Let's Google Our DNA on a Chip

Now you can search a gene sequence digitally, instead of using PCR.

A Drop of DNA on the Chip Delivers the Confirmation of the Presence of Specific Genes

We know that every gene encodes a specific protein, and every protein has its function and plays a crucial role in the body. It could be an enzyme, a surface receptor, or a structural component. The mutation of these genes causes many hereditary diseases because it cannot generate that specific protein normally from the DNA strand. For example, mutations on chromosome 5 in a gene called SMN1 (Survival of motor neuron 1), which is responsible for making the motor neuron protein (SMN). Without this SMN protein, one is unable to move the muscles because of the nerve cells unable to signal the muscle cells from the spinal cord. Another example is Duchenne Muscular Dystrophy (DMD), characterized by the mutation on the X chromosome that passed on by the mother can cause Duchenne, where it failed to make a normal dystrophin protein that used by the muscle cells. This X-linked disease primarily affects boys because girls have two X chromosomes, so girls have a higher chance of having a healthy gene that encodes the normal protein than boys.

The traditional way of finding a specific gene through roughly 3 billion-letter human genome is using the technique called polymerase chain reaction (PCR). The method of PCR is to generate millions of more copies of a particular segment of a specific DNA segment and then using Quantitative PCR (qPCR) to sequence the DNA sequence. However, the PCR method is tedious, time-consuming, and error-prone.

The newly invented method of identifying a specific gene on the chip is quick, inexpensive, and highly accurate. This brilliant invention is called CRISPR-Chip. As you may have heard about gene editing in recent years, CRISPR empowers scientists to do gene editing. CRISPR is a group of DNA sequences found in bacteria used to defend bacteria virus or bacteriophages by using a combined effort of Cas9 protein and CRISPR sequences. The antiviral mechanism works by keeping some samples of DNA sequences from previously encountered bacteriophages. The Cas9 protein acts as both a finder and a scissor that looks for these sample sequences against the foreign DNA strands. If the Cas9 protein found a match, it will activate the cutter side of the protein and cut and destroy the phage DNA that injected by the bacteriophages.

By learning the mechanism of antiviral used by bacteria, scientists, Jennifer Doudna and Emmanuelle Charpentier, devised a CRISPR gene-editing tool in 2012, which consists of guide RNA, a map to the target location with the Cas9 protein, and donor DNA. Once the desired sequence is matched, the Cas9 cuts the DNA then swaps in the donor gene for the mutated one in a process called homology-directed repair (HDR).

On the side of electronics advancement, Andre Geim and Kostya Novoselov revolutionized the new transistor in 2004 by using graphite to create a single layer of carbon lattice to build a brand new type of transistor. Unlike the traditional bipolar junction transistors, it is a field-effect transistor (FET) that consists of a semiconductor channel, the source, and the drain. It can be used in many applications, such as biological and chemical sensors.

The CRISPR genetic locus provides bacteria with a defense mechanism to protect them from repeated phage infections. (Source: Wikipedia)

By uniting the advancement in gene editing and transistor innovation, Kiana Aran, a scientist at UC Berkeley, brings the two technologies together to create the CRISPR-Chip. By immobilizing the CRISPR complexes on the surface of graphene-based transistors, a drop of DNA on the CRISPR-Chip will allow the CRISPR protein to unwind the strands of sample DNA naturally. If there is a match between the desired gene sequence and the sample DNA, it will bind together. The binding creates a change in the conductivity of the graphene material in the transistor. Later, the handheld reader (developed by Cardea Bio) received signals from the transistors and display whether a certain gene is detected. In case you are like me, want to dig further on its mechanism. The Cas9 protein on the chip does not cut the DNA strand when it finds and matches the sequence as in the gene-editing process because the Cas9 used on the chip is dead or inactive catalytically, but its recognition function is still intact.

A team of engineers at UC Berkeley and the Keck Graduate Institute (KGI) of The Claremont Colleges combined CRISPR with electronic transistors made from graphene to create a new hand-held device that can detect specific genetic mutations in a matter of minutes.

CRISPR-Chip is another example of uniting digital and biochemistry fields, and for the first time, this invention looks like an instrument used in Star Trek. If you think about it, CRISPR-Chip technology is a powerful tool since it is like Google for the genome. Instead of using the amplified technique PCR, now you can program the tiny CRISPR-graphene transistors to accept the “search term” by manipulating the desired guide RNA or Duchenne guide RNA if you want to detect the DMD genetic disease. The programmed CRISPR will run through the entire genome and scan for target sequences and then deliver the search results electronically.

This CRISPR-Chip technology opens many doors for its applications. In the area of disease diagnostics, it can help to identify many genetic and non-genetic diseases such as cancer. It can assist the quality control of gene editing and improve immunotherapy. It also opens a future of possibilities, such as combining other nanoscale electronics devices with modern biology. According to Aran and her research team, the CRISPR-Chip technology is quite sensitive as it can detect and locate for single-point mutations. The testing process with the CRISPR-Chip is amazingly fast, and it usually takes less than an hour. Imagine if we can uniting the CRISPR-Chip technologies with IoT devices in the future, we can transform the IoT sensor devices to another level of applications, and we may be able to report findings in real-time in any location.