Its a knockout !

Most of our genes code for proteins, the building blocks responsible for the smooth running of our body – but what if there’s an alteration in one of the genes? Such an alteration (a variant) could mean that a particular protein isn’t produced, or that it’s completely inactivated. For instance, a protein enzyme may become inactivated because a variant may alter its shape.

Often such variants are well tolerated: we inherit two copies of every gene, one from each parent, so if one copy is inactivated, the other may (at least partly) make up for it. However, when parents are related the chance of inheriting two inactivated copies is significantly increased. The resulting offspring may then lack the respective functioning protein. This person, in effect, is a natural ‘knockout’ for that particular gene – also known as a ‘loss of function’ variant.

Sometimes, having one or both copies of a gene knocked out has no effect – humans have a lot of protein redundancy; a separate protein may have the same or similar function to the inactivated one. In other cases, having a gene knocked out has the potential to offer an advantage or a disadvantage. The study of such inactivated genes is particularly interesting - this helps the development of medicines or treatments to block ‘bad’ genes and enhance ‘good’ ones.

In order to explore the function of a particular gene and study the effect of its loss, scientists historically used genetic engineering to create knockouts in laboratory animals such as mice. (Conversely, scientists can also create ‘knockins’ – where a gene is inserted into the genetic material of a laboratory animal in order to study its function). Once the function of a gene is known, researchers can work on developing drugs that either block (‘bad’ gene) or enhance (‘good’ gene) its function.

There are, however, disadvantages to such scientific techniques. Not only are they difficult, costly, and time-consuming, many people feel it’s unethical to use animals in laboratory research. On top of this, humans differ considerably from other animals, so a gene found to have a certain function in laboratory animals may not have the same function in humans.

Although techniques for creating human knockouts (and knockins) are being developed in human cells lines (i.e. human cells that are grown under specific conditions in the laboratory), this in itself has its own set of technical problems and ethical dilemmas, and extrapolating results from cells lines to individuals is also wrought with difficulties.

The above examples highlight the benefits of finding naturally occurring gene knockouts in humans; the function of a knocked out gene can be explored without having to create artificial animal knockouts. In turn, this can be used to develop new treatments. For example, scientists discovered a gene called PCSK9 among a group of French families with very high cholesterol levels – a ‘bad’ gene. Other researchers subsequently found that people with a defect in one copy of the gene had low cholesterol levels and rarely developed heart disease – suggesting that having decreased function of this gene is beneficial. One middle aged adult who was a PCSK9 knockout (two defective copies) was perfectly healthy. Importantly, this suggested that a drug that blocked PCSK9 (and thereby lowered cholesterol, and heart disease / stroke risk) would be safe in humans. As a result, drugs blocking PCSK9 have since been developed and will be available in the near future^[1],[2],[3].  Since then, further naturally occurring human knockouts with similar therapeutic potential have been discovered^{[4],[5],[6],[7]}.

Knockouts are rare; studying huge populations would be required to find them. However, as mentioned earlier, the chances of finding knockouts is increased when parents are related. This means researchers are particularly interested in studying certain communities where parents are more likely to be related to one another (such as some South Asian communities).

South Asian communities also suffer from higher levels of certain medical conditions – such as diabetes or heart disease – studying them may (alongside helping the broader population) result in new or better treatments that can directly benefit the community under study. This is particularly important as there is evidence that different ethnicities vary in their response to different drugs – many drug research (clinical) trials to date are not carried out across a broad enough spectrum of ethnicities^[8].  

Our own team has already carried out some studies on the British-Pakistani population (not yet published) and it’s hoped that East London Genes & Health will lead to much more research in the future, by scientists here and around the world. By taking part in our study, fit and healthy community members walking about today with knockout genes have the potential to be the lifesavers of tomorrow.