7 June 2022

There is a long running interest in the idea of machine-organism hybrids, although the integration of electronic and biological systems remains underdeveloped. Professor Kirill Alexandrov and his collaborators received Human Frontier Science Program (HFSP) funding to explore the 'undoable'. Multidisciplinary teams are a must and spur new creative projects.

Photo: QUT

2018 - Grant Awardees - Program Grants

Controlling cellular biochemistry with electronic signals – a step towards bioelectronic hybrids

Professor Kirill Alexandrov 
Professor of Synthetic Biology, Queensland University of Technology 

Professor Evgeny Katz 
Professor / Milton Kerker Chair in Colloid Science, Chemistry & Biomolecular Science, Clarkson University - Potsdam, NY 

Professor Ciara O' Sullivan 
Department of Chemical Engineering - Universitat Rovira i Virgili - Tarragona – Spain

Read more in the abstract.


Please describe the research project you undertook with the funding support from HFSP? 

The funding supported a Synthetic Biology project aimed at creation of bi-directional communication between living organisms and bioelectronic devices. 

There is a long running interest in the idea of machine-organism hybrids, although the integration of electronic and biological systems remains underdeveloped.

Our team of protein engineers and electrochemists developed a novel approach for constructing artificial allosteric enzymes capable of producing electric current when activated by different biological inputs such as peptides, small molecules, and biochemical activities (proteolysis). 

The applications of the developed approaches are potentially far reaching. What we are looking at are fundamental molecular technologies that can enable living systems and electronic devices to exchange information seamlessly. In other words, it is the core toolbox for building cyborgs.

Yet we won’t wake up one morning and everybody is a cyborg. Instead, you wake up one morning and this person has got glasses, that guy has a walking stick, that person has an insulin pump, they’ve got an artificial pancreas.  There is a whole road of steppingstones from replacements to enhancement and to fully-fledged cyborgs that are interfaced with non-human intelligence.  

How did this funding program enable you to undertake your research?

HFSP funds research that is undoable and unfundable through national funding schemes. Our project fully fell into that category. 

HFSP is looking for disruptive innovation: is this novel? 

There were objections to what we were proposing as it was considered to be not ‘doable’. The granting committee said, if it's not doable but visionary then it fits the objectives of the scheme.

By bringing an Australian protein engineering team together with a US team of electrochemists and a Spanish team of electrical engineers, we were able to attack the problem in the manner that would not be possible by an individual laboratory. 

How has collaborating with international researchers support your research effort, and your research career?

HFSP collaboration resulted in a range of publications in top journals as well as joint research grants from other funding agencies such the US Department of Defense.  Joint workshops and conference attendance have spurred new creative projects. 

What are the advantages about collaborating internationally, both scientifically and for developing professional relationships/networks? Are there any challenges?

We all have limited cognitive capacity. There is no such thing as biology because biology is just a subdivision of polymer chemistry. As a matter of fact, there is no such thing as chemistry as it's an empirical subdivision of quantum physics. The reason why we call them disciplines is just because we are unable to make sense of this unified world that exceeds our cognitive capacity by orders of magnitude. 

Therefore, the multidisciplinary teams are a must. There's no other way. As long as we don't have functional, general-intelligence AI, we have to put our pitiful brains together.

We’ve never actually been in the same room with our US collaborators. I met the Spaniards, twice, but I’ve never met the US Chief Investigator. Because of COVID, we will probably finish the project before I manage to travel to the US. 

But just because we’re separated, it’s the same way we’re separated by different disciplinary boundaries, we can still share information.

We do a lot of zoom calls. It was a great collaboration and a testimony to the modern communications. 

Physical objects can be shipped and we did a lot of shipping to the US. 

What have been the outcomes of the research?

We made very significant progress in developing proteins that can produce electric current on encountering the analytes of choice. Such molecules are excellent candidates for the next generation of diagnostic and physiological monitoring devices. 

It has been like discovering a goldmine. We’ve developed prototypes of miniature diagnostic devices that were reasonably easy to target to different biomarkers. We were very tempted to go and try to do different things with it. Can we measure this drug? Can they measure that drug? Can it be made out of metal, can be made out of carbon? Can it work in saliva, can it work in serum? Can we measure continuously? Can we measure two things at the same time?

Each of those questions led to its own publications. Essentially, we’ve created a body of evidence that this can be done, that this is an important, that this is feasible, both scientifically but also technologically.

We have published 10 papers and received an additional grant from the US Department of Defense on cyborg biology. We will be applying for more joint grants. The HFSP grant was very important for both labs and for the project in general.

What have been the longer lasting benefits of this HFSP grant and working with international networks?

The collaboration that we established will live long past the lifetime of the HFSP grant and will further advance the objectives of the original program. 

Further reading:

Towards cyborg biology - electrochemical biosensors of everything
HFSP website

Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices. 
Guo Z., Smutok O., Johnston WA, Walden P., Ungerer J., Peat TS, Newman J, Parker J, Nebl N., Hepburn C., Melman A., Suderman R, Katz E. and Alexandrov K.,  Nature Communications 2021, 12 (1), 1-13

Connecting Artificial Proteolytic and Electrochemical Signaling Systems with Caged Messenger Peptides.
Bollella P, Edwardraja S, Guo Z, Vickers CE, Whitfield J, Walden P, Melman A, Alexandrov K, Katz E.
ACS Sens. 2021 Oct 22;6(10):3596-3603. doi: 10.1021/acssensors.1c00845. Epub 2021 Oct 12.
PMID: 34637274
Circular permutated PQQ-glucose dehydrogenase as an ultrasensitive electrochemical biosensor.
Alexandrov K, Guo Z, Smutok O, Wayne A Johnston WAJ, Ergun Ayva C, Walden PM, McWhinney B, Ungerer J, Melman A, Katz E.
Angew Chem Int Ed Engl. 2021 Oct 11. doi: 10.1002/anie.202109005. Online ahead of print.
PMID: 34633119
Self-powered molecule release systems activated with chemical signals processed through reconfigurable Implication or Inhibition Boolean logic gates.
Bollella P, Guo Z, Edwardraja S, Krishna Kadambar V, Alexandrov K, Melman A, Katz E.
Bioelectrochemistry. 2021 Apr;138:107735. doi: 10.1016/j.bioelechem.2020.107735. Epub 2020 Dec 28.
PMID: 33482577
Control of allosteric electrochemical protein switch using magnetic signals.
Bollella P, Edwardraja S, Guo Z, Alexandrov K, Katz E.
Chem Commun (Camb). 2020 Aug 11;56(64):9206-9209. doi: 10.1039/d0cc04284f.
PMID: 32662462

Professor Kirill Alexandrov obtained his Masters degree in Invertebrate Zoology at the Leningrad State University, Russia, and completed his PhD in Cell Biology at EMBL Heidelberg, Germany. He went on to postgraduate work at the Department of Physical Biochemistry at the Max-Planck Institute in Dortmund and joined the Institute for Molecular Bioscience and the Australian Institute for Bioengineering and Biotechnology of the University of Queensland, Australia, in 2008 as an Australian Research Council Future Fellow. He co-founded the German biotechnology company JenaBioscience GmbH and the UK/Australian Synthetic Biology company Molecular Warehouse Ltd. In 2018 he joined Queensland University of Technology as a CSIRO-QUT Inaugural Professor of Synthetic Biology.