What is Gain of Function?

What is Gain-of-Function (GoF)? It has been a trending topic in the recent years because of the covid-19 (SARS-CoV-2) virus. We will go through the definition of Gain-of-Function from the perspective of oncology (study of cancer) and virology (study of biological viruses).

Gain-of-Function in Oncology

Oncology is the study of cancer. And cancer is caused by changes to DNA within a cell. The changes are also called mutation. Since the DNA is packed into the individual genes of a cell, changes to DNA causes mutations in genes of a cell. Genes, as we know, are a fundamental heredity unit; they carry important instructions that define many characteristics of the body, like the color of eye, the color of hair or the height of a person. They also carry the instructions to make the right types of proteins.

The mutations of genes of a cell may disrupt the normal activity of the cell. For example, accelerate the growth and division of cells. This rapid growth and division lead to the accumulation of the same type of a cell. We called it uncontrolled growth. Mutations can make the DNA repair process erroneous. All these failures are signs of the development of cancerous cells.

Now, basics explained, we are ready to move ahead with our main topic "Gain-of-Function mutation". Gain-of-Function mutations are uncontrolled growth that causes rapid cell division and accumulation. Gain-of-Function mutations are the result from the mutation of proto-oncogenes. A proto-oncogene is a healthy gene that is responsible for making healthy proteins.

Pro-oncogenes store vital information pertaining to cell growth and division. They are also responsible for regulating functions of cells by inhibiting cell differentiation and stopping apoptosis (death of cell). When undesired mutations occur, pro-oncogenes are turned into oncogenes, which are cancerous. Oncogenes change the purpose of cells and produce the proteins that push abnormal cell growth. Such mutations are dominant and called Gain-of-Function mutation.

On the other side, tumor-suppressor genes are responsible for regulating uncontrolled proliferation of cells. They gate-keep and check the abnormal cell growth and induce apoptosis. Any mutations in tumor-suppressor genes may also result in oncogenes. Such mutations are termed as "Loss-of-Function" mutations.

Note: Mutations can have positive effects sometimes, but unlike sci-fi movies in the real world, they can be harmful and undesirable.

Gain-of-Function in Virology

In the context of virology, Gain-of-Function is the ability of a virus (an organism) to acquire or obtain, or gain new functions (or new characteristics).

Mutations are common things happening in all organisms, including humans. However, disease-causing mutations are uncommon in organisms. Mutations can be self-harming, like cancer in the human body or it can enhance the functionality of the organism. For example, bacteria evolve to be resistant to antibiotics due to genetic mutation; this happens naturally.

It is also true that mutations, alteration in the DNA of genes, can be accomplished with human endeavors. This artificial method of enhancing the biological functions of an organism is an active, new area in medical research, and we call it "Gain-of-Function Research".

It involves enhancing the functionality of the genetic system to ameliorate the survival skills of viruses and pathogens, this include pathogenesis (development, progression, and maintenance of disease) , transmissibility (transmission of viruses from infected host to other groups), or host specificity (ability of pathogens to infect certain host range).

A common question that arises in the minds of readers is why we want to make viruses and other pathogens more deadly. Wouldn't editing the genome of the viruses to make them more stronger, transmissive, and hostile is self-destructive to human society? Yes, it is, but there are some advantages too. Below we list advantages and disadvantages of Gain-of-Function research:

Advantages

• Helps to identify certain parts of the genome, which is infectious
• Broaden our understanding and knowledge of viruses and other pathogens
• Research helps to reveal targets and helps scientists to predict the possibility of the development of future viruses.
• By the identification of infectious parts, scientists can develop new and better vaccines and therapeutics.
• We can prevent or be prepared for future pandemics.

Disadvantages

• Biosafety and biosecurity is a topic of concerns
• Leakage of artificially modified viruses can cause widespread infection, killing innocent masses
• The consequences of the failure or lack of regulations are far more adverse.
• Technology may be breached and go into the hand of terrorists (bioterrorism)
• Governments can develop advanced bioweapons and threaten one another, much like what they are doing with nuclear weapons. 

Gain-of-Function research has been viewed with good intentions by many scientists to improve our understanding of viruses. But it has some critical downfalls too and as many critics believe cons outweigh pros. As of this day, this research is debatable and has not been received unanimously by various organizations and institutions across the globe. 

The US and Europe regulators have made efforts to address this issue. But to this day, it remains an experimental research.

The SARS-CoV-2 virus or (covid-19) virus was believed by many as an artificial modified virus developed by The Wuhan Institute of Virology, China. The statement remains speculative and no assertive conclusions are drawn.

One of the notable experiments in Gain-of-Function research is "Influenza A virus". H5N1 avian influenza, a subtype of influenza A specific to birds, was serially passed into ferrets by scientists. The experiment was successful since a bird-specific virus was able to infect a different host range, the ferret. The virus was able to proliferate from one ferret to another via respiratory droplets. The World Health Organization (WHO) welcomed the outcome of the experiment and concluded the experiment widens our better understanding and discovered new properties of these viruses. However, such experiments have been frowned upon by some critics and more consensus is needed prior to experimentation.