Combatting Antibiotic Resistance with Nanotechnology, Robotics, and AI

Q: What will this first product treat?  

We focused on urinary tract infections because they’re a common indication for antibiotic use, so introducing an alternative treatment is a great way to immediately reduce antibiotic prescriptions and help slow down antibiotic resistance. We partnered with wastewater facilities to collect a huge range of phages and acquired samples of more than 1,700 uropathogenic E. coli (UPEC) strains, which is a subtype of E. coli found in digestive tracts that are responsible for most UTIs. Out of these, we chose 356 for our testing panel; all these strains were isolated from actual patients across the U.S. and 29% were multi-drug resistant. Our fully automated processes allowed us to test 2.5 million different phage-host combinations to find the best cocktail. The resulting drug candidate is a mixture of six phages. Some are still wild-type and some of the ones we identified have been engineered to be even more potent against the E. coli. In lab trials done by Locus Biosciences, the cocktail was 96.4% effective against the 356 strains, and demonstrated a strong safety signal with suggestive efficacy indicators in the phase 1 clinical trial.

Q: Now you’re back at Berkeley Lab working to automate discovery for quantum materials, but also still working on biology?

Yes, what I’m trying to do now is develop what are called “single particle assays,” so tests that are sensitive enough that you only need the tiniest sample — as little as one particle of what you’re interested in. Because you don’t actually have to do an entire 100 microliter reaction volume to know if a phage kills the bacteria. All you need to do is be able to have a phase contrast micrograph or a fluorescent tagging micrograph to show that there’s a lysis event with high statistical probability or have a single-cell sensing modality to detect lysis events. So that’s what my research is focusing on here. I run a microfluidics and nano fluidics fab at the Molecular Foundry trying to figure out how to use nano-scale magnetic sensors and nano-scale plasmonic antennas, like those used in the hard drive industry, to make miniaturized biosensors that could offer an alternative to the biology-based methods that use antibodies or fluorescent tag molecules and lots of pipettes and little well plates.

I’m trying to work on sensors that would be able to detect a single molecule, like a single nucleotide or amino acid or sugar, as well as its position, so we can do atomic resolution biology. And it’s very hard! It’s probably going to take ten years, but it would have a lot of applications, for example, early detection of cancer. The current assays [on the market] are very sensitive for even a small number of molecules in a sample, but what you’ve lost along the way is knowing exactly where the molecule is coming from. These biological techniques [like PCR] are like using a magnet to pull a needle out of a haystack. You found it, but where had it been? Our process uses plasmonic sensors — which are already used in validated technologies like pregnancy tests — and tunnel junction sensors, which use the wavefunction character of electrons, to show you the source of a particular molecule in a single cell or virus particle. That missing information will tell us a lot more about the disease and how it develops. For example, this technology could be used to study a newly discovered protein that is made by pancreatic cancer cells, potentially allowing for earlier detection and a better understanding of early-stage disease.

The other advantage is that by creating these highly sensitive antennas to broadcast information from single molecules we hope to enable what’s called label-free diagnostics, where you don’t need any tagging molecules or stains or other products that potentially interfere with how the cell you’re studying behaves. You’re looking at the cell or virus in its natural state, while it is in close proximity to electronics or optical antennas that broadcast information about the biological status.

Q: Are you continuing to work on phages alongside the other researchers at the Lab?

Yes, the Phage Foundry is amazing. Vivek [Mutalik] and the team are working on really interesting basic science problems in phages without a commercialization agenda. They’re building a biobank of well characterized phages, phage datasheets consisting of information on receptor usage [which receptors phages use to enter bacterial cells], gene essentiality, and AI/ML workflows predicting phage effectiveness on different strains and how phages affect microbiomes. It’s an incredible resource to have to continue my research on phages and for other groups, because thankfully there are other people developing phage therapies. If I, or someone else, want to study phages relevant to antibiotic therapy, we can go to this public repository of phages, and it’s a huge boon because it’s very, very expensive and challenging to set up phage growth and screening efforts to study phages like we did at EpiBiome and Locus.

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Lawrence Berkeley National Laboratory (Berkeley Lab) is committed to groundbreaking research focused on discovery science and solutions for abundant and reliable energy supplies. The lab’s expertise spans materials, chemistry, physics, biology, earth and environmental science, mathematics, and computing. Researchers from around the world rely on the lab’s world-class scientific facilities for their own pioneering research. Founded in 1931 on the belief that the biggest problems are best addressed by teams, Berkeley Lab and its scientists have been recognized with 17 Nobel Prizes. Berkeley Lab is a multiprogram national laboratory managed by the University of California for the U.S. Department of Energy’s Office of Science. 

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