I know much more about lysosomes and their normal function because of a task I set my first year human physiology students a couple of weeks ago. I've been teaching that class for nearly 4 years now and have had many occasions to report about how difficult it can be to get the workings of the human body to sing to them. Try as I might, I can't get them to appreciate that glucose is smaller than insulin; heck-and-jimminy, I can't even get them to grasp that glucose is smaller than the pancreas. ANNyway, I do talk about lysosomes as 'the cell's stomach' and assert that these little membrane-bound sacs are full of various digestive enzymes. Here on The Blob, I've mentioned a couple of diseases - Tay-Sachs and Morquio Syndrome - which are caused by dysfunctional enzymes whose site of action is in the lysosome.
The task I set my HumPhys students was to write out a list of 20ish lysosome storage disorders and ask everyone to own one of these exotic sounding conditions and find out something about it: a mini-research project. Here are some to conjure with: Gaucher, Pompe (infantile), Salla, Sandhoff, Schindler, Niemann-Pick, Farber, not to be confused with Fabry, Hunter, Hurler and Pseudo-Hurler, Kufs, Sly and Danon and, of course, Tay-Sachs and Morquio. For each syndrome, I asked them to report
- mode of inheritance
- age of onset
- prognosis from diagnosis
- frequency in Ireland and other populations
- the enzyme involved
- the symptoms
- any chance of a cure?
There are a few themes that run through the dataset of broken enzymes.
- Like Morquio, many of them have enzyme replacement therapies ERTs launched or ready to launch. This is the idea that you can inject the missing enzyme on a regular basis and it will course through the circulatory system and percolate to the lysosomes of every cell where it is required. Seems to work in some cases, and MegaPharm is scrambling for a seat on the band-wagon. ERT is a very blunt instrument, as we saw for treating haemophilia with artificial Factor VIII: instead of dribbling out a steady stream of enzyme, such as you and I do every second without a thought, ERT delivers a jolt of the stuff once a week and the body makes what it can from the buffet.
- Many of these diseases are vanishingly rare, frequently on the order of 1:million or 1:100,000 live births. Compare this with Down Syndrome or Cystic Fibrosis where the rate is about 1:1000 births. That makes me think of Dr Johnson's oafish quip about "Sir, a woman's preaching is like a dog's walking on his hind legs. It is not done well; but you are surprised to find it done at all." [prev]. The lysosome, and the 50 or 60 clean-up tools which it wields, is so crucial to day-to-day function that any substantive change in the tool-kit is fatal. Many of the poor wee scraps who come to term have a very short painful life ahead of them fighting against neuro-degeneration, digestive disorders, seizures, developmental anomalies and, recently, coping with diverse surgical and medical interventions.
- Some tribes and ethnic groups - Ashkenazim, Berbers, Cajuns - seem to have a much higher frequency of some peculiar and particular defect. This has helped with the genetics of tracking down which enzyme is involved and where it is located on the human genome.
- Because each syndrome is rare and each is caused by a very specific lesion, the drug people have to develop a different therapeutic agent for each disease. With only a tiny patient base, the costs of development are amortised over a small number of customers, so the cost per dose is fabulously frighteningly expensive.