In the spring of 1997, William Boyle, a microbiologist at Amgen Inc., a drug company based near Los Angeles, placed a telephone call to Dr. Josef Penninger, an immunologist at the firm's Toronto offshoot, the Amgen Research Institute. Boyle wanted Penninger's help in determining the function of a protein - and the gene that produces it - which Boyle's team had encountered in the course of cell research. Boyle suspected the protein played a role in bone growth. Penninger and his research assistant, Young-Yun Kong, set about creating genetically altered mice in which the animals' version of the gene - which is almost identical to the human one - was missing. Without the gene, young mice developed abnormal bones that caused misshapen heads and other deformities. The Toronto researchers, whose findings were published last week in the journal Nature, had revealed one of the key controls in bone formation - and bone loss. The discovery, along with work done in Boyle's laboratory, could lead to drugs capable of preventing the ravages of osteoporosis, a bone-eroding disease that afflicts about 1.4 million Canadians. "The implications of this finding," said Penninger, "are really amazing."
The results of Amgen's research are already undergoing early testing on humans - though it could be years before a successful osteoporosis drug reaches the market. Last August, doctors in California began injecting an experimental drug in post-menopausal women - the segment of the population most at risk of developing osteoporosis. A disease that usually strikes after the age of 50, osteoporosis leads to loss of bone mass, bone fragility and a high rate of fractures. The disease strikes one out of every eight men - and one in four women. The current trials, Boyle emphasizes, are to determine safety - and only if it is clear there are no dangerous side-effects will the drug go on to larger trials to determine whether it can actually slow or halt bone loss. "I tend to be very analytical and cautious," says Boyle. "But we're excited by these findings."
The discoveries shed new light on the intricate biology of living bones. Unlike the solid structures seen in human or animal skeletons, living bones are dynamic organisms that constantly break down to release minerals such as calcium, magnesium and phosphorous for use elsewhere in the body. At the same time, bones regularly suffer tiny fractures as the result of normal activities - and repair themselves as necessary by forming new bone.
Boyle's group began showing precisely how some of these processes work with a finding published last May involving a protein called osteoprotegerin (OPG), which indirectly plays a major role in increasing bone mass. It does this by blocking the action of another protein called osteoprotegerin ligand (OPGL). Boyle concluded that the function of OPGL is to activate cells on the surface of bone called osteoclasts, which erode bone and release calcium into the bloodstream.
To test the relationship between the two proteins, Boyle turned to Penninger, an Austrian native who came to Canada in 1990, initially to work under Tak Mak, the distinguished immune system expert who heads Amgen's Toronto institute. Boyle decided to get help from Penninger - who now runs his own lab - "because he is very fast and very good at his work." Within six months, Penninger and his team had the answer: in mice that lack the OPGL gene, the normal gradual loss and regrowth of bone is halted, leaving a skeletal structure that is unnaturally dense and solid.
The active ingredient currently being tested in California is OPG - the protein that can block OPGL and prevent bone loss. The findings by the two Amgen laboratories also opened up new avenues of research into other major diseases. One possibility is that the osteoclast-control genes may play a role in osteoarthritis, a disease in which bones fuse rigidly after ligaments in body joints wear away. As well, the genes may be involved in bone cancer, a disease that often sets in after cancers spread beyond their original site. "If we can figure out whether OPG or OPGL are involved in this," said Penninger, "we might be able to help cancer patients." But for now, the greatest interest is bound to focus on the trials of Amgen's experimental drug, as the baby boomers in their 50s struggle with osteoporosis and the hip, spine and wrist fractures that so often come with it.
Maclean's February 8, 1999