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Why Don’t Some Dwarves Get Cancer?

The dwarves of a village in Ecuador never succumb to cancer or diabetes.

We now know why the dwarves of a village in Ecuador never succumb to cancer or diabetes.

By Michael Waters & Andrew Brooks

Understanding the molecular mechanism that prevents dwarves from getting cancer and diabetes could lead to treatments for a range of diseases, and even hormone-free aquaculture.

The dwarves of a village in Ecuador never succumb to cancer or diabetes. After 40 years of studying how growth hormone functions at a molecular level, we now know why. This knowledge could lead to novel treatments not only for cancer and diabetes, but also many other conditions. It could even help us to grow fish more efficiently without the use of growth hormones.

While it’s true that hundreds of genes contribute to our height, growth hormone is the most important factor. Without it our average height is around 1.3 metres, while an excess of growth hormone can result in a 2.6-metre giant.

Growth hormone causes the band of cartilage at each end of our long leg bones to proliferate. When this cartilage is converted to bone we have a longer tibia or femur.

Growth hormone is made in the pituitary gland at the base of the brain. The secretion of growth hormone into the blood is regulated by the hypothalamus, which sends chemical signals down the pituitary stalk to the pituitary gland. The growth hormone then travels in the blood to all tissues in the body, where it binds to its receptor on the surface of all cells in the body except red blood cells.

From here the signal goes to the nucleus, where the readout of hundreds of genes is then altered. This results in cell multiplication, cell growth and changes to many cellular functions.

Human growth hormone has been manufactured in bacteria since 1985, and has been used to treat thousands of short children with dwarfism. However, dwarfism can also be caused by a molecular defect in the cell receptor, thus blocking its actions.

Intriguingly, there is a group of such dwarves in a village in Ecuador who were displaced from Spain during the Inquisition. When the cause of their deaths was examined recently, it turned out that they do not die from cancer or diabetes. This finding has been supported by studies of other such dwarves in the Middle East. Curiously, rather than cancer, they die from accidents, alcoholism or cerebral seizures.

What this means is that finding a way to block the action of the growth hormone receptor could result in a useful treatment for many kinds of cancer. Knowing the exact molecular motions of the receptor when it is activated by growth hormone allows us to identify where drugs can be targeted to block its action. However, this could not be a long-term treatment in children, and even in an adult it would be best combined with other specific cancer therapies identified from gene sequencing of the tumour.

There is another dimension to the cancer story here, but to understand it we need to look at how the receptor works in more detail. The receptor is a large protein of 620 amino acids. Part of it lies outside the cell membrane, where it binds minute amounts of blood-borne growth hormone with high affinity.

Within the cell, the inner part of the receptor protein binds to a special enzyme called a Janus kinase – like the Roman god, it looks both in and out of the doorway into the cell. When growth hormone binds to the outside of the receptor, the Janus kinase becomes activated. Now we know how.

The Janus kinase adds a phosphate ion to the amino acid tyrosine, both on the receptor itself and to other protein targets of Janus kinase. These phosphates come from ATP, the energy currency of the cell, and they act like little magnets that attract transcription factors that control the expression of genes. When these transcription factors bind to the phosphates on the receptor, they are held in place so that the Janus kinase enzyme can put phosphates onto them as well, and this activates these transcription factors to travel to the nucleus and turn on or off genes in the cell’s DNA. In this case, the transcription factors are called STATs, and gene defects in these can also cause dwarfism.

It transpires that particular mutations can keep the Janus kinase turned on, and this leads to several kinds of blood cancers. Recently, inhibitors of Janus kinase have been developed to treat these cancers, but we have not known how the Janus kinase is activated by its receptors.

Our work has now shown how this occurs, and it was most unexpected. Basically, there are two Janus kinases, each bound to its receptor, and they are held in a basal state by cross-inhibition – one Janus kinase inhibits the other via pseudokinase domains that look like the kinase enzyme part but are non-functional. When the growth hormone binds to the receptor, it causes the inhibitory part to slide away from the other kinase. This brings the two kinases together so that they can activate each other (Fig. 1). How this happens is shown in our animation at http://tinyurl.com/m4fso5o

Apart from designing inhibitors of the receptor and Janus kinase to treat cancers, how else can we use this knowledge ?

First, the Ecuadorian dwarfs do not appear to develop diabetes. Similarly, we have found that transgenic mice lacking the STAT signal are particularly insulin-sensitive. Since diabetes can result in proliferative retinopathy, an agent blocking the growth hormone receptor could preserve eyesight and ameliorate renal failure in susceptible diabetics. Second, our findings do not just apply to growth hormone but to 30 medically important hormone and colony factors of the same type as the growth hormone receptor. When we cloned the growth hormone receptor it was unique, but subsequently it has been shown that erythropoietin receptor (blood cell synthesis), the prolactin receptor (lactation), the leptin receptor (obesity), the thrombo­poietin receptor (blood clotting) and a number of key immune receptors are all in this family, so it is likely that we now know how they work too. Again, this offers new drug targets.

There are also applications in aquaculture. Transgenic growth hormone in fish has been used for some time to enhance the growth of farmed salmon in North America, but some people object to having a “growth hormone” in fish. By elucidating the receptor activation process we have developed receptors that are pre-activated, and do not need growth hormone to work. These provide “hormone-free” growth that in our experimental studies has been more effective than growth hormone itself. Since abalone, shrimp and lobster all respond to growth hormone, this could improve the output of aquaculture, and hence lighten the load on wild fisheries.

These developments have taken quite some time, and were contingent on new technologies developing – such as the use of fluorescent jellyfish proteins fused to the receptor to see how it moves in a live cell, and the ability to observe single molecules – as well as recombinant DNA technology, which did not exist when we began to study this receptor.

Michael Waters is Laboratory Head of the Molecular Cell Biology Division at the University of Queensland’s Institute for Molecular Bioscience, where Andrew Brooks is Senior Research Officer.