I've always had a soft spot for the film and have seen it a few times. I spent most of the 1990s as a lipid biochemist purifying diacylglycerols (diglycerides) so it was nice to come across a film in which lipids had a rather heroic role regardless of the accuracy of the science or feasibility of the oil as a treatment.
|"The holy oils of cooking" by Flickr user churl - interestingly it was reading the description churl added to their photo while writing this post that made me realise the Catholic relevance (strongly felt in the film) of 'oil', as churl says "If you're Catholic, you know that there are three oils: oil for baptism, holy chrism, and oil for the annointing of the sick. However, in the kitchen, my 3 oils are extra virgin olive oil, sesame seed oil, and canola oil." - Canola oil (Canola means "Canada oil, low acid" and is from the same plant from which you get one of the key ingedients of Lorenzo's Oil.|
Hearing the back story to a film is always a treat and this year I've had the pleasure of hearing from Harry Gregson-Williams, Terry George, Brendan Fraser, Nick Emerson, Philip Ridley and Nick Bicat talking about films they've been involved in and most recently Boris Karloff's biographer, and Boris' daughter, talking about his career in films. I've also enjoyed 'Micro and Macro' which showed a series of scientific films from the 1900s to the present day with explanatory talks about the science and the history of each film. A couple of years ago I went to see The Dish which had a side-order (see what I did there) of explanation from a physicist about matters relating to the film (landing on the Moon, satellite dishes and communications) ... so this was exactly my sort of event.
It was nice to hear Keith Layden give a brief overview of lipid chemistry, a lecture I've given myself umpteen times. I think the audience was largely made up of members of the RSC, I got the impression it was quite a sciencey bunch - the lecture was very good and very interesting but a non-specialist audience might have found some aspects of it a bit technical. Not everyone would have an intuitive understanding of an ester linkage for example, but I suspect that the main point - that there are different types of fats based on the length of a chain of carbon atoms, and the way they're linked together - was pretty clear to everyone there.
He also explained the genetics behind the condition. Adrenoleukodystrophy (ALD) causes an error in the way a particular enzyme works, and this error is inherited. The enzyme is meant to be handling very long chain fatty acids (VLCFAs) but because it doesn't work properly these VLCFAs build up in the tissues causing damage, particularly to the coating (myelin) of nerves. This results in the nerves being unable to conduct signals correctly and leads to weakness in muscles and paralysis, including difficulty in swallowing, and loss of vision and hearing. It progresses pretty relentlessly and, at the time of Lorenzo's diagnosis, had a timecourse of a couple of years before death.
Lorenzo's parents taught themselves about the biochemistry of the disease and Augusto (Lorenzo's father) contributed to the understanding of the faulty enzyme. At the time of L's diagnosis there was a trial in which one source of the body's VLCFAs were restricted - by eliminating them from the diet. This wasn't successful because the body's own production of these VLCFAs (mutinously assisted by the erroneous enzyme) carries on regardless and makes even more if enough aren't coming in through the diet. They needed a plan B.
They suggested that the enzyme could be distracted from producing the VLCFAs by giving it a longish fatty acid to play with and developed a mixture of triglycerides with oleic acid (18:1 - see appendix below) and erucic acid (22:1) as the fatty acids attached to the glycerol backbone. According to the film this lowered Lorenzo's VLCFAs to near normal however this translated into only modest improvements in his functioning. From what I can gather the oil probably makes more of a difference in people who've not yet developed the symptoms of ALD (ie they are asymptomatic). In boys who already have signs of the condition I don't think the oil makes a huge amount of difference - the Wikipedia page for Lorenzo's Oil has some links to info on the various clinical trials.
|A field of rapeseed from which erucic acid can be extracted (although the strain in this picture is actually low-erucic variety). Picture credit: from Flickr user Charles & Clint "Rapeseed Viewed from Ashley Hill in UK"|
Keith and Cristina both made the point that Augusto Odone found himself in the position of coming up against the 'medical establishment' to some degree. Plenty of people didn't take his ideas seriously, which certainly makes for a good story.
Cristina also pointed out the various groups that weren't fully supportive of the strategies involved in developing a treatment. Although not stressed in the film animal rights groups weren't happy at the work being done in remyelination (the Shaking Pups are mentioned in the film, a strain of dogs lacking myelin, as a model of the myelinopathy in ALD). The anti stem cell brigade weren't happy because, at that time, a lot of remyelination research involved foetal stem cells from aborted foetuses. Even the patient support group weren't too happy with the Odones - in the film a couple of them suggest that perhaps the children with ALD don't want to live through it and it would be a kindness to let them die. But also they seem to have been unhappy with the Odones challenging the doctors rather than meekly acquiescing.
Keith wondered what would happen if someone like Augusto Odone approached Croda today with a request to rustle up some erucic acid and turn it into glycerol trierucate. The current climate isn't particularly conducive to that sort of thing, however he mentioned that although the oil isn't much of a moneyspinner it did pay dividends in terms of opening up other avenues of research, in particular the omega 3 oils.
Questions after the film included some interesting discussion on the efforts patients and carers have had to go to in order to understand things about their disease - as I was leaving I chatted briefly to someone there and told them about Patients Participate! which is trying to get patients involved in the writing of summaries of medical research papers that are understandable to people without a medical or science background. Anyway, a thoroughly enjoyable evening and I could have quite happily have rewound the evening and sat through it all again, both film and talks.
Thanks to the RSC, Keith Layden from Croda and Cristina Odone for a fantastic evening.
In filling in the 'suggest other films relating to chemistry' bit of the evaluation form I put in a bid for Extraordinary Measures. That stars Harrison Ford and Brendan Fraser so I might be a tad biased in favour but it's a great story. It's about John Crowley (Fraser) who mounts an expedition to find something to stop his children, diagnosed with Pompé disease, from dying. His company develops a candidate enzyme replacement therapy which isn't a cure but keeps his kids alive.
I suppose there are some (superficial) similarities between the two films - if I was curating a chemistry film season I might put a couple of films between them - ALD relates to an enzyme found in peroxisomes, Pompé to an enzyme in lysosomes (it's a lysosomal storage disorder). I'm not sure if ALD relating to lipids and Pompé to carbohydrates helps make them seem that different either. The chemistry of the treatment is quite different though, with the oil for ALD involving organic chemistry and lipid synthesis whereas that for Pompé seems to involve recombinant goings on in bioreactors. Lorenzo's Oil makes several references to the family's Catholic faith, I don't remember any such references in Extraordinary Measures although I think the title is actually of theological origin.
Hopefully the RSC will put Extraordinary Measures on though - it does involve science relating to chemistry in the context of a human interest story. Having said that, the Guardian didn't like the film. Philistines etc etc. There are some interesting blog posts about the science behind the treatment, highlighting the role of animal research, I've listed some below in the footnotes.
I might also be tempted to focus on the role of tetrodotoxin in the putative 'zombie powder' in The Serpent and the Rainbow which scared the bejesus out of me at 3am one morning, around about the time people in my lab were using tetrodotoxin and conotoxins to stimulate cells and look at the activity of calcium signals inside them. Films about toxins tend to scare me anyway but 3am, extra zombies and live burial certainly help. The film is based on work done by Wade Davis, who gives rather interesting talks (I've only seen them online).
I am not a geneticist but...
The error that results in a faulty enzyme is found on part of the X chromosome. Everyone has at least one of these - women have two (one from their mum and one from their dad) and men have one (from their mum, but none from their dad - they're men because they've received a Y chromosome from their dad instead). So women are XX and men are XY with the orange denoting the mum's contribution and green the dad's.
A woman is unlikely to have two faulty copies of the gene (on both X chromosomes). This is because ALD is generally rapidly fatal and few boys with the condition would reach adulthood and be able to reproduce. But having one copy of the gene won't cause a problem for a woman directly because she has a 'spare' copy of the gene on her other chromosome and that will override the faulty one. Men don't have this protective spare X chromosome (the Y chromosome doesn't have a copy of this gene) and so develop symptoms of ALD.
I was a lipid biochemist however...
Butter and oil are examples of fats or lipids and they are structurally very similar. Both consist of lots and lots of triglyceride units, these are made of four elements bolted together (1 molecule of glycerol and 3 fatty acids). The fatty acids are chains of carbon chains with hydrogen atoms arranged around them and a bit on the end that can link up to one of the three 'hooks' on the glycerol 'backbone'. Fatty acids generally have an even-number of carbon atoms and vary in length between 2 and 26 carbons, I think the most common ones are 14-20 carbon atoms - any longer and they're very long chain fatty acids.
Each carbon atom sits in the middle of two others (one to the 'left', one to the 'right') forming the fatty acid chain and there's a hydrogen atom above and below each carbon. One carbon forms four links (two to other carbons, two to hydrogens). Carbon atoms can also drop one of the hydrogens and form a double bond with one of the other carbons sitting next to it. A fatty acid written as 16:0 means it has 16 carbon atoms and no double bonds, whereas 18:1 means it has 18 carbons and 1 double bond. The position of the double bond(s) is important too.
Lewis Gidez (1984) "The Lore of Lipids" (PDF) Journal of Lipid Research Vol 25: 1430-1436. This is a short, easy-read history of fats and oils and their use in ancient societies up until nearer to the present day.
|Fatty acids - carbon atoms have four bonds to play with. Each carbon atom in the chain is attached to the two carbon atoms sitting next to it (which takes up two of the available four bonds) and the other two bonds grab onto hydrogen atoms. In the fatty acid on the left every carbon atom has its maximum number of hydrogen atoms attached (two per each Carbon atom, so it's said to be 'saturated with hydrogen', can't take any more) and on the right two carbon atoms have formed a double bond between them. This means that the carbon atoms participating in the double bond have one bond attached singly to another carbon, but two bonds attached (hence 'double' bond) to the other carbon leaving only one bond free to grab a hydrogen atom. This means that the carbon chain is unsaturated with respect to hydrogen, it also means that the molecule isn't balanced - it doesn't have an equal number of hydrogens on both sides. This makes the uneven electrostatic charge try and balance out by repelling and you end up with a kink in the molecule, and that has all sorts of important things to do with the way these molecules pack together in living cells. Picture credit: "Fatty acids" from Flickr user AJC1|
(1) in the film Don Suddaby played himself and was the person who purified erucic acid which, in the triglyceride form, contributes to the dietary oil that was given to Lorenzo as part of his treatment. It's a mixture of 4:1 glycerol trioleate and glycerol trierucate. The purified erucic acid was then combined with glycerol to form the triglyceride.
(2) Lorenzo died in 2008 a day after his 30th birthday. Given that boys diagnosed with ALD generally die within a few years of their diagnosis this is pretty staggering. Though I daresay there are outliers in ALD mortality too.
Bits about Pompé disease, relating to the film Extraordinary Measures.
- Pompe disease - a starring role for animal research (SpeakingOfResearch.com) 25 January 2010
- Extraordinary Measures - Pompe disease and animal research updated (Scientopia) 25 January 2012