My appearance on Inside Story didn’t work out (travel mixup–someone confused Kenyon with Ohio State) but still generated some blog discussion on one of our favorite themes:
- When will computers be as smart as humans?
- What about their lack of common sense, intuition, and other intrinsically human qualities?
- What happens to humans once singularity is achieved?
Bacteria Lab students are wrapping up a paper on “polar aging” of E. coli. What does that mean? Every time a bacterial cell divides, each daughter cell inherits an old pole (preexisting cell division) and a new pole (formed by division). Inevitably, a line of cells inherits an old pole for many generations. In the colony above, the old poles are marked yellow; the new poles are green, and inbetween generations are marked other colors. The white line marks the divide between two half-lineages of the original ancestral cell, for which we don’t know which pole was old or new. A small portion of a colony lineage is diagrammed:
Under certain conditions, the cell with the superannuated pole (yellow) tires out. You can see where the green-yellow cell has given up dividing. The old-pole cell division slows, and the cell eventually dies of old age–despite inheriting a new pole too. It’s like Rowling’s Death Eater that got its head stuck in a time-turner jar, and turned into a baby’s head: half old and half newborn.
Can bacteria ever “reverse” their “polar age”? Not E. coli, we think–but other kinds of bacteria do. Mycobacteria, which cause tuberculosis, grow differently by extending one pole only (Bree Aldridge, Science 2012).
The extending mycobacterial pole makes a newborn cell that accelerates cell division (Age 2) while leaving behind an old-pole cell that pauses (Age 1). But then–in the next generation, the old pole accelerates division–leaving its new pole behind, suddenly old. In effect, a mycobacterium is a time-turner, its young pole growing old and its old pole growing new. Though not an endless loop, the lineage endlessly generates deadly infectious cells showing age-dependent resistance to various antibiotics.
Why do bacteria age? As best we can tell, they age for the same reason humans do. Humans are animals that partition their biomass into an immortal germ line (the sex cells) and a mortal soma (the rest of our body.) The mortal body (the bacterial old pole) “eats death” by inheriting all the mistakes, the misfolded proteins, while keeping the germ line young. In humans, similarly, our brains accumulate the misfolded proteins associated with Parkinson’s and Alzheimer’s. But our germ line (new pole) remains the potential baby, while it’s still part of one’s own body. Like E. coli, we’re all the hapless Death Eater stuck with half a baby.
A 3D tracheal splint was custom designed for each baby, suffering a rare disorder in which the baby can’t breathe out. The splint holds the trachea open, then dissolves naturally as the baby grows and no longer needs the help.
No doubt this is just one of many such ingenious devices to come out of future printers.
We’ve discussed before how ancient endogenous retroviruses evolved into our own human genes, including HERVs (human endogeount retroviral genes) that encode essential products such as placental syncitin. So far, though, it has been assumed that the viruses themselves were extinct; that only their nucleobase sequence (ATCG etc.) remained, adapted to a human function.
Now, researchers show that human embryos produce actual virions–virus particles–containing retroviral sequence and capsid. These truly endogenous retrovirus particles actually serve as part of the human immune system to protect us from viral infection. This is, bizarrely enough, the very opposite of what HIV (the most famous retrovirus) does to adult human immune systems.
The retrovirus studied was HERVK, which infected humans while we were still diverging from chimps–relatively recently in our evolution. Multiple infections left signs of their nucleobase sequence in our genome; in fact, since humans show different versions of HERVK in their genomes toda, the virus must continue some activity in our population, in the last 200,000 years. Thus, HERVK would be a good bet to exhibit some virus-producing ability. At Stanford, Joanna Wysocka and colleagues used fluorescence microscopy and various specific fluorophores (glowing molecules that bind specific proteins or genes) to show the presence of HERVK virus-like particles emerging from embryos.
Why embryos? In adult humans, HERVK appears to be suppressed by DNA methylation, a chemical modification of the nucleobases that generally turns of gene expression (the making of a gene’s product). But in the embryos, the HERVK DNA is free of methyl groups. So, the embryo condition allows expression of retroviral genes. The gene expression is not random, but is regulated by known embryonic regulators, such as the OCT4 transcription factor. The OCT4 is known as a gene expressed only during very early embryos–or in tumors, under abnormal conditions.
Surprisingly, the HERVK activation leads to production of virus-like particles (particles that look like viruse under electron microscopy). Even more surprising, HERVK activation causes upregulation of the anti-viral defense protein, Interferon-induced transmembrane protein 1 (IFITM1). Interferons are a class of protein that host cells commonly express in response to being infected–to tell their neighbor cells to avoid infection. In this case, however, the HERVK may be protecting the embryos from infection of other possible pathogens during a vulnerable period in the womb, before the adult immune system develops.
You may be wondering, where do the researchers get all these human embryos to study? Early human embryos at the stage of blastocyst (hollow ball of cells) are obtained from IVF donors; couples who seek in vitro fertilization for reasons of infertility or other causes. The IVF procedure routinely produces “supernumerary” embryos, a fancy word for “more than needed.” Such embryos are commonly donated to science, under government regulation.
Headlines promote a breakthrough in “artificial photosynthesis.” It’s exciting technology, but–artificial? So what are those bacteria doing twined around the photocathodes?
The Berkeley scientists’ article in Nano Letters is titled “Nanowire–Bacteria Hybrids for Unassisted Solar Carbon Dioxide Fixation to Value-Added Chemicals.” What they seem to have made is:
(1) A silicon-nanowire array (the “photoanode”) splits water (H2O) like chlorophyll does in photosynthesis. The light-absorbing reaction removes an electron. What you get is H+ and O2 (O2 being the good clean oxygen we breathe). Where the other H goes is not clear; presumably it also gives up an electron, without toxic oxidizing radicals, which real photosynthesis produces.
(2) The electrons travel down the nanowires to a source of CO2, in the presence of photocathode wires. But here’s where we need the bacteria, Sporomusa ovata. The bacteria use an ancient evolved pathway of metabolism to reduce (add electrons to) the CO2, making acetic acid, CH3CO2H. Notice a lot of extra steps in there.
The use of Sporomusa ovata in a fuel cell was actually shown a few years ago by Derek Lovley’s lab, which has a long history of pioneering work in bacterial electricity. Lovley’s students used an electrical current to make Sporomusa bacteria reduce CO2 to acetate, a building block for various industrial products.
Here are Lovley’s electrode biofilms of Sporomusa. The implication is that hybrid nanoelectrode-bacterial fixation of carbon could directly make fuels and plastics, without the usual production of biomass (sugar polymers etc.) and thus without all the carbon waste along way.
While high-minded researchers earnestly debate the necessity for caution on editing the human germ line, it appears that everyday bacteria and fungi have done so for millions of years–perhaps ever since the evolution of multicellular life.
We are talking about horizontal gene transfer (HGT), that is, the “illegitimate” transfer of DNA from one organism to another, without vertical (parental) inheritance. Shades of Bleak House come to mind. For decades, HGT via bacteriophages and plasmids was relegated to microbes. Surprisingly, the emerging recognition of viral sequences throughout the human genome has done little to alter this non-recognition of bacterial genes. Part of the reason is that until recently, genome sequencing required a step of amplification that involved cloning within bacteria. It was hard to avoid contaminating bits of bacterial DNA; so researchers excluded any bacterial sequences they found, as likely contaminants.
Today’s third-generation sequencers such as Illumina are orders of magnitude more sensitive and may sequence DNA fragments that have never seen a bacterial vector. Nevertheless, bacterial and even fungal genes emerge.
The figure above represents some of the “non-metazoan” sequences found in a human genome. Authors Alastair Crisp, Chiara Boschetti and colleagues identified genes of microbial origin based on their bitscore, that is, how many of the base pairs line up. Class C genes (red) show overall better alignment with microbial genes (threshold score 30) and best match with a particular microbial gene (score 100). Class B genes (blue) show scores of >30 for all orthologs of the gene in other species; orthologs meaning “the same” gene due to shared ancestry. Class A genes (gold) are a subset of class B genes with even poorer homology to genes of metazoan (multicellular) organisms. In contrast, all other garden-variety human genes are shown as gray. But the take-home is that red, blue, and gold genes abound.
What are some of these genes, and what do they do? Most do surprisingly fundamental cell tasks.
- ABO blood type. The histo-blood group transferase gene (transferase A or transferase B) encodes variant forms of an enzyme that make the A or B antigens on the surface of blood cells, defining blood of type A or B. This gene appears to derive from bacteria.
- Hyaluronan synthase. A gene of fungal origin encodes an enzyme that makes hyaluronan, a sugar polymer found throughout our cell membranes. An adult human body typically contains 15 grams of hyaluronan.
Other human genes of suspect origin encode enzymes of amino-acid synthesis, the innate immune system, and anti-oxidant defense.
So how do all these bacterial and fungal genes get into the monumentally protected human germ line? One commenter helpfully points out that sperm delivery offers a convenient means of “natural” insertion of foreign DNA into an egg. In the laboratory, sperm-adherent DNA delivery has been demonstrated in mice. An alternative source, the human placenta abounds with bacteria–hence the placental microbiome project.
Meanwhile, in other news researchers report that “Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity.” That is, digestive bacteria can be engineered to produce “potent anorexigenic lipids”. Apparently, the potential editing of our microbiome does not yet raise the same alarms as editing of “our own” cells. Perhaps it should.
Back to the future—Award-winning scientists propose to ban their own Franken-genetics? Jennifer Doudna, bacterial molecular biologist, called the meeting, along with Nobel winners David Baltimore and Paul Berg. Back in 1975, Berg’s Asilomar conference famously called for banning certain kinds of “recombinant DNA,” the splicing of DNA from one species into another. A long time since then, we’ve gotten used to multiply spliced bacteria making antibiotics, and mice glowing with Green Fluorescent Protein from a squid.
But altering human embryos remained relegated to science fiction. Until now. We how have techniques that can effectively (if imperfectly) edit the genomes of various mammals, including mice and human embryos. The most effective of these “editing” techniques is called CRISPR (clustered regularly interspaced short palindromic repeats). CRISPR was presented by Ultraphyte recently as a potential means of cutting HIV genomes out of the chromosomes of infected patients.
As shown in this Wikipedia diagram, CRISPR in nature is a mechanism by which bacteria obtain bits of DNA from invading bacteriophages (viruses) and use them to store information against the next time–A bacterial immune system. The mechanism requires inserting the viral DNA into the bacterial chromosome, then making an RNA copy next time, which combines with a protein complex to snip the invading viral DNA.
But the key part for editing is the CAS protein complex, which acquires the viral DNA and splices it into the host DNA. This mechanism turns out to work for any DNA, even mouse or human. Already, many applications are in progress for treating human diseases by editing DNA of somatic cells (body cells, not inherited). The difference is that if the technique gets too efficient, we’ll use it on embryos, to prevent disease and select baby’s eye color.
I wonder, though, if the battle isn’t lost already. Science fiction writers have threatened to change baby’s eye color for maybe a century now, and the threat’s getting old. The very terms used–“editing,” in place of recombination–makes the prospect hard to get worked up about. What’s a little “editing”?
Back in the 50s, when natural human recombination was a serious business (Catholics didn’t marry Protestants) the odd things bacteria did were labeled “illegitimate recombination.” The horror of “illegitimate” required no explanation. It took several decades for scientists even to admit humans (and our viruses) do that sort of thing. Today, bacteria have “pangenomes” (access to infinite genes) and young people fashionably call themselves “pansexual” (attracted to infinite genders).
I know the consequences should concern us, but until we come up with more concrete issues than “editing” and “limits of our knowledge,” parents and their doctors are going to press ahead with clinical trials. Mitochondrial transplant (involving triparental embryos) is already out the door, as is embryo selection to save the life of a sibling. Anything to save the life of a child.