Glowing Blue Honeycomb

Michael Heltzen, CEO and co-founder of Cardea Bio, a San Diego startup integrating tiny bits of biology into modern electronics, believes that the way researchers have been observing biological signals is about to change.

Our ability to “see” detail in space and time is limited by resolution. Take, for example, the noisiness of a person’s image on a digital video camera. At a low signal-to-noise ratio, an image is indecipherable, but with increasing sensor quality the image becomes progressively recognizable as a face and then a specific individual. If we only have one frame to look at, the image will be static, but with consecutive images appearing on a display we can see the person blink or make a change in facial expression.

This rings as true for human sight as does for any analytical measurement, especially in the life sciences. For example, when we want to examine a 3D genome, we amplify the genome to have enough of it to get a reflection out of it by illuminating it with a laser. But this “genome” is not in its dynamic, natural state—it is fragmented and static. This genome has typically been run through a molecular meat grinder, ripped up into small fragments, boiled to make it fall apart, and amplified with artificial nucleotides. It’s almost like using a hammer to probe a computer and smashing it up to study the pieces.

But creating these genomic snapshots does little to provide richer information of real-time biological interactions. “Using optics to observe live biological signals means that we only have one narrow perspective on a whole orchestra of different biological signals,” says Heltzen. “We can listen into one vertical, either genomics or proteomics, and it will often limit the signals that we get instead of being able to interact with them.”

A new gate to nature’s signals

In Roman mythology, Cardea was the goddess of door hinges and handles who prevented evil spirits from crossing thresholds. So, it is not surprising that at the core of Cardea Bio’s technology is their graphene-based, biology-gated transistors—called “Cardean Transistors.” These transistors leverage graphene, a nanomaterial that, in contrast to the common semiconductor material silicon, is biocompatible and a near perfect conductor due to only being one atom thick. Graphene’s conductive qualities can therefore provide interactive live-streams of biological signal analysis, replacing optical static observations.

“It’s a different way of thinking about life science research because we’re basically saying that all signals of biology are binding interactions,” says Heltzen. “That’s how information is transferred from one molecule to another. When we take transistors and make one site of that binding interaction as the gate, if the binding interaction is there, there will be a change of the gate. This basically flips life science thinking upside down because there’s no optics. There’s no analyte type of conversation. There’s no laser. There’s no heat. There’s no data sets to be converted from optical signals.”

Since Cardea Bio’s system is based on binding interactions, it can probe any combination of biologically based binding interactions.

For example, if you want to probe for a protein biomarker, you would exploit the unique capturing mechanism between an antibody to an antigen. In this scenario, the antibody would be linked to the gate in the biological transistor—if the antigen and antibody bind, the gate closes, and, if not, the gate remains open. This ability yields a computer chip that, when introduced to a sample containing the biomarker, will change gate states the same way that the transistors in computers change gates for ones and zeros. On top of that, you now have a live signal for that one biomarker.

“The Cardean Transistor technology opens up the potential for new insights into biomarkers and molecular signals,” says Tad Weems, managing director, Early Stage Partnerships at Agilent Technologies. “The technology reads dynamic molecular signals as a function of time which means researchers will be able to interact directly with biology and observe changes in the biomarker signals. Additionally, the technology has multi-omic applications in that it will allow researchers to observe DNA, RNA, and protein biomarkers simultaneously. We believe there is not only a large market potential for these multi-omic devices, but the technology also has the potential to change patient lives.”

Heltzen believes this will be the start of a paradigm-shift in many areas of life science and biotech, due to the multi-omics data streaming of DNA, RNA, and protein signals from biology fed to computers in near real time. “We were very adamant about the need of a multi-omics system where the analytes on their own can keep doing what they do because otherwise this integration up against computers is not going to work,” says Heltzen. “If we’ve destroyed the signal in the process of detecting it, it doesn’t make sense. With this, we are getting to the next generation of systems biology.”

A digital CRISPR world

Cardea launched its breakthrough chipset called CRISPR-Chip built with its proprietary transistors. The chipset uses CRISPR as the transistor gate, and thereby harvests CRISPR’s powerful natural ability to search through genomes for genetic sequences of interest, enabling the user to observe the CRISPR search activity and results in real-time on a computer screen. “CRISPR has this feature of being able to run through a genome in record speeds and find specific areas,” says Heltzen. “So, we have made CRISPR the gate, and when it finds its target—for example, a gene with a certain mutation—it changes the gate signal.”

CRISPR-Chip technology
Built with CRISPR-Chip technology, Cardea Bio touts the Genome Sensor as the world’s first DNA search engine.

In addition, Cardea Bio is working with partners to create a new generation of applications. Recently, it announced the global launch of a CRISPR quality control tool—its first proprietary “Powered by Cardea” product in partnership. This idea was born out of CRISPR researchers wanting to take a guide RNA and, live on the screen, measure the kinetic strength of the guide RNA’s binding to the Cas protein. The result was CRISPR-BIND, the first of a series of quality control applications that will come out of a partnership with CRISPR QC. This tool is a fast and sensitive high-throughput liquid handler that performs quality control of CRISPR-Cas complexes and gRNA. It can also be used to optimize CRISPR designs and identify the most optimal conditions for each CRISPR experiment.

Transistor diagnostics for pandemics and COVID-19

With pandemics like COVID-19, the diagnostic bottlenecks are PCR and DNA amplification. “The world right now is basically doing a PCR test that is a reverse-transcription of the RNA into DNA that is just a super artificial step that then goes through the whole amplification phase,” Heltzen says. He believes PCR doesn’t reveal anything about virus load, virus versions, or even if the virus is alive or dead—the readout is simply that those nucleotides were in the sample.

When it comes to COVID-19, Cardea Bio takes multi-omics approach. “So, you have this RNA virus itself that comes and looks at an ACE2 receptor that is an entrance into a cell,” says Heltzen. “We can test for the virus RNA. We can test for the use of the ACE2 receptor by using it as a gate to say that the virus is basically here now. We can look at the spike proteins or even the different sub domains of the spike protein.”

To leverage their unique technology, Heltzen says Cardea Bio is creating a future pandemic solution based on handheld devices that can provide deeper insight into not just whether a person has the virus, but how their immune system is reacting to it. He believes that getting these answers, in real time, at scale will save lives. “We know how to use the semiconductor industry infrastructure to make tests, and there’s no other industry that knows how to make billions of units at the same time,” says Heltzen. “That is really the numbers we need—tens of millions—and over time billions.”

A plug and play toolbox to query life

Although the long-term goal for Cardea Bio is medical impact, it has applied its technology first in agriculture.

“We’re not going to mess around with things as important as human life until we have all technical bugs out of the platform,” says Heltzen.

The medical impact Heltzen sees is a future where doctors query all the biological systems of a patient during an office visit. “We already have the best security systems and surveillance systems—it’s called the immune system,” he says.

“The cells are communicating to each other, systems are communicating to each other, but the doctor standing there doesn’t have a way of listening to that,” Heltzen continues. “We need the doctors to have live streams coming from the patients, and we already have the wildest technology stack, the patient himself, sitting there, ready to give the signals.”

Heltzen says that Cardea Bio’s long game is to build chipsets that query all the relevant biological channels, no matter what the binding interaction is. He calls them chipsets because he envisions eventually providing ready-made modules with digitized biology at its core and infrastructure built around it.

“Think of it like Legos (sic), where you can get a catalog of all the different LEGO® blocks and you can be the creator,” says Heltzen. “We want to open up a developer community of people that understand the diseases, the opportunities, the problems, much better than us because we’re not going to tell people what to build.”

Heltzen believes that such a community will take all the components that have been developed by biology over the past few billion years and start using them as a technology to release a new generation of natural resources on this planet.

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