Table of Contents:
- a. The Discovery of Cells, and that ‘All Life Is Made of Cells’
- b. The Discovery of Cell Division, and that ‘Cells Only Arise by the Division of Other Cells’
- a. The Structure of DNA
- b. How DNA Works
- a. Crossing the Species Barrier: Meet Freckles, the Spider-Goat
- b. Genetic Engineering and Medicine
- a. The Registry of Standard Biological Parts
- b. The iGEM Competition
As the blueprint of all that lives, deoxyribonucleic acid (DNA) may be said to be the key to understanding life itself. It is incredible to think, then, that the structure of DNA was only discovered some 60 years ago (thanks especially to the work of James Watson and Francis Crick). Since that time, many significant advances in genetics have been made—including the deciphering of the genomes of numerous species (including our own); and, even more impressively, the successful manipulation of the genetic code to introduce the features of one species to another (for example, having a goat produce spider’s silk out of its milk).
As impressive as these feats are, though, they are but the beginning of what promises to come from the study of genetics. Indeed, compared with other sciences, such as physics and chemistry, genetics is still in its infancy, and we can be assured that the most significant discoveries and applications are yet to come. Even now, geneticists are making substantial progress in uncovering the origin of life—meaning answering the question of just how life may have sprung out of lifeless chemistry—and are also making advancements in turning genetic manipulation into a standardized engineering science that is capable of churning out technological solutions in everything from food production to energy to medicine (a field that has been dubbed ‘synthetic biology’). It is these recent advances in genetics that are the main topic of Creation: How Science is Reinventing Life Itself by science writer Adam Rutherford.
Rutherford begins by giving us a refresher in basic biology, by way of running through the 3 ideas that stand at the heart of modern biology: 1) cell theory; 2) Darwin’s theory of evolution by natural selection; and 3) the structure and operation of DNA. Each of these ideas leads us to the conclusion that life began at a single point, but does not address the question of how life began in the first place. Now, though, this question is being addressed, and Rutherford updates us on the progress.
A living organism requires both a structure that can be replicated, and some energy to carry out this replication; thus the question of the origin of life comes down to the question of how this structure originally came to be organized, and where the energy came from to allow for the replication. With regards to the first part of this question, scientists have been able to trace out the likely original constituents of the first organism, and have also established that many of these original constituents readily self-organize into the form that they take when the right molecules and conditions are present—thus while the question of the original structure of life has not yet been solved entirely, geneticists are hot on the trail of doing just this.
Second, with regards to the energy problem, it has been established that, originally, the energy needed for replication could well have come from outside of the biological structure itself—the most likely candidate at this point being the energy from hydrothermal vents at the bottom of the ocean. Experiments are currently underway that recreate the physical and chemical conditions at the bottom of the ocean near hydrothermal vents—but the hit and miss nature of this procedure means that there are no guarantees these experiments will be successful in procuring life.
When it comes to creating life from scratch, the better bet might be that this will come from synthesizing the basic biological parts and manipulating them into the organization that is needed for them to carry on into perpetuity. This is the domain of a new science called synthetic biology. Of this domain we learn that geneticists have already been able to synthesize many biological structures—and have even synthesized DNA and introduced it into a cell where it functions normally, like any other DNA.
While creating life form scratch is one goal of synthetic biology, it is subordinate to a much larger goal, which is to take full control of genetic information in order that it may be used for any number of purposes, from incapacitating viruses, to creating synthetic biofuel, to fabricating food stuffs that carry any biological feature we may want. Scientists have in fact already made considerable progress in these areas. However, they have also run into some significant barriers along the way—largely having to do with the sheer complexity of biological systems. Still there is hope that this complexity will ultimately be tamed.
One part of this taming effort comes from the endeavor to create standardized genetic components that are capable of carrying out a specific function. The spirit of this enterprise is captured in the iGEM competition—an international competition that brings together teams of university students from every corner of the planet with one goal: to demonstrate a unique biological function using standard genetic parts, called ‘BioBricks’ (drawn from a library of these BioBricks that the students are themselves encouraged to add to in the course of their projects). The iGEM competition has already churned out some very impressive applications, and the speed of progress is very encouraging.
The following is a trailer for the book:
*To check out the book at Amazon.com, or purchase it, please click here: Creation: How Science Is Reinventing Life Itself. The book is also available as an audio file from Audible.com here: Audio Book
What follows is a full executive summary of Creation: How Science is Reinventing Life Itself by Adam Rutherford
PART I: THE FOUNDATIONS OF MODERN BIOLOGY: CELL THEORY; EVOLUTION BY NATURAL SELECTION; AND THE STRUCTURE & OPERATION OF DNA
Our scientific understanding of biology is built on the framework of 3 great discoveries: cell theory, the theory of evolution by natural selection, and the structure and operation of DNA. Let us now briefly run through each.
a. The Discovery of Cells, and that ‘All Life Is Made of Cells’
Modern biology truly begins with the discovery of the cell, which occurred way back in 1673 (loc. 191). The feat was accomplished by one Antonie van Leeuwenhoek, who was a Dutch linen merchant by trade, but who also dabbled in microscopy as a hobby (thanks in some part to the fact that ever finer optical lenses were an advantage in his work—since they allowed the linen merchant to more accurately appraise the quality of fine fabrics [loc. 196]).
Testing his optical lenses out on virtually everything around him, van Leewenhoek eventually got around to peering at biological things—including his own blood—which is where he hit pay dirt: “In a letter published in the Royal Society’s official journal Philosophical Transactions in April 1673, Van Leewenhoek wrote, ‘I have divers times endeavored to see and to know, what parts Blood consists of; and at length I have observ’d taking some blood out of my own hand, that it consists of small round globuls [sic].’” (loc. 208). When it comes to these small, round globules, as Rutherford explains, “we think that he was looking at red blood cells, and this appears to be the very first recorded sighting of individual cells” (loc. 208).
Van Leeuwenhoek didn’t stop with his blood, though; he went on to inspect the plaque on his teeth, pond scum, and even his own semen (with regards to this last, Antonie insisted in his journal that he acquired it “not by sinfully defiling myself, but as a natural by-product of conjugal coitus” [loc. 213]). On each occasion, the Dutch merchant once again observed cells, thus “Van Leeuwenhoek was the first person to definitively see individual red blood cells, sperm, bacteria, and free-living single-celled organisms” (loc. 217).
It was eventually observed that no matter what living tissue you looked at, from plants to animals to single-celled organisms, cells were always the basic building blocks of the tissue (loc. 257). And thus the conclusion was finally drawn that ‘all life is made of cells’ (loc. 300). This simple statement is in fact the first half of cell theory as we know it today (loc. 300).
b. The Discovery of Cell Division, and that ‘Cells Only Arise by the Division of Other Cells’
Now, the next major discovery in cell theory was that new cells could emerge through cell division. A discovery that was hit upon by the Polish biologist Robert Remak. As Rutherford explains, “for a decade, [Remak] studied all manner of animal matter, including muscle and red blood cells as they grew in frog and chicken embryos; he only saw cells splitting, with one pinching in the middle like a belt on a balloon until it became two” (loc. 272).
These repeated and consistent observations led Remak to the conclusion that cells only emerge through cell division. Now, this is in fact the second half of cell theory as we know it today. However, it would take some time before this postulate came to be regarded as certain. For while it was acknowledged that cells could emerge through cell division, it still wasn’t proved that they couldn’t also emerge through spontaneous generation—that is, out of thin air. This belief had been around since ancient times, and had simply refused to die in modern times (loc. 208-29).
The theory of spontaneous generation had in fact enjoyed a resurgence in 1860, when the French scientist Felix-Archimede Pouchet demonstrated that mold sprang forth from hay, even after the hay had been sterilized through being boiled with water and cooled down with liquid mercury (loc. 288).
Fellow Frenchman Louis Pasteur, though, spotted a flaw in Pouchet’s experiment: he believed that the mold on the hay had in fact been introduced from the outside by the liquid mercury (loc. 287). Lucky for him, Pasteur thought up a way to debunk Pouchet’s experiment, and simultaneously sink spontaneous generation once and for all. As Rutherford explains, Pasteur “designed the simplest experiment imaginable. His version of Pouchet’s setup was to have two flasks containing a sterile but rich broth, one that would soon go cloudy if exposed to microbial life. One flask was left open while the other had an S-shaped curved neck protruding to one side. Pasteur figured that microbes carried on airborne dust particles would reach the broth in the first flask, but that the swan neck would not allow these contaminants into the broth in the second flask. Within days the open flask was cloudy. But the swan-necked flask was perfectly clear, and remained so indefinitely. As a control, Pasteur snapped off the swan neck and observed the broth growing cloudy over the next few days. Pasteur… was duly elected to France’s scientific elite” (loc. 292).
Below is a simple recreation of Pasteur’s simple experiment:
Thus with one fell swoop the theory of spontaneous generation was brought down, and cell theory was complete. The theory, as mentioned above, can be summarized in 2 sentences: “1. All life is made of cells. 2. Cells only arise by the division of other cells” (loc. 300).
Simple though these statements may be, the implications are profound. To begin with, the first part of the theory implies that the diversity of life on the planet derives entirely from the incredible range of cells. (loc. 309). As for the second component of the theory, it suggests that life’s diversity ultimately has a single common origin: the first cell. But this then raises two questions: 1) How did the first cell come about?; and 2) How did this first cell, and cells thereafter, change along the way to produce life’s great diversity?
We shall return to the first question below. For the moment, though, let us address the second question; for it finds an answer in the final 2 pillars of modern biology: Darwin’s theory of evolution by natural selection, and the structure and operation of DNA.
Just as spontaneous generation was in the midst of being put down for good, Charles Darwin was on the cusp of unleashing his grand theory of evolution by natural selection (which he did in 1859, in his On the Origin of Species [loc. 316]). Now, while cell theory operates at the level of the cell (and begs questions about how cell diversity arises), Darwin’s theory operates at the level of the species, and provides an answer as to how a species changes (evolves) over time (we shall see the connection between the two theories very soon). Let us see how Darwin’s theory emerged.
Darwin had observed that there is natural variation among the members of a species when it comes to their peculiar physical features, and that these peculiar physical features are passed down from parent to child (loc. 316, 325). So, for example, anteaters may differ in just how long their tongues are, and these differences are passed down from parent to child (loc. 321).
Darwin further observed (or, rather, surmised) that certain features confer an advantage in terms of survival, and that this advantage would then translate into greater reproductive success for the organism carrying that feature. So, for example, “in an imaginary population of anteaters, one with a slightly longer tongue than his contemporaries may be able to root out more juicy termites and may be better fed and healthier as a result. This could have the effect of making him live longer or maybe making him a more attractive mate to a female anteater. Consequently, this anteater may have more baby anteaters, each potentially carrying that longer tongue” (loc. 322).
As anteaters with longer tongues continue to out-reproduce those with shorter tongues from generation to generation, eventually the longer-tongued anteaters will come to dominate the population—thus we can see how a species comes to change (evolve) over time (loc. 325).
As simple as the theory is, its explanatory power is immense. As Rutherford explains, “natural selection is the overarching force that has shaped the living world in which we live. It’s a system of trial, error, and revision. Evolution is blind and has no direction. Species are not more or less evolved, nor are they higher or lower, as they were once and sometimes still are described. Through iteration, they are merely better adapted to survive in their environments” (loc. 333).
Like cell theory, though, Darwin’s theory of natural selection leaves us with 2 unanswered questions: 1) How are features passed down from parent to child?; and (even more importantly) 2) Natural selection selects for some traits over others, but how do novel features arise in the first place?
Now, as you may have noticed, cell theory does in fact offer us a partial answer to the first question, for it suggests that features may be passed down from parent to child through their cells, and the process of cell division (loc. 353) (though it leaves unanswered the precise mechanism by which this occurs). As to the second question, the answer would have to await the third and final pillar of biology: the discovery of the structure and operation of DNA.
a. The Structure of DNA
By the time James Watson and Francis Crick got around to uncovering the structure of DNA in 1953, a long line of discoveries had convinced scientists that DNA was in fact ultimately responsible for inherited characteristics. The kicker came when Oswald Avery, Colin MacLeod and Maclyn McCarty manipulated the cell components of the bacteria responsible for pneumonia and found that only when the DNA of the cell was destroyed was the bacteria’s virulent quality extinguished (loc. 434).
Still, what was not known was just how DNA pulled off the trick of inheritance—until, that is, its structure was deciphered. Drawing on the X-ray images of DNA by Rosalind Franklin, Raymond Gosling and Maurice Wilkins, Watson and Crick finally solved the puzzle in the early 1950s: “it was with their insight and genius that they deduced from Franklin and Gosling’s photo that DNA took the form of a twisted ladder: the iconic double helix. On April 25, 1953, in a brief paper published in the scientific journal Nature, Crick and Watson showed that the rungs of this twisted ladder contained paired chemical letters—A for adenine, T for thymine, C for cytosine, and G for guanine. Each letter is bound to one vertical section of the ladder and pairs up with a corresponding letter on the upright to form a rung. It is this pairing that makes the helix doubled, and the pairing is very precise: A always pairs with T; C always pairs with G” (loc. 449).
Here are Watson and Crick in their moment of glory. (Below is a model of DNA in some detail).
It is the constancy of the pairing of the bases of DNA that provides the clue as to how DNA handles inheritance. A clue that was not lost on Watson and Crick—for they themselves pointed it out at the end of their seminal paper (loc. 449). Here’s Rutherford to explain: “This is the first marvelous thing about DNA. If you split the double helix into its two component strands, you immediately have the information to replace the missing strand: where there is an A, the other strand should have a T, and where there is a C, the other strand needs a G. Therefore, DNA possesses an ability, inherent in its structure, to provide the instructions for its own replication. Thanks to Crick and Watson, building on the work of Wilkins, Gosling, and particularly Rosalind Franklin, we were given a molecule that could be copied and passed from generation to generation” (loc. 458).
b. How DNA Works
One finally mystery remains, though. Just how does the DNA that is replicated and passed on from one generation to the next translate into the physical characteristics that we observe at the macroscopic level? This mystery too would eventually be solved. Briefly, it works like this: DNA code (the arrangement of As, Ts, Cs and Gs) directs the construction of strings of amino acids (that are found in the cell) to form various proteins. And these various proteins form the basis of every biological structure and substance in your body—from your cells to your tissues to your organs (loc. 471-79, 493-540).
Here is an excellent video on how this works–as the video indicates, there is an updated version, but I personally think the draft is better; the message on the screen goes away after a few seconds (I refer back to this video later in the article):
O.k., so DNA transcription and translation (witnessed in detail in the video) explains how DNA translates into physical characteristics, and DNA replication explains how DNA (and the features it translates into) are passed down from one generation to the next, but how do wholly novel features arise? Simple, the answer lies in ‘errors’ in DNA replication.
DNA normally creates copies of itself that are incredibly faithful (loc. 1133). Occasionally, though, ‘errors’ in replication are made (called mutations), and the DNA product is slightly different form its parent DNA. Since DNA translates into physical features based on the precise arrangement of its code, modifications in this code can translate into changes in physical features (loc. 1133). Thus we can see how entirely novel features arise.
We have now answered the 2 questions that we were left with at the end of the section on evolution by natural selection. Specifically, we have answered the question of how features are passed down from parent to child (through DNA), and we have also answered how wholly novel features are formed (through mutations in DNA).
In the process of answering these questions, we have also answered the second question that we were left with at the end of the section on cell theory. Specifically, we have answered the question regarding how the first cell, and cells thereafter, change along the way to produce life’s great diversity (once again, through mutations in DNA).
Putting it all together, we may say that biology works like this: DNA is responsible for the physical structure and functioning of an organism by way of coding for the production of proteins that make up this physical structure (beginning with the cell, and scaling up to organs). Different organisms and whole species have different physiological features based on differences in their DNA. DNA is replicated and passed down from parent to child thus explaining how physiological features are passed down from generation to generation. However, DNA can also mutate which can lead to whole new features not seen before.
Certain features are more favorable than others in terms of promoting the survival and reproduction of an organism in the environment that it inhabits. Organisms that have more favorable features out-reproduce those that have less favorable features, thus leading to an over-representation of the former in the gene pool. Favorable features come to dominate a species, whereas less favorable features are eventually extinguished. This is how species change (evolve) over time.
Because successful species spread out and come to occupy different environments, the members of a species will evolve differently in these different environments, until eventually they are so different from one another that they will no longer be able to interbreed (which explains speciation—how a single species branches off into multiple species).
The 3 pillars of biology lead us to one conclusion: that all life originated at a single point, with the first cell (and then branched out from there through cell division and evolution by natural selection). As Rutherford explains, “the origin of cells from parent cells and the origin of species via slowly changing genes in those cells both bear the hallmarks of a single origin. Those three aspects of biology—cells only from existing cells, DNA changing through imperfect copying, and modified descent of a species as a result—logically unveils a single line of ancestry that inevitably leads back to a single point in our deep, deep past” (loc. 596). This hypothetical first cell even has a name: Luca (for Last Universal Common Ancestor) (loc. 637).
This leaves us with just one unanswered question: How did the first cell (Luca) come about? This one is tricky. Let’s turn to it now.
In approaching the question of how life originated we are immediately presented with, appropriately enough, a chicken-and-egg problem (more than one, in fact, but let us start with this one). The problem is as follows: “DNA encodes the proteins that enact cellular functions including metabolism, and these functions enact the decryption of the code itself” (loc. 1099). In other words, DNA directs the creation of cell structures that are themselves required for DNA to do its work.
Fortunately, this problem has a relatively straightforward solution. And the solution is ribonucleic acid (RNA). Specifically, the RNA world hypothesis, which has it that the code of life was originally held in RNA, and only later came to be transferred over to DNA (or, more accurately, that DNA evolved out of RNA and took over as the carrier of the life code—more on this below).
RNA is similar to DNA in that both carry genetic code. The two are different, though, in that RNA is single-stranded. Also, RNA replaces the base thymine T, with uracil U, and the deoxyriobse sugar with a ribose sugar (loc. 1320). The 2 are compared below.
In the cell, RNA has two functions. First, RNA reads DNA in the nucleus of the cell, and carries this genetic information to the ribosome where it is used to manufacture proteins (as seen in the video above) (loc. 1193). Second, RNA is the material out of which the bulk of the ribosome itself is created (loc. 1198). To put it another way, RNA acts both as code-carrier and protein creator (loc. 1371) (in the cell, RNA gets some help from proteins in its role as protein creator, but RNA has in fact been shown to be capable of acting as a protein creator all on its own [loc. 1206-59]).
This is significant, because it means that if RNA were the original life-code carrier, it would avoid the chicken-and-egg problem that DNA runs into. As Rutherford puts it, “RNA molecules… have both information and function. With RNA as the forefather of DNA on the early earth, the paradox of DNA and protein—the former encoding the latter and the latter making the former—vanishes. This idea is referred to as the RNA world hypothesis. We can get around the chicken-and-egg problem by not needing either. At some ancient juncture from mere chemistry to biology, the central dogma of ‘DNA makes RNA makes proteins’ was simply ‘RNA makes.’” (loc. 1202).
The theory, then, is that RNA was the original life-code carrier and that at some point in time DNA mutated out of RNA and took over its role as code-keeper. Just what advantage did DNA bring that allowed it to successfully usurp RNAs role? Well, it has been shown that DNA is a far more faithful transcriber of information than RNA, thus there is reason to believe that once RNA mutated into DNA, the DNA stuck and spread due to the advantage it gave in terms of information transfer (loc. 1176-85). Thus a neat division of labor formed wherein DNA took on the role of code-keeper, while RNA stayed on as transfer-er of genetic information (from the nucleus to the ribosome) as well as protein creator (through its role as part of the ribosome itself).
This solves one chicken-and-egg problem, but it still leaves us with 2 more. First, while the original RNA may naturally have self-replicated (just as DNA does now), how did it come to form in the first place? Second, the original RNA would have needed energy in order to operate—including the operation of self-replication (just as DNA does now). Nowadays, this energy comes from cell processes, but before life bootstrapped itself into existence these cell processes were not around, so where did the energy come from that allowed the original RNA to self-replicate in the first place?
Let us begin by way of addressing the conundrum concerning how RNA established its structure originally. The simplest answer, really, is that RNA somehow managed to self-organize. What we would hope for, then, is to demonstrate that when we throw in the elements needed to make RNA, the elements naturally arrange themselves in such a way as to form RNA. So do they? Well, all attempts to make fully formed RNA in this fashion thus far have failed, so the short answer is that if RNA is capable of self-organizing out of its elements, then it must need some fairly special circumstances—and perhaps a bit of luck (though given the evidence that enduring life only arose once, this is something that we should perhaps have expected anyway).
Nevertheless, there is at least some reason to believe that the feat is possible, for it has been shown that some of the basic building blocks of RNA do in fact self-organize. RNA, as we have seen above, consists of 4 chemical bases: adenine, cytosine, guanine and uracil (which replaces thymine in DNA). Each of these chemical bases is attached to a ribose sugar (hence ribonucleic acid—the chemical bases of DNA are attached to a deoxyribose sugar [which has one less oxygen atom than its cousin], hence deoxyribonucleic acid). And these compounds are themselves linked to one another by a phosphate (a compound of phosphorus and oxygen) (loc. 1313).
Now, the evidence indicates that RNA may well have started out with fewer chemical bases than it now has. For biologists have been able to get an RNA molecule to function out of only two base pairs (uracil U, and the modified nucleobase dihydrouridine D) (loc. 1279). And this is where things get interesting, because biologists have shown that the natural base pair here (uracil) does self-organize, and connect up to a ribose sugar, simply when the component parts of these compounds are thrown together in the presence of a phosphate (in fact, it turns out that the phosphate [which is the third element needed to form RNA] is the key ingredient in ensuring that the uracil forms) (loc. 1332-45).
In addition, naturally occurring uracil, as well as other primitive bases, have even been found in nature (in meteorites, no less) (loc. 1353-57), thus we know that chemical bases are something that form not only in the lab, but under entirely natural conditions.
All of this is highly suggestive evidence that RNA may well have self-organized originally, but as yet biologists have not been able to get fully functional RNA to form out of lifeless chemicals, so it yet remains but a tantalizing theoretical possibility.
Assuming that the first RNA did self-organize, though, this still leaves us with one final conundrum: the original RNA would have needed some energy to allow it to self-replicate, so where did this energy come from?
In approaching the energy problem it is useful to take a look at just how energy is produced in a cell. In the cell, energy is produced by the cell structure known as the mitochondria. How it works is that the mitochondria acts like a turbine, churning hydrogen atoms from one side of a membrane to another (loc. 1551). The simple act of shifting hydrogen atoms from one side of the membrane to the other results in an energy surplus that is then stored in the molecule ATP (adenosine triphosphate) for use in the cell (loc. 1551). As Rutherford explains, “a modern cell’s energy currency comes in the form of a molecule called ATP… The process by which this happens is a complex metabolic cycle that relies on there being a gradient of electrically charged hydrogen atoms (protons) across a membrane, a maintained imbalance. In our cells, that power generation happens in the mitochondria… Special proteins on [its] membranes act like turbines, and the flow of protons through these turbines results in the energy being generated, which gets stored in ATP, which is used to power all the processes of the cell” (loc. 1550). Here is a brief animation of how this process unfolds:
The best place to look for a natural form of energy, then, that might have been used by the original RNA is to look for a naturally occurring process that involves the continuous flow of a proton gradient (preferably near a mix of chemicals that might have formed the original RNA). Now, it just so happens that we have an excellent candidate for this very confluence of circumstances—though to find it we have to travel all the way to the bottom of the ocean.
The candidate is hydrothermal vents at the bottom of the sea. As Rutherford explains, speaking of these hydrothermal vents, “due to the precise qualities of the chemicals bubbling up from the reactions between the rocks and the sea, they form natural proton gradients in the swirls around the honeycomb rocks… in a sense, the bubbling vents are a mixture of the right ingredients in such a way that biology can emerge from chemistry… in the vents it’s the circulating gasses flowing out that maintain the thermodynamic imbalance. Specifically, protons stream around the pockets in the rocks, to be concentrated into the alkaline interior away from the acid sea. At the bottom of the Atlantic Ocean is a bubbling bioreactor with a thermodynamic imbalance of streaming protons preventing retirement to equilibrium… As a site for the origin of life, hot vents fit seductively well” (loc. 1567).
Interestingly, these hydrothermal vents even now teem with life. Indeed, one of the lead scientists working with these vents “Deborah Kelly from the University of Washington in Seattle told Nature in 2001, ‘You can’t even see the rock because of the amount of bacteria’” (loc. 1540). The question now is whether this might truly be the place where life began. The following is a very good video on hydrothermal vents and the origin of life:
In order to get to the bottom of the issue, the biologist Nick Lane has taken it upon himself to recreate the conditions of these hydrothermal vents in his lab, to see if he can’t coax out biology from chemistry (there are, in fact, a few studies of this kind) (loc. 1521-44). Lane’s experiment is still very young, and the results are as yet unknown, but it may just produce life from non-life (loc. 1568).
Geneticists efforts to get to the bottom of life have yielded not just knowledge of how life works, but have also pointed the way towards how to manipulate life (via genes) for specific practical purposes. This endeavor grew under the name ‘genetic engineering,’ which primarily involved cutting and pasting the genetic material that already exists in nature. Now, however, biologists have come to learn how to synthesize many of the basic building blocks of life, and are in the process of learning how to put these parts together to create biological structures, products and even entire organisms that are entirely unprecedented in nature. The new science is called synthetic biology, and it already boasts a number of impressive advances. We will get to these in a moment; but first let us explore the beginnings and evolution of genetic manipulation.
The structure of DNA may only have been discovered some 60 years ago, but we humans have actually been practicing genetic manipulation for thousands of years. The practice begins with agriculture, wherein farmers select certain plants and animals over others for breeding purposes. Farmers act as gate-keepers allowing certain plants and animals (with certain genes) to be over-represented in successive generations, and thus are the first true genetic engineers. As Rutherford explains, “for more than ten thousand years, since the dawn of agriculture, we have identified appealing characteristics of the natural world and attempted to enhance and exploit those properties. This is farming, a process that is at heart the precise opposite of natural selection, though it harnesses the exact same means. Instead of survival determining what unintelligently designed adaptations evolve, we choose characteristics that we find attractive and breed species to optimize production of that trait, whether it is fruit or land used to grow crops; livestock for meat, dairy, or leather; or dogs and plants bred for behavior or aesthetics. Farming is evolution by design” (loc. 1792).
Of course, farmers operate exclusively at the macro-level (and not the molecular level), and thus what they do is very different from today’s genetic engineers. And, as it turns out, this difference is not superficial, for in manipulating natural selection at the molecular level today’s genetic engineers are able to accomplish something that traditional farmers never could: take the traits of one species and insert them in another—in other words, cross the species barrier (loc. 1794).
Before we get to this, though, let us first take a look at how genetic engineering works. The practice became possible for the first time in 1968 when the biologist Hamilton Smith discovered a mechanism by which to cut a strand of DNA at a particular juncture (the mechanism borrows from one that already occurs in nature—bacteria cut their DNA when they detect that an invading virus has installed itself in their genome [loc. 1852]). As the author explains, “this naturally occurring editing tool enabled scientists to treat DNA and genes as we now use word processing software: to cut, copy, and paste from one section to another” (loc. 1859).
With this tool in hand, geneticists were free to start experimenting with mixing and matching genes. Now, if only genes were so simple that 1 gene coded for 1 trait, and they were influenced neither by one another, nor the environment, then genetic engineering would be a very simple endeavor indeed. Genetic engineers could easily figure out what genes are responsible for what traits, and manipulate them in a very straightforward way to get the results they wanted. Unfortunately, this is not how things work. As Rutherford explains, “genes never work in solitude. Instead, they are parts in cascades of networked activity, like a series of conditional instructions. Every cell contains every gene in that organism’s genome, regardless of whether it is needed. The choreography of gene activation is therefore of paramount importance. The activation of one gene might trigger the activation or expression of another, or tell it to stop, and by this process we develop from a single fertilized egg cell to a collection of hundreds of coordinated cells, each performing different functions as a result of the expression of specific sets of genes, rather than an amorphous blob comprising identical cells” (loc. 1887). Elsewhere, the author adds that “living things are immensely complex, with thousands of genes encoding thousands more proteins that interact with one another and the environment to produce millions of cells” (loc. 2008).
In other words, genetics is enormously complex, which makes genetic engineering enormously complex. Still, this complexity is not beyond being understood, and so long as biologists are able observe the macroscopic effects of the microscopic manipulations they make (though even this is not always so easy [loc. 1873]), progress can be made.
And progress has been made. For one thing, genetic engineering can be used to greatly speed up the process of selective breeding that has been practiced by farmers for thousands of years. But also, and even more impressively, genetic engineers can greatly improve this selective breeding by way of drawing from the genetic pool not just of the species they are trying to breed, but other species as well. With this combination of methods, genetic engineers “have been able to modify crops to be resistant to blights, grow larger, tolerate frost, and even produce vitamins that protect diseases” (loc. 1965) among other things.
a. Crossing the Species Barrier: Meet Freckles, the Spider-Goat
When it comes to crossing the species barrier, one of the more dramatic examples of this has been the successful transferring of genetic material from a spider to a goat (named Freckles), that allows Freckles to produce spider’s silk out of her milk. This feat was accomplished by a team of researchers led by Randy Lewis working out of Utah State University (loc. 1780). Here’s Rutherford to explain: “To the casual observer, and to professional goatherds, [Freckles] shows no signs that she is not a perfectly normal farmyard goat. In fact, Freckles is utterly extraordinary. While almost all of her genome is what you would expect a goat to have, there is a foreign corner in her DNA taken from Nephila clavipes, the golden orb-weaver spider… It has been inserted at a very specific point in Freckles’ genome, adjacent to a coded instruction that prompts the production of milk in her udders. As a result of this genetic intrusion, when Freckles lactates, her milk is replete with spider silk. / In spiders, dragline silk is made of short strands of protein, which align and self-assemble as they are pushed or drawn out of the spider’s spinneret… Randy Lewis’ goats produce the short silk proteins in abundance, which float freely in the milk. The fat is removed from the milk, which is then pushed through a high-pressure processor. From there, with just a glass rod, I lift a single thread of spider silk from the goat’s milk, and the noses and tails of the shorter fibers link together as I draw them from the liquid. It is strong enough to wind onto a spool by the foot” (loc. 1780 / 1820).
Lewis’ experiment is not a mere novelty act. Spider’s silk is an incredible fiber in that it is both strong and flexible (loc. 1784). In fact, it combines more strength and flexibility than any fiber we have yet been able to manufacture (loc. 1784). And this makes it a very valuable commodity, for a fiber that is both strong and flexible is extremely useful in many applications (loc. 1825-29). Now, unfortunately, spiders are not a species we can farm (their tendency towards cannibalism makes this impossible [loc. 1831]). But by introducing the spider’s genes to the goat we can overcome this barrier and thus farm spider’s silk. (Having said that, it should be pointed out that the silk that comes out of Freckles’ udders does not have quite the strength and flexibility that spider’s silk does—though it is hoped that further experimentation may yet improve the fiber [loc. 1821]). The following is a niece piece on spider-goats, and their silk (that features Randy Lewis):
b. Genetic Engineering and Medicine
Aside from manipulating genes for the purpose of breeding species with favorable characteristics, it can also be used to help study diseases. As Rutherford explains, “a typical experiment to determine the function of a human disease-causing gene would be to isolate it in a family that suffers from that disease, using the same principles of genetics and pedigrees we have known about for a century. Once purified, it gets copied a million times, so there is more DNA to play with. That makes inserting the modified gene into a precise orientation in a DNA envelope much easier and it can then be posted into a bacteria… Every time the cell then divides, the inserted gene will be copied along with the host genome… The next step is to destroy the bacteria and leave only your modified DNA. At that point, you can do what you want with it, such as make RNA versions of it, which will show where the gene is active in preserved tissue on a slide, in an organ, or even in a whole animal” (loc. 1911).
As far as using direct manipulation of genes to treat a genetically-based disease, this too has been shown to be possible in animals—though the procedure has not yet been tried in humans (loc. 1916). The simple fact of the matter is that there is still much we do not understand, and the possibility of introducing unintended consequences through genetic tampering are still too high to make this a viable option for human subjects. As Rutherford puts it, “decoding the obvious faulty mechanisms of diseases and designing successful programs are certainly the aims of genetics… Yet understanding noise and catering to it remains a puzzling obstacle” (loc. 2245).
Many of the applications of genetic engineering that we have seen to this point are certainly impressive. However, it should also be clear that further advances are being bogged down by the limitations we face in controlling genes and their activity (something that is itself due largely to the incredible complexity of biological systems, and the operations of genes).
What would be helpful in many cases is if scientists could take full control of the protein-creating process and produce biological features and structures (and even whole organisms) of their own design. It is this very effort, in fact, that is behind the new science of synthetic biology, which is where we shall turn our attention now.
There are several overlapping hallmarks to the new science of synthetic biology, but one of the leading ones is the aim of producing standardized biological components that perform specific functions (loc. 2046). This endeavor truly took off in the first year of the new millennium with two projects. The first involved creating a genetic circuit that effectively makes an E. coli bacteria glow green in slow pulses. Here’s Rutherford to explain: “by piecing together three sections of DNA that naturally prevent other genes from producing their proteins, Michael Elowitz and Stanislas Leibler at Princeton University constructed a circuit that dictates not merely that a gene is ON or OFF, but is ON and OFF in an oscillating wave… The output of the circuit was the expression of the gene for green fluorescent protein (GFP), and so the cells would glow green in slow waves” (loc. 2089).
Here is a time-lapse video of this process in action:
The second project was very similar in nature to the first, but rather than flipping a gene ON and OFF in an oscillating wave, it effectively manipulated a gene to flip between two functions. As Rutherford explains, “the second component part was made by a team from Boston University led by Timothy Gardner. They built a genetic version of a type of electric component known as a bistable, or more evocatively, a flip-flop. These types of switches flip between two states, but each of these positions has a function” (loc. 2093).
In the past decade, our ability to control genes in these types of ways has absolutely exploded. As Rutherford explains, “these two inventions are rightly seen as the first synthetic biology parts: microscopic tools designed to enact a program but built from DNA. The synthetic biology workshop opened with these first parts built, and what followed was a cascade of other mechanisms, tools, parts, and pieces, all made out of DNA, taken, modified, fused, and redesigned from evolution’s toolbox. In the last ten years we have gone from the species-barrier-breaking insertions of genetic engineering to an ever-expanding toolbox packed with widgets. There are now switches, pulse generators, timers, oscillators, counters, and logic calculators” (loc. 2101).
So, just what are all of these biological widgets good for? Plenty, in fact. As the author explains “the combinations of these and many other components have extended our control of living systems to genes, protein function, cell growth and reproduction, metabolism, and the ways cells talk to one another” (loc. 2104).
As you can well imagine, the increased control over these systems and processes has opened up the potential for many new practical applications. Let me mention just 2 here: one from medicine, and one from energy.
The first application is no less than an effective treatment of cancer. This is currently being developed by a team led by Ron Weiss out of MIT. The treatment essentially involves manipulating a string of DNA to enter the body, search out cancer cells and destroy them on the spot. Here’s Rutherford to explain how it works: “by using the logic and language of computer circuits combined with biological components, [the team] had built a tool that effectively acted as a cancer assassin. The terminator circuit is an assembly of DNA components, built to serve a singular mission: to identify and kill a type of cancer cell. Once built, the circuit slots into the genetic code of a virus, itself modified to grant us control over its natural tendencies. When introduced to malignant cells it infects them and, just like all viruses do, adds its synthetic genome (including the assassin program) to the host’s DNA. Obliging the natural trickery of virus infections, that host cell unwittingly decodes the killer circuit and enacts the program that will bring about its own downfall” (loc. 2058).
The treatment has already been shown to work with isolated cells, so the next step will be animal trials (loc. 2076). This is where things get dicey, though, since the “degrees of control will be challenged further by the more chaotic and dynamic noise of working with a creature” (loc. 2076). Still, the treatment looks promising (loc. 2076).
From medicine, now, to energy. The world is running out of oil, this much we know. What is not yet certain is just where we will get our energy from when we do finally run out. One solution to the problem is to create synthetic fuels, and at least a few companies are currently attempting to do this through synthetic biology (loc. 1930).
Take the company Amyris, for instance. The company was founded by University of California professor Jay Keasling, whose aim is to manufacture biodiesel from live cells (loc. 1930). The technique works like this: “their designed tool has been a genetic circuit consisting of around a dozen individual chunks of DNA, which they implant into the genome of brewer’s yeast, a cell that naturally ferments sugar into alcohol in beer. / The cells that have taken up the circuit don’t need much more encouragement. Incubated, they simply leak diesel. At Amyris’ headquarters in San Francisco they have a three-hundred-liter test tank churning out diesel” (loc. 1934 / 1946).
The process is already fairly efficient—to the point where the biodiesel is in fact being sold commercially, on a small scale (loc. 1958). However, Keasling has run into problems that have kept him from ramping up production to the level that he had originally intended, and that would make the diesel economically viable on a grand scale (loc. 1958-62). (Though Keasling’s biodiesel enterprise has not gone as well as he had hoped, it turns out that his efforts to draw diesel from a bacteria led him to a discovery that may hold even more potential. Specifically, his team serendipitously found a way to manufacture synthetic artemisnin, which is used to treat malaria [loc. 2779]. This synthetic form of artemisinin is economically viable, and is now expected to be commercially available within the next two years [loc 2795]).
Returning to biodiesel for a moment, though, the prospect of using synthetic biology to manufacture this fuel is not a dead dream. Indeed, the endeavor has shown itself to be doable, and the science of synthetic biology is still very young, and advancing in leaps in bounds (as we have seen above).
At least part of the reason why synthetic biology has been able to advance so quickly has to do with the fact that a real effort has been made to ensure that all of the parts used therein are standardized. Standardized parts make it easier for researchers to build on the work of previous researchers, thus helping advance the science (loc. 2301-05). And this brings us to another reason why synthetic biology has been able to advance so quickly, which is the open and collaborative nature of much of the research. Giving scientists open access to each others’ work allows them to build-up the science much more easily, and this has been the spirit of synthetic biology since the very beginning (loc. 2449-77).
a. The Registry of Standard Biological Parts
To begin with, out of the desire to develop standardized parts, and also to ensure open access to the research, an open library was established early on wherein standardized biological components (called BioBricks) could be deposited and borrowed. Known as the Registry of Standard Biological Parts, the institution was established not long after the first biological components were themselves created. Here’s Rutherford to explain: “in 2003, the BioBrick project was conceived by Drew Endy at Stanford, Tom Knight (then at MIT), and Christopher Voigt at University of California, San Francisco (UCSF). The BioBrick part is a useful and simplified way of plugging in bits and components so that everyone who signs up doesn’t have to redesign each idea and each part for him- or herself. BioBrick parts are to genetics what the sampler is to music—a system for freeing up the elements of the rich biological past and the ingenuity of others’ designs in order to foster extreme forms of creativity by standardizing the assembly of DNA components so that they don’t need to be redesigned every time… Each [part] is a piece of DNA and is delivered in the mail as a dot on some blotting paper. Drop it into a solution, and the DNA floats off the paper, ready for assembly. Some BioBrick parts are genes, some are regulatory instructions, and some are combinations of both, already assembled to be integrated into new circuits. All have been standardized so they can be knitted together for new creations” (loc. 2314).
Though established little more than a decade ago, the Registry already houses over 10,000 biological parts (loc. 2310). Indeed, new parts have been coming in so fast and furious that technicians at the lab are falling behind in verifying new entries (loc. 2400).
b. The iGEM Competition
Some of the biggest contributors (and users) of the components at the Registry are the competitors in what is known as the International Genetically Engineered Machine (iGEM) competition. The competition was established in the same year that the Registry was introduced (as part of the same project to make synthetic biology standardized and collaborative). Here’s Rutherford to explain it: “each year, teams of undergraduate students devise a problem and design and build their proposed solution using only the components available in the Registry of Standard Biological Parts” (loc. 2317)—in addition to any new parts that they themselves build and contribute back to the Registry (“the registry website declares that users ‘get some, give some’” [loc. 2322]).
Though the participants are mainly undergraduate students, and though they are only given the summer to complete their projects, some of these projects have been very impressive indeed. One, submitted by a team from the University of Texas at Austin in 2004, involves a circuit embedded in bacteria that absorbs a beam of light to produce a photographic plate (loc. 2335). A second, submitted by a team from Cambridge University in 2009, involves a component that can be tuned to turn different colors in the presence of different substances, thus acting as a sophisticated biosensor (loc. 2342). A third project, submitted by the Slovenian national team in 2010, uses genetic structures to reorganize the cell in such a way that optimizes the production of protein (loc. 2354-62). One final project, submitted by a team from the Imperial College of London in 2011, involves a genetic circuit that nurtures root growth for the purpose of counteracting soil erosion and desertification (loc. 2350).
The following is an excellent documentary that tracks an iGEM team from Imperial College as they prepared for the 2006 competition:
As we can see, these are not just quirky projects that seek to stretch the boundaries of what is possible in genetics; rather, each project (and many more over and above these) has significant, real-world applications. And this is, in fact, another hallmark of synthetic biology: the intent to use biology to address real world problems. As Rutherford puts it, “the protagonists of the purest form of synthetic biology have engineering as their key guiding principle and, even more specifically, the commoditized version of electrical engineering. These aims are not merely to investigate and understand how living processes function, but to re-create, remix, and build living organisms that address global problems” (loc. 1730).
Synthetic biology, as we have seen, has upped the ante when it comes to taking full control of genetic information. However, limitations yet exist here. At least some of these limitations have to do with the fact that the biological components of synthetic biology often need to be introduced into an existing bacteria in order to function—and these bacteria are somewhat unpredictable and uncontrollable. What would be better by far, in many circumstances, would be to create a life-form from scratch over which we have far more control. And this endeavor is in fact already under way.
The famous biologist Craig Venter is leading the way in this enterprise and he has managed some significant progress thus far. Venter’s ultimate goal is to create the simplest possible life-form–from scratch (loc. 1714-18). As Rutherford explains, “the plan was (and is) to determine the smallest number of genes and the minimum amount of genetic code required to sustain a living cell… the long term plan [is] to establish the minimal amount of DNA required for a cell to exist and reproduce, so that they could use that genome as a foundation on which they could build new functions” (loc. 1718).
This project requires 3 conditions: 1) discovering the simplest possible genetic code that is capable of sustaining life; 2) synthesizing all of the component parts (including the DNA) that are needed to produce this life-form; and 3) organizing these component parts in such a way that a life-form is in fact created and able to reproduce.
When it comes to the first condition, the simplest genome that we know of belongs to a parasite known as Mycoplasma genitalium. Its genome consists of just 517 genes and 582,000 letters of genetic code (“compared with 4.6 million bases for the more common lab microbe E. coli, or 3 billion for humans” [loc. 1714]). Venter is currently experimenting with this parasite (through a simple process of elimination) in order to discover the minimal amount of genetic code that is capable of sustaining life.
When it comes to the second condition, it has already been shown that all of the basic building blocks of life can be synthesized in the lab. This includes the letters of the genetic code, strings of the genetic code (even whole genomes, as we shall see in a minute), amino acids, and proteins (loc. 3070).
When it comes to the final piece of the puzzle, Venter has already shown that it is possible to take the genome of an existing species, modify it, synthesize it in its modified form, reintroduce it into a host cell that has been eviscerated of its DNA, and have that cell survive and reproduce just like any other cell. Venter named his new creation ‘Synthia’ (loc. 1699). Here’s Rutherford to explain: “Synthia represents a proof of principle, that it is possible to construct an entire genome synthetically, albeit a very small one. And it is possible to get it into a cell, so that the cell functions and, crucially, reproduces like any other bacteria” (loc. 1726).
As we can see, then, Venter has already made significant progress in realizing his project. Just how long it will take him to complete it, though, and whether he will be able to solve all of the difficulties that will inevitably come up is unknown. Given Venter’s track record, though, it’s a good bet that he will succeed. Just whether he’ll be able to beat Nick Lane in becoming the first person to create life out of non-life, though, is another matter.
As we reach the stage where we are able to demonstrate how life originated, and are also able to create a man-made form of life from scratch, the conclusion will no doubt be drawn that we will have become god-like in our understanding. And as we apply these new understandings to practical applications, it will no doubt be concluded that we are in fact behaving like gods. The question, then, is whether we will have the wisdom to match our power. And whether we can be sure that the technology will not be used for ill as well as good.
There are some who believe that the dangers are too great, and that, therefore, we should cut the science off at the knees, before these powers are upon us. For Rutherford, though, this is a misguided way to approach the situation. The fact of the matter is that the advances are coming. There is little we can do to stop the forward march of scientific discovery. Nor is this a bad thing, for the benefits stand to be great. At the same time, we must acknowledge the potential dangers (for they are real) and prepare for them accordingly. Fortunately, this is already happening, as codes of conduct have been set down to ensure that positive results are maximized and negative ones minimized. In addition, Rutherford argues, we must ensure that each new application of the science is assessed anew, in order that we may decide collectively if and how it is to be used. Our future holds great advances, but also a great responsibility to see to it that these advances do more good than harm.
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