AND gene circuits to NOT diseases (An introduction to Synthetic Biology – Part II)

Synthetic Biology may have answers to better Cancer treatments. And the key lies in reducing unintended effects of Chemotherapy. The human brain is such a complex structure, yet at the basic level, the cells interact with basic logic. Read on to find out more.

The Scope of Synthetic Biology


The field of synthetic biology is multi-faceted. The first step involves translating wire diagrams into resolvable equations. It’s similar to using Kirchhoff’s and Ohm’s laws that are used to model electrical circuits. Next up, an excerpt of the equation on the form a ‘design criteria’ is required. For this, computer science tools are coupled with applied mathematics. Using the extracted design criteria (specifications) gene networks are built using recombinant DNA techniques. To monitor the process through a visual aid, fluorescent genes are used. Lastly, to compare the predictions for the model as well as to refine it further, precise single-cell measurements are taken.


With humans, the complexity is multi-fold. There are 30,000 genes that form the basis of our genome. It is through their activation that proteins are produced on a regular basis. This process is furthermore, dependent on the environment. The interaction based operation of the genes is what differentiates us from each other and from other animals as well. The reason these genes create such diversity is through their interplay in combinations that reach astronomical numbers. And so, each of us is unique, with our own fingerprint (even within identical twins, since they start with the similar set of genes).



Logic in the human brain


The human brain is made of 86,000,000,000 neurons! Some of the brain cells are digital in nature, i.e. they have a brain cell – neuron – fire approach that connects and bring about though and sense. The trigger is, of course, pulled only when a sufficient number of inputs flow into the neuron. It is termed as ‘Action Potential’ where the neurons are in OFF state until they are turned ON (similar to digital systems). The real wonder of the human brain seems to lie in the fact that these brain cells contain thousands of connections with each other. These vast networks of interlinked neurons and cells together operate through ‘hundreds of trillions of switches’, working continuously throughout our lives. No wonder then that the brain itself consumes 20-25% of the total energy generated in our bodies. Logic is hidden within these innumerable connections, making it a subject of very high complexity and thus difficult to discern.


Many other types of cells govern processes in the human body that aren’t so binary, sometimes being more elegant or dependent on a variety of inputs. Their output can also be varied, something akin to a sliding gauge. The genes, like the brain cells, function on an ON-OFF structure. But the intricate nature of them can mean that sometimes they are ON for a long time or have functions dependent on the nature of work as well as their location. This might help explain why mutations of a particular gene can cause different sets of issues. The complete set of genes and the mysterious ways in which they operate is analogous to a symphony, the beauty of which can only be experienced when the entire set works in unison and not as a sum total of notes and instruments.


This magnanimity of the complex gene make-up may tempt us to conclude that unlike a symphony, the human anatomy might be more like noise. The truth is that we are still unable to dissect every last detail that is there to know. Synthetic biology is a natural progression on that path, to investigate the intricacies of this supposed mess.


Hitting the target


When we talk about cancer, one of the toughest phases apart from living with the disease itself, is the chemotherapy. The radiation therapy, coupled with medications target different stages of cell development, also called cell cycle. This helps the doctors to understand more specifically which drugs when taken in what quantity will help the patient overcome the health issue. The drugs that are thus used to treat are grouped based on the similarity between them (of structure, nature of work and general compatibility).


Chemotherapy is also recognized by the associated side-effects. Those cells in the bone marrow that are involved in blood-formation are damaged. People may lose their hair follicles while some cells in the mouth, digestive tract as well as in the reproductive system are impaired. The expanse of such treatments is like carpet bombing, with some unavoidable collateral damage. Synthetic Biology may have a solution for this. In 2011, researchers at the Massachusetts Institute of Technology, led by Ron Weiss published a study regarding targeted cancer treatment. They aim to use logic and computer circuits, combining them with biological attributes and develop an assassin to combat cancer.


Classifier circuits (cell type) are being developed towards a better solution for screening and treatment of cancer. It works in the following manner. Consisting of DNA components that are assembled to identify and kill a cancer cell, the test circuit consisted of resolving five questions. At every stage, it checks for the unique properties of a cancer cell. If the output is negative, then the program is halted while the cell undergoes its natural cycle. When the answers are in the affirmative, a gene placed within the code directs the cell-suicide process, after making repeated attempts to verify the nature of its target.


In simple electrical logic gate terms, the circuit consists of several AND & NOT (to flip between ON and OFF) components. Once the treatment passes all regulations and tests, offers a revolutionary method to treat cancer-affected patients. Cancer is a combination of ailments and mutates quickly, thereby making it similar to a moving target. As such, compared to the chemotherapy, the classifier circuits act as snipers, thereby eliminating only the affected cells.


Notes:


  • This series is inspired by Chapter 9 – “Logic in Life” of the book “Creation: How Science is Reinventing Life Itself” by Adam Rutherford. [Rutherford, A. (2013).Creation. New York: Current.]

  • Cancer.org. (2018).How Chemotherapy Drugs Work. [online] Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html

  • The severity of side effects (how bad they are) varies greatly from person to person. Be sure to talk to your cancer care team about which side effects are most common with your chemo, how long they might last, how bad they might be, and when you should call the doctor’s office about them. – Cancer.org. (2018).Chemotherapy Side Effects. [online] Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/chemotherapy-side-effects.html

  • Researchers at MIT built a classifier circuit to detect and enact a programmed response under complex intercellular conditions– Xie, Z., Wroblewska, L., Prochazka, L., Weiss, R. and Benenson, Y. (2011). Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells. Science, 333(6047), pp.1307-1311.

  • The biological clock is called the Repressilator – Elowitz, M. and Leibler, S. (2000). A synthetic oscillatory network of transcriptional regulators.Nature, 403(6767), pp.335-338.

  • Bistability is the presence of two coexistent attractors in a dynamic system—e.g., two stable fixed points or a stable fixed point and a stable limit cycle. [Source: https://medical-dictionary.thefreedictionary.com/bistability]

  • The bistable component is called a toggle switch – Gardner, T., Cantor, C. and Collins, J. (2000). Construction of a genetic toggle switch in Escherichia coli.Nature, 403(6767), pp.339-342.

 

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