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The Holy Grails of Chemistry

Like knights-errant, modern chemists are questing to achieve ultimate, highly desirable goals. Although difficult beyond all imagining, these research challenges promise revolutionary payoffs, including new industrial or commercial products and profound insights into basic science.


Chad Waraksa
Thomas Mallouk and Chad Waraksa (pictured):
Professor and student quest
for artificial photosynthesis.

Chad Waraksa is on a quest. The second-year chemistry graduate student at Penn State is searching for what is widely regarded as one of the most desirable, yet difficult, goals in the field of chemistry—a Holy Grail, if you will. He seeks the “chemical switch” to turn sunlight into energy by using it to split water into oxygen and hydrogen, which would in turn power a fuel cell.

If Chad found a way to use light to “artificially photosynthesize” water into an efficient, durable, and cheap source of fuel, we could reduce our dependence on a finite oil supply. We could stop worrying about greenhouse gases and global warming and smog. Cities like Mexico City and Rome would sparkle again, and acid rain would stop eating away at the ancient treasures of Athens.

In short, Chad wants to save the world. But right now, he’s not even close.

So Chad keeps searching for better materials for his system. He spends days synthesizing a new compound that might just make a better light sensitizer. He refluxes and he purifies; he filters and analyzes and mixes. At each step, he loses more of his precious material, and in the end he may not even have enough to test. So he begins again.

“The long-term goal sometimes seems so very far away,” he says. “But it’s out there, and bit by bit we’re getting there.”

Holy Grails are the legendary quarry of knights in armor. They are the key to fame, fortune, and foundation prizes. Most important, they inspire and impassion. They are what lights a fire under a chemist’s flask.

“We need to have these dreams,” says Richard Zare(ACS ’79), a chemistry professor at Stanford University and chairman of the National Science Board. “Without dreams we can’t get anywhere. That’s why Holy Grails are so important. That’s why it’s not a waste of time to talk about it, and to talk about it most grandly, too.”

Richard Zare
Richard Zare: "We need these dreams."

Chad’s Holy Grail is only one of many, of course. No two chemists will list the same Holy Grails, because none share the exact same dreams. But a group of chemists did throw down the gauntlet in 1995, publishing a list of Holy Grails inAccounts of Chemical Researchand challenging scientists to aim high and to follow the example of Linus Pauling, King Arthur of chemists, to whom the issue was dedicated.

The coeditors identified such lofty goals as the ability to manipulate atomic matter, the discovery of a room-temperature superconductor, enzyme-like catalysis on demand and by design, and artificial photosynthesis. Zare, who was an editor of theAccountsissue, says he would add other, broader goals such as the ability to create life chemically.

It was Allen Bard(ACS ’58), chemistry professor at the University of Texas–Austin, who pitched the idea of the Holy Grail issue to his fellow advisory board members. Capturing the elusive grails, he says, might lead to practical applications in science and technology. But their pursuit is bound to unearth discoveries and rewards not yet imagined, even if the day-to-day usefulness isn’t immediately apparent.

“Suppose I could sit down in the laboratory and synthesize an ant,” Bard says. “That would be a great thing to do, right? But there’s no practical use in making more ants.” He laughs. “Nonetheless, it would be something I’d like to do.”

And though creating life in the lab veers dangerously close to tilting at windmills and B movies, it also makes a superb Holy Grail.

The Mother of All Holy Grails:
The Chemistry of Creation

How did life begin? Could we make it happen again? Could we find a new way to make life?

No, Dr. Frankenstein, it’s not about stitching together body parts and zapping them with lightning. Right now, it’s about creating a system—a molecule—that can store information, copy itself, and evolve.

One widely held theory about the origins of life holds that before complicated DNA structures and protein enzymes, biology was based on RNA alone in what’s been dubbed the RNA World. In that world, which existed roughly four billion years ago, RNA would have had to replicate without the benefit of protein enzymes—which nowadays are crucial players in the business of DNA or RNA replication. It’s a chicken-and-egg problem: Genes need enzymes to replicate, but enzymes are made by genes. So how did the whole thing get started? RNA offers a possible solution to this puzzle. In a remarkable show of virtuosity, RNA can act as an enzyme (known as a ribozyme) as well as a storehouse of genetic information.

The trick is to get RNA to replicate with only ribozymes and without enzymes made of proteins. Such systems “would be capable of initiating de novo evolution by Darwinian selection and would open up a new field of chemistry,” wrote Leslie E. Orgel(ACS ’67) of the Salk Institute for Biological Studies (San Diego, CA) inAccounts. It’s a trick big enough to qualify for Holy Grail status, and it seems tantalizingly close. David Bartel, a biochemist at the Whitehead Institute in Boston, is one of the researchers leading the charge.

“He’s got an RNA enzyme that is beginning to copy. It looks like an RNA polymerase, but it doesn’t have any protein in it,” explains Orgel. “It’s made up of RNA. That’s probably the most advanced single result toward getting replication in a test tube.”

Another riddle in the quest for the Holy Grail is that somehow the world had to evolve from a primordial soup to RNA, and many researchers say that RNA is too complex to have serendipitously come together from a chemical broth. Orgel has shown that the nucleotides, which are the building blocks of RNA, were more likely to join together while clinging to the surface of clay or mud, rather than while floating in a Darwinian pool. He and others are also investigating the possibility that self-replication first began with a molecule other than RNA. As he said inAccounts, “There is no obvious reason why accurate template-directed synthesis and … replication would be restricted to systems involving nucleotide bases.” Research in that area is just beginning, he says, and has a long way to go.


An artificial enzyme that combines a cyclodextrin binding group with a metal ion catalytic group. It catalyzes the hydrolysis of substrates that bind into the cyclodextrin cavity, even those, such as p-nitrophenyl acetate, that do not normally coordinate to a metal ion.

The first step toward recreating that original spark of life on Earth or, for that matter, toward creating life in a modern laboratory without duplicating primitive Earth’s conditions, will be that tiny molecule that can store information, self-replicate, and change according to its environment.

“How soon they’ll succeed is anybody’s guess,” says Orgel. “There are very significant problems. One of the problems is that systems we have at the moment are quite likely to succeed in copying, but once you’ve copied something, you have a double strand which you have to somehow pull apart to get started on the next round. That’s a problem that has not really been addressed even with RNA, let alone with something else.

“It’s still a very difficult problem, but you know, Holy Grails are hard to achieve or find—or whatever you do with Grails.”

Shake, Rattle, and Roll: Manipulating Matter on the Atomic and Molecular Scale

Chemistry is not a science for wallflowers. These chemists don’t want to just sit in their chairs and watch the dance. They want to boogie. In fact, they want to choreograph the whole thing. This means, on an atomic level, that they not only want to watch as molecules bond, collide, vibrate, or jiggle, but they also want to get their fingers inside those tiny little devils and shake things up a bit. Break this bond here and put another one over there. Reaching this Holy Grail means someday putting atoms together the way we want them and making them stay that way.

It’s acontrol thing.

A lot of labs are hot on this grail’s tail, because the tools and technology to do this kind of work have exploded in the past few years. Laboratory workhorses such as the scanning tunneling microscope (STM) can be used to slide single atoms around on a metal surface, allowing scientists to arrange 48 iron atoms into a circular “quantum corral,” for example, or use xenon atoms to write out the word IBM. It looks spectacular, but STM pro Phaedon Avouris(ACS ’93), an IBM research chemist, pooh-poohs such showmanship.

“That’s not chemistry—chemistry is not geometry,” he says. “You can make very nice circles and whatever because there is nothing permanent. But in chemistry, you want to be able to put an atom there, bond it, and it stays there.”

“The chemical goal, subject of this Holy Grail, is to be able to make a chemical bond where you want and make a permanent, useful structure.”

One way to actually create covalent chemical bonds on those metal surfaces, he says, is to first deactivate a surface, such as silicon, by saturating it with hydrogen. Chemists then can use the tip of the STM to remove selected hydrogen atoms in whatever configuration they like. The dangling silicon bonds, unsaturated and waiting to couple with something, can be mated with oxygen to make an oxide ring, or with oxygen and ammonia to form nitrites. With this technique, Japanese researchers are placing gallium atoms in a row to make gallium wires and the tiniest possible electronic devices.

STM and other proximal probes, Avouris says, have the power not only to shoot a stream of electrons at a single chemical bond, exciting the bond all the way up its vibrational ladder until it disintegrates, but also to image the events at an atomic level. Chemists have unprecedented control over atomic events, but not yet enough. Avouris is now trying to exercise such control over chemical reactions so that he can energize two atoms to react but not the two next to them.

Other seekers of this Holy Grail brandish other weapons. Chemists wield lasers of high intensity or ultrashort blasts that can pin a molecule still or illuminate it at its moment of conception. These tools provide a deeper understanding of chemical reactions, which hopefully will lead to even greater control. Researchers such as Ahmed Zewail(ACS ’77) at the California Institute of Technology are using ultrafast lasers to take pictures of the previously mysterious zone in a chemical reaction between reagents and products—the elusive transition state. Chemical reactions take place in femtoseconds—a thousandth of a trillionth of a second—and only recently have Zewail and his lasers been able to capture events happening in that unimaginably small time scale.

Meanwhile, chemists such as Zare at Stanford University and George Whitesides(ACS ’61)at Harvard University are getting a grip on individual cells and molecules using high-intensity lasers as “tweezers” to manipulate matter in solution. Whitesides says that recently it’s become possible to grasp a molecule and stop its jittering and jiggling long enough to sit and watch it, like a bird in a cage.

“In chemistry, what we’ve always done is look at collections of molecules and look at their average behavior,” Whitesides says. “One of the things that will happen in the future is that we will look at individual molecules and see how the behavior of individuals differs from the average behavior. The idea that you can grab a molecule and put it in place and watch it for a while is a very powerful idea.”

George Whitesides

Whitesides says that laser tweezers are helping researchers gently hold on to individual cells during experiments, and he is using them to test the strength with which viruses adhere to cell surfaces. It may also be possible to use the lasers to build optical crystals or other structures and to watch the behavior of individual atoms and molecules through time.

“I think we’re going toward a physicist’s way of doing chemistry, in a much more controlled way,” says Avouris. “In chemistry, we’re used to making things in beakers, in large quantities. We never deal with individual molecules and their properties and their manipulation. But physicists come from that end. So if we could couple the two, we’d have a way of doing chemistry in a very specific way. If we want to break this bond, we’d be able to break it, and if we want to form a bond, we’ll form it. We’ll be able to have total control of the chemistry.”

More Holy Grails

• Richard Zare likes the big questions: What’s the chemistry of aging, and how can we control it? He also wants to understand the chemistry of thought and how memory and learned response work.

• George Whitesides lists the understanding of memory and perception as a Holy Grail, but he says that almost no one works on that in chemistry because “it’s not clear what experiments you’d do, it’s not clear how you’d interpret it, and it’s not clear that it actually has anything to do with molecules (not in a grand architectural sense).”

• Allen Bard would like to see a room-temperature, fast, economical fixation of nitrogen to ammonia in the manner of nitrogen-fixing bacteria. With such a catalyst, he says, “you could have a fertilizer that you throw down once, and that’s it. It takes nitrogen and makes ammonia as long as that catalyst lasts.”

• Arthur Sleight thinks that a much better battery than the ones we have today would be a worthy Holy Grail. It’s a very practical Holy Grail, he says, but “scientific advances are absolutely required to do it.”

Fred McLafferty
Fred McLafferty

• Fred McLafferty of Cornell University describes the Holy Grail of doing medical diagnoses using instrumental analysis—knowing which molecules are specific for a disease and how to analyze for them. For example, he says, “If we had an analyzer that was totally general for molecules, then all you’d have to do is get 100 people without colon cancer and 100 people with colon cancer and run their blood through this analyzer. You’d see which molecules are in the cancer patients and not in the other ones, and you’d be all set toanalyze.—R.S.

It’s the Economy, Stupid: (Cheap) Solar Splitting of Water

Chad Waraksa’s Holy Grail would probably be a lot closer if gasoline were more expensive. But it’s not; so solar-generated fuel has got to become less expensive—and more efficient.

Chemists have understood the mechanics of solar water-splitting for some time. Photons of sunlight smash into a semiconductor’s electrons, sending those electrons wandering about in a higher energy level. The “holes” left behind act as a positive charge, and the positive charges and negatively charged electrons are directed in opposite directions by other materials. This movement creates an electric current. Direct this current to metal electrodes, stick the whole system under water, and bang—you’ve got a way to electrolyze water into its hydrogen and oxygen atoms. Next, pump the hydrogen into a fuel cell, and you’ve got a source of energy that requires only sunlight and water and gives off only water as waste. Eureka!

The obstacles to this grail are that the creation of electricity from sunlight and the electrolysis of water have had to take place in two steps, draining away efficiency. And it’s been an expensive process compared with fossil fuel energy.

But two developments earlier this year have propelled chemists like Waraksa in the right direction. Japanese researchers at the Tokyo Institute of Technology discovered that cuprite acts as a photocatalyst for making hydrogen and oxygen from water, and it’s nice and cheap. Unfortunately, the catalyst is not very efficient.

Perhaps even more important, chemists John Turner and Oscar Khaselev at the National Renewable Energy Laboratory figured out how to take the two-step process down to one. With that little coup, they managed to push the energy efficiency up to about 12.5 percent—which nearly doubled the previous record. The drawback to their system is that it requires expensive materials and is costly to build.

Chemist Thomas Mallouk(ACS ’84)of Penn State, Chad’s advisor, says that researchers are waiting for the breakthrough materials that will make this Holy Grail a reality.

“It’s not an easy problem,” Mallouk says, “but it’s technologically feasible.”

What’s the Plan, Stan? Room-Temperature Superconductors

Ten or 12 years ago, everyone seemed to think that this Holy Grail was only an experiment or two away. But things have stagnated.

The remarkable property of superconductivity was discovered in 1911, when scientists found that mercury lost all resistance to the flow of electricity when it was cooled to the temperature of liquid helium—9 kelvins (K), or about –452 °F. Since then, researchers have sought materials that would exhibit superconductivity at higher, more practical temperatures. They pushed the temperature to about 13 K in the 1970s and caused an uproar in 1986 with a copper oxide/lanthanum ceramic that became superconducting at 35 K.

Physicists in particular were all aflutter with this discovery, showing up at the 1987 meeting of the American Physical Society at double capacity and turning the event into the “Woodstock of physics.” The 35-K mark turned a corner for superconductors because liquid nitrogen could be used to cool materials at that temperature, a much less expensive alternative to liquid helium. Since then, scientists have reached 135 K in their search for a room-temperature or 300-K superconducting material. Such a discovery, it is hoped, would revolutionize the electric power industry and permit the creation of trains that levitate, faster computers, and powerful new medical imaging devices.

But chemists have pretty much stumbled onto the discovery of superconductors and fumbled onto better ones. There’s no overarching theory that would give researchers a road map for coming up with materials that will superconduct at certain temperatures.

Arthur Sleight(ACS ’71), a chemist at Oregon State University who described this Holy Grail forAccounts of Chemical Research, says that scientists have made significant advances in superconducting theory in the last year or so and in the development of superconductor applications. But he doubts those gains will result in higher-temperature superconductors.

Arthur Sleight
Arthur Sleight: Room-temperature superconductors

“We really have run out of ideas of what to do next,” Sleight says. “[The new theory] has provided us with a better understanding of the nature of the electrons in the superconducting state. But unfortunately, it’s not a guide to getting the temperature higher.”

Knights can spend their lives searching for an elusive Holy Grail—or they can know when to quit. Sleight says he’s gone on to other projects for now, but that doesn’t mean this Holy Grail is a lost cause. “The fact that some of us have given up for the moment doesn’t mean it’s not going to happen; it just means we don’t have any particularly good ideas as to what to do next,” he says. “But on the other hand, the way superconductors have made advances was more by accident than by people really trying to do it, anyway.”

Room Service Reactions:
Catalysis on Demand

Catalysts make things happen, and nature has produced catalysts—enzymes—that make scientists wild with admiration and envy. Chemists would love to be able to create objects that catalyze chemical reactions with the speed and specificity of naturally occurring enzymes.

“We can either sit back and admire them, or we can figure out how to do that ourselves,” says Columbia University chemistry professor Ronald Breslow(ACS ’52).

To achieve this Holy Grail, researchers have proceeded mainly in two directions. There are those, like Breslow, who attempt to rationally design and synthesize enzyme mimics, which are also called “artificial enzymes”; and there are chemists, such as Peter Schultz(ACS ’85) at the University of California-Berkeley and Richard Lerner(ACS ’84)at Scripps Research Institute, who isolate catalytic antibodies, called “designer catalysts.”

Schultz and Lerner were the first to persuade antibodies—those immune system warriors that fight off pathogens—to behave as enzyme-like catalysts. The immune system can customize the antibodies it produces according to the structure of invasive molecules, and researchers can exploit this ability to produce catalytic antibodies. Scientists send molecules, in particular, that flag the immune system to generate antibodies with specific catalytic abilities. “You can basically dial in the specificity at will,” Schultz said in a University of California–Berkeley publication. Using this powerful tool, they have been able to find catalysts that don’t exist in nature, and they have also catalyzed chemical reactions that are quite hard to carry out using any known chemical methods.

Whereas Schultz and Lerner work with nature to produce their catalysts, Breslow says he prefers to go at the problem using only chemical synthesis, in a strictly rational manner. Also unlike the catalytic antibodies, the molecules he is designing are not proteins, which are big and unstable under harsh conditions and can cause allergic reactions. Breslow’s enzyme mimics follow the blueprint of a natural enzyme: They usually feature a cavity into which the guest molecule can fit and bind, and nearby functional groups that interact with the guest, catalyzing its conversion to products. He also designs and builds molecules in three dimensions, rather than relying on the spontaneous folding of natural proteins for three-dimensionality.

Breslow says that scientists are hoping to find drugs that could act as catalysts inside the body—catalyzing, for example, the hydrolysis and destruction of RNA in dangerous viruses. His lab is working on an artificial enzyme that would destroy cocaine in the system. Meanwhile, a lab at Stanford University recently constructed an enzyme mimic that exactly copied the action of naturally occurring galactose oxidase, which converts alcohols to aldehydes.

“Some of it has been quite successful,” Breslow says. “It’s not just hope any more. It’s not just an idea or a gleam in somebody’s eye. It actually does seem to work.”

The Quest, Not the Grail?

The chemist’s quest for a Holy Grail may lead to success, and it may not. But the journey, in the end, may turn out to be more important than the destination. The point, says Arthur Sleight, is to keep your eyes wide open and recognize the surprises when they come. “If you find what you’re looking for, that’s good,” he says. “But if you find something completely different, that could turn out to be utterly fantastic.”

Hey! What About… ?

If we overlooked any of chemistry’s greatest research challenges, drop us a message by mail or by e-mail with a brief description of the grail and its significance. Then watch the next edition of Chemistry, when we publish a list for consideration by our readers. —The Editor

Robin Sussingham writes frequently about science and environmental topics. She lives with her husband and two sons in Niceville, FL.