implications for the burgeoning science of enzyme 

 replat oment therapy in a variety of genetic diseas- 

 es. 



Dr. Neufeid and her associates had previously 

 shown that patients with Hurler's and Hunter's 

 syndromes — disorders characterized by skeletal 

 deformities, cardiovascular disease, mental retar- 

 dation, and early death — lack in their cells specific 

 proteins which they named the "Hurler corrective 

 factor" and the "Hunter corrective factor," re- 

 spectively. The terms derive from studies in vitro 

 that revealed that the basic biochemical flaw in 

 each disease could be corrected by replacing the 

 missing protein in cells cultured from the patients. 



In subsequent research, the investigative team 

 showed that tissues of Hurler patients have a 

 deficiency of the enzyme a-L-iduronidase, where- 

 as cells of Hunter patients lack the enzyme idu- 

 ronate sulfatase. The Hurler and Hunter correc- 

 tive factors were found to have iduronidase and 

 iduronate sulfatase activity, respectively. How- 

 ever, these corrective factors have something 

 more than the ability to function as enzymes: they 

 have special chemical structures that enable them 

 to enter the cells where they will perform their 

 function of breaking down mucopolysaccharides. 



A significant clinical application of Dr. Neu- 

 feld's research is precise diagnosis — including 

 prenatal diagnosis — of the mucopolysaccharide 

 storage disorders. Another is the identification of 

 carriers of the gene for Hunter's syndrome. 

 Because this disease is transmitted by X-linked 

 inheritance (like hemophilia), the sisters and other 

 female relatives of Hunter pajients can pass the 

 disease to their sons. These women can benefit 

 greatly from reliable information about their ge- 

 netic status. 



But clearly the most exciting applications lie 

 ahead — in the hope of effective enzyme replace- 

 ment for genetic disease. The discovery that en- 

 zymes must have specific "address labels" to 

 guide them into the right cells will make the task 

 of preparing enzymes for replacement therapy 

 more challenging but also more likely to succeed. 



Tumor Biology and Reverse Transcriptase 



In 1970, Drs. David Baltimore of MIT and 

 Howard Temin and Satoshi Mizutani of the Uni- 

 versity of Wisconsin simultaneously reported the 

 discovery of an enzyme later demonstrated to be 

 the key to the life cycle of the RNA tumor virus- 

 es. The enzyme is now believed by some scien- 

 tists to be a clue to the cancer-causing properties 

 of these viruses. 



RNA tumor viruses differ from most other 

 forms of life in the chemical composition of their 

 genes. Most cells have DNA (deoxyribonucleic 



acid) as their hereditary material, and their genes 

 are expressed by a process involving the tran- 

 scription of DNA into RNA (ribonucleic acid), 

 which then carries the genetic information to sites 

 of protein synthesis in the cell. This relationship 

 has become known as the "central dogma" of 

 molecular biology. RNA tumor viruses, however, 

 are an exception to the dogma; they have the first 

 part of the process reversed. In these viruses, 

 RNA serves as the hereditary material, and it is 

 transcribed into DNA. Reverse transcriptase, as 

 the newly discovered enzyme became known, is 

 what makes the process possible. 



When an RNA tumor virus particle is about to 

 infect a cell, it already contains reverse transcrip- 

 tase, along with the RNA that makes up the viral 

 genes. It attaches to the surface of the cell and, 

 by a mechanism still not understood, passes its 

 RNA and the reverse transcriptase enzyme inside 

 to the cell cytoplasm. Once inside, the enzyme 

 uses the viral RNA as a template and synthesizes 

 a viral-specific double-stranded circular DNA out 

 of the cell's supply of building block molecules. 

 Then the DNA, which is known as the "provi- 

 rus," becomes attached and stably integrated into 

 the cell's own DNA. This is thought to be the 

 reason why these viruses are sometimes able to 

 cause cancer. Once integration has occurred, the 

 synthesizing machinery of the cell becomes avail- 

 able to the virus for its own purposes, and several 

 different events may take place. The virus may 

 take control of the cell's transcription and protein 

 synthesis capabilities and direct the production of 

 new viral RNA and proteins for the formation of 

 new infectious viral particles; this is the active 

 reproductive phase of the virus. It may also direct 

 the synthesis of a "transformation protein" which 

 causes certain alterations in the growth properties 

 of the cell; in such a case, a tumor is formed. On 

 the other hand, the integrated viral DNA may 

 remain "silent," i.e., unexpressed, either tempo- 

 rarily or for many generations. 



Integrated provirus DNA is replicated just like 

 ordinary cell DNA in the sequence of events 

 preceding cell division. So when an infected cell 

 divides into two daughter cells, viral genes are 

 passed on to the progeny in the same way as oth- 

 er genes of the dividing cell. Virtually all types of 

 normal animal cells have silent virus-like genes, 

 acquired not by infection but by inheritance from 

 their ancestors. The question of where the genes 

 came from and what function they perform is one 

 of the fascinating riddles of modern molecular 

 biology. Some scientists think they may be nor- 

 mal animal genes that happen to resemble viral 

 DNA; others think they are viruses that infected 

 the animal's ancestor and have been maintained in 

 the genome by evolution because they confer 



HEALTH, EDUCATION AND WELFARE 107 



