We now know that cells interact with their environment through receptors on their cell surface
that internalize specific molecules bound to it
to influence the biology of the cell, which in some cases, includes the secretion of other molecules
This very eloquent way of establishing harmony between the cell and its environment
was only discovered in 1973, thanks to clever experiments from Joseph Goldstein and Michael Brown
in their the paper titled "Identification of a defect in the regulation of HMG-CoA reductase associated with overproduction of cholesterol"
published in the Proceedings of the National Academy of Sciences
These scientists wanted to understand the mechanisms causing a very curious disease called familial hypercholecerolemia
which is a genetic disease transmitted from parent to child in an autosomal dominant way
where one mutant copy of a gene is sufficient to cause disease
but no one knew what the disease gene was or what it did
in individuals with two mutants of the gene was more severe with death before the age of 30
but the more striking feature of the disease was the accumulation of low density protein called LDL, also known as "bad cholesterol"
in pockets underneath the skin visible to the naked eye, in blood, and in the wall of arteries
causing heart disease in teenagers
normally each LDL has 1500 molecules of cholesterol
LDL has a form of negative feedback, which means when there is too much LDL in the blood, LDL inhibits its own production
in order to keep levels at a healthy state
when LDL levels are low, the proteins responsible for producing LDL are active
releasing the inhibition
in FH, LDL accumulates in the blood, seemingly without control
Determined to find out what causes FH, these two scientists devised experiments in order to answer this very important question
Because LDL production was under negative feedback control,
this gave the scientists a clue that the regulation of LDL metabolism, the cycle regulating its synthesis and break down,
maybe to blame
First, they wondered if the LDL produced from FH patients was different from that produced in normal individuals
Rendering the FH LDL unable to regulate cellular cholesterol production
They took LDL in blood from an FH and a normal patient,
and put it into a surrounding media of cells in a petri dish
they measured whether the LDL from the two individuals had different effects
on the production of cholesterol within the cell
But both samples of LDLs were able to prohibit the production of additional LDL to the same extent
as you would expect from negative feedback regulation
So the LDL produced from FH patients was normal
and able to block synthesis of additional cholesterol
In that case, how did LDL keep accumulating in those patients?
Next, the scientists took cells from a 12 year old girl suffering from FH
and a healthy patient, to grow them in a petri dish
they were curious to examine how the presence or absence of LDL in the media would affect the cells' production of cholesterol
When LDL was absent, FH and normal cells produced large amounts of cholesterol
But when LDL was added back, the normal cells stopped producing cholesterol, but the FH cells kept up cholesterol production
80x higher than normal cells, seemingly unaware that the LDL levels in the media had changed
These experiments suggest that the cell itself was not able to respond to LDL levels outside the cell
breaking the communication of the inside and outside of the cell
this led to the important discovery of the LDL receptor on the cell surface
LDL outside the cell bind to the LDL receptor, it is internalized and broken down to release cholesterol
which can then inhibit the cholesterol producing enzyme from making more cholesterol
The LDL receptor then returns to the surface, making one round trip every 20 minutes
this is an example of receptor-mediated endocytosis
through a few important experiments, these two scientists discovered that FH was due to a mutation in receptor for LDL
rendering it disfunctional
Without this receptor, LDL outside the cell can't signal to the machinery inside the cell and stop its activity
Instead, LDL keeps being produced in the cell and accumulates everywhere in the body
This was the first example of receptor mediated endocytosis
Which has since been demonstrate an important mechanism for cells to communicate with its environment
In this really great example, studying a rare genetic disease informed our understanding of a basic biological pathway
relevant to all cells and to everyone
Brown and Goldstein won the Nobel Prize in Physiology and Medicine in 1985 for their research
They run a joint laboratory and have been collaborating and sharing discoveries with each other for over 40 years.
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