#alien genes

Spark of life! Image from Mel Brookes Young Frankenstein 1974

The engineers say that you do not truly understand a system until you can build it from scratch. Previously we have explored the cell, the building blocks of our tissues that in turn make up our organs.  They are a sort of basic unit of human structure and function.  Clearly it is an amazingly complex system with many interlocking parts.  Also, many mysteries.  Thus, we might conclude that there is no way to make one synthetically from simple chemicals.  Certainly, that was the prevailing attitude.  Schrödinger a brilliant physicist famously said that for the most part biologic life was far too obscure to generate first principals.  Introducing the subject matter of his book What is Life he argued that he would avoid mathematical deduction “not that the subject was simple enough to be explained without mathematics, but rather that it was much too involved to be fully accessible to mathematics.”

But daunting complexity has not deterred engineers in the past and that can-do spirit continues undiminished.  Many years ago in order to understand the origins of life, attempts were made to recreate the primordial conditions that led to the generation of life. Reasoning that primitive life was a culmination of favored chemistry scientists tried to create a closed system that contained the bare minimum necessary to produce the chemicals that formed the basis of life.

Known as the Miller-Urey experiment special vessels were employed to combine methane, ammonia and hydrogen in a chamber with water vapor. The water vapor came from heating water in a separate chamber of the sealed vessel. Continuous electrical sparks were discharged through water vapor mixed with the chemicals.  At the end of the reaction time the mixture was cooled and contents collected and analyzed.  The idea was to simulate the early earth’s atmosphere, in part a product of volcanic activity and lightening.  The result was striking and resonates even today as the experiment has been recently reanalyzed and has been repeated many times in many different ways.  The reaction produced the building blocks of life…amino acids that when combined produce proteins and peptide chains.  In fact, although they didn’t know it at the time, reanalysis has shown that many more amino acids were produced than originally thought, including some that do not appear naturally in extant life.

Synthetic pieces can build a cell Image from Pixabay

Proteins alone though cannot make a cell, they do not reproduce robustly and do not transmit genetic information.  That is the domain of RNA and DNA.  The conundrum though is that producing RNA and DNA as we know it now requires biosynthesis in living cells.  So how did they come about before there was life.  Just like for the amino acids that make up our proteins the basic chemical bits that are needed to synthesize RNA and DNA could plausibly have been generated by conditions and materials on early Earth before life began.  

Recently scientists have taken on the challenge of creating artificial genetic information and creating cells where all of the genetic information is wholly synthesized in the lab and then added to an existing cell with its genetic material removed to create a new cell, in this case a kind of bacteria. The methods to produce the synthetic DNA genome in these bacteria utilized the same chemical bits that were likely generated on early Earth.  That is, chemically defined synthesis without materials from living cells.  In fact, the entire genetic code of the bacterium was digitized and stored in a computer! Modifications to the code were made to show that the synthesized DNA that was put into cells were the man-made molecules. Initially scientists replaced the DNA and thus the genes of the bacterium Mycoplasma with DNA synthesized in the lab, containing 1 million base pairs, the basic letters of the genetic code. Recently they have synthesized a much larger DNA complement of 4 million base pairs and used it to rebuild the bacterium E. coli having edited out redundancy in the genetic code.  This to try and understand what are the minimum requirements for life!

Bacteria with wholly synthetic DNA, genes built in the lab Image by Derinck and Ellisman, UCSD, Sci 329, 35, 2010, Gibson et al.

So, since the synthesized DNA was put into existing cells it could be argued that the other components of the cells, proteins, lipids etc. were not man-made.  However, it could be shown that after several dozens of divisions there was no natural cellular material left, it having been diluted at each cell division. The startling fact is that the engineered bacteria could divide, metabolize and remain viable solely on the basis of the synthesized genetic code. The authors of the work said, ”the DNA software builds its own hardware”!

In fact, in a startling advance on the approach other scientists have created artificial genetic codes that utilize 2 base pairs (the letters of the code) that are not seen in nature!  These alien base pairs were taken up into the DNA and faithfully copied when the cells divided.  This leads directly to the possibility of using new, synthetic genetic information to make novel proteins, structures or therapeutics.  It is an amazing affirmation of the notion that the genetic codes found in our natural world are not the only possibilities for renewable and heritable traits. There are great implications both in practical and ethical terms for this, including how extraterrestrial life might form.

Gene expression (blue) in artificial cells Image from Dekker Lab, Delft, part of the BaSyC consortium

Of course, a cell needs to be packaged in a stable format that allows for existence in an environment, for the movements of nutrients and signals into and out of the cells and yet remains self-renewable and scalable upon division of the cells.  Here as well the engineers of cellular life have made progress with synthetic materials.  Scientists working in a new field of engineering called microfluidics have taken major steps toward accomplishing this. Tiny jets of chemicals can be controlled to produce hollow droplets like miniscule bubbles that are the size of cells. 

Tiny droplets flow in microfluidics to produce synthetic cells, then components can be added (bottom) the bar = 0.0001 meters Image from Nature Communications 2018, https://phys.org/news/2018-06-path-artificial-cell.html

Advanced engineering has provided the means to add proteins to these synthetic cell-like structures that perform specific cellular functions, importantly including generation of energy. Not surprisingly these scientists have teamed up with the groups synthesizing genetic material, who as discussed have determined that some few hundred genes are all that are required to sustain synthetic life. 

Artificial cells made from plastic can send and receive signals. Purple cells signal grey cells and change gene expression to make green cells.  Bar = 0.000025 meters Image by Henrike Niederholtmeyer from M. Leslie doi:10.1126/science.aaw1173

A similar approach used a plastic to form an outer envelope (membrane) and these structures also had “nuclei”.  Genetic material containing instructions for a green glowing protein was added to the “nucleus” and it functioned.  The scientists also demonstrated that the completely artificial “cells” could signal each other turning on the production of this green protein thus mimicking an important characteristic of natural cells.

While these advances hardly herald the zombie apocalypse the work raises fascinating and important ethical questions that not surprisingly are more or less left on the table with no particular approach to resolution as the engineering proceeds like a train rushing through the night!