckles beyond their normal range and/or direction of motion, you actually temporarily separate the synovial capsule of the joint into two or more distinct areas of high and low pressure. As you continue to pull/push/twist/flex the joint, dissolved gasses come out of solution in the synovial fluid and rapidly form bubbles in the area(s) of low pressure.

As you continue to pull/push/twist/flex, the synovial capsule stretches further, and at some point the physical seal produced between these high and low pressure areas can no longer be maintained. At this critical failure point, the synovial fluid under high-pressure rushes to the area of low pressure, rapidly collapsing the bubble(s) of gas, which causes the cavitation and the audible “crack.”

Since the synovial capsule has now been temporarily stretched in such a way that prevents adequate sealing of the joint capsule into the necessary areas of high and low pressure, you cannot immediately re-crack that joint (at least not in the exact same manner.) Only when the synovial capsule shrinks back to its normal size/shape, and can again support a temporary seal between potential areas of high and low pressure, do you regain the ability to “crack” the knuckle.

Admittedly, I do not have the requisite detailed knowledge of joint anatomy and physiology that is required to precisely explain how each joint capsule becomes temporarily compartmentalized in my theory of this process. As a result, I would love to hear from any rheumatologist, or orthopedic expert who is sufficiently knowledgeable on this subject and can either verify my theory, or offer a more accurate and technically valid description that doesn’t gloss over the actual process.

Mycobacterium tuberculosis is one of the most virulent pathogens, infecting one third of the world’s total population (1). Tuberculosis (TB), of which M. tuberculosis is the causative agent, has become a frightening epidemic, killing almost two million people annually (1). The development of the Mycobacterium bovis bacilli Calmette-Géurin (BCG) vaccine in 1921 and its subsequent routine use in infants in developed countries has succeeded in reducing the incidence of TB (2). The effectiveness of BCG varies greatly though with geographic location – ranging from 0-80%. The failure of BCG is of particular importance in the developing world where rates of TB are much higher. This is thought to be due in part to an increased exposure to environmental mycobacteria, and is further propagated by the reduced socio-economic status and HIV pandemic in these countries that encourage the spread of TB (2). Here, the pathology of tuberculosis, the successes and shortcomings of BCG, and novel vaccine approaches to prevent tuberculosis will be presented.

How is TB spread?

The mechanism of infection for Mycobacterium tuberculosis has been well established and is clearly understood. The infectious bacterial particles are inhaled as aerosol droplets, typically formed as a result of a cough or sneeze by an infected person. These exhaled particles are known to linger in the air for several hours, and the amount of bacteria required to cause an infection has been estimated to be only a single bacillus (3). Once in the lung tissue, the bacteria are phagocytosed by alveolar macrophages. Normally, a pathogen is taken up into a phagosome within the macrophage whereby a decrease in acidity within this environment causes it to fuse with a lysosome. Exposure to hydrolytic enzymes cause degradation of the pathogen and thus limits the infection – this being the classical role of the macrophage in the immune response (3). It has been demonstrated in vitro that macrophages infected with M. tuberculosis fail to acidify and do not fuse with lysosomes (4). The ability of M. tuberculosis to alter the function of the macrophage and evade degradation underlies its pathogenicity by allowing its replication within the cell to occur, and the infection to persist.

Infection of the lung tissue leads to an inflammatory response involving the induction of cytokines that recruit mononuclear cells (neutrophils, natural killer cells, CD4+ and CD8+ T cells) from the bloodstream to the area of infection. These cells surround the infected macrophages in an attempt to contain the infection and form what is known as a granuloma. This is the landmark of tuberculosis – a mass of infected macrophages contained by foamy macrophages, lymphocytes and a web of extracellular matrix (collagen fibers) for structural support (3). This form of M. tuberculosis infection is latent – there are no symptoms of the disease and the person cannot pass the infection on to others. Containment usually fails when there is a change in the immune status of the person, and the infection becomes active. The granuloma necrotizes, and rupturing of the cells releases the replicating bacilli into the airways. A productive cough forms and droplets of bacilli are then released to the air where they can infect another person. Changes in immune status that force a latent infection to an active one can be anything from old age or malnutrition, to HIV infection. The latter two lend support to the high rates of TB in underdeveloped countries where HIV infection and inadequate food supply put many people at risk of contracting tuberculosis (3).

BCG – Hardly Prevention Perfection

BCG is currently the only vaccine that exists against TB, and is the most widely used vaccine in the world (5). BCG is an attenuated strain of M. bovis and was developed in France in 1921, and then distributed internationally 3 years later. More than 3 billion people have received this vaccine and the end of the TB epidemic in Europe was attributed to its administration (2). Clinical studies have confirmed that BCG can be effective – in fact, BCG is extremely effective in infants and consistently protects against TB. The vaccine is also very effective in animal models. In contrast, BCG fails when administered to adults, as well as those with a positive tuberculin skin test. Additionally, the variability in effectiveness across the globe is an issue, particularly the inefficacy of the vaccine in developing countries where TB rates are highest (5).

How can the inconsistencies in BCG effectiveness be explained? Failure of BCG have centered on the theory that exposure to environmental mycobacteria has a negative effect on the action of the vaccine. The two most popular hypotheses based on prior sensitization to mycobacteria are the masking hypothesis and the blocking hypothesis (2).

Masking vs. Blocking Hypotheses

The masking hypothesis suggests that previous exposure to mycobacteria will confer some degree of protection against M. tuberculosis due to a high amount of antigenic similarity between strains of mycobacteria. BCG, then, may not be effective because it does not offer a great deal of protection above what has already been acquired. The blocking hypothesis also maintains that prior sensitization negatively impacts vaccine efficacy, although it proposes that exposure to environmental mycobacteria interferes with the replication of the vaccine. This replication is required for the vaccine to ‘take’ and its ability to develop an immune response against the antigen.

Both hypotheses are feasible explanations for the failures of BCG mentioned earlier. It is reasonable to think that most adults will have been exposed to some mycobacteria in their lifetime by the time BCG is administered. It can also explain the geographical differences in BCG take – poorly developed countries (particularly the tropics and Africa) have a greater environmental mycobacteria load and therefore, would not respond as well to BCG. Likewise, individuals with a positive tuberculin skin test have clearly been exposed to M. tuberculosis or a related strain. These hypotheses also support the efficacy in neonates and animal models – both have had no exposure to mycobacteria of any kind and so it would be expected that the vaccine would work most efficiently for them.

There is clearly a relationship between mycobacteria sensitization and BCG efficacy but is still unclear which hypothesis provides the true explanation. It is likely that both theories have a role to play. Another drawback to BCG is its limited course of effectiveness. The protection offered by vaccination is not life-long, with most studies showing that BCG is protective for only 10-20 years (6). It has been suggested that the development of an improved vaccine for the prevention of infant tuberculosis is not necessary, and the focus should shift to the development of a BCG booster vaccine to prolong the protection offered by vaccination (6).

Novel TB Vaccines

Potential TB vaccines currently in clinical trials fall into one of two groups: live mycobacterial vaccines or subunit vaccines (7). Live vaccines, such as BCG, are made by attenuating or genetically modifying M. tuberculosis or a related strain. Adding or deleting certain genes has proven effective in animal models as a way to increase the efficacy of the original vaccine. The goal of this approach is to inactivate virulent genes while still retaining the ability to induce an immune response. The live BCG urease-deficient mutant is just one of these vaccines that are being investigated. This mutant is unable to stop the phagosome from maturing, and it contains a gene addition that damages the phagosome membrane, potentially increasing the amount of antigen that can leak out and be presented to T cells (5).

Conversely, subunit vaccines deliver specific mycobacterial antigens (as protein, peptides, DNA or live vectors) (5). They stimulate specific CD4+ cell populations that recognize the antigen versus a live vaccine which stimulates many T cell populations simultaneously.

Of course, with the development of a new vaccine it is important to consider the shortcomings of the original BCG and try to ‘fill the holes’ so to speak. Any live strain, whether recombinant or attenuated, would be ineffective in a pre-sensitized individual. The same problem arises with subunit vaccines – any pre-existing antibodies to another vaccination for instance, might block the activity of the vaccine antigenic molecule.

New vaccines that are effective against primary infection by M. tuberculosis are only half the battle in the prevention of TB. The ability of M. tuberculosis to infect a person and remain dormant for many years is an important feature of TB and must be considered when developing a novel preventative approach. How can those with latent infections be treated? Can the progression to active tuberculosis be prevented? What about individuals that have already been exposed via environmental mycobacteria? And how to prevent re-infection in someone who has already been vaccinated but is no longer protected? The answers to these questions will shape the path of future TB vaccine development.

References

1. DeAngelis CD, Flanagin A. Tuberculosis – A Global Problem Requiring a Global Solution. American Medical Association 2005 293(22): 2793-94.

2. Andersen P, Doherty TM. The success and failure of BCG – implications for a novel tuberculosis vaccine. Nature Reviews Microbiology 2005 3:656-662.

3. Russell DG. Who put the tubercle in tuberculosis? Nature Reviews Microbiology 2007 5: 39-47.

4. Mwandumba HC et al. Mycobacterium tuberculosis resides in nonacidified vacuoles in endocytically competent alveolar macrophages from patients with tuberculosis and HIV infection. J. Immunol. 2004 172: 4592-4598.

5. Franco-Paredes C, Rouphael N, del Rio C, Santos-Preciado, JI. Vaccination strategies to prevent tuberculosis in the new millennium: from BCG to new vaccine candidates. Int Society for Infectious Diseases 2006 10:93-102.

6. Sterne JA, Rodrigues LC, Guedes IN. Does the efficacy of BCG decline with time since vaccination? Int. J. Tuberc. Lung Dis. 1998 2: 200-207.

7. Martin C. Tuberculosis vaccines: past, present and future. Current Opinion in Pulmonary Medicine 2006 12:186-191.

Basically, an almost last call for entries. And to reiterate, a humour piece is needed, plus (plus) additional captions can be supplied if you want to take a chance at modifying your score for better or for worse. Also, note that the prize rocks! (full details below)

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PDF | JPG
The Science Creative Quarterly seeks science humour pieces for entry into our awesome new contest. Judging will be based on a number of criteria that can be annotated as follows:

Briefly, final Score (FS) is equal to the the base score of the humour piece submitted (S), times a number (n) of modifiers (fs) which are dependant on captions provided, and their humour level. Note that captions may be submitted separately even at multiple dates after initial humour submission. Number of captions provided by author is flexible but can be no more than 1 for each image (a maximum of 17) – image sources from here.

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In other words, if we state that the maximum base score is 10, and an author is also able to present 17 “very funny” (as determined by a laugh/gag reflex) captions, the following maximum score is possible:

However, 17 unfunny captions would negatively impact and result in the following possible score:

Submissions and captions should be sent to tscq@interchange.ubc.ca, subject heading “MATH.” Contest deadline is March 31st, 2007, and entries may be published in the interim. The winner will be announced during the first week of April, 2007 and will take home whatever happens to be the latest model in the video iPod category or a gift account of equal value at Amazon.com (winner’s choice).

“And there are even some engineers in this [biology] class!” – a seemingly innocent remark, but one that contains sentiments often expressed in the biological realm: engineers just don’t really fit in. At first glance, nothing seems out of the ordinary with this statement – and both parties would probably agree – of course engineers don’t fit in. There is just something fundamentally different between these two disciplines, the respective parties would say (or between biology and the other physical sciences, for that matter). An attempt to justify this would then be given in some remark about engineers being good at math, and the matter would be dismissed. But where did this underlying thought come from, the thought that an engineer working in biology is a bit odd? How did these two sciences, birthed from the same fundamental origin, become so “culturally” different? Is there something deeper going on here?

This issue has been in the works for the better part of 70 years, if not more, as the field of biology has matured and became more mainstream. Already at a young age it is ingrained into our children, but we struggle to put our finger on what exactly the issue is. In high school, it’s the dorky, socially awkward kids (generally guys, lets be honest) who have nothing better to do than to write Fortran 77 code to calculate Mandlebrot patterns for the pure fun of it that go into engineering (if you don’t know what I’m talking about here, chances are I’ve proven my point already). The cool kids, the ones who have enough self-confidence to feel that it is actually ok to be smart, often head towards the biology side of things. I won’t even get into the arts.

So what then is this divide that we are so keen to point out and abide by, yet can’t seem to articulate? As I alluded to earlier, the common belief is that engineers are the ones who are good at math, able to do complicated calculations in the blink of an eye. I find this very unsatisfying, as it leaves biologists in a marginalized position: apparently unable to do math, and so relegated to their own corner of the scientific arena. While this stereotype has perpetuated itself and has certainly been true in some cases, I think there is a more prominent difference, namely the ways in which we approach a problem. Let me explain.

In my opinion, the broad scope of the biological approach to understanding something is probably best described as “Top-down”. The system is described as a whole, and understanding is developed as the system is broken down into smaller and smaller functional units. Engineering on the other hand is better described as “Bottom-up”. Here, the fundamental building blocks are uncovered and then pieced together to form the entire system.

Perhaps an example will better illustrate what I mean. I’ll take something we are all familiar with, at least to some extent, the personal computer (here I’m using the computer as my system of interest, but it could just as easily be a recently discovered organism, for example). If an engineer were presented with a computer and asked to figure out what it does and how it works (assuming no prior knowledge), she would most likely end up taking it all apart. She would then proceed to find out what each individual part does before reassembling it and finding out what everything does put together. This process can be very painstaking, especially if the individual parts are very small, but it yields a very thorough understanding of the computer. Hence the “Bottom-up” approach. A biologist, on the other hand, might begin in a completely different manner. He may begin by unplugging the monitor, then the mouse, pulling out the hard drive and so on, until the aspect of the computer he was interested in stopped working. He may then put in a different hard drive, attach a new mouse and find a completely different monitor to see what the resulting changes produce. This can give some big-picture understanding reasonably quickly, but it can be difficult to get to the low-level pieces. This is “Top-down” analysis.

Here you might be getting defensive if you favour a particular approach, but each has its merits, so don’t get me wrong. And certainly the nature of the system of interest dictates to some extent the more favorable approach. But what if, and the scientific community is beginning to realize this, we could apply both approaches to a problem? I’ll leave you pondering because we’ll get to that in a moment. But first let’s have a quick look at the history of how biology and engineering may have diverged in their scientific outlook.

In today’s world of specialization, we are continually narrowing the scope of our thinking while trying to retain a sense of a bigger picture. Things were quite different, say even 150 years ago, when no formal scientific disciplines existed. Charles Darwin himself contributed to numerous fields, such as geology, geography and of course biology. Going back even further, people were not called scientists, but scholars. People like Leonardo da Vinci contributed immensely to the arts, as well as to many areas of science, such as anatomy, engineering, physics and many others. In many ways it seems that in our process of scientific discovery over the ages we have evolved from very general thought into distinct discipline-oriented modes of thought. These modes have become very particular to their associated discipline, and we now continue to use them, often without a second thought, because they are the norm. Granted, it is a little harder to take apart a cell than a computer, but the conclusion remains the same: how we approached the individual sciences affects the progress made within them.

So lets get back to my previous question. Can we apply both the top-down and bottom-up approaches to a single problem? Can engineers begin to work with biologists in a way that compliments them both? This is, of course, a big question. Many institutions now advertise “multi-disciplinary research”, but do they really know what this means? Do we know how to handle such a strange entity like this with two potentially competing modes of operation?

As with most things of this nature, progress has been slow, but indeed it has begun. Universities struggle with the logistics and politics of such a collaboration, and are still exhibiting growing pains. Groups previously resistant to change are now seeing the value and benefit from this new union. But arguably the biggest change that we are seeing is the slow, general realization that maybe science is more complicated and interconnected than we initially might have thought. So not only are our ideas of science changing, but how we think about science has resultantly had to change. And I think this is for the better.

In the paper “Biology’s Next Revolution” Goldenfeld et. al.[1] alludes to this changing attitude. Recent discoveries in biology indicate that the widely accepted notion of species is not what we know it to be. The discovery of horizontal gene transfer is to blame for this, as it predicts that genes can be transferred outside of the typical, vertical gene transfer paradigm predicted by Darwin. At the microbial level it means that cells can no longer be treated as individual organisms, but rather must be viewed as an entire community of individual organisms. Suddenly, the interactions and statistics of a many-body system come into play, beyond the scope of traditional biology. Thus enter the physicists and engineers, who have the expertise to handle this problem, together with the biologists. Goldenfeld sees this as a major turning point for biology, one that will extend into other areas and other disciplines, and I agree. His revolutionary title may not be that far off.

So what is next? If we truly stand on the cusp of a scientific paradigm shift, there is much to be excited about. New questions will be asked, and perhaps some old questions will be answered. The key will be continuing the dialogue between the sciences in an open and fresh way, lest we once again revert to our narrow fields of view. Lets hope that engineers and biologists can learn to get along.

P.S – I hope this title wasn’t misleading. If you were looking for something on intelligent design as the title may imply, I apologize because you won’t find anything, but I couldn’t resist its use. On the other hand, if you’ve actually read this far, it might indicate that the title’s design was intelligent…

References:

N. Goldenfeld, C Woese, “Biology’s Next Revolution” Nature, vol. 445, 369 (25 Jan 2007).

Lab rats, let’s face it. Sometimes, some of us in science sometimes sacrifice hygiene for extra time in the lab. Got a 2-hour incubation, why not go for a jog or catch a spinning class? Have to start your 12 hour ELIZA at 4:30am to make it to your 5pm seminar, why bother showering before you show up in the morning? Got soaking wet walking to the lab in the rain, why not dry out your shoes and socks on the heater? Had some funky smelling take-out 3 nights before, why not heat up the leftovers in the microwave right outside our lab? All of these circumstances have happened to myself or someone I’ve worked closely… perhaps too closely on that particular day… with. What I’m trying to say is that, on more-than-rare occasions, people in our lab stink. We’re a close group (5 female graduate students), and rarely mention to each other if we notice that each other smell foul. That would just be rude. But… if each of us has only one smelly day a week that could constitute a continual stench that no one would ever think to comment on.

Luckily, our co-op student, Paul “the boy” Heibert, isn’t quite so well mannered.

“Hey, do you guys smell something?” Paul mentioned one morning.

“Like what?” I replied.

‘Like something, I don’t know, died.”

“Ummm… no, not so much.” I replied glancing down at my gym shoes that I had stashed under my bench space. I nonchalantly squatted down to take a whiff, and they certainly didn’t smell good, but not enough to warrant “something died” status. I glanced across to my bench mate, Wendy, the only other one in so far this morning. Her slightly greasy ponytail suggested that she could have jogged to the lab this morning.

“Hey Wendy, did you go for a run this morning?”

“Nope, I was going to go after work. Why?”

“Oh no reason, just wondering.”

As Wendy reached for a new box of tips from the top shelf, she tilted her head to the side, into the arm coat of her lab coat, and inhaled. Her expression didn’t change, so she probably wasn’t the culprit. As I returned to study my lab book, I think I did smell something worse than usual. Maybe Paul was right, maybe something other than our co-workers DID stink. A few minutes later, Rani, another of our crew, came into the lab.

“Hey Rani,” Paul chimed, “do you smell something?”

Rani gave Wendy and me a once over. “Nope, not really, why?”

“Because something stinks. I’ve smelled it for 3 days now. How is it possible that you guys can’t smell anything?”

“I don’t know, Paul.” Rani walked over a grabbed a few old Starbucks cups from her secret hiding place behind the “NO DRINKING/EATING/SMOKING” sign, smelt them, and threw them out in the garbage can outside the lab door.

“Paul, I have no idea what you’re smelling.”

I took my eyes off my lab book and started looking around the lab… I hoped it wasn’t me that stuck. Did I shower this morning… yes… I think so. What did I have for breakfast? Granola. Granola doesn’t stink. Did I step in something on the way? I glanced at the bottom of my left shoe, nothing significant there… and the right shoe? Looks okay, too. Maybe it’s the emergency umbrella that we have rolled up, hanging on the wall between the 4* fridge and the bench that we run the gels for our Western Blots on. I slid off my stool and walked over towards it. The smell was certainly stronger over on this side of the lab.

Hmmm… maybe this umbrella stinks. It could be mildewy from not drying out properly. I opened the umbrella, and to my disappointment, it didn’t stink. I closed it, and decided to chance insulting someone.

“Hey, I think it smells worse over here.” I felt pretty safe saying this, as it was far away from all our bench spaces, thus ruling out that the unfortunate odor belonged to one of my co-workers. Rani, Wendy, Paul and Hongyan our technician, joined me in the smelly corner.

“Do you guys think someone could have spilled TEMED?” TEMED is this nasty smelling component that you add to Western Blot gels. The smell is comparable to dead birds.

“I might have spilled some β -mercaptoethanol when I was making my media yesterday,” Paul said. β-mercaptoethanol is also foul smelling; I like to think it resembles rotting rotten eggs.

Hongyan put her nose to the bench paper, and like one would look for radioactivity hotspots with a gigar counter, systematically scanned the area for TEMED or β -mercaptoethanol. She’s by far the bravest and inquisitive of our lot. “I don’t smell anything, but we could change the bench paper anyway.”

“I wonder if it could be the skim milk from my blots,” I pondered. We’ll keep skim milk in the fridge for weeks, rarely it goes bad, but when it does, it does! I took my tubes from the fridge and sniffed the outside of each one. “I don’t think it’s these.”

“Hey, has Dan been down to check the traps lately?” asked Rani.

“Traps?” inquired Paul.

Okay… time for a little background. We work in the basement of St. Paul’s hospital. St. Paul’s hospital is old. Really old. So old that the original convention heating has been replaced. Replaced, but not removed. There is an intricate network of pipes not closed off that used to supply heat to the building. The perfect breeding grounds for rodents. We often see little brown reminders of their visits in corners, under the lunchroom tables, on windowsills, and once on the ultra centrifuge. Never though have we encountered the real thing. At our request, Dan, our maintenance manager, placed numerous traps around our lab. It had been a quite few months, and he hadn’t bothered to check all the traps frequently.

“Traps… for the rats,” spoke Wendy, quietly. One of our deep dark secrets in the bowels of the hospital. If you don’t acknowledge the presence of the rats, they might not exist.
Now… all of us girls in the lab have extensive animal training. But there’s something different about rats and mice that aren’t in a cage in a sterile environment, never been exposed to the great outdoors or eaten anything that wasn’t processed, guaranteeing that they don’t have parasites. We know how to handle the little inbreeds so that they don’t bite us, and when we do sacrifice them, it’s done in a very humane, controlled, neat and tidy fashion.

“You guys think there might be a rat trap back there, behind the fridge?” Paul asked, with mild amazement.

Hongyan pulled firmly on one side of the fridge, pulling it out a few inches from against the wall. What was released trumped any potential TEMED spill… and what looked like a brown, fury, tail.

“EEK!” She screamed and jumped back into the bench.

Even though we’re scientists, animal surgeons, and future pathologists by trade, the double X chromosome phenotype prevailed.

“EEK!” “AHH!” “EWWWW!” “URG” “BLAAAAH”

Now there’s 4 screaming shuddering, shrieking women.

I couldn’t handle the smell, so I ran outside the lab. I was followed closely by Rani, Wendy, Hongyan, and a slamming door. We all watched Paul through the glass window of the door.

“What am I supposed to do now?” Paul mimed.

Rani cupped her hands up to the window of the door, “THERE’S BIOHAZARD BAGS UNDER THE SINK”

Paul grabbed a bag from under the sink, held it up for approval, which he got from 4 nodding heads.

It was my turn to direct through the viewing glass “PAUL, WEAR GLOVES.”

Paul put on gloves.

Wendy’s turn, “PAUL, DOUBLE GLOVE.”

Paul put on an extra pair of gloves.

He walked over to the fridge, took a knee, reached behind the fridge, and like a proud fisherman, held up his catch with a slightly amused, slightly disgusted expression. The only thing recognizable about the rat was its tail, ears, and toes. The whole torso had been sliced open, and semi-dried guts and blood and fur expelled out of it. No wonder it stunk so bad.

“IN THE BAG! PUT IT IN THE BAG!!!!!”

Paul dropped it in head first into the red biohazard bag. The tail and hind legs were sticking out. This was one big, stiff rat. He turned to us, and shrugged, “now what?”
We all acted out various versions of ‘tying a knot’ but that mini biohazard bags were way too small.

“I know,” exclaimed Rani, “I’ll go get the bags from the animal facility.”

While Rani ran to go get a carcass bag large enough to contain the source of our rat, Paul stared at us through the window.

“PAUL. JUST HOLD ON.” Poor Paul…. Wearing his double gloves and lab coat, holding a biohazard bag at arms length not knowing that we had sent out for help. By now the smell had amplified diffused out through under the door and we all had to step further from the door.

Eventually, one of the maintenance guys came down to our lab, put on a mask, removed the trap (apparently St. Paul’s recycles!) and helped out Paul with a proper sized bag for the carcass. We also called house keeping to help clean up the blood and guts that was left on the floor behind the fridge.

Finally, when the carcass was removed from the lab to be sent to the freezer, us girls were brave enough to re-enter.

“Phew… it still REALLY stinks in here!” I said, fanning the air in front of my nose in vain.

“Really?” said Paul, “I don’t smell anything. You guys ready for lunch?”

March 14, 2007, 3PM: Mildred, the maid leads me onto a sandstone patio, and I have to stop and take in the marvelous view of the San Francisco Bay. Immediately, I know that this is a place for the rich and famous, appropriate for a king or queen perhaps, and certainly fitting for a fast food icon.

“It’s a fucking nightmare, that’s what it is.” he says as if it were a matter of fact, shifting heavily in his lawn chair. “Those bastards, the things they do…” His voice unexpectedly trails off. “Sorry,” he looks vacantly at the shimmer bouncing off his swimming pool “My ex-wife always said I swore too much. It’s just horrible, that’s all. Just horrible.”

You wouldn’t think that someone like Grimace could show this much body language, but you would be wrong. He is obviously hurting, he is obviously angry, and sadly, he is obviously purple.

“You know I was one of the first GMOs ever.” he explains, “Cloning as science fiction was all the rage back then, with books like the ‘Boys of Brazil,’ and ‘In His Image’ hitting the lists. The public never knew what hit them. I never knew what hit them.”

And I suppose therein lies his pain. Like an orphan looking for answers, he is haunted only by what he doesn’t know. Namely, what exactly ‘he’ is. Grimace is a prime example of what is both wonderfully right and terribly wrong about genetic manipulation. Due to the marvels of this technology, he has luxury, wealth, fame, as many women as he desires, and yet he has no identity, no origin. If ever there were such a thing, he is an organic black box.

Officially however, from the mouth of corporate MacDonald’s if you will, Grimace started off as “Evil Grimace” who with four deft arms went around stealing milkshakes from children. Then in 1974, a change of heart and a loss of two arms lead to his current incarnation – a warm, fuzzy, and apparently living representation of the “embodiment of childhood.”

To which he replies, “My friend, that is a heaping load of shit. What the hell does ‘embodiment of childhood’ mean anyway?” He stops to light a cigar. “You know, my friends once told me to hook up with that Barney the Dinosaur dude. They said that ‘He’s big, purple, waves a lot like an idiot. Maybe he knows what you are.’ Except that the bastard never returns my calls.”

“What about your work peers?” I press, “They must know something.” He explains that ever since they let him go, he doesn’t really speak to his buddies anymore. Intrigued I ask. “Even the ‘man’ himself?”

“You mean Ronny?” he smirks and pauses, “We don’t really get along you know? And I can’t really talk about him, if you know what I mean. Let’s just say that that S.O.B. is one nasty clown and leave it at that.” And as quickly as it began, the interview is over and I am politely but firmly led away by Mildred.

For the next week, I can’t stop thinking about him. Even I want to know what he is. With his connections, he must know that a simple genetic test would divulge the secret. But I suppose that the irony in all of this is that people testing genetics was what started the whole thing anyway.

(This first edit eventually became this)

Most of our lives are spent obtaining food, preparing food, cooking food, and taking the time to savor food. Food is colourful, flavorful and simply delightful. The only drawback is wondering what our next meal is going to be. A simple solution for most working class people in the world: eating out. With such an abundance of neighborhood fast-food restaurants or take-out place at competing prices, eating out has become the latest trend in filling the stomach of many. In fact, the idea of purchasing pre-cooked meals has become such a widely accessible concept that people choose this alternative over the time- and energy-consuming method of simply cooking their own meals. However, there are consequences to this alternative.

Although we have a mindset of what unhealthy food is, sometimes ignorance is bliss, and a full stomach is all we need in order to continue with our day’s work. We constantly worry and monitor our fat and caloric content of what we eat; however, there may be more important aspects that we should be worried or concerned about. For example, monosodium glutamate, or more commonly known as MSG, is added to almost every fast food and take-out meal we eat. The majority of people pay no attention to it simply because they are either unaware of its presence in food or are unsure of what MSG really is. MSG may have more detrimental effects on the human body than simply being a food additive. So what exactly is MSG? Why is it added to foods? What are its effects on the human body? Is it harmful even though it is approved by the Food and Drug Administration (FDA)?

Monosodium glutamate (MSG) has been used as a flavor enhancer for over a century. In 1908, Kikunae Ikeda, a Japanese scientist, extracted glutamic acid from the seaweed Laminaria Japonica and discovered its flavor-enhancing properties, thus was the birth of MSG. MSG is a free amino acid salt with one sodium atom attached to the amino acid glutamate. Amino acids are basic building blocks linked together to form larger proteins. However, there are amino acids that aren’t linked and perform vital functions on their own. For example, glutamate is an excitatory amino acid neurotransmitter, that is, a chemical messenger that triggers the nerve cells to fire. Glutamate is naturally made in the human brain and present within the muscle, kidney, and liver.

Not only is glutamate naturally made in our bodies, but exists in many of the foods we eat, such as, parmesan cheese, tomatoes, mushrooms, walnuts, etc. This is why many of these foods are used as flavor enhancers for various dishes. However, the food industry is not satisfied and wishes to harness this flavor enhancer so it can be added to all foods. As a result, MSG is created by hydrolyzing vegetable protein or by fermenting corn and starchy foods. The final product of MSG is a white crystal that can easily dissolve into foods. The MSG manufacturers argue that processed MSG is a pure salt exactly the same as the glutamate in our bodies, whereas, the MSG antagonists argue that processed MSG is impure and also contains a different isomerism, a mirror image of glutamate from the ones naturally made in our bodies. Moreover, by hydrolyzing vegetable protein, glutamate becomes “free” and is able to act as a neurotransmitter. Excess free glutamate can, as argued by neuroscientists, lead to many disease states.

MSG in foods acts through our taste buds on the tongue giving us the “umami” taste sensation, which means delicious in Japanese. This “umami” taste is termed the fifth taste sense of our basic tastes, and is described as meaty, brothy, and savory. From the tongue, this signal is relayed up to the cerebral cortex in the brain telling us that what we’re eating is delicious. Ingested glutamate is absorbed through the intestines, where it is transaminated and subsequently, metabolized by the liver leading to the release of glucose, glutamine, lactate, and other amino acids into the blood circulation. Glutamate is not considered to be an essential amino acid since we are able to produce it ourselves, but constant excess of glutamate from oral ingestion could lead to other problems.

MSG has various detrimental effects, which include triggering asthma attacks and exacerbating migraine headaches. Studies have shown that oral ingestion of MSG can provoke asthma attacks in patients diagnosed with asthma, and bring about symptoms of the Chinese Restaurant Syndrome (CRS). The CRS is a collection of symptoms that include sweating, headache, flushing, and in more serious cases, swelling of the throat and chest pain. Although it was believed that MSG is the cause of CRS, no empirical studies have found a causal link between them. There have been studies showing MSG to exacerbate migraine headaches as well. Excess glutamate, acting as an excitatory neurotransmitter, causes over stimulation in the brain prolonging the migraine attacks. In more serious cases, MSG may even cause neuronal death due to over stimulation.

Not only is MSG found to induce asthma and migraine attacks, but is also linked to diseases such as obesity, Type 2 diabetes and Alzheimer’s disease. Metabolizing glutamate after a MSG-rich meal induces the release of glucose into the blood stream. This in turn triggers the secretion of insulin by the pancreatic islet cells, so that muscle cells can take up glucose. Obesity is characterized, in part, by high levels of plasma glucose and insulin. Studies have shown that mice injected with MSG became obese and eventually lead to insulin-resistance and the onset of Type 2 diabetes. Moreover, MSG has been shown to stimulate appetite in humans. Subjects that had MSG-rich meals exhibited more stimulation to eat and ate more often than control subjects. The elderly are more susceptible to over stimulation of the brain caused by MSG, and risks degeneration of nerve cells in the brain leading to Alzheimers.

In spite of the detrimental effects of MSG, the FDA approves of MSG in our food products based on its “naturally occurring” ingredient. Because glutamate is also found in nature, MSG is a safe food additive. Many manufacturers rename the monosodium glutamate ingredient to euphemistic terms such as, malt extract, corn syrup, cornstarch, or hydrolyzed “anything”.

So why do food companies and restaurants add MSG to foods in spite of the problems it causes? MSG fools your brain into believing you are consuming nutritious and tasty food, stimulates appetite, and reduces costs for the food processors. Glutamate triggers the umami taste sensation and leads you to believe the food in your mouth is high in protein and nutritious. For example, simply adding MSG to a bowl of noodle soup immediately adds a savory taste to it, bringing the misconception that the soup is truly delicious. MSG stimulates appetite by inducing insulin release so that glucose is taken up, despite not having consumed anything with carbohydrates (sugars). As a result of high insulin concentrations, your blood sugar level drops and you end up being hungry again only hours later. Because MSG gives the impression of tasty and savory food, it allows food processors to put in less of the real food. For example, fast-food restaurants have mastered this technique in their beef patties for their burgers. Adding MSG to the beef patties gives the same meaty, savory taste as real beef. Therefore, fast-food processors have no need to use a 100% beef patty, and thus are able to reduce costs. MSG is practically the most profitable ingredient in the food industry – stimulating palability so that consumers eat more or come back for more while cutting costs in their food products all at the same time.

Monosodium glutamate is only one of the many ingredients we should be aware of before consuming any food product, whether from home or (especially) at restaurants. Those with asthma or are susceptible to migraine should be even more conscientious. Although we cannot control what the food industry does as a whole, we do have the power to choose what food we eat. As technology advances, many ingredients become processed, and foods become engineered. Food processors may take advantage of lower costs and disregard how healthy their food products really are. We must raise our awareness to what we consume, and what we allow our children to consume, for there may not be any real, natural food in the future.

References

1. Allen DH, Delohery J, Baker G. 1987. Monosodium L-glutamate-induced asthma. J Allergy Clin Immunol. 80 (4): 530-537

2. Bellisle F. 1999. Glutamate and the UMAMI taste: sensory, metabolic, nutritional and behavioural considerations. A review of the literature published in the last 10 years. Neuroscience and Biobehavioral Reviews. 23: 423-438

3. MSG – Slowly Poisoning America. [online]. Available here. [accessed 10 February 2007]

4. Nagata M, Suzuki W, Iizuka S, Tabuchi M, Maruyama H, Takeda S, Aburada M, Miyamoto K. 2006. Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate. Exp. Anim. 55 (2): 109-115

5. Scher W, Scher BM. 1992. A possible role for nitric oxide in glutamate (MSG)-induced Chinese restaurant syndrome, glutamate-induced asthma, ‘hot-dog headache’, pugilistic Alzheimer’s disease, and other disorders. Med Hypotheses. 38 (3): 185-188

6. Thirone AC, Carvalheira C, Hirata AE, Velloso LA, Saad MJ. 2004 Regulation of Cbl-associated protein/Cbl pathway in muscle and adipose tissues of two animal models of insulin resistance. Endocrinology 145 (1): 281-293

7. What exactly is MSG? [online]. Available here. [accessed 10 February 2007]

8. What is MSG? [online]. Available here. [accessed 10 February 2007]

The bubbles in my bath are white;
try as I might
they never change
despite a range
of gels and goos in rainbow hues -
pinks, greens and blues.

The chemists say
it’s child’s play
to reproduce the scent of fruits,
herbs, flowers and roots.

But still the foam
is monochrome.

Cryonics, the technique of freezing dead rich people and their pets, is generally disregarded as a big lame waste of money by most scientists and doctors. The goal of cryonics is to preserve all cells in the body well enough such that in the distant future, after scientists have figured out how to successfully “thaw” these high-stakes ice cubes, doctors [robots? Femto-sized germ soldiers?] could take a stab at curing your previously lethal disease. Then you would be free to marvel at the brushed stainless steel landscape, the crushing loneliness, and how everyone has a cell phone in their brain and can take pictures with their eyes. You wouldn’t have those things yet, or any friends, but you wouldn’t have cancer anymore. Isn’t being a higher eukaryote grand?

No way! Every time I make a glycerol stock of my yeast cultures I shake my head and sigh longingly. Each dense little subpopulation, safely frozen away in their viscous aliquots, will eventually be given the gift of reanimation. At some undisclosed point in the future, a gob of the stock will be plated on growth media and life will begin anew.

I’d like to imagine that this is exciting for them. The generation of cells grown in liquid media would have no recollection of their ancestors growing up on solid media, and so one way of thinking about this is that, for yeast, the past is a thrilling future every time.

Heavy.

(Click here to enlarge graphic)

The Scientists base their research on a principle hypothesis that complex systems can be understood by seeking out its most fundamental constituents. In other words, the complex problems are resolved by dividing them into smaller, simpler and more tractable units. Hence, physicists search for the basic particles and forces; chemists seek to understand chemical bonds; and biologists explore DNA sequences and molecular structures focusing on a particular gene or a protein in their efforts to understand organisms. This approach of “divide and conquer” is termed reductionism (Williams, 1997; Ahn et al, 2006a).

The Biologists Reductionism approach is a science of convenience and complacency. Complacency, however, does not imply correctness. This is best illustrated by John Godfrey Saxe’s poem “The Blind Men and the Elephant”. The poem is based on a story originating from India. The story is about the six blind men who want to know what an Elephant is like. Each blind man describes the Elephant to something different (side=wall; tusk=spear; trunk=snake; knee=tree; ear=fan; tail=rope,) because each one assumes the whole elephant is like the part he touched (Wikisource). In a similar way, the Reductionist biologists investigate individual molecules to understand the complex life processes. Further they extrapolate dogmas from their observations and claim that is the true account of the complex process.

In the last 50 years, the reductionist approach of analyzing individual constituents of biological systems has been successful in revealing the chemical basis of numerous living processes. It has had a profound influence and still impacts on the biological and biomedical research of today. However, due to this level of success, the holders of the reductionist point of view assume that the reductionism, by itself, is sufficient and they can be likened to a parent generation who want their children to walk the same path of success as they did. The reductionist view fails to notice that their approach does not account for the big picture of complexity and robustness of life and similarly the parents seem to be unaware that the world has changed and nothing is the same (Katagiri, 2003).

The reductionsist thinking of biology has encompassed clinical medicine to an extent where the clinicians focus on individual parts to explain the whole. They focus on the disease rather than the state of the person contributing to the disease. They emphasize homeostasis and restore it back by correcting the deviations. They look for one risk factor-one disease because of their inability to work with multiple factor and comprehend their collective influences. They treat each disease individually assuming minimal effects on the treatment of other or additive response of the individual treatment (Ahn et al, 2006a).

One of the proponents of reductionism – Francis Crick. The co discoverer of structure of double helix model of DNA molecule the great physicist turned molecular biologist turned neuroscientist Francis Crick wrote a book Of Molecules and Men. He wrote “The ultimate aim of the modern movement in biology is in fact to explain all biology in terms of physics and chemistry.” This serves as a creed for the congregation of reductionist community, who try to explain the complex life processes based on the physicochemical properties of the individual components. Some neuroscientists belonging to the reductionist community go to the extreme and view consciousness and mental state as chemical reactions that occur in the brain (Gottschling, 2005). They seem to have oversimplified the equation of man and molecules in order to understand the working of brain.

“Men are made up of Molecules
Molecules do not mean Men
Men are more than Molecules”

The complex biological activity is not due to specific individual molecules. To understand the nature of life, an organism cannot be treated similar to machine, a mere collection of components. All living organisms have a unique ability to self damage themselves and self repair any damage to themselves due to ordinary wear and tear. There is no machine replicating this level of complexity. The best and the most sophisticated ones that the humans have built undergo a self test to a very small extent and warn their operators of the faulty components. When the computers fail to carry out the instructions, they communicate to us their failure. They cannot self repair. They are dependent on external agencies for repair and replacements of components (Bowden and Cardenas, 2005).

An organism is a complex system with dynamic relationship and interactions between the components leading to a behavioral system. In order to have a better understanding of the system wide behavior, three factors need to be considered: (1) context – the inclusion of all components involved in a process. (2) time- to consider the changing characteristics of each component; and (3) space- to account for the topographic relationships between and among components (Ahn et al, 2006b). This is comparable to a soccer team. A particular player as an individual irrespective of his strength and skill may not impact the game. All the eleven players or may be ten in certain situations should communicate, adapt to the situation and boost each other to play as a team and emerge as the victorious.

Systems biology is an in-depth investigation of individual biological components at a systems level to understand how a process, a cell, a group of cells, or an organism works as a whole. This will help in understanding the interrelationship of the different components of a process, how they interact, influence and regulate each together. This would be possible by developing theoretical system models that will help us to understand the observation of experiments and design multi-scale experiments that can provide data to confirm or refute the previous model and lead to creation of new models (Ahn et al, 2006a; Sorger, 2005). Systems biologist need to work just like a soccer coach. To start with the coach has a game plan for his team to work on and then based on the team performance makes substitution during the game. Then for the next game, based on the detailed analysis of the team’s performance, he may make minor changes or may come up with a new strategy and different combinations of players.

Systems biology of modeling and multi-scale experiments is a call for the key striker molecular biologist to come together with the other players the chemist, physicist, computational scientist, mathematician and statistician and work as a team to score and unravel the unique complexity of biological systems. The decoding of the human genome, the high-throughput functional genomic tools microarrays DNA array, RNA expression profiling, nanotechnologies and bioinformatics software would provide the data for the biologist to stimulate the complexity of biological networks and systems. These stimulations will help us to speculate the reactions of the systems to a small extent, although we may not be able to spot each and every interaction that takes place (Van Regenmortel, 2004).

The systems approach with its focus on interactions and interrelationship of the components explains the behavior of the system. In chronic diseases such as diabetes, coronary artery disease the equation is non-linear with multiple factors. The multiple factors lead to complex interactions and thus the conditions keep evolving. Therefore the systems approach is appropriate to investigate the chronic conditions. Although not very often we have certain conditions where the reductionism is helpful and systems approach is not. The acute and simple diseases is a pure “penalty shoot-outs” the perfect one – one. The acute condition is such that a particular interaction influences the behaviour of the system. The two approaches are complementary to each other. Thus the approach has to be custom oriented to the needs of the situation (Ahn et al, 2006b).

Edward de Bono (De Bono, 1994) writes about the thinking approaches. The traditional western thinking is based on search and discovery by going deeper into the core of subject. It is rock logic, and uses set rules and definitions. It splits the problem and sets up the dichotomies and contradiction. It uses adversarial arguments and refutations to explore a subject. This system was fashioned by the Greek Gang of Three (Socrates, Plato and Aristotle). It is supposed to be complete comprehensive and perfect. It may have worked then but it has failed in rapidly changing world. It is not flexible and hence cannot deal with the changes. The system is inadequate and complacent. Bono does not merely criticize, but suggest an alternative approach of ‘parallel’ thinking. Parallel thinking uses the flow of ‘water logic’ and accepts the possibilities without judgments. It takes into account both the sides of contradictions and look to design a way forward. Parallel thinking is cooperative parallel thinking

The Traditional and Parallel thinking of the above represent the reductionism and systems biology respectively. The reductionism had failed to decipher the biological complexity. It has also failed in drug development and vaccines design (Van Regenmortel, 2004). The failure is because of the limitations of the reductionism to account for the interrelations and complex interactions of the different components of the biological systems. This has led to the rise of the system approach. Once the systems biologists recognizes the necessity of a systems perspective. Incorporating the systems approach into biological and biomedical research is challenging. These are technical problems such as working with multiple nonlinear variable, generating quantitative information of complex interactions and accounting for uncertainties due to lack of measurements and observation. These challenges are difficult but not impossible to overcome. The biologist along with the physicist, chemist, mathematician, computational scientist and statistician need to work as a team. They need to put together their resources and skills to have system-level understanding of human health and disease at the organism and community level. Thus, the systems biology approach has great potential for the advancement of biomedical research (Ahn et al, 2006b).

References

William, W. (1997) ‘PHILOSOPHY OF SCIENCE: Biologists Cut Reductionist Approach Down to Size’, Science 277.5325.476

Wikisource contributors, ‘The Blindmen and the Elephant’, Wikisource, The Free Library, 27 June 2006, 02:35 UTC, link [accessed 14 February 2007]

de Bono, E. 1994 Parallel Thinking 1st ed. Viking Penguin Group, pp IX-X

Ahn AC, Tewari M, Poon CS, Phillips RS (2006b) The Clinical Applications of a Systems Approach. PLoS Med 3(7): e209 link

Ahn AC, Tewari M, Poon CS, Phillips RS (2006a) The Limits of Reductionism in Medicine: Could Systems Biology Offer an Alternative? PLoS Med 3(6): e208 link

Cornish-Bowden, A. and M.L. Cárdenas, M. L (2005) Systems biology may work when we learn to understand the parts in terms of the whole Biochem. Soc. Trans. 33, 516–519

Sorger, P.K. (2005) A reductionist’s systems biology: opinion. Curr Opin Cell Biol. 17(1):9-11.

Gottschling, V. (2005) The mind reduced to molecules? Phenomenology and the Cognitive Sciences 4: 279–283

Crick, F (1966) Of molecules and men. Seattle: University of Washington Press.

Katagiri, F. (2003) Attacking Complex Problems with the Power of Systems Biology Plant Physiology, 132, pp. 417–419,