Larger than Life

Life is a four-letter word 

We have all been told that we look and talk like our parents because we inherit their genes. But we may not always realize how fundamental genes are to our existence. The instruction manual of life is written in the language of genes. But what are genes exactly?

Genes are defined as regions of DNA. Like a pearl necklace is made of repeating pearls held together by a string, DNA is made of building blocks called nucleotides. All DNA in nature, be it inside bacteria or humans or the extinct dinosaurs, are and have been created with four kinds of nucleotides, code-named A (Adenine), T (Thymine), G (Guanine) and C (Cytosine), arranged in different permutations and combinations. In a more philosophical sense then, we are all made of the same stuff; we are more alike than different at the most fundamental level. Life is, therefore, a four-letter word; both in English and in the language of genes, the most ancient language in the world.

In one of the most famous discoveries of the twentieth century, work by James Watson and Francis Crick and others revealed to the world that DNA is a double helix, a structure reminiscent of spiral staircases of yore. They also showed that the two helices of a DNA double helix stick together because the DNA letter A likes to stick to T and G likes to stick to C via weak forces called hydrogen bonds. This A-T and G-C pairing rule is instrumental in setting up the genetic code, like the computer binary code, that is always running in the background but hidden from our consciousness.

DNA is the instruction manual for life, but it does not do the work itself, just like the blueprint of a building does not provide the physical space. Nature has devised a simple workflow for this: the DNA instruction is copied onto another molecule that looks like DNA called RNA. This RNA tape of information is read by the protein-making factory of the cell, known as the ribosome, and different proteins are made according to the sequence read from the RNA. In this way, the message originally contained within DNA is translated by the ribosome to make proteins, the functional currency of the cell.

A simplified representation of how genetic information is converted to cellular function

Expanding the alphabet of life

For decades, scientists have wondered why there are just four letters in DNA and more importantly, why these four. We still don’t know if this was a historical accident of chemistry or there were evolutionary benefits of having your DNA/RNA made with these four letters. Proteins with more than twenty amino acids at their disposal are chemically versatile; it is not surprising that most of biology is powered by proteins. We can create more words and sentences (in short, more information) with an alphabet of twenty-six letters than we could if the English alphabet was made of ten letters. Similarly, an artificially expanded DNA (and consequently, RNA) alphabet will store more bits of biological information than its natural counterpart. The creation of artificial genetic alphabets, therefore, is at the foundation of the emerging field of synthetic biology.

A recent multi-institute collaboration, led by Dr. Steven A. Benner of the Foundation for Applied Molecular Evolution (FfAME), endeavored to synthesize DNA with eight letters (instead of the natural four). The four new letters called S, B, Z and P are special because they follow a digital pairing rule similar to the natural letters of DNA. Like, A selectively pairs with T and G with C, letter S pairs exclusively with B and Z with P. Therefore, these letters, although artificial, play by the same rules of nature. The four artificial DNA letters were made using synthetic organic chemistry, and a DNA duplex was created with all eight (four natural, four artificial) letters. This DNA contained new Z-P and S-B pairs, in addition to A-T and G-C pairs. The structure of this DNA duplex was confirmed by a technique called x-ray crystallography, where x-ray instead of light is used to look at molecules in atomic detail. Curiously, this same technique was instrumental in the discovery of the DNA double helix by Watson and Crick sixty-six years ago. It was found that the four artificial letters formed perfect pairs, just like their natural cousins. This verified the initial design hypothesis.

The transfer of information from DNA to RNA is an essential step in the flow of genetic information. To demonstrate the successful transfer of information, a special sequence of DNA was made with an expanded genetic alphabet that would be copied to an RNA molecule, one which exhibits fluorescence in the presence of a particular dye. The enzyme that copies DNA to RNA was engineered to faithfully copy unnatural eight-letter DNA to eight-letter RNA. The RNA molecule made in this way emitted a green fluorescent glow, in presence of the dye establishing the first of its kind, successful information transfer from Hachimoji DNA to Hachimoji RNA (‘hachi’ is ‘eight’ and ‘moji’ is ‘character’ in Japanese). Transfer of genetic information from 4-letter DNA to 4-letter RNA has been at the heart of biology for at least the last 3.5 billion years. This was the first time it was done with 8 letters.

What does an ‘eight-letter’ future hold?

The creation of eight-letter DNA/RNA reveals new horizons for the future. Information contained in DNA (or RNA) follows digital pairing rules. Adding two more pairs will enhance the capacity to carry information. DNA is already being used to store information by companies like Microsoft. DNA is a cheap commodity and a cubic millimeter of natural four-letter DNA can store a billion gigabytes of information. Imagine what DNA with double the information density can do! With the increased chemical variety of letters, more selective sensors can be made with DNA/RNA that would detect toxins, proteins, viruses, disease markers and so on. DNA with six letters have already been used to recognize and bind to proteins and even cells. The information in DNA is ultimately used to make proteins, therefore an artificially expanded DNA might be useful in making unnatural proteins with novel biochemical properties.

Expanded genetic systems have the potential to transcend earthly boundaries. When searching for extraterrestrial life, we might encounter DNA signatures; however, alien DNA might not use the same four nucleotide letters we use on earth. Since the number of nucleotides that can create stable DNA duplexes is limited by their chemistry, it is in our interest to explore DNA with all possible combinations of letters. This might help us recognize the DNA signatures of alien life forms.

When mountaineer George Mallory was asked why he scaled Mt. Everest, he famously said – “Because it’s there”. One cannot discount this sentiment when it comes to scientific research. On a more practical note, once we figure out the physical and chemical rules that govern biology, we can use those rules to create new biology – this time we would do it our way. And if history is to be trusted, we will be able to eradicate many of our human weaknesses, like we have done already with vaccines and machines. We might even unwittingly unleash unimagined horrors as humans are often prone to, but for now, any dangers posed by this type of fundamental research is limited to the speculative minds of science fiction writers. For all we know, we might even play an active role in triggering the next step in human evolution. Only Homo futuris can tell!

Original research: Leal, N. A., Hoshika, S., Kim, M-J., Kim, M-S., Karalkar, N. B., Kim, H-J., Bates, A. M., Watkins Jr., N. E., SantaLucia, H. A., Myer, A. J., DasGupta, S., Piccirilli, J. A., Ellington, A. D., SantaLucia Jr., J., Georgiadis, M. M. & Benner, S. A. “Hachimoji DNA and RNA. A Genetic System with Eight Building Blocks.” Science, 2019, 363, 884-887

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Author:

Saurja Dasgupta is originally from Kolkata, India. He obtained his Ph.D. at the University of Chicago, where he studied the structure, function, and evolution of catalytic RNA. He is currently doing his postdoctoral research at Massachusetts General Hospital, Boston, where he is trying to understand the biochemical milieu that could have given birth to life on earth (and elsewhere) and reconstruct primitive cells. One of his scientific dreams is to observe the spontaneous emergence of Darwinian evolution in a chemical system.  When not thinking about science, Saurja pursues his love for the written word through poetry and song-writing (and meditating on Leonard Cohen’s music). His other passions are trying to make science easier to understand, and fighting unreason and pseudoscientific thinking with a mixture of calm compassion and swashbuckling spirit.

Editors:

Roopsha Sengupta is the Editor-in-Chief at ClubSciWri. She did her Ph.D. at the Institute of Molecular Pathology, Vienna and postdoctoral research at the Gurdon Institute, University of Cambridge, UK, specializing in the field of Epigenetics. During her research, she was involved in many exciting discoveries and had the privilege of working and collaborating with a number of inspiring scientists. As an editor for ClubSciWri, she loves working on a wide range of topics and presenting articles coherently, while nudging authors to give their best.

Illustrator:

Arghya Manna is a comics artist, illustrator, and a Ph.D. dropout. He began his career as a doctoral student at Bose Institute, India. He had been working on Tumor Cell migration in a 3D environment. Along with this, he was an active participant in several projects related to tumor immunology and cancer stem cell. After leaving the lab without bagging the degree Arghya found refuge in art and got involved in drawing comics. He is an enthusiast in History of Science and has been running a blog named “Drawing History of Science”. Arghya wishes to engage the readers of history and science with the amalgamation of images and texts.