Posted by Scott 10/29/10 -- pictures and maybe more to come later

At one time, I harbored ambitions of becoming a professor and running my very own research lab.  Don't worry -- I have since been cured of them.  But like all graduate students and science enthusiasts, I had all kinds of ideas for projects that, sadly, will probably never see the light of day.

For some time, I've kept them to myself, thinking someday I might get the chance to do them for real on my own.  But those prospects are looking ever dimmer.  Since I don't want to spend my life begging for grant money, and I don't think I'll ever be able to scrape the money together myself, I figure I'll just give the suckers away. 

So, if you're a researcher or a dreamer looking for ideas, feel free to take a look at these.  Maybe most of them are obvious and you and every other researcher has already come up with them, but just maybe you'll find something useful.  Just let me know if you do use them -- I'd really like to see how/if they pan out.

Biological Solar-Hydrogen Generators

The use of solar power to produce hydrogen has been a scientific holy-grail for some time now, which means it is probably a tough nut to crack.  Many have tried, and to my knowledge almost all have failed, at least in terms of economically viable ideas.

So here's mine, in as much detail as I care to type out for free.  I will admit it would be a very long and drawn out project; possibly it would take a lifetime or more.  But I'm almost certain that it would work, given, you know, infinite time and resources.  The reason I'm going with this approach is that I think it can be made more economical than other biological approaches.  Mostly, it's going to involve protein engineering and directed evolution.  (Check that link if you don't know what directed evolution is.  It's a key concept in a lot of these ideas.)

The basic idea would be to re-engineer the PSI photosynthetic system, stripping out the superfluous steps (for our purposes) that establish the membrane proton gradient for ATP production and the electron carrier interchanges.  This would be combined with a well known hydrogenase activity that converts reduced NADH to hydrogen gas and NAD+.  The 'final product' of PSI is NADH, so, assuming the single electron excitation at the photocenter could be coupled to the double electron reduction of NADH, the final hydrogenase step would be trivial and the post-excitation half reaction (free electrons plus protons to form hydrogen) would be complete.  I'll adress those complexities and experimental designs below.

The First Half-Reaction

The first half reaction (water to oxygen plus free electrons and protons) is the more difficult.  Obviously, one would again want to strip out the proton gradient establishing membrane proteins and the electron transport interchanges, but that's the trick, isn't it?  Here's my approach, for what it's worth.

The oxygen-generating complex is well-known and modestly well characterized, at least well enough to know that it's a delicate process.  My suggestion -- use directed evolution to get the sucker working well enough in a glass dish that you can hook it up to the light absorbing complex later on.

You're going to need a couple of things to do this.  First, your going to need a complex that can at least rip off enough electrons to give you hydrogen peroxides.  If you can get that far, there are other catalysts that can get you to molecular oxygen (laccase and superoxide dismutase).  Second, you're going to need an extremely powerful oxidizing agent to fuel the enzyme complex that can serve as a the electron carrier to the light capturing complex.  Which is to say, you'll need a recyclable electron carrier to ferry those electrons from the (reduced) oxygen generating complex to the (oxidized) light absorbing complex.  That's not such an easy order to fill.  Fortunately, I've got plenty of suggestions, since I won't be doing the work.

The best thing I can think of would be to look at several soluble, globular metal binding proteins, maybe like a hemoglobin or hemocyanin, or something that binds maybe a chromium or some other such transition metal.  Try to find one with a redox potential in the range you need.  Then, you'll be doing, once again, directed evolution to get it to bind to the oxygen generating complex.  That shouldn't be hard, since you'll have the absorption of the metal to assay for binding.  Come to think of it, you'll be able to see redox reactions by UV/vis as well.

You should be able to get binding by engineering in a pair of binding sites on the two in a region that will put the redox centers in close proximity.  There are at least a zillion binding pairs you could use -- pick one.  While you're at it, you can put the same binding moeity on the light absorbing complex as you put on the oxygen generating complex.  Try to evolve the pair to give you equilibrium binding at reasonable concentrations, i.e. 50/50 binding at normal concentrations (maybe .1 mg/mL for each protein.)

Next, you'll want to get it to bind to the light absorbing complex.  Same basic approach.  Once you've got that going, you'll be able to monitor the redox capabilities of the electron carrier.  There are many known electron acceptors that can take the electrons from the light gathering complex off your hands.  If you spike the reaction with an excess of these acceptors, you can see if your half reaction works. 

Under conditions of illumination, the electron acceptor will take the electron off the excited light absorbing complex, giving you oxidized complex.  If your electron transporter is working okay, it will reduce the light absorbing complex and become oxidized.  You should be able to see this by UV/vis.  If it doesn't work (it probably won't), you can diagnose the problem by checking your electron acceptor.  If none has been reduced, the light complex isn't working and needs some tweaking/molecular evolution.  If some is reduced, but not all and your electron transporter is just sitting there, the light complex probably works, but the electron transporter needs some evolution.  Alternatively, the light transporter may need some modification to interact adequately with the electron transporter.  This could be sticky, but I'd probably work on the transporter first to see if you can't get at least some little bit of conversion.  The light absorbing complex is more likely to be operable as is than the transporter.  If you can get just a little activity, you can optimize later.

Once you've started generating 'hot' electron transporter (the oxidized state will be far more reactive than the reduced state if this thing has any chance of success), you can introduce the oxygen complex to see if it is operable.  You can probably do this by adding a large excess of electron acceptor with small amounts of all the components.  If more acceptor is reduced than the molar amount of protein you put in, the thing is probably working.  You will probably need to do a lot of evolving on the carrier at this point, because you've gor to tune the redox potentials into they proper range, and they probably won't be even close unless you've chosen your electron carrier very carefully.  Once you've got a working system, you can optimize at this stage, evolving each protein in turn (light complex, oxygen complex, electron transporter) until you have a pretty efficient system.

Alternatively, you could just make a fusion of the light absorbing complex and the active part of the oxygen complex and evolve the thing and pray that it can rip electrons off water on its own.  It might, and it would save you some trouble, but it would make things messy later.

The Second Half Reaction

I haven't forgotten about the second half reaction.  This one presents some difficulties, especially getting from a one electron process to the two electron reduction needed to make the hydrogen.

For this electron carrier, I suggest the use of a NAD+/NADH surrogate, possibly --

You'll obviously need to evolve the hydrogenase to use this carrier, which should be simple enough assuming the electron carrier works, but we haven't gotten that far yet.  First, you'll have to figure out a way to get the light absorbing complex to reduce this substrate.

I suggest a light absorbing complex fusion with some kind of a flavin/nicotinamide oxidoreductase.  Flavins can receive electrons one at a time, so two light dependent electron-excitation events can be used to reduce the flavin, then that pair used to reduce the nicotinamide.  There are many such enzymes known, it is just a matter of getting the two active sites in the fusion protein to work together.  Directed evolution.  Monitor by UV/vis.

Once you've got that done, slap in your evolved hydrogenase, and you're done!

Obviously, I've overlooked many cofactor issues, but that just comes with the territory.  You'll have to be sure that all your proteins are being produced in an environment that will properly load 'em and fold 'em so that they're functional.  Most of the cofactors should be pretty cheap and not any real problem, except possibly the chromophore for light excitation.  That could possibly be overcome by using some kind of synthetic magnesium loaded porphyrin and evolving the enzyme to use the synthetic substrate once you got the thing working.

No problem, right?  The key to success wil be setting up each experiment to isolate each step and evolve it untill it's successful.  But given a few lifetimes, I think it would work.


The reason I think this'll be more economic should be obvious -- all the expensive materials (proteins and cofactors) are catalytic and used in small quantities, and all the bulk materials (water, pretty much) are close to free.  Most such bio-hydrogen processes have attempted to use live organisms, which obviously is goint to be cost prohibitive because you've got to feed the bugs to keep 'em alive.

The trick is to get an efficient enough system that 1) the catalysts are as cheap as possible and survive a lot of turnover and 2) the energy extraction is efficient with respect to incident light/real-estate occupied.

The way to get the enzymes cheap is probably to look into production in plants rather than bacteria once you've got an efficient protein system designed.  You'll also need a cheap protein isolation system, obviously, but you're not exactly going for food grade here.  There's plenty of literature devoted to the topic so I won't go into it.

For now...

Waste Reprocessing

The major problem with virtually all recycling programs is that you are dealing with extremely cheap materials in typically extremely complex mixtures, a.k.a., 'trash,' that must actually be sorted to be recyclable.  The solution, naturally, is to invent either some extremely cheap method of sorting, or invent a process that requires no sorting.  I'm going with the latter as the more feasible.

Most such efforts in this vein have focused on reprocessing of biomaterials either industrially or with fermentations to convert them into some other useful material, so technically, this isn't really recycling.  But hey, at least it gets rid of the trash to produce something useful.  I think this is a great idea, but I think the biological approaches too often focus on living fermentations.  Chemical processes have almost always supplanted biological process where the two have overlapped.  Chemical methods are just typically cheaper than biological methods, probably for one main reason -- chemicals don't have an extraneous metabolism to support.  So I think that for biology to become more competitive with chemistry in industrial applications, its probably a good approach to lose the whole life aspect at the point of application, if that's possible.  Biological approaches should try to fill a catalytic role, given their expense, in my opinion.  Cell-free approaches look to me to be the best way to go.

I think that it'd be really great idea to take the cellulose hydrolyzing enzyme being developed for cellulosic ethanol production and see if you couldn't evolve it to be robust enough to act on basically a mixed pile of trash.  A huge fraction of discarded waste is composed of cellulose, probably at least 50 percent.  If that could be broken down to glucose, you could think about diverting this to all other kinds of useful processes, while cutting the waste load substantially.

Here's another idea -- cell-free metabolic processes for converting that glucose into fuel.  Say, hexane.  With sufficiently nonspecific enzymes, there would really be only a few reactions involved.  If a good source of hydrogen was ever really developed, you could get useful reducing power by running a hydrogenase in reverse in the presence of hydrogen pressure to give an NADH-type electron carrier to reduce the aldehydes and alcohols of the sugar down to alkanes.  I would think that this would be an exothermic process, e.g., it could be run at room temperature without addition of any energy.  But I might be wrong about that.

Many other components of trash are also polymers, which I would think could be mobilized by similarly evolved systems.  I can just imagine a trash facility of the future, where truckloads of waste are dumped into giant vats and mixed with powerful enzymatic mixtures.  They are sealed up and allowed to 'stew,' then volatile fuels are distilled off and the remaining bits of debris trucked off for further processing and disposal.  Almost no manpower and very little energy would be required -- one of the quintessential qualities of a potentially economically successful idea.

Hey, it's an idea.

Biosynthetic Organic Synthesis

This one seems to me to be obvious, but for some reason I don't see it being done in a systematic way.  Again -- cell-free is the way to go.  If biology is ever going to compete with chemistry, biology is going to have to become like chemistry.

Most useful drug molecules that come from living systems are made by only a few synthetic pathways -- terpenes, polyketides, non-ribosomal peptides, and a few others.  There are a few organic synthetic methodologies that try to tackle the problem in a systematic way -- the Evans oxazolidinone approach to polyketides, and of course solid phase methods for peptide synthesis.  But most biosynthetic approaches are still relatively crude fermentations.  It would seem to me prudent to develop robust, cell-free biosynthetic systems to keep costs down.  Especially for the neglected family -- the terpenes.

Terpenes almost all go through the same few steps up to the point that they become oligomerized isoprenes, at which point the get cyclized and decorated by various means.  But the biosynthesis is anything but simple, elegant, or efficient.  Much better, cheaper, and simpler synthetic methods can be imagined that could be enzyme catalyzed in one pot approaches to give valuable advanced intermediates.  Evolve a few terpene cyclases, oxidases and acylases, and you've got ready pathways to a whole swath of highly valuable pharmaceuticals.

Seriously, this is a no-brainer.  Somebody should do it.

Hypoallergenic Ragweed

This would not be profitable at all, but I really wish somebody would do it anyway.  It would make the world a far less miserable place.

Somebody should develop tissue regeneration and cloning techniques for ragweed and produce a genetically modified hypoallergenic strain.  Then they could grow up tons and tons of the stuff and dump it everywhere over several years.  Eventually, it would genetically displace the native varieties and save millions of people (including me) from the misery of seasonal allergies.  That has to be worth something.

This is an excellent non-profit idea that some philanthropist should really give some thought.  I don't want to hear any GMO hyperventilating crap, either, okay.  Seriously, name one person that has become ill from a GMO, and I can probably find millions who are ill because of perfectly natural ones.  This is a really good idea.

Space Exploration

I don't know why, but lately I've become very opinionated on the topic of space exploration.  I don't exactly have a great deal of interest or any expertise in the subject, but I just get irritated seeing NASA bureacrats waste taxpayer money ferrying people back and forth to the idiotic space station to do inane 'experiments' that lead nowhere.  If scientists are going to waste money like that, at least they ought to waste it on something worthwhile that might actually make some kind of economic sense.  So, at the risk of possibly making these blood-sucking farts look good by stealing what might actually be a decent idea, I'll give two that I think would be much better uses of taxpayer money than this low-orbit rocket bullcrap.

The Space Elevator

The glaring, obvious problem with space travel is its reliance on rocketry.  Anybody with two functioning brain cells knows that this is the case.  They are way too inefficient and it costs too freaking much to get into space.  There's never going to be any serious space exploration until there's significant profit to be made in doing it, and there is slim chance that there'll be much profit while it costs $100K or whatever to put a kilogram into orbit.

The obvious thing to do is replace rocketry as the primary way to escape the greater portion of the earth's gravitational field.  That is where most of the energy/money burn occurs.  One solution that has been proposed for many years but somehow never seems to get done is to build a space elevator.  This is basically a really, really long cable with a significant mass attached at the end, such that the spinning centrifugal force of the earth keeps the mass at the end of the cable aloft in space against the force of gravity.  Kind of like whirling around a tennis ball attached to a length of string.  The circular motion keeps the string outstretched against whatever other forces are acting on it. 

The problem, of course, is getting that mass up into space with the cable attached without killing anybody, and finding a cable strong enough to withstand the immense tensions involved yet cheap and light enough to be economically feasible.  Other than that, it's a piece of cake.  With a cable set up straight into space, all you've got to do is climb up.  Much cheaper than rocketry.

I propose what should be (and probably is) an obvious solution -- screw the cable and fancy materials, which may ot may not ever materialize, just build the sucker with steel and concrete.  Build a skyscraper straight up into the sky, so that you just take an elevator to the top floor and step out into space.

OK, that may seem crazy, but I think it may not be.  I anticipate two objections.  First you'll say it's not economical.  But neither is the space proogram as it stands.  I'd seriously like to see a mechanical engineer take this home as a two-week project and give a rough estimate of costs, then compare that with ten years of NASA's budget -- which is a wildly optimistic guess as to how long it would take to build, anyway.  I'll bet it doesn't look that bad.  I'll bet it looks even better when you think about the fees NASA could charge to put things into orbit, and they could leave us taxpayers alone.

The second objection is likely that its not mechanically feasible -- except that I'll bet that it is.  Modern materials are light years better than in the days of the Tower of Babel.  Today's skyscrapers are insanely high, and from what I've heard, no modern design has really pushed the mechanical limits.  Mostly, it's a matter of profitability.  At some point it just doesn't make any sense to go any higher, bragging rights be damned.  Nobody bothers to think about something that tall.  A space elevator building would have far fewer mechanical limitations, as it would not be also serving as office space.

I would imagine the biggest problem would be wind knocking the thing over.  But that's a similar problem to the new deep-water oil rigs that face strong storms and currents.  They just use turbines to push back with and keep the thing standing straight.  I'll be the same thing would work on a really tall, narrow building that didn't catch much wind anyway.

Once you've built it so tall, the centrifugal force of the spinning earth counteracts gravity and actually pulls the thing up.  Once you've passed that point, the building goes into tension instead of compression and you're golden.  You've just got to be very careful getting there.

Once you've got a space elevator, you've got a flexible, cheap launching platform out into space, not to mention an absolutely superb observatory.  Now you can start to think about a really serious space program.

Space capitalism, even.

Screw the space shuttle and all this other wasteful claptrap.  Put a big nuclear plant on some island out in the Pacific and start building.

Interstellar Hubble Telescopes

This one's a little further fetched, if you can imagine that.  One day, people might like to start thinking about interstellar travel.  Problem is, well, manifold, and I don't really have solutions to any of them.  However, it does seem stupid that anyone should try to go to a place that nobody has ever seen, given that it'd take so long to get there and you'd pretty much be stuck there if you did.  So, it'd be great to plan ahead a bit and see if you couldn't get at least some good pictures of those 'planets,' which so far are only detectable as planetary wobble.

Enter the Interstellar Hubble.  Once the space elevator's built, I propose launcing Hubble-type telescopes with really big mirrors at the nearest several stars.  Equip them with solar sails or whatever technology exists to push them as fast as possible out of the sun's gravitational field and towards those other stars.  Also equip them with powerful radio transmitters to communicate back to Earth.

After about twenty years or so, they'll probably be far enough away that they might actually be able to see those systems better than we can see them from here.  They'll be at least a tiny bit closer, and the background light of the sun won't be anywhere near as bright.

By the time they get close enough to actually see those supposed other planets and give some hard information about them, maybe we'll have worked something out here to actually have a shot at getting there.  In the meantime, we'll keep the eggheads busy snapping pictures of all kinds of other stuff.  Keeps them out of trouble.  Hubble has kept people busy for at least twenty years now.  I'll bet this would be even better.