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  From Finding a Gene to Developing a Cure: An Uncertain Journey

By Camille Mojica Rey, PhD

Reviewed by Amanda Ewart Toland, PhD
Last updatedJanuary 22, 2001

This article originally appeared as a Genetic Health Special Feature — a regular aspect of Genetic Health's members service. Members have access to our full range of special features as well as news stories with commentary that help put daily news in perspective. For regular access to these additional articles, register for a free MyGeneticHealth membership.

The headlines are becoming increasingly familiar: "Scientists discover gene that causes (fill-in-the-blank)." From the Fat Gene to the Bald Gene to the Diabetes Gene, these regular announcements raise hopes of a quick cure for inherited diseases or conditions. But the reality is that the road from finding a gene to curing the disease is a long and uncertain one. An eventual cure also involves the help of thousands of people willing to participate in the clinical trials that help researchers both understand the disease and devise treatments.


The Pace of Gene Discovery

The human genome contains roughly three billion base pairs and 50,000 genes.
In June 2000, scientists announced that they had sequenced the entire human genome. They estimate that this three billion-letter-long sequence contains anywhere roughly 50,000 genes. Each of these genes holds the code for a protein and, together, these proteins make up a functioning human being.

To date, scientists understand the function of only about ten percent of the genes within our genome. They are actively searching through the remaining 90 percent for genes that, when defective, cause disease. It's these newly discovered 'disease genes' that make the headlines. But in order to turn those headlines into a widely available treatment or cure, scientists must:

  • Determine the function of the protein for which the gene codes
  • Identify candidate drugs or gene therapy treatments
  • Test potential therapies in animals
  • Conduct clinical trials in animals and humans to determine effectiveness and safety

Under the best of scientific scenarios, this lengthy process often takes more than a decade, sometimes involving thousands of study participants and teams of researchers working around the globe. The eventual goal is a treatment or prevention for the disease that targets the protein-gone-awry. This could mean a chemical that can interact with the altered protein and block its action; an inserted gene that can produce a working copy of the protein in question; or if nothing else, a genetic test so doctors can both identify people who carry mutations and begin preventive treatment. In some cases, these new therapies will treat the disease when it develops; in other cases, doctors may be able to prevent the disease from occurring in the first place.



Identifying Protein Function

Knowing that a given gene, when mutated, can cause a disease doesn't help researchers unless they understand the normal function of the protein for which the gene encodes. This part of the process is significantly easier if the gene happens to code for a protein that's similar to other well-studied proteins, said Dr. Richard Jude Samulski, Ph.D., a gene therapy researcher at University of North Carolina in Chapel Hill. In these cases, researchers have a starting point for better understanding the protein.

"If it is an unknown gene, then someone has to go through the arduous process of knocking the gene out of a mouse model," Samulski said. A "knock-out" mouse lacks the gene being studied. Scientists can use these mice to work backwards from what happens when the gene is missing to what it might do when it's present. Although these studies often do reveal a protein's function, other proteins remain mysterious despite years of probing by scientists. The BRCA1 and BRCA2 genes that are involved in breast cancer, for example, bear little resemblance to other proteins. The two genes still have researchers somewhat baffled despite the many research hours and dollars that have been devoted to understanding their function. Because researchers don't understand precisely what these genes do, they can't devise therapies based on BRCA1 or BRCA2.

Working out a protein's function can take even longer in complex diseases such as diabetes, where mutations in several different genes can add up to a risk for disease. In those cases, the scientists have to understand the complex interactions between the genes — and how those gene interactions relate to lifestyle factors such as weight, diet, exercise, and smoking — before moving forward. These experiments alone can last decades, and involve the participation of hundreds or thousands of individuals and families with the disease. If the disease is sufficiently complex, a gene-based therapy may eventually be ruled out as a possibility.

Even when researchers understand the protein defect that causes the disease – as in sickle cell disease – sometimes they are not able to find a treatment. This may be because they are unable to find a drug that fixes the altered protein. In other cases, they may find a way to fix the protein in the lab, but they can't deliver that treatment to the right place in the human body.



Designer Drugs and Gene Therapies

Only when researchers understand how a given gene can cause a disease does that gene become a target for therapies.
Only when researchers feel that they fully understand how a given gene can cause a disease does that gene become a target for therapies. But finding these therapies is a field of research that's in its early stages. "We're still trying to understand the terrain that we're working in," Samulski said. Because gene-based medicine is so young, the process is still being explored. Samulski and his colleagues are trying one approach – they're developing a technique in which they introduce new genes into muscle cells. These cells then produce enzymes normally made by the liver, thereby replacing lost liver function. This approach could be used in people with mutations in liver genes, or in people who have lost liver function for other reasons.

Other scientists are working on ways of repairing the mutated DNA itself. Within a year, the first gene repair in a human will attempt to cure a case of Criglr-Najjar, a rare and fatal liver disease, by correcting a single mutation within liver cells. These are just two of many gene-based approaches that are underway.



Animal Models

Any potential treatment must go through animal testing before it's tested in humans. "It's much easier if you have an animal model that mimics what the patient is experiencing,' Samulski explained. Without an animal model, the search for a gene-based cure may stop in the laboratory. This phase of testing determines both whether the treatment has merit and whether it has any obvious side effects. This phase is particularly crucial in gene-based therapies because the techniques are so new. Researchers don't know what side effects to expect. They are also still experimenting with techniques to deliver new genes into animal cells. Unfortunately, for some genetic diseases the animal model does not mimic what takes place in a human with the disease. In these cases, animal models are not able to help in developing a gene-based therapy.

However, even with a well-understood protein and a good animal model, companies may still balk at developing a treatment for the disease. This is because some genetic diseases are quite rare, and the cost of developing a drug and testing it in humans is extremely expensive. For some diseases, it may not be cost effective for a drug company to develop a treatment or prevention for the disease because their market for the drug will be so small it won't cover the cost of development.


Clinical Trials

The most time-consuming effort in the post gene discovery process is making sure therapies are safe and effective for humans. These trials are carefully monitored by the Food and Drug Administration. "It's the regulatory process that's setting the pace," said Alan Engbring, a spokesman for Vical Inc., a San Diego, California-based gene therapy company. Engbring's company is currently conducting human clinical trials for gene therapies for skin and prostate cancer, as well as other cancers.

New drugs or treatments must go through three rounds of carefully monitored trials before they can be released to the public.
New drugs or treatments must go through three rounds of carefully monitored trials in human participants before they can be released to the public. This series of clinical trials usually take about 10 years, and that's under the best of conditions. "Things are often different in humans than in mice," Engbring said. "We try to hone in on what's going to work best for people."

The Future

With these barriers to overcome, it's no wonder that after the first big headline new genes go unheard of for so long. Even scientists whose careers center on curing a disease respond to news of a gene discovery with caution. The recent discovery of a gene that predicts susceptibility to type 2 diabetes, for example, resulted in a mixture of hope and concern among diabetes experts.

The hope is that the gene, Calpain-10, will allow scientists to identify treatment strategies to cure the molecular defect at the root of the disease, said Dr. Giuseppina Imperatore of the Centers for Disease Control in Atlanta, Georgia. The new gene may be used in the future as a marker to identify populations at risk and allow implementation of preventive strategies — including diet and exercise — to reduce their risk, Imperatore said.

"Genetic testing raises concerns of possible stigmatization, discrimination, breaches of privacy and confidentiality, and loss of insurance coverage and employment"

— Dr. Guiseppina Imperatore

However, Imperatore added, the cost of these benefits may be a high one for both individuals and society. "Genetic testing raises concerns of possible stigmatization, discrimination, breaches of privacy and confidentiality, and loss of insurance coverage and employment," she said. The fear is that if a person is known to have a disease — or even be at a greater risk of disease — employers and insurance companies may not want to become legally bound to pay for the long-term care of that person. These ethical issues need to be resolved before the health care industry begins widespread testing of individuals for genetic mutations linked to any disease."

Historian Terry Sharrer said he believes ethical issues will not hinder long-term progress of genetically-based cures and treatments. "My guess is that the legal, ethical and moral questions will be of no consequence," said Sharrer who is the Curator of Health Science at the American History Museum in Washington, D.C. Rather, it's the regulatory process that may hinder this growing medical revolution. "The real issue is how long applications will sit on the FDA's shelf," he said.


References (Personal Communication)

Alan Engbring, Spokesman, Vical Inc., San Diego, CA

Dr. Giuseppina Imperatore, MD, Ph.D., Medical Epidemiologist, Division of Diabetes Translation, Centers for Disease Control, Atlanta, Georgia.

Dr. Richard J. Samulski, Ph.D., Director of The Gene Therapy Center and Professor, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina.

Dr. Terry Sharrer, Ph.D., Curator of Health Science, Smithsonian Institution, American History Museum, Washington, D.C.


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