Living Medicines Could Disrupt Pharma
By: Sofia Sanchez
Tags: Health, Biotechnology, Synthetic Biology, Microbiome, Biology

One lesson that I’ve learned this year, is not to underestimate the power of tiny things. Viruses are not even alive, they are less than 800 nanometers in size (very, very small), but still could literally change the world.

I know everybody is sick of COVID-19. I won’t touch that topic again. I just wanted to introduce you to the microscopic world, which also includes bacteria and the living cells that make you and me up.

Just as underestimated, after reading this, I can assure you that you will be surprised of what these tiny beings can do inside your body. That’s correct, there are not thousands, nor millions, but trillions of bacteria living in your body right now.

The craziest thing is, that we maybe wouldn’t be able to do a lot of things without these guys. Scientists have been noticing this recently, and we now want to leverage the power of genetic engineering to take advantage of our microbiome.

Trillions in your body?!

Exactly. The microbiome comprises the community of tiny organisms, living inside a host, as well as their surroundings and genomes. These tiny organisms can be bacteria, archaea, fungi, algae, and small protists.

In this sense, the distinction between the microbiome and the microbiota, is that the microbiome is the integration between most factors, and the microbiota refers more specifically to the organisms themselves.

Now, these inhabitants can be divided into pathogens, neutral, and symbionts, depending on their interaction with their host. This means, that they can be either good, bad, or neutral.

This said, what exactly are *100 trillion microbes (equivalent to 1kg) doing in our colon?

Estimates may vary according to the source. The colon is the main place

where these organisms reside.

Eating your food? 🍔

What gut microbiota is best known for, is digestion and nutrition. They can generate nutrients from substances that are otherwise indigestible by the host.

The microbiome is indeed, a crucial component to the human body, even since we are babies. Some of the bacteria that first begin to grow, are Bifidobacteria, which digest the healthy sugars in breast milk.

Now, one of the most interesting things about the gut microbiome, is that you can shape it. This can get a little confusing. The seed for our microbiome comes from our mother. The phrase “You are what you eat” can make more sense when you know that there are microbes that are in charge of processing different kinds of nutrients.

Image credits to Kurzgesagt in a Nutshell

Some of them like greasy things, others like veggies and so on. If you are vegan for example, you’re gonna be feeding the kinds of bacteria that process minerals and vitamins more than those which process lipids.

At the same time, this is a two-way street. Since those microbes are looking after their own well-being, they may also influence your appetite for certain types of food: the type of food that those microbes like.

Mind-blowing! Actually, it’s been proven that your microbiome can communicate with your brain, influencing the your food cravings. Still not surprised?

The obesity epidemic could be contagious as a result of obesity-causing microbes transmitted from person to person. A social network study of 12,067 people found that a person’s chance of becoming obese increased by 57% if a friend had become obese.

Controlling your thoughts? 🧠

I’m still not 100% of how true the answer to that question could be. Yet, for now, the results are impressive. Our microbiome does indeed, communicate with our brains.

As it’s been mentioned before, this could have feeding purposes. However, that’s not the only thing. Disorders such as depression, autism and schizophrenia, just as qualities like intelligence could also have a very close relation with our microbiome.

The gut microbiome and the brain communicate bidirectionally through the microbiota-gut-brain axis (MGBA). The vagus nerve, the longest nerve in the human body is the main channel through which microbes do this. Other means include the blood or circumventricular organs.

Digging deeper into the this, vagal fibers are distributed to all the layers of the digestive wall, but are not in direct contact with the microbiota inside the gut (luminal). These fibers can only sense indirect signals through the diffusion of bacterial compounds or metabolites, or thanks to the signals of other cells in an outer layer.

This said, it’s the perturbation of this axis that is involved in the development of neurodegenerative disorders. Still not surprised?

Serotonin is the “hormone of happiness”. 90% of it is produced by our gut microbiome.

Fighting disease? 🦾

Interactions between the microbiota and the host immune system are numerous, complex, and bidirectional. For example, microbes liberate short chain fatty acids (SCFA), which are an important energy source for intestinal mucosa and critical for modulating immune responses and tumorigenesis in the gut.

They also help in the development of anti-inflammatory regulatory T cells, which help fight disease, and overall as we’ve seen before with food, the more diverse our microbiome is, the less dietary problems we will have.

Contaminating our dreams? 🌙

Sleep problems affect 70 million Americans. Melatonin, the hormone of sleep, when there is absence of light, is produced by the pineal gland in the brain, and then released into the bloodstream. Could our microbiome be affecting this process too?

It has been found that total microbiome diversity is positively correlated with increased sleep efficiency and total sleep time. There is also a a positive correlation between total microbiome diversity and interleukin-6, a cytokine with sleep effects.

As we’ve mentioned before, this is a two-ways system. The microbiome could be affecting sleep as much as our sleep could be affecting our microbiome. However, this is apparently true in the short-term. In the long-term, sleep deprivation apparently doesn’t have this effect.

IL-6 levels were positively correlated with time in bed and total sleep time as well. Nevertheless, this wasn’t as significant as the relation between bacteriodetes and phyla with sleep efficiency. The mechanisms and/or metabolites that link these systems remains unknown.

An army of microbes

What does synthetic biology have to do with all of this? Well, synbio is the intersection between engineering and biology. It’s such a new field that no one has come up with an official definition yet. All we know, is that it is all about standardizing life.

That’s right. Working with synthetic biology principles, we can think of genes as biological parts that have a specific function. These parts can be assembled between each other to form much more complex systems, such as genetic circuits.

Nowadays we can make the comparison between computational logic, and genetic logic. We can use promoters or inhibitors to modulate gene expression. There are genes for almost everything we can imagine. From sensing conditions in the environment to creating new materials and substances.

Of course there are “easier” ways to do this, but there is a little detail about willing to impact the microbiome. The actual way in which this is can be done may not be so desirable for many patients. It’s a fecal transplant.

Now, for pragmatic reasons, I’m not going to get too much in detail, but if you’re anything like me, you’d be looking for better ways to do this. Let me introduce you to…

Microscopic doctors 🦠

Living medicines are organisms such as bacteria, which have been genetically modified to perform a specific function or produce a therapeutic agent.

Animal, bacterial, fungal cells, or a viruses are genetically engineered, and are then injected into a patient. Sounds simple, but there are still some limitations and complications that we have to look after.

One is that even though synbio is about standardizing life, we can’t be 100% about all the factors that are either external, or internal to the organism we are working with (eg. bacteria). This is the reason why we will always want to do mathematical models to know as much as possible about the chemical reactions that would be taking place thanks to our genetic circuits.

Another factor to consider is how our living medicines could interact with the already-existing microbiota. Could they do some horizontal transfer? (pretty much like exchanging genes between bacteria), could they override other organisms? What will happen after the host releases them?

One strategy for the last concern are kill switches such that are designed for triggering cell death when bacteria escape. This way, the host’s inner environment would have control over the survival of those bacteria.

A question that we would also like to ask when we want to produce living medicines is “which type of bacteria should I use?”. Well, this will depend on the target site in the host body and the expected responses, including immune reactions. Lactic acid bacteria (LAB) are used in the food industry and have recently been used to deliver therapeutics.

The forms of administration may vary according to the target. These can be oral, to move along the gut and are be then removed from the body, intravenous, or intratumoral, which can assure a higher efficiency for cancer treatments.

Last but not least, we should consider that the rate and amount of medicine that is delivered will depend on how the genetic circuit. Promoters and ribosome binding sites (RBS) are some of the most important parts to take into account.

Fictional representation of a genetically engineered bacteria

Synlogic 🧬

Thankfully, there are already some companies in the field working to make living medicines possible. Synlogic is a Cambridge-based biotech company, that is currently in clinical trials to treat metabolic disorders. Their Synthetic Biotic™ medicines have the potential to treat a range of conditions including rare diseases, metabolic conditions, and even cancers.

Taken orally (no worries, it’s only bacteria from a lab), the medicine was created to remain inactive until it reaches its final destination. Then sensing the internal environment, a programmed “switch” in the medicine is activated triggering enzyme production.

The keys steps to make this possible are:

Assess the problem: understand the disease mechanism. Target identification and validation, predictive modeling, and bioinformatics Design solutions: test prototypes. Cutting-edge DNA assembly, mathematical modeling, selection of an optimal microbial “chassis” Build the synthetic biotic: insert the designed genetic material into the genome of the microbe. Process development research and optimization Administer to patient: oral or injected. Use of biomarkers and bioinformatic tools to predict the response

The practical benefits of an oral administration are obvious, but why is this possible? Well, they want to ensure that the necessary biological activity is achieved at the right place and time, without persisting or accumulating in the body.

Ginkgo x Synlogic 🤝

The way that I personally like to measure how innovations are changing the world is by knowing if there are already companies looking to bring those technologies from academia to the market.

Well, synologic isn’t only a company that is already doing clinical trials. It’s already partenered with a synthetic biology giant. Ginkgo bioworks has invested $80M in Synlogic.

“Ginkgo has built a world-class infrastructure for programming and optimizing microbial strains at a large scale which will be instrumental in the development of our portfolio of Synthetic Biotic medicines”

Current gaps

During the period of research that I did, I wasn’t able to find a lot of scientific papers that demonstrated solid results in very specific topics. This is, there were a lot of reviews around the gut microbiome as a whole, but not many scientists have actually gone very deep into areas such as the relation between the microbiome and sleep.

Thus, it’s clear that there’s still a long way until we understand more about the trillions of guests living inside of us. We are beginning to discover important insights, such as the Microbiota-Gut-Brain Axis. Still, we are missing to apply that knowledge to specific research projects.

Image credits to Grow by Ginkgo

As of synthetic biology, more progress is being made overall. From the creation of new biological parts, to new software tools that are being used to facilitate the Design-Build-Test cycle.

Living medicines are a way to could combine our knowledge about the gut microbiome, and cutting-edge research in the principles of synthetic biology. The possible gaps that we may find here, are in terms of biological containment, as well as interaction between those genetically engineered bacteria and the “natural” ones.

Predictions for the future

The future is now. Two of Synlogic’s treatments are in phase 1 clinical trials. Another one has is already in phase 2. Although this company is focusing more on weird metabolic diseases at the moment, we could be seeing some other very interesting applications of this technology sooner than we think.

One that I’m personally very excited about is living medicines that can absorb fats or carbohydrates in a much more efficient way, in order to fight obesity, prevent a healthier aging, or enhance sleep.

After having mapped our microbiome, we will be able to understand how semi-synthetic life could be interacting with nature, and use this to our advantage, even to enhance humans in certain ways. Perhaps we could even see our selves leveraging the communication between the microbes and the brain, how it affects our mood, or how they create and process nutrients for us.