Biochemistry at the Movies

 
EXTRAORDINARY MEASURES: A movie about GSD Type II (Pompe’s Disease)
 
  
 
More information about this movie at:
 
 
 
THE MADNESS OF KING GEORGE: The Porphyria Hypothesis.
 
 
Porphyrias in fact are a group of diseases characterized by impairment in the synthesis of the Hem group, with accumulation and increased excretion of some intermediaries and byproducts.

 The synthesis of Hem is a complex process, with reactions in the mitochondria and reactions in the cytosol.

 

 There are different kinds of Porphyrias depending on the affected enzyme in the pathway. These porphyrias can be classified, according to the predominant symptoms, in Cutaneas (the main symptom is skin photosensitivity), Neuroviscerals (characterized by abdominal pain, neuropathy, psychosis) and Mixed, with both kind of symptoms.

 

Affected Enzyme

 

Associated Porphyria

Type of Porphyria

 

 

 

 

δ-aminolevulinate (ALA) dehydratase

(porphobilinogen synthase; 4.2.1.24)

 

Doss porphyria/ALA dehydratase deficiency

Neurovisceral

hydroxymethylbilane (HMB) synthase (or PBG deaminase; 4.3.1.8 )

 

acute intermittent Porphyria(AIP)

Neurovisceral

uroporphyrinogen III Synthase (4.2.1.75)

 

Congenital erythropoietic porphyria (CEP)

Cutanea

uroporphyrinogen decarboxylase (4.1.1.37)

 

Porphyria cutanea tarda (PCT)

Cutanea

coproporphyrinogen oxidase (1.3.3.3)

 

Hereditary coproporphyria(HCP)

Mixed

protoporphyrinogen oxidase (1.3.3.4)

 

Variegate porphyria (VP)

Mixed

Ferrochelatase (4.99.1.1)

 

Erythropoietic protoporphyria(EPP)

Cutanea

 

It has been suggested that King George III, whose insanity episodes are very well described in historic documents, suffered of Acute Intermittent Porphyria (some authors say it was a Variegata Porphyria).

 

King George III suffered of intermittent episodes of mental confusion, hallucinations and insanity, accompanied with dark colored urine, abdominal pain, vomiting…and his well known family history reveals some crisis in his grand mother, Maria Stuart, and his grand grand father, James V of Scotland that could be attributed to porphyrias.

 

In patients with neuroviscerals Porphyria, there is a deficit of HMB synthase that provokes a deficit in the synthesis of Hem. Since Hem is an inhibitor of δ-aminolevulinate (ALA) synthase, (the main regulatory enzyme in the synthesis of Hem, the enzyme is not inhibited), so the production of intermediates continue and they accumulate, provoking neurotoxic effects. These patients do not show the photosensitivity found in those with cutanea porphyrias.

 

Intermediaries as δ-aminolevulinate and Porphobilinogens are eliminated in great quantities in urine, and it becomes red or dark when exposed to light.

 

 The movie “The madness of King George” describes the behavior of King George III during the crisis, with diverse references (taken from historic documents) about the changes in the color of the urine of the patient during crisis and during recovery periods.

 

 

 The Physician and the King

   

 

 

 In the final credits, the movie explains the behavior of King George as a consequence of Porphyria.

 

Now go! Rent the movie! Even if you don’t like Biochemistry, the quality of this movie (Oscar to foreign Movie) will give you enough satisfaction!

 

More information about King George alleged porphyria, can be found in:

 

Macalpine, I; Hunger, R.:

“The Insanity of King George III: A Classic Case of Porphyria”.

 British Medical Journal,  65-71, 1966

 

Macalpine, I. et al:

 “Porphyria in the Royal Houses of Stuart, Hanover and Prussia: A Follow-up Study of George III’s Illness”.

British Medical Journal,  7-18, 1968

 

Rohl, John C.G., Warren Martin,& David Hunt:

 “Purple Secret: Genes, Madness and the Royal Houses of Europe”.

 Bantam Press, London, 1998

 

Cox T.M. et al:

“King George III and porphyria: an elemental hypothesis and investigation.” Lancet;366(9482):332-5, 2005

 

 

The following sites contain information about King George disease:

 

Madness of King George: may have been his doctors fault (This article suggest that arsenic contained in medicines could have triggered King George Porphyria attacks)

 

Attacks of King George linked to key metabolism molecule

 An historic perspective:

Insane King George III

History of Porphyria

King George III and Porphyria

About the movie

A king takes a trip to the funny farm

 

PORPHYRIAS AND THE PHANTOM OF THE OPERA

 

There has been a long discussion about the disease that affected Erik in the classic novel by Gaston Leroux “Phantom of the Opera”.

Leroux was looking for a disease that explained the disfiguration of Erik, without affecting his intelligence and his genius as an architect and as a musician.

Apparently Leroux’s notes indicates that he considered Von Recklinghausen neurofibromatosis, since the first papers about the “Elephant man” were published around those years, but later a physician told him about a disease called Porphyria, that could affect the skin producing blisters and erosions in exposed areas of the skin, and affected the liver of the persons, given a yellow color to the skin. Later, according to some sources, Leroux saw pictures of some patients with a very advanced and severe Porphyria Cutanea Tarda in a German medical journal. This information contributed to develop the main character of “The Phantom of the Opera”

Several versions of this novel have been filmed. Some notable adaptations are the following:

The silent version of the Phantom of the Opera, with Lon Chaney Sr.  (It follows the novel description od Erick more strictly than other versions)

The “acid causing deformities” version appeared in the 1943 movie and ulterior movies and is not related to the novel; the novel imply that it is a congenital disease since Erick explains that his mother avoided to kiss him and obliged him to wear a mask when he was a child (Of course the author took also a lot of freedom to describe the “patient” condition)

In the 1962 version, the Toccata and Fuga in Re Minor from Bach is associated for the first time to the Phantom.

http://en.wikipedia.org/wiki/Image:Toccata_et_Fugue_BWV565.og

 Joel Schumacher’s The Phantom of the Opera (2004), based in the Andrew Lloyd Webber and Charles Hart musical, has been one of the most successful versions of recent years:

 

 

Music of the night

 

 

Angel of Music

 

Think of me

 

 

More information:

If you want to read the book:

Free e-book

http://www.literatureproject.com/phantom-opera/

 

 

VINCENT VAN GOGH: THE PORPHYRIA HYPOTHESIS.

 
The life of Vincent Van Gogh has been represented at least in 5 major films, with superb actors and directors:
 
 
 Kirk Douglas and Anthony Quinn 

 

Lust for Life (the scene of Van Gogh and Gauguin)

 

 

Tim Roth in Vincent and Theo

  

 

The eyes of Van Gogh

 

 John Simms: The yellow house

 

 

 

Dreams  (Akira Kurosawa, Part 1)

 

 

Dreams (Akira Kurosawa, Part 2)

 
L.S. Loftus and W.N. Arnold published in 1991 an article in the British Medical Journal where they present Van Gogh disease as  a case of Acute Intermitent Porphyria.

According to the authors,  “Vicent’s ailment was characterized by episodes of acute mental derangement and disability, which were separated by intervals of lucidity and creativity. Moreover, attending physicians – and the artis himself- were surprised and encouraged by the rapidity of the recovery after each crisis. His serious illness developed late in the third decade and played into the fourth; elicited frequent gastrointestinal complaints and at least one bout of constipation requiring medical intervention, caused fits with hallucinations, both auditory and visuals; and evoked seizures. The periods of incapaciting depression an physical disconfort were severe and grave enough to provoke self mutilation and eventual suicide. Some of his bouts of sickness may have been associated with fever and sexual impotence. His ailment was exacerbated by overwork, malnutrition and fasting; environmental exposure; excessive ingestion of alcohol, specially the liquor called absinthe, and a proclivity for camphor and other terpenes. The symptoms were palliated during institutionalisation with better diet and abstinence from alcohol and treatment with bromide. In spite of the severity of the attacks, he did not experience any permanent, functional disability after any attack. There was a family history of mental illness. Notwihtstanding the restraints of retrospective analysis on a definitive diagnosis, the gamut of symptoms and response is consistent with accute intermitent porphyria, a hereditary metabolic disease that provides a unifying hipothesis”

Those interested in reading the complete article can follow this link:

Loftus, L.S., Arnold, W.N. 1991. Vincent van Gogh’s illness: acute intermittent porphyria. British Medical Journal 303: 1589-1591   

 

   

For more information about the different hypothesis that have been considered to explain Van Gogh signs and symptoms, you can read: Vincent van Gogh’s medical condition 

 

 

 PORPHYRIAS AND VAMPIRE LEGENDS

 

 Different authors have related the legend of vampires with some signs of patients suffering of porphyria; Pale persons, with pink teeth, that sleep or remain indoors during the day, and walk in nature at night, and whose skin shows blisters when exposed to sun… Some papers relating porphyria to the legends have appeared in books and in prestigious scientific journals as the Proceedings of the Royal Society of Medicine, Science, and Scientific American.  

 

Illis, in 1964 (“On Porphyria and the Etiology of Werewolves”), Garden, in her 1973 book “Vampires”, Dolphins in the eighties (Porphyria, Vampires and Werewolves: The etiology of European Metamorphosis Legends”), Tylor in 1998, Lane in the XXI century have considered, supported or suggested this possibility.

 

If the relation between the disease and the origin of the legends is true, then it would be enough for saying that porphyrias are one of the most popular groups of diseases in the movies.

 

The first vampire movie was Nosferatus, a jewel of German expressionism.

 

 

Nosferatus was also one of the first films that suffered a premeditated persecution that intended to destroy all the existent copies.

Who was the person that asked to the legal system to order the destruction of all the copies of Nosferatus? Was a moralist? Was a conservative? A puritan? Somebody based on ethics or religions issues?…. Easier than that: that person was Mrs. Stoker, the widow of Bram Stoker, the author of Dracula.

The movie was inspired, according to the moviemakers themselves,  by the Dracula novel, but they forgot to ask for permission or make a deal with Mrs. Stoker, that owned the rights of the novel.

 

Happily, some copies of this movie survived to the persecution and they are part of the History of Movies.

 

Herzog, Malkovich and Defoe joint talents to recall this movie in “Shadow of the vampire”.

 

In 1931, Universal releases “Dracula” with the most famous interpreter of this rol; Bela Lugosi.

 

 

The vampire movies saga continued during the whole XX century and is present until now: “Van Helsing”, “Dracula 2000”, “Underworld”, “Underworld Evolution”, “30 days of night” are just some examples of some of this movies.

  

Related posts:

 

 Biochemically linked movies  

 

 Porphyrias at the movies

 

More information about Porphyrias and Vampire legends, you can follow the following links to two Scientific American articles:

 

Born to the purple

 

New light on medicine

 

For interesting quotes from Vampire movies, please visit the “Quote and something else Page”

 

 For comprehensive information about Porphyrias, visit these sites:

 

http://www.nlm.nih.gov/medlineplus/porphyria.html

 

http://www.genome.gov/19016728

 

http://www.porphyriafoundation.com/

 

http://www.porphyria.org.uk/

 

 

  LORENZO’S OIL 

 

 

Probably the movie in the commercial circuits in which Biochemistry plays one of the most important roles is “Lorenzo’s Oil” (George Miller, 1992). This movie, featuring Susan Sarandon and Nick Nolte, is an inspirational story based on the true characters of Michaela and Augusto Odone,  a couple whose son, Lorenzo, developed Adrenoleukodistrophy (ALD) at the age of 5 years. When the Odones discovered that there was not any specific medication available for his son’s condition, they began to look for solutions by themselves. Augusto, an economist, and Michaela, a linguistic, began to learn Biochemistry in order to understand the disease and to be able to help their son.

ALD is a peroxisomal disease in which the beta-oxidation of Very Long Chain Fatty Acids (VLCFA) is affected. Dietetic limitations of VLCFA has not proved to be effective in decreasing the levels of VLFC in affected patients, so endogen production is the most important source of these acids in our body and as is usual in metabolism, an equilibrium exist between the production and the degradation of these compounds.

 While the beta oxidation of medium and long chain fatty acids occurs in mitochondria, the oxidation of VLCFA is initiated in the peroxisomes. In ALD there is lack of a functional ABC membrane protein, apparently necessary for the uptake of VLCFA by the peroxisomes. As a consequence, VLCFA, like hexacosanoic acid (C26:0), accumulate and damage the myelin affecting mainly the brain and the adrenal glands.

The gene ABCD1, that codify the affected protein, is located in chromosome X. It explains why this disease appears in full in males, and is also called X-ALD. The clinical manifestations are diverse, from a cerebral form seen in childhood up to a mild form that can be confounded with an Addison Disease.  In the childhood cerebral form, the early development of the patients is normal (Lorenzo Odone was able to speak English, Italian and an African language before he was 5 years old), but between 4 and 8 year old neurological manifestations appears: seizures, ataxia, adrenal insufficiency, and a vegetative state is reached in two years, that usually conduct (or precedes) to an early death.

The most important complementary test for the diagnosis of this disease is the determination of VLCFA in blood, and MRI studies can show characteristic bilateral demyelization in the parieto-occipital region of the brain that also affects the corpus callosum. Genetic testing is also available in some centers, allowing prenatal diagnosis and identification of carriers.

Lorenzo’s Oil movie describes the painful process that affects Lorenzo, and his parents’ battle to sensitize the medical and pharmacological community about Lorenzo’s condition and this “orphan disease”. The story shows that while the disease was orphan, Lorenzo had the most devoted and committed parents.

The devotion of the Odone to his son and other patients afflicted with the disease, who they get to know during their journey, yield them to the discovery of a mixture of fats that improved the condition of his child: the Lorenzo’s Oil.  Lorenzo’s Oil (LO) is a mixture of 4:1 glyceryl trioleate –glyceryl trierucate (neutral fats formed by one molecule of glycerol and three molecules of oleic acid, and one molecule of glycerol and three molecules of erucic acid respectively)

George Miller, the director and writer, studied Medicine before studying film direction, and after being MD he practiced medicine to rise funds for his first low budget movie… “Mad Max”, that launched Mel Gibson to the international screens. Certainly his medical experience was paramount in the writing and direction of “Lorenzo’s Oil”.  (George Miller screenplay and the superb performance of Susan Sarandon as Michaela Odone received Oscar’s nominations for this movie)

The relation of George Miller with Medicine, could explain why the process by which Augusto Odone begins to understand the biochemical basis of the disease is explained in some detail in the movie: by reviewing the available information about the metabolism of fatty acids, A. Odone found a paper describing that the same microsomal system that participates in the elongation of saturated fatty acids to form VLCFA, also elongates erucic acid (22:1 n-9) to form nervonic acid (24:1 n-9). It gave him the idea of using a biochemical mechanism of competition, that he had learned previously, for decreasing the endogenous formation of VLCFA by administrating erucic acid to his son. To convince the medical community about this idea and to find a reliable source of erucic acid (purified glyceryl trierucate) was the next big battle of the Odones that appears reflected in the movie.

The levels of VLCAF in Lorenzo’s blood began to decrease a few weeks after the “oil” was administered to him. Lorenzo did not die during the usual average of two years after the diagnosis of ALD. In fact, he has lived until the twenties. Nowadays Lorenzo’s Oil is used in the treatment of some patients suffering of ALD (FDA considers it an experimental drug yet).

Lorenzo’s Oil is not a cure, but apparently it has increased the quality of life of many patients suffering of this disease. It appears to be particularly useful in slowing the development of the disease in boys with asymptomatic ALD and normal MRI findings (Mose, H.W. et al. 2005)    

Recommended Reading:

Odone A, Odone M. Lorenzo’s oil: a new treatment for adrenoleukodystrophy. J Pediatr Neurosci. 1989; 5:55-61.

Mose, H.W. et al.: Follow-up of 89 Asymptomatic patients with Adrenoleukodistrophy treated with Lorenzo’s Oil, Arch Neurol. 2005; 62:1045-1046, 1073-1080

NINDS (National Institute of Neurological Disorders and Stroke)

The Myelin Project

The Adrenoleukodistrophy Foundation 

The Stop ALD Foundation

United Leukodystrophy Foundation

Recommended Movie:  “Lorenzo’s Oil” (George Miller, 1992) Susan Sarandon, Nick Nolte.

Recommended Music:

“Lorenzo”, Phil Collins.

“Once upon a time I made a lion roar –
he was sleeping in the sunbeams on the old zoo floor.
I had gone to see the park where my papa used to play,
it’s called called Villa Borghese and it’s on the way
to East Africa.
Down on Grand Comoro Island, where I grew past four,
I could swim and fish and snorkel on the ocean floor,
and the wind laughed, and the wind laughed
through the trees as if to say,
here’s a child who’ll want the world to go his way
in East Africa, in East Africa.
Suddenly for me the world turned upside down –
far from my friends the lions and the
dolphins came this awful sound.

Dark shadows, sounds of thunder raging over me,
came this monster called ‘A-dre-no-leu-ko-dys-tro-phy’
Where’s my East Africa?
Well they said, they said, they said (the ones who know it all)
they said from now on for you there will be no more standing tall,
so I took my parents’ hands, I lifted my head to say
I’ll just have to be a hero, there’s no other way!
Back to East Africa
Back to East Africa
Back to East Africa
Come with me I’m going back, going back to East Africa.”
 
(Please, see related post from May 30, 2008 about Lorenzo Odone’s death)
 
 
 
 

 UNBREAKABLE: OSTEOGENESIS IMPERFECTA CASE PRESENTATION.

 

Dr. Mathison: It appears that your baby has sustained some fractures while inside your uterus… his arms and his legs are broken.
[Elijah’s mother bursts into tears]

 

 

 

Elijah Price (Jackson) is born with Type I Osteogenesis Imperfecta, a rare disease in which the bones break easily.

 

Osteogenesis Imperfecta is in fact a group of diseases from a mild form to a very severe. It mainly affects bones, and the milder forms are characterized by bone fractures that often result from minor traumas.

 

Sever forms can present bone fractures even before birth, short stature, hearing loss and respiratory problems. The most sever forms (Type II) include a small rib cage, underdeveloped lungs and often die shortly after birth.

 

(Apparently, Elijah makes a reference to lung problems in this disease (an also to a Gaussian curve) when he says: “Your bones don’t break, mine do. That’s clear. Your cells react to bacteria and viruses differently than mine. You don’t get sick, I do. That’s also clear. But for some reason, you and I react the exact same way to water. We swallow it too fast, we choke. We get some in our lungs, we drown. However unreal it may seem, we are connected, you and I. We’re on the same curve, just on opposite ends.”)

 

 

Osteogenesis Imperfecta results from mutations of some of the genes related to the synthesis of collagen.

 

In most mammalian species, collagen comprises more than 1/4th of the entire protein mass. Collagen is a major structural protein, forming molecular cables that strengthen the tendons and sheets that support the skin and internal organs. Bones and teeth are made by adding mineral crystals to collagen. Collagen provides structure to our bodies, protecting and supporting the softer tissues and connecting them with the skeleton.  

 

Actually, collagen is a family of proteins. Recent advances point to their role in other biological functions, such as mediating the cellular processes of migration, proliferation, and differentiation.

 

Mutant forms of collagen are associated with a wide variety of diseases, especially of bone, connective tissues, and skin.

 

There are at least 8 different kinds of Osteogenesis Imperfecta.  This condition can result from mutations in the any of the following genes:

 

– COLIA1 (Collagen, type I, alpha 1): codify pro-alpha I chain in Collagen Type I

(Type I collagen is the most abundant form of collagen in the human body). Mutations in this gen are responsible for 90 % of Osteogenesis Imperfecta Type I

 

– COLIA2 (Collagen type I, alpha2): codify the pro-alpha2 chain in Collagen Type I

 

– CRTAP (Cartilage Associated Protein): codify the Cartilage Associated Protein, a protein that is part of a complex necessary for the conversion of proline to 3-hydroxyproline in the collagen molecule.

 

– LEPRE1: (Leprecan, prolyl 3-hydroxylase1): codify the enzyme leprecan, part of the complex necessary for hydroxylation of proline (this enzyme apparently participates in other processes also). Mutations in this gene produce osteogenesis imperfecta Type VIII.

 

When Elijah first meets David (the Bruce Willis character) at the gallery, he says that he has Osteogenesis Imperfecta Type I, which is the mildest form of the disease. But Elijah then states that there are types II, III and IV, and that type IV patients don’t last very long. Actually there are at least eight forms of the disease, and the types are not in order of severity: Type II is the most severe form.

 

One of the most famous lines of this movie is when Elijah describes his condition by saying how he was called as a kid:

 

 

 

 A BEATIFUL MIND:  Hypoglycemia and Insulin Coma Therapy

 

The trailer:

 

 

This movie is based in the life of John Nash, a mathematician that managed to develop a work in his field that deserved the Nobel Prize, while he battled schizophrenia 

 

Interview with John Nash:

 

 

During the treatment of his disease, John Nash received Insulin Coma Therapy, a controversial procedure that was used in the treatment of schizofrenia. One of the treatment sessions is reflected in the movie: after the administration of insulin, the patient begins to develop signs of hypoglycemia, including seizures and coma. After the patient has reached a coma status as a result of the hipoglicemia, he/she is maintained in supervised coma during approximately one hour, and then he/she is awake by administrating a glucose solution. This procedure was widely used during more than 30 years in the United States, from the thirties to the sixties, and apparently it is used sporadically in the former Soviet Union and China. (In a personal note, I recall that while I was rotating as medical student in Psychiatry in 1970, I saw one Insulin Coma treatment in an schizophrenic patient in the Provincial Hospital Saturnino Lora in Cuba. I do recall also that I felt disappointed when my professor was not able to answer me which was the mechanism of action of this kind of treatment in schizophrenia. I learned later that it was not his fault: nobody knew).

 

John Nash experience with the Insulin Coma Therapy is related in this interview.

 

Other patients describes a different experience.

 

For more information about Insulin Coma Therapy, visit the following links:

 

Fink, Max; Karliner, W.: A Brilliant Madness.

 Primary Sources: Insulin Coma Therapy.

 

Insulin Shock Therapy. (Wikipedia)

 

Jones, K: Insulin Coma Therapy in Schizophrenia

JR Soc Med 93(3) 147-149, 2000

 

 Crammer, J.L; Leter to the Editor about “Insulin Coma therapy in Schizophrenia”.

JR Soc Med: 93(6) 332-333, 2000

 

 Hypoglicemia, Wikipedia

 

Related post

 
 

15 thoughts on “Biochemistry at the Movies

  1. Pingback: Biochemistry at the movies: Lorenzo’s Oil « The Biochemistry Questions Site

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  3. Pingback: Dies Lorenzo Odone, the ALD patient subject of “Lorenzo’s Oil” movie « The Biochemistry Questions Site

  4. Pingback: Porphyrias at the Movies « The Biochemistry Questions Site

  5. Pingback: Van Gogh medical condition: a biochemical disorder? « The Biochemistry Questions Site

  6. Pingback: Did the Phantom of the Opera suffer a biochemical disorder? « The Biochemistry Questions Site

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  8. very interesting blog ant topic. I’m psychology professor in criminological psychology and this theme is a great unknown…. I will study in deep the question.
    Thanks.
    Antonio

  9. Thanks, Antonio.
    Gracias a ti por tus palabras!
    Estuve por tu blog.
    Si te da por analizar las peliculas desde el punto de vista de tu especialidad, no tienes para cuando acabar.

    David

  10. Pingback: Breakable: Mr. Glass and Osteogenesis Imperfecta. « The Biochemistry Questions Site

  11. Pingback: Blogs I Like: Biochemistry Questions Site « EBM and Clinical Support Librarians@UCHC

  12. hi ,Inspiring me very nteresting blog ant topic. I’m psychology professor in criminological psychology and this theme is a great unknown…. I will study in deep the question.arabic translator movie blog m-yegy.blogspot.com

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