This week’s issue features excerpts from the “Genetic Variation” chapter of The Biotech Primer, our 200-page book that provides an in-depth look at the biotech industry and the science that drives it. In this chapter, we explain the different types and causes of genetic mutations and then explore their relationship to disease and therapeutics. Today, we begin with a discussion of genetic disease and end with a promising drug target (53).

Just as Superman is drained of strength by kryptonite, the Guardian of the Genome (53) loses its capacity to fight disease when it is rendered powerless by mutations. Just like Peter Quill (Star-Lord from Guardian of the Galaxy), the Guardian of the Genome does not always get it right either. Mutations and disease: the spice of life.


Mutations play a large part in disease. In a monogenic disease, changes in one gene cause the disease. Examples of monogenic diseases include sickle cell anemia, cystic fibrosis, and Huntington’s disease. In contrast, polygenic diseases are caused by the interactions of many different genes. Polygenic diseases are more common than monogenic diseases and include cancer, heart disease, Alzheimer’s disease, and Parkinson’s disease.

Polygenic diseases often have susceptibility genes associated with them, which increase the likelihood of the person developing the disease, but do not absolutely predict its development. The ultimate disease outcome will depend on other genes in the individual’s genome, as well as environmental factors. An example of susceptibility genes are the association of breast cancer with the BRCA 1 and BRCA 2 genes.


Cancer is described as uncontrolled cell growth. Healthy cells have tight controls on cell division and only divide in response to outside signals promoting cellular growth and division. Non-cancerous cells also respond to signals that tell them to stop dividing. for example, most exhibit contact inhibition, meaning if they touch a neighboring cell, they stop dividing. Cancer cells have lost many of these controls or checks on cell division and start dividing and continue to divide inappropriately.


The p53 gene is the most frequently mutated gene in human cancer and the p53 protein it produces is often called the “guardian of the genome”. Its role is to make a decision whether to repair DNA or kill the cell in response to DNA damage. To perform this function, p53 has to bind to DNA in a very specific manner.

Below on to the left is the structure of p53 bound to DNA. Four domains of the protein bind to DNA in a cooperative manner. On the right is one of the domains bound to DNA where the DNA-binding surface of the p53 molecule fits into the grooves of the DNA helix. Most of the mutations that occur in human cancer—mutation “hotspots”—occur in the DNA binding domains, close to the DNA-binding surface. Changes to domains can be enough to disrupt binding of p53 to DNA and disrupt p53’s guardian duties. Research into how protein structure abnormalities cause cancer and other diseases is leading to the discovery of new drugs, some of which are designed to target the aberrant protein structures.


Cystic fibrosis (CF) is an extreme exemplar of polygenic disease. There are over 1,000 genetic mutations that are known to cause CF. Vertex Pharmaceutical’s (Boston, MA) Kalydeco (approved in 2012) targets a mutation that impacts only 4% of all CF patients.


Any protein defective in more than 50% of cancers is a tantalizing drug target; however, targeting p53 has proven to be tricky. Using today’s technology, it is much easier to inhibit an overactive protein than to activate a defective protein. One possibility for patients with mutated p53 gene sequences is gene therapy—delivering a correct copy of the gene. Gendicine (Shenzhen SiBiono GeneTech) is one such therapy approved by the Chinese State Food and Drug Administration in 2003. The FDA rejected a biologics licensing application for a similar therapy in 2008.

Although many p53-associated cancers are caused by mutations to the p53 gene itself, about half are the result of p53 inactivation caused by the tight binding of a second protein, MDM2, to p53. Drugs that inhibit or prevent this MDM2-p53 interaction could potentially result in restoring full activity to p53, enabling it to carry out its cell-protecting mission. Amgen, Roche, and Sanofi are among the companies pursuing MDM2 inhibition therapies.

Share This