PKU

PhenylKetonUria PKU is a rare [1 in 10,000 live births] "inborn error of metabolism". It is caused by a defect in the gene PAH which means insufficient availability of an enzyme phenylalanine hydroxylase. And what that means us that phenylalanine / Phe / F one of the 20 amino acids that are the building blocks for proteins cannot be converted to Tyrosine / Tyr / Y. Absent PAH, Phe is processed by an alternative pathway to phenylpyruvate and phenylacetate which accumulates in the body to toxic levels with terrible progressive effects on the growing child = hyperactivity, seizures, mental retardation, eczema, learning difficulties. Clinician know what condition they are dealing with from two characteristic symptoms a) the strange musty-mousy smell of phenylacetate b) super pale hair and skin. The pale skin is because tyrosine is an essential precursor for the production of melanin the tanning and black lives matter pigment. Getting the disease is rare because carriers of the banjaxed gene are rare but still about 2% 1:50 of the normal singing-dancing population. It's one of the arguments against falling for your first cousin [or your sister!]. 

The disease was described by Ivar Asbjørn Følling, a Norwegian doctor, in 1934 but it wasn't until [I was born] 20 years later that a neat cure, based on a low Phe diet, was developed and rolled out at least across the developed world. 20 years after that, I was in college and I attended a lecture on the utilitarianism of health interventions. In Ireland, 60,000 children are born each year (it was the about same in 1975: smaller base population + higher birth rate). On average 6 of those will have PKU, which if detected early and The Diet implemented religiously, will have a fine fulfilling life in society paying taxes. If not detected, those children will be a handful needing a lot of support and/or being put in A Home. Call that €100,000 a year each or €600,000 every year to the tax-payer. You can detect PKU reliably by taking a blood-sample with heel pin-prick and a Guthrie Card and getting that processed at the National Children's Hospital. That costs €10 a pop or €600,000 a year. So Guthrie cards pay for themselves in the first year . . . quite apart from immeasurable benefits of having a healthy child rather than one who is deeply compromised.I am currently reading Carl Zimmer's She has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity which is excellent. Written for Jo Public but full of information which I, a professional geneticist, although no longer near the cutting edge, found interesting and informative. One of the early chapters is about Pearl Sydenstricker who grew in China with her missionaring parents. She grew up and married an agronomist Lossing Buck and their daughter Carol [shown R] was born in 1921 with blue eyes and straw-white hair and increasingly troubling distressing behaviour. The marriage didn't survive that jolt and Pearl was left holding the baby. She needed to earn money to support her micro-family and turned to writing novels, the second of which The Good Earth became flavor of the month, Book of The month and won her a Pulitzer Prize (1932) and a Nobel Prize (1938).

Having grown up foreign, and fluent in Chinese, Pearl had zero tolerance with labelling people, especially children based on their skin pigment. She co-f[o]unded Welcome House an international interracial adoption agency which went on to place 5000 orphans in homes where their future was brighter than a Third World orphanage. I think of her life [2010 biography] as being a bit like The Verger's: if Carol had been born without PKU it is unlikely that her mother would have written her best seller and gotten it published to such acclaim. And without the acclaim, there would have been no money or drive for Welcome House. In that sense Carol took one for a team 5,000 strong. tsk! more Utilitarian reasoning!

Variation and lots of it

It's m'mother's birthday today!  95! Born in 1920 - not before the First War but as a consequence of it.  Her contribution to science has been immeasurable: just think that without her, there would be no Blob!  Turns out she shares a birthday with a much younger chap called Dick Lewontin (b. 29 Mar 1929) whose impact on my field, evolutionary biology, has been far greater than mine.  I'll give you one example today, it would tax your patience if I was to summarise all his contributions which include The Genetic Basis of Evolutionary Change which in its day (publ. 1974) was the definitive textbook.  In 1953, Crick and Watson worked out the structure of DNA, which could be recognised as the birth of molecular biology.  In 1966, however, two papers burst of the scene that made us question everything that we knew about the way evolution worked.  Lewontin and Jack Hubby published their findings on variation in the fruit-fly Drosophila pseudoobscura and Harry Harris published another paper showing very similar levels of variability in Homo sapiens.

What Lewontin and Hubby did was isolate proteins from a number of different flies, treat them in a scientific protocol of their own divising, load each sample into a little hole at the top of a slab of gel and apply a strong electric current [don't try this at home. kids] to sort them by their electric charge.  Some amino acids have positive charge, some negative and most are neutral. What they saw was really surprising: about a third of the proteins they investigated showed a pattern similar to that illustrated [L ripped from their original paper].  Each column represents an individual fly, some of which have 'fast' proteins, some 'slow' and some, called heterozygotes, have both varieties. What does it matter? 

It matters because the evolutionary gospel at the time was that Nature had been honed to a high level of perfection by millions of years of evolution.  Yes yes, of course there were exceptions, but almost all the exceptions were identified as "inborn errors of metabolism" such as phenylketonuria PKU, a disease which is tested for with the heel-prick test in all Western newborns.  We could accomodate such disease states in our worldview because, although they had effects that were bad for the propagation of the species, they were rare.  If 1:1200 babies are born with CF, and 1:10,000 have PKU, we are losing an insignificant fraction of the next generation.  But if a large proportion of the genes are 'deleterious' [bad!], the algebra suggests that we'd need to produce offspring like cod - which drop a million eggs at a sitting - to have a reasonable chance of having any humans (or fruitflies) in the next generation.  Suppose that 1:1000 children carry gene-variant X which means that they don't survive to have children of their own; that means that 0.999 of the population do survive to breed.  If the 'genetic load' in the population is two such duff genes, then only 0.999^2 of each generation = 0.998 survive.  But it is an exponential equation: 0.999^10 = 0.99;  0.999^100 = 0.90 (losing 1 in ten of all children born - before the ravages of infection, train-crashes and tsunamis have an impact); 0.999^1000 and 2/3 of the children don't make it.  Harris's data suggested that about 7,000 of our 23,000 genes are variable.

SO, the holy writ of then current evolutionary theory must be wrong!  Lewontin & Hubby and Harris forced us to re-appreciate our view of genetic variabilty.  There was a bitter rear-guard action by the 'selectionists' who held to the old view but by the end of the 1970s the 'neutralists' had won the war.  I was for years a naive pan-selectionist because my mind is so inert it takes a tock on the head with a bloody big hammer to change it.  But now I have joined everyone on the good ship neutralism and it shakes down well with my wider world-view.  There is a lot of variation out there; we are all different and we should celebrate it rather than labelling 'different' as 'worse'.

Alkaptonuria

When I was learning genetics in the 1970s, it wasn't quite possible that an ambitious graduate would know ALL there was to know in the field; but it was surely a lot simpler and less extensive back then. The half dozen standard text-books all re-hashed the same war stories to illustrate the most exciting or the most fundamental aspects of genetics. One well-worn story was about resistance to malaria effected by being a carrier for the haemoglobin variant that causes sickle-cell anaemia. That revelation was largely the work of a single medical geneticist called Tony Allison. Another of the paragons was Archibald Garrod [R as a suited Edwardian walrus] an English physician who pioneered the field of inborn errors of metabolism. We would call them genetic diseases now. The deal is that:

1. people are clearly not well; 
2. their adverse symptoms make a distinct syndrome which can be recognised in other patients
3. some of those other patients are relatives of the first case. The disease runs in families, to the extent that, in some cases, you could find distant cousins by their shared medical peculiarities.

What is remarkable about Garrod is that he worked out the genetics of Alkaptonuria and published it in 1902. This was barely a year after Carl Correns, Hugo de Vries, and Erich von Tschermak-Seysenegg rediscovered Mendel's laws of inheritance. Effectively, when Garrod started his investigations, there was no useful knowledge of Genetics, so he was working blind. Alkaptonuria is rare, distinctive and peculiar. The most obvious early symptom is that patient's pee turns black in the piss-pot which must be disconcerting  when first noticed. As these symptoms kick in before weaning, it is the parents who are distressed. Garrod didn't know what the biochemical cause was, but he mapped out pedigrees and proved that it was inherited as an autosomal recessive. That phrase means that the disease is a) as common in boys as girls b) it requires both parents to carry the defective gene. Years later, it was established that the black stuff was homogentisic acid; a metabolic breakdown product of the amino acids tyrosine and phenylalanine. It gets peed out because a key enzyme in its metabolic pathway, homogentisic acid 1,2-dioxygenase, is missing or defective. There is no cure and the disease is progressive: the homogentisic acid can't all be forced through the kidney tubules, so the toxin accumulates in the joints, under the skin,around the heart valves and in the eyes. It's a bit like gout, therefore, where uric acid crystals accumulate in joints. Longevity is not affected but quality of life definitely goes downhill and modern treatments involve hip and knee replacements when these joints become too painful to use. Phenylketonuria PKU is another inborn errors of metabolism from the same aromatic amino acid degradation pathway. That condition is identified within hours of birth with a heel-prick test to yield a few spots of blood on fiche of blotting paper.

Being of historical interest and colorful is not sufficient to trigger a Blob on alkaptonuria but a four page article in last week's Nature adds sufficient weight. A father’s fight to help his sons - and fix clinical trials - Nick Sireau’s quest to give his sons weedkiller could help thousands struggling with rare genetic conditions. That about sums up the sensational aspects of the essay. The problem is that nobody should want to 'fix clinical trials' unless it is the share-holders and sales-force of the pharmaceutical company which is marketing the therapy. Mr Sireau's boys were born with alkaptonuria and he was determined to find a cure, preferably before the lads grew up and started to show the worst of the symptoms - typically in their 30s.

There is a cure, of sorts, but because alkaptonuria is so rare it is hard to get sufficient numbers to carry out a clinical trial of its efficacy. Nitisinone [structure L] also interferes with the correct function of the tyrosine degradation pathway but one enzyme upstream as shown in the metabolic pathway [above L]. Under this drug's regime there is no accumulation for homogentisic acid because there is no accumulation of its immediate precursor. This means that other tyrosine degradation products, from further up the chair, do accumulate. Although the diet can be restricted to minimise the intake of tyrosine and phenylalanine, and that helps also.  The pathway, as we now understand it, shows just how complicated things can be to keep things turning over and keep essential nutrients like tyrosine and phenylalanine in homeostatic balance - so that they are present in just right Goldiloxian amounts. And for most of us, most of the time, it all works nicely, but disable any one of the multiple steps and the whole elaborate pipeline is banjaxed.

Nitinisone costs about $50,000 or $60,000 per person per year and they've done the figures on using it to treat Type I Tyrosinaemia a disease caused by a defect in the same pathway as alkaptonuria and PKU. Mr Sireau believes that it will have positive effects for his chaps but there is no good evidence that it makes the adverse symptoms measurably better. The US Food and Drug Administration FDA won't allow the drug to be marketed without that sort of positive benefit data. Nobody should be allowed to pay so much for something that doesn't work. Especially, this should be stopped if somebody else is picking up the bill. It seems that Sireau's advocacy group has blagged the European authorities to accept a less standard of 'success'. If, under treatment, the concentration of homogentisic acid falls significantly then that will be enough - it will be what is called a surrogate marker.  We-the-tax-payer will then start paying for the drug regardless of whether the 'real' adverse symptoms like pain, joint flexibility, heart dysfunction, eye disease improve. If it don't work; don't pay for it. It's better to grimace and bear it without treatment than to grimace just as much and be out of pocket. I dunno, I'm not certain about the ethics or economics here: you read the Nature piece and decide where you want your share $50,000 allocated. Trolleys? More nurses? Pay-hike for nurses? Mental health? New children's hospital? OR "I'll keep my share of tax-dollars, thanks very much, less tax will mean I can build my much desired (and to be admired) gazebo in the back garden"

A final grimace and bear it irony. Archibald Garrod had three sons. They all joined the army in WWI and they were all killed: Thomas 10th May 1915; Alfred 20th Jan 1916; Basil  4th Feb 1919 (Spanish 'flu). No amount of money could save them.

Where's my protein at?

I have a remarkable and remarkably energetic neighbour who has been working in the catering trade for years. One wing of this service to the community is her activity on the Foodcloud front. She has recently landed a job teaching refugees how to cook . . . with what's available in Irish stores . . . and Foodcloud? If you grew up in Ethiopia, y'might like to know what can substitute for teff, like. That's started her on a rather more academic interest in food, diet and nutrition. A couple of weeks ago, I was plongeing the supper dishes and my phone rang (a rare event for Sudsy-no-pals me): "please help, I need a reputable source to make sense of the blizzard of claims about protein in food". On it, I replied, do you want it by your 9 o'clock tomorrow class?

Despite the answer being NO!, I sat down and started that night . . . and ran out of steam shortly after 0900 hrs the next morning. I surprised myself and that might be of interest.

Chef Bob on Protein

Well may you wail about truth, science, diet and marketing bullshit. There’s a reasonably entertaining BBC Podcast called Sliced Bread [whc prev] which takes a product (bike helmets, ecological diapers, sourdough bread), finds to experts and decides whether the Thing is:
SB the best thing since Sliced Bread or
BS marketing bullshit
case in  point the High Protein cheese I found in LIDL last week [L]. Biggest number on the packet is 54g. Implying that this cheese is 54% protein, but the small print explains it is 54g per 160g pack-o-cheese. Nevertheless that's 34% protein while normal cheese is only 25%, so it does be High in protein - although how that is achieved is a mystery story for another day.

In our first world you’d have to work quite hard and eat quite peculiar to be short on protein. It’s different in sub-Saharan Africa if you get all your calories from cassava or corn-meal and you can’t afford lentils, let alone chicken. There is an argument that not all protein is the same because each source will have a different mix of the amino acid components of protein. BUT in general, protein is protein is protein unless you have a very narrow range of diet.

Proteins are made up of strings of 20 different amino acids. These building blocks have different properties and so build different proteins. They are not all equally common (in us or in food) but broadly the rare ones are rare everywhere and we only need a little.

• Serine, glycine, alanine are generally common. 
• Cysteine, tryptophan and proline are rare.
• Leucine and isoleucine are very similar; as are (+-charged) Lysine & Arginine
• Glycine is tiny, tryptophan is large
• Glycine and glutamate also act as neurotransmitters
• Phenylalanine, methionine, leucine and isoleucine have a great affinity for fat
• Lysine, arginine, {acidic - charged) glutamate, aspartate are, in contrast, water soluble

Essential Amino acids: 9/20 of the amino acids have to be obtained by eating: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. The others can be manufactured internally by mix n matching from what the diet provides. But in the real world, this doesn’t make much difference because all food contains some protein and almost all proteins include some of all the 20 AAs – some foods are deficient in some AAs [next para] but for most of us, most of the time this is not a worry. Call BS if marketeers tell you different!

Complementary amino acids and protein combining

We have a copy of Diet for a Small Planet by Frances Moore Lappé from the 1970s. She was trying to get Americans to eat less meat but found that grains [rice, corn, wheat] are slightly deficient (for us) in lysine; while beans [+ lentils, garbanzos, peas] are slightly deficient (again for us) in methionine. She made a big story (and a lot of money) out of the idea that, by combining a diet of corn and beans together, Mexicans were able to complement the dietary deficiencies of each food group and make the combo a sort of super-food. She lived long enough to appreciate that this analysis was superficial, if not wrong, and realise that it was possible to get a diet adequate for usable protein fairly easily, so long as you lived in the country (and got to eat grasshoppers, salad-weeds, fruit). The urban poor, getting all their [starch heavy because cheap] food from the bodega on the corner were /are a different matter. 

Protein requirements

International Recommended Dietary Allowance (RDA) for protein is 0.8 g per kg of body weight (bw), regardless of age. For me that’s 60-70 g or dietary protein every day. But meat is mostly water!! 100g ground beef will have only 15g of protein and 20g of fat. That much meat supplies about 10% of the calories required per day. So one quarter pounder won’t cut it: I need 4 or 5 hamburgers to keep up. Source. Obvs, I can trade some of those burgers for chicken or chick-peas. 100g of dried lentils are mostly carbs 63%, with protein at 25%; water at 10%; fat at 1%.  More calories than meat because proportionately less water. Source. In contrast to what some are wont to say, old people with lower metabolic rate do NOT require less protein: rather ~50% more. Source.

PKU a special case

All babies are tested (with a heel-prick blood sample on a Guthrie Card) at birth for phenylketonuria PKU. Bloboprev If they test positive, it’s because they lack an enzyme which the rest of us use to metabolize excess phenylalanine, one of the 20 amino acids. Toxic by-products build up which prevent proper development of the brain. Solution: give the child a diet which is very low on  phenylalanine (which is one of the 9 essential AAs so we all need some). But actually the prescribed diet is just “low protein” avoiding meat, eggs and dairy ?while supplementing the other 19 AAs as a pill. Also NO aspartame sweetener – because it is converted into phenylalanine ! Source.

A balanced diet WWI edition

check out Elsie Widdowson, who with others in WWII worked out that IF, on average, everyone got

• 125g fat
• 150g sugar
• 175g UK fruit [apples mainly]
• 50g egg [that's one egg] 7g protein
  
• 125g cheese 32g protein
  
• 450g animal protein 68g protein
  
• ad lib wholemeal bread, potatoes, cabbage
• each week!

THEN they'd be fine. The dietary protein sources thus provide for only about 2 days worth of the protein RDA. The brown-bread and spuds are doing a lot of heavy lifting here. Nevertheless, this diet kept 40 million Brits walking, working, thinking and fighting for 6 years so it can't be too far off the minimum requirements. Source: bloboprev