By Robert Hazen, George Mason University
Many scientists are focusing on the process of manipulating genes: taking segments of DNA and RNA, for medical and commercial purposes, and doing interesting things with them. Genetic engineering is the process of consciously altering a coded sequence of DNA or RNA. By far, the most urgent applications of genetic engineering are the cure of inherited genetic diseases.
Human Genetic Diseases
More than 3,000 inherited human genetic diseases are now recognized: we have cystic fibrosis, muscular dystrophy, sickle-cell anemia, juvenile arthritis, hemophilia, heredity forms of cancer, along with numerous other genetic ailments that are now understood at the molecular level. Each of these diseases arises from a different gene defect, and each of them has to be investigated independently, individually.
In some instances, it’s a single mistake in a gene’s nucleotide sequence that leads to a defective protein. That is, the protein has an amino acid that is wrong, and so the shape is wrong, the active site is shaped wrong; the protein can no longer fill its function.
Sickle-cell Anemia and Huntington’s Disease
The sufferers of sickle-cell anemia possess a defective gene for a vital blood protein, hemoglobin. There is one incorrect genetic letter out of 363—a T instead of an A—that results in a protein in which one amino acid is wrong. Valine incorrectly substitutes for glutamic acid in one critical position in that hemoglobin, so the hemoglobin is shaped wrong, and it doesn’t efficiently carry oxygen anymore. The change in shape alters the function.
In the case of Huntington’s disease, there’s a different problem. This gene defect is related to a variable number of CAG codons, which give long strings of the amino acid glutamine and the corresponding protein.
Everyone has these genes, and everyone has, in that gene, a sequence of CAGs, meaning that there is a whole series of glutamine in the amino acid sequence. In Huntington’s disease, we have too many of these. Individuals with healthy genes typically have from 11 to 34 repeats, while individuals that have 36 or more CAG repeats are likely to suffer this disease. Furthermore, a higher number of repeats, above 36, seems to correlate with earlier and earlier onset of the disease.
Diagnosing Genetic Defects
There is an extraordinary new technology that may result in routine and accurate diagnosis of all different kinds of genetic defects. It is a process that is now under commercial development.
We take a glass plate, or what is called a ‘chip’, and we etch away tiny squares—up to 60,000 tiny squares in the designs that are now being looked at. Each of these squares is no more than 1/250 of an inch square, so it is a glass plate with many, many little pits in it.
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DNA Analysis
A different, specific nucleotide sequence of about 10 base pairs is synthesized onto each square, using computerized techniques; these are much like the techniques that are used to process microchips in the computer industry. A single chip can contain thousands of variants of different DNA sequences, both normal sequences and abnormal sequences of a known gene; for example, one associated with breast cancer, or with cystic fibrosis, or some other disease. A patient’s genome, then, is amplified by PCR.
The segments that are targeted then bind to the appropriate square, the one that exactly matches our sequence. We can then, using another process, look for fluorescent highlights in this 60,000-chip square; the ones that correspond to our specific genome will light up, and so it is a very quick and reliable way of seeing which sequence we have, whether it is a good one or a bad one. Someday, as many of the variants of each gene are discovered, this type of DNA analysis is going to provide everyone with a very quick, in-depth genetic medical screening, perhaps even before birth.
Altering and Repairing Genes
Moreover, as we learn new ways of altering genes, the prospects for genetically engineered products—new foods, new drugs, maybe new pets, maybe even new kinds of people—seem almost unlimited. Many useful products are already coming from this research. We have microbes that produce large amounts of drugs. We have plants that now produce plastics. We have new breeds of animals that are used for research, animals that have very specific tendencies in terms of tumor development, or other sorts of behavioral traits. Like all new technologies, genetic engineering also poses problems, both in terms of public safety and in terms of the ethical questions involved in modifying life forms.
Our success in engineering life depends to a large degree on the type of organism we are trying to engineer. Single-celled bacteria and yeast can be engineered by attempting to modify large numbers of cells, and selecting those few cells that are successfully altered. Plants, similarly, can be engineered, because a single modified cell can often be used to grow an entirely new plant. But the cells of animals differentiate, and so it’s much, much more difficult to clone an entire animal from a single modified cell.
Ultimately, our greatest concern is going to be the repair of defective human genes. The challenge, though, is how and whether to fix those broken genes.
Common Questions about Handling Genetic Diseases and Defects
The sufferers of sickle-cell anemia possess a defective gene for a vital blood protein, hemoglobin. There is one incorrect genetic letter out of 363—a T instead of an A—that results in a protein in which one amino acid is wrong. Valine incorrectly substitutes for glutamic acid in one critical position in that hemoglobin, so the hemoglobin is shaped wrong, and it doesn’t efficiently carry oxygen anymore. The change in shape alters the function.
Many useful products have come out as we learn new ways of altering genes: we have microbes that produce large amounts of drugs; plants that now produce plastics; and new breeds of animals that are used for research, animals that have very specific tendencies in terms of tumor development or other sorts of behavioral traits.
Single-celled bacteria and yeast can be engineered by attempting to modify large numbers of cells and selecting those few cells that are successfully altered. Plants, similarly, can be engineered, because a single modified cell can often be used to grow an entirely new plant. But the cells of animals differentiate, and so it’s much more difficult to clone an entire animal from a single modified cell.
