Friday 2 March 2012

My thesis



Running Head: Neurogenesis





 Neurogenesis:
 A Practical Application to Humans
Thesis Paper
Kinesiology
Guelph Humber University
April 4, 2012
Gregory Roe










Neurogenesis: An Overview of Research
            For many years humans believed that the earth was square and then we decided that the earth was round. Humans also initially believed that earth was the center of the universe and after much deliberation we all finally agree that the earth rotates around the Sun, which is the center of our solar system. Constantly science has made new discoveries that have changed the outlook of our very existence. Once again science is making a new discovery which was once believed to be impossible; the rebuilding of damaged neurons. The concept of progenitor cells, cells that have no distinct function, being turned into neurons is called neurogenesis and it was believed for a long time that this phenomenon could not occur in the brains of mammals. Through extensive research it has been discovered that neurogenesis does occur in the brain of certain mammals, rats being the most popular test subject.
 A study done in 1965 was one of the first to show that neurogenesis does occur in the rat brain. A Thymidine-H tracer was given to the rats and using this tracer the proliferation of new neural cells could be observed. This was a scientific breakthrough because it showed that neurons can indeed be created post-natally. This opened up an entirely new field of research into neuroscience that one day hopes to find cures for brain illnesses. After watching the migration of cells in this study it was evident that undifferentiated cells migrate from the lateral ventricles of the brain to the hippocampus and more specifically the Dentate Gyrus of the brain. This study showed that there was a 6 times increase in neurons that migrated to the Dentate Gyrus after 3 months from birth. The study also demonstrated that there was a higher increase in neurogenesis with rats that were given testosterone. This study hypothesizes that hippocampal cells may act as receptors for gonadal hormones such as testosterone. However this study did not test other hormones, sexual and non-sexually related, which leaves other studies room to elaborate on the subject₅. Another study done on birds showed that testosterone increased neurogenesis as well. This study was the first ever to show the results of testosterone on a European male songbird. This study simply showed that there was an increase in neurogenesis in the ventricular zone and the auditory zone of the European Sterling. This neurogenesis was further increased with the incorporation of testosterone. This study  also showed that there was a decline in the production of testosterone and therefore, neurogenesis with age. This study went a little further than the previous testosterone study by showing that testosterone increases the amount of progenitor cells that actually become neurons in the hippocampus rather than increasing the number of progenitor cells in total. An age related decline in proliferation of cells was shown in this study as well. This increases the evidence of age related decrease in neurogenesis. Why exactly this decrease occurs was not discovered by this study. An interesting note near the end of the study shows that there may be a correlation with the singing activity to the amount of neurogenesis. It raises the speculation that there may be a connection between the amount of singing or the type of singing that is done by the song birds and the amount of neurogenesis₆.
 Many different research groups have shown that rats have neurogenic properties post natally however researchers are looking for evidence of neurogenesis in humans. Researchers started studying the guinea pig because the guinea pig has been shown to have a brain more closely related to a human brain rather than a rat or mouse. This study followed the same tracing protocol as the previous studies that have been discussed and used a Bromodeoxyuridine (BrdU) tracer. This tracer was followed in the guinea pig and similar results were shown compared to other neurogenic studies. There was a large increase in neurogenesis within the first month after birth followed by a steady decline until death of the specimen. This study decided to test the affect of glutamate receptors on neurogenesis. The results show that there was an increase in neurogenesis compared to the non- glutamate receptor group. This is interesting because it seems every study is finding a new chemical that increases the proliferation of neurons within the brain₇.
The concept of neurogenesis in human subjects has eluded scientists for some time and due to advancements in the scientific community an entirely new branch of human study has opened up.  Peter Eriksson was the first person to conduct a study that showed adult neurogenesis in the human brain. Before this study, only rodents and monkeys had shown neurogenesis in the brain.  It is believed that the body’s inability to reproduce progenitor cells in the brain is a direct cause of brain diseases and malfunctions. Eriksson performed research on patients who had recently died of cancer and a BrdU radioactive tracer was used. This tracer was followed through each of the patients and the proliferation of cancer cells was monitored. This tracer showed that there are three distinct areas of neurogenesis within the human brain. The Subgranular Zone (SGZ) of the Dentate Gyrus shows the largest amount of neurogenesis. The Granular Zone shows less neurogenesis than the SGZ but there is more neuron apoptosis in the Subgranular Zone compared to the Granular Zone. The Hilus of the Dentate Gyrus shows the least amount of proliferating cells however it has the least amount of cell death as well.  This also shows that progenitor cells seem to be greatly located in the Subventricular Zone of the brain and that these cells migrate to other parts of the brain to become different cells based on their individual roles within the brain. Furthermore, injury and external environmental stimulation seems to influence the rate of neurogenesis. Unfortunately this study was unable to prove that the progenitor cells within the Subventricular Zone (SVZ) had any function₁. Eriksson shows a graph of the three distinct areas of proliferation and their neurogenic correlations.(See appendix, figure 1 for graph).
California researchers were able to show the path of the progenitor cells once they left the Subventricular Zone. This study also used the BrdU marker to follow the cell proliferation within the body.  This study showed that progenitor cells reside at the border of the Hilus and the Granule Cell Layer (GCL) and travel into the Granule Cell Layer (see appendix, figure 2). In the GCL these cells have been shown to express NeuN and Calbindin, which are neural proliferation markers. Along with other scientist these researchers showed that neurogenesis decreases with age in the adult rodent. When the researchers compared the amount of neurogenesis within a 27 month old rat to that of a 6 month old rat the younger rat showed much more cell proliferation. Along with the decrease in neurogenesis the older rats showed an inability to react with the Polysialylated Neural Cell Adhesion Molecule. This molecule is crucial for the migration and axon elongation of new cells. This study shows that a decrease in neurogenesis is caused by a decrease in Granule Cell precursors.  This means that a decrease in neurogenesis can be attributed to a lack of new cells being created rather than cells dying. Most neurons are made prenatally. However, in mice, rats, rabbits, guinea pigs and cats, granule cells are made post-natally. These new Granule Cells are able to elongate their axons to the cerebellum, also known as the mossy fiber tract. This helps in two ways. First, it allows less glucose to be used for the cell so that glucose is not unnecessarily used. Secondly, it allows for less synaptic junctions to be made so the brain is less congested. This allows the brain to function better because it can have better control over all the different neural paths₂.
 Scientists from Great Britain led by PhD Drapeau showed the age related decline in neurogenesis in the SVZ and the Dentate Gyrus. It has been shown that in these two areas, the decline of new neurons being formed is the greatest out of all the neurogenic areas within the brain. (see appendix, figure 2 for a picture of the different areas of neurogenesis). Along with the Eriksson study, these researchers also showed that external environment had a huge effect on the decline of new neurons being formed. Researchers have actually been able to reactivate neurogenesis in the aging brain of humans. This proves that neurogenesis is not simply an inevitable cell process, but a cause of an environmental stimulation. Researchers in this study found that memory loss and neurogenesis had a direct correlation. Based on this analysis, researchers hypothesized that the formation of new neurons was responsible for memory processing. It was further hypothesized that age related memory failure was due to a decrease in neurogenesis is older populations. Interestingly enough this article found that the aging affects the proliferation of new granule cells rather than the absolute number. This theory is backed up by the fact that cell apoptosis is slowed down in the Dentate Gyrus. Rodents that were studied showed that there was a 3-4 times decrease in cell proliferation in middle aged rats compared to young rats. Cell markers were used to determine the amount of active precursor cells in the test subjects. What they found was that the number of precursor cells did not change in young, middle and old aged rodents. This may mean that aging is not correlated with the total amount of precursor cells, but is correlated with the amount of activated precursor cells. A decrease in the proportion of active precursor cells is associated with age-related changes in the brain’s environment. The article goes on to say that a potential reason that cells stop proliferating could be due to a decrease in mitotic stimuli. This could be for two  reasons. (1) The signals that increase neurogenesis diminish in the older populations and the inhibitory signals of neurogenesis increase with age,(2) neurogenesis can be increased by reversing the inhibitory signals and increasing the proliferating signals. It has been shown that neurogenesis does not increase by speeding up the cell cycle, but by increasing the amount of precursor cells in the brain. It is interesting that cells can stop proliferating but still retain ability to do so under the right stimulus₃. This study concludes that more research needs to be done on age related neurogenesis correlations however it does make some interesting preliminary ideas₈.
 Many other research and review articles show that proliferation of new neurons decreases with age, however a study done at a University in Germany shows the relationship better than any other. The German researchers studied proliferation of neurons from 0-100 years of age and found very conclusive evidence that the studies on rats can be recreated to be done on humans as well. This group of researchers were trying to connect the rodent brain to the human brain by finding common cell proliferation markers. Doublecortin (DCX), one of the markers used is a marker used in rodents that shows neurogenesis in the Dentate Gyrus of the rodent adult brain. This same marker was used on human tissue where 54 humans were tested positive for DCX expression from 0-100 years of age. The total amount of cells that expressed DCX decreased over time which backs up the findings of the above study.  Along with DCX, other markers were expressed in human tissue and some of these markers were expressed until 100 years. This research was the first to demonstrate the link between rodent neurogenic research and human research₄. This article showed a great graphical interpretation of different tracers and their lifespan in the body. (See appendix, figure 3). The researchers admit more work needs to be done on finding a link between rodents and humans. However it was a breakthrough none the less.
The proliferation of cells within the brain causes new neurons to be formed within the brain, which we have examined in this paper. However there is evidence to prove that the brain is not the only nerve structure in the body that can be reproduced after an injury. A study done on rats showed that, after death, the rat’s spinal nerve cells were grown in vitro. It was hypothesized near the end of the report that the precursor cells are derived from neuroepithelial cells located within the rodents’ embroytic neural tube. The cells within the neural tube can replicate into any form of nerve cell and it is believed the cells are migrated towards the spinal cord during an injury. This study did not go into very much detail due to the fact it was one of the first to demonstrate that spinal cord reproduction is even possible. The researchers showed that when certain protein expression was increased in the culture cells it would cause an increase in neuronal cells. Neuron Specific Enolase (NSE), Neuron Specific B-Tubulin  and Glial Fibrillary Acidic Protein were given to the rats. Neuron Specific B Tubulin showed a much larger increase in neuron proliferation compared to the Neuron Specific Enolase. The former is a protein used to develop the exoskeleton of neurons and NSE is a protein that is known as a Phosphopyruvate Hydratase which cleaves oxygen and carbon bonds. The research would suggest that because an increased proliferation of the cells given Neuron Specific B Tubulin, that it plays a more important role in the proliferation of neuronal cells within the nervous system rather than the NSE₉.
  Many different articles have tried to show that neurogenesis is controlled by the external environment rather than solely the internal environment. Drapeau led another study wanting to determine if exercise, forced or from free will, would show an increase or decrease in neurogenesis in rats. This study showed that there was a two-fold increase in proliferating cells within the rodents that were able to run freely on a wheel rather than being forced to remain in a confined area. Rats were forced to do the water maze test and the Yoked swim test and the results showed no increase in neurogenesis with this form of training. This suggests that these tests alone are not enough to stimulate neuron growth.  Other studies used treats as a positive re-enforcer; however this study did not so that all nutrition based proliferations could be excluded from the study.  The rats were kept in groups of three or four and showed a small increase in neural proliferation which suggests that social interaction can be a contributing factor to neurogenesis₁₁. Another study showed that there was an increase in neurogenesis with the rats that got better results in the water maze test. These researchers used the same protocol as the others with the BrdU tracing and examined rats performing the water maze test. The rats who had a lower latency period showed an increased number of BrdU positive cells which suggests that there is an increased neurogenic proliferation with spatial learning. The researchers hypothesized that the formation of new neurons is correlated to the development of new learning and formation of memories₁₂.
 A study done in 2006 does not back up these findings but showed that rats could learn and retain information similarly with rats that had irradiation treatment. The researchers made a control group and a non-neurogenesis group from the rats. The control group, along with the non-neurogenesis group were injected with BrdU tracer and a comparison of learning was observed. One group of rodents was also given 10 minutes of gamma radiation for two consecutive days because it had been shown to reduce neurogenesis by 78% without any side effects. The other group was not given any radiation. The control and irradiation rats were shocked and underwent fear conditioning in a special chamber. The end results were that there was no significant different between the control group and the irradiation group. The researchers note this and refer to other researchers that found results on both sides of the argument, one being that neurogenesis causes increased learning and the other being that neurogenesis  does not affect all types of learning. The researchers conclude that spatial learning has been shown to increase with neurogenesis and also state that much more research needs to be done in the topic₁₃.
Even though there is not a very definite link between neurogenesis and certain forms of memory retention and learning there is a much stronger correlation between neurogenesis and depression.  Serotonin seems to be the big neurotransmitter that is increased during anti-depressant therapy. It has been previously shown that serotonin has neurogenic effects especially during development of the CNS. The 5HT 1A receptor seems to play a big role in the neurogenic effects of serotoninD,1-fenfluramine, a drug used as an anti-depressant has been previously shown to increase neurogenesis ₁₄.  It was also shown that activating the 5HT 1A receptors increased the survival of new born cells. Another study showed that the depletion of serotonin or the destruction of serotonin producing neurons caused drastic decreases in neurogenesis. Another article used Fluoxetine, a well known anti-depressant that increases serotonin within the brain, and showed that there was a 70% increase in neurogenesis. Serotonin is not the only neurotransmitter that has been shown to increase neurogenesis. A study done on glutamate and GABA relationships in the brain showed that GABA may be a negative feedback loop to decrease neurogenesis by destroying DNA. Also it showed that glutamate may be a positive feedback loop causing the increase in proliferation of cells in the SVZ. A different article went further to say that Metabotropic Glutamate receptors within the neurons have a direct correlation to neurogenesis. More specifically the mGlu5 receptor was found in early life, postnatally in areas of the brain that showed neurogenesis. The mGlu5 receptor was found in the External Granule Layer(EGL) of the cerebellar cortex and within the SVZ. BrdU staining successfully showed proliferation of new neurons in these regions of the brain. This study concluded that either the mGlu5 receptor was responsible for directly proliferating new neurons or differentiating them from progenitor cells₁₆.
Adenosine Triphosphate’s (ATP) also have come up in the battle for neurogenesis. This research found that ATP was created from progenitor cells that released energy in bursts. An increase in ATP in the brain has showed that neurogenesis increased because an increased amount of progenitor cells differentiated into neurons₁₇.
Along with different neurotransmitters, stress has been shown to have an effect on neurogenesis. One study showed that in monkeys, neurogenesis decreased. A group of monkey’s that had either early or late stress pregnancies showed a decrease in neurogenesis. The researchers did not find a significant difference regarding the time of the stress during the pregnancy. The early stress monkeys had a 21% reduction in neurogensis compared to the controls and the late stress monkeys had a 23% reduction in neurogenesis compared to controls, using BrdU tracing₁₈. Not all stress on the body is bad however because another  article showed that exercise had a direct correlation with increased neurogenesis in the dentate gyrus. Researchers measured the cerebral blood volume in the brain with MRI techniques and found that the blood volume in the brain directly correlated with cognitive and cardiopulmonary functioning. This study showed that exercise specifically targets the dentate gyrus which has been shown to have a direct correlation with cognitive aging and memory₁₉.
The brain uses fats for membrane phospholipids and it is essential in the development and the maintenance of the brain and its functions. Docosahexaenoic acid was experimented on rats to determine if there was a neurogenic effect on the brain due to fat ingestion. The results showed that Docosahexaenoic acid did have a correlation with neurogenesis in the rat brain. Researchers found that there was a decrease in neurogenesis in the brain with a reduction of this lipid₂₆.
Lipids are not the only important nutritional requirement for neurogenesis; it turns out that a malnourished state also halts neurogenesis. Rats were given 4% DRI of protein (casein) (Malnurished) or 24% of DRI (nourished). The results showed that the malnourished group had less proliferating neurons in the brain compared to the nourished group₂₁. A very interesting study revealed that statins may have a positive influence on neurogenesis in the brain.  The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitors have been shown to reduce the production of cholesterol and isoprenoids, which are lipids that regulate cell function. Statins have been shown to protect against Alzheimer’s disease (AD) as well which affects the dentate gyrus. Statins have been reported to increase blood flow to injured areas of the body and to increase cerebral blood flow. After a stroke, two different types of statins were given to rats and the results show that statins increase blood flow to the injured area of the brain and this causes an increase in neurogenesis after a stroke₂₂.
Alzheimer’s disease is a neurodegenerative disease where for previously unknown reasons the neurons within the brain begin to deteriorate. It has been a long path in the science world to discover why exactly neurons just randomly degenerate. A study showed that the build up of B-Amyloid plaques and fibrillary tangles are one of the causes of this form of dementia. How exactly these are formed is still a question for scientists however. This study showed that neurogenesis does occur in the CA1 part of the brain within the Dentate gyrus and if neurogenesis can be increased artificially then Alzheimer’s and related diseases can potentially be reversed₂₃. Inflammation of the neurons and the surrounding structures within the brain, have been reported cause for a decline in neurogenesis and a cause of AD. This study took an inflammatory blocker, indomethacine, and gave it to rats to determine if neurogenesis could be increased after radiation was induced. The results showed that the inflammation was decreased and caused an increase in neurogenesis. Patients with AD are given anti-inflammatorys as part of their regular medication₂₇.
 Many different proteins have been studied to try and determine if any may hold the key to increasing neurogenesis. One study showed that Reelin, an extracellular protein that is instrumental for brain development and neuron migration that functions through a lipoprotein receptor, may have a positive effect on neurogenesis. It has been shown that Reelin is expressed by GABAergic neurons and is crucial for the development of dendrites. These dendrites create new synapses which can fix broken chains in the brain. Reelin has been shown to be deficient in patients with AD and therefore has been linked to many neurodegnerative diseases. This study done on mice conclude that an over expression of Reelin can cause neurogenesis in the adult forebrain in mice by causing progenitor cell differentiation₂₄. Many different proteins need to still be experimented on and research is currently trying to find the links between neurogenesis and protein structure. Hopefully one day a protein that can be synthesized can be given to certain populations that are in need of new neurons in their brains.
A 2005 study showed a relatively unique concept for increasing neurogenesis in the brain. Researchers from this article reported that lithium can be used to treat patients with neurodegenerative diseases such as AD. Lithium is reported to be a mood stabilizer for patients with depression and neurodegenerative diseases. It is reported that lithium up-regulated the proteins involved in cell survival such as Brain-Derived Neurotropic Factor (BDNF). This study showed that lithium may prevent or even reverse neurodegeneration₃₃.
Future Research:
The world of neurogenesis has vast amounts of possibilities that all seem to try and point to a cure for brain malfunctions. Now knowing that neurons and supporting structures can be remade in the brain after injury, the race is on for a legitimate cure for those who need it. Many different brain diseases such as Alzheimer’s and other forms of dementia would be greatly affected by a synthetic way to create neurons. Due to hippocampal degeneration these neurologic diseases have been previously thought to be incurable. The solution based on research may even start with the basics, a well balanced diet. A study on patients with Alzheimer’s showed an increase in memory when given a proper diet₂₅. (See appendix, figure 4 for graph). Not enough humans get a well balanced diet in society due to the busy lifestyles many lead. Europe has a mandatory 6 week-off vacation period every year and many get more time off based on their jobs. Europeans are also healthier then North Americans and in a recent study done comparing 14 countries it was shown that Europeans have a higher life expectancy then Canadians and Americans₂₉. I believe that this is because of the fact that Europeans have longer vacation periods annually₂₈. As noted above by Coe et al., stress diminishes neurogenesis in the brain which may be an underlying factor to why North Americans have an increased incidence of neurodegenerative diseases₁₈,₂₉. I have always believed that too much stress in one’s life can only do more harm than good. I believe a mandatory day off every 4 days should be administered to North Americans to see if there is a decrease in degenerative diseases such as dementia. Unfortunately if people started taking more time off businesses would face hard times having to pay more money to keep the business running. I believe that military funding should be cut and transferred to human life expectancy programs. Such programs would include mandatory vacations larger than the 2 weeks allowed currently. A week break every few months would be a great start I believe. Muscles get over used during repeated use without sufficient rest so why should we believe that the brain does not function the same way? Research has not really answered the question as to “what happens when the brain is over used?” .Personally I believe it will shut down and that different forms of dementia are the bodies way of telling people it has had enough and the brain begins to die. Stress has been shown to slow down neurogenesis and I believe that we need to take that as a warning that North Americans need to change the way we are living. I believe constructing time off is needed. This may include sports, musical learning, constructive hobbies such as building models, art etc. The brain needs to be used, like muscles in order to maintain a certain level of functioning, however we need to be careful what we do in our spare time.  Our society revolves around monetary values, but maybe we need to focus on well being rather than destroying our neurons to get a new Mercedes Benz.
Neuroscience is currently working on ways to put small electrodes in the brain that will conduct electrical signals around the brain in manipulated ways. Some researchers are using this science to block pain while others use it to try and increase reaction time. What if we used electrodes to create a bridge between inactive neurons and restore brain function?  In 2002 electrodes were put into patients with Parkinson’s disease which is a neurodegenerative disorder like Alzheimer’s disease₃₁. Eloctrodes were put in the brain that vibrated very fast and caused cells in the brain to be more active. The results showed that if stimulation around 130Hz was achieved, then the patient’s involuntary contractions would cease. If electrodes were put into the brain theoretically that would either, (1) stimulate neurons in the brain to keep firing or increase activity, or (2) be formed in a way that the electrodes could form a bride between active neurons that passed inactive cells. This has not been tested yet, however scientists do have the equipment to do this. This suggestion does bring in an ethical issue however. Some people may argue that surgery is very invasive and that patients should not have to go through that procedure. I believe that if you have patients with neurodegenerative diseases a chance to live an increased normal life, to any degree that they would agree. If they don’t agree then nothing says they have to participate. Until a clear electrode based solution is constructed I believe that we have an untapped human resource for testing. Death row inmates have no rights because the government is telling them that they do not have the right to life any more. So why not use these inmates as experiments. If they are going to be killed anyways, scientists should at least put their death to use. Penitentiaries could go as far as to say that if long term inmates that are not on death row volunteer for scientific experimentation, that time would be taken off their sentence, or if they are a true public threat, that they get benefits in their sentence such as extra yard time or a choice in food. Many will argue this point strongly, however I don’t see how anyone can say they will end a life and that that falls within moral constraints but then say that the inmates have the right to not be to use.  Why inmates have sit around and use people’s tax money? Why not make them useful in some way?
Scientists have been struggling to find many different supplements that may increase neurogenesis and many have been successful in showing ways to increase the number of proliferating cells. These methods have already been implemented into treatment processes. Scientists are looking for a larger solution that will either stop neurogenesis all together or restore brain function to vast degrees that has not been discovered yet. The area of Gene modification has been shown to be a potential solution down the road when researchers can gain a better understanding of exactly how to manipulate genes. For example (Pattyn et al, 1997), did a study on the effects of the Phox 2a and Phox 2b genes and their role in Neurogenesis. This study showed that the activation or the increase of expression of these two genes increased neurogenesis in the hindbrain. The many genes that cause neurogenesis and diminish it have been identified through many different research projects but recreating these genes and implementing or inactivating them still poses a problem. Scientists do not have the equipment to be able to manipulate the human genome in live subjects in this way. Simply, further research needs to be done in this area because the route of all success and failures of the human body stem from the blue print, ie. genes.
If researchers can label, recreate or activate/ inactivate genes relating to neurogenesis then many possibilities open up, one of them being a cure to many mental diseases like dementia. An equally large benefit from discovering these genes is the possibility to cure paralysis in certain subjects. Paralysis is a nerve that has been broken or disconnected from the rest of the nervous system causing the affected area to not respond to mental or physical stimulation. If scientists can either rebuild neurons from the inside (neurogenesis) or create artificial bridges in the body then potentially people can learn to regain function of lost body segments. Unfortunately researchers are trying to fight fate because death is inevitable and the research that is being done is simply trying to delay death. Humans are living longer lives than previously but the root cause of death itself is still unknown. Why exactly do humans die?  Some believe it’s the body getting tired and finally calling it quits. Some believe it is the constant pulling of gravity on the human body and after so many years the genes and proteins of the body, as well as its tissues simply break down. Whatever the reason is, scientists are theoretically trying to make humans live longer by altering genes and discovering a way to increase neurogenesis is one of the pathways.



Appendix:
Figure 1: Fig 2 full size
Figure 1 a graphical depiction of the number of BrdU cells labelled in the brain after a certain amount of days- note the decrease in numbers with increased age


An external file that holds a picture, illustration, etc.
Object name is acel0007-0569-f1.jpg Object name is acel0007-0569-f1.jpg
Figure 2-  a graphical interpretation of the areas of high proliferation of new neurons within the brain. Note the layers of the GCL, SGL and the Hilus. This picture shows the path of progenitor cells as noted on page 5, par 2 ( Khun et al.)


 http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0008809.g006&representation=PNG_M
Figure 3- life span of different tracers in the body
Figure 4: http://www.ajcn.org/content/74/5/687/F2.medium.gif
Figure 4 - graph showing the effects of different macromolecule nutrition levels on memory scores in patients with Alzeimer's Disease















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