Known Unknowns

I was reading an article about the experience of someone who sequenced their DNA to find out the mutations in genes that increase her chances of getting cancer.  Right now they report a panel of 21 genes that have shown a direct association with incidence of various cancer (Breast, Ovarian, Prostate). A known mutation is these genes can predict with high level of confidence about the chances of getting a cancer in ones lifetime.  If there is a mutation in 11 of them, you have high risk of having cancer. Mutations in 3 others are classified a moderate risk and rest are called ‘newer genes’. There are some obvious names in the panel. Tumor Protein 53 (TP53) for example, is a well-studied tumor suppressor gene. When a cell get rogue by starting to proliferate uncontrollably (i.e. turn cancerous) this protein get alerted and decides whether that cell has to commit suicide (apoptosis) or stop dividing by enter into a stage of arrested development. But if there is a mutation in this protein, it will not be able to do this job properly, resulting is propagation of rogue tumor cells and full-blown cancer. Therefore, as expected, mutation in this gene can cause almost 100 % chance of getting tumor in females and 73% chance of getting tumor in men.

Now, the next question is what can we do about it. If there is mutation in some specific protein, for example, BRCA1 in females, it significantly increases the chances of getting breast or ovarian cancer in them. So one preventive measure is to remove ovaries or breast in women with this mutation. Such ‘prophylactic’ removal of high-risk organs can reduce the chance of cancer occurrence by 95%.  This is a good thing. But what about mutation in proteins like TP53, which are indicated in cancer in many organs such as breast, brain, ovaries, soft tissues and many more. We cannot remove all these tissues fearing death by cancer. One possibility is to watch out for tumor. Death due to cancer can be significantly reduced if cancer can be detected very early on in its development. An alternated scenario is to correct this mutation in selected high-risk tissues. I.e. if there is a change in one letter (nucleotide) in DNA sequence, just fix it, similar to the spelling check application in MS Word work. There are multiple problems here, first and foremost, how to edit the wrong sequence? There are some ‘genome editing’ technologies (TALEN, CRISPR, etc.) that area coming up to address this issue. Second question is can we edit it in all the cells in all the tissues? Probably no. So where should we correct it. One possibility is to remove the whole tissue from your body (E.g. bone marrow, in case of leukemia) and replace them with corrected marrow that is synthesized from your own precursor cells for marrow. There are other alternatives such as corrected stem cell therapy or synthetic lethality approaches and few more, but may be a topic for another more technical blog. These may sound like science fiction. But it is becoming a reality with modern biomedical research.

Another point mentioned in the article I mentioned is about mutation of ‘Unknown Significance’. These are mutations (because it varies from vast majority of other individuals) but no studies have shown its association with any diseases yet. So we medical science cannot say whether this mutation put you in any danger yet. But future studies may show some correlation; some times there may not be any health impact for them. That is where the current sequencing result analysis stands. Well this is the risk assessment for cancer only. There are some other mutations associated with other health conditions such as Parkinson’s, Alzheimer’s disease, various heart and immunological disorders.  But again the catalogue is not very long.  What does it mean, there is still a lot of unknowns the genome. We still do not know what different mutations means. Our technological capability to sequence the genome has far out competed our existing knowledge base to properly interpret the data coming out of that technology. The sequencing machine to a geneticist is equivalent to complete works of Shakespeare to a four year old. But the medical field is catching up. How long will it take to completely assess the risk of individual mutations and other alterations in the genome? A good 50 years is my guess.

Inspired by the article ‘Unknown Significance’ by Couzin-Frankel, J (2014, Science).