AskScience AMA Series: I'm Birgül Akolpoglu, a doctoral researcher at the Max Planck Institute for Intelligent Systems in Germany. I work on microalgae and bacteria-based microrobots that could one day be used to deliver drugs and battle cancer! AMA!

Submitted by AskScienceModerator t3_10px8sa in askscience

Hi all: I'm interested in finding new uses for medical microrobotics, which are developed by combining biological agents such as bacteria with synthetic materials. I recently constructed "bacteriabots," by equipping E. coli bacteria with artificial components. My team and I were able to navigate the bots remotely using magnets to colonize tumor spheroids and deliver chemotherapeutic molecules.

In July 2022, this work was featured in Interesting Engineering (IE) and made it to the publication's top 22 innovations of 2022. IE helped organize this AMA session. Ask me anything about these "biohybrid microrobots" for medical operations and how these may one day help treat a whole range of diseases and medical conditions.

I'll be on at 2 pm ET (19 UT), ask me anything!

Username: /u/IntEngineering

1,903

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spot_o_tea t1_j6n7a2x wrote

How do you prevent genetic drift of the biological components?

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intengineering t1_j6oa7nq wrote

Hi! I am no expert on genetics since I am trained as a Chemical Engineer, I may not be able to answer your question fully. As far as I know, genetic drift cannot be stopped from occurring since it is an event based on random chance. In bacteria, we can rather talk about mutations, which would happen over a long period. In our case, the envisioned therapy is very short term: injection, therapy, and removal. Therefore, current projections do not give us any reason to be concerned about the possibility of bacterial genetic drift or mutation.

All the best,
/birgül

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yigitjohn48 t1_j6nhv97 wrote

Hi hocam! My question is how microrobots behave after colonized? (idk right term) Do the bacteria colony behave different than u programmed for? I mean is it emergent or it is behaving similar to computer program, it behaves exactly what you programmed to? Congrats hocam!

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intengineering t1_j6oadaj wrote

Thank you for your questions. Here in our study, what happens is that we attach nano-sized magnetic particles to bacteria, and therefore, we are able to control those bacteria using external magnetic fields. You can imagine a single bacterium turning into a tiny magnet that can be navigated using a larger magnet, or electromagnetic setup. As for the colonies, with our optimized method, we were able to generate millions of these bacteria (we call them bacterial biohybrids), carrying the magnetic nanoparticles, meaning that we were able to control the swarms of bacterial biohybrids using external magnetic stimuli. Magnetic control mechanisms are quite robust since magnetic fields are safe to use in clinics and it allows for precise control over tiny swimmers. We can technically “steer” them using our electromagnetic coils, they go right when you press right, and go up when you press up on the control panel!

Hope this answers your questions!
All the best,

/birgül

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lawless_c t1_j6obb8z wrote

Is this making them swim i directions you choose or is it more like dragging them about?

Does the magnetic tool(s) that control them have to be super close, like contact with the body?

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intengineering t1_j6oeuco wrote

It is not dragging but rather aligning them. So what happens is that the nanoparticles on bacteria align with the applied magnetic field. Therefore, bacteria follow that path. We could also create so-called "magnetic gradients", which would cause dragging or pulling. But we want to use their own motility rather than pulling them.

As for the second question: No, they don't. We use electromagnetic coils (see: https://www.sciencedirect.com/topics/engineering/electromagnetic-coil) that generate enough magnetic field in the center of the setup to steer the microswimmers. These setups are designed for microscopic use, i.e., we attach them to a microscope to simultaneously visualize the motion of bacteria under magnetic fields. Of course, you would need much larger setups for use in humans in the future, but even in that case, it wouldn't be in contact with the body.

Thanks for the Qs!
All the best,
/birgül

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DeDragoner t1_j6okrhi wrote

How do you envision to implement this in vivo? There will be innumerable additional challenges (navigating 3D space, tissues etc.) How do you plan to reach tissues? A delivery by the bloodstream would cause heavy immun reactions.

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Bierbart12 t1_j6mstxc wrote

How close are we to be able to see widespread use of nanobots in medical applications?

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intengineering t1_j6o9vyb wrote

Thank you for your question!

To be able to reach that point, where we can safely administer medical micro- and nanorobots to human bodies to carry out various medical tasks, some challenges remain to be tackled.

Firstly, the micro- or nanorobot should be safe for injection – meaning it should be biocompatible for its application, and should still be actively controllable to target specific regions. This requires extensive research on material development, safety tests, and wireless control mechanisms (such as magnetic fields, light, acoustics, etc.). Currently, hundreds of different medical micro and nanorobots are tested on Petri dishes and animal models, and many promising candidates could perhaps one day turn into clinical success.

However, that is not the end of it. Once your tiny robot is good to go, then we need real-time medical imaging techniques to be able to precisely detect and visualize these robots inside the body. Currently, many imaging systems are developed to increase the resolution and overcome the imaging limits such as our tissue penetration depth. Another important aspect that is commonly overlooked is the removal or elimination of the biohybrid microrobots after the treatment. Approaches regarding retrieval of the microrobots should be investigated as well. Additionally, active control mechanisms should be scaled up for human use, since currently reported setups are mostly designed for proof-of-the-concept studies and small animals.

We need many more in vivo and then pre-clinical studies that rigorously investigate the feasibility of these tiny robots. Therefore this is currently not a “ready-to-use” technology that our society can benefit from when it comes to treating patients, however, it holds great promise, and considering the exponential increase in the research of nano- and microrobots to overcome mentioned challenges, it is not far-fetched to imagine the use of medical robots in clinics in the future.

All the best,
/birgül

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M-2-M t1_j6nn3a4 wrote

What’s your prediction if large amounts of these nanobots end up in waste water and the impacts of this on the environment ?

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intengineering t1_j6obxgn wrote

Thank you for this interesting question! If we come to a point where these biological nano or microrobots are used in clinics, the treatment of hospital waste would technically become a concern. Once out of the body, the bacteria-based microrobots described in our study could easily be disposed of by sterilization techniques, such as using a detergent solution or by simply heating to sterilize. So you basically treat it as any other hospital waste.

I mentioned in another answer, so I am repeating that bacteria should be removed from the host body after the medical task is completed, therefore another concept, which is named termination switches, could be also added to bacteria to terminate them after they had carried out their task through NIR-triggered hyperthermia, antibiotics or bacterial lysis. THis way once the agents are outside of the body, they are already harmless.

Hope this answers your question!
All the best,
/birgül

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R3pa1r3d t1_j6naghs wrote

How closely, if at all, are these type of projects monitored by the government or intelligence agencies?

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intengineering t1_j6ohuu6 wrote

What an interesting question!

I am a researcher at one of the many Max Planck Institutes in Germany, and the Max Planck Society (MPG) is mainly financed by public funds from the federal government and the federal states. Therefore, all research done within the MPG is published as scientific articles in journals and conferences and they are 100% open to the public. Some publishers have a paywall, but virtually all research and results can be accessed. I wouldn't know if anybody is out there reading these papers for a specific reason other than gaining scientific knowledge from them! :)

Thanks and hope this answers the question!
All the best,
/birgül

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intengineering t1_j6oj33o wrote

Birgül here again!

A huge THANK YOU to everyone for the great questions! I enjoyed so much answering them! I tried to answer as much as I could, but I couldn't get them all. If you want you can follow me on Twitter for further questions: https://twitter.com/akolpoglu

Cheers,

/birgül

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Germanofthebored t1_j6nkh6g wrote

How do you use magnets on E.coli? Did you use the sensory systems of magnetotactic bacteria?

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intengineering t1_j6oas7f wrote

Thanks for your question! We attach nanomagnets on E. coli and control them using bigger magnets (centimeter scale) or electromagnetic coils for precise steering. Magnetized bacteria still swim using their flagellar propulsion, but follow the magnetic field lines, therefore making it possible for us to control them externally using magnetic fields.

All the best,
/birgül

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AdministrationLimp71 t1_j6mq0fp wrote

hi! curious layperson here: how do you physically equip the bacteria with something unfamiliar to them?… do you ask nicely? 😁

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intengineering t1_j6ob4pf wrote

Hi! Oh, I would love that, that could make life MUCH easier if bacteria could listen to the voice of reason! But no, we do it pretty scientifically!

In our work, the synthetic components were integrated onto Escherichia coli. We use a strain of E. coli that allows for one-step binding of such nanoparticles through a physical complex known as “biotin-streptavidin complex”. Basically, these bacteria have “biotin” protein that binds to the “streptavidin” protein that is on the surface of the nanomaterials we use here. We mix them together under certain conditions (temperature, shaking, and the type of liquid media are all very important), et voilà, your bacterial biohybrid microswimmers are ready.

Thanks for the Q.
All the best,
/birgül

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ShyHumorous t1_j6mpy3x wrote

If I am super rich and predisposed to a type of cancer how much money would I need to get to that point as to afford using new science and tech that you are using?

What could be the side effects of this type of technology?

What is your opinion on the last of us and the fungi turning people into zombies?

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intengineering t1_j6oao5y wrote

These are very interesting questions! Let me try to answer as much as I can.

As I mentioned in a previous question about “how close we are to using these medical tiny robots in clinics”, currently this technology is not there yet. There are many, many promising studies with animal models, for example, showing the localization of microrobots on tumor tissues for targeted drug release. Nevertheless, we still need extensive research on other aspects including safety, imaging, tracking, and controlling of these robots. Therefore, I cannot exactly give you numbers, since they are currently not commercialized.

As for the second question, the biggest concern would be safety. If the material(s) used in the robotic design is immunogenic, there is already the risk of an immune reaction. This could not only eliminate your tiny robot before it can do its job but also generate a health risk. Additionally, let’s say you plan to administer your robot through the circulatory system, then the size and shape of the robot are crucial since you wouldn’t want the clogging of the vasculature.

And for the last question, I haven’t played the game or seen the show (yet), but I am currently reading a book on fungi (it’s called Entangled Life: How fungi make our worlds, change our minds and shape our futures, by Merlin Sheldrake, it’s a super cool book, 100% recommend) and just recently found out about Ophiocordyceps unilateralis, aka zombie ant fungi. The mechanism of taking control over an ant compared to a human is drastically different. Turning people into “zombies” is rather sci-fi than science, but many organisms (viruses, bacteria, fungi, parasites, etc.) do have an enormous impact on human life that we cannot disregard.

All the best,

/birgül

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Yoda_VS_Fish t1_j6n48yv wrote

How difficult is it to construct such small components and equip bacteria with them?

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intengineering t1_j6obfg5 wrote

There are many technical challenges. All the synthetics parts that you want to equip your bacteria with should add an extra function to your swimmer. For instance, in our case, magnetic nanoparticles are added for swimming control using external magnetic fields, and nanoliposomes loaded with drugs are added for the demonstration of on-demand, localized drug release. One needs to carefully choose these synthetic components for the desired application, and design them accordingly. They need to be compatible, non-toxic, ideally smaller than your microorganism, and fully functional. Also, your microorganism should be able to accommodate the attachment of these synthetic cargoes. We use something called “biotin-avidin” interaction to equip bacteria with the components, and this had previously required the genetic modification of bacteria to express “biotin” on their cell surfaces, which is not a simple task either. Microorganisms also shouldn’t stop swimming after the addition of the synthetic components, because we want to harness their motility for active therapeutic applications.

Overall, designing a tiny robot out of a living, motile microorganism requires extensive planning and design on material development, genetic engineering, microscopic imaging, and viability checks after modifications and testing of their functions after the construction is complete.

Thanks for your question!
All the best,
/birgül

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BadassGhost t1_j6nkjr7 wrote

Do you believe that biological nanobots will be more useful for medical purposes than hypothetical artificial nanobots?

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intengineering t1_j6oblcy wrote

Thanks for the question! In contrast to their synthetic counterparts, biological nano- or microrobots can sense and respond to changes in their local environment, providing a higher level of autonomy. Also, most microorganisms can achieve high propulsion speeds (tens of their body lengths per second) and interact with their targets at the same size scale (1–10 μm). Such advantages make biohybrid cellular microrobots attractive candidates for medical applications, including targeted drug delivery. These are the main advantages, however, this is not to say biohybrid microrobots are always superior to synthetic ones since the selection of the micro and nanobots is highly application dependent.

All the best,
/birgül

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a_k_96 t1_j6n4ptr wrote

What is the potential of microalage in oil spill cleanup and management of petrochemical based carbon emissions in the atmosphere?

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intengineering t1_j6oced4 wrote

Thanks for the question! Although I am no expert in bioremediation, I know that several large-scale wastewater treatments with microalgal technologies have already demonstrated the capability of detoxifying organic and inorganic pollutants. Microalgae can remove contaminants through three different pathways; bioadsorption, biouptake, and biodegradation. For further information I would recommend these publications:

https://aiche.onlinelibrary.wiley.com/doi/epdf/10.1002/btpr.3098

https://pubmed.ncbi.nlm.nih.gov/31382151/#:~:text=Microalgae%20have%20demonstrated%20potential%20for,%2C%20bio%2Duptake%20and%20biodegradation

Our research on microorganism based microrobotics mainly focuses on their medical functions, but I am always interested in finding out more on other uses of these tiny swimmers!

Hope I could answer your question!

All the best,

/birgül

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Camel-Kid t1_j6nu5rk wrote

What are the complications with those baceteriabots attacking good cells/tissue?

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intengineering t1_j6od431 wrote

This is a very important question! This is exactly why we are opting for a system that is active and externally controllable. Using a tiny machine that can be selective towards non-healthy tissue, that can be externally controlled to accumulate in a specific location (i.e., tumor) and that is equipped with an on/off switch to release its cargo on-demand are all the desired features in bacteriabots. This way, you minimize the side effects on non-target healthy cells. Realistically, it is almost impossible to cause no harm to a healthy cell even with an active controllable system. In that case, our bodies have defense mechanisms (immune system) that can fight unwanted agents. It is crucial to make sure that the bacteriabots are safe for administration below a certain dose and that they are not causing any pathological response.

All the best,
/birgül

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tu-k t1_j6nz018 wrote

how much we need these "microalgae and bacteria-based microrobots" in our body to defeat cancer? Can they reproduce? And how will you manage their reproduction?

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intengineering t1_j6ocn8t wrote

Thank you for your questions. Depending on the size and location of cancer, we would need millions to more than billions of them to localize and generate enough therapeutic effect.
Yes, they reproduce and multiply, which can be undesired for biohybrid bacterial agents, because reproducing means dilution of the synthetic components. That means new bacteria without enough magnetic material on them, causing loss of steerability. However, there are genetic tools that stop microorganism growth, which could be ideal here. Reproducing should also be under control because your injected dose could be in the millions range, but you could easily reach billions within a matter of hours, since the duplication time of microorganisms can be just minutes (e.g., around 20 minutes for E. coli). Additionally, bacteria should be removed from the host body after the medical task is completed, therefore another concept, which is named termination switches, could be also added to bacteria to terminate them after they had carried out their task through laser-triggered hyperthermia, antibiotics, or bacterial lysis.

All the best,
/birgül

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neablis7 t1_j6o0nqh wrote

What are the important characteristics of the bacterial component to make this system work? Anything beyond motility and engineerability?

Is the surface display of biotin attachment peptides limited? Do you think you could see significant gains by using other bacteria, like clinically derived probiotics that are better adapted for nonpathogenic colonization? I'm thinking Lactobacillus here.

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intengineering t1_j6oh4gc wrote

In addition to motility and engineerability, (both very important, most probably the most key features you need in this system) bacteria can sense and respond to changes in their local environment, providing a higher level of autonomy (such as chemotaxis, pH taxis and even magnetotaxis in the case of magnetotactic bacteria). Their size is also an important feature, being in the sub-micron to 2-3 micrometer range helps for better tissue filtration.

It is definitely not limited, and other bacterial species are currently being used in such studies as well. Especially prebiotic and probiotic bacteria (e.g., E. coli Nissle; EcN) is a promising strain as well.

I didn't get into the specific role of bacteria in cancer therapy but here is my all-time favorite review paper on the subject, where you can find out more about the use of various bacterial agents in cancer immunotherapy!: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802035/pdf/IJMICRO2016-8451728.pdf

All the best,

/birgül

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neablis7 t1_j6oizso wrote

Thanks for the response! Interesting review article.

It does seem like a lot of these studies focus on either in-depth engineering of the bacteria (Like Tal Danino's lab) or lots of post-growth chemical/physical modification. It seems like there might be an opportunity to combine those approaches.

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[deleted] t1_j6o0vpt wrote

[deleted]

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intengineering t1_j6ocxk8 wrote

Merhaba!

As I mentioned in another answer, bacteria should be removed from the host body after the medical task is completed, therefore another concept, which is named termination switches, could be also added to bacteria to terminate them after they had carried out their task through laser-triggered hyperthermia, antibiotics or bacterial lysis. If no such mechanism to remove them is in place, you would expect them to be neutralized by the immune system (granted that they are below a pathological dose). Since they are of cellular material, they are also fully biodegradable.

All the best,
/birgül

P.S.: I actually have a Turkish keyboard!

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illuminaee7 t1_j6of4fp wrote

Hi Birgül!

I read that the mechanism for the treatment could be injections, considering that these are microorganisms alive and in high quantity, could they produce a high inmune response that reduce their ability to deliver the medicine?

It sound amazing!

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rex1030 t1_j6o10k1 wrote

Most “microbot” innovations require magnetic fields to run them. How far are we from truly autonomous microscopic robots?

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LeahBrahms t1_j6o3zne wrote

Is there any crossover in your studies with The Last of Us fungal pandemic scenario? Could your studies produce a defence to it?

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ames89 t1_j6o5lvr wrote

Hello! It's so awesome to meet you! Thanks so much for the breakthrough that you are working on! It's amazing!

One question! How do you encapsulate the chemical transported inside the bacteriabot to avoid interacting or being metabolized by the bacteriabot itself until it gets to it's destiny?

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Brockelley t1_j6p2bu3 wrote

microbots vs Ideonella sakaiensis (the bacteria that eat plastic)

Which will win the race in cleaning our waters and lowering the number of microplastics on the planet?

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jdogburger t1_j6nyenj wrote

What's to stop Putin from using them for assassinations?

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SimulatedNumbers t1_j6o8j3g wrote

Could they be used to take control of a brain?

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tyd12345 t1_j6o8xzp wrote

In what ways (if any) could this type of technology hypothetically be abused or used with ill-intent? Would it be possible in the future for someone to weaponize this type of technology? How would this be counteracted?

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aunrs t1_j6oadoo wrote

Super interesting work. I happen to work in related field. What is the advantage of using bacteria as drug carriers compared to nonliving systems? For example, similar targeting approaches have been explored using superparamagnetic iron oxide. Is there a concern that chemotherapeutic could be metabolized by the bacteria? Thanks!

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Ebayednoob t1_j6odio2 wrote

Do different wavelengths of light modify mitochondrial power output for microalgae or bacteria?

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Recent-Ad-6576 t1_j6oewj9 wrote

How many of these nanobots do you think you could manufacture and is it expensive, and if so for what reasons? Could these hypothetically be used to do something like clear prions from the brain if you had enough of them, or could you make smaller ones? Thank you.

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-brownsherlock- t1_j6og6w7 wrote

Did you do any research which bottomed out, but you secretly think will be super relevant one day?

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Vetjul t1_j6oi98l wrote

Hi ! Can the biohybrid pass their modifications to other bacteria ? Have they any effect on the human microbiata ? And finally, do you plan to apply this king of technology to the animals (for exemple cows or pigs in the food industry) or even in food safety ?

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illegalsmile34 t1_j6ojp02 wrote

Are there military applications of this research?

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LearnedGuy t1_j6olrcv wrote

It appears that the U.S. CIA has been making contributions to universities for the study of extremophiles. Do you know wgat the use-case would be for them? They are at such depths and pressures that they might be a stepping stone organusm to study. If ghey could be coaxed to work in a more moderate context , then they might be able to assist in processing magnesium, iron, or rare earth minerals.

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SorryButButt t1_j6ombrf wrote

What is something you are most proud of?

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neonquasar424 t1_j6omvi6 wrote

do you happen to have a favorite quote?

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AlienEroc t1_j6oyozq wrote

Can you use what you’re doing to directly attack other bacteria? Like, borrelia burgdorferi, for example

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amigo-vibora t1_j6ozmfe wrote

when can such a treatment become a reality to fight cancer? are we talking decades? is affordability ever contemplated in these type of research?

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canis11 t1_j6p5vzg wrote

Anything that could help pancreatic cancer! Amazing work keep it up

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Man_The_Machine t1_j6pawcw wrote

Hi! Any plans to combine this with other nano particle based delivery like lipid nano particles or polymer scaffolds?

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Zealousideal-Hunt343 t1_j6pbden wrote

Hi , Amazing work!
Just wanna share some of our research on controlling the spatial variance of such microbots. We propose a light weight motion primitive based control method for aggregation of a swarm using global magnetic input. hope you find this interesting.

https://link.springer.com/article/10.1007/s11370-022-00421-x

Hi, Amazing work!
Just wanna share some of our research on controlling the spatial variance of such microbots. We propose a lightweight motion primitive-based control method for the aggregation of a swarm using global magnetic input. Hope you find this interesting.

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