The Genetics of Aggression- Brunner Syndrome and Ethical Nightmares

 I’ve decided to do a very controversial medico-ethical issue this week. Although it’s not an issue that frequently comes up, I chose it because it’s a good example of when scientific research has started to threaten our ethical principles.

  Hans Brunner et al.¹ identified a rare genetic disorder in a large farming family. Certain males in the family displayed mild impairment of cognitive functions and abnormal impulsive aggressive behaviour such as arson, rape and violence. Brunner showed that in the affected males there was a mutation in the gene for the enzyme monoamine oxidase A (MAOA). The enzyme deactivates the hormones and neurotransmitters epinephrine and norepinephrine, more commonly known as noradrenaline and adrenaline. (The terms are effectively interchangeable, adrenaline and noradrenaline come from Latin and epinephrine and norepinephrine from Greek. Despite the Latin terms being the most commonly used they are known medically by the Greek terms to avoid confusion with a pharmaceutical drug marketed as the annoyingly similar adrenalin.)

Epinephrine

Norepinephrine

 Both epinephrine and norepinephrine are part of the body’s “fight or flight” response (80% of the hormones released are epinephrine and 20% norepinephrine). This is the body’s response to dangerous or unexpected situations. The effect is the dilatation of the blood vessels to the muscles, the stopping of digestion and the increase in heart and breathing rate. This prepares the body for persistent muscles contraction in life-threatening situations. In this hyper-excitable state there is increased male aggression.

 Sufferers of Brunner syndrome have lower amounts of the MAOA enzyme so deactivate epinephrine and norepinephrine much more slowly. After getting provoked or startled they could remain in the aggressive, excitable state for hours or days after the initial trigger. The effect was also demonstrated in MAOA-mutant mice (which bit the experimenter more than non-mutant mice) and in the relative number of fights between macaque monkeys.

  The link however between genetics and violence however is fraught with difficulties. All sort of environmental and genetic factors combine to form behaviour as complex as aggression. Of the 14 MAOA-mutant men Brunner found 5 were arsonists, 5 were convicted of rape or attempted murders but the remaining 4 showed no obvious signs of excessive aggression whatsoever.

Worryingly a different mutation in the MAOA gene (which became known as the ‘Warrior gene’ in the flood of research following Brunner’s paper) was found to be roughly 10 times as common in African-American men than white American men.³ It has been suggested this a reason why African Americans commit five times as many violent crimes per capita as white Americans.³ (although personally I think social and economic factors are probably more likely). For some this line of thinking leads to a Nazi-style eugenics nightmare.

  The problem of how the law should deal with individuals with a genetic disposition towards aggression is a thorny ethical issue. Law and order relies on people being responsible for the bad things they do. If science is throwing doubt on this principle of moral responsibility then what are we to do? As yet no one have been found innocent due to a genetic predisposition to violence although an argument based on child abuse and a mutation in the MAOA gene was successful in down grading the punishment of first-degree murder from the death penalty to 32 years in prison in a 2009 criminal trial. Although it appears we have some time to debate this issue it appears that the advance of genetic science will inevitably continue to threaten our moral beliefs.

1. Brunner HG, Nelen MR, van Zandvoort P, Abeling NGGM, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA. “X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism.” American Journal of Human Genetics. 52: 1032-1039, 1993.

2. Beaver KM, Sak A, Vaske J, Nilsson J. “Genetic risk, parent-child relations, and antisocial phenotypes in a sample of African-American males.” Psychiatry Research. 175: 160-164, 2010.

3. http://www2.fbi.gov/ucr/cius2009/data/table_49.html

Asthma Treatment

I’ll continue my quick dip into the technicalities of asthma this week by looking at asthma medicines. Obviously the easiest (and not to mention cheapest) method of preventing asthma attacks is to reduce contact with the antigen you react to. However this is only probably possible with antigens such as animal fur or cigarette smoke. For anything else some sort a medication is required. Asthma drugs fall into two types: short term relievers and long-term preventers. I’m on one of each. For people with mild asthma or who only have rare attacks a simple reliever is enough. For people with more than two attacks a week some sort of long term preventer is needed to manage the symptoms.

  

A Salbutamol molecule

Sort acting beta₂-adrenoceptor agonists (SABA’s) such as salbutamol (brand name ventolin) are the commonest form of asthma relief. They usually take effect after about 10 minutes and last about 6 hours. The drugs act on a receptor on the cell surface membrane of the muscles of the bronchi of the lungs. This relaxes the muscles so the airways widen and the symptoms are relieved.  Beta2-antagonists are good because they usually only effect the lungs unlike non-specific beta-agonists such as the older drug ephedrine which affected similar receptors in the heart causing tachycardia (the heart beating too fast) and arrhythmias (the heart beating irregularly). SABA’s are usually inhaled from a simple inhaler (or in a hospital a more powerful nebuliser) so the drug is delivered straight to the lungs. In very serious case in can be given intravenously.

  

Long-term prevention of attacks is done by a different set of drugs. I use Symbicort (brand name) which is a mixture of the chemicals budesonide and formoterol. The formoterol part is simply another drug to relax the bronchi muscles but a little long lasting. Budesonide is a glucocorticoid. I’ll just unpack that term piece by piece. Glucocorticoid (comes from glucose+cortex+steroid) is type of steroid hormone. A steroid is a molecule with four alkane rings (such as cholesterol and testosterone) and therefore tend to look like quite cool molecules. A hormone is a molecule released by a gland to effect cell elsewhere in the body. Glucocorticoids bind to a receptor present in most animal cells and are part of the body’s feedback loop that turns down immune system and inflammatory activity. This means they are used to treat diseases caused by an over active immune system such as asthma. Unfortunately they have various other effects so aren’t sold over the counter.

A Budesonide molecule

 Other drugs used to prevent symptoms are long-acting beta-adrenoreceptor agonist (LABA’s) and mast cell stabilizers.

Asthma

I’ve decided to do a post on a condition I suffer with this week, partly so I can learn more about what I actually have and partly because its going to be one of the typical things any doctor is going to meet fairly regularly. About 10% of children aged 5-12 years old have asthma with boys about twice as likely to have it than girls. Most sufferers tend to grow out of the condition however although sometimes it can get worse. There is no definite reason why some people are asthmatics and other aren’t but there is almost certainly a genetic factor. The condition also appears to be getting more prevalent in many countries for indefinite reasons; pollution being the most likely. Although my asthma is mild and fairly well managed asthma severity varies greatly from sufferer to sufferer.

 At its very simplest asthma is the muscles of the airways tightening and the lining becoming inflamed and swelling in response to an asthma trigger. Both of these cause the airway to be constricted and gas can’t travel as easily in and out leading to shortness of breath and wheezing. Common asthma triggers are exercise, animal fur, stress and pollen. It is believed (but obviously can’t be completely proven) that it is possible to make any one have asthma-like symptoms given enough time and enough chemicals. Severe asthma attacks can cause the oxygen concentration of the blood to drop significantly and gives the lips and tongue of blue colour of cyanosis. Some very extreme case when the damage caused by asthma is irreversible the condition can be included in COPD (Chronic Obstructive Pulmonary Disease), a combination of bronchitis and emphysema where the respiratory system is progressively more obstructed and eventually fatal.

 On a cellular level the inflammation caused by asthma is very complex. Various different types of white blood cells all play a role including lymphocytes, eosinophils, neutrophils, basophils and mast cells:

• ·      Eosinophils are white blood cell designed to combat multi-cellular parasites. They contain small granules inside them containing various nasty enzymes for killing the parasite. Asthma causes eosinophils to build up in the lungs (where they are normally never found) and discharge their toxin mix inappropriately. This causes the damage to the air passages seen in cases of serious asthma.

A Eosinophil cell

A Histamine molecule

• ·      Basophils are cell in the blood containing granules of histamine. Mast cells are essentially the same but live in tissues not the blood. Histamine is the chemical that triggers the inflammatory response in many allergies (in minor allergies such as hay fever the disease can effectively be managed by taking antihistamines that negate the effects of histamine but for asthma antihistamines are generally ineffective). Normally these cell release histamine when a pathogen is detected so the capillaries widen and allow white blood cell better access to the infected tissues. In asthma no real threat exists so the histamine just causes inflammation, which blocks the airways. 
• ·      Lymphocytes are the cell that recognise threats to the body and react to it. Asthma can be caused by the lymphocytes reacting to something that is not actually a threat.
• ·      Neutrophils are a type of phagocyte that normally engulfs bacteria. In asthma they contribute to the inflammation response.

Next week I’m planning to continue this post on asthma with the various treatments currently available and how they work.

The AMT

 I have chosen to do a quick mid-week update just to review a topic raised in my work experience, which I have been lucky enough to have this week. I shadowed an orthopaedic house officer on a hectic on-call seeing lots of elderly hip facture patients. After checking the patient’s Xrays the doctor went to see each patient and did the AMT (Abbreviated Mental Test). This is a speedy check of metal functions to check for any confusion, delirium or dementia in elderly patients. Over the course of the day we saw a range of patients with AMT score from the maximum 10/10 to patients too confused, deaf or ill to take the test.

 The test consist of 10 questions, each worth one point, delivered in roughly this order:

1)    What is your date of birth?

2)     So how old does that make you?

3)     Can you tell me where you are at the moment? (hospital name, ward name, city etc.)

4)     What year is it at the moment?

5)  What did I say my job was? (expecting an answer of doctor or similar)

   Then: Can you just remember this address and repeat it back to me? (Say an address twice such as “42 West Street”. Then say that you will ask for that address again later.)

6     When was the start of the First World War?  (Embarrassingly I failed this one but through lack of historic interest more than any long term memory problem)

7)    Can you tell me who the monarch is at the moment? (can substitute prime minister ect. but no one too obscure)

8)    Can you count backwards from 20 to 1 please?

9)      What time of day would you say it is now? (answer to nearest hour or so)

10   Can you just tell me that address I told you earlier?

 The advantage of the AMT test is that is that it can be done very quickly and can give a very rough idea of the patient’s metal functions that can be followed up if necessary. A score below 7/10 may suggest cognitive impairment of some kind. The test also has the advantage of well received by both doctors and patients.

 However inconsistencies in the way the test is given and marked make it unreliable in some cases. Many doctors chose to omit some of the questions such as asking for date of birth and some incorrectly try to introduce half-marks. Consequently patients with the same mental state may have wildly different AMT scores. Also the test may not be valid in ethnic minorities due to some culturally specific questions like asking for the date of the First World War. The test is also going to require changing as questions such as the monarch and early 20^th century history become may become less significant information to people so are less likely to be known not for a metal problem but for lack of cultural value. Another big problem is the patient’s physical state at the time of the test. Simple factors such as dehydration, tiredness or hunger may affect the AMT score giving anomalous results. Despite all these faults the test is still likely to be used (possibly in an adapted form) due to its speed and efficiency in evaluating mental state.

Suxamethonium

A tracheal Intubation

  Suxamethonium chloride (otherwise known as succinyl chloride or “sux”) is a drug used to create short-term muscle paralysis. The drug can effectively stop the action of all skeletal muscles in the body in 30-60 seconds enabling doctors to perform a Tracheal Intubation (placing a flexible plastic tube into the trachea to maintain an open airway as shown in the diagram) without the patient struggling. The effect typically lasts 5-10 minutes meaning that the patient does not need to have artificial breathing for too long.

 

   Suxamethonium works by works by depolarising the cell membrane of the muscle fibres for much longer than normal (I’ll explain what that means soon). In normal muscle contraction the signal is sent by the movement of sodium and potassium ions through channels in the membrane. First a few sodium ions move into the cell through. This causes the charge inside the cell to increase from its normal slightly negative state. If the inside of the cell is positive enough then channels open and sodium ions move into the cell making the inside of the membrane even more positive and the outside more negative i.e. increasing the difference in charge. One sodium channel opening causes a chain reaction until all are open. When all of the sodium channels are open a different process starts. The sodium channels close and the potassium channels open and potassium ions leave the cell; this makes the inside of the cell more negative until the charge is about normal (there is a slight overshoot then readjustment to prevent the electrical signal going backwards).

   The increase in the charge of the cell from negative to positive (hence lowering the difference in charges between inside and out i.e. depolarisation) involves a molecule called acetylcholine bonding to the sodium channel causing it to open. The acetylcholine is then broken down in milliseconds by an acetylcholinesterase enzyme.

Suxamethonium works because it is made of two acetylcholine groups joined together. This means the acetylcholine ends can open the sodium channel but the molecule is two big to be broken down by the acetylcholinesterase enzyme. This means the channel is kept open and can only close when the suxamethonium molecule is eventually broken down by cholinesterase enzymes that are only present in small amounts and can therefore only act very slowly. This mean the impulse is stopped half way through and the signal cannot cause a contraction in the muscle.  

A suxamethonium chloride molecule

   Suxamethonium is not unique in this property. Various different molecules consisting of two acetylcholine groups were synthesised and have a similar effect. Suxamethonium was chosen because it started more quickly and stopped more slowly than other variations. The discovery and development of suxamethonium led to a Nobel Prize in medicine for Daniel Bovet in 1957.

   Suxamethonium is sometimes used as a student entertainment by participants injecting a small amount of it into each thigh and then trying to run as far as possible before the paralysis kicks in.