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Why Missing Genes Could Save Lives

Why Missing Genes Could Save Lives

The Human Knockout Project: a new twist on the human genome.

The Human Genome Project (HGP) is an international scientific research project with the goal of determining the sequence of chemical base pairs which make up human DNA. The project was a massive undertaking, which spanned more than a decade and cost $3 billion dollars. It was an international effort, with more than 1,000 scientists forming collaborations and partnerships that might otherwise never have occurred. When the human genome sequence was completed in 2000, there were all kinds of lofty predictions about finding new innovative and effective treatments for many diseases.

However, fourteen years later, cancer, diabetes, cardiovascular disease, and Alzheimer’s are still very much a part of our lives. The importance of the Human Genome Project cannot be overstated, but the hopes for quick cures founded on it were false.

Let’s take a look at the impact of the Human Genome Project.

The traditional approach

Classically, doctors began with a disease and then examined a patient’s genome for mutations that cause their symptoms. This method helped scientists identify the CFTR gene which is mutated in cystic fibrosis patients in 1989. Despite this success, the approach doesn’t always work. A large scale study looking at 100 genetic predictors of heart disease followed 19,000 women for 12 years. At the end of the study, doctors concluded that family history is a better predictor of heart disease than DNA.

Hunting for missing genes: a new approach

A recent article in Science focuses on a new approach to using genomic data. Daniel MacArthur, a researcher at Harvard, is looking for healthy people who are missing certain genes without harmful effects. MacArthur’s previous work shows that most people have about 100 non-functional genes, and for about 20 of these both copies are missing, which creates a knock-out. Healthy knockouts can show scientists which genes may not be necessary, and in some cases, lacking these genes can actually improve health.

The knock out genes

The most famous of these knock out genes is PCSK9. PCSK9 codes for an enzyme which regulates bad cholesterol, known as low-density lipoprotein (LDL). Mutations in this gene lower LDL levels, which in turn lowers risk of heart disease. Pharmaceutical companies were quick to recognize the potential of this discovery, and developed drugs which target the PCSK9 enzyme. Clinical trials indicate that they are extremely effective at lowering cholesterol. There is another gene, SLC30A8, in which a polymorphism lowers the risk of developing type 2 diabetes by 65%. The zinc transporter encoded by this gene moves zinc into beta cells, where it affects the crystallization of insulin. The protective effect of this mutation has not been determined yet, but provides attractive candidates for drug development.

The Human Knockout project: pros and cons

The enormous project proposed by MacArthur and his colleagues has several drawbacks. First, the effect of missing genes may not be observed until someone is exposed to a chemical or pathogen. This makes it difficult to tie cause and effect together. Second, large amounts of genomic data will not be useful without extensive clinical data to link genes and phenotypes. This requires large databases and lots of time.

Despite the obstacles, the potential benefits of the human knockout project could change the course of medicine. Eventually.

Genomes Unzipped.
A Decade Later, Genetic Map Yields Few New Cures. Nicholas Wade.
Study pinpoints protective mutations for type 2 diabetes. Haley Bridger.
The Hunt for missing genes.

Rebekah Morrow

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