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We Built the World’s Simplest Cell—but Dunno How It Works

The idea was daring, radical—dangerous even. Is it possible to build a living organism from scratch that’s smaller, simpler, more bare bones than anything now alive? Can we outsimplify nature itself and maybe get a peek at the raw machinery—nature’s secret formula—for the essence of life?

We—you and I—are dense with working parts. A human cell has more than 20,000 genes, fruit flies 13,000, yeast cells 6,000. But if we look for the simplest creatures on the planet, we will find a wee bacterium that lives happily in the digestive tracts of cows and goats: Mycoplasma mycoides.

Drawing by Robert Krulwich
Drawing by Robert Krulwich

 

It builds itself from a very modest blueprint—only 525 genes. It’s one of the simplest life-forms we’ve ever seen.

The Big Dare

So, suggested Craig Venter eight years ago, why not take the next step and try to engineer something even simpler? A new life-form with even fewer parts? Venter is perhaps biology’s most wily, most celebrated entrepreneur (famous for spurring the great race to build the human genome). He assembled an ace team of cell biologists and asked, If we put our minds to it, could we strip life so bare that we’d create a living, replicating creature with, say, only 500 genes? Or 400? Or 300? As Chubby Checker used to sing (while dancing the limbo years ago), “How lowwwww can you go?”

Last month, we got an answer.

On March 24, Venter and his team of scientists unveiled a man-made cell stripped down to—sound the trumpets!—473 genes. The simplest creature ever. They call it JCVI-syn3.0 (That’s the J. Craig Venter Institute, third try). It’s not Botticelli beautiful.

Picture of the jcvi syn 3.0 cell
All featured photographs by Tom Deerinck and Mark Ellisman of the National Center for Imaging and Microscopy Research at the University of California at San Diego

 

Actually, it’s kind of boring. “It doesn’t do anything magical rather than live, eat, and self-replicate,” Venter says. But then again, he crows, it’s “the first designer organism in history.”

The Big Shock

But it’s also—and no one saw this coming—deeply mysterious. Almost embarrassingly so. The folks who built this cell know it’s alive. It reproduces in its laboratory dish every three hours. Yes, it has 473 genes and almost every one is presumed essential. “You cannot live without all but one or two of the genes in this genome,” says Venter.

That’s how they built the thing: They started with a goat intestine bacterium, copied its chemistry, booted it up, and then, one by one, they looked at each and every gene and removed it. If the bacterium died, they put it back—it was necessary. If it wasn’t, out it went.

But now, staring at the 473 survivors, weirdly, Venter’s team has no idea why it’s these genes? Why are they the ones necessary for life? (For this creature’s life, anyway.) What exactly are they doing? And the answer is … they don’t know.

“It’s a very humbling set of experiments,” Venter says.

It’s how much they don’t know that’s really shocking.

Of the 473 genes, 324, or 68 percent, are clearly there for housekeeping. They make proteins, protect DNA, repair the cell’s membrane. The usual stuff.

 

Source photo by Tom Deerinck and Mark Ellisman of the National Center for Imaging and Microscopy Research at the University of California at San Diego

Roughly 32 percent of the whole, or 149 genes, have no known function. “We don’t know what they provide or why they are essential for life,” Venter told Ira Flatow on PRI’s Science Friday.

Some of of “the Unknowns”—about 70—look structurally familiar. A gene might look, say, like it transports something in or out of the cell but, “What we don’t know is what does it actually transport,” Venter says. His team can fiddle with the cell’s environment to see if the transporters are still needed. There are trial-and-error ways to figure out what some of these genes do.

But then come the Total Unknowns—the black holes.

The 79 Mysteries

There are 79 genes in this group that no one has seen before. “We don’t know what they do,” Venter says. “That’s probably the most important finding,” he told Science Friday, “and it’s frustrating, it’s humbling … ”

When they began this project, Venter’s team imagined that after years and years spent comparing human genomes, mouse genomes, fruitfly genomes, yeast genomes, and plant genomes, biology had a working script for what produces life. They thought they knew the basic parts—or most of them. But the truth is, they didn’t.

“The scientific community has been basically suffering from the delusion that we did know all of biology,” Venter says. “We’re truly like aliens from another planet trying … to work out what these parts do.”

Even more humbling, these “unknown” genes have been doing what they do for millions of years (or, as the biologists say, they’ve been “conserved” by evolution) for some important reason.

So how could we not recognize them? How could the simplest life-form ever be one-third unknown?

There’s something about the essence of life we’ve missed, thinks Venter.

Perhaps, he says, life isn’t built from independent parts, like something in a machine shop. Maybe you can’t take a bunch of well-known genes, clamp them together, each one doing its own thing, and then, when you tighten the last screw, suddenly—SHAZAAAM!—a new creature sparks into being. Instead of focusing on genes, maybe we should consider the whole operating system—not the genes but the “genome,” a functioning whole.

Life may not be machine-like. We may be orchestral.

Genes whisper. They amplify. They turn other genes on and off and make them louder, softer, even silent. They cause cascade effects, sending notes through the system that loop back, creating loops within loops. A living thing may be a constantly changing melody, orchestrated by its constantly changing parts.

For too long, Venter thinks, biologists concentrated on genes for this and genes for that. “We can’t just look at the function of a gene,” he says. What those 79 mysterious genes may be doing—some of them, anyway—is they may be pulling the parts together so they fit, compose, and hum themselves into being.

How they do that may take us a while to figure out. Maybe a long while. Life, it seems, is darkly (richly?) complicated.

32 thoughts on “We Built the World’s Simplest Cell—but Dunno How It Works

  1. I am waiting for the breakthrough with artificial life, so that it will change the world for ever !
    Thank you very much my dearest scientists.

    1. Let’s be honest – they just cheated. They took what already was there and just modified it. It is not news anyways…

      “That’s how they built the thing: They started with a goat intestine bacterium, copied its chemistry, booted it up, and then, one by one, they looked at each and every gene and removed it. If the bacterium died, they put it back—it was necessary. If it wasn’t, out it went.”

  2. For too long, Venter thinks, biologists concentrated on genes for this and genes for that. “We can’t just look at the function of a gene,” he says. What those 79 mysterious genes may be doing—some of them, anyway—is they may be pulling the parts together so they fit, compose, and hum themselves into being.

    Okay, I’m only a layman interested in biology, not a biologist, but that’s pretty much the message I’ve been reading from biologists for years now. It’s not a very ground breaking or controversial statement from Venter, just repetition of what plenty of others have already been saying.

  3. I guess I should have added that this was a very interesting article and a very interesting study. I didn’t mean to sound too negative in the previous comment.

  4. I agree with Jeff! Biologists have been looking at far more than direct protein transcription or direct simple functions for decades, and yet this trope is still put out, usually by groups tooting their own horns loudly like ENCODE or some of Venter’s stuff. I am tired of reading it.

  5. This was a very honestly written article. I hope Veneer and his team will keep searching, keep seeking, and keep knocking. I’m confident the door will be opened one day. It’s like a search for hidden treasure. Rewards come to those who stay honest, humble and hungry.

    1. There is, I guess, the possibility that we will NEVER figure out exactly how life self organizes and respawns itself — that this is one of those mysteries that those who call themselves “mysterians” and many people of faith think is a miracle and will never confess itself to our human minds. I sometimes warm to this idea, because not knowing something is, for me anyway, always a little more exciting that knowing it. But I have a feeling that like so many other once magical things, lightning, gravity, flight, magnetism, life itself will eventually become get naked and tell us how it works. That won’t happen in a day, or a century, probably — it will be layered like an onion with a little Cheshire Cat mixed in — things that seem clear will unclear and pull us in deeper. But it does seem like one of the great adventures we’ve been assigned by nature (or by Whomever). After all, we’ve got these brains. Might as well use ’em.

      1. Robert Krulwich and ron braithwaite, thank you for your comments. They resonate really strongly with me. I usually ponder over this kind of things while reading my textbooks (I study molecular and cellular biology). I am just not that skilled in putting those thoughts into words. 🙂

  6. The above findings have major significance for the origins of life, either on this planet or elsewhere. Given a ‘perfect’ biological soup–whatever that might be–the odds against an accidental biochemical combination to produce the very first gene must be long, indeed. The odds against the accidental production of dozens of quite different genes and then having them accidentally join together in the absolutely necessary arrangement, also must be mathematically enormous.

    Also, such an initial life form MUST have had mechanisms to protect its own nucleic acid with incredible perfection, otherwise its reproduction products [‘daughers’] would not have had the minimal ‘stuff’ possessed by their own minimal, maternal ‘cell’. These imperfect daughters would have been nonviable and immediately faded into the surrounding ‘soup.’

    Now, given an early earth with an ideal biological soup containing all the building blocks necessary for that first life, there must have been an incredible number of failed ‘life’ experiments. Still, as a materialist, I must wonder about the probability of the whole thing. We are presented with the evidence that ‘life’ arose spontaneously AT LEAST once but the numbers seem to be very much against it even given ideal circumstances.

    1. There is, I guess, the possibility that we will NEVER figure out exactly how life self organizes and respawns itself — that this is one of those mysteries that those who call themselves “mysterians” and many people of faith think is a miracle and will never confess itself to our human minds. I sometimes warm to this idea, because not knowing something is, for me anyway, always a little more exciting that knowing it. But I have a feeling that like so many other once magical things, lightning, gravity, flight, magnetism, life itself will eventually become get naked and tell us how it works. That won’t happen in a day, or a century, probably — it will be layered like an onion with a little Cheshire Cat mixed in — things that seem clear will unclear and pull us in deeper. But it does seem like one of the great adventures we’ve been assigned by nature (or by Whomever). After all, we’ve got these brains. Might as well use ’em.

      1. With advances in AI and sensoring systems and the “Internet of Things”, I think you will be surprised how quickly we might find most of these answers when you have scientists utilizing AI working together in a hive mind that has the ability to “see” better at the micro-level and process the data in real time instead of spitting out a bunch of data for humans to parse through and try to interpret with limited reference.

    2. I like your probability insight. Could it be that One whose wisdom is unsearchable said one week “Let there be…..” The details and complexities and interdependencies seem far too unlikely to have slowly evolved.

    3. We seem to always make the assumption that everything will be like it is here – why?? We have a periodic table and we keep filling in the holes but the structure stays. We have lots of assumptions about the ultimate, but then we exceed them. Why are we not more open? There may be game changers to come. So far they have continuously come so why stop now. We consider ourselves, our environment and our universe far greater than they may in reality be. Our realm is so small that it worries me that we try to extrapolate it be infinite.

      Are we maybe overlooking something with such a narrow view??

  7. Life no longer spawns from earth except through propagation.

    Deductively one could presume the life force that sparks life into inanimate objects takes place from a cosmic formation in our universe under very special conditions and tremendous force. A combination of supermassive black holes comes to mind as they burp life force into the universe and spark life into places where the conditions are conducive such as earth. Since black holes warp time space the span between these special conditions may take place repeatedly at the black holes center but relatively takes billions of our years to happen.
    if this is not true one should be able to remove a critical gene that disables the bactirium then add the critical gene to jump start it again. Like reviving a dead person just doesn’t happen but maybe in a simple system it is possible.

  8. “The scientific community has been basically suffering from the delusion that we did know all of biology,” Venter says. “We’re truly like aliens from another planet trying … to work out what these parts do.”

    Ummmmm, no. This statement is not an accurate assessment of what biologists think or even other scientists think about the scientific study of biology. As a scientist I take issue with these over the top, self-aggrandizing statements. What he and his group have done is incredible enough, why hype it beyond its merits? Science is already under attack by right-wing fundamentalism and capitalist dollarmongering. Why do actual scientists, who have done incredible work need to undermine science? No area of scientific inquiry should presume it has it all figured out.

    1. When we speak of “GOD” we attribute this god with the trait of being a higher life form. But what if “GOD” is a stunningly simple/complex expression. As we drill down into the microcosm and launch into the universe I think we will come full circle to find they are one and the same expressions of “GOD”

  9. Just some thoughts about the 79 genes which could not explained by the researchers;
    I believe that a distinction may be made between genes that are essential during the life time of an organism and on the other hand genes that contribute to a higher pace of evolution. For example, gene replication allows for faster creation of new genes. Translations of DNA allow for rearrangements to be made within the genome. Routes within complex pathways may be re-routed to allow for genes to change significantly without depriving the organism from its ability to live. I believe that especially the last mechanism enables the flow of evolution to escape local minima and hence stimulate progression during evolution.
    To conclude the above, not all genes are aimed at only the life time of an organism.. so they may be knocked out, but lower level systems may then be defected, which is very hard to detect or understand.

  10. We didn’t build anything. We just modified an existing living cell, which is still a great achievement. I hope sometime we could really understand life.

  11. Hi Robert, this was an interesting read!
    I’m a marine biology student/microbiology nerd and thought I’d chime in with my thoughts.
    In experiments where they removed genes from yeast, the eponymous “they” found similar things to this study; genes that served seemingly little function but the yeast couldn’t survive without. They came to the conclusion that genes don’t work in isolation, that there may in fact be networks of genes that collaborate to carry out their function. That may be what we’re seeing here too, as you say.

  12. For a scientific/technical paper, please use proper grammer, no such word as “Dunno”, it should be “Dont know” not a good example to our children is it?

    1. Pete–
      While I’m flattered, these posts are in no way, no, no, no way “scientific/technical papers’. This a blog. It’s me thinking out loud, with a little research and hoping to poke the audience into conversation. “Dunno”, therefore, seems right. I think what you’re saying is that you found the tone of the thing a little too informal, given the subject. That, as it happens, is a compliment. The tone of these pieces is intentionally conversational. Cause that’s what I’m hoping to get going, a conversation.

  13. I suppose that this is just another one of those observations that re-inforces my belief that the universe, as a whole, is some kind of very large organism… No… I am not talking about “God” as one of my humanist friends suggests. I am speaking of a system… an extremely large system which seems to have a form of life… Certainly the universe (and all the meta-universes) are infinitely complex and we can’t hope to understand it completely in any reasonable time period… Systems as simple as this cell, and yet seeming to work in complex ways are an example of a kind of “mini-brain” that is simple in construction, yet complex in operation… The entire universe, as complex as it is, would then have almost infinite complexity in operation… Remember… we are a result of that operation… No matter how complex living organisms on Earth are, we are a part of the complexity of the universe as a whole, therefore, the entire Cosmos is very complex indeed!

  14. I trust this new entity is held under lock & key under extremely strict biohazard level 1 conditions.

    We need to clarify all the ethical issues that this work raises before any further R&D is undertaken.

  15. Perhaps the parameters of the experiment were a bit too strenuous. The cell actually DYING is only one marker that might be used. I can think of a lot of my important constituents that wouldn’t cause me to DIE if they were removed, but which are what collectively make me viable. But I also acknowledge that the cell’s dying is a sure marker, easy to see and perhaps the only one a researcher would ever be sure about.

  16. The “fittest” in evolution is not always the strongest or the most virulent. It is for certain that many times in the evolutionary history of this planet a strain of bacteria came to thrive and took over other strains of the same kind, because it learned not to kill the host. And it was probably accomplished in many different ways. Sometimes it may even be BENEFICIAL for the bacteria to be detected by the host immune system by expressing “non-functional” proteins on its surface, because by allowing the host to keep the colony of the bacteria from taking over the host the colony would be able to live longer and spread more.
    How would Mr. Venter know that he and his colleagues are not turning off some of the genes that are keeping the bacteria from being monstrously virulent, when he does not know what so many of the genes are doing?
    SCIENTIFIC experiments have to be based on at least some degree of UNDERSTANDING.
    This experiment sounds too much like somebody is trying out all the keys on the key ring for the maximum security prison without knowing what’s behind each door.

  17. I agree with John Thomas. You might have just constructed the ultimate disease organism. You took it from a gut. What if it gets loose into our unsuspecting wide world and then we find out what the mystery 79 genes can do … to our horror.

  18. This was a worthwhile attempt and I hope it continues (three is not enough attempts) BUT I disagree with the notion that something complex can not be understood from it’s parts. Something can be very complex and very hard to understand but the last few hundred years of science has been one amazingly complex thing after another yielding to our understanding at a chemical, physical level. Where is the thought in a neuron is like asking where is the meaning in a word or the equation in a number or the program in a binary string – these are components of a language but you have to understand the language first – a book is not a bunch of pages with squiggles that can only be understood as a whole image and that does not go against systems engineering/biology, it is part of the systems approach.

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