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The Dawn of the Retroviruses–in Human Embryos

April 25, 2015

Blastocyst_Wysocka_2015Human blastocyst (early embryo) produces virus-like particles (green)

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.

Bacterium Meets Photocathode

April 19, 2015

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.

 

 

If We Don’t, the Microbes Will

April 9, 2015

Bitscore

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.

Edit the Human Genome–Or Not?

March 29, 2015

Back to the futureAward-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.

 

Make It in Space

March 17, 2015

As we pointed out, yes, beaming “clean” energy to Earth still produces waste heat. So we want to spend as much of that energy as possible out there–in space. Amazingly, this is more than science fiction–NASA is doing it. Yes, despite all the sequester-hungry Congress, NASA has contracted with Tethers Unlimited to build large parts of spacecraft in space. Solarrays, solar sails, pieces of unprecedented size.

How will this be done?

By 3D printing, also known as “additive manufacturing” because you build up the structure layer upon layer. NASA just announced the first 3D printer at the International Space Station. It printed a part to repair itself–prudent thinking. But the same technology–unlimited by gravity–can print out anything anywhere, of any size.

To power up such factories, the solarray is the obvious solution. The only question is, what source of atoms? Moon and asteroids?

This gets back to our moonbase idea, but serious engineers are proposing to build whole space ships out there.

Space Energy for Planet Earth

March 14, 2015

This past week saw an advance in our long journey toward energy from spaceAs I have argued, and depict in my Frontera series, energy from space is our only hope for long-term protection of our home planet.

The idea of beaming energy from solar collectors was just that–an idea–back in the twentieth century. But Japanese industry takes it seriously. Mitubishi just reported a significant advance in technology. They managed to transmit 10 kilowatts via microwave across 500 meters. That may not sound like much, compared to the 36,000 km distance that will be required from a geostationary satellite. But it’s an important step forward.

Why is space energy so important? Because all energy use generates waste heat–more and more of it, as more of us do more stuff. And fundamental physical laws limit the rate at which our planet can get rid of waste heat.
Even before the theoretical limits kick in, we can see how upscaling any Earth-based power supply eventually brings disaster.

Solar. Solar power works great on a local scale–every home should have a few solar panels. But scale it up to power cities? Cover the Mohave desert? Black absorptive panels replace white reflective sand. It turns out that large-scale solar may cause half as much global warming as burning carbon fuels. So the planet cooks a bit more slowly. Not a solution.

Geothermal. Geothermal works great to heat your home–even in rural Ohio. We all should go out tomorrow and install geothermal. (After my papers to grade.) But on large scale? Remember when Germany and Switzerland were putting in giant geothermal bore holes. They caused earthquakes.

Wind. Wind is a promising solution for many local areas, from New England to Antarctica. Get used to the turbines–they look as decent as telephone poles. But larger scale wind farms will actually disrupt atmospheric currents, with unknown effects on climate.

Nuclear. Yes it’s clean now, and it’s cost effective–so long as you ignore the next 10,000 years of waste site containment. If today’s ISIL bulldozed the 3,000 year-old Nimrud, what will future crazed groups do?

“Clean” coal, oil, natural gas, fracking. Anything with C in it ends up as CO2. And half of fracked gas escapes, methane, an even more potent greenhouse gas.

Energy in space is where we’ll have to go. And more–we’ll have to spend it there, too, putting all the heat-generating factories there to build our “stuff” and ship it down the gravity well. So let’s get started now.

Looking forward to seeing some of you at ICFA in Orlando.

You Are your Child’s Sex (?)

February 26, 2015

It’s been a while since Ultraphyte blogged on biological sex. Since Brain Plague in 2000, I’ve felt there was little more to be said on the postgender world. However, trust the cell biologists to reveal twists even more bizarre than science fiction.

For perspective: Back in the sixties, we were taught that people came in two sexes and four crayon colors (brown, red, yellow, white). Now we know that sexes, like colors, are a spectrum, like infrared through visible and UV. Some examples, in this open-access Nature review:

  • People are mosaic–perhaps 1% of us. Mosaic means we have large chunks of cells with a chromosome count different from other chunks of cells. So, maybe, your womb is female (XX) but your legs are male (XY). Or your testes are male (fathering children), then your surgeon “discovers” a womb tucked behind.

How can this happen? Several ways, each more bizarre than the last:

  •  Cell divisions in the early embryo make a mistake called “non-disjunction”; that is, at mitosis, chromosomes replicate but both copies go over to one daughter. So, for instance, YX –> YY XX –> daughter cells Y and YXX instead of YX, YX. The Y cell dies; but the YXX can recover by spitting out the Y, leaving XX. Now, a part of the body continues developing YX (the original cell line) whereas the others go XX.
  • A pair of fraternal twins (XY and XX) start out on their own, but then stick together and “merge” into one body. Now you genetically consist of  two different people, with two different chromosome sets.
  • Your autosomes (all the chromosomes other than X or Y) carry other sex-regulating genes–dozens of them. Any one of them can go missing at cell division, leaving you with some other kind of mosaic, say a male body that “ignores” the screaming male hormone. You end up a super beautiful female (outside) without functional reproductive organs.

It gets weirder. When you’re pregnant, what becomes of all those fetal cells that wind up in your own blood stream–enough for a blood test that precisely details your child’s sex and any genetic defects? Virtually 100% of mothers are mosaic with their children’s cells.

Some of those fetal cells wind up part of your tissue, even entering your brain and hooking up with your own neurons. So, decades later, you still have your child’s cells forming part of your brain. Your child, too, has some of the mother’s cells. So, a mother and a male child each share part of each other, including each other’s gender.

Where this all leads, we don’t yet know, but here’s a valentine for someone who knows why.

 

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