NK Linked Lecture Series: "Stress, Neurodegeneration and Individual Differences"

I am proud to present an interesting lecture by Dr. Robert Sapolsky, a professor at Standford University and the author of many excellent scientifically themed books aimed towards non-scientists.

Dr. Sapolsky's research interests crosses many fields and disciplines but centers on elucidating how stress mediates its effects on the body from a biochemical perspective.

Wnt Signaling Cascades: Pointing in the Right Direction

A reoccurring theme in signal transduction is for a single spanning trans-membrane receptor to form a homodimer upon signal ligand binding, this step is often crucial for the signal to be transduced into the cell. This applies to numerous hormone receptors, such as the PDGF receptor and the insulin receptor, although the insulin receptor pre-exists as a covalently bound homodimer regardless of an extracellular signal. Based upon a recent publication from Niehrs et al, it appears that the single trans-membrane spanning receptor LRP6 in the Wnt signaling pathway takes this theme up a notch and doesn’t just form a dimer but a large multi-protein oligomer, an in vitro protein aggregate that is an essential for signal transduction in the Wnt pathway. 1
The Wnt signaling proteins, a family of paracrine signaling growth hormones, are crucial to embryogenesis and limb formation in animals and perhaps unsurprisingly has also been implicated in several forms of cancer. Abnormal levels of the Wnt second messenger, Β-catenin, correlate to basal cell carcinoma. The abbreviation Wnt is an aggregation of Wg, as Drosophila Melanogaster flies that had genetic mutations in this pathway were “wingless” and INT, genes found to be involved in vertebrate integration in mice.
At the biomolecular level the Wnt pathway is activated when a Wnt signaling protein binds to two localized receptors; low-density lipoprotein receptor related protein (LRP) and frizzled (FRZ).2 Niehrs specifically analyzed the Wnt3a signaling ligand, which binds to LRP6. After this binding event, LRP6 undergoes phosphorylation by CK1-γ. Once activated, axin binds to the phosphorylated LRP6. For axin to bind to the activated receptor complex it is recruited from a β-catenin degradation complex, that includes axin, GSK-3 and APC; removing axin from this complex results in a loss of this quaternary protein complex’s catalytic power. As a result local Β-catenin concentration increases, permeates into the nucleus and interacts with various TCF/LEF transcription factors, ultimately upregulating gene expression.
Although it was known that Wnt signaling ligands bound to FRZ, it was unclear why it did so as the transduction mechanism appeared to be solely mediated via LRP6 phosphorylation. Why would a cell express two unique receptors, when only one was involved in signal transduction? Furthermore, an additional protein disheveled (Dvl) was implicated in this pathway as a scaffold protein that bound axin and FRZ, but as activated LRP6 also bound axin, the role of Dvl was clearly not well elucidated and seemed somewhat redundant. Additionally, how LRP6 activation occurred by CK1-γ was not clearly defined. With the presence of numerous rogue scaffolding proteins involved in this pathway it was clear that although the overall picture was in focus, the details had still yet to be refined.
Visualizing Wnt signaling by fluorescent labeled Wnt pathway proteins via real-time confocal microscopy, Niehrs found that this pathway involves the formation of ribosome sized aggregates near the cell membrane in Xenopus embryos, HeLa, P19 cells. Niehrs found that these aggregates included: the receptors, LRP6 and frizzled; the sequestered adaptor protein, axin; caveolin, a protein known to be involved in endocytosis and GSK3, an additional protein from the Β-catenin degradation complex and Dvl.
Upon further analysis of these aggregates, Niehrs found that the scaffolding protein Dvl was crucial for the phosphorylation of LRP6. In RNAi knockdown experiments of dvl in MEF cells and the equivalent homolog dsh in Drosophila cells, decreasing dvl levels strongly inhibited phosphorylation of LRP6 through Wnt ligand activation, even though CKI-γ levels were still at a natural level, showing that Dvl is necessary for CK1-γ action. Further experimentation needs to be conducted to determine how Dvl mediates CK1-γ activity towards LRP6; it may act by recruiting CK1-γ to LRP6 or by possibly inducing a conformational change in CK1-γ, inducing activation.
The exciting aspect of this research is the sheer magnitude of the signaling complex. The mass of the signalosome was determined by sucrose density sedimentation via centrifugation, without Wnt3a signaling LRP6 sedimented similarly to a 670 kD protein but upon Wnt3a signaling phosphorylated LRP6 aggregates cosedimented with ribosomal rich fractions. Signal transduction mediated by large-scale protein aggregation is rather unorthodox in the current signal transduction. As a result, our view of signal transduction may need to undergo an expansion.
Most phosphorylated receptors need to undergo endocytosis to remove the phosphate group and return to an inactivated state. Past research by Kikuchi shows that phosphorylated LRP6 undergoes endocytosis by a caveolin-mediated pathway.3 Would this entire complex then undergo endocytosis? It would be interesting to measure the size of these LRP6 endocytosed vesicles, which would allow for an inference of how much of this, as Niehrs states, “LRP6 signalosome” accompanied LRP6. It seems unlikely that the entire aggregate would undergo endocytosis due to the high energy costs associated with forming a lipid bilayer around such a large object. Furthermore, assuming that endocytosis only occurs when the cell wants to terminate the signal, it does not seem plausible that axin would be sequestered, as it would be inhibited from reforming the β-catenin degradation complex.
As this signaling system is crucial to limb formation, it is likely that some sort of gradient or oriented response would be mediated inside the cell. Could the formation of these aggregates, these highly concentrated and localized bundles of activated receptors, be the biomolecular mechanism that governs and orients proper limb formation on an organismal level? Although one can ask numerous questions related to the mechanisms and nature of interactions between these “signalosome” proteins the real issue would be to determine if and how this system creates a gradient of β-catenin into the nucleus and if that then correlates to specific uni-directional cell proliferation.
In highlighting a unique feature in the Wnt signaling pathway, Niehrs discovered a interesting signaling phenomena, which may happen to be the signaling mechanism that mediates oriented limb growth.

References:
1. Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-Dependent LRP6 Phosphorylation. Niehrs et al., Science STKE. June 2007: 1619-1622
2. LDL Receptor-related proteins 5 and 6 in Wnt/B-catenin Signaling: Arrows point the way. Zeng et al. Development. April 2004. 131(8): 1663-77
3. Regulation of Wnt Signaling by Receptor-mediated Endocytosis. Kikuchi et al. J Biochem. April 2007. 141: 443-451

The Histone Code

Lately there’s been a lot of buzz within the scientific community about a “Histone Code”. What is it and why is it important? To understand the importance of this code, we need to set our focus at the origin of this topic. The story starts off with DNA.

The genome, comprised of DNA, is arguably the most important molecule in a cell. Encoded within a DNA molecule are the endless permutations of a repeating code comprised of only four repeating elements, the genome contains the all information needed for that organism to thrive and function; it represents the instruction manual encoding all the instructions on how to build the all the necessary machinery that will be required throughout the organism’s lifetime. The magnitude of this is simply astounding. The situation with DNA is analogous to having every instruction booklet required to build an airplane on one piece of paper, but the paper’s dimensions is that of an extremely long fortune cookie fortune; simply put DNA is a long molecule. Too long, in fact, for a cell to keep it laid straight and still keep it inside the cell. So the cell does the same thing that we do when we have a long piece of rope or unruly string of Christmas lights; the DNA is kept rolled up until it is needed. To accomplish this the cell utilizes a set of proteins, called histones, to start this process of condensing the DNA. In fact the cell uses to so many histones to do this, that it is one of the most prevalent type of proteins in a cell.

Proteins, like DNA, can be thought of as strings (albeit much much smaller) of repeating sequences of different amino acids. These strings of amino acids are almost always folded into different structures. Sometimes proteins are “woven” into sheets, other times into these globular structures as if the string had been tied into a large knot. Interestingly enough, it is that the order of the amino acids themselves that is the main determinant for what kind of shape the protein will form into; this is the case for histones. The sequence of amino acids for a histone causes it to fold into a predictable shape. There are a few different kinds of histones in cells, each with a unique sequence of amino acids and therefore a unique shape. From a cell’s histone arsenal, it utilizes a few different histones to create a multi-protein structure that resembles a neat barrel-like structure that DNA can wrap around; this is referred to as a nucleosome.

Once the DNA is rolled onto these histones, the cell still needs an easy method to lock the DNA away (so it cannot be unrolled) and to release it (so it can read the encoded blueprints); this process is accomplished by histone modification. These modifications are relatively small compared to the overall size of the histone, but they have profound effects.

A cell might modify a histone by adding an acetyl group, a small functional group, to it. In some instances, this modification causes the histone to loosen its grip on the DNA; sometimes it causes a different histone to tighten that grip. Now it might seem a little weird that the same modification causes opposite results. But returning to this “proteins are like strings” analogy, imagine what happens if you take the two ends of a knotted string and pull. What happens? Sometimes the knot gets tighter, other times the knot unravels; the outcome depends on what kind of know it is. A similar situation is occurring with these histones, the result of the modification depends on the structure of the histone.

This is what is the term “histone code” refers to, the attempt to decipher how modifications result in changes in DNA accessibility. Studying the outcome of histone modifications and how they effect the interaction between DNA and histones is currently a hot area of research. The implications of this effect are significant, if a segment of DNA cannot be removed from a histone, the blueprints encoded on the sequence of DNA cannot be read and the cell will miss out crucial pieces of instructions (imagine a plane without a left wing). On the other hand, if a histone cannot hold onto a DNA segment, that segment will be read inappropriately causing to the cell follow the instructions (imagine a plane with extra wings sticking out at odd angles of its body). This is why the histone code is so important; it acts a set of mechanisms that allow the cell the to control when the message from a DNA segment is enacted upon. Histone modifications don’t change the information in a piece of DNA, they just regulate if the message can be read or not.

The NK Linked Lecture Series: The Uniqueness of the Human Brain

An outstanding presentation given by Dr. V.S. Ramachandran. This presentation focuses on neuronal cross-wiring resulting in phenomena such as phantom limbs and synesthesia. This presentation is part of a lecture series by IBM.

A Protein's Manifest Destiny

Do human beings have free will? Or are we subject to some form of manifest destiny, that our calling is pre-ordained? Many people have invested much thought and effort to questions relating to these themes. Due to the nature of such questions and the way that our society works, perhaps there will never be a unified consensual agreement to the answer of these questions.

If we look, an analogous situation is presented in cells. Proteins are subject to diffusion and brownian motion, the molecular equivalent of free will albeit mindless free will. They diffuse haphazardly, randomly; such could be said for an individual's life. A protein could interact with other proteins, aggregating for a while, moving on down a chemical or electrical gradient. But they are not completely free to wander around the cell aimlessly. Within the protein itself exists a manifest destiny, it's signal sequence. Many secretory proteins have an initial sequence that will ultimately be cleaved by a peptidase, but nonetheless this sequence acts as a address on an envelope, labeling the protein. This label determines where it ends up, free floating in the cytosol, packaged into a secretory vesicle, or firmly planted into a membrane.

Maybe the determinants among us can take this as an argument that bolsters their theory but it necessarily isn't. There are exceptions to this rule, many proteins are not labeled with a signal sequence. Once translated they are free to wander about as they please, until they find a suitable partner to interact with or until they age, becoming less functional and eventually inactive.

Free will or determinism. Even a molecular level, we cannot say which is the case.

Science and Engineering Indicators 2006

Find yourself wondering about the state of the science enterprises in the US or abroad? Well, allow your pondering to be inundated with data from the, Science and Engineering Indicators 2006. This report was prepared by the NSF and contains a ridiculous amount of facts, figures and survey results about K-12 science education, labor forces, industry and academic R&D, public attitudes and world-wide S&E economic trends.

A sample of entertaining, interesting and/or depressing data:

"According to one report, "TV weathercasters are often the most visible representatives of science in U.S. households" (NIST 2002)." 1

According to a survey 1/4 of the US population in 2004 did not know that the earth revolved around the sun. 2

"...doctors and scientists received the highest prestige rankings out of 22 occupations. In fact, these were the only occupations seen by more than half of adults (52%) as having very great prestige." 3

The NK Linked Lecture Series: Nobel Laureate Richard Roberts

Nobel laureate Richard Roberts begins the lecture by advocating open-source publishing, where the content of a journal is made freely available on the internet by a website such as PubMed Central. He then goes to speak about restriction enzymes.

Enjoy.

Prions

Zombies at the Molecular Level

We've seen the cheesy zombie films. Mindless living dead creatures with the only goal to harass the living, often with the intent to dine on their brains. Where the newly and unfortunately lobotomized victims soon after also become zombies with the same insatiable platelet. Soon after everyone in town is transformed.

As incredulous as this sounds, a story along these lines is a plausible threat and a cause for much concern. Although the gravity of the situation is great, the scale at which these mutants operate is minuscule. I refer to the "mutated" proteins known to as prions.

Prions arise from endogenous proteins (referred to as PrPc) found in brain tissue, its native function has not been fully elucidated. The functional PrPc can undergo a conformational change (the exact mechanism is also not fully elcudiated) altering it to the infectious prion state (dubbed PrPSc). The conformational change is initiated by contact of PrPSc with PrPc. The basic reaction scheme is listed below.

PrPc + PrPSc → 2PrPSc

Just one inital infectious protein, PrPSc, could be enough to transform all native PrPc. While the main transformation method requires PrPSc, it is not fully understood how the first PrPSc is formed; the twist on the chicken or egg conundrum. Although there is evidence showing that cows that have ingested the brain matter of diseased cattle will also contract the disease, the question on how the formation of the inital PrPSc occurred is still unanswered.

If the conformation into the PrPSc form resulted in a minimal behavioral difference from PrPc, there probably would be little cause for concern. Unfortunately, this conformational change coincides with drastic functional changes, reinforcing a main staple of biochemistry that "form equals function".

Once formed, PrPSc begins to congregate extracellularly, forming amyloid plaques that will ultimately disrupt the normal function of the tissue. Amyloid plaque formulation results in transmissilbe spongiform encephalopathies (TSE), a lethal condition. The most notable disease caused by prions is "mad cow disease" due to past media attention. In humans, prions have been associated with Creutzfeldt-Jakob disease, Gerstmann-Straussler-Schninker syndrome, Fatal familial insomnia, sporadic fatal insomnia, Alpers syndrome and Kuru.

The NK Linked Lecture: DNA and the Brain

A lecture given by Dr. James Watson that was made possible by Authors@Google series. Dr. Watson comments on his role in the discovery of the DNA double helix and reports on some of the research being conducted at Cold Springs Harbor, of which he is The Chancellor (I assume this position is equivalent to the director).

Most notable quote of the lecture: " This century will see the coming together of psychology and biology in the way that the last century was the coming together of chemistry and biology."

Dr. Watson's lecture focuses on the genetic roots of autism. Autism being a neurological disorder, which the disease manifests via spectrum as opposed to "present/not present". Looking for phenotypic patterns present in the progenitors of autistic children, Dr. Watson comments on research where subjective mental state assessments have been gathered for autistic progenitors and then compared to the prevalence of autistic child births between these individuals. An example being that the average IQ for autistic progenitors is 112, when the over-all average is 100.

Here's where it gets tricky though. Another researcher, Simon Baron-Cohen, came up with the categories of the female mind and male mind (Which in my opinion is a very poor choice of names for these categories). Where the male mind is defined as a systemizer, an individual that is mathematics based, logical and the female mind is defined as an empathizer, an individual that is good at connecting with other individuals. I believe that the terms male and female mind need to go; just use empathizer and systemizer instead. This choice of nomenclature will just inhibit these findings by miring them in unnecessary politically correct battles. Aside from the poor nomenclature, Dr. Watson states, that two individuals who are assessed as systemizers (male-mind oriented) are more likely to have an autistic child.

This appears to make sense, that individuals with a phenotype to systemize as opposed to empathizing will produce offspring more prone to systemizing, assuming that empathizer-systemizer spectrum holds true. But what genetic or neurological reasons are there for these parameters to be mutually exclusive? I believe that I have encountered many people who I would categorize as both strong systemizers and empathizers. Furthermore, according to this theory, that autism can be described as an individual at the extreme systemizer end of the empathizer-systemizer spectrum,then there should also be examples of neurological disorders on the opposite end of this spectrum.

Although I found this lecture engaging, I believe that I need to read more of Baron-Cohen's research to fully understand his position.

Well, enjoy the presentation.

A New Addition to Scientific American

The July 2007 copy of Scientific American boasts a new and unique section entitled Updates. This new section offers a brief follow up on some of the big breakthrough stories of previous issues. This is a neat way to keep the public informed about how a novel discovery develops over time and what can happen to it. The editor stated that it will also help to decrease public jadedness over an apparent lack of follow-through; that a major discovery has been announced but yet the status quo is maintained, e.i., no flying cars.

This column will help remind the public that scientific discoveries do not just get lost on the book shelf but are part of an ongoing narrative.

Check it out!

An Internal View of Cellular Processes

An excellent cgi video put together by Biovisions of Harvard University.



The following video contains a commentary about what is going on in the video.



Inner Life of the Cell animation conception and scientific content by Alain Viel and Robert A. Lue. Animation by John Liebler/XVIVO. Here is a link to their website: http://multimedia.mcb.harvard.edu/

Simple as Hitching a Trailer

At a molecular level, nature loves multiplicity. Why use one link when you could use a few million. When we, as a species, manufacture something we tend to employ a single component. Galvanized steel, reinforced ceramics and the like are often the bread and butter of engineers. Nature, on the other hand, uses whats been most readily available, namely organic molecules. On the whole, it is easier to break something organic (a piece of wood) as opposed to something inorganic (a piece of steel). Nature has compensated for this deficiency by just upping the amount of organic compounds involved in the bond. It is analogous to hitching a trailer to a truck by the use of innumerable twisty-ties.

It is multiplicity that allows for the astounding height of the redwoods and the hardness of the rhino's horn. So why you might scoff at using twisty-ties in place of a hitch, remember that nature has had great success at holding things together with weak components. On that note, I'm off to hitch a trailer.

On The Nature of Grad School

As I prepare to enter grad school, I've been pondering on the nature of the beast that I will soon be jumping into.

I believe that the purpose of graduate study (at least for the science Ph.D.s) is to move the individual from a "student" to a "fully functional independent researcher". That when you get your diploma, you should be able to start your career later that hour. Granted there might be a training period where you will get up to speed on current literature (especially in industry), but other than that you are ready to go.

I think that this is applicable to students pursuing a career in either academia or industry.

Although there are often no formal classes required after a few years, students will still be learning as much as if they were. If your research delves into the depth of some topic that you are unfamiliar with, you are going to have to master it to be able to persevere. Signifying a move from class-oriented learning to self-oriented learning.

Genetically Modified Organisms in Drug Production

I believe that the importance of the synthetic chemistry in large scale drug production will be overshadowed and eventually eliminated by synthetic biology via genetically modified organisms (GMOs). Furthermore, I surmise that this shift will occur before I retire from my research career (of which I am just beginning).

The traditional methods used to manufacture drugs rely on organic chemistry. While time tested and effective, these methods often create large amounts of toxic waste and require high amounts of energy (such as temperature or pressure).

Nature, on the other hand, has the evolved the ability to create molecules of equal (and much greater) complexity at normal atmospheric pressure, with no toxic waste products and with whatever the temperature happens to be. For mammals, the temperature is typically constant (body temperature) but unicellular organisms are at the mercy of ambient temperature.

With an optimized GMO, one literally feeds the thing sugar and it spits out any product that it was modified to create with little to no toxic by products.

The notion that a bacteria produced your heart medication might seem far fetched and slightly futuristic. But Dr. Keasling was awarded the distinction of Scientist of the Year in 2006 by Discover Magazine for his research on using GMOs to produce an anti-malarial drug.

I believe that as pressures for "green" or eco-friendly science increase and as GMO technology is further validated and refined, it will quickly become the main method of choice for drug production.

The Pros of GMOs

I believe that GMOs will quickly become a more cost effective method in drug production than traditional synthetic chemistry due to the:

• low cost of starting materials (Sugar, or other cheap carbon source)
• lack of toxic waste products (Saving disposal costs)
  
• low cost to escalate production (As many GMOs can be created from the same base organism, the required manufacturing infrastructure would also be similar)
  

One Photosynthetic Organism To Synthesize Them All
- The Pinnacle of GMO Tech

In theory, a GMO could contain the genetic instructions to create thousands of drugs. A manufacturer might create a GMO that could produce every drug that the company has the rights to produce. The company would then tell the organism which set of genes to turn on via some messaging pathway, and then extract the product.

One could even create the GMO from a photosynthetic organism. Now the GMO gets its energy from the sun and uses naturally occurring carbon dioxide as the carbon source. Imagine a world, where carbon dioxide emissions are partly controlled by the production of the current erectile dysfunction pill. I shudder at the potential marketing campaigns.

Where the Technology Stands Today

Instead of a GMO creating the entire drug, the technology is at a stage where a GMO completes only one step in the process. This is due to the difficulty of getting several artificial genes to work together in the cell.

Realistically as companies start to take advantage of this technology, it will not immediately replace traditional synthetic chemistry but work in tandem with it. Where five steps of the synthesis are done via traditional methods, two steps might be completed with GMOs.

As it takes a long period of time to validate the safety of new drug manufacturing methods, it will be a while before GMO manufacturing really hits full steam.

Why Synthetic Chemistry Will Never Disappear Completely from Drug Manufacturing

Although synthetic biology will be the main choice for large scale drug production, I think that drug manufacturers will still have a need for synthetic chemistry.

The greatest strength of synthetic chemistry is that it has a quicker turn around time, in terms of from the drawing board to the bench top, than synthetic biology does. This means that if a company needed a batch of some previously never before synthesized compound for preliminary testing, it would be quicker (and probably cheaper) to utilize synthetic chemistry.

Synthetic chemistry is faster because it allows an "any means available" paradigm to the synthesis process. If the most effective process employs a toxic agent, thats okay. By utilizing an a-biotic reaction system, the scientists are free from the constrains of only using compounds that are non-toxic to the GMO. This allows a scientists to use the most effective compound regardless of its affect on some organism.

Furthermore, GMO creation is a time-intensive and empirical process. Inserting additional genetic material into a cell is analogous to adding car manufacturing capabilities into an aircraft carrier. The system already is already chalk full of cellular machinery and one is trying to insert more. If the newly inserted genetic material affects any of the other pathways operating in the cell, it can easily cause the cell to die.

Additionally, the required genes need to be found (taken from other organisms) or created (if an adequate match does not exist).

What These Production Plants May Look Like

To surmise what plants based on synthetic biology technology may look like, we can look towards current systems that employ organisms in the production process. Beer. Beer production employs yeast, a unicellular organism. The yeast is added to vats containing the reaction mixture, allowed to react for a specific time and then the mixture is removed and separated.

I believe that other production plants utilizing GMOs would be very similar in nature. The beer industry has very high standards for constant sanitizing, which would be necessary in any plant utilizing microorganisms. It is interesting to think that the plants that make our life sustaining medication might look oddly similar to the plants that make our beer.

What This All Means for the Chemist

As GMOs gain prevalence in the industry, there would be a corresponding decrease in demand for synthetic chemists as GMOs fall in the domain of biologists. So what can a chemist do to maintain employability?

When synthetic chemistry first started, its goal was the creation of compounds utilizing any means available. In the past, these means were mainly inorganic. Today, these means include living organisms. To maintain competitive in the synthesis domain, chemists will have to become more familiar with the technology offered through synthetic biology.

The truly competitive individual will not label themselves as a synthetic chemist or synthetic biologist but as a synthetic biochemist - utilizing "any means available" for the synthesis of a target compound.

My Nerdiest Possesion - An Autographed Periodic Table

My most prized science related possession is a periodic table signed by Dr. Seaborg.

Dr. Seaborg is (and will be) the only person to have an element named after him while he was still alive.

Dr. Seaborg's research included the discovery and characterization of 10 undiscovered elements and 100 undiscovered isotopes. His research mainly focused on the heavy f-block elements.

Few researchers are able to claim so many fundamental discoveries to their name. As Lois and Clark's exploration revealed a plethora of information about the U.S., Dr. Seaborg's scientific career did the same for our understanding of the heavier atoms. Not only did he discover a large number of elements but he also elucidated the fundamental theories regarding their behavior, allowing for the prediction of undiscovered isotopes and the placement of these elements into the Periodic Table. This is quite amazing, if you think about it. It is analogous to Lois and Clark not only charting much of America's terrain for the first time, but then also elucidating the major geological processes that created them.

Dr. Seaborg was awarded a Nobel Prize in 1951.

On the Complexity Molecular Pathways

I remember the first cellular transduction pathway I encountered at the college level. Well, mainly I recall my bewilderment. Why on earth, I thought, would you need a 10 (or more) step sequence to get some desired result? I remember thinking that the corresponding diagram for the pathway made a Rube Goldberg device seem completely straightforward and rather elementary.

At first glance, it appears that cellular processes are the epitome of an inefficient red-tape laden bureaucratic system. That before messenger "A" can cause response "B" it might need 17 signatures, two stamps of approval, three forms and an official endorsement all in triplicate.

The mechanics and intricacies of these system is simply astounding. When studying most cellular pathways, one would be almost certain to find that:

• Each protein in the pathway will have numerous sites for activation and inhibition.
  
• Each protein, itself, can be made of multiple proteins, all working in unison.
  
• Internal messengers will be made to tell the system to "Start" but without any chemical alterations to that messenger, they will eventually cause the system to stop.
  
• The activity for each step in the pathway can be individually tweaked to create an astoundingly large range of possible rates for the entire pathway.
  
• Each activated molecule in this pathway is likely to play a key role in some completely different cellular pathway, which will initiate even more cellular responses.
  
• Despite the number of steps involved the message gets to the end destination on the millisecond time scale.
  

While the complexity of signal transduction is humbling, it does offer us some promising insights that we might be able to pass onto our everyday life. Mainly, if a non-thinking entity, such as a cell, is able to negotiate a highly regulated multi-level controlled system instantaneously, surely, we (a race of some-what intelligent beings) can one day figure out how to make it so we don't wait for hours at the local D.M.V.