TIME, APRIL 19, 1971

for the operation of that particular cell. The rest are "turned off" by protein repressers, which wrap themselves around

from transferring their coded information to messenger RNA.

A number of such repressers have since been found in bacteria. Scientists have also isolated enzymes that turn the genes back on. These inducers, as they are called, work by unlocking the repressers on the segment of DNA. But even in E. coli, such switching can become bafflingly difficult: the repressers and inducers, for example, require controlling enzymes of their own. These enzymes, in turn, apparently need the help of still other molecules, such as the recently discovered sigma, rho and psi factors. in recognizing the appropriate genes. In fact, it is because of the very complexity of these processes that leading molecular biologists like Crick find the questions arising from cell differentiation so fascinating. How in the human embryo, for instance, are certain genes switched on so that by the end of the first week after conception identical cells have begun to grow into cells with differing characteristics?

SO FAR T

O FAR THESE fundamental questions are largely unanswerable, although some clues have been uncovered. For one thing. it is thought that in higher. multicellular forms of life, repressers may be a special class of proteins called histones: these are not found in bacteria. When histones are removed. Rockefeller University's Vincent Allfrey has found, RNA production soars by 400%. evidence that formerly repressed segments of DNA have become active. In addition. it has been learned that the cell membrane itself appears to play a crucial part in switching genes on and off. When a membrane is merely brushed by certain hormones-a large class of molecules that serve as intercellular messengers--the membrane will respond as though jolted by an electric probe. It will instantly send off a signal to the nucleus, triggering RNA production by the genes. That finding could eventually have medical application for diseases -like diabetes-resulting from vital genes that are inexplicably turned off.

Many more puzzles remain unsolved. Why are there small bits of DNA located outside the nucleus in energy-producing cell centers called mitochondria? Does this mean that there are other, unknown repositories of hereditary information? In spite of such questions and complications, the basic structure of DNA postulated by Crick and Watson 18 years ago has withstood the test of time remarkably well. More important, it has given man a profound new understanding of basic life processes-and the means to control and alter them.

TIME, APRIL 19, 1971

The remarkable advances in molecular biology during the past two decades have given man an understanding of the basic processes that shape his life and have placed within the realm of possibility medical achievements undreamed of a scant few years ago. As more and more of the once-mysterious life forces within the cell are defined in the logical language of chemistry, the way is being opened not only for permanent cures of genetic diseases but also for drastic changes in man's genetic makeup. The acquisition of the power to eliminate genetic imperfections and engineer entirely new characteristics for humans is, for all of its promise, a frightening prospect for those who be

Fully 25% of all conceptions fail to reach an age at which they can survive outside the womb, and of these, at least a third have identifiable chromosomal abnormalities. Still, as many as five out of every 100 babies born have some genetic defect, and Nobel-Prizewinning Geneticist Joshua Lederberg believes the proportion would be even higher were it not for nature's own process of qual ity control.

The most obvious deformities result from chromosomal abnormalities. Down's syndrome, or mongolism, which occurs once in every 600 births, is caused when one set of chromosomes occurs as a triplet rather than a pair. Hydrocephalus, or water on the brain, and

LEONAND MCCOMBE-LIFE

polydactyly, the presence of extra fingers or toes, also result from faulty genes.

But the majority of genet ic stigmas have somewhat more subtle symptoms and occur when defective genes fail to order the production of essential enzymes that trigger the body's biochemical reactions. Phenylketonuria (PKU) is caused by the absence of the enzyme necessary for the metabolism of the amino acid phenylalanine; as a result, toxins accumulate in the body and eventually cause convulsions and brain damage. Cystic fibrosis, which causes abnormal secretion by certain glands and respiratorytract blockage that can lead to death by pneumonia, is the most common inborn error of metabolism; it is believed to be caused by a deficiency in a single gene. Most people are unaware that they are carrying defective genes until they have a deformed, diseased or mentally retarded child. While medical science has not yet developed the techniques for repairing the bad genes, it can increasingly determine that they are present. Genetic counselors can thus advise prospective parents on the possibilities that their offspring will be born with genetic diseases. Properly informed, a couple that runs a high risk of producing a defective child may well decide to forgo having children.

DIABETIC WOMAN UNDERGOING AMNIOCENTESIS

Eliminating the uncertainty.

lieve that man should not tamper with his inheritance. Yet even before the structure of DNA was defined and the genetic code broken, doctors had begun. mostly by trial and error. to develop techniques of genetic medicine.

Man today is heir to a host of inherited imperfections, ranging from diabetes to degenerative nerve disease. Each individual, geneticists have determined, carries between five and ten potentially harmful genes in his cells, and these flawed segments of DNA can be passed down to his progeny along with the messages that determine whether a child will have red hair or blue eyes.

Nature itself takes care of the worst genetic mistakes. One out of every 130 conceptions ends before the mother even realizes she is pregnant because the defective zygote, or fertilized egg, never attaches itself to the wall of the uterus.

If both parents carry genes for diabetes, for example, the chances are one in four that their children will inherit an increased risk for developing the disease. If either parent actually suffers from diabetes, the odds are even worse. Members of one large South Dakota family afflicted with a rare

The New Genetics.

degenerative nerve disease have been advised, for example, that the odds are 5050 that any children they have will suffer loss of balance and coordination and die, probably of pneumonia, by age 45 (TIME, Jan. 25).

Genetic counseling once relied more heavily on mathematics than medicine to predict the chance of hereditary handicaps. But it is now possible for doctors to identify and catalogue chromosomes. If there are certain chromosomal abnormalities, the prospective parents are informed that they will almost definitely produce deformed offspring. While this knowledge may take some of the mystery and romance out of procreation, it also eliminates much of the uncertainty. As one geneticist puts it, "There is nothing very romantic about a mongoloid child or a deformed body."

An even more important technique enables physicians to examine the cells of the unborn only months after conception and to determine with accuracy whether or not the infant will inherit his parents' defective genes. The procedure is known as amniocentesis, from the Greek amnion (membrane) and kentesis (pricking); it is performed by inserting a long needle through the mother's abdomen and drawing off a small sample of the amniotic fluid, the amber liquid in which the fetus floats. Physicians then separate the fetal skin cells from the fluid and place the cells in a nutrient bath where they continue to divide and grow. By examining the cells microscopically and analyzing them chemically, the doctors can identify nearly 70 different genetic disorders, most of them serious.

Amniocentesis, performed between the 13th and 18th weeks of pregnancy, is not without some risk to both mother and baby. But in cases where family history leads them to suspect genetic defects, physicians feel that the benefits more than justify the danger; for the tests, which have been carried out on more than 10,000 women in the U.S. alone in the past 40 years, have proved extremely accurate. Using amniocentesis, Dr. Henry Nadler, a Northwestern University pediatrician, diagnosed mongolism in ten of 155 high-risk pregnancies tested. Subsequent examination of the fetuses showed that his diagnosis was correct in all cases.

nesses. An amniotic test for fetal lung maturity, for example, has helped warn doctors when a child may be born with hyaline membrane disease, which blocks proper breathing. In those cases, birth can be delayed by sedation until tests show the baby ready to breathe on its own. Tests that permit prompt postnatal detection of PKU give doctors an opportunity to place babies so affected on special diets that prevent the accumulation of the deadly toxins and allow them to live relatively normal lives.

Some treatments are even possible before birth. Physicians routinely perform intrauterine transfusions on fetuses suffering from Rh disease, a genetic condition that results from the incompatibility of maternal and fetal blood.

Artificial insemination, once the exclusive province of livestock breeders. also offers escape from some genetic mis

JON-DAILY MAIL LONDON

NA

"GOOD MORNING, DADDY."

haps. An estimated 25,000 women whose husbands are either sterile or carry genetic flaws have been artificially inseminated in the U.S. each year, many of them with sperm provided by anonymous donors whose pedigrees have been carefully checked for hereditary defects. Some 10,000 children are born annually of such conceptions.

Doctors also see possibilities in artificial inovulation, a procedure in which an egg cell is taken directly from the ovaries, fertilized in a test tube and then reimplanted in the uterus. By carefully scrutinizing the developing embryo in the test tube, doctors could spot serious genetic deficiencies and decide not to reimplant it, thus avoiding an abortion later on. If the embryo is normal, it could even be reimplanted in the womb of a donor mother and carried to term

there, enabling the woman either unable or unwilling to go through pregnancy to have children that were genetically her own.

Even test-tube babies, once the stuff of science fiction, are now not only possible, but probable. Dr. Landrum Shettles of Columbia University and Dr. Daniele Petrucci of Bologna, Italy, have shown that considerable growth is possible in test tubes. Shettles has kept fertilized ova growing for six days, the point at which they would normally attach themselves to the lining of the uterus. Petrucci kept a fertilized egg alive and growing for nearly two months.

NDEED, ONLY

development of an "artificial womb" capable of supporting life stands in the way of routine ectogenesis, or gestation outside the uterus, and now even this problem may yield to solution. Scientists at the National Heart Institute have developed a chamber containing a synthetic amniotic fluid and an oxygenator for fetal blood, and have managed to keep lamb fetuses alive in it for periods exceeding two days. Once their device is perfected, the baby hatchery of Aldous Huxley's Brave New World will be a reality and life without birth a problem rather than a prophecy.

Man may eventually be able to abandon sexual reproduction entirely. That startling and perhaps unwelcome possibility has been demonstrated by Dr. J.B. Gurdon of Britain's Oxford University. Taking an unfertilized egg cell from an African clawed frog. Gurdon destroyed its nucleus by ultraviolet radiation, replacing it with the nucleus of an intestinal cell from a tadpole of the same species. The egg, discovering that it had a full set of chromosomes, instead of the half set found in unfertilized eggs, responded by beginning to divide as if it had been normally fertilized. The result was a tadpole that was the genetic twin of the tadpole that provided the nucleus. Gurdon's experiment was also proof of what geneticists have long known: that all of the genetic information necessary to produce an organism is coded into the nucleus of every cell in that organism.

Man, say the scientists, could one day clone (from the Greek word for throng), or asexually reproduce himself, in the same way, creating thousands of virtually identical twins from a test tube full of cells carried through gestation by donor mothers or hatched in an artificial womb. Thus, the future could offer such phenomena as a police force cloned from the cells of J. Edgar Hoover, an invincible basketball team cloned from Lew Alcindor, or perhaps the colonization of the moon by astronauts cloned from a genetically sound specimen chosen by NASA officials. Using the same technique, a woman could

TIME, APRIL 19, 1971

The New Genetics.

even have a child cloned from one of her own cells. The child would inherit all its mother's characteristics including, of course, her sex.

Dramatic as cloning may be, it is overshadowed in significance by a technique that may well be practiced before the end of this century: genetic surgery, or correction of man's inherited imperfections at the level of the genes themselves. When molecular biologists learn to map the location of specific genes in human DNA strands, determine the genetic code of each and then create synthetic genes in the test tube, they will have the ability to perform genetic

HE CONCEPT IS

not as farfetched as it sounds. Real viruses are merely segments of DNA (or RNA) surrounded by largely-protein sheaths; they penetrate the cell nucleus (leaving their sheaths behind) and take over the cellular DNA.

The potential of the technique is already being tested by an international research team in the treatment of two children whose hereditary inability to produce the enzyme arginase had resulted in severe mental retardation. The team infected the youngsters with a natural virus, the Shope papilloma, which contains DNA that triggers arginase synthesis. Although the experiment is expected to produce no improvement in the children's men'al condition, it may belatedly trigger th production of the missing enzyme and prove that viruses can carry beneficial messages to the cells.

There is other evidence that the beginning of genetic sur ery is not far off. Dr. Sol Spiegelmat of Columbia University has synthesize 1 an artificial virus that is indistinguishable from its natural model and has used it to infect bacteria and produce new viruses. He and his colleagues have little doubt that they will also eventually create "friendly" viruses and use them to cure disease rather than cause it-by using the viruses to stimulate the production of the chemical products upon which health and life itself depend.

Prophylaxis is important, but man's molecular manipulations need hardly be confined to the prevention and cure of disease. His understanding of the mechanisms of life opens the door to genetic engineering and control of the very process of evolution. DNA can now be created in the laboratory. Soon,

TIME, APRIL 19, 1971

LAMB FETUS IN ARTIFICIAL WOMB man will be able to create man-and even superman.

Researchers have found that they can increase the life span of laboratory animals by underfeeding them and thus delaying maturation. This phenomenon. they believe, occurs because a smaller intake of food results in the formation of fewer cross linkages-connecting rods that link together and partly immobilize the long protein and nucleic acid molecules essential to life. If scientists can retard cross linking in man, they may well slow his aging process. Scientists also hope that they can some day do away with disease, genetically breeding out hereditary defects while breeding in new immunities to bacterial and other externally caused ailments. Finally, they look forward-in the distant future and with techniques far beyond any now conceived to altering the very nature of their species with novel sets of laboratory-created genetic instructions.

Current predictions about the appearance of re-engineered man seem singularly uninspired. Some scientists argue that man's head should be made larger to accommodate an increased number of brain cells. They do not, however, explain what man would do with this additional gray matter; there is good reason to believe that man does not use all that he presently possesses. A few others note that the efficiency of man's hands could be increased by an extra thumb and his peripheral vision enhanced by protruding eyes-improvements that seem unnecessary in the light of man's expanding technology.

DOME FAVOR LESS

obvious alterations. They have suggested that man be given the genes to produce a two-compartment stomach (a cow has four) that could digest cellulose; that mutation could be advantageous if man fails to increase his food supplies fast enough to feed the planet's growing population, but superfluous if he does. They also want man programmed to regenerate other organs. such as he now does with the liver, so that he can repair his damaged or

SEVEN-WEEK-OLD HUMAN FETUS Acquiring Promethean power.

diseased heart or lungs if necessary.

Others call for even more specialized humans to perform functions that in reality will probably be done better by machines. British Geneticist J.B.S. Haldane called for certain regressive mutations to enable man to survive in space, including legless astronauts who would take up less room in a space capsule and require less food and oxygen (larg er and more powerful spacecraft would seem to be an easier and less monstrous solution). Haldane also suggested apelike men to explore the moon. "A gibbon," he said only half-jokingly, "is better preadapted than a man for life in a low gravitational field."

Eventually, scientists fantasize, man will escape entirely from his inefficient, puny body, replacing most of his physical being with durable hardware. The futuristic cyborg, or combination man and machine, will consist of a stationary, computerlike human brain, served by machines to fill its limited physical needs and act upon its commands.

Such evolutionary developments could well herald the birth of a new, more efficient, and perhaps even superior species. But would it be man?

43

At present there are only three main ways of treating cancer, which will kill more than 335,000 in the U.S. alone this year. Doctors can cut tumors out with a knife, burn them out with radiation or kill them cell by cell with drugs. Though these treatments can be effective in combination, each has its drawbacks. Now, cancer researchers have turned to molecular biology, which shows promise of providing new and more effective means of dealing with the disease.

No one really knows what causes cancer, which is actually more than 100 distinct diseases, all sharing two common characteristics: rapid cell growth and a terrifying tendency to spread from one part of the body to another. Most researchers agree, however, that the vil

CANCER CELL OF CHICKEN

UCLEUS

VIRUSES EMERGING FROM CELL

CELL INFECTED BY TUMOR VIRUSES The defenses are down.

lain is a virus, a miniature packet of nucleic acid with a membranous coat that was shown as early as 1911 to cause tumors in animals.

Unable to reproduce themselves, viruses invade normal cells and use their hosts' chemical mechanisms to produce more viruses. Eventually, the infected cell ruptures. releasing the newly formed viruses to infect other cells. Dr. Howard Temin of the University of Wisconsin has shown that some tumor viruses behave differently. They reverse the normal order of genetic transmission, and with the aid of a recently discovered enzyme, use their RNA messenger molecules to produce DNA, the doublehelix master molecule. In a way not yet understood, this triggers the cellular genetic machinery to order cell division. causing the cancerous growth that is then perpetuated in succeeding cell

generations.

The new enzyme associated with Te

min's discovery was at first believed to be unique to cancer cells infected by viruses. Thus when Columbia University's Sol Spiegelman and the National Cancer Institute's Robert Gallo found high enzyme activity in the cells of leukemic patients, medical science had a solid clue that leukemia might be caused by a virus. Even more important, some researchers speculated that if the Temin enzyme was found only in cancer cells, the spread of cancer might be halted simply by inhibiting the enzyme.

Their hopes for an immediate cancer cure were short-lived. The NCI's George Todaro and other researchers have since found similar enzyme activity in normal cells as well. They have also found evidence of these enzymes in human and animal embryonic tissues, thus help

ing to confirm the views of many scientists who believe that cancer is probably an aberration of normal cellular growth.

If it is. Temin thinks he knows why it occurs. According to his hypothesis, normal cells manufacture RNA, which moves to neighboring cells in the form of a protovirus, or template. and stimulates the production of a new form of DNA. But, theorizes Temin, if this wandering RNA somehow transmits the wrong message after entering the cells, it can cause the production of altered DNA that orders the cells to grow abnormally.

Dr. Robert Huebner of the NCI speculates that cancer is caused by a noninfectious virus that is a normal part of every living thing. According to Huebner, the virus, which he has labeled the "C particle." is a part of everyone's genetic heritage, a tiny bit of RNA that is passed vertically from one generation to another and perhaps helps normal development by causing the cells of an embryo to grow. The C particle should become inactive as the fetus matures; if it fails to do so. the result is the rapid cell growth that characterizes

cancer.

MANY
MANY RESEARCHERS

believe that the best method of attacking cancer is to use the body's own genetic mechanism to order cancerous cells to stop growing. Transmitting such orders may be difficult. DNA programmed to carry the command would be digested almost immediately by the body's enzymes if it were injected into the bloodstream. thus making conventional

methods of administering medication impractical. But RNA viruses, which produce DNA, have proven their ability to move directly into the cells and could easily carry such communications. Scientists speculate that benign viruses could be made in test tubes with proteins and synthesized RNA. The viruses, injected into the body, would home in on the cancerous growth and shut down the cells' runaway reproductive mechanism.

AVENUES

VENUES OTHER THAN

virology are also being explored in the search for a cancer cure. Researchers have long been aware that animal cells growing in a culture medium will stop multiplying once they come in contact with one another. But in some recent experiments at Princeton, Biochemist Max Burger found that when he stripped normal mouse cells of their membranes, they continued to grow wildly-as do cancer cells even after they had touched. Burger thus speculates that the loss of a cell's protective coating, possibly as a result of viral infection, could lead to cancer by exposing a sensitive area that signals the cells to continue growth. If the protective covering could be restored, he suggests, it might be possible to stop the genes of cancer cells from ordering further growth.

It may even be possible to use the body's immunological mechanism, which now helps to protect it against other diseases, to combat cancer. Some researchers note that organ transplant recipients, who take large doses of drugs to suppress their immune reactions and prevent the rejection of foreign tissue, may develop cancer. Also, the immune system often fails to respond to many cancer cells, although they have unique antigens that should alert the body to their presence. Accordingly, doctors have begun exploring ways of beefing up the body's defenses and immunizing man against cancer in the same way that he can now be vaccinated against polio and other viral diseases.

In a unique series of experiments. Dr. Loren Humphrey of Atlanta's Emory University inoculated patients with a vaccine made, at least in part, with tissues taken from tumors similar to their own. He then followed up the inoculations by cross-injecting the patients with white blood cells from fellow patients who had presumably been sensitized to the tumor antigens. Though only long-term testing will tell if Humphrey's approach is effective, the preliminary results appear promising. One patient with bowel cancer has been free of the disease for three years, while three others have evidenced definite remISSIONS.

44.

TIME, APRIL 19, 1971