Animals in Scientific Research
Science of the Future - Personalized Medicine
Historically medicine has been practiced based on statistics. You did not want to be treated as an individual when ill, you wanted to be treated as a statistic because you were more likely to get well by being treated as a statistic.
If you suffered from an infection and research showed 98% of people with that infection responded to antibiotic X, then you would want antibiotic X not antibiotic Y or Q. It may turn out that you were among the very small minority that needed antibiotic Q in order to survive your infection, but more likely than not you needed X and since there was no way to determine beforehand if you were among the vast majority or minority, your best bet was to take antibiotic X.
Personalized medicine allows doctors to treat you like an individual, not a statistic. This increases the likelihood of success. (But without personalized medicine, statistics-based treatment is still preferable to anything else.)
Many drugs are very effective and safe in certain individuals but kill or seriously harm others. Even men do not react the same way to drugs as women. These deficiencies do not come to light in animal tests due to their lack of predictive value, and they are often not revealed in clinical trials because the trials are so abbreviated. (Pharmaceutical companies use the ineffective animal trials because they are much cheaper than performing adequate clinical trials for new drugs. This means drugs come to market sooner thus making more money for the company. For more on this see What Will We Do If We Don’t Experiment On Animals? by Greek and Greek.)
With personalized medicine your treatment for a disease might be different from your brothers, even if you are identical twins. Even identical twins may express genes differently hence require different treatments. A drug that is efficacious in one may not be in the other.
We know that people metabolize drugs differently—and thus have different pharmacological and toxicological responses to drugs—because of variations in their genes. As Guenther Heinrich, Ph.D., founder of Epidauros Biotechnologies AG, a company that applies the principles of pharmacogenetics to the drug development process, has concluded based on the analysis of human genes: “It was quite clear to me why drugs don’t always work: It’s because two unrelated people differ in some three million letters of the biochemical alphabet of the DNA.”
The advances described below are part of a field referred to pharmacogenetics and are a keystone of the future of Personalized Medicine. Pharmacogenetics identifies complex patterns of gene variation in larger populations and attempts to correlate these patterns to different drug response types. Personalized Medicine is tailoring therapies to individuals.
In June, MSNBC reported (Personalizing cancer care: Doctors seek to tailor treatments to individual patients, by Jacqueline Stenson) that cancer therapies may soon be tailored to the patient instead of the one size fits all as it is now done. “ ‘The Holy Grail for a lot of people in oncology is that we will individualize our treatment for every patient,’ says Dr. John T. Cole, head of oncology at the Ochsner Clinic Foundation in New Orleans.”
Currently patients are given standard doses and combinations of drugs to treat specific cancers. Unfortunately, most times the treatments are toxic and ineffective. In the future, the cancer patient will have his genotype taken prior to therapy and the treatment tailored to minimize risk and toxicity, and maximize the probability of success.
Certain genes are associated with toxic side effects while others are associated with successful treatment using specific drugs.“ ‘Based on my crystal ball, I think this is going to be very important,’ says Dr. David Johnson, president of the American Society of Clinical Oncology (ASCO) and director of oncology at Vanderbilt University in Nashville, Tenn.”
For example, scientists have found that:
Lung cancer patients with specific genetic mutations in their tumors were highly likely to respond to the new drug Iressa, while those without the mutations weren’t. The finding explains why the drug, which targets the cancer-fueling epidermal growth factor receptor (EGFR), only works in about 10 percent of these patients — just those with abnormal EGFR genes.
This means only certain patients, the ones that will benefit, will take Iressa. All others will not be exposed to the risk associated with the drug, as there is essentially no chance they would receive any benefit.
Other examples include:
Predicting which patients undergoing hematopoietic stem cell transplants for leukemia will experience liver damage from chemotherapy, based on how fast they metabolize an initial dose of the drug…In breast cancer patients, one study found that the expression of certain gene patterns in tumors could predict which women with early-stage disease would respond to tamoxifen given after their surgery to prevent disease recurrence. And in postmenopausal women with advanced disease, researchers reported that gene alterations could predict how well a patient would respond to the drug Femara.
A study of patients with advanced lung cancer found that those with a certain gene variation were twice as likely as those with a normal copy of the gene to suffer severe gastrointestinal side effects from their radiation treatments and chemotherapy.
Pharmacogenetics is the reason for these advances, and is light years away from dosing an animal with a chemical and hoping for the best, and then dosing a human based on what is perceived to be favorable animal data. Pharmacogenetics means instead of testing drugs on animal models, today we have the capacity to test human tissues, find gene signatures, use high throughput screening for efficacy and toxicity and then test humans with the appropriate genotype.
“ ‘It’s a field [pharmacogenetics] that has really taken off over the last few years,’ Cole says. He predicts that within the next five years, individualized cancer care will be routine for many patients. The technology to test patients’ genes is widely available, Johnson notes, but just how soon it will be applied to personalized cancer care depends on how fast the discoveries come and can be validated with additional research.”
Genetics research is clarifying why humans respond to drugs differently than other species and why we even respond differently among ourselves.
Today we know that mice and humans have the same genes that in mice result in a tail. Humans don’t grow a tail.
In 2001, ten medications were withdrawn from the market. Eight of the ten were withdrawn because of side effects that occurred primarily in women. Men tolerated the drug, but women did not. If men cannot predict what a drug will do in women, how can a species that grows a tail?
With scientists now discovering more each day about the genetic variations between individuals within the same species—humans—and how that influences drug response, what does that say for conducting preclinical testing of drugs on mice and monkeys, and expecting the results to extrapolate to humans? Clearly, not much.
The emerging discipline of pharmacogenetics holds the promise of reducing the incidence of adverse reactions, while optimizing dosing regimens. Armed with precise data based on an individual’s genetic profile, doctors will be able to administer the exact dosage a patient needs to gain maximum therapeutic effect. This will cut down on hospitalizations, as well as the number of visits to physicians’ offices. And most importantly, pharmacogenomics will provide more successful outcomes, thus eliminating the wasted effort and disappointing results caused by ineffective therapy.
Pharmacogenomics will also increase the number of therapeutic drugs available to consumers, as well as the speed with which they are brought to market, by enabling researchers to conduct smaller, more effective, and more cost-efficient clinical trials.
Given the fact that the clinical trial phase of drug development is the longest and costliest part of the process, the savings in time and money by compressing the clinical trial phase would mean that new drugs would reach patients sooner at lower costs. Experts believe that pharmacogenomics will change the way clinical trials are conducted, and that by 2007, fifty percent of all clinical trials will involve genotyping. Drugs will need to be tested only on individuals who have the appropriate genetic profile.
Most intriguing of all is the possibility of bringing back drugs that were recalled due to severe adverse effects in some patients.
For example, a drug that was recalled because it causes kidney failure in 30 percent of people could now be given safely and effectively to the remaining 70 percent of people identified by their genetic makeup not to be at risk for kidney failure.
Very soon, pharmacogenomics will make today’s one-size-fits-all approach to drug selection and dosing as outmoded as an 18th century apothecary’s cabinet, delivering a host of social and economic benefits as described by Alan Roses, head of genetics research at GlaxoSmithKline:
"Selection of predicted responders offers a more efficient and economic solution to a growing problem that is leading governments and healthcare providers to deny effective medicines to the few because a proportion of patients do not respond to treatment. The economy of predictable efficacy, limited adverse events, lower complications owing to targeted delivery and increased cost-effectiveness of medicines will improve healthcare delivery and eliminate the need for rationing."
Using animals to test new drugs is a failed paradigm and should be—and, in many cases is being—replaced by pharmacogenetics, in vitro and in silico analysis, and other emerging research methods. If these methods are advanced, the future looks promising.
If two sisters are diagnosed with the same type of breast cancer on the same day, because of one’s unique genetic profile, she may receive a very different chemotherapy regime from the other.
Even though they have far more genes in common than you and a genetically modified mouse or even a chimpanzee, one twin may have a gene that would cause a severe adverse reaction to one of the medications the other twin will receive, hence another will be substituted.
Or, one twin may receive a larger and more frequent dose of the same medication as the other twin receives, because the first twin is a rapid metabolizer of that drug. Or, both twins receive very different treatment regimes because, even though the cancer is of the same type, one twin may have genes that will allow it to progress more rapidly than the other and hence need more aggressive therapy.
This is not science fiction; these advances are taking place even as you read this, and many are already in clinical use.
As the knowledge of new technologies like pharmacogenetics becomes more widespread it will be harder and harder for the vested interest groups to justify animal experiments.
If the research needed to perfect personalized medicine is funded, Francis Collins predicts the future will look something like this:
By 2010
- Genetic testing will be available for 25 common conditions, such as colon cancer.
- Interventions will be available to decrease a person’s risk of most of these genetic diseases. For example, patients found to be at high risk for colon cancer will be encouraged to undergo regular colonoscopies beginning at age 25.
- Gene therapy will prove successful for several conditions.
- Most doctors will begin practicing genetic medicine.
- Pre-implantation genetic diagnosis will be widely available.
By 2020
- Gene-based designer drugs will be available for common conditions, such as diabetes and high blood pressure.
- Cancer therapy will be targeted to the molecular fingerprint of the tumor.
- Pharmacogenetic applications will be standard practice for the diagnosis and treatment of many diseases.
- Genetic diagnosis and treatment of mental illness will be available.
- Geneticists will learn how to perform germ-line gene therapy, which would introduce genes into a patient’s reproductive cells, without affecting other genes, and hence human germ-line therapy will be declared safe and ethical.
By 2030
- Genes involved in aging will be fully catalogued.
- Clinical trials will be underway to extend maximum human lifespan.
- Use of a full computer model of human cells will replace laboratory experiments.
- The complete genomic sequencing of an individual will be routine and cost less than $1,000
By 2040
- Complete genome-based health care will be the norm.
- Individualized preventive medicine will be available and largely effective.
- Illness will be detected earlier, before symptoms develop, by molecular surveillance.
- Gene therapy and gene-based drug therapy will be available for most diseases and the average lifespan will reach 90 years.
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Personalized Medicine | |
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