Molecular Biology and Medicine

After his fiftieth birthday, Don's wife urged him to get a long-delayed medical checkup. He felt well, but realized that this was a good time to be screened for the various diseases that affect people as they get older. Don's routine blood count showed a surprise: Normally, people have about 5,000 white cells per milliliter of blood; Don had 40 times as many. Within a day, he was diagnosed with chronic myeloid leukemia, a serious cancer where white blood cells from the bone marrow proliferate out of control.

An oncologist (a physician who specializes in treating cancer) put Don on an aggressive regimen of chemotherapy. The three drugs Don took were designed to kill dividing cells—hopefully in the tumor, but such drugs also affect normal cells. One drug blocked microtubules from forming, thus preventing the mitotic spindle from assembling; another inserted into the double helix and damaged DNA replication; the third drug inhibited an enzyme involved in nucleotide synthesis.

Although the side effects were hard on Don, his white cell count gradually got lower. But after 8 months, the decline stalled at 80,000 cells/ml—still dangerously high. Worse, most of them were not mature white blood cells, but were undifferentiated cells from bone marrow. The chemotherapy drugs had killed Don's normal bone marrow cells. Without these specialized mature white blood cells, Don would die within months.

The timely development in the 1990s of a molecular understanding of this leukemia led to a therapy that saved Don's life. Scientists had known for several decades that chronic myelogenous leukemia cells have a particular chromosome translocation between chromosomes 9 and 22. With the advent of DNA sequencing, it became clear that this translocation fuses together parts of two genes: half of a gene called bcr on chromosome 22, and half of a gene called abl on chromosome 9. The abnormal protein made from this fused gene has strong protein tyrosine kinase activity.

As described in Chapter 15, protein kinases activate proteins by phosphorylation, binding a phosphate group from ATP. During the 1990s, the leukemia protein kinase was purified, crystallized, and the geometry of its binding site for ATP was described in molecular terms. Armed with this knowledge, organic chemists designed a drug that fit into and obstructed the binding site for ATP on the abnormal kinase, inactivating the enzyme. The drug, called Gleevec, was given to Don, and within a few weeks his white cell count was 5,400— normal! The cancer had been virtually wiped out.

The development of Gleevec is an opening chapter in the molecular medicine of the future. Unlike conventional chemotherapy, which uses

A "Smart Drug" The drug Gleevec (shown here as the red molecule) binds to a protein kinase made by certain leukemia cells, preventing the cancer cells'reproduction. Gleevec is the first example of a rationally designed, specifically targeted cancer-fighting drug produced using the knowledge and techniques of molecular medicine.

Phenylketonuria (PKU)

Q| The enzyme that converts phenylalanine to tyrosine is nonfunctional.

broadly acting nonspecific drugs that stop division in all cells (cancerous or not), Gleevec is highly selective. The new drug is targeted to a specific protein that only occurs in a particular cancer cell.

In the first section of this chapter, we identify and discuss the kinds of abnormal proteins that can result from an abnormal allele of a gene, whether the allele is inherited or has its origin from a mutation. Then we will consider the patterns of inheritance of human genetic diseases. Precise descriptions of these genetic abnormalities at the DNA level has come from molecular biology. This knowledge has been extended and applied to the treatment of cancer, among the most dreaded of human afflictions. The rise of molecular medicine is most dramatically shown by undertakings such as gene therapy and the sequencing of the human genome, which are discussed at the end of this chapter.

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