Cellular Engineering: Cutting-Edge Cell Manipulation Technologies

Research into cellular engineering through genome editing technologies such as CRISPR/Cas9, TALENs, and ZFNs has grown over the decades since their revolutionary introduction to medical treatment. This article will provide an overview of cellular engineering and the latest technologies used in cell manipulation for the innovative treatment of various human diseases.1

Image Credit: Yurchanka Siarhei/Shutterstock.com

Image Credit: Yurchanka Siarhei/Shutterstock.com

Introduction to Cellular Engineering

Cellular engineering can be described as the application of engineering principles and strategies to problems in cellular and molecular biology. This enables the quantification of data, establishment of interrelationships, as well as modeling of biological, chemical, and physical concepts.2

Cell manipulation technologies through gene therapy were initially introduced in the 1960s with the development of recombinant DNA technology. More than 1,900 clinical trials have been conducted since the early 1990s for the treatment of genetic diseases and cancers using predominantly viral vectors.1

Advancements in Cell Manipulation Techniques

The advancement of genetic engineering led to the establishment of genome editing tools, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) in the 2000s, as well as the more recently developed technology, CRISPR/Cas9 (clustered regularly interspaced palindromic repeats), which induces genome modifications at specific target sites.1

ZFNs include fusions of the non-specific DNA cleavage domain of the Fok I restriction endonuclease and zinc-finger proteins that result in DNA double-strand breaks.1

TALENs consist of fusions of the Fok I cleavage domain and DNA-binding domains, which are derivatives of TALE proteins. TALE proteins include multiple 33-35 amino acid repeat domains that recognize a single base pair, resulting in targeted double-strand breaks, which is similar to ZFNs.1

CCC | What is Cellular Engineering?

Additionally, optogenetics can also be used to precisely control and monitor the biological functions of cells, tissues, and organs that have been modified to express photosensitive proteins. The photosensitive proteins are optical sensors that provide fluorescent readout for biological activity changes.3

Genome editing tools have led to the development of novel treatment approaches for a range of different diseases and disorders, including genetic diseases and cancers. CRISPR/Cas9 and TALEN technologies have resulted in breakthroughs, including improving the effect of cancer immunotherapy through genome-engineered T cells.1

Interestingly, engineered T cells express synthetic receptors (chimeric antigen receptors (CARs)) that have the ability to recognize epitopes on tumor cells, and the Food and Drug Administration (FDA) has approved two products for B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma that utilizes CD19-targeting CAR-T cells.1

Applications in Medicine and Research

Cellular engineering is a revolutionary advancement for the field of medicine as well as for medical treatments, with CRISPR/Cas9 technology leading to a high volume of genome editing approaches being applied to a range of genetic disorders and cancers. This has a significant impact on inherited genetic diseases with known gene mutations, which have the potential to be corrected using this novel innovative technology.4

Many recent clinical trials have been using genome editing technologies for the treatment of various diseases, including CRISPR/Cas9, which is involved in trials under development for multiple myeloma, leukemia, and B-cell malignancies with the use of CAR-T cells as a vector. Additionally, TALENs technology has also been used with CAR-T cells for B-cell acute lymphoblastic leukemia as well as acute myeloid leukemia. In contrast, ZFN has used hematopoetic stem cells for the treatment of sickle cell disease, B-thalassemia, and HIV in clinical trials.1

These revolutionary scientific advancements provide hope for treatments of many diseases and disorders that may have had a lower prognosis with traditional treatment options or may not have had a viable treatment option, such as the treatment of brain tumors.1

Challenges and Future Prospects

There are many challenges to overcome to achieve safe clinical application of these powerful genetic engineering tools, including off-target effects that have been demonstrated in many studies involving Cas9/guide RNA complexes.1

However, research in this area has led to the selection of unique target sites without closely homologous sequencing, which has subsequently caused minimum off-target effects to be seen.1

Other CRISPR/Cas 9 genetic editing tools have been developed to minimize off-target effects, including guide RNA modifications with slightly truncated guide RNAs with smaller regions of target complementarity of less than 20 nucleotides. Affirmative screening processes of off-target effects are also used in order to ensure the genome editing tool is applied safely.1

Application of genome editing technology can also be challenging, with gene therapy involving both in vivo and ex vivo strategies. The in vivo strategy consists of vectors that contain therapeutic genes that are delivered directly to the patients, with the genetic modification occurring in situ.1

Ex vivo strategies involve harvested cells that are modified by gene editing tools in vitro through recombinant viruses and genome editing technology, with the modified cells then being delivered back to the patient through autologous or allogeneic transplantation after the off-target effects have been evaluated.1

Conclusion

While there are challenges facing these innovative cellular engineering technologies for the treatment of diseases, the optimization of vectors and novel techniques promises a significant impact on medical treatment in the future.1

CRISPR/Cas9 is considered to be one of the most powerful genetic engineering tools because of its high efficiency, low cost, and ease of use. While it has progressed since its introduction, this technology is expected to advance continuously in order to provide safe clinical applications for a range of human diseases.1

Sources

  1. Tamura R, Toda M. Historic overview of genetic engineering technologies for human gene therapy. Neurologia medico-chirurgica. 2020;60(10):483-491. doi:10.2176/nmc.ra.2020-0049
  2. Nerem RM. Cellular engineering. Annals of Biomedical Engineering. 1991;19(5):529-545. doi:10.1007/bf02367396
  3. Joshi J, Rubart M, Zhu W. Optogenetics: Background, methodological advances and potential applications for cardiovascular research and medicine. Frontiers in Bioengineering and Biotechnology. 2020;7. doi:10.3389/fbioe.2019.00466
  4. Dimitri A, Herbst F, Fraietta JA. Engineering the next-generation of car T-cells with CRISPR-Cas9 gene editing. Molecular Cancer. 2022;21(1). doi:10.1186/s12943-022-01559-z

Further Reading

Last Updated: Feb 22, 2024

Marzia Khan

Written by

Marzia Khan

Marzia Khan is a lover of scientific research and innovation. She immerses herself in literature and novel therapeutics which she does through her position on the Royal Free Ethical Review Board. Marzia has a MSc in Nanotechnology and Regenerative Medicine as well as a BSc in Biomedical Sciences. She is currently working in the NHS and is engaging in a scientific innovation program.

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