TOM FENNELL July 15 1991



TOM FENNELL July 15 1991




The irrepressible joy of childhood all but masks the disease that is threatening six-year-old Ashley Dyer. The happy, outgoing girl, who lives with her parents and infant brother in a village just south of Barrie, Ont., was born with cystic fibrosis (CF), a hereditary respiratory disorder that usually kills its victims before they reach their 30s. But because geneticists are making remarkable advances in their understanding of how genes, the elemental building blocks of life, function, Ashley Dyer may escape an early death. She has reason to be optimistic. In August, 1989, scientists at Toronto’s Hospital for Sick Children pinpointed the gene that causes CF and they are racing to discover how to correct it. Ashley, whose luminous brown eyes brim with determination, says that she is confident that the geneticists will succeed. Said Ashley: “After they found the gene, I really knew that they could find a cure.”

Around the world, scientists are poised at the forefront of a scientific revolution that is rapidly decoding the secrets of life contained in the body’s genes, the molecular strands that hold the recipe of life and dictate everything from a person’s shoe size to many of the diseases to which he or she may fall victim. Geneticists are working on projects that they say could dramatically expand the human lifespan by eventually curing many of the approximately 4,000 genetic diseases that afflict mankind. Some critics question possible gene therapies that literally could be applied at the beginning of life. But the scientific establishment is encouraging the remarkable voyage of discovery. Last month, Marla Sokolowski, a genetics professor at Toronto’s York Universi-

ty, received an $845,000 grant to conduct research that may lead to cures for psychological disorders such as manic-depression.

Attacks: And on June 20, geneticists working in Quebec City, Vancouver and other cities reported in The New England Journal of Medicine that they had isolated a gene mutation that elevates fat levels in the blood and can cause heart attacks in French-Canadians. Said Dr. Michael Hayden, director of the Adult Genetics Clinic at the University of British Columbia: “We are looking at a totally new form of medicine. The hope is that we can use genes to predict the risk of a disease, then modify something to prevent it.”

Such a breakthrough would be a godsend for

thousands of victims of genetic diseases like Ashley Dyer’s. Stephen Dyer, 31, a structural assembler for Boeing of Canada Ltd. in Toronto, and his wife, Caroline, 30, who works in the patient bookings department at the Hospital for Sick Children, say that the disease consumes their family life. Despite the fact that Ashley is spending much of the summer playing happily in a small swimming pool at her parents’ home in Bell Ewart, Ont., she still must take as many as 26 enzyme capsules a day to help her digest food. The girl also has to undergo daily physiotherapy sessions to dislodge mucus from her lungs. And she must inhale a potent mix of chemicals twice a day to open airways in her lungs. But the girl’s par-

ents say that they are confident that there will be a medical breakthrough to help their daughter. Said Caroline Dyer: “With a disease like Ashley’s, optimism is everything.”

Like the Dyers, many geneticists are optimistic that genetic medicine will revolutionize health care. And under a massive international program called the Human Genome Project, geneticists plan during the next 15 years to identify almost all of the approximately 50,000 to 100,000 genes in the human body. Their findings, along with those from dozens of other major research programs, will be widely applied in society. Industries may be able to genetically screen employees to determine whether specific workplace chemicals will trigger cancer in their bodies. Doctors may be able to determine which individuals are prone to skin cancer and to protect them from illness by, as they commonly put it, “turning on” the genes that produce anti-cancer chemicals in their bodies. In Ashley Dyer’s case, doctors say that they may be able to arrest her disease by transplanting healthy genes directly into her lungs, where cystic fibrosis strikes.

Cancer: One of the pioneering events in gene therapy began on Sept. 14, 1990, with a revolutionary operation at the National Institutes of Health in Bethesda, Md., when a medical team that included a leading U.S. cancer surgeon, Steven Rosenberg, transplanted new genes directly into the body of a dark-haired four-year-old girl. The child, whose name has not been made public, suffers from adenosine deaminase deficiency, a rare genetic disease that prevents the body’s immune system from functioning properly. The same disease killed a 12-year-old boy in 1984 who had become famous as the “Bubble Boy” after he spent most of his life in a sterile plastic shelter. Following the operations in Bethesda, doctors said that for the first time in her life, the girl was producing normal numbers of white blood cells. But scientists said that it would be a year before they could determine whether the new genes had cured the child’s disease. Said geneticist Dr. Michael Blaese, a member of the Bethesda gene-transfer team: “I predict that in the next decade, we will see

human gene therapy used against diseases such as cancer.”

Decoding the riddles contained in human genes also is producing remarkable medical technology that increasingly will be used to analyse the human body for a host of genetic

diseases. Some geneticists _

say that in the future, genetic testing, in which molecular probes are used to determine whether a specific gene could trigger a disease in the future, will be used to produce a detailed genetic blueprint of the human fetus and the physical life that lies before it.

Said Hayden: “We are going to be able to predict who is likely to develop certain cancers and screen those individuals so that we detect them early and do appropriate procedures to make sime that this cancer never occurs or is unlikely to occur.” Already, the use of genetic screening and testing technology is rising dramatically in Canada (page 36).

At the same time, genetic technology is turning the human body into a storehouse of

powerful new genetically en-

gineered drugs. Using a technology known as protein engineering, scientists can now alter the behavior of genes or create new genetic products (page 38). Doctors are already exploring the use of genetically designed drugs to treat breast and ovarian cancer.

But each advance in understanding how genes work raises disturbing ethical questions. Robert Haynes, a geneticist at York Universi-

ty, says that some nations, including Iraq, may have already attempted to devise weapons containing genetically engineered bacteria that would be immune to battlefield vaccines. And some critics say that geneticists may some day be able to alter fetal cells to produce highly

_ intelligent, physically perfect

children for a price—while fetuses with the slightest imperfection will be routinely aborted. Geneticists are already concerned about whether or not society will allow imperfect fetuses to grow. Asked Ronald Worton, geneticist-in-chief at the Hospital For Sick Children, who in 1987 helped discover the genetic causes of Duchenne muscular dystrophy: “Should we abort a fetus if the disease is characterized only by wideset eyes, mild retardation or extra toes?”

Screening: The question is not an academic one in the g field of gene research. Macis lean’s has learned that scien^ tists at University Hospital in g London, Ont., plan to conduct jg experiments in screening hus man pre-embryos that will s dramatically transcend the traditional bounds of human development. Dr. Jeffrey Nisker, a reproductive endocrinologist, said that his research team received permission in late June from the University of Western Ontario’s human ethics review board to remove cells from four-day-old pre-embryos that have been fertilized in the laboratory and are suspected of carrying genes that cause mental retardation. Although the procedure

_ has been carried out on mice,

forefront Nisker said that his team

would be the first in Canada—and only the second in the world—to perform it on humans.

The pre-embryo program was launched only after an extensive analysis by the human ethics review board, which found the experiments to be within guidelines for genetic research. A number of parents whose children would likely be bom severely retarded have been asked to participate. The prospective parents would have their sperm and eggs joined in the laboratory. The resulting pre-embryo, the earliest ¿o form the human being takes in its development, would be 3 allowed to grow to the eight§ cell stage. Nisker said that at I that point, two of the cells z would be removed and tested i to see if they carried the


genes that cause mental retardation. Only the pre-embryos that did not carry the genes would be placed in the woman’s womb to develop. Said Nisker: “We would only be screening for severe retarded syndromes that would be incompatible with any quality of life. If the pregnancy went ahead, it would result in abortion or the death of a child.” Because the procedure would not attempt to alter the genetic structure of the pre-embryo, the ethics committee agreed to allow it.

Embryos: If successful, Nisker’s experiments would open the door to a stunning possibility: human beings at their earliest stage of development could be examined for potentially hundreds of genetic diseases, but only those pre-embryos that were healthy would be allowed to develop. Nisker said that he is interested only in removing damaged cells from the pre-embryos. But some critics say that at some point in the future, geneticists could intervene at the pre-embryo stage to try to change the genetic structure of human cells. Nisker said that he does not believe such procedures should be carried out, and that any attempt to do so should follow a thorough ethical review. Said Nisker: “I am the first to recognize that this technology could be used for unethical purposes. I believe strongly that it should be subject to a complete ethical review.”

Before the promise of the genetic age can be fully realized, scientists will have to fully decipher the genetic code. The code is embedded in a substance called deoxyribonucleic acid, the principal component in the nucleus of every human cell. As the genetic codes become understood, scientists say that by manipulating the four chemical substances that make up DNA, they will be able to cure many of the

genetic diseases that plague mankind. But determining what is wrong with a malfunctioning gene can be a slow and difficult process. Said UBC’s Hayden, who has spent seven years searching for the flawed gene that causes Huntington’s disease, a degenerative disorder of the nervous system: “Just imagine that I had two piles of 10 telephone directories and in one of those directories there is a spelling error. Our task is to identify that spelling error.”

Despite the painstaking work involved, scientists’ understanding of how genes function is expanding rapidly.

One of the most promising breakthroughs so far occurred in August, 1989, when a research team led by Lap-Chee Tsui, a Shanghaiborn geneticist at the Hospital for Sick Children, and Francis Collins, a medical geneticist at the University of Michigan in Ann Arbor, discovered the gene responsible for the disease afflicting Ashley Dyer.

Tsui’s laboratory on the 11th floor of the Hospital for Sick Children contains little to suggest that it was the site of a major medical discovery.

There are no powerful electron microscopes or other large pieces of sophisticated equipment. Instead, reams of computer paper detailing the chemical components of a gene and clues as to how it

operates clutter the office. Tsui said that after he and his colleagues made their discovery, excitement swept the staff as they waited for the results of their work to be published in the authoritative Science magazine. Said Tsui of the search for the cystic fibrosis gene: “We marched from one end of the gene to the other. In the end, it was like a jigsaw puzzle. Every piece of evidence was put in its right place. I cannot describe the excitement and the pleasure at that point.”

Searching: Tsui’s family fled Communist China for the British Crown colony of Hong Kong in 1953, when Tsui was 3. After being educated in Hong Kong, Tsui enrolled at the University of Pittsburgh in 1974 and received a PhD in biological sciences in 1979. He moved to Toronto in 1981 to join the CF research team at the Hospital for Sick Children, and now is searching for something even more spectacular than the CF gene: a new treatment for the disease itself. Tsui said that it appears that the defective gene produces a protein that does not allow the movement of chloride ions through the cell walls of the lungs. As a result, malfunctioning lung tissues cause the respiratory system to falter. Mucus builds up in the lungs of a CF victim, eventually causing severe lung damage.

In the search for a way of more effectively treating CF and saving the lives of victims like Ashley Dyer, Tsui said that researchers at the Hospital for Sick Children and Toronto’s Mount Sinai Hospital are trying to breed genetically altered mice containing the defective cystic fibrosis gene. Tsui said that experimental cures will be tested on the mice in an attempt to trigger a correct response in the gene. Eventually, his research might make it possible for doctors to transplant new genes into the lung cells of CF victims, thereby overriding the defective cells and causing the lungs to function properly. Said Tsui: “Gene therapy is a very simple idea. A healthy copy of genes will hopefully cure the problem.” In another pioneering development, surgeon Rosenberg (who treated president Ronald Reagan’s colon cancer in 1985) took the first step in using gene-transplant therapy to fight cancer on Jan. 29, 1991. He did this by altering cloned genes to enhance their cancer-fighting agents, and injected them into patients suffering from malignant melanoma, an often fatal form of skin cancer.

Rosenberg said at a medical conference in Houston in May that the early test results

were encouraging. Cancer completely disappeared in one out of 10 patients and was dramatically reduced in another 15 per cent. Rosenberg said that he now plans to inject the gene directly into tumors, a process that has already proved successful in animal experiments. He said that if tests on human volunteers are successful, an anti-cancer vaccine could eventually serve as a powerful new weapon in the fight against some cancers. Added Rosenberg: “We are at the birth of a new era in treating cancer through gene modification.”

Elusive: Geneticists at UBC say that they hope that their research will lead to a breakthrough with Huntington’s disease, a fatal degenerative nerve disease that causes victims to progressively lose control over their bodies. So far, the gene responsible for Huntington’s has proved to be elusive. Hayden said that members of his research team have cloned at least three different genes in their search and currently are hunting for a clue that will give them a key to the mystery. Said Hayden: “Proving you have the Huntington’s gene is immensely time-consuming and tough.” Once the Huntington’s gene is located, Hayden said, it may be possible to treat the disease with gene therapy, which would also involve transplanting healthy genes into the victims.

Meanwhile, Canadian researchers have located a gene that they say may be responsible for some types of heart disease. The researchers at UBC and Laval University in Quebec City said that they had found the gene that causes a disease that affects fat levels in French-Canadians. Charles Scriver, a professor of genetics at Montreal’s McGill University, said that the genetic flaw, known as familial chylomicronemia, causes a deficiency of an enzyme that allows fat cells to rapidly collect in the blood, cutting off the supply of oxygen to the heart. Hayden, who led the UBC research team, said that now a genetic screening technique could be developed that will identify carriers.

In their search for the chylomicronemia gene, the teams at UBC and Laval were aided by the fact that it appears to trigger the disease only in certain population groups, including those French-Canadians who can trace their family roots almost all the way back to the first waves

of immigrants who settled in Quebec in the early 1700s. Scriver, who is investigating why certain defective genes are found only in some groups, said that Canada is ideally suited for this type of research because of the homogeneous nature of certain communities. “In Quebec, you can identify people at risk for chylomicronemia by screening,” said Scriver. “Or you can ask one question about their family history, and if they can trace their roots to northeastern Quebec, the person might be at risk.”

The causes of such debilitating mental illnesses as schizophrenia may also lie hidden in human DNA. York University’s Sokolowski said that she hopes to learn how genes influence behavior and, in the process, answer questions that have plagued psychiatry for decades: what

is normal behavior, and how is it produced? “There are certain behaviors that seem to have some kind of genetic component,” said Sokolowski. “I think for something like manicdepressive patients, there is potentially the possibility for transplanting normal genes into the brain.”

In Princeton, N.J., officials of DNX Inc., a biotechnology firm, announced last month that scientists working for the firm had injected two sets of human genes into pig embryos and that subsequently the adult pigs produced human hemoglobin, the element in human blood that carries oxygen. Ultimately, the company hopes to market artificially produced hemoglobin for human use following extensive trials that may begin as early as next year. If successful, the process could produce large quantities of bacteria-free blood substitute for hospitals and ease the threat of patients’ contracting AIDS through transfusions.

Recent genetic breakthroughs have given Caroline and Stephen Dyer hope that their daughter will live a full life. But at the same time, they have forced the couple to confront an agonizing decision. Should they have had their second child, seven-month-old Nicholas? Said Caroline Dyer: “My fetus was screened at 10 weeks and it did not have CF.” But she cannot help wondering if she would have chosen to have an abortion if the screening had shown that the unborn child had the diseased gene. “It’s a terrible disease,” she said, “and you just do not want to pass it along.” Clearly, as scientists uncover more secrets of heredity, medical miracles and anguished decisions will become a part of the lives of increasing numbers of Canadians.


i n cystic fibrosis, defective genes .eventually cause the victim’s respiratory system to fail. To prevent that, geneticists may be able to take a gene from a healthy person and clone, or copy, the gene (1). The new, healthy genes are then introduced into defective

virus particles (2). The virus is used to carry the healthy genes into a culture [ II

of human cells (3), and the resulting I /1

mixture could be surgically implanted in the patient’s respiratory tract (4). If successful, the implanted genes could ensure the normal functioning of the lungs.