ARTIFICIAL LIFE
Frankenstein (1931) (Quotes)
Victor Moritz: You're crazy!
Henry Frankenstein: Crazy, am I? We'll see whether I'm crazy or not.
Henry Frankenstein: Look! It's moving. It's alive. It's alive... It's alive, it's moving, it's alive, it's alive, it's alive, it's alive, IT'S ALIVE!
Victor Moritz: Henry - In the name of God!
Henry Frankenstein: Oh, in the name of God! Now I know what it feels like to be God!
Henry Frankenstein: The brain you stole, Fritz. Think of it. The brain of a dead man waiting to live again in a body I made with my own hands!
Dr. Henry Frankenstein: The neck's broken. The brain is useless. We must find another brain.
Dr. Henry Frankenstein: You're quite sure you want to come in?... Very well.
[Locks door and pockets key]
Dr. Henry Frankenstein: Forgive me, but I'm forced to take unusual precautions.
Henry Frankenstein: Dangerous? Poor old Waldman. Have you never wanted to do anything that was dangerous? Where should we be if no one tried to find out what lies beyond? Have your never wanted to look beyond the clouds and the stars, or to know what causes the trees to bud? And what changes the darkness into light? But if you talk like that, people call you crazy. Well, if I could discover just one of these things, what eternity is, for example, I wouldn't care if they did think I was crazy.
Doctor Waldman: You have created a monster, and it will destroy you!
[first lines]
Dr. Henry Frankenstein: Down! Down, you fool!
Artificial life is only months away, says biologist Craig Venter. “Artificial life will be created within four months, a controversial scientist has predicted. Craig Venter, who led a private project to sequence the human genome, told The Times that his team had cleared a critical hurdle to creating man-made organisms in a laboratory.
“Assuming we don’t make any errors, I think it should work and we should have the first synthetic species by the end of the year,” he said.
Well, Dr. Frankensteen, I mean Dr. Venter, just how close are you to creating artificial life?
The answer is: not very. And for Dr. Venter, as the Beatles wrote, “I get by with a little help from my friends”.
Not to disparage Dr. Venter’s accomplishments, but let’s just see what he’s talking about.
In 2007, Dr. Venter succeeded in replacing the genome of the bacteria Mycoplasma capricolum with that of a closely related species Mycoplasma mycoides, thereby changing one species into another. Not a trivial feat, but the virtually naked donor chromosome from Mycoplasma mycoides (almost pure DNA) was introduced into a whole Mycoplasma capricolum cell containing all of the cellular machinery (e.g. proteins, enzymes etc and a cell membrane). The Mycoplasma mycoides genome was then selected in the recipient Mycoplasma capricolum cells by virtue of an antibiotic resistance gene present on the donor chromosome which allowed for the selection and segregation of cells containing the Mycoplasma mycoides chromosome.
Using a series of specific primers in PCR amplification (Polymerase Chain Reaction), genomic sequencing and Southern blot analysis to verify only the presence of Mycoplasma mycoides DNA, the research group concluded that “the above results were all consistent with the hypothesis that we have successfully introduced M. mycoides LC genomes into M. capricolum followed by subsequent loss of the capricolum genome during antibiotic selection”.
However, as the authors acknowledge “We cannot rule out the possibility that small regions of the donor genomes recombined with identical regions of M. capricolum recipient cell genome; however, those regions would be very small.” Because both genomes are initially present immediately following the introduction of the donor DNA during the transplant process, any shared identical stretches of DNA can lead to homologous recombination. Therefore the creation of hybrid genomes must be considered in appropriate cases.
The bottom line here is that the cell membrane (and components) and cellular machinery of M. capricolum were required for this significant advance of species change.
Subsequently, Dr. Venter’s group succeeded in synthesizing the genome of Mycoplasma genitalium by introducing short synthetic fragments of the genome into the bacterium Escherichia coli for amplification and assembly into larger DNA sequences followed by a final genome amplification and assembly step in the yeast Saccharomyces cerevisiae. The use of short identifier sequences in intergenic regions (regions between genes) called watermarks allowed for rapid tracking of the designed sequence.
The resultant genome was confirmed to be that of the original designed Mycoplasma genitalium by shotgun DNA sequencing. Dr. Venter’s group relied on biological organisms to produce the complete genome which had originally been synthesized as independent, short synthetic DNA fragments.
Dr. Venter presumably aims to then replace the genome of a recipient cell with that of Mycoplasma genitalium, using a similar genome transplant process as used for the replacement of the M. capricolum genome.
If Dr. Venter’s claims that “Artificial life is only months away”, rests solely on the premise that DNA is the sole requirement for artificial life (“software creates the hardware” of life), he is ignoring the initial required contribution of the cell membrane/components and the intracellular machinery.
If Dr. Venter is referring to the synthesized M. genitalium genome as the guiding blueprint for artificial life, it must be pointed out though, that the designed genome is simply “a 582,970–base pair Mycoplasma genitalium genome. This synthetic genome, named M. genitalium JCVI-1.0, contains all the genes of wild-type M. genitalium G37 except MG408, which was disrupted by an antibiotic marker to block pathogenicity and to allow for selection.” This is a nature designed genome.
The minimal genome essential for M. genitalium’s, or any organism’s, viability has not yet been established, Dr. Venter claims artificial life is only months away. I repeat, it is not yet known how many and what genes are required to form a minimal genome.
The purist would maintain that not until all of the required minimal components for life have been identified, isolated and assembled into a viable organism can the creation of artificial life said to have been achieved. Dr. Venter would say that this is a new artificial organism (assuming changes were incorporated into the synthesized genome) and that the software (artificially synthesized DNA) created the hardware; i.e., subsequently all other cellular components which are replaced during subsequent cell divisions.
However, any required epigenetic factors (changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence), would have been initially supplied by the recipient cell’s environment.
Furthermore, the time investment and financial cost of assembling large stretches of DNA by starting with short oligonucleotides to produce a genome is questionable. The conventional approaches of using DNA delivery systems such as viral vectors and/or directed recombination methods offer many advantages over whole genome replacement strategies.
If whole genome or chromosome replacements are desired, synthesized DNA stretches such as genes can be added to sequenced, cloned fragments of biological origin using current methods and then used in replacement strategies.
And lest we forget, a chemically synthesized somatostatin gene that produced somatostatin in E. coli was constructed at Genentech in 1977. The synthesis of somatostatin represented the first synthesis of a functional polypeptide product from a gene of chemically synthesized origin. Soon after this landmark achievement, a synthetic insulin gene was constructed at Genentech in 1978 and used to produce insulin in E. coli and a synthetic human insulin gene shown to produce insulin in yeast in 1983 Gene. 1983 Oct.; 24(2-3):289-97.
Dr. Venter’s work, while being a technical tour de force, is an extension of work accomplished thirty-two years ago.
None the less, Dr. Venter’s approach offers the ability to create a defined, manipulable platform to investigate designed systems. Using Dr. Venter’s or more conventional methods, the obvious targets of medical investigations, ecological applications etc., will pale before the inevitable queries of creating colonial life, tissues and finally complex organisms.
The Dummies Guide to Human/Chimpanzee Genetic Similarity
The popular media is awash with the astounding claim that humans and chimpanzees are 98.6% identical at the DNA level. But, as with most complex subjects, this simplistic statement is somewhat misleading, and bears further examination.
And, just what do genetic similarities and differences between humans and chimpanzees mean anyway? How close is current Science to understanding just what makes us human?
Let’s really cut to the chase here. Just what is the biochemical basis for our unique trait of human intelligence, which separates us from all others in the animal kingdom? These awesome god-like faculties of intelligence and language that have allowed us to divine our own blueprint and write the Book of Life.
Just imagine the mechanical difference in ability between a bicycle and the space shuttle, and remember that chimpanzees don’t even have bicycles (or underwear). Well you say, but look at the number of different parts and mechanisms between the two devices. However, as we shall see, the number of genetic differences (parts) between chimpanzees and humans that determine intelligence is probably quite small: perhaps a few hundred genes. Wow.
However, as will be revealed later in this article, how these parts are used may well be a crucial component of the engine of intelligence.
Before we start, we need to review the basic central paradigm of Molecular Biology: DNA is the blueprint that encodes RNA, including Messenger RNA. Messenger RNA (mRNA) is then translated to synthesize proteins composed of amino acids. The regions of DNA that encode proteins are called genes or coding regions. Proteins are primarily responsible for generating our physical bodies (phenotype), serving both as structure (hair, skin, cellular architecture) and as enzymes which regulate our metabolism and create our skeletons. Proteins also serve as signals between our nerve cells and as the switches that regulate neural and gene activity.
There are also other categories of DNA that do not code for proteins. These include switches to turn the genes on and off (promoters), introns (sections of DNA that are transcribed into mRNA but which are spliced out to make the tapes that synthesize proteins, non-coding RNA and so called “junk DNA” non-coding DNA which may provide the scaffolding for the organization of genes, but may have unknown functions. DNA also encodes other classes of RNAs which do not encode synthesized proteins. Think of DNA as a tape recorder which produces a tape which is then played on a system to produce music.
Therefore, two initial principles are established:
1) It is the coding regions of DNA which encode selective proteins which are most likely responsible for the formation and function of the unique human brain.
2) DNA needs to be read to make “a tape” to encode proteins or RNAs. The process of turning genes “on or off” in specific areas of the body, at specific times and in producing specific amounts of RNA or proteins, is called the regulation of gene expression.
3) In addition, proteins may interact with each other and/or DNA to form what is called a “combinatorial code.” Thus the code specifying a specific brain cell might be Protein A + Protein B but not Protein C etc., = a brain frontal cortex cell. This code creates a specific cell type and proteins are in the main responsible for the formation of a specific cell type and in turning specific genes on or off. Think of the hormone insulin, produced only in beta cells of the pancreas. The beta cell having been created by a series of on-off gene expression events during development from a stem cell (a cell which can give rise to many different cell types) to a beta cell.
The claim That 98.6% of Human and Chimpanzee DNA Is Identical.
1) What is the percentage of DNA similarity between Humans and Chimpanzees?
From the research article “Initial sequence of the chimpanzee genome and comparison with the human genome” “The draft chimpanzee sequence here is sufficient for initial analyses, but it is still imperfect and incomplete…The draft genome assembly—generated from 3.6-fold sequence redundancy of the autosomes and 1.8-fold redundancy of both sex chromosomes—covers 94% of the chimpanzee genome”
In order to understand what human chimp DNA similarity means, a critical reading of the article is absolutely required. A brief overview is presented.
So, only 94% of the Chimpanzee genome was used for the comparison.
With this caveat, the authors conclude: “Genome-wide rates. We calculate the genome-wide nucleotide divergence between human and chimpanzee to be 1.23%, confirming recent results from more limited studies12, 33, 34. The differences between one copy of the human genome and one copy of the chimpanzee genome include both the sites of fixed divergence between the species and some polymorphic sites within each species. By correcting for the estimated coalescence times in the human and chimpanzee populations (see Supplementary Information 'Genome evolution'), we estimate that polymorphism accounts for 14–22% of the observed divergence rate and thus that the fixed divergence is 1.06% or less.” (Polymorphic refers to genetic differences between individuals in a population).
Figuring in insertions and deletions of DNA in the compared genomes, “On the basis of this analysis, we estimate that the human and chimpanzee genomes each contain 40–45 Mb of species-specific euchromatic sequence, and the indel differences between the genomes thus total 90 Mb. This difference corresponds to 3% of both genomes and dwarfs the 1.23% difference resulting from nucleotide substitutions; this confirms and extends several recent studies63, 64, 65, 66, 67.”
But note that many nucleotide substitutions in DNA are silent because the changed DNA codes for the same amino acid and therefore the same protein. Amino acid changes may also not influence the function of a protein.
So, for the samples studied, adding nucleotide substitutions to the insertions and deletions yields a similarity of chimpanzee and human DNA of approximately 96%.
But wait shoppers! As the beginning of this article stated, it is a little more complex than that, and it’s how ya look at it. As stated in the article “Human-Chimp Difference May Be Bigger”
“Approximately 6 percent of human and chimp genes are unique to those species, report scientists from Indiana University Bloomington and three other institutions. The new estimate, reported in the inaugural issue of Public Library of Science ONE (Dec. 2006), takes into account something other measures of genetic difference do not -- the genes that aren't there...Using a statistical method they devised, the scientists inferred humans have gained 689 genes (through the duplication of existing genes) and lost 86 genes since diverging from their most recent common ancestor with chimps. Including the 729 genes chimps appear to have lost since their divergence, the total gene differences between humans and chimps was (sic) estimated to be about 6 percent.”
The authors of this article then point out that “"Our results support mounting evidence that the simple duplication and loss of genes has played a bigger role in our evolution than changes within single genes."
“Orthologous (proteins having the same function in different species) proteins in human and chimpanzee are extremely similar, with 29% being identical and the typical orthologue differing by only two amino acids, one per lineage.” But, oh yeah, small differences can be crucial ones.
It’s Gene Expression Not Just Different Genes That Is Probably Also Responsible For Differences Between Chimpanzee and Human Brains]
Elevated gene expression levels distinguish human from non-human primate brains :“We identified 169 genes that exhibited expression differences between human and chimpanzee cortex, and 91 were ascribed to the human lineage by using macaques as an outgroup.”
Just because the DNA is highly similar is only a small part of the story.
From the article: Both Noncoding and Protein-Coding RNAs Contribute to Gene Expression Evolution in the Primate Brain“Analyses of these data support three basic findings. “Second, approximately 15% of genes are differentially regulated among human and chimpanzee frontal cortex, and enrichments of functional categories for the protein-coding transcripts reveal that many differentially regulated genes are related to neuronal signaling and energy metabolism, especially aerobic energy metabolism. Third, a subset of coding transcripts come from genes showing both significant differences in expression and a signature of positive selection on adjacent, putatively regulatory, regions. This overlap provides a way to identify candidate mutations responsible for gene expression differences between species and to enlarge the set of candidate genes containing mutations that underlie the origin of uniquely human cognitive traits.”
“The second approach was to look for genes where the human level of expression was significantly different from both the chimpanzee and macaque, but the chimpanzee and macaque were not significantly different from each other. Using this criterion, we found that 309 genes are specifically and significantly different only on the human branch. In contrast, there are 1,326 genes for which all three species are significantly differentially expressed.”
But, keep in mind that like all organs, the brain passes through a series of developmental stages in which genes are turned on and off in specific spatial patterns as the brain forms during neurogenesis from the humble embryo to the mature organ. The developmental nature of organogenesis presents additional mysteries to be solved in the quest for the Holy Grail: the creation of human intelligence.
Transcription Factors Guide Differences in Human and Chimp Brain Function
As stated earlier and eloquently revealed in the preceding article, turning genes on and off and adjusting the levels of proteins made, likely produces significant differences in chimp and human brains. According to the authors above “"The chimp network looks very much like the human one except there are a few transcription factors in different positions and with different connectivity," Stubbs said. "Those are of interest from the point of view that they signal a major gene regulatory shift between species, and this shift may help us explain some of the biological differences."
Transcription factors are proteins that regulate gene expression, turning genes on and off and adjusting the levels of gene product.
Most Human-Chimp Differences Due To Gene Regulation -- Not Genes
THE BIG PICTURE: The HOLY GRAIL OF BRAIN EVOLUTION
So are there any specific genes which may be involved in the unique formation and function of the human brain?
From the article Positive selection on the human genome “The other is positive selection (also known as Darwinian selection), which promotes the emergence of new phenotypes.” That is, via the emergence of new specific genes found only in humans.
“One behavioral trait uniquely associated with humans is language. FOXP2 is a gene implicated in language abilities in humans, with mutations in this gene leading to a language disorder (99). Corroborating the role of FOXP2 in language are studies showing that the gene may also play a role in song-learning in birds (100). Evolutionary studies showed that FOXP2 has evolved faster in the human lineage than in several other mammalian species. This, coupled with human polymorphism data, suggests positive selection on this gene during recent human evolution (101,102). This is a tantalizing finding, though additional research is needed to assess whether the gene indeed plays a role in the origin of human language.” See also Why Can't Chimps Speak? Key Differences In How Human And Chimp Versions Of FOXP2 Gene Work
Brain development
“The evolution of human anatomy is marked most prominently by the dramatic expansion of the brain. This is especially true in the last 2–3 million years of hominid evolution, during which the brain more than tripled in size (103,104). Two genes, ASPM and Microcephalin, have been implicated in the evolution of brain size. Both genes, when mutated, cause primary microcephaly, a disease characterized by a severe reduction in brain size without any other gross abnormalities (105,106). Given the important, and specific, role of these genes in regulating brain size during development, it is enticing to hypothesize that they are also involved in changes of brain size during evolution.
Going on this hunch, several groups investigated the evolution of ASPM and Microcephalin in primates and other mammals. They found that, indeed, both genes showed robust evidence of positive selection along the primate lineage leading to humans. In particular, this lineage had much higher rates of protein sequence evolution as compared with lineages leading to non-human primates (107–111). For ASPM, the intensity of selection is strongest in later portions of the lineage leading to humans, i.e. from ape ancestors to humans. For Microcephalin, selection is most pronounced in earlier portions of the lineage, i.e. from simian ancestors to ape ancestors. This suggests that these two genes might have had differential contributions to brain evolution during different periods of the primate lineage leading to Homo sapiens.
“A question of particular relevance to the understanding of human origins is whether the selective regimes driving human evolution are of exceptional quality or are more typical. One reason to suspect that selection on humans is exceptional is the remarkable rapidity with which some key traits were acquired. Allometrically scaled brain size, for example, grew by an order of magnitude since the lineage leading to humans diverge from old world monkeys some 20–25 million years ago, with a tripling in size occurring in just the last 2–3 million years of hominid evolution (104). Such a dramatic change within such a short period of time is extraordinary for any tissue system, but is particularly so for the brain, an exceedingly complex organ for which the growth in size is necessarily accompanied by the increase in organizational complexity (128). In the theoretical framework of ‘punctuated equilibrium’ (129), the enlargement of the human brain represents no less a stunning punctuation to an evolutionary equilibrium. The identification of positively selected genes, especially those relating to brain development and cognitive abilities, may offer molecular evidence for the exceptional strength of the selective pressure driving the evolution of our species.”
Gene Mutation Responsible For Human Intelligence Tracked Down?
“Exactly why our mental and linguistic capabilities are so far ahead of our chimp cousins now looks closer to being explained, thanks to a new study in the journal Human Mutation. It shows that a certain form of neuropsin, a protein that plays a role in learning and memory, is expressed only in the central nervous systems of humans. Importantly, it seems that it originated less than 5 million years ago and scientists believe they now know the mechanism behind its production.”
Another candidate gene which may be involved in human specific brain formation is HAR1F.
SUMMARY
The high degree of similarity between humans and chimpanzees at the DNA level is a beginning for the explanation of the difference between human and chimpanzee intelligence. Hardware directs the software.
Species-specific relatively small differences in DNA which encodes proteins may have significant effects.
The actual number and identity of genes involved in human specific brain formation and function is not known. There is no single protein that has been shown to account for human chimp brain differences. Nor is it likely. It is almost certain that a combinatorial developmental code of interacting genes and regulation of levels of gene expression will explain human chimp differences in intelligence.
However, the number of genes involved in brain formation and function that are what makes us uniquely human are likely to be only a few hundred. And the number of human-specific genes much smaller.
In addition to the above mentioned comparative approaches in primates which will lead to a greater understanding of why we are human, studies performed on genes involved in learning and memory in relevant pathways of insects and other mammals, as well as insights gained from studies of human intelligence (such as family trees, genetic diseases affecting intelligence etc.) will also point to crucial genes involved in brain development and function.
Hopefully, the human race will use this knowledge for gain and not degrade these understandings in some Brave New World type scenario.
Further reading:
The neuroscience of human intelligence differences
