Synthetic Biology in Cancer Treatment
Humans have always suffered from terrible diseases. It was not until the rise of enlightened thought throughout the 19th century that mankind began to effectively combat illness. Since then, advances in biological and medical sciences have defeated virtually incurable and formerly fatal diseases. However, despite our successes, there is a group of age-related cellular pathologies – commonly known as cancer – remaining as one of the last strongholds to conquer, as both the incidence and severity of cases are alarming.
The challenge of treating cancer arises from the fact that it is a malignancy caused by our own cells, which means that our cytotoxic cells of the immune system do not recognize them as pathogenic units. Nor are traditional drugs effective, since they all take advantage of the biological differences between infectious agents (usually viruses and bacteria) and human cells. Because of this, cancer has been treated with necessarily invasive treatments such as radiotherapy and chemotherapy, with little success (between 20% and 80%, depending on the type of cancer). However, we know more and more about the molecular mechanisms of this uncontrolled cell replication. This has made it possible to find fundamental differences in the expression of cancer cell genes that will allow much greater specificity in future treatments. Let’s look at some of the most promising ones:
The expression of tumor cell receptors is altered to promote tumor growth. There are even some that appear only in tumors, which can be used to discern them as a therapeutic target. This, together with advances in synthetic biology and genetic engineering, allows us to design fragments of genetic material to introduce in cancer cells, encoding information that either adds functions or modifies them (interrupting an essential gene in malignant cells, for example). This can be done by means of a multitude of biological agents (deletion or synthetic viruses) or physical agents (direct injection, liposome transport). Some examples of start-ups using non-viral gene therapy would be American Gene Technologies, Generation Bio, or Evox Therapeutics.
If a higher specificity is desired, gene therapy with viruses can be used. This is the bet with the greatest public investment and private start-ups behind it, as it is one of the simplest approaches to the theoretical model. However, there are some drawbacks, such as the fact that the capsid proteins can interact with the organism, provoking an immune reaction. This is not at all desirable, although fortunately, it is avoidable: regions of the virus genome that may interfere with the desired outcome can simply be eliminated. Adenoviruses are commonly used, although there are many more strategies available, such as baculoviruses, herpesviruses, retroviruses, or parvoviruses (often called adenoassociated).
A great, very promising start-up using virus platforms would be PsiOxus Therapeutics, a novel company focused on an oncolysis strategy, i.e., physical tumor destruction using T-SIGn virus derivatives.
Engineering Cell-based immunotherapies
Apart from these gene therapies focused on destroying cancer cells, other ways of dealing with proto-oncogene deregulation can be devised. The current best alternatives consist of indirect action, reprogramming healthy cells so that, in one way or another, they are in charge of keeping tumor proliferation at bay. The target cells in this case would not be cancerous cells, but normal somatic cells. There are two main approaches: enhancing the action of CD8 cytotoxic T lymphocytes or altering the behavior of non-immune cells, which will eventually mimic lymphocytes.
Although for now, the most promising strategy is to modify T lymphocytes to recognize malignant cells in solid tumors, the attempts developed are still toxic or ineffective (except for one type of cancer-related to B cells). This is where the hierarchical approach to molecular circuitry seems to help T cells improve their accuracy. One quite effective way would be to perform multi-antigen-sensing T cells since the sum of various stimuli from assorted antigens can lead to decision making thanks to the circuitry implemented in the T cell. This is called Next Generation Therapeutic T Cell Engineering. The largest financing for this endeavor is provided by the Chinese start-up JW Therapeutics.
Other gene therapies that directly modify the genome of tumor cells use the “immune system” of bacterial endonucleases, the now-famous CRISPR-Cas9. Since relatively recently, both the specificity and the efficacy of this type of editing have greatly improved, so much so that survival statistics have multiplied experimentally up to 80%. Unfortunately, for the time being, this type of initiative is ethically out of favor, since in vivo gene editing could lead society to eugenics. Perhaps in the near future, they will be used more often in the clinical setting. It is certainly the most effective and promising gene editing system so far. In the case of cancer, it would be used to disrupt the gene expression of proteins related to tumor development. One solution to the moral problem is to use mRNA since it does not modify human genes. This is another very powerful strategy being pursued by Moderna Therapeutics.
A few decades ago, the discovery of zinc finger endonucleases (ZFPs) brought about a revolution in the field of gene editing. No one thought that the innocent discovery of a bacterial immune system could displace ZFPs in efficiency. Not only that but it also turned out to be several orders of magnitude cheaper. This should be proof positive that there are currently very interesting proposals for cancer treatment, but probably one will emerge from among them with the right formula. It will eventually displace many competitors and establish itself as the star treatment. What is certain is that synthetic biology holds the key to developing humanity’s ultimate weapon against this scourge.
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