The SpudCell is a sophisticated exercise in molecular assembly that ultimately highlights the immense, unbridged gap between biochemical engineering and autonomous life. It serves as a sobering reminder that mimicking the components of a cell is a far cry from mastering the coordinated complexity of a living organism.
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Did Scientists Just Create Life? The Conversations Team Dissects SpudCell
Added:This round circle here represents a cell built from scratch. It's called spud cell.
>> Biologists created a cell entirely from scratch.
>> They can feed, grow, and replicate like a natural cell. What do you think about that?
>> Well, I have been overwhelmed with emails urging me to address this article where people say that they've made a synthetic cell.
>> It's the first real proof that it is possible to generate life from non-life.
>> And so, we're joined now by a lead scientist, Kate Amadali. This pencil is on the kind of a macro level just like a natural cell.
>> This has been so hyped up prior to peer review. We'll talk about what she did she and her group and what they have not done. It's going to be interesting to see what happens to this paper.
Well, I have been overwhelmed with emails uh urging me to address this this article where people say that they've made a a synthetic cell. Have they created life and things like that? So, here we are. We got the conversations group to to really look at this. This is the article that that people are are wondering about. And I know most people have not read this article. Most people have read what the press had to say about it. The article is entitled a chemically defined synthetic cell capable of growth and replication. And the senior author here is uh professor Adamala at the University of Minnesota.
And so she has done uh some remarkable work here. Certainly worth commenting upon. We'll talk about what she did. She and her group and what they have not done. We're going to first have Rob give us just a general overview of what's going on here and then mention a couple of the press articles. Royal is going to go into the very deep details of the biochemistry and the chemistry that's going on here. So, if you're not deep into details, uh the first part, the first 10 minutes or so will will be for you and then then it's going to go deep and and we have to do this in order to really really look look at what's going on here. But that's sort of the scenario and uh that's how we're going to proceed. So, Rob, I'm going to turn it over to you.
>> Yeah, thanks Jim. I want to start off by heaping a little bit of praise on on these authors here because uh not only because they're from my hometown here in Minnesota and my wife is also a professor of engineering there at the University of Minnesota but um they did some genuinely ingenious and creative work in a very difficult area to work upon. Um, we're going to go through a lot of the details, but uh, when you see all the optimization efforts and we're talking about nanocale manipulation of of molecules in order to get some of these results, it's really quite impressive.
Um, I know an you've you've looked at this too with some glaring eyes. Yeah.
>> Yeah. I think when I first looked at it and uh, it's just really impressive.
Lots of, you know, the engineer in me is like, wow, that that was very clever.
lots of very uh clever and smart uh hacks and tricks to pull together, you know, a handful of existing synthetic cell ideas and like composing them in a new way, composing them in a new way that uh I think does yield some really interesting uh new results. And I think to their credit, you know, maybe they've added a little bit to the hype that we've all been experiencing by sort of making this more of a media event before it got published. Um, but uh I think in their words by and large they've been reasonably reserved uh about the claims they're making and they're not they're not really pushing too hard into the the hype narrative we've been hearing. But uh yeah, I think from an engineering point of view, it's it's really it's really quite something. And so I'm excited to dig into the details together. It's also interesting to note that we're in kind of a new world where this is note that this is not a peer-reviewed paper we're showing here.
This is a it's a pre-review paper which used to be that you couldn't create any hype before publication but now we're in a new world which is kind of weird. Um this is a bioarchchive paper and there's a lot of hype about it. So I wanted to step back and look at the really big picture here the really grand picture of how people are trying to study how life began and trying to see what is the requirements for life. Help us to define what life is and what it isn't. And here's a way of looking at it. If we just put complexity on this axis, you know, things that are more complex move to the top. There are people who are studying this problem with with more of a top-down approach, meaning that they're taking existing life, you know, even the simplest kinds of existing life, and then working to try to dumb them down, strip out things that aren't necessary to try to reach this boundary of what is life and what isn't life. And the most famous example of that is from Craig Venttor's group. May he rest in peace. But Craig Venttor passed away about a month ago. But he took um mopplasma which is a really simple bacteria. Very very simple bacteria. It only has like 985 genes. And it's only found in the in ruminants. Uh it lives uh it basically causes pneumonia. And uh so it's kind of a parasite. You know, it needs some other living organism to live. And it's quite simple, but Craig Venttor's group worked quite hard to strip it down and they took it down to what they call JVCI sin 3A. And that organism has only 493 genes. So that's quite an impressive simplification. Most of what's left is essential. And some of what's left, they still don't understand what it does, which is really interesting. But this organism is is really simple. It can really live only in the lab because it requires this kind of coddled environment. It's kind of like an intensive care unit kind of support system because you have to give it exactly the food that it needs in the right concentration, the right pH and you have to clean up its waste um and do all the work for it basically. Now contrast that with a very robust organism. Uh this one I pull out is called Dulerus adoxier. Uh this was found 2.8 8 km underground in a in a mine and it is said to be the only known organism that lives in its own ecosystem all by itself and it's got 2157 genes.
So this is an analogy. You would say this is like a contestant on the on the TV series alone. It has to live completely alone in its own environment and take care of everything for itself.
You know, very robust, very resilient, very resourceful kind of organism. And as we as we look at how stripping things down, you know, this JVCI SIN 3A is more analogous to like a 90-year-old who's in intensive care unit on dialysis, you know, with various machines hooked up to it trying to keep it alive. It's quite different from this very complicated organism. So we can kind of I hope we can all agree that the number of requirements placed on the organism is being simplified here as we try to dumb it down and try to find a boundary of where life is. But what you don't often hear about and I've never actually seen anyone discuss this, but as you reduce the requirements on the organism, all you're doing is actually dumping those requirements onto the environment.
You see down here the environment has to do everything for this organism providing just the right food just the right pH the right concentrations clean up the waste you know whereas up here there's very few requirements placed on the organism so it's not like requirements go away it's just that they get displaced and and put over here onto the environment. So there is um a boundary here that is not well defined because people aren't we're not really able to define exactly what life is. So this is fuzzy, not so clear. But we can say that at some point you'll reach this boundary where life itself can't exist or isn't sustainable anymore. And to have sustaining life, you know, it has to be self-replicating, has to have a metabolism. And to think about it in thermodynamic terms, you know, everything up here is able to exist perpetually in a state that is far from thermodynamic equilibrium. It's in a highly organized, high energy state.
Whereas we go below the line, you know, it's everything is moving toward thermodynamic equilibrium. You could say it's returning to dust. Everything is falling apart. Um, that's one way to try to define the boundary. Probably not the best way. Now, there are people who are approaching this challenge the other way, from the bottom up, and that's what today's paper is about. So they're trying to take basic chemicals, work on things in a lab, build up the chemicals to try to move towards something that could be called living. And progress is being made there. And I would say, you know, this is all relative and cartoonish here in the diagram, but I would say the spud cell is the spud cell is the cell we're talking about, the synthetic cell. They came up with this cute name Spud cell for it, but it has 36 genes. And uh Royal is going to give us all the details of how you have to try to keep it moving. Uh but it it basically is falling apart over time.
And that's very clear. No one is claiming that this thing is alive. And we'll go through a lot of the limitations of it. But one thing that I'd like to point out here, and this is probably a little controversial, is that in order to get to the bud cell, we need a lots of intelligence and lots of technology. And as we advance, we try to push forward, we're going to see more and more of that. And I believe and I think the evidence really strongly supports this that the amount of intelligence that's going to be required to advance is going to be explosive.
It's going to go up exponentially if not more than exponentially.
And that's because as you go from like 36 genes of complexity up to something like 400 500 the complexity kind of gets factorial because of the interact because of the regulatory requirements all the all the interactions that these different components can have that could be detrimental uh more easily than they are uh beneficial. So congratulate I'm not trying to say this group has low intelligence here. Don't don't read that. There's a ton of intelligence and technology going into Spudell, but there is a vast in increase in that that's on the horizon if they want to do approach, you know, something toward life. My own thinking, my own bias is that they will never get to a living a true living organism, but that's yet to be determined. And that's kind of why I draw the curve in this regard. One thing that surprises me the most about all of this is that the people working on it, like the authors we'll talk about today, they are working very hard with all of their intelligence, all the technology, and yet somehow seem very willing to believe that life did begin originally from purely natural processes that chemistry and physics and random mutations ended up producing life. And that's so surprising to me because of how much intelligence they are putting into this.
And I want to put a few quotes here. We can we can have a discussion then. But um there's a lot of hype from the media we mentioned, but there's also some hype from scientists themselves. This is from Cybernot, who is a well-known origin of life researcher, and he says, "This is a big step forward to the holy grail of making a living thing out of dead components. It's not completely there yet, but it's definitely getting quite close. And Royal is going to help us to see how close or not close it actually is, but there's some there's some real hype there. And then from the the real the author of the paper, Kate, uh we've replicated in chemistry what only used to be possible in biology, the complete set of behaviors of a cell. It proves that the most fundamental functions of life like growth and replication do not need a mysterious magical spark. And I'm not sure how she would define mysterious magical spark, but the amount of intelligence and technology that they have put into their work, I think, is already beyond what natural processes are going to accomplish. And somehow she doesn't want to give credit to their their own intelligence in doing that. So discussion anybody um want to jump in and give some perspective to this?
>> I I like your comment Rob about um the the intelligence it is clear that their approach was a holistic top-down concept. They knew what they had to accomplish. They knew they needed subsystems and they had to figure out how to put each of the things together independently. So yeah, clever and everything else far far from what life does, but it's pointing very clearly uh in the direction that real life could not have reasoned by itself.
>> Yeah, I think it it you know what these things tell us and teach us repeatedly is the amount of control that you need to bring to the table in order to put something like this together is is profound. Um, and you're constantly, as Royal is going to dig into. We'll see lots and lots of examples of this, but you're constantly having to fight uh, you know, entropy, right? The thing wants to fall apart and you're you're working hard to, uh, orchestrate the putting together of it. Um, I wonder if if the mysterious magical spark comet is less about how that first life gets made and more about more a statement about, you know, the ongoing operation of life, you know, being like a small machine, like a material process that doesn't need constant external intervention, right? Um, which I I would say, yeah, that that's fine. Uh, not a problem there. It's just uh how did you get that first ongoing uh self-driving thing and how do you continue to refine it? Those are the open questions that we're wondering about. So many of us here have made claims you know that um building a cell from chemistry building even with the greatest of chemists and so forth is is so so far away that we and the goalposts keep moving further that it's hard to imagine it will ever happen. And when this paper came out, there was all this media shock and stuff. But we we as a team, I don't think have felt like anything has changed in our thinking as a result of this. Even more so because of the intelligence they've put into this and we see how far they are from actual life. I think it gives more credibility to our thinking. Yeah, Rob, I'll I'll reserve my comments to the chemistry side when Royal takes us through this because the the the the details are in the chemistry. And so, let's let's uh this is a good segue to to uh turn it over to Royal to take us uh in in into the the details of this.
So, for those of you who uh who who are not particularly science-minded um and if you're having insomnia, we're going to cure that for you right now. Um, but for those of you that that love the science, uh, this is this is where where the rubber meets the road right here.
Royal, >> buckle up.
>> Yeah, buckle up.
>> Well, thanks, Rob. Uh, that was a very helpful introduction. I hope that this will not be as intimidating as uh perhaps uh implied. What's important here is that I don't overlook and skip some details that are fresh in my mind, but uh have not been stated directly.
So, as Rob said, we were all quite a bit shocked by some of the statements that we came across. CNN scientists say they have made a sale from scratch for the first time. I I heard coffee cups dropping all over the internet.
Researchers have created a synthetic cell that can adapt, learn survival skills, etc., etc. Okay, let's not go into all the examples, but clearly something interesting has happened here and our job now is to examine a little bit more carefully what this means. This is of course interesting because we know that cells are very very complex. they are irreducibly complex. The issue here is that all the different parts are mutually dependent. We know that DNA is needed for all the coded instructions and RNA to transport the coded messages.
All that is worthless without ribosomes to translate to form the proteins. We need amino acids to form the proteins, tRNAs for the code.
We have to link the amino acids to tRNAs through the synthetasis.
We need a whole bunch of proteins for for many many purposes. Nothing works without ATP.
Clearly, we're talking about a uh very complex system that is holistic with mutual dependencies. DNA itself uh cannot be synthesized without a whole bunch of protein enzymes both to form the nucleotides to assemble things to to replicate meaning the polymerases.
However, those proteins themselves could have only been coded for by DNA. The same is true of anything you look at.
The ATP itself requires dozens of proteins uh to assemble the machinery but the machinery itself requires ATP.
Therefore, when I and others heard that that living cells or lifelike cells complete with a cell cycle been created from chemicals clearly that raise our eyebrows.
Now one important concept that we will be referring to many times in this talk is a cell cycle. So let me introduce it uh once up front and we'll give you the same idea from other authors over and over again. A cell cycle is fundamental to life. Uh the idea here is let's look at Albert's and his standard book on molecular biology. Some of us have used it in our own studies.
A cell reproduces by performing an orderly sequence of events in which it duplicates its content and then divides into. This cycle is known as a cell cycle and it is the essential mechanism by which all living things reproduce. To maintain their size, dividing cells must coordinate their growth i.e. they increase in cell mass and this coordination must be with division. So the cell mass means everything a cell needs including the ribosomes and all the other uh molecular machines and all this has to be coordinates replication of DNA and then a division to form uh two new uh bacteria or cells. This is per definition by definition a cell cycle.
So, Spudell, hype or scientific breakthrough?
I can hear I can read an's uh mind clicking away. He said, "Oh, >> I just saw a little I just saw a little cruise boat. That that was that was delightful in the little treasure chest."
>> Okay. Okay. But I'm sure you're thinking to yourself, it could be both, of course. Now, um Rob already said one technique to building a minimal cell is to start a complex with a real living cell and remove as much as possible carefully keeping it still alive to see what is uh dispensable.
Spud cell is built bottom up. Yeah, they they knew what had to be accomplished by by the still to be to be lifelike and so they started adding components and these uh components include a so-called pure mixture. This pure mixture goes back about 30 years. It's a standard concoction used in biotech.
the different biochemicals and and parts and elements needed uh to work with to work with synthetic uh cells. So this per se is not new but it was modified by the team that's why it's called pure prere and it includes a few other things specifically a so-called uh 529 polymerase we'll talk about that a bit uh synthetic lipid membrane a very specific linker a nickel base lipid uh linker and seven or eight circular plasma med. So they are working bottom up, bottom up and that has a lot of merit because that way you're you're minimizing complexity. You know what is there and uh you keep adding uh elements one after the other as opposed to working with complex cell extracts which have things which we often don't know what they are even doing. So like I said this pure mixture we'll be hearing about again and again again is not new but it is very very fundamental to their work. In addition there are a couple of externally delivered uh materials externally mean by technicians. They're added straight in and necessary for some experiments.
One is a protein stripen and the other is a specific antibbody uh with biotin uh linked into it. So that's the biotin anti- flag. Important is that spuds is incapable of manufacturing any nutrients through metabolism um by design. Okay, keep things simple.
All uh were continually provided. So we'll explain this when we understand how this scheme was set up. So it cannot manufacture any nutrients. So let's look at the top down engineering concept. Now look at this. It makes me want to go back to grad school, you know, because this is super cool. you know, you know what the the system needs to do and you can sort of um toss together whatever components you can to satisfy those engineering requirements, but you're trying to do this as simply as possible.
So they handled the DNA replication part by taking advantage of what I think is the simplest known DNA polymerase known. It comes from a virus and this is known as the F29 um polymerase. transcription meaning uh conversion of the gene into RNA copies was done through a tRNA polymerase which is well known and very very often used uh and these kinds of studies that also comes um from a virus and because they use this particular polymerase then every gene they worked with required and the suitable promoter for that particular polymerase.
Translation uh was performed by pre-assembled uh ribosomes that were continuously fed in uh spud cannot do this on its own plus all the various amino acids and tRNAs and the synthetases and translation factors. These things were all then uh fed in and not carried out by the cell itself.
They put together a uh lipid billayer based on three well yeah three uh lipids cholesterol included.
They also added some important uh energy molecules like we all know about ATP and others. Those with a biochemical background will at least recognize the terms uh felinic acid, NDA, COA etc. These are all necessary for the energy requirements and a series of uh small molecules a whole bunch of them. And what's important also is they had to carry out the division of the entire cell. So the cell division was carried out using two mechanisms. One is a mechanical extrusion through a small pore and the other one uh using a specific protein tagged with a so-called flag.
And I mentioned technicians needed to add two things. Here's where they're doing that. They're adding an anti- flag, an antibbody, and then to the antibbody uh a protein then binds. I'll explain uh how this is actually done.
>> Okay. Can I just make one comment here so that folks understand these things are not randomly just floating around on an early Earth. These are very advanced structures uh that many of these in fact most of these have never been made in a prebiotic by a prebiotic method. Not even close. And so, you know, when you get to a structure like a tRNA, I mean, nobody's ever made anything like that.
Uh ATP, uh uh nobody's ever prepared something like that. and and even even using advanced methods, you normally start with with small components that you get from cells already and then you build up from there. So all of these building blocks, all of these building blocks were brought in and they're they're not floating around on an early earth. They're nowhere close. This bacteria phage for transcription, this T7 RNA polymerase, I mean these are very complex molecules. uh even even the basic pieces of this have not been made in a stereogenically controlled sense uh even even using advanced chemistries. So it's it's uh uh we're starting with all the components made already and so it it it really doesn't hearken back to an origin of life. Have I said that properly, Roy?
>> Yeah, that is correct. for for an origin of of life. This provides uh no insights or or no hope that it could somehow have been an easy process. This is strictly an exciting and fun engineering exercise. How can we get certain things to work by, you know, um I keep want to use a German word bastilang. It means to tinker to tinker things together.
>> Yeah. Well, I want to add also real quick just to piggyback on what what Jim said. Not only uh uh you know, doesn't early Earth not make these things, but Spudell doesn't make most of these things either, right? I just want to clarify this for folks who who are watching. Um most of these pieces uh are brought in externally through these feeder molecules that I think Royal you're about to talk about. So, so keep that in mind as you as you continue.
>> That's right. Uh good introduction. You can't uh inflate strong enough. Keep that in mind because that is a a very very uh fundamental part uh that needs to be understood and remembered. So uh indeed spel cannot self sustain for various reasons. It is simply not efficient as at producing required proteins. Uh they they know they they they compared everything they did using cell extracts versus the actual materials that uh they had experimented with with later. and the cell extracts were were considerably um more more effective, more efficient for things like carrying out translation and whatnot. Though admittedly, I don't think anybody knows exactly why there's so many things in cell extract. What everything is doing, nobody knows, but it is simply a fact that this uh splat cell is not self-contained.
So the components are consumed and must be replenished or the whole thing is f fizzles out. Now molecules are lost through pores. This idea of pores I will come back to is very very important but it's another reason why the things have to be replenished. Therefore so-called feeder liposomes are necessary to keep the system running and we'll explain that in a second. So how does that work?
These pores here are created by so-called alpha HL uh proteins. Seven together are linked and they form a pore. Um I'll give Rob a chance when the at a suitable time maybe to comment about what is very special about these kinds of pores and of HL proteins. Uh these pores create a hole. this these are holes through which literally required uh nutrients and biochemicals and other things are going to be fed in.
So these are proteins about 295 amino acids uh long each. Then you've got the so-called feeder liposomes that have to be that are manufactured and collaborate together. And there's some weird things here sticking out. What are they?
These red little globular things are uh nickel based linkers. So they're attached to lipids and these lipids then anchor them in uh the membrane. The key here is nickel must be present and then the counterpart on spud cell.
These proteins being used, the alpha HL protein here also were engineered to include a six uh repetitive sequence of histadines and I'm showing this in red. So all this together uh are part of the of HL and like I said there's seven of them and all them together make a pore. But the important thing is and this is what's clever and this goes back to what what uh Anen and others have alluded to this this this cleverness of our of our friends here.
Um these histadines are known to bind very very strongly to nickel. So now we can start seeing what these guys engineered. Okay, the nickel here binds very very closely to this portion of the pore. It draws it in closer and closer and closer. Again, these lipid membranes come into contact and whoopd um the content of these um fetal liposomes get fed in. That's why these pores are exactly that. they are holes and this is very clever you know um the size of this interaction here has got to be just right that's why uh this was pretty ingenious by using only six histadines and a a really small tag here that meant that when these things came close together they were really close together and that allowed there for the merging of the two so that's the idea of the uh the feeder liposomes a very very important concept. So direct quote here the feeder liposomes were designed to replenish grab onto your seats now all the enzymes and small molecules needed for synthetic cell metabolism for example RNA polymerase the F29 pier system etc. This is what ANC has finished saying. Let me elaborate. All the components needed for said uh spud cell to function meaning the ribosomes, the RNA polymerases, the DNA polymerases, the ATP, all the salts, the nucleotides, amino acids, the transnas, you name it.
Every biochemical necessary was first provided to the cell initially and then constantly fed in except for one and the one is the alpha HL protein that is being used to build the pores.
Everything else is being constantly uh replenished. If I may jump in about the pores, if it's okay, go ahead. The um these pores, you know, life needs a membrane that that keeps bad stuff out and keeps the good stuff in, right? And that that requirement makes it a very complicated membrane. And they're trying to skip all the complexity and make a super simple bi-pid layer membrane here.
But a lipid membrane on its own would just be a tomb because it would keep all the toxins inside, all the waste products inside. You got to be able to get stuff in and out. Well, in life, the way to get stuff in and out is very complicated proteins that pass through or are part of the membrane. In the simplest of life, uh, like a microplasma genitalium, there's like 140 different proteins that live in the membrane actively importing and exporting things.
So, they have none of that here. a very simple membrane but they have to get stuff in and out and so what they did actually this alpha HL you have here is a protein that comes from staff stafloccus orius and it's actually used by that bacteria to kill other cells it's a special protein that can insert itself in the membrane basically drilling a hole and leaving a hole in the membrane so that other cells die. So th this is actually there for the purpose of killing cells, but they're putting it here because it's able to insert itself into a bi-pid layer and it's able to make a permanent hole.
Making a permanent hole is death because the cell needs to have gradients across that membrane. But this cell, if you call it a cell, it's never going to have any gradient across the membrane because it has holes all through it.
What that means, going back to what I said about the environment having more requirements, it means that the environment provides the homeostasis.
The environment has to have everything needed outside the same as inside the cell. In other words, it's not really a separate entity, this sort of cell. It's their environment is is sort of the cell.
um and they're using something that's supposed to kill in order to try to keep this thing moving. And so at what point does progress towards synthetic life actually make use of something that is an impediment toward actual life? And that's this that's what this is here using this alpha HL is an impediment toward real life that actually helps them out in this particular situation through clever engineering. Ah, clever engineering.
That is exact point and that's why that works. You see, you're right, Rob, that the heaven's pores could hardly be a good idea unless you optimize everything. For example, if the feeder leosones are very very concentrated with multiple copies of just the right uh ensemble of materials and very high concentration such that you can feed in the material fast and the pores are leeching it out again. And you know if the pores are just the right size and you prepare the liposomes so that they all have about the same size. If you optimize everything then you can cleverly um you know get the system to do what you want to do. That's that's the trick >> right. So you know I've I've often talked about the the lipid billayer. The lipid billayers in in in real living systems have to be the inside has to be different than the outside. And we don't even know how to do that in a laboratory uh uh with all our modern techniques.
And so certainly that wasn't solved here. And so you you go back to just making holes. This is like leaving leaving all the doors and all the windows of your home wide open. No screens, nothing. Just wide open. And then trying to heat your home in the wintertime. I mean, it just doesn't work. You You get all these heat molecules going out. You get the these molecules with with high energy going out. You get you get these these molecules with low energy coming in. And uh you just say well you know this this is the best way we can transport things in and out of our home. We have to leave leave holes in it. And so this is why why this didn't these didn't last very long. But uh uh so you see you take a very complex system and you try to modify in some way that will allow you to do just go through a few cycles and then and then uh u make a claim. But it it's it's very far from being a system that that could work.
>> Um, but go ahead.
>> It's never it's never winter for spudsell. It's this eternal spring that's maintained by the outside and it doesn't have to cook in its kitchen. It gets this whole food delivery every day and that's what sustains it.
>> Food and no poisons.
>> Food food leaks out as well as it leaks in. But what you do is keep the food delivery. You put a lot of food on the outside so that it more more moves in than than is moving out. It's It's >> couch potato.
>> Yeah, >> there you go.
>> Couch potato.
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So now it is interesting back to my original thought about how could they have satisfied all this enormous complexity requiring DNA and ATP and everything else starting with simple chemicals. Well, okay, they didn't. Uh they did indeed engineer um different components that included all the things that a real cell does indeed need. So it was uh kickstarted already with DNA and ribosomes, amino acids, ATP, tRNAs, synthetases, proteins, DNA and RNA u polymerases, nucleotides, membranes, everything initially and then all these things were then continually fed in afterwards except for the alpha HL.
uh and as I said they did uh of course observe that these uh pure compon pure e components that they added was less effective than cell extracts but at least it got started so there was a huge amount of optimization which this is not criticism that's uh a credit to the cleverness to to to get the things going they they uh for example had to um determine carefully how much HCl to use, the concentration.
Um you want to have enough so you're feeding enough material to replace uh what's being consumed or leashed out, but too much creates a stability and and destroys the cell uh and etc etc. So you know a lot went into optimizing to get the thing to work. So um I want to look um just a little bit more into the actual content.
Like I said, it was initiated with all the enzymes and small molecules needed.
In addition to what I mentioned before, they had um seven or eight plasmids depending on the experiments. these plasmids or what they call they call in the genome because they have um you know engineered some genes there. So initially you've got about 11 copies of each plasmid and this doesn't really resemble a bacteria too much but who it doesn't matter we're using our you know engineering ingenuity to make something work. Now these are the plasmids that were added.
Uh so we see that what is interesting here is the plasmid can code for the DNA polymerase or replicate DNA. It can it can code for the RNA polymerase.
It can also code for the amino acid tRNA synthetasis.
all 20 of them and several of the elongation factors and that's it. But nothing else, not the ribosomes or anything else. I think here is where 2 minutes before the talk I added uh a comment. Um I'm going to ask you guys a question to see if um you can see why I make a certain comment. It's not a difficult question, but it's kind of it's kind of obvious. So I'm going to ask it anyway. Um before I do that then as I mentioned about 11 copies of each of these plasmids were engineered initially on average uh to the synthetic uh cell the spud cell. Right. After about five of these so-called generations, calling that generation is is a little farfetched. On average about 30% of the daughter liposomes had one or more copies of plasmids.
So you see the problem here. Okay.
Starting off with 11 and after a very short time it's losing the entire genome. Um, right.
I can't see the question because I'm blocked a little bit, but I recall what I wrote. I'm Can you see the question at the bottom? I'm claiming that a key experiment uh should have been done and reported. It is so fundamental that if I were a reviewer, I would say I need this experiment before this gets published. The key experiment is engineer a spud cell without any of these plasmids except for the alpha HL. Repeat all the experiments and tell what you find. I'm claiming that that is a fundamentally important experiment to help understand so much what's going on here. Do you understand why this experiment is so important? Uh, I think you're trying to say that um the feeder cells have enough that's needed in order to so the initial condition of the cell has all you need to translate the alpha shell and build the pores and then continue the feeding cycle. You don't need all of these other pieces. Is that what you're trying to get at?
>> All your sins have been forgiven for for the next two months. Brilliant.
>> Oh my goodness. All right.
That that is precisely the point when we talk about uh the genome replication everything else. It is not at all apparent if the contribution being made by these plasmids is of any relevance. It is it we can determine by reading carefully what was done that the contribution is very very small compared what is being uh dumped in from the feeder liposomes. It is a very very small contribution. The question is, is it even relevant? And that is a very very painful question because if the answer is not relevant at all and we see we're not even transmitting um the PL is reliable to the follow to the daughters and who even cares because uh the system doesn't even need it. That starts to put things in a very unpleasant perspective.
Let's not dwell on it, but um that is something that should not have been overlooked. The fetal liposomes, they were manufactured separately. Um, step one, combine the three lipids needed with all of the components of the pure puree uh concoction, the ribosomes, amino acids, all the different salts, you know, 36 or so enzymes, everything else.
mix it all together for sele.
So you're getting things all of about the same size.
Um and that is how we are uh manufacturing the liposomes. And of course uh they have to be engineered with this nickel linker on the outside.
That's how that's where the the the feeder liposomes come from in in a laboratory. Okay.
Now uh we need to spend a minute or two talking about the cell division. I'm not talking about DNA. I'm talking about the entire physical cell. How does this happen? The primary mechanism used in almost all the experiments reported.
We'll call this mechanism one.
um used for the multi- uh generational studies, the so-called selection studies, all the competition experiments, everything else involved a technician uh taking this um mixture and forcing it through a small extruder having a specific pore size. And this uh physically ensured that you are breaking up then uh the cell that has grown thanks to being fed from the laposone feeders and that's how the division occurs. This is by far the most effective mechanism and only it was suitable and therefore used for any of the other experiments including the five generation experiments.
>> Okay. So let me let me let me get this straight.
>> Mhm.
>> When they say that it had five generations.
>> Mhm.
>> Uh which means it divided and then th those divided and those divided five times. This happened through going through a mechanical extruder.
>> Yeah. Um I will I will I I will show you a precise quote in a in a couple of slides step by step as to the actual process. So let me wait until I show the precise quote step by step as to what they are calling a generation and when they fit an extruder and that way it will be clear to you what is meant by generation and how the experiments were done.
>> Okay. But but Roy royal none of this none of this is in is in the the the press talking about these these generations. I mean, >> I know.
>> Yeah. Interesting.
>> Just just to keep it clear, there's two different cell division mechanisms, and the first one is this one, and it's the one that gave them enough fidelity to run the five generation experiment.
Royal is also going to talk about the second one in a bit.
>> Okay.
>> That is Yes.
>> Sorry. A naive question for you though.
If I take if I take salad dressing, you know, you've got some small bubbles of oil inside the vinegar, whatever, and I just put it through a screen, I it's an extruder.
>> Don't the big bubbles of oil turn into smaller bubbles of oil?
>> Yeah.
>> And that therefore, I've had division. I mean, I'm not trying to be sarcastic.
I'm just wondering how is this different than that?
>> No, this is exactly that.
>> It's precisely that. And then and then now because you got the alpha HL uh pores uh so yeah you're able then to feed in the ribosomes and all the other materials so that these initially very very small droplets become bigger droplets. It's exactly that nothing more than that. Again, good engineering, clever, perhaps someday useful, but let's just say this is not for reasons I I'll really really really hammer. This is not we're talking about when we're talking about life or life like and I'll come back to that in a minute.
>> Roy, we do this in my own lab all the time. We make sure we make vesicles >> and those vesicles we allow them to olude things when they're forming >> and then we put them through an extruder and those vesicles will break up into smaller vesicles.
>> Exactly.
>> And this is this is a very common laboratory technique >> certainly >> designed by human beings to do this. So this is not the way cells normally divide. This is >> oh we do this in industry all the time you know to to extract vitamins and hormones and stuff. Yeah. Yeah, this is this so I think I think it was Rob uh and and Anzie both alluded to the idea that a lot of clever known um biotech uh principles and concepts were simply put together in clever ways to you know to achieve a particular goal. Okay. But as a said there is a second mechanism I'll talk about and this is super important not the mechanism but keep in mind this is what is referred to whenever you read the term genetically encoded. Whenever you read any um let's say hype about genetically encoded division things like that it's talking about this. So how does it work?
Start off with the uh original spatzel.
I'm pointing right now to the H alpha HL pore and the pore includes in this case now a different tag. It's not the six histadines but a slightly larger tag uh cleverly designed uh and known because uh it is known that it binds very very strongly to biotin but I'm getting ahead of myself. The next step is a um lab technician wakes up, drinks some coffee, goes to the laboratory and then adds um some specific antibbody linker to this uh mixture manually.
So these uh antibodies I'm pointing at a little uncertainty in the paper a little ambiguous whether they're talking about the fullund 1,300 amino acid or a fragment. It's a little ambiguous. It doesn't really matter. Uh it's an antibbody that contains the biotin flag.
What does that mean? This flag here has this sequence right right here. And this is the anti- flag. That means it has an amino acid sequence right out here that is able to recognize precisely and very very strongly uh the flag uh sequence there. So binds right obviously hook binds all over place. The next step is the left technician takes a lunch break and then adds a stripped vidin a protein about 300 amino acids more or less to the concoction because these uh proteins are known will bind uh very very strongly um to the antibbody.
So that's how these things are coming together. Why do you do that? Aha.
Because these interactions are are physically so strong, more and more these proteins are come together creating the so-called crowding effect.
And when it crowds, it bends the membrane and bends and bends it. And you know if you have enough of them then eventually sometimes you will cause part of the original cell to break off creating a liposome. It breaks off. So this is mechanism two.
So when they say it is genetically encoded, please don't overlook what it seems like everybody's overlooked. Uh so far it is only referring to the A alpha HL which has this particular peptide sequence engineered onto it that is genetically encoded and expressed on purpose. Everything else then is added uh by the technician afterwards to create the cell division. So, as I'm sure Jim will be happy to tell us, um a system like this is not going to be nearly as reliable as forming liposomes in extruder. You've got no control over >> So, so the extruder did five cycles. How many cycles did they get from this? They quit after one, of course.
>> Right. Yeah. Because now now it's covered with these with these uh uh these proteins, these antibodies and strep avid and so so I these are standard techniques um that that are known uh you you start adding things to the surface of of your billayers >> and they will neck down and and form two vesicles and then you're done. Because here that this is bound so strongly. So again this is not really cell division.
This is not cell division. This is not cell division. This is why it couldn't be used again because these things are binding so strongly and it's a dead end.
So um >> it's a dead end for for for several reasons. So all of that >> so so all the cell division that we've seen one is going through a mechanical extruder >> right and and uh and it is it is a very common method. You you put things through actually a screen is what it does. is is is it a a two micron little hole? And then this other one is you just flood the surface so much that that uh uh these contact forces want to swing around and uh and and then break. So okay, thanks for bringing clarity to to a matter of exactly. So this is a matter then of optimizing exam the the concentrations and what not to get that effect. That's what it is. Uh and the yield was as expected very very very low and uh not reported but um pretty obvious. The contact itself would be pretty much random you know depending on the timing of many many many things. Now um let's talk about step by step exactly what was done it almost all the experiments. All this can be summarized uh by quoting one paragraph, but we're going to take it step by step by step.
We're going to look at this with the exactness of a theologian looking at a Bible verse. Okay. What did they do?
First of all, this paragraph starts off with cell cycle rounds of feeding and growth is one of the hallmarks of life.
Right? Well, agree. We combined genetically encoded feeding and growth.
What does that mean? Okay, feeding and growth. Feeding that just means that the alpha HL created pores. And because they had the these uh six histadine tags as part of the pore that was able to then to draw in the feeder liposomes. So that is what we're calling uh feeding. when Rob said that there are dozens or hundreds of um specific transmembrane proteins on the surface of of cells. That's because each one of these is attracting a specific class of nutrients. Here is one type dumping in the entire content of the liposome feeder. Right? So everything needed is being replenished except of course the HCL gene. So that is feeding.
Feeding is just creating a pore and bringing everything out and bringing everything in. and growth. Well, growth is just they have this uh RNA polymerase which is encoded on one of the plasmids and that is being transcribed as anie very very cleverly pointed out. Uh it's not clear that it's even making much of a contribution to say that it is genetically encoded is correct. But if that fully functional polymerase is being fed in from the feeder liposome, then it may be doing all the action anyway. So keep all of these things in mind as we go through step by step.
Reading this one paragraph, which is technically correct. This paragraph shown on the left part of the screen is saying in one paragraph what they actually did in most of the experiments.
And this is important and I wish more people would emphasize uh this. Then they said that DNA replication and mechanical division uh followed into a synthetic cell cycle.
Okay, DNA replication that is being carried out by the F29 and it's go is occurring on all the plasmids continually and nonstop. As long as you've got the material needs, you know, the the uh the nucleotides, the ATP, the actual polymerase itself, yeah, it's going to replicate the the plasmids over and over and over again. a mechanical division. Uh-oh, that is not good.
>> Can I jump in here with one point? This this F29 that does the DNA replication, it's useful only for short strands of DNA.
>> Any kind of like a bacterial DNA, which is circular. Other studies have shown that you need a minimum of 14 different enzymes made up of 25 different proteins in order to replicate real DNA. This can only handle little short strands because it doesn't have like too rays which unwinds um kinks in the DNA. So as this little 521 replicates, it just sort of strips the two two strands apart and replicates them. But you can't do that if it gets too long because it'll kink up and there's nothing to un take the stress out of the DNA and the replication fork will stop advancing and it just gets stuck. So, it's only useful for this kind of non nonlife size DNA.
>> Thank you for pointing that out. Um, I could have forgotten to mention those details. That's why they had 7 to eight plasmids cuz it's shorter. The F29 is about 5 to 10%. The speed of a bacterial uh polymerase is very very slow. It has no error correction. So let's just say for very very short strands of RNA it serves their purpose purpose. It's as absolutely simple as possible which is you know what they want. That's great.
Uh it's very slow but you've got so many copies of the plasmids to compensate.
That's part of the design. And uh the tradeoff and sorry for the getting sidetracked here. The trade-off is that's why you've got to have eight different plasmids instead of one big plasmid. And that leads into the problems of keeping the proportion of genes correct because you're not inheriting one big plasmid with everything, but you're sort of stochastically inheriting different plasmids. But that is a consequence of using F29.
It's only about 700 amino acids. So, it is ridiculously uh smaller than the very very complex bacterial ones. But you're absolutely correct. It doesn't uh serve, let's just say, the long-term purposes of creating a real lifelike uh organism.
Now, um back to to Jim and the ex uh extrusion. Each cell cycle and it hurts my stomach whenever I read that cell cycle starts with a 12-hour incubation of cells in the presence of feeder.
Okay? And then after 12 hours, the synthetic cells are mechanically divided every 12 hours. Again, all of this is one paragraph in the original paper. So you may want to read this a few times to get a very very clear understanding which is absolutely correct. This is exactly what they did. And then keep in mind here let's just say uh my commentaries to the theological text as to what is actually being done here so that you uh can understand. So very problematic is that human beings are the ones that are deciding when it replicates. They just decided, you know, 12 hours plus or minus uh and you simply replicate it and then they mix everything with a fresh population of feeders and it starts a new generation.
>> So if I if I can just mention feeding these things with with more liposomes, this is this is well known. You take you take a vesicle, you put in >> you put in more more of these things and they get bigger and bigger and at some point they're going to burst and they'll they'll divide. I my guess is that that it wasn't really working very well and so they had to do this mechanically.
They had to force it by going through a a humanmade mechanical extruder. Uh but but um anyway, go ahead.
>> Yeah. Yeah. The extruder has many advantages. has a specific and and obviously optimized pore size >> and it makes it go you you extrude it through this the big ones get get sliced apart. Yeah, that's what >> happens. You want you want the stuff to divide not just hang around and it becomes you know fairly homogeneous also compared to just letting it sit around you know and doing whatever it wants to do. So obviously from an engineering point of view and design point of view they're doing the right thing you know clearly. Now, here is where I get a little bit of a stomach ache here because everybody with a little biology background knows what a cell cycle is.
And when we read all of these overhyped statements about how they created lifelike um cells that perform a complete cell cycle, even five times, a cell cycle has a precise definition.
Okay, let's look let's just look at the picture here. At the top, you've got a bacteria. It starts to replicate the DNA and it starts to replicate everything else needed for it to to survive as two copies including all of the the lipid content of the membrane, the ribosomes, the ATPs, everything, right? And then when you and then you split these two things up and dog gone it, it sure looks awfully similar each one of these to the original. That's precisely the point that is a cell cycle that is fundamental to the definition of life and that is was absolutely remarkable and miraculous um that this works. So let's look at this cell cycle. Let's look at some of the claims that we read here. Here we demonstrated a complete cell cycle for a synthetic cell undergoing selection with genome replication, growth, resource by feeding and genetically encoded division. Okay, they're throwing everything together here because when we look at resource acquisition and everything else, when you look at all of this here, um, it is not it doesn't resemble what is actually going on here.
I'll explain a little bit more carefully uh what I mean about that, but let's look a few more quotes. the first minimal cell they claim to have created with a cell cycle genetically encoded growth and division. It is the first time such a system has demonstrated a complete cell cycle etc. We demonstrate five generations of the overall cell cycle including DNA replication, feeding and growth. Why is this so disturbing?
Because a cell cycle has a precise definition in biology. It's not cell cycle like or whatever. A cell cycle is a cell cycle. What does it mean? If you recall, I prepared you in slide one or two already with a quote of what is a cell cycle from Albert. Remember? Well, let me give you some more quotes because they're all saying the same thing. The cell division cycle is a sequence of of events by which a growing cell replicates all its components, okay, and divides them into two nearly identical daughters so that each daughter cell receives all the machinery information necessary to repeat the process. Now, this is clear.
If it was not the case, the stuff of any any any any bacteria would fizzle out.
If it doesn't have everything it needs, generation 2 is dead. If it's missing DNA and missing a membrane, missing ATP, missing ribosomes, whatever, it's dead.
So that's precisely uh what is so remarkable about life and the definition of a cell cycle. Another quote, all cells grow in steady state must ensure a one to one to one relationship.
among doubling of the cell mass, rounds of chromosome duplication and the division. In other words, the things are coordinated. I hope I have a good statement here. Yeah, coordinated.
And that's precisely where this thing falls apart. And I'm going to explain why quickly. We're almost at the end.
Hang on there. Each one of these very clever, highly engineering subsystems is not coordinated together. Okay? And that's why it has to fizzle out. It has no future. That's why Jim when you talked about um about liposomes uh forming and and whatnot in this case even though they were extruding it through precisely the right pore size screen to optimize the amount and and division and content. They ended up with less with about 30% having one copy of each plasmid even though they started off with 11 copies initially because it was incapable of synchronizing the replication of DNA with its uh separation into the daughter cells and the timing of the division in the mechanical division. So they only did this for mechanical division and we'll come to the other example in the next slide. These five generations was only done with mechanical division. There is no regulation or coordination. This P29 polymerase replicates these multiple plasmids, the circular plasmids continuously. If the nucleotides, magnesium and everything else it needs all the material is available. As long as available, it replicates, replicate, replicates. Okay? Sometimes too fast, sometimes too slow. It just replicates.
If it runs out of material, you end up with a plasmid which is only half a plasmid or two/ird of a plasmid. So you could have a mixture of of plasmids that are half completed. Okay? All of this is just going on mechanically and unsynchronized with everything else. The same is true of the P7 RNA polymer pymerase that converts each of the plasmid DNA into RNA. Same same story.
It just just runs all by itself as long as everything it needs the building material is still available. It just chugs away, chugs away, chugs away. And the cell division is initiated by the experiment not by the cell in a living cell like a bacteria. What is so absolutely remarkable is that these generation times can vary between minutes and thousands of years. This is decided by the bacteria those internal regulation.
So depending on the external conditions this nutrients, temperature other things that then is regulated through decision making internally and the bacteria decides okay should I undergo the uh cell division. Can I and have I duplicated my DNA? Do I have all the building materials? This could take minutes, hours, days, weeks, years, centuries, millennia. It all depends.
But here, instead of there being a checkpoints to do this correctly, it is all controlled by an external human being. They just go and they just crank the thing through an extruder and who knows what happens. Okay? Sometimes you can end up with a whole bunch of plasma, sometimes like none at all. in this case because the environment and good point from Rob because the environment is pretty much fixed the fetal liposome concentrations and whatnot are are are fixed then some of the damage here is is minimized but in reality none of this is controlled. This is per definition not a cell cycle and it's just far far worse when the division is done by the uh so-called genetically coded division.
They did not attempt to do this more than one cycle because um first of all the yield was very very very low. The actual physical splitting was very very low and they quickly determined that the amount of plasmid produced and distributed was significantly less than had been present in the population generation zero. So these are uh concentrations in the total first generation population and we see that uh the amount of plasma goes up and down quite a bit. So on average the concentration was about 2.7 nanomles in the original population zero population generation zero and it went down to about one. So it means the DNA is just not forming rapidly enough and it's pretty much random. So it means that after uh one generation it becomes um very very likely that very very few of these little liposomes that were formed and very very very few were formed would have had one copy of each the plasmids even though they start off with 11 copies initially. So clearly this is this is this is dead. You know the second generation doesn't going to work. So that's why it's so important to understand these quotes from biologist across all domains of life. Cell proliferation requires that the chromosome replication and a cell division cycles are coordinated to ensure that every cell receives a one copy of the genetic material. In other words, they they and the hypers, if I can invent a word, um should not be using the word cell cycle because that is not what's happening here.
>> This is not replication. It is not. This is the claim. But you you've shown it is not to have something at 30%.
the efficacy is so low because all of the other 70% is going to make more mess if you don't get get rid of those. So, so uh um >> yeah.
>> So, so remember if if you don't have 99.999% that little bit ends up getting translated into into other garbage. Here they have 70% of the mixture is getting translated into more garbage. And this is this shows the fidelity of of this just go goes goes haywire. And that's in a mechanical way. When you go to this, you keep saying that the yield is very low. What is the yield? Is low 1% is low.1% do they say?
>> No. All they could all they could do is is is look at the total population and say through uh PCR they were able to determine that some um the plasmids um was present. All the plasmids were present somewhere distributed among all of these. So in other words, when when you when you don't put a yield, it generally is embarrassingly low.
>> So this this isn't replication. So all of this stuff that we hear in the press >> that that this is shown replication.
This is not shown replication. And replication is you have to have a a duplicating thing. So what happens in the real cell is just what you showed.
You get this distribution to the two sides, >> right?
>> And then there's this necking down and this cleaving in the middle. when you do this mechanically or this this other quote unquote uh uh genetic method which is just just uh uh covering the surface with something so big that it eventually has to break in half uh uh you don't have that distribution and the thing just just just peters out so this really is not replication all the claims of this and I would be you know it's going to be interesting to see what happens to this paper during the review process because this has been so hyped up prior to peer review. What are these peer reviewers? Are the peer reviewers going to go through and put the time that you've put into this to show? I think that this is going to uh uh end up having to be modified a lot in order in order to uh uh you know even sustain these claims. I'm not even sure that they're going to sustain a claim of of getting any replication here. This is not replication.
>> This is not these are not daughters. I I I want to I want to make one statement just so that nobody misunderstands. Uh it's not splitting in half. That's just too good to be true. Uh the genetically coded you simply means whatever pores are close enough and the striin uh managed to link them together and now split off. But the size of location is random. It means you could you could you you could chew off multiple pieces of the same parent and who knows what you end up with in terms of distribution plasmids. I think for the sake of time, I'm I'm I'm going to uh not belabor other examples of very very questionable wording, but I think I'll at least put this on on the screen so people can think about this. This whole idea of selection and uh competition. I had a discussion with Anie about this. Uh the claim is that um using a stronger promoter they call this uh T7 max on the alpha HL plasmid led to faster feeding etc etc and this was an example of selection I wasn't very happy with that u here's the logic yeah more alpha HL protein creates uh more feeder fusion you know you got more pores and everything else they creates bigger cells faster.
Correct. More daughter cells per 12-hour period. So far so good, right? However, be careful. The other plasmids are not being produced faster. The other plasmids that means that any uh DNA from the other plasmids is not being produced faster, but everything else is to create more daughter cells. So what would be the consequence uh after a few generations? Well, what's happening here is that you're diluting the DNA per daughter cell. The daughter cell is growing faster. There's more of it the way this experiment was done. That sounds great. But it's all occurring because the fuse the fusion liposomes is keeping things going. The DNA itself probably doesn't even have to be there.
So in reality this is a very very poor example of selection. If you go too high more alpha HL creates leakage. The these pores get too big. The whole system becomes unstable. Adding more alpha HL creates a metabolic cost. You know you got to translate and transcribe everything uh etc. So it works short term for what I think are very artificial reasons. But even this wording about it is able to undergo Darwinian type selection and whatnot. I think that is really quite a stretch. So um let me just wrap up now quickly. What I believe is going to happen here is future work is going to require a dramatically increase in genome size. Rob called this uh a higher investment in intelligence which is correct that the genome inevitably is going to have to be larger for for for many reasons and many of them they themselves have already pointed out they pointed out that the uh F29 polymerase is inacceptable because eventually they got to put all these plasmids together into one big plasmid so that everything gets inherited jointly or the proportions of genes get all messed up and now that means okay well how are you going to replicate these larger plasmids where you need a a much much better pymerase and that means many many more cells got to be regulated. So the bottom line here is a whole lot of things are going to be needed. They're going to need a system to correct errors whether they plan to use this for industrial purposes perhaps or for research purposes. If these cells cannot self-correct, then you're going to have to go back every few hours and start all over again with a brand new batch again. You got to have air correction. These things have got to metabolize, you know, hundreds of their own biochemicals. It's got to have a proper skeleton to actually divide properly, etc. And this is the most important one. The cell cycle got to be orchestrated. So I don't want to go into a long discussion here but you guys know enough about the topic to realize that anything resembling a real cell including producing assembling your own ribosomes etc is going to go beyond the handful of genes that they start off with. And as Rob also pointed out, instead of depending uh 99.9% on the external liposome feeder, all this stuff's got to be done internally.
If you're talking about a life life organism, okay, a life organism where 99% of all the work is done externally is a pretty strange concept of life. So final slide here. People may be wondering um why did all this look so easy and simple and whatnot? Well, it's because spud cell is simply not doing so many things that a lifelike uh organism would be doing. The ribosome is not being produced. Uh protein folding, protein degradation, internal and 10,000 other things. The list is pretty big.
There's no DNA repair, RNA processing, turnover, whatnot. So all of these things are found in even the most simple autonomous lifelike bacteria, but they're missing. So I think they've had a lot of fun here. This is some pretty cool engineering, some good um ideas. I could probably give some ideas myself to some of the stuff they should be testing. Let me not let me not make any conclusions. Let me just open it up for your own observations. This doesn't really satisfy my expectations from all the hype that I had read. What do you guys think about how to evaluate um what was done with Bitzo? I think I think Jim, you asked earlier about reviewers and actually I pulled it up here. Science I think magazine is what it is. Science magazine did a piece on this work. I'll just read this paragraph directly. Uh some have also grumbled about Adamala. the uh PI Adama's efforts to draw attention to the work which she says was rejected by Cell after one reviewer said Spud cells were not real biology and you know I I think that speaks to like the professional reaction that's going to come out around the paper which is very clever incredible kind of bringing together of pre-existing uh pieces in novel ways is to generate something that you know uh I think of it as like the uncanny valley. It's like it's like a mannequin. It kind of looks alive but the more you learn about it the more you feel like this is not life as I know it. Um and without that control that feedback mechanism it's it's really not biology. It's I think to your point if if you're not get if you have that 99.9999% maybe but we're nowhere near that.
>> Right. and and and a reviewer comment of just one line like that is not the complete reviewer comments. I'm sure there were many many more specifics that may have been the the last summary bottom line summary statement. I think this is going to have some real troubles in a in a peer review. It's gotten a lot of hype. So, it's really going to get critiqued critiqued quite well. But but to have had this reviewed and not accepted by Cell and then you put it out with this kind of fanfare is not the normal protocol. It's just really not the normal protocol that that uh there must have been some real concerns here.
And these concerns only come through when you get into the 190 pages. This is a 190 page document. Uh and and it's not easy. I mean, Royal, you you you obviously put a lot of time into this into understanding what went on because it's not at all apparent from the quick read of of the manuscript. Uh you got to get into the details of this, the supplemental to see it. But, uh Rob, what do you think? Well, I think we also have to remember that the lesson from top down trying to simplify life and you know, Craig Venttor had it down to 493 genes and that's a barely alive kind of cell that needs life support. And here we're talking about 36 genes. So each of those genes you could say is is sort of a an item that's essential for life. And how many boxes did this spud cell check of the essential list of items? You know, it only checked a few boxes barely. So there's a lot a lot of work to go and and that takes me back to my point that to go further is going to be exponentially harder and trying to get 10x the number of genes is not 10x harder it's going to be a millionx harder so it's going to be difficult progress from here on let me comment about that I want to go back to an very astute I really have to praise him that he so quickly uh understood what I was driving it Um listen um these genes we don't know uh are doing anything useful at the moment uh to be blunt about it. So I think a first start would be after kickstarting the system which is okay and that's fine.
They have to stop feeding in every little bit of functional folded protein complex needed and see if the system can take off on its own. And then and only then can they see are these genes necessary and are they being able to be used in an adequate manner. Are they being translated effectively enough? Are they being assembled effectively enough to survive on its own? And then only then do they have to start adding the extra complexity that you alluded to. At the moment, at the moment, we have no they have no idea where they where they stand because all they're doing is um creating a protein, creates a pore that floods the system, man with with everything it needs. and all the the the genome the rest of genome is probably not necessary which means so what in the world is the gene doing is still doing we don't know I'll give you my thoughts on this I think I've already expressed my thoughts this is this is not cell division you don't go through through a an extruder and claim cell division this is done all the time we do it even in my laboratory and I'm I'm I don't even have a biochemical laboratory. I have a nanotech laboratory. We do this all the time. You put things you start packing in more liposomes. Uh these these more more lipids, the liposomes grow and they will eventually burst and form two smaller ones just to just to minimize the surface free energy. So their genetic method of piling on things on the surface is reminiscent of that as well. and they had lots of extra lipids around for these things to to deal with if they needed it. Uh this is this is a master class in going way too far. And and I have said in the past I said it it is the statements of the researchers that catalyze the statements that come into the press with an order of magnitude higher uh extrapolations.
And so so uh um yes the researchers have done some amazing things. I don't want to to uh uh uh bismerch that at all. But to have made some of the statements that you have showed um uh Royal and then and then uh uh seen this seen this go and and run a muk in the press so that it has been so confusing to the general public is not helpful to the field. It's in the end it's not going to be helpful because now the the the general uh the the general impression of the of the common person is that hey you guys have made synthetic cells. I mean you you can make life. I mean you took these pieces and you created life. Remember none of these pieces came just just uh uh randomly. These all came from living organisms. So, you've taken all the pieces out of a li living organism and you've put them together. And something that I have long said is that can you deconstruct a cell and then take the pieces, put them back together and have them operate? And I've said no. Nowhere close. No one would say such a thing. So now they've taken all these pieces from living systems and they've put it together and they've pushed on it with mechanical methods and and and pried it around and everything. Is it alive?
Well, they've they've claimed that it's gone through this this replication cycle which life has to do. It didn't replicate. It didn't replicate. The things that it made were not daughters.
They were not the same as what it came from. They were quite different structures which happens all the time when you do things in a nanotech lab to not get exactly the same thing uh uh happens all the time. These things are not life. But the expectation now because of a a a non-per reviewed paper getting out there and then making these claims by the researchers themselves. I wouldn't be surprised if if when this goes through peer review if the reviewers say, "Hey, look, you've got to you've got to take these statements out.
This is not replication. This is not psy cycles." This is not uh uh I wouldn't be surprised if they if if the published paper is in a very different form and and presents this very differently. Not that it's bad work. No, it's very interesting work because they they've taken a lot of known components and they put them all in in in one place. Uh uh but you could just as well have done this in a test tube. You really could.
And and actually all of these steps have already been done in test tubes. What they did is they put it inside a liposome and and and uh uh made it have this appearance if you you have all these extrapolations. So that's that's kind of my view. I know people are going to say tour, you are Mr. No. You're always, you know, throwing throwing cold water on the thing. But I'm I'm just I'm just calling it like I see it. Uh I'm I'm going to give Unie I'm going to give each of you the last word and then we're going to we're going to uh close the curtain of mercy on this on this uh this act.
>> That's great. Uh I I think I I honestly largely agree. you know, they uh some of the commentary, I think the author themselves, they described this as like a Kittyhawk moment. And not to confuse it with a 737.
Um, and you know, I don't know that I would bet against human ingenuity necessarily figuring something out in the end that looks a bit more like life than this does. I don't think this looks enough like life that maybe it even should be called the Kittyhawk moment.
But I think the point is it will take human ingenuity and it will take human ingenuity operating on complex things that life already gives us to get there.
And that's that's a big gap when it comes to thinking how about how this applies to origin of life. And to their credit, they're not thinking about origin of life necessarily. They're I think more interested in industrial applications. And I think there's a whole conversation there. But um yeah, I I I think maybe we're a bit ahead of our skis in terms of the hype. So I it's Thank you, Royal, for kind of bringing us back from the precipice and showing us what's actually happening here.
>> Very well said, Anie. I honestly have nothing to add. I think we've we've talked this through. Um and uh you guys are so smart. You said all the right things and uh I think you got it covered.
>> I'm I'm with Anie. Um we we don't know how super intelligent teams of people could re-engineer things perhaps to be to be you know to be interesting to to show some lifelike properties that to be very very interesting. Um they know how complicated all this is and therefore they are very very pleased they were able to get some results. Um, I think starting off with things like C29 and their way of splitting up um the cell dividend are dead ends. They're going to have to back out again because this is going nowhere. They starting off with with seven or eight plasmids is is a dead end.
>> Um, so they've had a they've had a good time. Um Um, I wish I was back in grad school doing this kind of stuff. Um and uh they were able to show something they knew would be extraordinarily difficult and of course you know they please themselves and whatnot. The hype is going to destroy them because expectations now are so high but the let down is so massive. They they they want to have open- source tools. They want to to create communities and everything else, but they're g they're gonna have to re-engineer this in a manner uh that's sustainable and has that that can move forward. And I think the hype here is is is is going to damage them seriously.
>> Well, let me just wrap this up. This is a master class in intelligent design. Uh this is this is what intelligent people do. And so for all the intelligent design proponents out there, uh this is this is a master class. This is what happens when you take very smart people doing very ingenious things, capitalizing on all that's known within humankind in in in uh in biotechnology and putting it all together. This is what you can get. And still we're not close to life. But but uh uh and and I'm not sure that that there's going to be a major letdown. The way these things normally happen, there is never a repentance. There is never they never come back and say, you know, this was just overhyped, you know, it just just was too much. And and then followed by a bunch of articles that would that would uh uh say, hey, you know, um uh a bunch of articles being there that would that would say, hey, we we we went too far.
They'll they'll never back off this.
It's just that it's just that uh um it it may it may make it much more difficult to have an encore, but I don't think they'll ever pull this thing back.
The press won't. Um that's that's kind of what I think. But in any case, gentlemen, you guys have dissected this like few people could. And that's what I love about this conversations group.
Each person is coming with with a different kind of expertise. and we're we're really, you know, you guys can can take a subject that that uh um most people can't and really dissect it. And that's that's what's been good about working with you guys. So, thank you very much. And so, for all the people that have been emailing me, these thousands of people have I that we've got to address this thing, we addressed it. And uh and there you go. God bless.
Bye-bye. conversation.
>> The chemistry cries out that it could not have happened this way.
>> But like it's this very powerful visceral question that I get struck by sometimes.
>> They try to find the best series of conditions to get a super high yield, >> a magical device. And the more we learn about it, the more marvelous it becomes.
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