Ever since the race to complete the mapping of the human genome in the 1990s, biomedical scientists have promised that understanding genetic mutations would directly benefit human health, allowing for the discovery of new cures and the elimination of diseases with a well-understood genetic component.
To the chagrin of these scientists, mapping the human genome in most cases did not translate immediately to disease cures, leading many to conclude that researchers oversold the science and under-delivered on the translated health benefits of the costly Human Genome Project.
Contemporary researchers have realized that their traditional approach of linking mutations to the human diseases they cause may not have been the lowest-hanging fruit — it turns out that linking individual mutations to specific diseases in anything even approaching a one-to-one relationship is very difficult, and scientists have largely been unsuccessful in pinning diseases to just one or even a handful of specific mutations.
In response, many geneticists have shifted their focus — effectively turning the field on its head — instead searching for helpful mutations that prevent common diseases such as cancer, diabetes, heart disease, and Alzheimer’s disease from manifesting themselves in patients who otherwise would be highly susceptible to these ailments.
Unlike with harmful, disease-producing mutations, helpful mutations map directly to disease-protective effects much more easily, and the pipeline from discovery of a helpful mutation to translational medicine and novel disease treatment options is much, much, clearer.
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Patients who are impervious to a given disease state despite having many other risk factors are relatively rare, and comparing the genomes of these patients can reveal common mutations quickly. At this point, researchers can perform experiments to show that any mutations common among disease-resistant patients directly cause the patients to be resistant. Once such a causal relationship has been established, researchers can look for the “smoking gun” — the specific, molecular mechanism that causes patients with the mutation to resist the effects of a given disease. With the molecular mechanism in hand, researchers and pharmaceutical companies can then begin to translate the research into something of benefit to patients who lack the helpful mutation, such as by creating a drug that copies the mutation’s effects.
When a gene is mutated, it generally produces its product (usually a functional protein) differently than the non-mutated gene would. Some mutations amplify the amount of product a gene makes, while others reduce the amount. Still other types of mutations cause a defective product to be made, which can have new and unpredictable effects.
Fortunately, scientists can make drugs that recapitulate each of these effects. If a helpful mutation amplifies the amount of gene product, scientists can design a drug that amplifies the function of that product. If a helpful mutation reduces the amount of product, scientists can make drugs that inhibit its production. If a helpful mutation produces a defective product, scientists can try to figure out what the effects of the defective product are, and can try to emulate those effects with drugs. In each case, scientists have translated the discovery of a helpful mutation into a potential drug that could treat or prevent a given disease.
Although most helpful mutation research is still in the theoretical stages, and not at the translational stage, a few noteworthy treatments are further along in the therapeutic pipeline.
Perhaps the most famous example of the helpful mutation concept being put into practice has been the development of so-called “entry inhibitors,” a class of antiretroviral drugs that are used to treat infections with human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS).
Researchers discovered that some people infected with HIV never progress to full-blown AIDS, and called these individuals “elite controllers” or “long-term nonprogressors.” Among these elite controllers, scientists discovered a subset of patients who had a mutation in a protein present on the surface of cells that allows HIV to gain entry, a protein called CCL5. Patients who harbored this mutation, called delta-32, had cells that were difficult to infect with HIV. By understanding this mechanism, scientists developed drugs that bound to the normal CCR5 receptor and recapitulated the effects of the delta-32 mutation, thereby preventing HIV from gaining entry to cells that otherwise would easily be infected. All of this research culminated in the development of the CCR5-receptor antagonist maraviroc, which is now an FDA-approved HIV drug marketed by Pfizer under the trade name Selzentry.
Recently, a second helpful mutation-based class of drugs has gained approval. In this case, scientists discovered a rare mutation that caused people to have shockingly low levels of low-density lipoprotein (LDL) cholesterol, the so-called “bad” cholesterol. Further investigation allowed scientists to discover that, in people with this rare mutation, a protein made by the PCSK9 gene, which normally regulates cholesterol metabolism, malfunctions. The malfunctioning protein allows people who produce it to clear LDL cholesterol from their bodies very rapidly. Scientists took advantage of this knowledge to produce a new class of cholesterol drugs called PCSK9 inhibitors, which recapitulate the effects of the rare, helpful PCSK9 mutation. Two of these drugs have recently been approved by the FDA: alirocumab, under the trade name Praluent, and evolocumab, under the trade name Repatha, both received approval this year.
To find new treatments, scientists at the Icahn School of Medicine at Mount Sinai have begun a large-scale research effort called The Resilience Project. The Mount Sinai researchers are taking advantage of the rapidly falling cost of whole-genome sequencing, using this technique to sequence the genomes of many, many people at once. They recruit healthy individuals to donate their DNA and look for known, harmful mutations that should have killed these patients by their current age. The researchers hypothesize that these “resilient” people must also harbor helpful, protective mutations that allowed them to survive to adulthood. By comparing the genomes of resilient patients, the researchers can quickly zero in on the specific mutations that cause the resiliency, and these mutations can then be further investigated to identify the mechanism by which they create their protective effect.
Taken together, existing drugs based on helpful mutation research and new therapies yet to be pushed through the drug discovery pipeline show incredible promise in treating or preventing a number of disease states. Indeed, helpful mutation research is finally making good on the broken promises of the Human Genome Project geneticists.