A new genetic engineering technique allows scientists to specify a particular level of gene expression in cells, which could lead to key insights about complex disease mechanisms. Image Credit: Flickr user FotoMediamatic

Researchers at Washington University in St. Louis have developed a novel genetic engineering technique that allows scientists to control exactly how much protein is produced from a particular gene. In January 2017, they published a paper in Nature Communications describing a method for generating hypomorphic mutations—that is, mutations that lead to a reduction in the amount of gene product.1

The authors have proposed a variety of scientific applications for this new method. For instance, it could be used to genetically engineer crops that are able to grow with less water. It could also be employed by biologics manufacturers who are trying to optimize product production.2 But perhaps the most immediate application is in disease research. This method can enable researchers to more closely evaluate the effects of particular genes on disease processes than they have in the past. As biomedical scientists start using this method to support their research, they can benefit from workflow authoring and execution software.

Research Advantages of the New Genetic Engineering Method

In the hypomorphic mutation engineering method described by the Washington University researchers, strings of consecutive adenosine nucleotides, also known as polyA tracks, are introduced into mRNA in order to lower the overall translation efficiency. PolyA tracks are cis regulatory elements that cause ribosomal stalling and frameshifts, so inserting them into the open reading frame leads to mRNA instability and the production of peptide chains that are targeted for degradation. As a result, less of the expected protein is produced.3

In complex diseases, like cancer and autism, scientists know that certain genes are downregulated, but they do not understand how that contributes specifically to the disease etiology. This method provides several key advantages for scientists who are studying complicated disease mechanisms:


  • Increasing the speed of research


Traditionally, hypomorphic mutations have been generated through chemical mutagenesis screens. However, creating a mutation that leads to the production of a specific amount of gene product requires extensive experimentation. Scientists need to isolate, identify and characterize the allele before they even begin to start creating genetic analysis procedures. That means it could be years before they start getting results. According to the Washington University researchers, their method could cut the process time to a matter of days.


  • Making it possible to study more genes


Another way that scientists have previously used to study downregulated genes is to knock out out one or both copies of the gene. However, standard gene knockouts are not always able to accurately replicate what actually happens in the cell. For instance, if both copies of the gene are knocked out, it is often lethal, so scientists cannot study the downstream or long-term effects. On the other hand, if only one copy is knocked out, there may be no effects, since one copy may be sufficient for normal function. With a more easily controlled hypomorphic mutation engineering method, scientists can reproduce the exact amount of gene that is produced in the disease state, or any other amount that they desire. This may make it possible to gain insight into the roles of genes that have previously been difficult to study due to lethality and haplosufficiency issues.


  • Applications to multiple species


The new method for generating hypomorphic mutations also stands out because it is applicable to multiple species. When running a chemical mutagenesis screen or preparing a knockout protocol, the method is usually unique to a single organism. However, because the mRNA translation machinery varies only minimally between organisms, adding polyA tracks can work in lots of model organisms, as well as in cell culture. Indeed, the researchers at Washington University in St. Louis demonstrated that their method works in bacteria, yeast, protozoans, Drosophila, mice, plant tissue and human tissue culture, so it is clearly applicable in almost any kind of disease research lab.

Integration Into Lab Procedures

Disease research labs that plan to start using this new genetic engineering technique for their work can benefit from workflow authoring tools that standardize the creation of procedures. This can be especially helpful for widely applicable techniques, like the creation of hypomorphic mutations through polyA track insertion, because the same general technique can be reused and tweaked in multiple protocols. For instance, a standard method can be altered slightly for experiments on different genes or in different organisms, without having to rewrite the entire protocol from scratch.

These protocols can also be supported by method execution applications, which provide an easy-to-follow interface for scientists who are conducting the experiments. Since hypomorphic mutation creation procedures are likely to be similar—but not exactly the same—for experiments on various genes and diseases, this software makes it easier to avoid overlooking project-specific methodological changes or accidentally skipping a step when implementing a new protocol. Plus, the procedural information is accessible from mobile devices, so researchers will have constant access to their notes as they walk around the lab.

BIOVIA Compose is a workflow authoring software application for standardized procedure creation, and it is supported by BIOVIA Capture, a standardized method execution application that is compatible with mobile devices like tablets. Contact us today to learn more about how these technologies can improve research efficiency in your lab when implementing new techniques like the recently-described genetic engineering method for hypomorphic mutation creation.

  1. “Hypomorphic mutation,” April 4, 2017, http://www.informatics.jax.org/glossary/hypomorphic
  2. “New genetic engineering technique could help design, study biological systems,” January 20, 2017, https://medicine.wustl.edu/news/new-genetic-engineering-technique-help-design-study-biological-systems/
  3. “Rapid generation of hypomorphic mutations,” January 20, 2017, https://www.nature.com/articles/ncomms14112