Science
A Gene Primer
It's as easy as ATCG.
Where is it all headed?
June 2000's announcement that the human genome had been mapped out well ahead of schedule merited the full lunar landing treatment. Nevertheless, at least one commentator reminded us that we haven't been back on the moon in more than 30 years, much less put it to practical use. An historic breakthrough yes, but we are talking in terms of decades before we start reaping the real benefits of our genomic knowledge.
According to Dr Francis Collins, head of the Human Genome Project of the NIH, writing in the New York Times that year, by the year 2010 genetic tests will help identify people at highest risk of particular diseases. By 2020, doctors will rely on individual genetic variations in prescribing drugs, and by 2030, clinical trials based on genomic information will be underway to extend the human lifespan. Thanks to our advanced knowledge, many experiments done on lab animals or humans can be completed on computers. By 2040, gene therapy and gene-based drugs will be available for most diseases, and the average life span will be 90 (the year this writer turns 91, to bring this down to a personal level).
One research scientist told this writer that Dr Collins may be painting an overly rosy picture in order to keep the funds flowing in. That may well be the case, but one should never discount the possibility of the unforeseen breakthrough, either.
Genes are responsible for making proteins, which are the working parts of human cells, serving a variety of purposes from acting as cellular ceiling joists to catalyzing chemical reactions. In the words of an article in the NY Times: "Understanding the role of every human protein - proteomics - will be one of the goals of the post-genome era."
But don't expect a Eureka! being cried out in some dark lab late at night over the discovery of a depression or bipolar gene. In all likelihood, mental illness stems not from a single gene, but from multiple genes acting with one another as well as reacting to environmental stressors.
Perhaps some of you recall the announcement made in 1987 by a group of scientists who were convinced they had found the bipolar gene. After an investigation of Amish families, they thought they had pinpointed the culprit near the tip of the short arm of chromosome 11, only to concede defeat two years later.
How naive we were.
Now, armed with the human genome, plus new technologies and insights, researchers are tracking how thousands of genes work together, as well as pinpointing suspect genes to specific chromosomal regions. Teasing out the mood genes remains a laborious process, but breakthrough findings are starting to come in from researchers who are looking for genes that switch on certain brain functions rather than elusive genes specifically identified with a disease type - everything from how too much dopamine may cause psychotic episodes to how a genetic malfunction sets off the fear response to how that same genetic malfunction makes certain people vulnerable to stress to how certain gene mutations may result in individual cells failing to properly convert food to energy.
According to an article in the New England Journal of Medicine: "We have recently entered a transition period in which specific genetic knowledge is becoming critical to the delivery of effective health care for everyone."
The authors are Alan Guttmacher MD and Francis Collins MD, PhD, deputy director and director respectively of National Human Genome Research Institute that mapped out a draft sequence of the human genome well ahead of schedule in 2000. Whereas genetics is the study of single genes, genomics, which only entered the lexicon about 20 years ago, investigates the functions and interactions of all the genes in the genome, including their causation on different illnesses.
Single-gene conditions such as cystic fibrosis, the authors explain, are the exception rather than the rule. More common are "multifactorial" disorders such as Parkinson's, tuberculosis, HIV, and Alzheimer's, the result of the interactions of multiple genes and environmental situations. We now know that the human genome comprises 25,000 genes, far fewer than originally thought, and mutations known to cause disease have been identified in about 1,000.
Genes are distributed over 23 pairs of chromosomes, and "express" or turn on or off the proteins that are responsible for everything from digesting food to transmitting nervous signals. This is accomplished through DNA spelled out in seemingly endless four-chemical sequences (A,T,C,G in various arrangements) segmented along three-chemical amino acid bases called "codons."
"A point mutation" involves the equivalent of a genetic typographical error, say a C where an A should be. Since 98.5 percent of genes do not code for proteins, most typos pass unnoticed. But then there are "functional mutations" that can range from causing Huntington's to inducing a bad reaction from eating fava beans. By the same token, mutations can also decrease the risk of disease, including one that makes certain people almost completely resistant to HIV type 1.
The illnesses that we have found genes for are highly "penetrant," ie their mutations lead to diseases in a fairly large number of people who have them. Breast cancer, diabetes, and Parkinson's are examples. Their "prevalence" across the general population, however, is slight, one in several hundred to one in several thousand. On the other side of the coin are genes less highly penetrant but much more prevalent, such as those that increase the risk of colorectal cancer and thrombosis.
Two unrelated people share more than 99.9 percent of their DNA sequences, but since three billion base pairs constitute the human genome, we vary at millions of bases. Researchers are looking to catalogue these variants, called "single-nucleotide polymorphisms" (SNPs) and correlate them with specific "phenotypes," or persons with certain clinical traits. An extension of this effort is to correlate "haplotypes," ie a group of variants that may be inherited together.
Once we can identify genetic causes and effects, we may be able to find treatments that work rather than half-work. As the authors conclude: "Genomics, which has quickly emerged as the central basic science of biomedical research, is poised to take center stage in clinical medicine as well." Here's hoping that psychiatry is part of that change.
Updated Feb 11, 2008
Articles on Genes
It's as easy as ATCG.
These days, we know better than to search for a depression gene or a bipolar gene.
New studies are changing the way we think about our illness.
A new science peels away another layer of the genetic onion.
Knowledge is Necessity
Copyright 2008 John McManamy Contact
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