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Can you stop feeling pain? Probably yes!

Every day any of us does some activities that can cause some damages. Some of them are slight, and people notice those after years and years, and that what happens with ageing; others are speedy and acute, such as what happens with car accidents or other types of injuries.

In all of them, there is a bill to pay. That bill is called pain.

What is pain?

We can describe pain according to two different definitions, biological and evolutional.

In all of them, we can consider pain as a consequence of a human response due to defence.

Indeed, when people needed to survive, pain was the only way to perceive if their activity were good or bad.

Biologically speaking, we can describe the feeling of pain due to the action of nociceptors.

Nociceptors are types of receptors. Receptors are generally mediate changes.

We can identify different type of nociceptors

Mechanical nociceptors

Activated by skin temperatures above 45°C or by severe cold

Chemically nociceptors

That responds to chemicals that have a considerable difference of pH with our skin or other substances such as proteins or chemicals that can activate inflammation. Some examples are such as bradykinin and histamine

Polymodal nociceptors

Activated by a combination of those stimuli

In general, a signal can be distinguished by different elements

  • Modality
  • Location
  • Intensity
  • Duration

Modality

A sensory receptor is specialised to respond to either mechanical, chemical, thermal, or electromagnetic stimuli.

We can define the form of energy to which a receptor is the most sensitive as an adequate stimulus. For example, in the case of the eye, the adequate stimulus for the rods and cones is light.

Sensory receptors can also respond to other forms of energy that is different from the adequate stimulus, the most liked one, but the threshold for these nonspecific responses is much higher. In other words, you need more energy to activate the same receptor.

Locality

Locality is where the sensory unit is located and the radius that is involved. Some places in your body far more receptors, and others don’t.

The places of your body where there are more receptors can give a higher sensibility (like what happens with your month). Others, instead, don’t have many receptors that leads to lower sensibility.

Intensity

The intensity of a sensation is determined by the amplitude of the stimulus applied to the receptor. When there is a stimulus with higher intensity, the main difference is in the signal’s frequency. Indeed, the higher the frequency, the higher the intensity. When we talk about pain, the higher the frequency, the higher the pain

Duration

If a stimulus is constant, our body doesn’t perceive it in the same way. That’s for a biological phenomenon called receptor adaptation. With receptor adaptation, we mean that we tend to give lower and lower importance to phenomena that don’t change in time. One example is light. When we wake up, we can’t see the light correctly, but we get used to seeing it without any problem after some time. Some receptors, such as the receptors related to noise, don’t have this feature.

Pain receptors are related to a class of receptors.

Many people suffer pain but, even if during our evolutionary history suffering was a point of advantage, now, we may not be able to say the same thing.

For example, many chronic diseases are due to an increase of different problems that, overall, people feel just for the pain perception.

These chronic diseases, in general, are not cured. People take drugs to reduce their effects. Eliminating the sensation of pain can be the end of all these problems.

In any case, pain can give a social advantage, and one point that we have to consider is its reversibility. In this article, we will explore different ways to make people stop feeling the sensation of pain.

SCN9A gene & Nav 1.7 protein

Everything started from a few cases of children that went to the hospital with one problem, they weren’t able to feel pain. People started thinking they were lying, like any child who wanted to imitate their favourite superheroes, after all. After different events and accidents, that idea went out of mind due to several mistakes that would not have been present if those people had felt pain. One of the most common examples were bursts, cuts and any others injuries due to ordinary activities. That sensation wasn’t pretty familiar, and it’s called congenital analgesia, CIP for friends.

CIP syndrome makes people who have it immune to the sensation of pain but with all the other present features. Those include the feeling of pressure, heat and touch, The genetic mutation is mainly related to the SCN9A gene that is linked to the Nav 1.7 protein. In patients with this genetic mutation (since they were born with it), there is a lack of pain perception.

Having this mutation is horrible because people always check if they are doing something that can damage them. Indeed, many people that have this mutation present different problems in their physical aspect.

The karma of Silicon Valley is that any problem is a billion-dollar opportunity.

In that case, it’s the same.

Many current drugs have the function to make people not feel pain and act with different approaches, but there are many side effects in all cases. Having the possibility to edit the gene or the protein can be extremely insightful to have a new drug that can treat the perception of pain potentially without any side effect. There are different ways to achieve this. Those possibilities include genetic, RNA and biochemical approaches. We are going to define all of them.

CRISPR

CRISPR is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea

CRISPR technology is a simple yet powerful tool for editing genomes. It allows researchers to alter DNA sequences and modify gene function easily. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases and improving crops. However, its promise also raises ethical concerns.

CRISPR technique has different proteins that interact with it. One of the most important ones is the Cas9 protein.

Cas9 is an enzyme that uses CRISPR sequences as a guide to recognise and cleave specific strands of DNA that are complementary to the CRISPR sequence. Cas9 enzymes, together with CRISPR sequences, form the basis of a technology known as CRISPR-Cas9 that can be used to edit genes within organisms.

The Nobel Prize recognised the development of the CRISPR-Cas9 genome editing technique in Chemistry in 2020, awarded to Emmanuelle Charpentier and Jennifer Doudna.

This editing process has a wide variety of applications, including fundamental biological research, the development of biotechnological products, and the treatment of diseases.

In that case, one of the possibilities would be to edit the SCN9A gene directly to make people don’t feel pain. Even if it may seem something straightforward, in reality, it’s not. Indeed, some problems still should be solved.

The first one focuses on how to direct the tool just to cells where those receptors are present. Indeed, if some people have a broken arm, the editing of the genome should just focus on the injured part.

The second problem is on the reversibility side. After the injury went away, how can we be sure that we can turn the situation back again? Are there any ways to do that? If we want to use CRISPR again, what may be the right time to make those people regain the pain sensation?

The third and most important question is: How do we know the time for protein degradation?

What does protein degradation mean?

Any protein degrades, there is a pathway, ubiquitin (Ub)–proteasome pathway, by which the proteins break down into smaller polypeptides or amino acids.

CRISPRoff

The possibility of silencing the gene without editing the DNA can be achieved by other methods, too. One of those is called CRISPRoff

What’s CRISPRoff?

CRISPRoff is a single fusion protein that programs heritable epigenetic memory, CRISPRoff is highly specific and has a broad targeting window across gene promoters. The great advantage of using CRISPRoff is its reversibility having another toll, called CRISPRon, that can activate the genetic expression again.

CRISPRoff is incredibly specific, and it can be beneficial not only for this kind of procedures but also for some epigenetic changes that could potentially last over different generations.

Going back to our main project, CRISPRoff can be another exciting solution not to wait that the genetic changes have to come back to their standard alone or if there is the need to edit the gene again.

Using CRISPRoff can also make patients know that they don’t need to worry about some potential genetic changes due to the CRISPR-Cas9 tool. Indeed, imagine what would happen if some of the genes edited the first time may have some problems and being edited again? What would you do?

When we talk about the Nav 1.7 protein, it is only present in some particular cells related to nociception (the perception of pain).

RNA Interference

The term RNA interference (RNAi) was coined to describe a cellular mechanism that use the gene’s own DNA sequence to turn it off, a process that researchers call silencing. In various organisms, including animals, plants, and fungi, RNAi is triggered by double-stranded RNA (dsRNA).

Researchers widely use this process to silence genes to learn something about their function, but it is much more than a research tool. RNAi encompasses an array of ancient and sophisticated cellular mechanisms that regulate a variety of biological processes.

Even the concept is intriguing. There may be different negative aspects that we should take into consideration.

Indeed, RNA is inherently unstable, potentially immunogenic, and typically requires a delivery vehicle for efficient transport to the targeted cells.

Biochemical approach

One of the most common and valuable solutions to consider in those cases is using a biochemical approach.

Indeed, the biochemical approach has been one of the most used ones in the last decades. Ion Channels ranked the second most important target for developing pharmaceutical drugs.

To consider a biochemical approach useful, we need to know how would the process work. Indeed, if in the previous cases, we eliminated the modification or the methylation of the DNA, in that case, we need to consider the protein directly.

There are two main ways to do so:

  • Interacting with the protein
  • Interacting with a kinase that interacts with the protein

The Nav 1.7 is an Ion Channel

We can define Ion channels as transmembrane proteins specialised in the fine control of the passive flow of naturally occurring ions (Sodium, Chloride, Potassium, and Calcium). They play crucial roles in living cells, from initiating and facilitating electrical signals propagation across membranes to regulating cell volume.

If you want to know more about channels, I would recommend this article.

In general, we can consider an ion channel as a gateway that can be close or open.

In the case of the nociceptor, we can define the channel close when the protein is inactivated (turned off, gone away).

Interaction with the protein

One of the most common ways to inactivate a protein is by targeting it directly. Nanotechnology has been super valuable for that, especially with supramolecular chemistry, which is the field that studies the abilities of different molecules to acquire “new powers” when they interact with each other. Those functions come from just the intermolecular links that are present.

Imagine what happens with bees. Animals can easily kill bees but, when you consider a hive, you may have no escape.

What I mean by that is a single bee can’t do so much, but the possibility to work in a group is super powerful to achieve amazing goals

Different drugs are super precise and can interact with particular biology elements like molecules that open up only when they are close to cancer cells.

One of the most exciting applications for precision targeting are linked to Halogen Bonds.

Halogen Bonds are short-range molecular interactions analogous to classical hydrogen bonds, except that a polarised halogen replaces the hydrogen as the acid in the Lewis acid/base pair. Such interactions occur regularly in the structures of many ligand-protein complexes.

In other words, they are particular types of intermolecular reactions that happen due to the polarisation of Halogen with atoms such as Sulfur, Oxigen and Carbon

Indirect Interaction

Interacting with a kinase that interacts with the protein, we need to define what a kinase is.

A kinase is an enzyme that catalyses the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. A Phosphoryl group is generally related to protein inactivation.

When the Phosphoryl group is present, the protein becomes inactive. When it’s not present, the protein is active. In this case, halogen bonds can be beneficial for those applications. Indeed, protein kinases provide an exciting opportunity to examine the role of halogen bonding in inhibitor recognition and binding.

One of the most interesting studies focuses on the “cJun terminal kinase 3” which is a neuronal-specific MAP kinase that is a potential drug target for treating neurological disorders.

The authors of the study concluded that the potency of these inhibitors could best be affected by altering the specific interactions between the inhibitor and the ATP binding site of the protein, suggesting that the halogen bond needs to be taken into account, along with all the other interactions, when trying to refine JNK3 inhibitors.

In both cases, there are many components to analyse, such as:

  • The molecular distance
  • The σ-Hole Angle.
  • The Spherical Angles
  • The Interdependence of Distance and σ-Hole Angle

Those features are advantageous if we want to consider the rational design process. That means understanding how biological elements work to create new potential drugs.

One of the most exciting applications will be with Quantum Computers that can simulate molecular interaction with higher accuracy and faster.

Different scientists worked on designing new approaches that can be either accurate or faster for this perspective. One of those is called semi-empirical QM (SQM), where you go from the rational design process of drugs that is focused on Force and Fields (that requires so much time) to other time of scores focused on knowledge, too.

Conclusions

This article described different possibilities that scientists can apply to stop feeling pain, either focusing on the SCN9A gene or focusing on its protein, the Nav 1.7, while other approaches with different techniques.

We also examined different methods. Some of them, such as CRISPR, are pretty known and famous. Others, such as Halogen Bonds and CRISPRoff, are relatively new but can provide exceptional solutions.

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Guido Putignano

Guido Putignano

Synthetic Biology + Quantum Computing for drug discovery