Staring at a Map of the World

We’ve come an extraordinarily long way, from being nought more than a single fertilised egg - a single cell in our mothers fallopian tubes or uterus - to the complex organism built up of trillions upon trillions of individual cells reading this post. Cells divide. And they divide prolifically. Some cells divide more than others, and many cells lose their ability to divide at some point but a cells potential to autonomously divide is one of the criteria which allow it to be considered a living thing. Division is reproduction.

The process of reproduction is integral to the very nature of life, without the existence of which there is no life. Reproduction makes life persistent. It keeps life going. It allows life to evolve and change. Cells divide, and this reproduction allows living organisms to perpetuate their existence either as a single multi-cellular organism repairing damaged muscles, or a bacterium dividing to form a colony, or rabbits copulating to produce offspring. Whatever the context, reproduction results in the production of new genetic material, and new cells. 

A cell needs to prepare to divide. This preparation in the cells which construct humans and every other animal, plant or fungus is even more complex than the rest of life, as we’re all multicellular organisms. Complex life needs to keep a check on how its cells divide. If our cells don’t divide enough, we don’t build organs properly. If they divide too much, they use up too much energy, and can also be cancerous.

The Cell Cycle

Before a cell can divide it needs to double in mass. It needs to create a copy of its own DNA, like copying a CD, and it needs to create a whole new set of proteins for the new cell. The cell undergoes an initial growth phase called ‘G1’. In this, the cell makes some new protein, and determines whether the local conditions are going to allow it to divide. This is often done by sensing the presence of chemical growth signals in the local environment of the cell. These signals are usually released from some cells in the body such as the follicular cells in the thyroid gland. If the local environment is permissible, then it will go ahead with making the new proteins and DNA. Certain cells in the body often release anti-growth signals to stop cell growth. This also keeps cell division in check.

The cell adds up all the factors which have been sensed in this G1 phase and makes a decision whether to go ahead with cell division or not. It is at this point that the cell commits to its fate of cell division, stasis (where it doesn’t divide, also known as senesence) or in hostile environments, apoptosis. Apoptosis is programmed cell death. The cell senses that the local environment is unfavourable to support life and kills itself. This cell suicide is an evolutionary mechanism for multicellular organisms where individual cells sacrifice themselves for the greater good. A cell may sense that the local tissue has been invaded by toxins, so rather than die a gooey, explosive death where it damages local healthy cells, it quietly and cleanly kills itself in a manner which isnt damaging to local cells. This is easily cleaned up by the body’s immune system.

The next phase after G1 is called ‘S phase’, or the ‘Synthesis Phase’. The point just before the S phase is a regulatory point in the cell cycle. During S Phase, DNA is replicated and new proteins are formed. Once the cell has produced a complete copy of its own genome, and produced all the relevant proteins, it can enter the actual process of cell division - what you may have heard of as ‘mitosis’. There are 4 phases of mitosis, which follow a strict order.

The 4 main phases of mitosis are Prophase, Metaphase, Anaphase and Telophase. There are other sub-phases, such as prometaphase mentioned in the diagram.

And the first Nobel Prize of the year has been awarded! This year, the Nobel Prize for Medicine and Physiology has been awarded to Sir John B Gurdon and Shinya Yamanaka for

“for the discovery that mature cells can be reprogrammed to become pluripotent”

So what does this mean?

All cells in the human body originate from stem cells, but what is a stem cell?

The scientific definition of a stem cell, is a cell that is capable of producing another stem cell, and a less potent progenitor. This means that when it divides,  it produces another stem cell like itself, and another cell which has less potential in what sort of cells it can divide into.

When the fertilised egg which was going to develop into the human being you now call yourself first started dividing, it divided into a population of stem cells. These stem cells had the capability to become any cell in the human body. The name for this capability in a stem cell is ‘totipotent’. The same stem cell could have produced a neuron, or a sperm cell, or a white blood cell. The precise, local chemical environment of the stem cell then caused it to specialise into a different, more restricted stem cell. This stem cell could perhaps only form different cells from the same organ, like the different types of neuron or glia which make up the brain. These stem cells, in response to their chemical microenvironment, would have divided and divided, and become progressively more and more restricted in their cell-producing potential that we end up losing the all-producing-stem-cells from our embryonic phase.

As the above diagram shows, there are many different types of stem cell, and they fall into different levels of the potency heirarchy depending on how far along development the organism is;

• Totipotent - The first stem cells formed from the fertilised egg are totipotent stem cells. These are capable  of producing any cell in the body - both embryonic cells and non embryonic cells.
• Pluripotent - The majority of the totipotent stem cells eventually become slightly more restricted in their cell-making potential. Pluripotent stem cells can produce most cells in the body, but no embryonic cells.
• Multipotent - From pluripotency, the potential becomes even more restriced. Multipotent stem cells can produce cells of a particular type of tissue. Like neural stem cells can produce any of the many different types of cell present in the nervous system, but they can’t produce cardiac muscle cells
• Unipotent - Are the most restricted type of stem cell. Unipotent stem cells can only generate one type of cell, but are regarded as stem cells as they can produce other unipotent stem cells.

Fast forward to adulthood and you have probably lost the vast majority of all your totipotent and pluripotent stem cells. Each organ will have a limited supply of local stem cells, likely multi- or unipotent, to allow for limited regeneration of cells.

Pretty much all of our cells contain the same DNA. Yet they are different. How does a stem cell become more restricted in what it can produce?

It’s done by genetic switches. All cells in the human body will contain the same genetic information (barring the egg and sperm, but they’re special), but will be vastly differ from one another. Look at neurons and muscle fibres, for example. This is achieved by expressing a particular pattern of genes. Some genes are switched off, and some genes are switched on. This produces various patterns of genetic expression, and it is this which produces the distinct cells which construct our various tissues and organs.

Different types of muscle fibre and neuron. All originate from the same totipotent stem cells, all contain the same DNA (within the same organism). In each different cell, different genes are switched on and different genes are switched off. these switches were determined by specific chemical signals in their microenvironment during their production from stem cells.

The original totipotent stem cells in the embryo would have responded to chemical cues in their microenvironment which would have signaled for them to change into more restricted pluripotent stem cells. These pluripotent stem cells would then have responded to different chemical cues to become even more restricted multipotent stem cells, and so on. The chemical cues would bind to receptors on the surface of the cells (or receptors within the cells), and these receptors would have signalled to the cell to switch on certain genes, and switch off other genes - producing the correct genetic pattern for that time and place. 

A. Are different types of chemical cues; B. Is a receptor; C. Is the Cell; D. The Nucleus; E. The genetic material within the nucleus, aka the DNA.

The diagram shows how chemical cues can induce genetic changes. They can bind to the receptor, and the receptor initiates a cascade of biochemical pathways within the cell to affect the genes, OR the chemical signals can pass through the cell membrane and directly affect the DNA itself.

With regards to the nobel prize, these scientists figured out how to reverse engineer these signals to turn restricted cells back into pluripotent cells - potentially allowing us to generate helpful stem cells from any other cell in our body. Stem cells can be hard to come by, but now with a method to actually produce them in the laboratory from easily obtained resources, we’re on track to better understand debilitating disease processes, and may even be able to adapt this technology for use in regenerative medicine.

Congratulations, guys! Well deserved!

Death. The ultimate inevitability for all living organisms. A fact of life. To be poetic about it, one could say death is more natural than life itself, being the state of the vast majority of all organisms ever to have existed.

The Oxford English dictionary lists death as:

• The action or fact of dying or being killed
• The end of the life of a person or organism
• The state of being dead the permanent ending of vital processes in a cell or tissue
• The personification of the power that destroys life, often represented in art and literature as a skeleton or an old man holding a scythe
• The destruction or permanent end of something a damaging or destructive state of affairs

The third definition is the most relevant with regards to the scientific definition of life, though it probably doesn’t come to mind when thinking about fellow humans or animals. For good reason I suppose - we have emotional attachments. Saying grandma has ceased to function at a cellular level may be a bit heartless. But death is death, and ultimately there’s no dressing it up. 

Living organisms have an intrinsic order to the molecules which construct them, as opposed to the molecules being disordered, flowing and flying all over the place like in a liquid or a gas. This ordered system has to be able to take up energy from the environment and utilise it to do work within the system, such as maintain the order (or structure) of the system, to replicate hereditary information and power metabolic processes. Furthermore, all this has to be autonomous. The system has to be able to self-sustain. What is evident from this is that life is not a state of being. Life is a process, or rather a collection of self-preserving processes. A dead organism would no longer be undergoing metabolism, and would no longer be maintaining (or trying to maintain) structural order. In short, cellular function has ceased. 

As cast iron and clear cut as this is, it’s only very easy to apply to individual cells as the cell is the fundamental unit of life. It is the most basic thing which can be considered ‘living’. With multicellular organisms (e.g. Us.), the picture becomes a bit more complicated. Within us, as in any of you reading this, the vast majority of the cells which compose you should meet the above criteria, hence they are living cells. However, some won’t. When we break ourselves down to our basic units, the picture is a lot different to what we perceive when we look at a multicellular organism as a whole. 

Additional criteria are added for multicellular organisms. Bonelli et al 2009 reduced these quite nicely; There has to be indivisibility of the mass of cells. Like, you can’t chop off your arm and that arm buggers off to live independently. The system has to be inherently dynamic - showing signs of mass metabolism and growth. There has to be integration within the organism - cells working together form sub systems (organs) which cannot function autonomously on their own, and must integrate with other systems. All this must be coordinated (In mammals and birds this is achieved by the nervous and endocrine systems). This all comes together to form a complete organism. So we have dynamics, integration, completion and coordination. The underlying concept with the cells of a multicellular organism is unity. They strive for the common cause of the whole. Like, cellular communism or something.

The two criteria for death in the clinical setting are circulatory death and neurological death. Circulatory death occurs when the heart irreversibly stops beating and the pulse (as detected from arteries) is abolished for upwards of 2 minutes. The key word here is irreversibly, as we have the technology to restart the heart. When the heart stops, oxygen ceases to be transported around the body and cells can no longer power their metabolic needs, so they stop functioning. Within the cells, ionic imbalances occur, toxins accumulate, water begins to diffuse freely along concentration gradients and general cellular structural integrity is compromised. As a result, the organs constructed by these cells stop working. In this way, stoppage of the heart leads to neurological death. Circulation must have ceased for some time before neurological death can be assumed, as the brain can survive for a very limited time upon cessation of cardiac function.

With the termination of brain function, there is absolute neurological death - or brain death. All of the properties which we deem to give us our ‘selves’ or our humanity is lost. Irreversible, global brain death means no more consciousness, no more ‘self’, no more thoughts, no more regulation of the rest of the body. The brain is no longer the electrically, chemically, physiologically, metabolically active organic computer, but is reduced to little more than a jelly like mass of inactive neurons encased within an inert bony cocoon. 

To be declared brain dead, a patient must meet the following criteria:

• The patient must be demonstrated to be in a coma
• The cause of the coma must be known and evidenced
• Doctors have eliminated confounding factors which can transiently alter brain functionality, these include hypothermia, drug usage and hormonal imbalances
• The absence of reflexes mediated by the brain stem, like the dilation of pupils in response to light
• No movement (kinda obvious)
• Absence of autonomous breathing (apnoea)
• Confirm above tests with repeat tests up to three days after initial assessment

Brain death exists as a criterion for death as machines can artificially sustain breathing (mechanical ventilation) and circulation - but can’t do the same for the complex function of the central nervous system.

The crucial part of the brain responsible for maintaining the life of a complex animal is the brain stem. This is the oldest, most evolutionarily primitive part of the brain which we humans share with reptiles, birds, amphibians and the rest of the mammals. It is the neurological bridge between the brain and the rest of the body. The brain stem is responsible for controlling and regulating basic life processes, including sleep, heartbeat, breathing and blood vessel dynamics. Brain stem damage leads to rapid death. 

Location of forebrain and brainstem

The thing is, even in the absence of neural inputs from the brain (say, in the event of absolute brain death, brain stem and all) the heart can beat. The heart is what is known as a ‘myogenic organ’. It generates its own contractions, however unregulated by the brain. With mechanical ventilation, a brain dead patient can remain technically living for years. Various biological functions have been observed to carry on as usual following brain death in mechanically ventilated patients. Such functions include the healing of wounds and the development and successful delivery of a baby.

Organ transplantation complicates the picture further. Using organs from cases such as these will probably give the freshest, best quality organs for transplantation - but at the same time the organ extraction becomes the actual cause of death for the person. The practice of using brain dead patients as donors is practiced widely in the developed world. Such donors are known as heart-beating donors, as their hearts may still be beating at the time of organ extraction. The idea here is that as the patient is brain dead, they are effectively dead and open for pre-consented organ harvesting. This is a very controversial topic in the medical community as the diagnosis of brain death makes assumptions about the patient’s state of consciousness. Some key forebrain structures in brain dead patients may still be intact. Such structures may be deep brain structures, as thus difficult to test for functionality.

Recent studies into the electrical activity of the brains of seemingly brain dead patients (electrophysiological studies, to use the correct term) have observed some electrical activity in response to auditory and tactile stimuli. Some brain dead beating-heart donors have been observed to exhibit the visceral responses (via observation of the response of blood vessel dynamics) and hormonal responses typical of those caused in response to perceived pain. This doesn’t say anything about the donor perceiving pain, but shows some level of centrally mediated processing of what would be perceived as pain. Additionally, a paper published in the journal, Neurology by Wijdicks and Pfeifer in 2008 on autopsy studies of brain dead patients showed that the brain stem appeared to be intact at the gross anatomical scale, and at the cellular scale in 60% of beating-heart donor cases. This may have implications for their actual conscious state at the time of organ extraction, and also for the reversibility of the donors initial ‘brain death’. 

However, when we go right back to the initial criteria for multicellular life, brain death does indeed disrupt the unity and coordination of the organism. Furthermore seemingly structural integrity of a brain structure doesn’t necessarily mean it is functionally stable. Cellular chemistry may be upset, or brain stem input and outputs may be disrupted.

So what of organ donation? If heart beat has indeed stopped for any period of time exceeding the 1 hour mark, there is no real medical controversy concerning organ donation. As long as the organs are in good condition and aren’t rejected by the recipient, s’all good. There’s no worry about the donor, they had no more use for the organs anyway. With apparent brain death, we enter a shady, fuzzy region of science and medicine. I guess the reason for the controversy here is simply due to a lack of understanding. Neuroscience research has undergone an explosion in recent times, but we’re still in the early stages of discerning how the brain precisely works. We have a very good understanding of many aspects of brain function but there are still fathoms of uncovered information hidden within the jelly of sulci and gyri that we call our brain.

Death is a complex issue at the scientific and medical level, and this complexity is amplified when we bring it to the table of general society because so many people have such strong feelings about death. Indeed, it is ingrained within the very essence of the biology of all living organisms to want to evade death. With humans, this is never more prominently expressed than in our thoughts. Many of us fear death. Others have stories and ideas of what happens after death, to make the actual event not feel so bad. What makes subjects such as brain death so perplexing is that in the laboratory and the clinic, human death is seen as a single and final event. Someone can’t be half-dead. This is down to our fundamental biology. We may be composed of trillions of individual living cells, but the cells are units of a single organism. Ultimately, they function as a mega society of specialised units, to preserve a basic genome. In this preservation of the genome, we get our organs, our capacity to think and communicate, our capacity to reproduce. Our sociable cells, in both the singular and organismal sense, live together and ultimately, when our times comes, whichever ones are left - will die together. 

We should all be familiar with the idea that food intake is energy intake. And when one eats too much, they are taking in too much energy - and if this energy is not used in active processes in the body, it will be stored. Most of it will be stored as fat. Obese states occur when energy intake chronically exceeds energy expenditure, as all the excess energy is locked up in the extensive fat reserves.

The specialised cells which store fat are called adipocytes, and fatty tissue is referred to as adipose. An interesting observation is that an adult who becomes obese has the same number of adipocytes as they did when they were lean. The idea being that at around the age of 8 or so, one stops producing any significant number of adipocytes. Past this, more fat is packed into the existing cells, so they just swell up. It seems that some people may be primed to put on more weight because of a greater existing number of adipocytes produced during childhood, because they have more ‘storage space’ in which to pack fat.

light micrograph of adipose tissue 

Adipose tissue is more than just a fatty store, though. It is also an active endocrine organ, releasing chemical signals into the bloodstream to signal to the brain and the rest of the body about its current energy state, so the body can adjust its function and behaviour to meet its current needs.

Obesity is more than simply being overweight, however. There are major imbalances that occur within the body prior to, and as a result which make this such an important disease in the modern world. During obesity, tissues become desensitised to chemical signals which would usually signal to them to decrease food intake, or to increase energy expenditure. Examples of this are the decreased effect of leptin in the feeding-control-centres of the hypothalamus, leptin on skeletal muscle and adiponectin on the brain and skeletal muscle. These are signals which would ordinarily decrease energy intake by modifying behaviour and metabolism, thus keeping weight down. But in obesity, they become dysregulated. As a result, cells become more prone to store energy as fat, and feeding centres in the brain become impaired. Furthermore, obesity is linked to type II diabetes. The excess expansion of adipocytes from all their fat uptake can stimulate inflammatory immune cells (via hypoxia-induced mechanisms) which can damage the insulin secreting cells of the pancreas. The excess fatty acids present in circulation can also act to inhibit the glucose sensing mechanisms in these insulin secreting cells. This leads to dysregulation of glucose homeostasis, and what we consider to be Diabetes mellitus, aka Type II Diabetes.

Adipose as an endocrine organ, and some of its roles in hormonal signalling

The underlying biochemistry of obesity shows that there may be certain genetic predispositions which make it more likely for somebody to enter an obese state. Some may shrug this aside as saying ‘You’re just giving fat people an excuse’. But that isn’t the point. Such sentiments merely reflect the negative social stigma attached to obesity, which leads to the psychological impact of obesity on the patient. These social pressures make obesity more than just a disorder of energy regulation, but a disorder which affects psychological state. Predispositions may occur via polymorphism of the structure of hormone-responsive receptors which mediate energy regulating behaviour or metabolism, through variation in horomone secretion patterns, the number of adipocytes one has, amongst many others.  Likewise, it’s progression into diabetes relies on multiple imbalances and factors which just complicate the whole diabetes/obesity picture somewhat.

The fact that developed countries such as the UK and the US have such high energy demands does mean that there is a disparity in energy distribution which leads to an unhealthy, sedentary lifestyle. So it’s a tough one. How do we deal with obesity? Drug development in this field is ongoing, but not ideal. It seems that the best way to tackle the problem is by nipping it in the bud and ensuring that one is in a good habit of getting a good level of exercise. And this doesn’t mean going for a daily sprint, or lifting weights, or even going to the gym.

Walking. Simple walking seems to be a very good way of averting excess energy storage and its consequences. Humans are a walking organism, our very structure is a testament to that. Our bipedal nature. We evolved to walk. And in our modern environment where obesity is running rampant, the key factor which is lacking is energy expenditure - because we do not walk enough. Our climate can tell us as much, with developed nations’ carbon emmissions going through the roof due to excess vehicle usage.

In a recent study in Nottingham, a high-diabetes-risk population was split into three groups. One group was given a placebo drug, which did nothing (though they weren’t told this), one group was given metformin - a very good diabetes drug, and one group were told to increase their daily walking. From monitoring them over the period of the next few years it was found that those who took the placebo had the highest incidence of diabetes out of the groups. The metformin group came second, and the walking group had the lowest incidence of diabetes.

Another study done in the UK showed that average calorific intake had decreased since the 70’s but obesity levels had sky-rocketed. But just look at the graphs below to see what increased with the obesity. In addition to cars, we have lifts to take us up to our offices, in which we sit at a desk for hours on end. Couple this with the decline in manufacturing industry in Britain and we have an interesting picture. The evidence really points to lack of exercise as being the catalytic factor in the obesity epidemic.

Trends in diet (left graph) and activity (right graph) in relation to obesity, in Britain. Figure from ‘Obesity in Britain: gluttony or sloth?’, Prentice & Jebb, 1995.

But onto the consequences of obesity and diabetes. Why does it matter? Why don’t we just leave obese people be? Well, firstly, we’ve determined that it, at least partially, isn’t entirely voluntary. Furthermore, the rising epidemic does mean it will strain the healthcare system. More people being admitted into hospital as a result of obesity and its complications (diabetes, cardiovascular disease, stroke, depression). Whereas exercise is perhaps the major determinant factor in exacerbating obesity, unhealthy eating still does contribute to the progression and morbidity of the disease. The high cholesterol and fatty physiological environment created in obesity primes one to progress into diabetes (as already stated) and massively increases the risk of cardiovascular disease and stroke. On top of all this, having a lot of extra weight puts pressure on the skeletal system, increasing the risk of arthritis. Obesity can also lead to depression, due to social ostracism and bullying. This could induce self-harming behaviour and and even increase suicidal tendencies in extreme cases. It is clear that from here we delve into the realms of psychiatric health, and we see that obesity has the potential to be a disease affecting mental states too.

Once one has entered an obese state, exercse isn’t easily implemented as the amazing cure-all. Exercise is best as a preventative measure, which is hardly headline-news. We have to remember that obesity isnt simply one pigging out on Ben n Jerry’s ice cream every night - it’s a gradual process, which relies on many different factors. Once one has obesity, there are currently no effective drug therapies that will reduce it. The only real solution is surgery, and that has complications and considerations of its own, not least financial burden.  Obesity is disease of multi-faceted origin and has no single causal factor. It is a composite of social, psychological, genetic, chemical and behavioural factors. And as such dealing with it will require a multi-pronged attack on various aspects of our lives.

 All of the aforementioned characteristics (in part 1) are acquired through mutations and DNA damage in normal genes which perform a more regulated version of the cancerous characterisitic being produced. In this way, a cell requires an accummulation of a few mutations before it will become fully cancerous. As a result, the incidence of cancers increases in older age groups. The longer one lives, the more likely one is to develop a cancer - due to the accumulation of DNA damage or mutations one will aquire through their lifetimes due to lifestyle, environment and plain-old-faulty genetics. The body has mechanisms to detect and eliminate cancer cells, as the immune system can be rather effective. But some kind of immunocompromise can open up a window for a cancer cell to go forth and spread its progeny. Either this, or additional mutations apart from these basic 6+, can make a cancer cell that much more potent and resistant to bodily defences. For the metastasis characteristic, a cell would require more than just a single mutation, as this is a product of a few mechanisms. In total, I would say a ballpark figure of at least 10 mutations would make a cell malignant. Due to genetic-mistake-correction mechanisms, a single cell accummulating 10 mutations in precisely the right genes, even in the presence of carcinogens, would be unlikely. This alone wouldn’t explain the massive prevalence of cancer in modern society.

I plucked this little statistic from my introductory lecture on Cancer

 What seems to be the case is an initial genetic instability event - A disruption in a common pathway in all cancers which opens up the genome to become mutation prone. The evidence and data suggest that this is due to the p53 pathway within cells. Disrupt this, and the basic mutations will be much much more likely to follow. p53 is a special, vital protein within cells, and is also referred to as ‘The Guardian of the Genome’ due to its ability to sense DNA damage, and decide whether it can be fixed, or if the cell should apoptose, amongst other responses to cell stress. But, an entire post could be written on p53 and still barely scratch the surface. So we’ll leave p53 at that for now. Suffice to say, p53 dysfunction is a major player in cancer, and currently is linked to over 50% of human cancers (and maybe even more).

The big white blobby structure represents the p53 protein. It’s a protein that can carry out many functions within the cells. Here, it is binding DNA to activate gene expression.

To this point, smoking over ones lifetime induces many mutations in DNA, and disrupts cellular function, increasing the liklihood of this complement of mutations - and much more - thus producing devastating lung cancers. The lungs feel the brunt of the high energy carcinogenic agents from the cigarette smoke, leading to the accummulation of more than just the basic 6 mutations, producing elaborate and ‘intelligent’ cancer cells which just won’t yield as easily to treatments. Lung cancers have a 50% chance of metastasising to the brain to cause secondary brain tumours, for this reason. All that carcinogen exposure has produced robust mutants which can seek out the best, and most deadly hiding places.

U mad bro?

In addition to all this, cancer cells are able to manipulate the healthy cells around them to make their environment favourable to live in. Some cancer cells can release chemicals which stimulate neighbouring non-cancer cells to release excess growth factors. Some cancer cells trick the immune system, so it doesn’t/can’t destroy them.

So, to surmise the extent of Cancer cell ingenuity

• They switch on mechanisms to give them immortal genomes
• They can seek out, and invade new environments in the body
• They can manipulate healthy cells to help nurture cancer cells
• They can switch off their natural death programmes
• They can trick the immune system
• They divert resources towards themselves

(This list isn’t exhaustive)

As a result, cancer cells are darn hard to fight. After all this, they are within our bodies, hiding amongst healthy cells. They are still kind of a part of us afterall. It’s why cancer therapies are so harsh. To kill the cancer cells, healthy cells also get affected. The disregulated mechanisms which give rise to these 6 characteristics are the prime targets for cancer therapies, but it does mean that some other cells will take a hit in the process.

I must iterate the point that cancer cells don’t have the ‘intent’ to kill, but exist as a product of darwinian selection. The production of their existence is as a blind consequence of a particular set of mutations, whose liklihood is either increased or decreased by environmental factors and lifestyle choices. Few things actually CAUSE cancer, as in - specifically switch cancer on as a product of their in vivo mechanics. Cells with this set of characteristics produce the cancer condition, because this is a convergant set of characteristics that allows a type of behaviour to persist - making cancer the devastating, horrendous condition that it is. Death is just a possible by-product of all this proliferation. These cells just have too much life - much to the expense of the life of the sufferer. And many people have been able to bear witness to that.

Picture from ‘The Hallmarks of Cancer’ by Hanahan and Weinberg, Cell, 2000

Cancer cells are normal cells, gone rogue. What’s so rogue about them? How are they ‘rogue’? There are 6 principle characteristics of cancer cells which differentiate them from the other cells in the body, and it is the presence of these characteristics which defines any given cell in the body as a cancerous cell.

1. Self sufficiency in growth signals

Self sufficiency from growth signals is a primary trait of cancer cells as cancer cells proliferate uncontrollably. Ordinarily, healthy cells need a signal to grow, from growth factors in the internal environment of the body (released from other cells in response to environmental and temporal cues to grow). Cancer cells are able to grow in the absence of growth factors, thus growing and dividing continuously.

2. Limitless replicative potential

Cells usually have a limit to their growth, due to the very nature of DNA replication. Cancer cells bypass this by making their genome immortal, so it isn’t damaged with every cellular replication - making a cancer cells ability to divide, limitless.

3. Insensitivity to anti-growth signals

Some signals tell a cell to stop growing. Cancer cells are desensitised to these enabling them to sustain their uncontrolled growth.

4. Sustained angiogenesis

Sustained angiogenesis is the ability of a cancer cell to switch on the growth of local blood vessels. If a cell is to be growing indefinitely, it’s gonna need a heck of an energy supply to meet this demand. Extra blood vessels increase the amount of oxygen and glucose available to allow this growth. The target of some current anti-cancer therapies is to inhibit angiogenesis, and it can be quite effective at halting tumour growth.

5. Evading apoptosis

Apoptosis is programmed cell death mechanism. Cells have an innate ability to kill themselves when the going gets tough. This is normal, natural and above all else, healthy. A cell senses it’s ill/mutated/not-needed so eliminates itself, thus alleviating its burden on the body. Cancer cells wouldn’t be very good if they apoptosed when their environment changed.

6. Tissue invasion and metastasis

Metastasis is the invasion of other parts of the body by cancer cells. Cancerous cells that can move around the body are devious and dastardly. If you remove one tumour, there may still be cancerous cells floating around in the blood stream blindly searching for a safer haven in which to nest and proliferate. It’s why tumour-removing surgeries are often only temporary resolutions to malignant cancers. Some metastatic cancer cells are still floating about the system, undetected, and they’ll flare up elsewhere - creating new cancerous growths, and disrtupting the bodily balance elsewhere. The safest haven for a cancer cell is perhaps the brain. Here, cancer cells are away from the brutal ravages of the systemic immune system, and also more protected from drugs (owing to the presence of the blood brain barrier, which excludes many substances to keep the brain safe from potential harmfuls). Metastatic cancer cells are what make a cancer malignant. Ultimately it is metastasis which is the most deadly characterisitic of a cancer cell (90% of cancer deaths are due to cancer metastasis). The other 5 characteristics enable a cancerous cell to form a benign tumour, which can be more easily controlled.

Yet another one of my two-part posts. Part two coming on the morrow, or there abouts.

Viruses are intracellular parasites. That is to say that they need to live inside, and exploit a cell to maintain their own survival. In fact, they need to hijack a cell’s machinery in order to reproduce. In light of this semi-autonomous reproduction strategy, there is much debate as to whether viruses should be classified as living organisms, or whether they should be classified as a biological pathogen… thingy. Anyway, not the subject of this post.

Human Immunodeficiency Virus (HIV-1), a retrovirus

Viruses are basically large protein particles, with some genetic material encased within them, and a tiny amount of carbohydrates and lipid here and there. They can’t synthesise any of this themselves, so they inject or insert their own genome into their host cell, and rely on the already-present host cell enzymes to carry out the task of copying and transcribing the DNA, and turning the transcribed RNA into virus proteins. Some viruses can insert their own genome into their host genome. As in, physically stick it into their host genome so it’s part of the hosts chromosomes.

General virus life cycle

Whenever the cell divides, the daughter cells will all be virus factories too because the daughter cells will have been given viral DNA from the parent cell. The parent cell can’t always distinguish between viral DNA and its own DNA very well, so it copies all of DNA present. Viruses are freakishly devious, exploiting our own systems to enhance their survival. When a cell produces more viruses, the viruses will cause the cell to burst open, releasing viruses into the local environment to infect local cells. Sometimes, when a virus-under-construction is taking in its DNA before it sets off into the big wide world, it takes in a copy of some of its hosts DNA. The virus now has some extra DNA within it, which it will spread to the other cells it infects. This is a process known as gene piracy. Like accidentally making a pirate copy of a DVD…

Viral lysogeny - the process of a viral genome laying dormant in a cell while it divides.

An example of this is from Rous Sarcoma virus (RSV), which can cause cancer in chickens (some viruses are capable of inducing cancer, even in humans - eg. Human Papilloma Virus aka HPV. It’s why women should be entitled to the smear test. To see if they have this virus. Over 90% of cervical cancers have been linked to HPV). Early in the scientific research on this virus, scientists found a gene called src. This gene, when inserted into the host cell can trigger its transformation into a cancer cell. This is because the src gene codes for a enzyme which responds to growth factor signals and stimulates cell growth, but this viral-encoded enzyme remains switched on even in the absence of growth factors - so it’s constantly telling the cell to grow and multiply. Initially, some scientists were like ‘WE FOUND THE VIRAL CANCER GENE! HUZZAH!’ Well… not quite right.

The protein coded for by the src gene. It is a protein-Tyr kinase.

Turns out that the gene is already present in many animals, including humans - like without viral intervention. It codes for an almost identitical enzyme as the viral src, but this enzyme deactivates when it isn’t needed. What appears to have happened is that a non-cancerous form of the virus infected an animal in its early evolution, then picked up the standard src-gene via gene piracy. This gene mutated over the course of the viruses’ reproduction, and coded for a constantly activated enzyme instead - making the virus a cancer-inducing virus. Causing tumours would be advantageous for the virus as the host cell would undergo excess uncontrolled proliferation, causing more replication of virus particles. This particular type virus would be classified as a RNA tumour virus.

Viruses, hijacking the intracellular seas since….  before Jack Sparrow at least.

All life on Earth can be divided into two domains. Eukaryotic and Prokaryotic. These domains describe the two types of cell which inhabit our planet. To those out of the loop, or yet to enter said loop - the cell is smallest unit of life. The most basic entity that can currently be considered as a living system.

Prokaryotes are the phylogenetically older of the two cell types, meaning they existed first. Other cells then evolved from them. Before the prokaryotes, would have been some kind of proto-cellular organism, which would have been semi autonomous, relying on the energetics of the primordial soup around it to power its longevity. Prokaryotes are much simpler organisms than eukaryotes and understanding their biology, as well as being crucial to medical knowledge, is also a glimpse into the past, and at our origins. Their structure is, in essence, a shell containing a soup of chemicals and some circular DNA. All bacteria are prokaryotes.

Cyanobacteria

Eukaryotes are much more structured (hence have a much more negative entropy if you remember PART 1 to this post). They contain organelles - which are like organs in a body, but instead, these are mini organs inside cells. These organelles are separate compartments within the cell, encased in membranes, to separate the particular mix of macromolecules and chemicals in them from other separate mixtures in other parts of the cell. This means that they can eacn carry out specialised functions in cellular metabolism, basically ensuring each region does its function properly and in relative isolation. The DNA is kept in an organelle called a nucleus, and the DNA is a linear strand, not circular like in a prokaryote. The DNA is also bound by loads of proteins and contains genetic switches. Eukaryotes thus require more energy to maintain this increased structure (or massively negative entropy), hence why they respire by an oxidative metabolism mediated by MITOCHONDRIA - the energy powerhouses of eukaryotic cells. All animals, plants, protists and fungi are eukaryotes Eukaryotic organisms are everything from amoebae to trees, to whales and mushrooms, to you and I.

Plants, animals, protists and fungi. The eukaryotic kingdoms.

Billions of years ago, mitochondria were once prokaryotic cells which were engulfed by primitive eukaryotic cells (which would only have been capable of anaerobic respiration via process known as glycolysis), and they formed a symbiotic union. The early mitochondrial precursor cell would have been able to use atmospheric oxygen to help in the production of massive quantities of ATP (the energy currency of all life on earth), and the eukaryotic cell would have provided it with stability, safety and nutrients. They would have reproduced in tandem, producing more eukaryote-prokaryote hybrids to the point they would have been undergoing symbiotic evolution. These days, mitochondria only function semi autonomously. They have their own genome, but most of their function is coded for by the main DNA in the nucleus if the host eukaryote cell. The process of mitochondrial-eukaryotic union is known as the Endosymbiosis event.

Endosymbiosis theory

This extra energy input made it possible for organisms to maintain larger more robust structures, become multicellular, and thus the entropy of life on earth decreased and decreased to the point we have us! Us. We require a lot of energy just to maintain our brain. The human brain is only 2% of our body mass, yet uses a staggering 20% of our oxygen intake. On top of this, We require a lot of energy to help build up the physically ordered societies and cities we see around us, and this comes at an energetic expense of the environment. We’re decreasing our entropy, and if you remember, there must be a corresponding increase in entropy in the surroundings from which the energy was taken (every action has a reaction… Newton!). This means more disorder in our surroundings. We use a lot of fossil fuels and throw away a lot of junk. Our massive energy dependence, and poor waste disposal is physically and biologically unsustainable.

Damn you physics.

Physically speaking, life can universally be defined as an autonomous system of relatively negative entropy, which transduces, takes in and assimilates energy for self maintainence and survival as a single system, and autonomously replicates information about its own system of being, to propagate itself.

It is a rather beautiful set of parameters, as it would apply to all living organisms. These parameters ARE life. When we look at living organisms, and we try to extrapolate the biology to what we may expect from space, we’re taking a shot in the dark and in reality, whatever the environment and time allows, will evolve. So in theory, life can take almost any form. But we can be almost certain that any kind of ‘life’ woould have to conform to these laws. These parameters define what differentiates a cell from say, a planet or an ocean. Key concepts define life:

• Negative entropy
• Energy intake
• Survival
• Reproduction
• Evolution

Entropy is the measure of order or disorder in a system. The universe is one giant system which can then be divided into countless subsystems (subsystems including you and I… hello! From this point, I shall refer to living organisms as ‘living systems’ - in order to describe biology in it’s most fundamental form: A product of chemical and physical processes).

More entropy = more disorder. Less entropy = more order.

Life is a structured, ordered phenomenon. Molecules and structures must behave in set ways, and are utilised in different regions in living systems. In this way, Life is ordered, therefore it has a relatively low entropy compared to, say, a bottle of water or something. The water is sloshing around, and evaporating, and the molecules are all over the place, dispersed almost randomly. The water is approaching an equilibrium with it’s environment.

The 2nd law of thermodynamics is that everything in the universe tends towards maximum entropy. This means, everything tends towards max. disorder, over time. Disorder is thermodynamically stable. In this way, living systems  cannot be thermodynamically stable. If we were, we’d be dead! A thermodynamically stable system would be at equilibrium with its environment, and a cell in equilibrium is dead. Living systems transiently reverse the natural trend towards entropy, by decreasing their own entropy, at the expense of the entropy around them. Or in laymans terms, as we build our ‘order’ or ‘structure’ up, there has to be a compromise in that it is reduced elsewhere. This ties in with the first law of thermodynamics that energy cannot be created or destroyed - only have its form changed, aka energy is transduced (eg, from light energy to potential energy).

Energy is taken in to living systems to maintain this negative entropy, as without external energy input, the living system would fall apart into disrepair. Energy intake enables the system to be maintained, and persist in the environment - thus it is surviving. Energy is taken in as organic molecules (food!). The energy is released from its molecular form and transduced into a more useable form which the system then uses to keep chemical processes going, reproduction, and maintaining structure (first law of thermodynamics again!) The universe doesn’t have any external energy source that we know of, and to try and reason this will require me going into a realm of physics which is clearly out of my depth. That being said, the universe will eventually stagnate as all molecules eventually decay and fall apart, in compliance with the 2nd law, a process known as ‘heat death’.

1. A living system dies.
2. Becomes molecules via some kind of decay/breakdown process.
3. The molecules become atoms.
4. The atoms decay into subatomic particles, which then decay further.

That all takes billions and billions of years, but it’s the fate of everything eventually.

As we have established, a living system is ordered. Something must define this order. There must be some sort of information within the system which coordinates all this order. In the case of Earth Biology, this information is DNA. This information must be reproducible, otherwise eventually that store of information would break down and fall apart (damn you 2nd law of thermodynamics!). This is where reproduction comes into the equation. The information must be reproduced to maintain its longevity, and it is the information which persists longer than the system it describes. After you die, your genes persist in any offspring you may have had. The body, brain and cells you are made up of are ultimately tools of survival for the set of chemicals known as your DNA. You are a survival machine for your genes, I suppose.

‘…But how we survive, it’s what makes us who we are.’

-‘Survive’ by Rise Against, from the album ‘The sufferer and the Witness’… It’s just so fitting!

Ultimately, it boils down to the fact that a genetic molecule has the means to preserve itself, that life actually exists. Current understanding is that genes came first. Cells and structures came later - via evolution, an aimless by-product of replication which helped the genes to persist longer. Evolution partially occurs because genetic copying mechanisms are imperfect.

DNA polymerase, the enzyme respnsible for DNA replication in many living systems

Because information must be replicated (eg, DNA replication), there can be errors in replication or even in information storage. This can be due to inefficient replication machinery. However, mistakes aren’t always a bad thing (we can also refer to them as mutations!). Evolution is actually the byproduct of a mixture of reproduction and competition. When organisms start competing for resources (eg. energy sources and things that help systems persist in the environment, and further replicate information), then the better adapted systems survive (survival of the fittest). The succesful systems are able to obtain energy, don’t fall into entropy and are able to persist long enough to replicate their underlying information which was able to underpin the advantage that conferred it persistence in the first place.

To surmise so far, Life exists to persist. If it didn’t do so, then it wouldn’t exist and we wouldn’t be reading this.

(Part 2 coming up very soon, to conclude all this. Splitting it into two otherwise it’d be one long-ass post)

Everyone say hello to German physiologist, and one of the founding fathers of modern Biology, Theodor Schwann! Theodor Schwann’s (1810-1882) contributions to modern science cannot be understated, and his work paved the way for modern medicine as we know it.

In my opinion (and possibly the opinions of others) his greatest contribution to science was the development of cell theory (or pepsi, if you like the stuff). The idea that some organisms (particularly plants) were composed of cells, was already in existence. But this man proposed that not only were animals composed of cells - but that all life on Earth is composed of cells. He took this further by saying that all cells must orginate from a pre-existing cell. And to this day, his theory holds true and is one of the undisputed facts of science. With cell theory firmly in place, modern histology could spring into existence, amongst countless other biological/medical ideas/innovations.

To relate this to Kneuro Knowledge, this man discovered the Schwann cell. A type of glial cell which wraps around peripheral nerves (a process known as myelination), and insulates nerves to make them conduct impulses faster. Knowledge of these cells is critical for the understanding of multiple sclerosis, nerve regeneration and various motor neuron diseases. Multiple schwann cells will wrap around a single axon.

Apart from this, he showed that fermentation was a biological process mediated by living organisms (yeast!), and discovered the digestive stomach enzyme Pepsin! Pepsin was later added to tonics, and sold at chemists under the name ‘Pepsi’. Apparently, he’s also responsible for coining the term ‘metabolism’.

Oh Theodor Schwann, you are a rascal.

The multitude of things which can go wrong with the human body should be enough to frighten me so much that I don’t want to get out of bed in the morning. Sometimes, it is a marvel that we are still alive, yet at the same time, if things had gone wrong we wouldn’t be alive to marvel at our own survival. It’s an odd situation like that. I believe such a scenario has a name, but I can’t remember it right now. Anywho. Staying in bed would still open one up to problems with the human body, and ultimately no matter what one does, the risk of cancer is omnipresent. Indeed, the fact that our cells divide, and that our DNA replication machinery makes mistakes, and that we are constantly exposed to some form of radiation (and I don’t mean from nuclear waste either) means that we can, in theory, spontaneously develop cancer. But more on cancer another day. Today, my good friends, we delve into the treacherous world of stroke, not least because 3rd year of university is around my corner, and I am doing both my final year lab project and my dissertation on a certain aspect of stroke (with the venerable D of E, of course). But much like cancer, stroke is a big killer in the modern world. I would give some statistics to back this point up, but that would involve opening a new tab and doing a google search, which is too much effort for me right now. #laziness

Let’s take a brief look at some neuroenergetics (as I’ve taken a huge liking to bioenergetics and biophysics recently). The brain makes up about 1-2% of our body weight, yet it consumes 20% of our oxygen intake. The brain is a hungry organ. 70% of the energy diverted to the brain is used to maintain the neuronal resting potentials - the basic charge that neurons have in order to enable them to transmit electrical impulses when stimulated. The brain is a hungry organ, and if you remember anything about basic aerobic respiration from biology 101, then you may remember the over-simplified equation of

Glucose + Oxygen —> Carbon Dioxide + Water

Indeed, when we reduce respiration to input and output, this is what we’re left with. So we’ll leave it at that for now. The brain takes in a lot of oxygen as we’ve established. It’s also gonna need some glucose to release energy from. The brain is pretty shite at storing energy (unlike the rest of the body which stores it as fat). Neurons pretty much only metabolise free glucose molecules for energy (though may use ketone bodies in starved states, but let’s not go there today). All this energy usage on top of basic energy requirements to keep the neurons alive, means they use up a lot of energy and quickly. As a result, they need a constant blood supply constantly bringing in oxygen and glucose, and disrupting such a supply will have dire consequences very quickly. These were demonstrated in experiments on prisoners in the USA in 1943 by J.P. Anderson, outlined in the paper; ACUTE ARREST OF CEREBRAL CIRCULATION IN MAN. To cut a long story short, Mr Anderson devised a contraption which would be put around the prisoners necks and would then compress the blood vessels supplying the brain, thus cutting off their oxygen supply. He would then cut off oxygen to different prisoners for varying lengths of time, and record the results. To my knowledge, prisoners were left with varying degrees of brain damage, or died. Brain damaging effects were exhibited after only 10 seconds of absolute ischaemia. 

Energy for brain…nom

But I digress. There are two types of stroke. Ischaemic and haemorrhagic. Ischaemic stroke. Blood supply to a region of brain is blocked. The region of brain it supplies no longer has access to oxygen and glucose. It experiences Hypoxia (lack of oxygen). Then Anoxia (no oxygen). Hypoglycaemia (lack of glucose). Then Algycaemia (no glucose). This creates an infarct zone in the region which was in the direct supply line of the blocked blood vessel, which dies within the minute. The region around the infarct zone is still receiving blood from peripheral blood vessels, but not much. This region will only sustain for so long, and will slowly begin to die also as energy demands are not being met. This ‘risk’ zone around the infarct is called the penumbra.

Ischaemic attacks usually present a wedge shaped path of pathology, from the point of cerebral artery occlusion.

Picking up on stroke quickly and getting medical treatment is what saves the penumbral region. The longer you leave it, the more of the penumbra dies, and the brain damage is pronounced. Neurons of the penumbral region actually die from a process known as excitotoxicity, we the lack of oxygen and glucose causes them to become overexcited and then kill themselves (which is one thing I shall be investigating in some depth in my lab project). Blood vessels are usually blocked by a dislodged blood clot or atheroma (fatty deposit in the blood vessel walls). The atheroma or clot usually forms elsewhere in the body, like in a leg or something, and then becomes dislodged and travels up to the brain in the blood where the narrow blood vessels cause the entity to become lodged and thus block blood supply. If such a clot or atheroma lodges itself in a coronary blood vessel (blood vessel supplying heart muscle), then we have a myocardial infarction. Heart muscle is starved of oxygen - heart attack. Which is why people with high fat diets are at much more risk of heart attack or stroke. 

Ischaemic stroke

Haemorhaggic stroke occurs when a blood vessel in the brain bursts, leaking the contents of the blood into the brain parenchyma. This isn’t very good. For one, it impairs blood supply to the local region. Two, apart from oxygen and glucose, nearly everthing else in the blood is going to be harmful to the neurons. Neurons are fragile and require a very specific environment to thrive in. Nearly all blood vessels in the brain have a function to ensure only the right substances from the blood come into contact with neurons. Such  functionality of cerebral vasculature is known as the blood-brain-barrier (BBB). All sorts of nasties in the blood come into contact with the fragile neurons, such as urea and excitatory amino acids. Furthermore, blood coming into contact with anything that isn’t the vasculature wall, causes it to clot. Clotting occurs around neurons, waste material accumulates, oxygen and glucose supply is impaired, excess water is entering neurons (causing oedema) - haemorrhagic stroke is just one big mess. Well, any stroke is a mess, but physiologically, haemorrhagic stroke is just so dang messy. How do blood vessels burst in the brain? It could be as a result of severe head trauma from a car accident or something, though that isn’t usually considered a stroke.

Usually, haemorrhagic strokes occur from the bursting of aneurysms, and the rupturing of weakened blood vessels. An aneurysm is a swelling in the blood vessel which is filled with blood. The swelling puts strain on the vessel wall, weakening it. Thus, it may rupture when the blood pressure gets too high, or the person suffers a knock to the head. Aneurysms can form in many parts of the body, but the ones that form in the blood vessels within the brain are the ones we look at regarding stroke. Aneurysms may form as a result of a genetic predisposition, (i.e. collagen mutation. Collagen is a structural connective protein which is involved in holding tissues together. If a genetic mutation makes this weaker, it may be more prone to stretch and may aid in the formation of aneurysms).

A little something I rustled together on paint because Tumblr kept turning the photo I uploaded vertical. Pfft.

Blood flow through blood vessels should be smooth. This type of natural, good blood flow is known as laminar blood flow. However, if blood flow is turbulent, and the flow currents are exerting pressure in multiple directions against the vessel wall, it may cause wall weakening (should there be enough strain). This turbulent blood flow occurs naturally where blood vessels fork off into different directions. These are usually not too much hassle. However, irregularities in the blood vessel inner lining, perhaps from fatty deposits from an unhealthy diet and lifestyle (atheroma!), can cause increased turbulence, thus contributing to aneurysm formation. Once again, unhealthy diet rears its ugly head in stroke. Smoking can also encourage aneurysm formation. It can do this by facilitating atheroma formation, and also by physically weakening the collagen itself. In this way, smoking also increases the risk of stroke (and heart attack).

Diagram of a berry aneurysm

It’s a very complex and multi-layered topic, and attempting to condense all of this into a post such as this is…. a difficult process. I’ve tried my best to make it coherent, and apologies if I’ve missed out minor details - which may happen as sometimes I assume certain things don’t need saying because they appear obvious to me. Of course, what is obvious to one person isn’t always obvious to the next so…. yeah.

Anyway, that’s a bit of recap for me, and a topic I find particularly fascinating. But now I must get back to studying astroglia mediated pH buffering systems in the central nervous system, and hypothermia therapy in the treatment and reversal of penumbral excitotoxicty following ischaemic stroke. S’all good.