Human Genome Research: 'The Consequences Will Be Enormous'
Human Genome Research: 'The Consequences Will Be Enormous'
In the not-too-distant future, drug therapy may be guided by a patient's genetic profile, and pharmacists may have a slew of drugs available to treat diseases that were once thought untreatable, according to Daren Knoell, PharmD, assistant professor of pharmacy practice and internal medicine in the colleges of pharmacy and medicine and public health at the Ohio State University. Knoell has lectured frequently on the topic of biotechnology.
This vision of the future comes courtesy of the U.S. Human Genome Project headquartered at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health. Scientists at NHGRI are within 3 years of completely sequencing the entire human genome and within months of completing a draft covering 90% of the genome. "The main reason we are doing this, is to try to understand and develop better diagnoses and, more importantly, better treatments for a whole list of human diseases," said NHGRI Director Francis S. Collins, MD, PhD, during a lecture in August 1999. "The consequences are going to be enormous."
Changes in Pharmacy
Those consequences will be felt by all health care providers, including pharmacists. "Will this change the practice of pharmacy? Absolutely -- for a variety of reasons," Knoell told Pharmacy Today. With genomics, it is very clear that we are going to make better decisions for our patients. We will be making more specific diagnoses, and genomics will change the way we use conventional drugs. It is also clear that it is going to open new paths for drug design."
Adenine, guanine, thymine, and cytosine are linked end-to-end to form a long DNA strand. Sequencing, in terms of genome research, means figuring out the order in which these nucleotides are arranged. A particular section of DNA, for instance, might have the sequence AATCGA. A complementary strand of DNA runs parallel to the first with adenine paired with thymine and cytosine paired with guanine. Approximately 20,000 to 30,000 nucleotides make up a typical human gene, and thousands of genes make up a chromosome. In total, there are about 3 billion nucleotides in the human genome, more than a billion of which have been sequenced. Remarkably, there is very little variation in the genetic sequence among individuals. "For two same-sex individuals, 99.9% of their DNA will be the same," Collins explained. In any two people, a single nucleotide difference occurs approximately one time in every 1,000 base pairs.
'Catalog of Human Variation'
The variations are called single nucleotide polymorphisms (SNPs), and ferreting out their location in the genome is a major goal of the NHGRI. SNPs are important because, as Collins explained, "they probably contain the reason why I might be at risk for cancer [and] you might be at risk for heart disease. Of course, they also account for the differences between us which are nonmedical." NHGRI hopes to create a great "catalog of human variation" that will correlate individual differences with particular SNPs. The catalog will list, for example, SNPs in the hair color gene that make some people redheads and others blondes or brunettes. There are approximately 10 to 30 million SNPs in humans. Each person is heterozygous at 3 million sites within their DNA.
Individuals vary in their ability to respond to and metabolize drugs, another effect of SNP variation. Several inherited differences in SNPs that are important in drug response are, in fact, already known. Patients with a variation in the gene coding for cytochrome P2D6, for instance, will experience little or no analgesic effect from codeine. Particular genes have also been found that correlate strongly with risks for certain diseases, such as breast cancer among young women.
Human genome research is expected to reveal hundreds more of these relationships. By comparing the SNP profiles of patients who do well on a given drug to those who do not, it will be possible to determine which SNPs account for variations in drug responsiveness. "It is not a great leap from this to want to [analyze the genotype of] that individual before you prescribe that drug," Collins said.
Pharmacogenomics
Gene-guided drug therapy is called pharmacogenomics, and it is being used to a limited extent in a handful of clinical trials. However, pharmacogenomics is expected to reach routine clinical practice in the next 5 to 10 years. Already, "DNA chips" the size of postage stamps are being developed that will use a blood test to predict if a patient is likely to do well on a given drug. The surface of the chip may contain all the possible SNP variations in the gene responsible for a given drug's metabolism. The patient's variant matches itself to its like variant on the chip. From this, the clinician will know if the patient's gene possesses the SNPs necessary for the patient to benefit from the drug. If not, another drug will be chosen.
"This technique will be directing our therapy," Knoell said, leading to safer, more effective drug use. "But it is also clear that pharmacists will have to be much better at understanding genetics and be able to help patients understand therapy." Genetics, he predicts, will be increasingly emphasized in pharmacy school curricula.
Functional Genomics
After the human genome is sequenced, comparative genetics is likely to emerge as a major field of study. The genetic profile of patients who have diseases such as diabetes will be compared with those who do not in order to locate disease-causing SNPs and map them to a particular gene. The next step is to design a drug that tweaks expression of a gene -- either turning it up or down -- for clinical benefit. If a particular gene is found to protect patients from disease, its protein product could be given therapeutically. This rational approach to drug design is called functional genomics.
"Functional genomics is a phenomenal revolution in the process used to find new drugs and find new targets," Ron Evens, senior director of professional services at biotechnology-giant Amgen told Pharmacy Today. "You identify the gene and determine its function, what proteins it makes. Then you find out what the protein does. It could be an enzyme, a colony stimulating factor, a number of things." Through this method, Amgen has found an enzyme that codes for cancer cell immortality. "So now we have a new target for therapy -- the enzyme." Evens said.
The efficient approach is a far cry from the sometimes-accidental way that drugs are discovered at present. Typically, thousands of compounds are tested to isolate those that have a desired effect, and, of these, perhaps only one will reach the market. Functional genomics is expected to bring hundreds of new products to the pharmacy. Already, Rockville, Md.-based Human Genome Sciences has discovered 40 new growth factors using this method, some of which are in clinical trials.
Of functional genomics Knoell said, "Basically, any disease will become a candidate. High blood pressure, atherosclerotic disease, pneumonia, you name it. Cancer." Millions of patients are expected to benefit. "It is certainly conceivable that new therapies derived from functional genomics will eventually become available in an oral dosage form. For the time being, most of the new therapies will be manufactured as complex macromolecules given in suspension by an injection."
Biotechnology Pipeline
Source: Pharmaceutical Research and Manufacturers of America.
In the not-too-distant future, drug therapy may be guided by a patient's genetic profile, and pharmacists may have a slew of drugs available to treat diseases that were once thought untreatable, according to Daren Knoell, PharmD, assistant professor of pharmacy practice and internal medicine in the colleges of pharmacy and medicine and public health at the Ohio State University. Knoell has lectured frequently on the topic of biotechnology.
This vision of the future comes courtesy of the U.S. Human Genome Project headquartered at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health. Scientists at NHGRI are within 3 years of completely sequencing the entire human genome and within months of completing a draft covering 90% of the genome. "The main reason we are doing this, is to try to understand and develop better diagnoses and, more importantly, better treatments for a whole list of human diseases," said NHGRI Director Francis S. Collins, MD, PhD, during a lecture in August 1999. "The consequences are going to be enormous."
Changes in Pharmacy
Those consequences will be felt by all health care providers, including pharmacists. "Will this change the practice of pharmacy? Absolutely -- for a variety of reasons," Knoell told Pharmacy Today. With genomics, it is very clear that we are going to make better decisions for our patients. We will be making more specific diagnoses, and genomics will change the way we use conventional drugs. It is also clear that it is going to open new paths for drug design."
Adenine, guanine, thymine, and cytosine are linked end-to-end to form a long DNA strand. Sequencing, in terms of genome research, means figuring out the order in which these nucleotides are arranged. A particular section of DNA, for instance, might have the sequence AATCGA. A complementary strand of DNA runs parallel to the first with adenine paired with thymine and cytosine paired with guanine. Approximately 20,000 to 30,000 nucleotides make up a typical human gene, and thousands of genes make up a chromosome. In total, there are about 3 billion nucleotides in the human genome, more than a billion of which have been sequenced. Remarkably, there is very little variation in the genetic sequence among individuals. "For two same-sex individuals, 99.9% of their DNA will be the same," Collins explained. In any two people, a single nucleotide difference occurs approximately one time in every 1,000 base pairs.
'Catalog of Human Variation'
The variations are called single nucleotide polymorphisms (SNPs), and ferreting out their location in the genome is a major goal of the NHGRI. SNPs are important because, as Collins explained, "they probably contain the reason why I might be at risk for cancer [and] you might be at risk for heart disease. Of course, they also account for the differences between us which are nonmedical." NHGRI hopes to create a great "catalog of human variation" that will correlate individual differences with particular SNPs. The catalog will list, for example, SNPs in the hair color gene that make some people redheads and others blondes or brunettes. There are approximately 10 to 30 million SNPs in humans. Each person is heterozygous at 3 million sites within their DNA.
Individuals vary in their ability to respond to and metabolize drugs, another effect of SNP variation. Several inherited differences in SNPs that are important in drug response are, in fact, already known. Patients with a variation in the gene coding for cytochrome P2D6, for instance, will experience little or no analgesic effect from codeine. Particular genes have also been found that correlate strongly with risks for certain diseases, such as breast cancer among young women.
Human genome research is expected to reveal hundreds more of these relationships. By comparing the SNP profiles of patients who do well on a given drug to those who do not, it will be possible to determine which SNPs account for variations in drug responsiveness. "It is not a great leap from this to want to [analyze the genotype of] that individual before you prescribe that drug," Collins said.
Pharmacogenomics
Gene-guided drug therapy is called pharmacogenomics, and it is being used to a limited extent in a handful of clinical trials. However, pharmacogenomics is expected to reach routine clinical practice in the next 5 to 10 years. Already, "DNA chips" the size of postage stamps are being developed that will use a blood test to predict if a patient is likely to do well on a given drug. The surface of the chip may contain all the possible SNP variations in the gene responsible for a given drug's metabolism. The patient's variant matches itself to its like variant on the chip. From this, the clinician will know if the patient's gene possesses the SNPs necessary for the patient to benefit from the drug. If not, another drug will be chosen.
"This technique will be directing our therapy," Knoell said, leading to safer, more effective drug use. "But it is also clear that pharmacists will have to be much better at understanding genetics and be able to help patients understand therapy." Genetics, he predicts, will be increasingly emphasized in pharmacy school curricula.
Functional Genomics
After the human genome is sequenced, comparative genetics is likely to emerge as a major field of study. The genetic profile of patients who have diseases such as diabetes will be compared with those who do not in order to locate disease-causing SNPs and map them to a particular gene. The next step is to design a drug that tweaks expression of a gene -- either turning it up or down -- for clinical benefit. If a particular gene is found to protect patients from disease, its protein product could be given therapeutically. This rational approach to drug design is called functional genomics.
"Functional genomics is a phenomenal revolution in the process used to find new drugs and find new targets," Ron Evens, senior director of professional services at biotechnology-giant Amgen told Pharmacy Today. "You identify the gene and determine its function, what proteins it makes. Then you find out what the protein does. It could be an enzyme, a colony stimulating factor, a number of things." Through this method, Amgen has found an enzyme that codes for cancer cell immortality. "So now we have a new target for therapy -- the enzyme." Evens said.
The efficient approach is a far cry from the sometimes-accidental way that drugs are discovered at present. Typically, thousands of compounds are tested to isolate those that have a desired effect, and, of these, perhaps only one will reach the market. Functional genomics is expected to bring hundreds of new products to the pharmacy. Already, Rockville, Md.-based Human Genome Sciences has discovered 40 new growth factors using this method, some of which are in clinical trials.
Of functional genomics Knoell said, "Basically, any disease will become a candidate. High blood pressure, atherosclerotic disease, pneumonia, you name it. Cancer." Millions of patients are expected to benefit. "It is certainly conceivable that new therapies derived from functional genomics will eventually become available in an oral dosage form. For the time being, most of the new therapies will be manufactured as complex macromolecules given in suspension by an injection."
Biotechnology Pipeline
| Therapeutic Catagory | No. of drugs in pipeline |
| Cancer and related conditions | 151 |
| Infectious diseases | 36 |
| HIV infection/AIDS-related disorders |
29 |
| Heart disease | 28 |
| Neurologic disorders | 26 |
| Other diseases | 22 |
| Respiratory diseases | 20 |
| Autoimmune disorders | 19 |
| Skin disorders | 14 |
| Transplantation | 14 |
| Diabetes and related disorders | 13 |
| Genetic disorders | 10 |
| Digestive disorders | 9 |
| Blood disorders | 8 |
| Growth disorders | 4 |
| Infertility | 4 |
| Eye conditions | 3 |
Source: Pharmaceutical Research and Manufacturers of America.
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