Brain-Machine Interfaces & Brain Plasticity

On Oct. 16, 2008, Julie Steenhuysen filed a report for Reuters entitled "Device helps monkeys move paralyzed wrists" describing a recent break through in fundamental research on brain-machine interfaces that considerably broadens avenues for the prosthetic control of limb movement. The findings are published in the journal Nature (Moritz and others, 2008). National Public Radio's Morning Edition provided an interview by Dan Charles entitled "Monkey Studies Could Help Paralyzed Humans" with the first author of the study. I have written about such interfaces in my post dated Jan 23, 2008.

The researchers at the University of Washington temporarily numbed nerves controlling arm movement in monkeys. Fine electrical leads were implanted into the area of cerebral cortex that controls limb movement known as motor cortex. The leads were used to record the electrical signals that nerve cells use to control skeletal muscle contraction. The signals were amplified, electronically transformed and fed into wire electrodes implanted into the muscles of the numbed arm. The monkeys learned to execute goal-directed movements with this limb. The results constitute a mile stone proving both the applicability of the electronic interface and the versatility of the motor system to utilize the new extraordinary tool in a meaningful fashion.

The nerve cells in our central nervous system that innervate the skeletal musculature are known as motor neurons. When peripheral nerve injury severs their axons, that is the nerve fibers that establish the connections with the muscle fibers, motor neurons can regenerate the disrupted connections. During this period, the cells are subjected to remarkable alterations. A glial reaction ensues in their vicinity. In my own experience, strong signs of the glial response can be detected on histological tissue sections within four days after nerve injury. The signs are visible on this micrograph from a transverse section through the brain stem of a rat.

microglia, courtesy of J.A. McKanna

The hypoglossal nerve, that is the twelfth cranial nerve innervating the muscles of the tongue, was damaged on the right side (left in the micrograph). The bodies of nerve cells are stained blue in the micrograph. Microglia are stained black. The cell bodies of the axotomized motor neurons (asterisk) are located left of the center of the section in an area called hypoglossal nucleus. Microglia (arrowhead) are gathered in great number among the axotomized motor neurons and wrap themselves around their bodies (arrow), detaching incoming nerve contacts known as synapses that convey command and control for muscle contraction from the fore brain. The motor neurons undergo chromatolysis and increase protein synthesis. David Bodian described the cellular changes using electron microscopy in great detail in the Johns Hopkins Hospital Bulletin (Bodian, 1964). Blinzinger and Kreutzberg (1968) were the first to identify the cells that insert themselves between the motor neuron and the synapses as microglia. After roughly two months the glial reaction ceases, the synapses re-attach to the cell bodies, and the motor neurons regain much of their original appearance. Major histo-compatibility complexes have been identified as one major group of signal molecules that control the observed glial and motor neuron responses to axotomy (Oliveira and others, 2004).

The ability of motor neurons to re-establish disrupted muscle innervation is a fascinating example of our brain's ability to recover from injury. However, it is important to note that the repair is imperfect. The novel innervation commonly remains below original strength and the endings of the motor neurons may not succeed in finding their original muscle fibers (Madaschi and others, 2003). Intriguingly, the nerve cells in the central nervous system are able to adjust to the altered peripheral innervation. Sprouting of novel connections has been proposed as mechanism (Fujito and Aoki, 2002). In fact, the plasticity of the motor system is so great that animals reportedly learn meaningful limb movements even after the surgical cross of nerves controlling antagonistic muscles [Sperry, 1941 (reviewed by Todman, 2008)].

Taking this enormous flexibility of the motor system into consideration, the directed arm movements of the interfaced monkeys Moritz and others (2008) observed may not entirely come as a surprise. Doubtlessly, the technology to transform the nerve cell signals recorded in the cerebral motor cortex into meaningful stimuli for the arm muscles is a daunting achievement. However, it is important to emphasize that the success of this method ultimately relies upon the nerve cells that alter their electrical discharges in order to produce the desired movement. As pointed out on the National Public Radio broadcast, the fascinating discovery is the rapidity with which the nerve cells learn to direct a movement under extraordinary experimental conditions. The question remains to be answered whether special cells or a special ensemble of cells is needed to produce fine-grain limb control.

Addendum

• On Feb. 10, 2009, Pam Belluck reported in her post entitled "In New Procedure, Artificial Arm Listens to Brain" for The New York Times on a promising variation of this idea published in The Journal of the American Medical Association (JAMA 301(6):619-628). With the new procedure, Kuiken and others (2009) planted wire electrodes over functional muscle groups that a patient with a lost limb can control. The electrical nerve signals recorded from the electrodes when the patient is using the underlying muscles are subsequently employed to steer a prosthesis replacing the missing limb. With practice, the patients learn to substitute the contractions of the intact muscles with prosthetic limb movements to the extent that they feel the limb manipulated when the skin over the muscles is touched (02/11/2009).

References

• Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Cell Tissue Res 85: 145-157.
• Bodian D (1964) An electron-microscopic study of the monkey spinal cord. I. Fine structure of normal motor column. II. Effects of retrograde chromatolysis. III. Cytological effects of mild and virulent poliovirus infection. Bull Johns Hopkins Hosp 114: 13-119.
• Fujito Y, Aoki M (2002) Distal forelimb cross-innervation effectively induces formation of corticorubral synapses. Neuroreport 13: 2121-2124.
• Kuiken TA, Li G, Lock BA, Lipschutz RD, Miller LA, Stubblefield KA, Englehart KB (2009) Targeted muscle reinnervation for real-time myoelectric control of multifunction artificial arms. JAMA 301: 619-628.
• Madaschi L, Di Giulio AM, Gorio A (2003) Muscle Reinnervation and IGF-I Synthesis Are Affected by Exposure to Heparin: An Effect Partially Antagonized by Anti-Growth Hormone-Releasing Hormone. Neurochem Res 28: 163-168.
• Moritz CT, Perlmutter SI, Fetz, EE (2008) Direct control of paralysed muscles by cortical neurons. Nature 456: 639-642.
• Oliveira AL, Thams S, Lidman O, Piehl F, Hökfelt T, Kärre K, Lindå H, Cullheim S (2008) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci U S A 101: 17843-17848.
• Sperry RW (1941) The effect of crossing antagonistic muscles in the hind limb of the rat. J Comp Neurol, 75: 1-19.
• Todman, D (2008) History of Neuroscience: Roger Sperry (1913-1994), IBRO History of Neuroscience

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Glioblastoma multiforme: The Octopus in the Brain

Cancer is a life-changing experience. Senator Edward Kennedy has been diagnosed with brain cancer. The ensuing media attention to this horrible disease has touched on a number of fundamental issues. However, the reporting has remained often vague. The vagueness is the inevitable result of the uncertainties involved.

To begin with, uncertainty is an integral part of any cancer. Prognoses of outcome for cancer therapies are probabilistic, diametrically opposed to our craving for definitive answers. We are challenged to beat odds. Yet, we only feel safe, when we know for sure what is going to happen to us. With cancer therapy there can be no assurance of success, only indications from prior experience that the therapy may prolong our lives and hope.

Senator Kennedy's tumor was located in the parietal lobe of the cerebral cortex. This area is large. Nerve cells on its borders process sensory information of mainly one modality. Nerve cells in its interior process multi-modal input, integrating information across multiple senses. The cortical regions that truly fit the idea of the center for a particular function are few. Primary sensory areas may fulfill this requirement best. They receive the most direct input from a particular sense organ and process predominantly information of this sense's modality. For example, a stroke in the primary somatic sensory area at the forward border of the parietal lobe predictably impairs the sense of touch. Therefore, this area may be designated a cortical center for touch. By contrast, injuries in the large swath of parietal cortex stretching backward from the primary somatic sensory area may only lead to subtle loss of sensory function. Attention, speech comprehension and short-term memory may be affected, dependent on the location of the damage. Hence, the uncertainty in the prognosis of the tumor's impact on brain function is rooted in our incomplete understanding of parietal lobe function. More research is needed in this area.

Even less is known about the nature of Senator Kennedy's tumor. Nerve cells and glia represent the most prevalent cell types in brain tissue. Nerve cells multiply at high rate only in the developing brain. In the mature brain, nerve cell proliferation is much reduced and restricted to a small number of regions. In contrast, glia retain the ability to multiply throughout life. The glia in the brain's gray matter essentially consist of astrocytes and microglia.

Astrocytes play vital roles in support of nerve cell function. For example, astrocytes remove the excitatory neurotransmitter glutamate from the space between cells. Neurotransmitters are substances that mediate the transfer of information between nerve cells. Too much glutamate in the extracellular space triggers a program in nerve cells leading to their death (apoptosis). Microglia support the brain's immune response.

After an insult to the brain, astrocytes and microglia increase in number at the site of the injury, owing to cell division and migration. Astrocytes form a glial scar encapsulating the damaged tissue. Microglia are known to incorporate debris of severed nerve cell connections (axons). The glial reaction extends from the site of the injury, following the tracts of severed connections. If the glial reaction progresses normal, the debris is digested and the tissue heals. The glia cease dividing and decrease in number.

At times, however, glia begin to proliferate abnormally without any known reason and the cells do not stop dividing. Aggressive, fast growth of a tumor ensues. Astrocytes develop the most malignant tumors known as glioblastoma multiforme, or GBM for short. Once the tumor reaches a certain size, the blood-brain-barrier is breached. Fluid invades the brain tissue, forming an edema. Nerve cell function is severely impaired, leading to seizures and often hemiparesis. Glia hitherto uninvolved in neoplastic growth react to the injury. The glial reaction possibly recruits abnormal glia and fans out along the disrupted nerve cell connections, infiltrating healthy brain tissue.

At this juncture, the steps to be taken for Senator Kennedy seem straight to the point. The tumor's bulk has been excised. The edema has been addressed. Now, the remaining abnormal astrocytes have to be stopped from dividing. Ionizing radiation will be used to damage the DNA of the cells dividing in the margins of the tumor, arresting the cycle of cell division. Cytostatic chemotherapeutics will be administered to stop astrocytic division in regions outside the focus of radiation. In addition, the growth of blood vessels into cancerous tissue may be slowed with drugs that inhibit angiogenesis (but see addendum, dated Apr. 10, 2009).

I lost my father and two good friends to glioblastoma multiforme and sincerely wish that this regimen will benefit Senator Kennedy in the best possible ways. However, as scientist I know that this vicious disease will only be defeated, once we identify the molecules that signal glial proliferation and devise a method that permits us to specifically inhibit the proliferation of astrocytes.

Addenda

• Most likely, the molecule signaling glial proliferation is epidermal growth factor (EGF) and the EGF tyrosine kinase receptor needs to be inhibited (8/30/08).
• Perhaps, the phosphorylated protein is Annexin/Lipocortin 1 (Melzer and others, 1998) (10/02/08).
• Glioblastoma multiforme is a rapidly growing tumor, showing regional differences from normal brain tissue in its metabolism of sugar as a source of energy. F.M. Santandreu and others (2008) provide a comprehensive description of such metabolic aspects in Cellular Physiology and Biochemistry 22:757-768. Since the tumor cells can store little sugar, the resource has to be delivered constantly with the bloodstream. The fast tumor growth induces growth of blood vessels. Therefore, anti-angiogenic drugs that inhibit vessel growth may help to shrink the tumor (02/18/09).
• Hai Yan and others (2009) report somatic mutations of the mitochondrial enzyme isocitric acid dehydrogenase crucial for sugar metabolism in 70% of astrocytomas and oligodendrogliomas as well as glioblastomas that developed from these tumors (New England Journal of Medicine 360:765-773). The mutations are discussed as potential predispositions for tumorigenesis (02/19/09).
• Microglia reactive to nerve cell injury are shown in my post dated Oct. 17, 2008 (03/04/09).
• To date, there is no compelling evidence that the use of contemporary cell phones causes glioblastoma multiforme. See my post dated Aug. 21, 2008 (03/05/09).
• You may be interested in reckoning with the odds in my post dated Mar. 5, 2009 (03/06/09).
• Erika Check Hayden summarizes the latest insights into the effectiveness and pitfalls of angiogenesis inhibitors in this weeks issue of the journal Nature, vol. 458: 686-687 (04/10/09).
• Using RNA interference (RNAi), Australian scientists developed a method with which the expression of tyrosine kinase receptors can be blocked, making tumor cells more vulnerable to chemotherapeutics and diminishing the tumor cells' ability of developing resistance against the drugs (MacDiarmid and others, 2009). Michael Perry reported on this progress in his post with the title "Scientists kill cancer cells with 'trojan horse'" published online on Reuters yesterday (06/30/09).
• Senator Kennedy passed away yesterday (08/26/09).
• Last Tuesday, Sep. 7, 2009, National Public Radio's Talk of the Nation aired an interview by Neil Conan with the British neurosurgeon Henry Marsh on his charity work in the Ukraine and general aspects of his profession. National Public Television's POV showed a movie on his work that evening. The movie, "The English Surgeon", will available on DVD Nov. 3. Particularly towards the interview's end, Dr. Marsh highlights in striking clarity the importance of finding an experienced neurosurgeon for the successful removal of a glioblastoma (09/10/09).
• A recent clinical study by Sampson and others (2010) reported promising results in the treatment of glioblastoma multiforme (GBM), using vaccines that target epidermal growth factor receptor variant III, or EGFRvIII for short. The receptor is extraordinarily prevalent on the surface of the most-aggressively growing GBM cells, owing to a genetic mutation. Thirty-five patients with GBM were enrolled in the phase II clinical trial; all underwent surgery, radiation therapy and chemotherapy with temozolomide. In addition, 18 were inoculated with vaccines.  Adding vaccines almost doubled median survival time from 15 to 26 months, extending the progression-free period from 6.3 months to 14.2 months. The vaccination eliminated all cancer cells carrying EGFRvIII, except in one patient. Half of the patients showed an immune response. Six developed antibodies specific for the receptor and three showed a T-cell response, supporting the contention that the increased survival may be associated with the immune response. Nine of eleven patients, whose recurring tumors were examined, tested negative for EGFRvIII, indicating that the cells with this mutation had been persistently eradicated. Taken together, the findings suggest that vaccines may prove a promising new avenue of treatment, though not a cure, for glioblastoma muliforme. Celldex Therapeutics and Pfizer developed the currently tested vaccine known as rindopepimut or CDX-110 and PF-04948568, respectively (10/05/10).
• Listen to this interview with Gordon Murray by Robert Siegel broadcast on National Public Radio's All Things Considered today and find words of strength and encouragement from a man with GBM who is making the best of his situation (12/17/10).
• Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).

• 

  Color-coded image of a transaxial FDG PET scan from a GBM patient with a recurrent tumor in the left cortical hemisphere.  High local cerebral metabolic rates for glucose starkly delineate the tumor (low rate - blue; high rate- white; courtesy L. Sokoloff). 

  The functional image above was acquired from a patient with a glioblastoma multiforme in the left cerebral hemisphere. The initial primary tumor and had been surgically removed. The removal was incomplete. When symptoms suggested a recurrence of the tumor, the surgery had altered the anatomy of the cortical hemisphere to such extent that an evaluation of structural brain scans was impossible. However, a new tumor could be localized with positron emission tomography and the [¹⁸F]fluorodeoxyglucose (FDG) method (Di Chiro and others, 1982). This method allows us to image and measure the local glucose consumption of brain tissue. The rate of glucose utilization was highly increased in the core of the new tumor. Under normal physiological conditions, brain cells metabolize glucose to produce adenosine-triphosphate (ATP) in an oxygen-consuming metabolic pathway called aerobic glycolysis. ATP represents a ubiquitous high-energy molecule that cells need to maintain vital functions. Because glia possess only a small capacity of storing glucose and oxygen cannot be stored at all in the brain, the blood supply must continuously deliver both to the brain tissue. An increase in demand stimulates angiogenesis, that is blood vessel growth. However, in fast growing tumors angiogenesis cannot keep pace with demand. Moreover, the activity of certain types of key enzymes for glucose metabolism, known as mitochondria-associated hexokinases I and II, can be increased as much as 200-fold in tumor cells, leading to extremely high rates of aerobic glycolysis (Warburg effect) which compound the local oxygen shortage. Moreover, using tumor genome sequencing Yan and others (2009) identified a mutation that changes arginine 132 in the product of gene IDH1 isocitrate dehydrogenase. Isocitrate dehydrogenase is a key enzyme in the Krebs cycle providing substrates for aerobic glycolysis. This change in amino acid modifies the function of the enzyme such that the enzyme's substrate isocitric acid is turned into a novel product which cannot be used in the Krebs cycle, hampering the efficiency of aerobic glycolysis. More than 70 percent of 445 tested central nervous system tumors were astrocytomas, oligodendrogliomas and glioblastomas that had developed from lower-grade tumors. These rapidly-growing, malignant cancers possessed the mutation. As a consequence, glucose may be metabolized in the malignant tumor's core without the use of oxygen, though this anaerobic glycolysis is much less efficient in generating ATP than aerobic glycolysis. The observations may be taken to suggest the possibility of starving neoplastic astrocytes to death with a diet extremely low in carbohydrates. Alas, cells in other tissues of our body, e.g. muscles, routinely use vast amounts of glucose in anaerobic glycolysis to meet rapidly increasing energy demands while oxygen is in short supply. A no-carb diet is not going to be selective for the tumor and may rather weaken the body's overall resilience. By contrast, avoiding high-fructose corn syrup and sucrose used to sweeten countless foods and beverages may be beneficial, because the fructose in these sugars may stimulate insulin-like growth factors that promote neoplastic growth (see Gary Taubes' article with the title "Is Sugar Toxic?" published online in The New York Times on Apr. 13, 2011) (01/13/2012).
• Dang and others (2009) report that when IDH1 mutations turn arginine 132 into histidine, the gene's changed product isocitric acid dehydrogenase may catalyze the formation of R(-)-2-hydroxyglutarate known to be conducive to tumor growth (02/06/2012).
• The leader of the four-decade effort to develop the deoxyglucose method for the use in tumor imaging (see image above) Dr. Louis Sokoloff presented a historical lecture for the public with the title "Development of the [18F]Fluorodeoxyglucose Method: A Serendipitous Journey From Bench to Bedside" on the endeavor at Brookhaven National Laboratory Oct. 19, 2012, to celebrate the designation of its Chemistry Department by the American Chemical Society as a historical site for its role in this accomplishment (10/29/2012).
• Personal accounts of GBM patients describing their experience with treatment are rare. Two days ago (Sep. 23, 2013), the Washington Post published Fritz Anderson's post with the title "Surgery, radiation and chemo didn’t stop the tumor, but an experimental treatment did" published online. Dr. Anderson, a retired cardiologist, writes about his situation eloquently with great sensitivity and encouragement. After surgery, radiation therapy and chemotherapy his tumor regrew and he decided to participate in an experimental phase I trial of a therapeutic that consists of an altered polio virus (PVS-RIPO) that glioblastoma cells preferentially bind, infecting and destroying the cells. The trial is led by Prof. Matthias Gromeier at Duke University's Preston Robert Tisch Brain Tumor Center. The procedure is invasive, requiring a craniotomy, because the drug must be administered directly to the tumor tissue in one six-hour session. The therapy shrunk the tumor decisively, and Dr. Anderson continues to enjoy life. Four of five treated patients were blessed with success to date (Sep. 25, 2013).

References

• Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden M G, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739-744.
• Di Chiro G, DeLaPaz RL, Brooks RA, Sokoloff L, Kornblith PL, Smith BH, Patronas NJ, Kufta CV, Kessler RM, Johnston GS, Manning RG, Wolf AP (1982) Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography. Neurology 32:1323-1329.
• De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE,Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14:3098-3104.
• Check Hayden E (2009) Cutting off cancer's supply lines. Nature 458:686-687.
• MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM, Brahmbhatt H (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol 27:643-651.
• Melzer P, Savchenko V, McKanna JA (2001) Microglia, astrocytes, and macrophages react differentially to central and peripheral lesions in the developing and mature rat whisker-to-barrel pathway: a study using immunohistochemistry for lipocortin1, phosphotyrosine, s100 beta, and mannose receptors. Exp Neurol 68:63-77.
• Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon II JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic Escape After Prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol: doi: 10.1200/JCO.2010.28.6963.
• Santandreu FM, Brell M, Gene AH, Guevara R, Oliver1, Couce ME, Roca P (2008) Differences in mitochondrial function and anti- oxidant systems between regions of human glioma. Cell Physiol Biochem 22:757-768.
• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-773.

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Fahrenheit -459.67

Molecules need to be on the move to react with each other. Inspired by his observations on the thermodynamics of gas molecules, the Irish scientist Lord Kelvin conceived it useful to set to zero the temperature, at which molecular motion must come to a standstill. Today, his idea is recognized in the international system for measures, and units of temperature have been named in his honor. Extrapolation from experimental observation has pegged -459.67° Fahrenheit to zero degrees Kelvin. At this temperature, the molecules reach the state of lowest kinetic energy and greatest stability.

However, at higher temperature, molecules are in motion and chemical reactions occur. As a result, energy may be set free. Although this energy can be used to fuel other chemical reactions, some will dissipate unused. The loss is called entropy. Entropy commonly increases with the multitude and the complexity of the reactions, summarily advancing our universe toward Lord Kelvin's endpoint.

Life is an effort to stem this progress. In order to survive, living things need to preserve energy like surfers tirelessly weaving up and down the face of a wave. Every descend fuels the next ascend. Organisms as a whole as much as the cells they are built from have to meet this challenge. This is our lot in life.

In the battle against entropy, nothing lasts forever. The building blocks of living cells are subjected to wear and tear. They need to be continuously repaired or replaced. Even constant upkeep may not suffice. Most cells possess a limited lifespan. Primordial cells must continue proliferation to make up for the losses.

To satisfy these needs, cells rely on two essential tools. One tool is a repository of construction plans for the cellular components. The DNA in the cellular nucleus encodes these plans. The other tool is the machinery that reads the plans, can duplicate them and use the instructions to synthesize the proteins needed to build the cells' components and even entirely new cells. It is existential to protect the plans and keep the machinery functional in order to prevent the manufacture of faulty, useless, and even harmful products.

Free radicals, e.g. highly reactive forms of oxygen, constitute a major group of agents that may modify the construction plans and interfere with proper protein synthesis. Aromatic products of the incomplete combustion contained in barbecue and cigarette smoke, e.g. benzo[a]pyrene, are another group.

Cells possess quality control and repair mechanisms to contain the damage such agents cause, entering into a ceaseless contest between destruction and restoration. If vital functions cannot be repaired, either because of the magnitude of the damage or because the repair comes to a halt, the cells die.

In addition, cells may contain programs that are specifically in place to enact their death (apoptosis) and are used in regular development. For example, skin fuses our fingers together early in embryonic development. Eventually, programmed cell death separates the digits. When the programs for cell death are disabled and programs for cell proliferation are falsely engaged, the tissue may grow out of control, a condition known as cancer.

In the battle for renewal, the brain holds a special place among our organs. Nerve cells proliferate only in a few places in the mature brain, e.g. the olfactory bulbs and the hippocampus. Replacement is a scarce option. Much of the maintenance and repair is left to different cells called glia. The picture shows an early rendering of these cells in the work of Auguste Forel. He called them spider cells.

To date, the precise role of glia remains little understood. Early scientists believed that they constitute the glue that holds the brain together. We know now that one major type, astrocytes, plays an important role in keeping the environment viable for the nerve cells. They remove salts and molecules from the fluid in the extracellular space, preventing levels that would trigger cell death. In contrast to nerve cells, astrocytes multiply after brain injury inflicted by stroke and trauma, producing a gliosis. Astrocytes are also known to enter proliferation erronously. The most deleterious brain cancer, glioblastoma multiforme, is of astrocytic origin.

Microglia are the other major type of glia in the brain.  Their role is more mysterious than that of astrocytes. The difficulty mainly arises from the fact that these cells change considerably in appearance as part of their reaction to brain injury. In the absence of direct observation, it is hard to ascertain whether and how the various cell forms are related that scientists identify as microglia. Hence, it remains difficult to pinpoint their origin. A scientist I worked with had evidence to believe that the microglia accumulating at the site of injury are derived from cell populations resident in the brain. Others believe that they consist mainly of bone marrow-derived white blood cells that infiltrate the brain from the blood stream through a blood-brain-barrier rendered leaky by the injury. Recent findings support both contentions.

Irrespective of their provenance, microglia are supposed to provide the immune response of the brain. They are known to incorporate the debris left behind by dying nerve cells. They attain a plum shape in the process and some remain unchanged on location for many years, even decades, after the insult. We do not yet understand, why they reside there and what purpose they still serve. Regardless, I take it that they are good soldiers in our cosmic fight against entropy and see to it that we do not reach Fahrenheit -459.67 too quickly.

Addendum
I omitted to mention a formidable tool of living cells to stem entropy: enzymes. Enzymes are catalyzing proteins. That is, they facilitate chemical reactions that may happen only at random otherwise by bringing the components of the reaction together, accelerating the biochemical processes important to vital functions of living cells. Compartmentalization of enzymes, that is confining enzymes in distinct parts of the cell, helps organize the reactions into orderly sequences of separate processes, enabling meaningful signal transduction and the regulation of enzymic activity involved in cell anabolism and catabolism as well as in protein synthesis, replication and proliferation. The eminent biochemist Jaques Monod argued in his famed book "Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology" that the first biochemical process of life in its simplest form might have been an enzyme synthesizing nucleic acids containing the information needed to synthesize this enzyme, hence empowering the protein to replicate itself. Alas, enzymic reactions are profoundly temperature dependent and come to a halt far above zero degrees Kelvin.

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