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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.

 

From Antarctica: It’s Alive!

February 7, 2015

Mat_Fryxell

You will recall from our Antarctic Upside Down Lakes that we came across some amazing alien life forms emerging out of five meters of ice, from another fifteen meters or more in the lake below. Our expedition was led by Rachael Morgan-Kiss, at Miami U-Ohio, sponsored by NSF–her research blog is here.
Cyano_Mat2These life forms are cyanobacterial mats–dessicated cyanobacteria (photosynthetic microbes) entwined with algae, protists, even possibly tiny invertebrates like water bears. At a touch, they fall apart and blow off in the wind, to find a melting hole in the lake, or in another lake downwind. Well, some of this one didn’t blow away–it ended up stuffed into the purple capped tube, and shipped at -20C to our home continent.

Tube_green

Here’s what one of the samples looked like, arriving back at Kenyon. Still a bit of green.

Is anything alive in there? To find out, we put samples into BG-11 cyanobacterial growth medium, a mixture of plain salts such as carbonate, nitrate, and phosphate–essential atoms, little more, since cyanobacteria build just about everything from scratch. Professor Chris Bickford kindly loaned his lighted incubator, which went down to 10C (50F). That’s not especially cold, but it’s the coldest our incubator will go. And actually, this temperature is reached within the depth of some of the Dry Valley lakes, as well as in sun-heated pools of meltwater during the Antarctic summer.

The samples from Lake Fryxell we put into 100-ml graduated cylinders, to give them both a surface for green algae and a depth for growth of the orange-brown ones.

Fryxell_Jan18

After two weeks–It’s alive! Green stuff bubbling oxygen. Remember–that’s where all the oxygen you breathe comes from.

Fryxell_Feb02

We also sampled some dark brown rubbery stuff that grew in the meltwater by Canada Glacier (the Antarctic glacier between Lakes Fryxell and Hoare).
Glacier_Jan18

After two weeks, you can see the glacier-melt brown stuff’s grown too, expanded and bubbling, while yellow stuff multiplies throughout the flask. We think the yellow stuff includes heterotrophs (organic food eaters) that suck up the oxygen, which is toxic to the photosynthesizers.

Glacier_Feb02We’ve looked under the scope–incredible range of shapes and sizes, even swimming things in there. Richard Dennis in our lab will provide micrographs soon.

Meanwhile, what to call all this stuff? Today, it’s all in the DNA. So we took some of the original samples to smash them up for their DNA.

20150203_094440

Here are samples of Fryxell mat (colored) and glacier mat (dark) ready for the PowerBiofilm bead beater: Tubes of sharp glass beads to shake in the vortexer.

So what’s in the DNA? Stay tuned, and let’s find out.

Index: Antarctica

Mars Life and Antarctica

January 9, 2015

Mars_life

This week, geologist Nora Noffke reports a study of Curiosity rover images that resemble Earth’s life forms. Noffke has long experience of interpreting fossils of ancient Earth in three billion-year-old rock formations such as Pilbara, Australia. In other words, writing grants persuading us to fund one’s camping in of Earth’s most scenic places.

The diagram above shows just one of her many images, with interpretation (the scale bar is 15 cm). It certainly looks like a modern microbial mat upon lake sediment, peeled back and rolled over in some places. Only organic life forms produce such flexible sheets of material, in layers associated with water (whose existence on Mars has also gained evidence). Surprisingly, perhaps, we have no statistical test to say, “that’s a microbial mat.” But the quality and quantity of the images may be our most compelling yet found.

Perhaps Noffke’s most convincing argument is that, were these rocks terrestrial, they would undoubtedly be accepted as fossils of ancient life. To be consistent: Either life existed on Mars three billion years ago–or it failed to exist on Earth.

Why is it so hard to find life on Mars? Microbial life can be incredibly subtle. I came to realize this during my explorations of Antarctica–arguably the best modern model for life without macrobiota.

Lake_BonneyThe Antarctic Dry Valleys are a landscape in which all life is microscopic–that is, microbial or tiny invertebrates requiring magnification to see. There is no soil–because “soil” is a product of living bodies, plant detritus chopped by arthropods and processed by worms, feces of larger life. No soil, only sand and pebbles.

But here and there–where there is water–the microbes congregate in forms called mats or biofilms. Seeing these biofilms can be tricky.

Stream_matIn this example, I have outlined the bit of “stream mat” so you can see it. To find it, I noticed (after hours of hiking the sand) a sort of pasty trail, a few inches wide, descending from a glacier. The glacier had melted previously, sending a trickle of melt water down to the valley. Where the stream flowed, cyanobacteria had photosynthesized like crazy, growing a mat in the stream. Once the stream dried up, the mat dried too–you can see the pebbles trapped in it. This summer, if the mat gets lucky, the glacier will melt again, and  water will ooze once more down the mat. If not, the mat will dry and crack–and the wind might carry it to a nearby lake, where the edge melts in.

If the cyanobacteria end up in a lake, what grows there?

Mat

At the bottom of the lake, with barely a few photons to capture, the mats grow into amazing castles. (See Kay Vopel and Ian Hawes). Their cells make oxygen bubbles that ultimately lift bits of mat up to the ice, where the wind continually scrapes ice away, and eventually the mat bits surface–again to blow off to other lakes.

Who knows if such a mat cycle once happened on Mars? If it did, finding it would be quite a trick today.

 

 

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