Electrogenetics: another tool for precision medicine?

A developing area in synthetic biology, electrogenetics is hoped to become a new avenue in precision medicine, helping with the treatment of certain chronic diseases. Chaitanya Erady talks about what electrogenetics is and the ambitions for its use.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.
 
In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.
 
If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

Make sure to read our briefings on electrogenetics and advanced therapy medicinal products too.

If you have any questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: Welcome to 'Making science work for health'. The PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. The progress being made by teams of scientists and researchers around the world is gaining more interest and attention. Many of the latest advances feature genomics and omics related technologies, the field in which the PHG Foundation has more than 25 years of experience, helping policy makers get to grips with practical on the ground delivery. 'Making science work for health' aims to look behind the hype and explain what new science means for patients, health professionals, and members of society. My name is Ofori Canacoo, part of the communications team at the PHG Foundation and host of 'Making science work for health'. 

For this episode, we're talking about the emerging field of electrogenetics, a developing area in synthetic biology. Electrogenetics is hoped to become a new avenue in precision medicine, helping with the treatment of certain chronic diseases. Dr. Chaitanya Erady, policy analyst in biomedical science at the PHG Foundation joins us to discuss what electrogenetics is and the ambitions for its use. 

Hello, Chaitanya. 

Chaitanya: Hi Ofori. 

Ofori: How are you?

Chaitanya: I'm good, thanks. How are you? 

Ofori: Yes, good. Thank you. So thank you very much for joining us today we are talking about electrogenetics. So to start off with, could you explain to us what electrogenetics is? 

Chaitanya: Yes, of course. Electrogenetics is an upcoming field in synthetic biology, and what researchers are trying to do is to create these cells where you can control gene expression using electrical or electrochemical stimulation.

Ofori: Where, so where exactly did the concept of electrogenetics originate from? 

Chaitanya: Believe it or not, it was actually bacteria, specifically electrochemically active bacteria. So this was back in the 1970s where researchers were studying these electrochemically active bacteria. The unique thing about them being their ability to sense electrical activity in the surroundings and in response control their gene expression. This was quite a unique property because mammalian cells, which are like human and mice cells did not have this ability. So it's sort of been an interesting progression to see how researchers have studied this electrochemically active bacteria, and try to recreate this electrical sensing and gene controlling ability into mouse and human cells.

Ofori: So what exactly about electrogenetics drew your interest? 

Chaitanya: I was quite unfamiliar with the field, and I was introduced to it at an engineering biology seminar where Professor Martin Fussenegger was talking about the range of very exciting research happening in his lab. So he introduced how they were creating modified cells designed to respond to a range of inducers.

This included electrical, sound, aroma, and even moisture levels. To me, at the time, this sounded straight out of sci-fi, but then it was fascinating to see that these cells were being tested in mice. For example, I really liked the part of his presentation where he talked about a mouse disco. 

So what they did was to use insulin producing cells, which were modified to respond to sound, and then these cells were implanted on the underside of the mice's belly. These mice were placed in a cage with a speaker, which acted as a sound source. They found that when they placed the mice on top of the speaker, such that the implanted cell was in close proximity to the speaker, the source of sound, it triggered insulin release when they played some music.

On the other hand, when the speaker was placed at the center of the cage with mice freely running around like in a disco, the sound was not of sufficient strength to trigger insulin release. And the funny thing is they also tested like different types of music to see which one had the right frequency, the wavelength or the strength to trigger insulin release, and the results were pretty clear.

We will rock you and the Avengers theme was ideal for triggering incident release in this mice. To me, seeing such wireless inducers have the potential to control gene expression and modify gene expression was quite fascinating. I think after the seminar was quite curious about what the landscape looked like, and I did my own research into this, the results of which I present in a blog and briefing on electrogenetics.

Ofori: So how exactly does electrogenetics work? 

Chaitanya: So I think I'll start by describing what the main components are, and there are three. So you have the input, the designer cell, and the output. So the input is the source of electricity. So the electricity could come from a conductive material such as palladium. Or it could be derived from chemical reactions such as ... which generate electrons and consequently electricity. The second component is a designer cell, which is a cell that's been modified or engineered to respond to electricity. And this can be achieved by the addition of electrosensitive receptors to these cells.

And then usually these cells have a target gene or the output, where when the cell receives an electrostimulation, this target gene is activated, and the output, which could be a transcript or a protein, is consequently produced. These three components together form a functioning electrogenetic cell. 

Ofori: So why exactly would we use it?

Chaitanya: I think the potential of this technology is quite exciting. You now would have the capability to wirelessly control the expression of genes, and imagine in diabetic patients what that could offer. If, for example, you have insulin producing electrogenetic cells, wirelessly you would control when and where this insulin is produced as and when needed by the diabetics.

Ofori: What stage is electrogenetics at in terms of research and implementation? 

Chaitanya: It's still very much in its infancy, although there's a lot of exciting research happening in this space. For example, researchers have developed functional electrogenetic cells, added them to bioelectronic implants, and successfully managed insulin levels in diabetic mice using these. There is still a long way to go before these are ready for use in humans. 

Ofori: What would the use of electrogenetics look like in precision medicine? 

Chaitanya: So electrogenetics is definitely something that could help with current precision medicine efforts when it gets there, and this is primarily in three main ways.

So compared to traditional medicines which are taken at specific time points, electrogenetics could help deliver therapeutic outputs precisely where and when it is needed. And because it's an electric signal, which is the input, you could possibly control the intensity and duration of the signal, which will translate to the amount of therapeutic output that is produced, allowing dynamic dose control and ensuring that patients don't overmedicate. And in combination with biomarker monitoring systems such as glucose monitors, electrogenetic systems could be used to trigger insulin release, as and when needed, enabling diabetic patients to manage their condition with minimal clinical intervention. 

Ofori: You've mentioned insulin a few times in our conversation, so I'm assuming a fair bit of research has gone into diabetes, but are there other areas of research that are being looked at with regards to electrogenetics?

Chaitanya: Yes. That's a good question, but it... and you're right that it does seem that most of the research activity is currently focused on type one diabetes, but it would be interesting to see how this might be extended to other conditions, particularly genetic conditions, which are protein or hormone imbalance based. So for example, chronic pain, cardiovascular disorders, and hypothyroidism. But as far as I'm aware, there isn't much happening in that regard. 

Ofori: So currently, what barriers are there or would there be for clinical implementation of electrogenetics? 

Chaitanya: So like I said before, they're quite far away from being ready for use in humans and in addition to the usual safety testing before these electrogenetic systems can be used in humans, it's also the question of scaling up, because most of them are currently produced for use in mice. So for example, bioelectronic implants, they use electrochips to hold the electrogenetic cells. And these electrochips need to be small enough, so that it minimises any potential side effects upon implantation in humans, but it also needs to be large enough so that they can hold enough amount of electrogenetic cells to be functional in humans. To give you a rough idea, in mouse models, these electrochips hold up to 3 million electrogenetic cells, but to be functional in human subjects, 150 times more cells might be required, and current electrochips aren't necessarily capable of doing that. The other thing is that the electric field source that provides that electrostimulation needs to be miniaturised. And if that is the case, if these bioelectronic implants can work with a miniature electric field source, there is potential of integrating them with wearables. In addition to that, any output from this electrogenetic system needs to be non-toxic and within normal physiological levels so they're safe for use in humans and the implants need to have long enough shelf lives such that they do not trigger the immune system in humans and risk being rejected by the patient's body. 

The one key area of research that still happening is around the leakiness of these systems. That is when genes, the target genes are activated even when the threshold for electrostimulation has not been met. Now to minimise leakiness, one thing that is being researched is optimising the receptor numbers. So that is, for example, increasing the number of electrosensitive receptors that is added to these cells, so as to improve the sensitivity of electrogenetic systems.

Ofori: So would you say wearable devices were the key to implementation for electrogenetics? 

Chaitanya: I think wearable devices could be the end goal, but as of now it's more so by electronic implants that's being researched. And there's three main ways this is being done. So you have the usual bioelectronic implants where the electrogenetic cells are placed on one side and the electronic components are on the other. These are then implanted under a patient's skin, and you have an external power source, which is used to activate the implant wirelessly. 

You have the piezoelectric devices, which are capable of producing electricity in response to a change in the shape of the piezoelectric material. So this device is about the size of a five pence coin, and when implanted beneath a patient's skin and when this device is pushed, the force causes the piezoelectronic membrane to bend and produce electricity, which provides a necessary electrostimulation to the cells. 

And the final one is DART or direct current actuated regulation technology. In this DART system, direct current is used to generate non-toxic levels of reactive oxygen species, which the cell recognises as electrostimulation. Electrogenetic cells are encased within biopolymers to prevent rejection by the patient's immune system, and then these are implanted into the patient. Now because this system uses direct current, which is similar to the batteries used in variables, adding small needles to variables which doubles as electrodes could be a useful way of linking these electrogenetic cells and electrogenetic systems with variables in the future. 

Ofori: Would electrogenetics fit into current regulatory laws for medical devices, or would new regulations need to be considered? 

Chaitanya: Because we don't have a defined clinical product yet in terms of regulation, which requires a product to be defined, we can only offer speculations at this stage.

So because they contain modified cells, it is likely that regulations around somatic cell therapy would apply, but because its clinical use requires it to be placed within bioelectronic implants, it is likely that they will be classified as a combined advanced therapy medicine product or ATMP. So these electrogenetic systems will need to adhere to ATMP regulations.

And other essential requirements as outlined in the UK medical devices regulations, assuming they're launched within the UK and there might be additional assessments by other approved bodies before it can be used in clinics. If you're interested in listening more about ATMPs, we have a colleague who's recently published a briefing on ATMPs that's published on the PHG website. 

Ofori: So Chaitanya, what would you say are the next steps for electrogenetics? 

Chaitanya: Well, we are definitely at a very exciting juncture. Obviously the research is still developing and that's something to look forward to. And the potential of electrogenetics to contribute to precision medicine efforts is massive.

From self-managing chronic conditions to allowing dynamic dose control of treatment, there is definitely potential to offer novel and safer ways to treat certain genetic disorders. But we do still have a long way to go before they can be used in clinics. And this requires addressing quite a few challenges, including ensuring that they're safe, they're not rejected by their human immune system and minimising leakiness of these electrogenetic systems. And there's also waiting for clinical utility assessments before they can be used in clinics. Beyond that, it awaits to be seen how these electrogenetic systems can be integrated with wearables, how feasible that would be and how that might allow management of diseases. 

Another interesting avenue is the combination of electrogenetics with other wireless technologies such as magnetogenetics and optogenetics, which uses magnetic field and light respectively as end users. What this might allow is a development of a multi-stimuli responsive designer cell where each stimuli is linked to a particular gene, a particular target, a particular output, thereby allowing researchers to address several patient deficiencies simul simultaneously. 

I think further ahead, it would also be interesting to see how artificial intelligence might contribute to this space. If electrogenetic bioelectronic implants are combined with wearables, perhaps AI could automate the treatment delivery by monitoring biomarkers to the wearable and adjusting the dosage as necessary through the electrogenetic system.

Currently some people with diabetes are offered bionic pancreas, which can monitor glucose levels and it uses some AI system to administer the right amount of insulin. And perhaps further research could be done in this space to assess whether electrogenetic systems could be incorporated to this bionic pancreas as an insulin source.

And finally, since most of the research is happening in type one diabetes, it awaits to be seen, what sort of other genetic disorders might benefit from electrogenetic systems? 

Ofori: Great. I think that's a good place for us to end this conversation. Chaitanya, thank you very much for coming on to talk to us about electrogenetics and hopefully we will have you on again soon.

Chaitanya: Thank you so much for having me, Ofori. It was a pleasure to discuss this very exciting science with you.

Ofori: And that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org.

And if you have any further questions about the topic, you can email us at intelligence@phgfoundation.org. Thank you for listening, and we look forward to bringing you a new topic in the next episode.