Staring at a Map of the World

Deviating somewhat from the standard theme of my blog, but it’s almost life-science related. Allusions to biochemistry and all that. Anyway, I’m sure most of you have heard the tantalising news of data emerging from the Curiosity Rover on Mars, suggesting that Mars had an environment conducive to life in it’s ancient past. I’ve had about a day to let that news sink in but it’s still exciting.

On facebook I follow a page called ‘The Universe’. It is probably my favourite page on that website. It doesn’t dumb things down, it keeps very true to themes about the universe and it’s not in your face and obnoxious like ‘I fucking love science’ sometimes gets (though it’s still a fun page to follow).

Regarding the recent data from Mars (the scientist in me is telling me to wait on confirmation data from the next set of experiments), ‘The Universe’ posted one of the most brilliant, beautiful summaries of the discovery on facebook. I felt it a bit of shame that it only went up on facebook, to me it bettered NASA’s own delivery of the gravity and implications of the discovery. Now let’s just hope the data presented by NASA isn’t anomalous (though all the cumulative data from Mars expeditions would make this somewhat unlikely)!

I like to keep the majority of the stuff I post on here original, and only reblog/quote in exceptional circumstances - and this is one of those circumstances. This is the excellent summary of the journey to find out if Mars could once support life, Copied from here. - 

 - “To tell that story, we have to go back to before the Mars Exploration Rover mission. When MER went to Mars, we sent 2 rovers, and we sent them to 2 different sites, both hunting for evidence of water. One went to a site that looked like a lake in the geomorphology, the other went to a site where orbital spectra indicated the presence of hematite, a mineral which likely formed in the presence of water. When we got to the two sites, we found the geomorphology site was filled with basalt, and the hematite-site was filled with sediments derived from a water-bearing environment. Eventually, Spirit caught up, and found evidence of a hydrothermal system, but really, the rover sent to the mineralogy site found the water first.

The Curiosity rover selection process was one of the most difficult decisions I’ve seen NASA make. Instead of 2 rovers, this time, they only had 1. They couldn’t miss. They basically had the same decision; picking between a mineralogical site and a couple geomorphology sites. The geomorphology sites resemble river deltas from orbit. The mineralogical site, a place called Gale Crater, had the spectral signature of clay minerals.

Clay minerals imply an environment we’ve never seen before on Mars. In very wet environments on Earth, clay minerals are the most important product. When a rock erodes in the presence of lots of water, the soluble elements are removed, and only the most insoluble elements remain. The 2 most insoluble elements in water are iron(III) and aluminum. 

On Earth, the continents are made of rocks like granodiorite and granite. These rocks don’t contain much iron, so Earth makes minerals that contain aluminum and water; aluminum-rich clays. Minerals like Kaolinite, aluminum clays. If you go to the Amazon River on Earth, coming out of a rainforest where water is abundant, the mineral you find coming out along with the water is kaolinite; water rich aluminum-clay. Clays tell you that the environment had a lot of water. They form in areas that have lakes and have oceans. They don’t form in dry settings, they don’t form in deserts, and they don’t form when water is only around for a short time.

Mars isn’t a granite world; it’s a basalt world. Compared to Earth, the rocks on Mars have much more iron. When you try to make clays out of these iron-rich basalts, the end result is an iron-rich clay called nontronite, rather than aluminum-clays. Seeing clay minerals implies not only that water was present, it implies a lot of water. It implies that so much water was present that all of the other soluble elements in the rocks were stripped out by water. This is a setting none of the other rovers saw, and this clay mineral was detected from orbit in abundance at Gale Crater. Quite simply, clay minerals are the #1 reason why the landing site was chosen. Last time, the mineralogical site found what it was looking for and the geomorphology site did not. So, with only 1 landing site, the mineralogical site, showing evidence of clay minerals and large amounts of water, was chosen.

The single biggest goal of this rover is assessing the rocks that contain clay minerals, the environment they formed in, and what that tells us about the environment on Mars when there was a large amount of water present.

That’s the backstory of this press release. Today, the Curiosity team announced the results of drilling into a rock called “John Klein” (drill hole pictured). The rover has been driving on what appears to be an alluvial fan deposit fed by a channel on the Gale Crater rim. The rover landed on coarse grained fan rocks, and drove to a place where the rocks appeared finer grained. These fine grained rocks are the rocks they drilled. 

They fed this first drilled sample into the CheMin instrument and the SAM instrument. CheMin is an X-Ray diffraction system. It is spectacular at identifying minerals. If you wanted to identify clay minerals, it’s exactly what you’d want. They fed the drilled sample into CheMin, and…it turned out to be made of iron-bearing, smectite clays. Also known as; nontronite.

They also fed the sample into the SAM instrument, a mass spectrometer. SAM can measure abundances of elements like carbon and sulfur, and hopefully also measure isotopes on those samples. They didn’t give us the isotope compositions in the press release, suggesting that they’re still working on those, but they did announce the presence of carbon and sulfate bearing minerals. 

Put all this together, and the most important part of today’s results is this sentence; we found what we were looking for. In the other 2 sites on Mars, we found evidence of some water, but not large amounts of water. Spirit found a hydrothermal environment, where small amounts of water circulated through the rocks. Opportunity found an oasis in a desert, where small amounts of water had moved through rocks and precipitated minerals like hematite. 

Curiosity went to a place where the orbital spectra say there should have been a lot of water. Clay minerals aren’t made when there is only a small amount of water; it takes a lot of water to make clay. It takes a lake, or an ocean, or at least long-lived water bodies. The other rovers found small amounts of water and the signatures of acidic environments.

To create a habitable environment, as we understand it, you don’t just need small amounts of water, you need a lot of water. You need enough water to drown the rocks, to move most of the elements around. The end result of this amount of water should be clay minerals. If that kind of environment ever existed on Mars, the signature should be nontronite clays. Those clay minerals could be trapped in mudrocks, like shales and siltstones on Earth, and if we’re lucky, they’d have carbon, sulfur, and other elements that life could make use of trapped within them that could be analyzed.

That rock type is…exactly what Curiosity drilled. We went to Gale crater hunting for clays. We picked Gale Crater because orbital spectra said there was clay. We wanted to see the rocks that hosted the clay, measure the chemistry of clay-bearing rocks, and interpret what the environment was that formed them.

There are a lot of other interesting details about this rock. It appears less-oxidized than the surface. It isn’t fully red; when they drilled the rock, they found it looked dark; meaning some of the iron hadn’t oxidized. It wasn’t fully altered. They also found olivine, an easily-erodible mineral, in the mudrocks. These results suggest that the clays were laid down with sediment that wasn’t as highly altered, because olivine and reduced minerals wouldn’t survive that much exposure to water. They also found both sulfates and sulfides, indicating partial reaction of the sulfur-bearing minerals, but not complete consumption of them. These details will take time to figure out, and I’m sure the team will target a whole lot of effort to figuring them out, as chemical reactions involving reduced minerals and sulfide minerals on earth provide energy that life can use to sustain itself. 

All of these are important and the team will keep working on them. But the message you should take from today’s press release is this; we went to Gale Crater looking for clay minerals like nontronite in the rocks, because those minerals would tell us that there was a very large amount of water when they formed. Today, they announced…they found what they are looking for. Curiosity is where it was supposed to be. We sent an organic chemistry laboratory to Mars to look at clay-bearing rocks. We now have an organic chemistry laboratory sitting on clay-bearing rocks. We found what we are looking for.

-JBB

Image credit: NASA/JPL-Caltech/Cornell/MSSS 

http://www.nasa.gov/mission_pages/msl/news/msl20130312.html

The image compares rocks seen by NASA’s Opportunity rover and Curiosity rover in two different areas of Mars. On the left is “Wopmay” rock, in Endurance Crater, Meridiani Planum, studied by the Opportunity rover; on the right are the rocks of the “Sheepbed” unit in Yellowknife Bay, in Gale Crater, which Curiosity has been studying. The images have been white balanced to show roughly what they would look like if they were on Earth. ” -

Psychosis principally consists of ‘reality distortions’. A person exhibiting psychosis has a skewed perception of reality - the result of faulty circuits in the brain which are involved in perception. Reality distortions are typically characterised by hallucinations and delusions.

Psychosis can occur in isolation, but usually occurs with other symptoms which together form a psychiatric syndrome. In a syndrome, patients exhibit a cluster of symptoms which individually could be seen as distinct disease states. Examples of such syndromes include bipolar depression, major depressive disorder and schizophrenia. Many patients do not exhibit the same set of symptoms. They probably share the same defining hallmarks of said disease, but also have other more variable symptoms alongside. These ‘extra’ symptoms complicate matters, as they usually arise from dysfunction in a different system of the brain, which could require a different course of therapy.

Schizophrenia is a psychotic syndrome. It is characterised by the presence of

‘positive symptoms’;  The psychosis. Psychosis is one of the defining and more recognisable symptoms of schizophrenia

‘negative symptoms’; Social withdrawal, decreased spontaneous speech, apathy, self-neglect and decreased emotional expression (flat affect).

Many of the neural circuits involved in perception and attention use dopamine as their neurotransmitter.  Dopamine is not exclusive to perception circuits, and neither are all perception circuits dopaminergic – but the point is there’s a lot of dopamine involvement.

There are 4 main dopamine pathways in the brain; mesocortical, mesolimbic, nigrostriatal and tuberoinfundibular.

The diagram hasn’t labelled the tuberoinfundibular pathway, though it is highlighted as the small pathway starting from the hypothalamus. Diagram from ‘Dopaminergic neurons’, Chinta & Anderson 2005, The International Journal of Biochemistry & Cell Biology

All of these tracts originate from roughly the same brain region. This region includes the structures involved in reward and motivation. The pathway of note in psychosis and perception is the mesolimbic (and to an extent, the mesocortical). In schizophrenia, the positive symptoms (psychosis) arise from excessive dopamine function in the mesolimbic pathway. Drugs which block dopamine neurotransmission are used to combat psychotic symptoms. Such drugs include haloperidol and aripiprazole; useful chemicals which bring perception back in tune with reality, removing hallucinations and bringing delusions down to a tolerable level.

chemical structure of Dopamine

A hallucination is a seemingly realistic perception which occurs without any sensory input; seeing something which isn’t actually there, but having no idea that it isn’t actually there. It is as real as your own two feet in your own thoughts, though objective evidence from the world around you would suggest it wasn’t there.

Hallucinations are thought to arise from impaired wiring in neural circuits involved in perception. One theory suggests that the neuronal networks involved in imagination are misconnected to the circuits involved in processing incoming sensory information into perception. As a result, thoughts which would be the domain of imagination are ‘perceived’ as information directly sensed from the environment. Electrophysiology studies using EEG to measure brain waves support this theory by showing aberrant electrical patterns from such sensory-to-perception circuits. The theory makes sense (and is one that has my backing, if it’s worth anything) given the nature of hallucinations, and it has reasonable evidence to back it up making it a strong candidate to explain, at least in part, how hallucinations occur. Neuroanatomical evidence to back this up is complex, with different regions involved depending on what sort of hallucination the person is undergoing. However, the impairments which give rise to hallucinations are only part of the story of psychosis.

A delusion is defined as a fixed belief derived by illogical reasoning or unjustified assumptions that cannot be explained by culture or religion. At the crux of a delusion is a premature conclusion - seeing a trend before enough information to rationally describe a trend has been presented. Delusions are generally culturally influenced, with delusions of old consisting of stories about ghosts and demons (stories which do still exist) to more modern delusions which involve government conspiracies and aliens. The cultural context of the story is variable, but rests on fixed, illogical conclusions which cannot be swayed by contrary evidence or reasoning. This sounds like a complex behaviour as opposed to a symptom of a disease state– but the real behavioural pathology here is the fixed misinterpretation of information to jump to early, and absolute conclusions.

The biological basis of delusions, which should hopefully begin to explain their role in psychosis, lies in a phenomenon termed by those in the field as ‘aberrant salience’. Normally at the level of neuronal computation, the brain makes predictions about events in the environment, and when such an event does not meet the prediction, dopamine is released in regions of the brain which drive reward and salience. There is a network of neuronal circuits in the brain called the Salience Network. The Salience Network is involved in influencing attention to environmental events. The salience network uses dopamine neurons (amongst others), and when the dopamine neurons in the salience network are active, they activate neuronal networks involved in drawing attention to this stimulus, and this begins analysis of the novel event – which will thus drive perception and thoughts of this new, interesting event.

Diagram showing regions of brain part of the Salience network and Central Executive Network. The Salience Network regions are highlighted in red and orange. Images obtained from fMRI neuroimaging. Diagram adapted from “Large-scale brain networks in cognition: emerging methods and principles”, Bressler & Mennon 2010, Trends in Cognitive Sciences

In a delusion, this dopaminergic system appears to be impaired, resulting in salience being attributed to irrelevant cues in the environment. This would imply excessive dopamine is being released. The theory put forward by Andreas Heinz and the various members of his research teams asserted that environmental stresses could induce ‘chaotic’ dopamine release in these systems, responding to irrelevant events as if they were relevant. This would lead to the formation of a thought or conclusion about a given event that was based on irrelevant or misleading information. This theory is supported by a wealth of evidence from rodent, primate and human studies. Such studies include verifying that social stress plays a role in dysregulating dopamine release in primates, and pharmacological and neuroimaging studies in humans has shown that ‘chaotic’ dopamine signalling can affect reward-prediction processing. In schizophrenia, there is already a malfunction leading to increased release of dopamine, so this would explain the existence of pathological delusions in the absence of environmental stressors in line with this theory.  More research is needed to conclusively verify this hypothesis of chaotic dopamine, but the trend of evidence is very promising.

Transient psychotic symptoms can be induced by some recreational drugs as part of their action. Such drugs include cannabis, amphetamines and cocaine. There is verified experimental evidence for acute transient psychosis (psychotic symptoms brought on during drug use) from cannabis and amphetamine, and population based evidence for such symptoms from cocaine. Long term use of cannabis, amphetamine and cocaine is associated with the development of a psychotic disorder later in life, but the there is great debate as to what the causation to this correlation is.

Chronic use of cannabis is thought to inhibit the generation of new neurons in the brain so it is possible that cannabis usage can interfere with brain development, leading to some miswiring events involved in psychotic symptoms. With brain development occurring well into the teenage years, it is thought that cannabis use may precipitate schizophrenia or psychotic disorder in teens who have a genes which make them susceptible to such disorders. Amphetamines and cocaine interfere directly with the dopaminergic pathways, and their role in producing psychotic symptoms during drug use is much more straightforward. Amphetamines directly increase dopamine function so by looking at their very chemistry and pharmacology, their predicted effect would be something similar to psychosis.

Psychosis and the effects of drug use on the brain demonstrate just how material our thoughts, emotions, personalities and memories are. They can be seen as another part of our body. This line of thinking should hopefully allow us to understand those who suffer from mental health issues. It shows that mental health disorders are a very real phenomenon, and not just people trying to be awkward. Such disorders are leading scientists to question the very nature of free will itself. Psychosis and the predictable effects of drugs on the brain are striking evidence of just how chemical we are at the deepest level of what we see as our soul.

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!

Attention Deficit Hyperactivity Disorder, more commonly abbreviated to ADHD, is a condition on which my perspective has changed considerably over the years. When I first was exposed to the idea of ADHD, I held the ignorant prejudice that ‘it didn’t exist and it’s all just made up.’. I then started exploring basic ideas surrounding neuroscience in college (aka high school, for those who recognise American English terminology) and then actually went on to study the subject in more depth in university where I came to conclusion that it’s a bit from column A, and a bit from column B. There is an underlying disorder, but perhaps it’s not precisely as we currently describe it.

ADHD is a collection of syndromes, the origin of which is still being figured out by science. ADHD presents with short attention span, increased distraction and impulsiveness and hyperactivity. It is likely this collection of syndromes do not have a single cause. People presenting ADHD have issues with motivation, and this is sometimes seen to impinge on basic planning tasks carried out by the brain. ADHD patients classicaly appear to find it difficult to offset future reward for favour of an immediate, smaller reward. This lack of anticipation is stark, and can contribute to the shortened attention span. These symptoms have to be such that they’re developmentally and socially disruptive, and must have been presenting since before they were 7 years of age.

This brings me to the the first perspective I held of ADHD. The affected functions in ADHD seem to be higher level processes, processes commonly attributed to the way we think and the decisions we make. As such, I guess it’s almost easy for people to blame the person for their behaviour in a sort of “They’re just poorly disciplined!”, kind of Dickensian, Victorian-era response to conditions affecting the mind. BUT, this is almost definitely not the case, as current evidence points out.

Anatomical studies on the brain have highlighted differences in brain structure which are linked to ADHD, in comparison to seemingly typical brains. Various neuroimaging studies in ADHD patients have consistently shown reduced brain volume in the white matter of the pre-frontal cortex, the corpus callosum, the cerebellar vermis and the caudate nucleus. The caudate nucleus is particularly interesting, as we shall see with further evidence. On their own, these anatomical differences don’t count for much - until we start looking at some genetics.

Location and structure of the Caudate Nucleus

Genetic studies have come across a few candidate genes which could be responsible for predisposing an individual to ADHD. Two genes most strongly implicated by studies are DRD4 and DAT1. DRD4 encodes for a protein which makes it possible for neurons to respond to contact with dopamine. DAT1 encodes a protein which removes dopamine from the synapse after it has been used in signalling, to prevent it from exerting too much of an effect on other neurons. The proteins are prominently expressed in the caudate nucleus, amongst other places such as the frontal cortex.

Bring in the neurochemistry which arises from these genetics and we start to paint a compelling picture. In the brain, different populations of neurons communicate with each other using different chemicals. It’s the method which neurons pass on an electrical impulse to the next neuron, to ensure a signal is transmitted to its destination. These chemicals are known as neurotransmitters. The caudate nucleus is highly receptive to a neurotransmitter called dopamine. Using radioactive-cocaine, scientists have been able to image the levels of these dopamine transporters in certain parts of the brain in ADHD patients. The evidence suggests impaired levels of dopamine transporter in ADHD, though different studies seem to show either raised or decreased levels. Methylphenidate, also known as ritalin, is thought to block the dopamine transporter. It is also used in the treatment of ADHD to improve attention. The successful action of this drug provides further evidence for impairments in dopamine signalling in ADHD.

Structure of Dopamine

Now that we’ve ticked off anatomy, chemistry and genetics, we can tie these together with electrophysiology, the actual electrical function of cells (in this case, neurons in the brain). The mechanisms underlying this have been linked, once again, to dopaminergic neurons. Early experiments into the basis of anticipation and reward, in the well-known reward pathways, identified the electrophysiological mechanism behind the conditioning of anticipation for a reward. The current theory for the lack of anticipation for reward in ADHD says that the correct electrophysiological response to conditioned reward aren’t generated properly, so the reward isn’t anticipated, therefore the person with ADHD wants whatever is on offer at that time instead of waiting. Evidence from functional imaging studies shows decreased activity in these pathways in teenagers exhibiting ADHD.

There’s a whole lot more, describing the basis of the malfunction in attention and hyperactivity, and dopamine has implications in both of these, and how defined networks of neurons seem to be miswired, but the picture is complicated enough as it is, so we’ll leave it that for now.

With multiple pieces of corroborating evidence, from different angles and sources, we can be pretty damn sure localised dopamine signalling is impaired, and it is linked in with symptoms of ADHD. The best, most general explanation that can be given for the onset of ADHD at this time is something along the lines of ‘it’s a mixture of genetics and environmental factors’. That sounds all well and good - until you realise that explanation can apply to most psychiatric conditions.

But - there is an issue. ADHD is a collection of syndromes, as said before. Not every patient exhibits the same set of symptoms. This is true for other psychiatric illnesses, from depression to schizophrenia. This issue goes right to the heart of diagnosis in psychiatry. Conditions such as ADHD and schizophrenia have been historically characterised and classified by their behavioural symptoms. This doesn’t account for the actual cause of the condition. It’s not a terrible system, it worked when biochemistry and molecular biology weren’t as developed as they are now. But with advances in genetics, and neuroimaging, we can now start to look at the heart of a disease. The once impenetrable black box of the brain is now becoming accessible, and this may need us to rethink how we look at psychiatric illness.

I allude to the endophenotype method of diagnosis - classifying diseases according to their underlying anatomy, genetics, biochemistry and physiology. Behaviour is the result of many different neurological processes, and can be affected in similar ways by varying mechanisms. Drugs are designed to act on biochemical targets to tackle the underlying causes of the symptoms. The reason some current drugs used in psychiatry can have varying effects from not doing anything, to making people better may be due to the patients actually having different biochemical causes of for seemingly similar illnesses. A drug designed to affect one chemical pathway may not be doing much for the patient because that chemical pathway is actually fine in that patient, and a different set of genes and neurons are actually the root of the problem. As a result, understanding the mechanisms which give rise to a symptom, be it behavioural or otherwise, will allow doctors to target better, more accurate therapies. For this reason, I think the endophenotype method can be beneficial, and may enhance psychiatric diagnosis. 

Science is still exploring many routes to identifying the causes of ADHD, but the evidence thus far makes at least one thing clear - it’s not a choice. Then again, how much of anything we do is a choice? But, that’s another topic for another day. And if you’ve gotten this far, I applaud your attention span. It has been quite a long post.

One more exam to go, tomorrow. Still studying on campus, it’s pleasantly warm. Biochemistry of disease is next.

This time tomorrow I will have finished my degree.

…

That’s just scary.

(Just noticed that one of the equations in the book isn’t balanced either. Ah well.)

According to my biochemistry lecturer who was teaching us about radiation induced carcinogenesis for the advanced biochemistry course, leaving a petri dish of cell culture out in the sun (with the lid off) in Denver, Colorado will cause cell mutations, producing some cancer cells. This is because Denver is quite a high altitude city and has high ultraviolet radiation exposure from the sun. The high energy UV rays damage the DNA in the exposed cells, and if the damage inactivates the right genes (i.e. tumour suppressor genes), then the cell will have nothing to stop them from proliferating uncontrollably.

UV radiation generates thymine dimers between adjacent thymine bases in DNA, which disrupts base pairing between DNA double strands. This can give rise to mutations during DNA replication.

 The moral, don’t go sunbathing in Denver…

(oh, and just in case there’s any misunderstanding: high energy UV is a carcinogen anywhere. It’s not only risky in Denver - use sunscreen if you’re exposing yourself to high levels of sunlight. But that’s just common sense.)

Subtract the water and the fat from any living organism and you’re left with a lot of protein. Protein makes up the majority of the dry mass of every living thing on this planet. Organisms are made up of thousands upon thousands of different types of these molecules, which in themselves are just folded-up chains of smaller molecules called amino acids. Living things use about 20 (technically 22, but like, the other two are relatively rare) different amino acids in varying quantities and sequences to build up proteins. This sequence of amino acids determines what role the protein is going to play in the living organism - and this sequence is coded for by the organisms’ DNA. So, now you know that protein is pretty important.

Structure of proteins. They’re built from amino acids!

Us multicellular organisms live amongst other organisms who think the inner environment of our bodies would be a safe, nutritious place to live. They just want a free ride, the rascals. Such organisms would be parasites and pathogens. We’re talking about some types of protozoa and fungi, bacteria and viruses (viruses are kind of organisms…). It wasn’t until the mid-twentieth century that a new type of pathogen was characterised. A non-living biological pathogen even more bizarre than our semi-living friends - the viruses. Enter, the prion. People had known about prion diseases for centuries before the actual idea of the prion emerged, they just didn’t realise what caused such diseases. Scrapie, a prion disease which affects sheep, was identified in the 1700’s. Prion diseases are termed transmissible spongiform encephalopathies (TSE’s) because they’re infectious, affect the central nervous system and have the characteristic of turning your brain spongy. Prion diseases in humans include Creutzfeldt-Jakob disease (CJD), kuru and fatal familial insomnia.

But what ARE prions? In all reality, the evidence is not yet conclusive - but the overwhelming response from scientific and clinical studies in humans and animals indicate that prions are little more than a type of infectious protein molecule. No DNA, no RNA, no membrane. Just a single molecule protein. This molecule of protein is a malformed version of a protein we already have, called PrP. The healthy version of PrP is called PrPc. The prion version is called PrPsc. This molecule of PrPsc somehow enters the central nervous system and replicates, making loads of other prions like itself which aggregate, forming rod like structures which gather in plaques around neurons, messing their function up and causing masses of them to die. This results in lots of pockets of empty space in regions of brain, giving it the spongy characteristic - hence the ‘spongiforme encephalopathy’ title.

Pathology of CJD, a type of TSE

In humans, before the BSE outbreak (I’ll get to that in a sec), the main way in which we got prion diseases was either through mutations and inheritence (the main causes of CJD and fatal familial insomnia), or through cannibalism (the mode of Kuru infection). Kuru was a prion disease which affected the Fore people of the Papua New Guinea highlands, a tribal people. They would eat the deceased as a ritual meal. This practice spread the prion responsible for Kuru, particularly in women. There was a 10:1 ratio of women infected, in comparison to men. It turned out that this patriarchal society would give the men the choice cuts of meat, and leave the rest to the women, including the intestines and brain. Eating infected brain increased chances of ingestion of prion proteins, and as such, the ratio reflected this.

Human prion diseases traditionally affected the elderly, as it seems that they have a very long incubation period. This is probably due to the proposed thermodynamics of prion function which rely on PrPsc being a less favourable form of the PrPc protein. The same stretch of amino acids can give rise to both shapes - BUT current theory suggests that the PrPc is the favourable protein form to take. However, with the right mutation, PrPc is more liable to overcome activation energy barriers and switch to PrPsc. Once one or a few have been formed and remain stable for long enough, they can bind to other healthy PrPc proteins, and make them change into PrPsc. Kinda like a zombie biting healthy humans, and turning them into zombies, which then go onto bite more humans, making loads more zombies. Well, current models suggest the same thing happens with prions, explaining why it takes so long from first contact, to full blown pathology. We’re talking 10-20yrs of incubation in humans here. For the first few stable PrPsc to become established requires the right conditions and a lot of time, but once they’re converting healthy PrPc, the progress of disease suddenly becomes rapid. Once symptoms are expressed, there is an untreatable deterioration until death within 1-2yrs.

This diagram is probably from some cool paper, but I don’t know which. I plucked it from my lecture notes. No copyright intended etc etc. Happy elsevier? Anywho, it’s a diagram explaining one prominent model of prion multiplication and pathogenesis.

Due to destruction of nervous tissue, prion diseases tend to result in rapid dementia like symptoms with severe motor deficit. So movements become severely impaired. This means, speech and swallowing, the ability to walk etc. tend to be lost. Tremors and spasticity also accompany prion diseases. Not nice ways to go. CJD is the most common prion disease in humans, affecting around 1 in a million people worldwide (they’re rather rare diseases, luckily). Following the chronology of the symptoms, the spread of pathology appears to start at the brain-stem and work its way towards the frontal lobes of the brain. This is confirmed in post mortem examination. Spongy pathology and gliosis (when glial cells invade the damaged areas of brain) corresponds with he early speech loss with damage in the brain stem. Coordination and balance loss correspond with cerebellar damage (the next stage of symptoms), muscle rigidity corresponds with damage to the basal ganglia and finally, dementia fits in with the pathology in the frontal lobes.

If you’re about the same age as me or older, y’all might remember some hubbub in the news about ‘mad cow disease’ or ‘BSE’. BSE is Bovine Spongiform Encephalopathy, a prion disease of cows. This disease actually did not exist before the 1980’s, it was accidentally created in dairy cows in the UK. So, dairy cows need to come inside during the winter because pastures no longer provide energy for milk production and it’s too cold outside. To supplement the cows energy demands, bits of meat we don’t eat (offal etc.) are processed and cooked and turned into pellets which are fed to cows. This provides them with protein so they can stay strong over the winter months. Make what you want of this practice, but it’s what happens. To make the offal sterile so it’s safe and un-diseased for the dairy cows to eat, the stuff is heated up and cooked before being made into pellets. To cut costs for dairy farmers, new legislation was introduced which lowered the temperature this offal could be heated to. This allowed prion proteins to ‘survive’ and enter the food chain. The initial prion protein probably entered the offal through a mutation in a population of cows. Once it entered the food chain it could multiply, and when these dairy cows entered the food chain themselves, so did the prion protein. Through this process, it entered cows which are used for human consumption, and then - into the humans.

CJD flared up at a rate higher than the standard 1 in a million in the UK. British beef exports were banned around the world. Thing is, this CJD was affecting young people, around the age of 20. This new variant CJD was termed vCJD. In the UK, vCJD cases peaked in the year 2000 with about 27 individuals succumbing to vCJD, approx. 10 years following the height of the BSE epidemic. Nowadays, there’s about 1 case of vCJD per year in the UK. What appeared to happen was the consumption of infected meat led to the entry of bovine PrPsc into the human system, where it did the same thing any other prion would do once it entered the central nervous system.

An interesting aspect of prion diseases is that they have only ever been noted in humans and domesticated animals. We have CJD, vCJD, kuru, fatal familial insomnia, Gerstmann Strausser Scheinker syndrome in humans, BSE in cows, scrapie in sheep (which doesn’t seem to affect humans), chronic wasting disease in mule, elk and deer (farmed for meat and skins), transmittable encephalopathy in mink (farmed for their fur).

The good news is, even in times of prevalence, prion diseases are rare. The bad news is, there’s no treatment for them. There’s a whole host of mutations associated with prion diseases, and carrying any one of these doesn’t make it certain that one will contract them. A mutation associated with every vCJD case is Methionine129 (an amino acid) in PrPc being substituted for a valine (another amino acid). Without going into what this could mean genetically or chemically, this mutation is thought to be present in 38% of populations sampled from Europe and the Middle East. Current theory suggests that PrPsc can be produced in us spontaneously, and this spontaneous conversion is accountable for 85% of CJD cases. Thing is, PrPsc appears to be rather unstable and is usually degraded quickly by cellular systems. So even genetic susceptibilities don’t make it likely you’ll get CJD. There is a large amount of chance involved. They’re rare diseases, but interesting ones at that. So… beef burger anyone?

so, where were we? Ah yes, those little antibodies.

The basic structure off the antibody protein. It is composed of multiple protein chains, and has a characteristic ‘Y’ shape. These can be embedded in immune cell membrane, or released into the surrounding environment (typically the blood).

Antibodies have a specific region which contains the binding site which actually latches onto, and holds onto invaders. This is the part that binds the antigen (interesting point: antigens are derived from Antibody Generating. An antigen is anything that causes an immune response). The specific part of the antigen which the antibody recognises is called the epitope. This is a stretch (or stretches) of amino acids (the building blocks of every protein). The chemical properties conferred to this region of antigen are conferred to it by the amino acids which construct it, and this contributes to the overall 3-D folding of the protein which makes up the antigen. As mentioned before, the shape of the binding site needs to complement the shape of the epitope. At the atomic level, this binding is mediated by non-covalent forces. The most common forces at work are Hydrogen bonds and van der vaals forces. Hydrogen bonding occurs between hydrogen and the highly electronegative moieties; nitrogen, oxygen and fluorine. Fluorine isn’t incorporated in proteins so isn’t particularly relevant in this context, but oxygen and nitrogen are present in abundance in proteins. The correct pattern of Hydrogen bond donors in the specific shape of the antibody binding site, must match the pattern of hydrogen bond acceptors in the antigen, and vice versa.

Nitrogen is highly electronegative. One reason for this is that it has two electrons orbiting it which aren’t usually involved in neutral bonding. (they can be involved in bonding, but when this occurs, nitrogen becomes positively charged). These electrons are known as a ‘lone pair’. The presence of a lone pair makes the nitrogen very electronegative. Hydrogen is relatively positive compared to nitrogen; particularly ionised Hydrogen, or hydrogen that has been bonded to a structure. This is because hydrogen is simply a proton and an electron. In its ionised or bonded form, the electron is either absent (ionised hydrogen) or in use in maintaining a bond. This leaves, in essence, a single proton available for intermolecular interaction. Protons are positively charged subatomic particles, and the relative difference in charge between a single proton and electronegative nitrogen means there is a very strong attraction between the two atoms (rule of thumb – opposites attract). This strong attraction is about as strong as intermolecular attractions get without them actually forming a covalent or ionic bond. Oxygen has 2 lone pairs, which makes it very electronegative, and also makes it highly prone to generating hydrogen bonds.

Examples of hydrogen bonding (using amino acids as models) The dotted line denotes the hydrogen bond. Hydrogen bonds are crucial throughout biology, and are one of the forces that enable proteins to exist - in doing so, enable life to exist.

Amino acids all contain oxygen and nitrogen, and some contain more Hydrogen bond generating groups than others. The content and arrangement of amino acids in the antigen binding site, and on the antigen itself is important in not only determining the shape of both of these sites – but also in determining the extent of hydrogen bonding which will occur. More hydrogen bonding will mean the attraction between the antibody and antigen will be much stronger, and will be more liable to elicit downstream immune effects. 

Van der vaals interactions are much less specific, operate under short distances, and are very weak. Van der vaals forces can arise from any atom  and are the basic, weak attractive forces between atoms which arise from the subatomic properties of the protons and electrons which help make up atoms. Stronger interactions probably bring the molecules together first, and the van der vaals forces probably add to the pre-existing strength of attraction between antibody and antigen.

The grey, red and blue atomic structure is the antigen binding portion of the antibody. The Green structure is the epitope of the antigen. The small yellow lines indicate hydrogen bonds between antibody and epitope. The shapes of both the antigen and antibody determine how the pattern of H-bond donors and acceptors will line up and give a stronger interaction. This interaction will result in a global change in the structure of the antibody which will mediate downstream effects which will produce the response.

The region of the antibody which binds the antigen can also be called the Complementarity Determining Region (CDR), and it is this region which is variable throughout antibodies produced against different antigens. The protein structure in this region is physically and chemically different for different antigens, and new CDR’s can be generated, to bind other epitopes. How is this complexity achieved? How does the seemingly fixed genetic code achieve production of an almost limitless potential in invader antigen detection?

It seems that the region of DNA that makes up the genetic code in the gene which codes for the CDR is chopped up and rearranged for the different B lymphocytes in the latent pool I mentioned earlier. Lots of small stretches of DNA are cut out and reshuffled, to be stuck together in a different order to produce a new genetic code. This is known as genetic recombination. Each different B lymphocyte has a different recombination of the CDR portion of the gene. The subsequent code then goes on to form a novel CDR (or antigen binding site, if you prefer that term) which may or may not bind to an antigen that may enter the body. It’s a blind process which tried to churn out as many variations as possible, in the hopes that some antibody-antigen binding will occur (different invaders may bear similar epitopes, so there may be some antibody binding from an antibody already primed to tackle a previous foe).

This genetic recombination of the CDR is precisely what puts the ADAPTIVE in adaptive immune system. It means that we don’t only have the defences we’re born with, but we can generate new ones without having to wait generations to evolve them. What’s more, these antibodies that we develop in our lifetimes have the potential to be passed on to our offspring. At least for mothers anyway. The colostrum, which is the initial breast milk produced following childbirth is packed full of useful proteins, some of which include the mothers antibodies which confers the newborn baby with extra immunity. It’s not particularly long lived immunity as the baby hasn’t received the Memory cells (remember them from the previous post?), but it’s a good start to life. For the budding biologist/medic out there - it may seem a bit odd. The baby drinks the protein concoction of colostrum - surely the proteins, including the antibodies would just be digested? Well, the newborn digestive system has limited capacity to take up whole proteins without digesting them, in a cellular process known as endocytosis, but that’s all complicated shit and another story for another day.

Soooooooooooooo. How on earth did such a system evolve? The adaptive immune system, in all its complexity evolved a very long time ago (about 500 million years ago) in the common ancestor of all jawed vertebrates (the gnathostomes) – birds, reptiles, mammals, amphibians etc. This common ancestor would’ve been some sort of fish like creature. The non-jawed vertebrates, the agnathans, appear to have a primordial version of the gnathostome adaptive immune system, but it does seem to be lacking a few key components which prevent it from reaching the versatility and complexity of gnathostome immune systems.

The basic phylogenetics of the immune system. The metazoans are all of the multicellular organisms. Agnathans are on the borderderline of exclusive innate immunity and adaptive immunity. Invertebrates have various complexities of innate immunity, but lack adaptive immunity as we know it.

The adaptive immune system has been largely conserved throughout all jawed vertebrates since then. Antibodies seem to have been adapted from pre-existing cell surface receptors, as many cell surface proteins bear structural similarities to antibodies (the immunoglobins), and the fact that antibodies can be cell surface bound. On a molecular level, this crucial genetic recombination mechanism which underpins our ability to adapt, develop and remember invaders, seems to have arisen as a result of peculiar genetic phenomenon known as a transposon. Transposons are stretches of DNA that principally exist for the sole purpose of existing. They may be remnants of early viral invasion in which some viral genes got left behind in the host genome and just kinda stayed there. Transposons are nothing more than special sequences of DNA which probably shouldn’t be there, and code for proteins which exist to cut out the transposon and stick it elsewhere in the genome, where it may be copied by some passing DNA replication machinery. Sometimes, transposons can stick themselves on the middle of an important gene and cause a disease state though this isn’t common. We have transposons in our genome. Irksome things, they are - largely pointless aspects of our biology that troll the genome.

An example of how transposons work. They will code for an enzyme such as a transposase which cuts out the transposon, resticks the host DNA, carries it to another region of DNA, cuts the DNA in that region and sticks in the transposon.

A couple of transposons known as RAG 1 and RAG 2 are thought to have inserted themselves in the region of DNA which coded for the primordial antibody, which may have initially been some sort of general receptor for invaders (so a part of the innate immune system), and helped construct enzymes which cut up and restick DNA together. This makes sense as transposons code for enzymes which cut their own selves out of the genome and stick them elsewhere. Turns out their cut & paste-trolling came in handy in the antibody coding genes where the enzymes they coded for seemed adept at cutting up and reshuffling these antigen recognition sites, helping to induce variability in the CDR’s of antibodies.

And that’s that. I like to think these two posts have covered the immune system right from the subatomic physical, through chemical and biological - right up to the systems level and what it means for life in general. I hope. The immune system is a shining example of the perpetual evolutionary arms race and warfare on the biochemical level. It involves reshuffling genetic code, matching shapes and differentiating between the biochemistry of ones’ own ‘self’ and ‘non-self’. The immune response extends from against other species to against cells from other members of the same species. The female immune system will even mount an immune response against incoming male sperm, and even against a developing foetus if it has the chance (luckily, the placenta is an awesome piece of engineering and makes sure maternal and foetal blood don’t mix - but it’s a fallible system).

It’s all about those important proteins presented on the cell surface. It’s a formidable defence which has helped to keep vertebrates alive against the odds. As a percentage of life on Earth, vertebrates make up a miniscule minority in comparison to the single cellular organisms we share this planet with. It may seem like a pretty shitty thing to do, to go and invade someone else’s body. But look at it from the point of view from the invader - just as much as we have the immune system to help us survive, they want to survive too. In light of this, not only will they have evolved mechanisms to get themselves into our bodies – but they’ll also have systems to exploit the weaknesses of and deceive our bodily defences. Survival is a constant struggle for all of us, even if we’re not aware of it.

These immunology posts were in response to a question by the venerable Shizumataka. Hope it was helpful! :D

The struggle for existence has pushed the plethora of life forms which inhabit Earth to colonise almost every niche available. Not only have organisms evolved to occupy and exploit relatively stable habitats such as oceans, forests and caves but have also evolved to inhabit the dynamic habitats that are other organisms.  Vertebrates have the capacity to generate or retain heat, break down complex biological molecules into small easily manageable parts and maintain their inner environment - ideal requirements for a tiny invader to slip under the radar and infiltrate to shelter from the chaos of the outside world. This would be costly to the host organism, which’d lose nutrients and could be damaged, resulting in detriment to its survival – in short, it would get ill.

The phylogenetic tree of life

Life on Earth is divided into two domains - the prokaryotes and the eukaryotes. The prokaryotes are the bacteria and the archaea. The eukaryotes are everything else – animals (us!), plants, fungi and the protists. Prokaryotes came first, and the eukarotes diverged from prokaryotes about 1.5 billion years ago. Eukaryotes and prokaryotes have had a long time to diverge, and as such are vastly different types of cells. Their fundamental structure and biochemistry has major differences, and these differences allow multicellular eukaryotes like us to detect and deal with them. There really isn’t much risk of confusing a bacterial cell with our own cells so detecting them within the body isn’t as hard as it could potentially be. A very important point is that prokaryotic cells are dwarfed by eukaryotic cells. Viruses are even smaller than prokaryotes. Yeah… viruses are awkward - technically not living creatures, but biological entities all the same.

Size comparison of eukaryote, prokaryote and virus.

The dry mass of all cells is principally protein. Proteins perform the vast majority of biological functions and as such are present in abundance on the surface membrane of every cell in existence. So every single one of our own cells is coated in various proteins. The same goes for your parents, your dog, your dog’s fleas, your cat, the bacteria in your cats gut, your houseplant and the yeast that went into making your beer. Viruses are basically little protein capsules. And these proteins on the surface every cell gives that cell an identity. Other cells ‘read’ for specific proteins on other cells to determine if they’re friend or foe (using proteins on their own cell surfaces). Life is protein-tastic (someone had to say it).

Even single cellular organisms are at risk of intracellular invaders and have to have some kind of invader recognition and destruction mechanism. This will involve detection of foreign proteins. Multicellular organisms would have been giant fortresses in comparison to single cellular organisms, and would have (and still do) attract invaders to take advantage of their cellular processes. This evolutionary push for resources in ever more niche places forced selection of multicellular organisms with specialist systems to deal with invasion of foreign bodies – enter the immune system.

The immune system is divided into two parts; the innate immune system and the adaptive immune system. The innate immune system is a very primitive, general form of defence which includes chemical/physical barriers such as mucus, skin and stomach acid, as well as cellular/molecular defences such as inflammation, macrophages and the complement system. This is very non-specific and largely fixed. Macrophages are cells of the immune system which engulf and digest other cells and particles. The complement system is a defence against bacteria which involves the release of multiple protein subunits which embed in the bacterial cell wall, forming pores in the bacterial wall. This allows the unregulated flow of water (via osmosis) into the bacterium, causing it to burst (lysis). The innate immune system is the first line of defence against invaders, and begins its response as soon as the invader is detected.

Complement pore results in the unregulated influx of fluid, resulting in cell lysis

This innate system relies on detection via the use of basic cell surface receptors which recognise general protein structures (antigens) which are commonly found on invading entities. Multicellular organisms would have evolved these kinds of special cell surface receptors very early on in their evolution, possibly by adapting a pre-existing cell surface receptor.

The adaptive immune system is very much more complex, has molecular specificity to individual invaders, and can ‘learn’ to fight new invaders while retaining a molecular ‘memory’ of previous invaders to fight them off with increased efficiency should they have the nerve to try and invade again. The adaptive immune system relies on the complex interplay between B lymphocytes, T lymphocytes, macrophages, antigens and antibodies. The lymphocytes are the main cells of the adaptive immune system.

We have a pool of loads and loads of B lymphocytes, each expressing a different antibody on its surface. Each antibody is specific to a different antigen. When the antigen carrying invader comes into contact with its latent B lymphocyte (assuming its actually present in the pool of B lymphocytes to begin with), the antibody changes shape and initiates a cascade of cellular biochemical reactions within the B lymphocyte which cause that particular lymphocyte to proliferate into loads of plasma cells and memory cells. Plasma cells are a subtype of B lymphocyte which actively release their specific antibodies into the surrounding environment en masse to seek out and neutralise invaders. The memory cells are long lived cells which carry the surface version of the antibody which remain in the body to hold a ‘memory’ of this invader, to detect and initiate a fast response should the invader return. This is known as clonal selection.

The theory of clonal selection is how B cells are selected for their good antibodies in response to invasion.

This system is particularly good against bacteria, parasites and protein based toxins which exist outside of our cells, but what about those other harmful invaders – the viruses and cancer cells? Viruses enter our own cells and hijack them to turn them into virus-factories. Cancer cells don’t come in from outside, but rather our own cells going rogue and turning nasty. Viruses are semi-living molecules which are even tinier than bacteria. For these invasions from within, the major histocompatibility complex (MHC) comes into play. The MHC is a protein complex. The cell recognises foreign protein molecules within it due to their differing biochemistry, so chops them up with proteolytic enzymes. This generates lots of protein fragments which are bound to the MHC. The MHC takes these protein fragments and and presents them on the surface of the cell as a flag saying ‘I’M INFECTED/ROGUE, KILL ME BEFORE I INFECT THE OTHERS’. Killer T-cells detect this signal using proteins on their own surfaces, and proceed to kill the infected cell.

Killer T cell (also known as Cytotoxic T cell) kills aberrant host cells

Macrophages (of the innate immune system) use another type of MHC to facilitate the immune response. When they engulf a bacterium, they digest it to generate fragments to of bacterial protein. These are presented on their surface to inform local T cells of an invasion, and kick them into gear to go tell B cells to proliferate and release their important antibodies.

Antibodies are the other major players of adaptive immunity. Antibodies are highly specialised protein molecules. There are various types of antibody, each with a different role to play in defence against invasion. They can be bound to the surface of an immune cell, or released freely into the blood. Once free antibodies released by plasma cells bind to the invader, they have targeted that invader for destruction. Some antibody types will bind multiple invaders and cause them to clump together (known as agglutination) to make it easier for macrophages to come along and eat many of them at once. Others will attract various other cells of the immune system to come along and neutralise the threat. T lymphocytes are also involved in the adaptive immune response and do so by releasing factors which enhance the function of more active B lymphocytes, as well as differentiating into T Killer cells, which are particularly important in defence against virus infected cells and cancerous cells. Such cells that have turned cancerous, or harbour viruses give off cues which give away their abberant nature, and this is detected by surface-antibody presenting T killer cells which then actively kill the cell. 

That’s a whistle-stop tour of how the immune system gets the job done. There’s a lot to it, and I couldn’t possibly cover every angle, but that’s the gist of how it works. But how does this work on the molecular level, and how did it evolve? Well, for the sake of not writing one single long-ass post (as if this isn’t long enough already), I’ll just put that in a subsequent post. I guess I just write these to the tune of my own attention span which probably isn’t representative of you guys - the great Tumblrverse, but the next post follows on from this and that explains some pretty interesting intricacies of immunology. At least I thought they were interesting, at any rate. So peace out! At least for the moment. Hmm, perhaps this is more of a ‘brb’ sign off. yeah - actually, that works better.

Primary brain tumours are tumours which originate from within the brain, as opposed to secondary brain tumours which are tumours which have spread from cancer elsewhere in the body. Whereas primary brain cancers aren’t as prevalent as other cancers, they certainly are amongst the most deadly. As cancers are byproduct of cellular replication and growth, it’s very rare that cancers will arise from neurons in the brain as cell division in the brain is minimal. However those other inhabitants of our brain, the glial cells, continue dividing throughout life, and these are the cells in the brain most susceptible to becoming cancerous. Cancers of glial origin are called gliomas. There are various types of glioma due to the varying types of glia in the brain. Ependycytes will give rise to ependymomas, oligodendrocytes will give rise to oligodendroglioma and astrocytes will give rise to astrocytoma.

Astrocytoma is the most common out of the gliomas as astrocytes are the most numerous and are the glia which divide the most, making them more susceptible to gaining mutations which cause errors in growth and division which give rise to cancer. There are various types of astrocytomas, the most malignant of which is glioblastoma. Glioblastoma is a relatively common form of brain cancer in adults, and has an average survival rate of about 1 year following diagnosis. Survival rate past the 5 year benchmark is less than 3%.

MRI scan of a glioma in the frontal lobe

An interesting and unique property of gliomas is that they express a protein on their surface which should ordinarily be expressed within normal cells. This protein is a type of chloride ion channel, and is involved in the movement of chloride ions (Cl-) within the cell. Gliomas express these on their surface to mediate movement of Cl- in/out of the cell, which is an important mechanism in the movement of glioma cells.

The deathstalker scorpion

The deathstalker scorpion of the Middle East secretes a powerful venom to paralyse and kill its ordinary insect prey. The venom from this aggressive and dangerous scorpion is a concoction of toxins, which target various ion channels, wreaking havoc with the likes of the neurons and other cells. However, one toxin from this concoction has been found to be of benefit in medical technology. Folks, may I introduce to you - Chlorotoxin, affectionately abbreviated to CTX. In humans, CTX preferentially binds to these glioma specific surface Chloride channels.

Protein structure of chlorotoxin (CTX)

Scientists have learned to exploit this peculiar biological harmony of CTX and glioma by isolating the chlorotoxin from the rest of the toxins in deathstalker venom, and attaching fluorescent molecular beacons to them. These ‘beacons’ emit harmless, non-ionising radiation which can be detected by sensors, but does no harm to the cells (not even harmful to the cancer cells). This signal is only emitted from the chlorotoxin-bound glioma cells, so scientists and doctors can pinpoint exactly where tumours are in the brain. This CTX-molecular beacon combo is known as Tumour Paint.

Process of glioma ‘painting’ in a human. The ‘day 1’ picture is the reference image before injection of CTX. The brain tumour is highlighted on day 1 for our reference, CTX hasn’t been applied yet. Between the ankles, the small blue blob is a CTX callibration point, as a reference point for the CTX signal. On Day 2 the CTX has already been administered you can see the CTX distributed throughout the system, and over time it all gets bound up in the tumour, and leaves general circulation. The bladder initially gives off an intense signal as some CTX is eliminated into the urine. On day 5, the glioma is glowing as bright as the callibration point. That’s a large glioma.

To enhance how we view brain tumours (without opening up the skull), magnetic nanoprobes can also be attached to CTX molecules. These magnetic nanoprobes are Iron oxide particles encased within a carbohydrate shell. The iron oxide distorts the signal read by MRI scanners, coming up as a black region. This kind of tumour painting is of much higher resolution, though it does require access to an MRI machine. 

There is even scope to specifically deliver anti-cancer treatments to glioma cells by attaching siRNA to CTX. siRNA is a type of genetic material involved in silencing genes. siRNA has been toted as a potential controller of many disease states including genetic conditions, but the main problem with this versatile new technology is that it’s hard to deliver it to where its needed in the body without the use of complex invasive surgery. As a result, it’s not yet used in mainstream clinical practice. Scientists could possibly engineer an siRNA which would silence the mutated growth genes involved in making the glioma cancerous, and CTX could be used to specifically target and deliver anti-cancer siRNA into the glioma, thus controlling it.

So painting tumours with selective scorpion toxins is potentially good news for sufferers of brain cancers. Some more good news is that brain tumours in general are of the rarer forms of cancer, and with further advances in this field perhaps we can confine the damning diagnosis of the brain tumour into history.

So I’m in the library deleting old text messages from my phone (which is relatively primitive and seems to run out of internal memory every day, and doesn’t allow me to move text messages onto memory card) and I come across this old message from amisanthropichumanist which says only this

“Crystal Meth looks like dopamine.”

 My first thought is ‘does it? hmmmmm’, looking for an excuse to procrastinate from the task at hand, which is deleting messages to free up space for more messages - which is just procrastination from the REAL task at hand - which is doing my dissertation (so this Crystal Meth/Dopamine conjecture is a form meta-procrastination, I guess).

 I promptly minimise the MS-Word file I’m apparently working on (cheerfully entitled ‘Efficacy of the clinical use of hypothermia therapy as a means of neuroprotection during ischaemic insult’, which is actually very interesting - when I’m not working on it. If that makes any sense. Anywho) and jump onto google.

Oh yeah! They are pretty similar. Just thought I’d share that with you. In fact, amphetamine looks even more similar!

amphetamine

Though now I’m getting adverts for ‘Talk to FRANK’ (which is a helpline for people taking illegal drugs). We neuroscientists have an odd internet presence.

(probably wouldn’t want to talk to this Frank)