Wall Street Will Go to One Who Knows How Proteins Fold
Pssst , wanna launch a multibillion-dollar industry and maybe win a Nobel Prize in the process? Then I have just two words for you: Protein engineering.
You’ve all heard of genetic engineering and the biotechnology industry it spawned. Well, protein engineering takes it all down a level; it’s the stuff that genes are made of. If you can play with proteins, you’re playing with the molecules that matter.
Proteins are the real building blocks of life. They’re how you build DNA, enzymes, membranes, hormones and all manner of organic materials. Everything that matters is made of proteins. The Nobel Prize-winning question (the answer to which will be as important as James Watson and Francis Crick’s discovery of the double helix as the medium of genetic communication) is: How do proteins fold? Figure that one out and they’ll write you checks from Stockholm to Wall Street to Tokyo.
Even though all proteins come from a basic vocabulary of only 20 amino acids, chemists have only the foggiest of foggy ideas why proteins assume the shapes they do. (Remember the enzyme lock-and-key analogy from high school biology? Well, it’s still being used.)
These amino acids are strung together in chains of polypeptides. But these chains aren’t just two-dimensional--they writhe, curl and fold. How they fold, if they fold, determines how the chemical processes of life take place. Think of protein geometry as a problem in origami-- but where we don’t understand the properties of the paper we’re folding.
“We’ve seen tremendous advances in the computational end of things but we aren’t much further along to knowing how to predict what a protein looks like than we did in the 1960s,” says Bill DeGrado, an organic chemist at Du Pont whose research in protein engineering is widely regarded as world class. Despite the absence of a solid theoretical foundation, DeGrado’s work indicates that protein engineering is a real technology and not just a set of toy-domain techniques.
Essentially, DeGrado has melded computer modeling with amino acid chemistry to whip up some crude but effective proteins. This approach--using synthetic peptides--allows you to “design novel proteins from scratch,” says biotechnologist Kevin Ulmer. “If you can string together peptides and figure out how the sequences fold, we can make anything we want.”
“We’re learning how to make molecular assemblies either from the ground up or by looking at biomolecules and cutting and pasting them,” says DeGrado. “It’s a lot like the ability to manipulate DNA--but more daunting and more chemical in focus.”
The University of Alabama’s Dan Urry has actually been weaving polypeptides into bio-elastic “fabrics” that have special properties--like the ability to filter impurities from water, prevent certain adhesions from forming in burn victims or “shape memory” (the ability of materials to return to their original shapes). The trick is, if we know certain proteins have specific properties, how can we custom-engineer materials that have only those special properties?
“If we can create repeating sequences of the right amino acids,” says Urry, “the idea is then that they become building blocks. You can make almost anything.”
In essence, protein engineering could let you “program” new materials in the same way that software lets you program computers. The key is knowing the right sequence of instructions and chemically executing them.
Indeed, not only could you build new proteins from the ground up but you could also get old enzymes to perform new tricks. For example, the folks at Genentech (best known for its genetic engineering work) figured out how to make a laundry enzyme more stable by getting it to cling to different molecules so the detergent could get clothes cleaner at higher temperatures. A trivial application (unless you’re Unilever or Procter & Gamble) but one that dangles tremendous potential for new drug treatments for everything from the flu to AIDS. Proteins could be engineered to boost the performance of existing medications.
What if we could alter existing proteins with the same facility with which we can alter DNA? The answer is that we could see an explosion of new materials with new properties, enhanced versions of existing materials and a fundamentally new approach to the way that pharmaceuticals are designed. This isn’t the sort of revolution that happens overnight but it is the sort of new technology that redefines the old ones.
By 1993, DeGrado says, “I would like to see people designing de novo enzymes handling processes that natural enzymes--even souped-up enzymes--are incapable of. I’d also like to have a beginning understanding of biological polymers (protein chains) so that we could create lower-cost polymers. What is it that gives elastomers (elastic protein chains) in nature their strength. . . . I think we’ll be able to create composite polymers” just as materials scientists now make composite metals. “This isn’t just theory, this is making materials.”
Which explains why Du Pont and other chemical giants are so interested. Protein engineering may be the key to adding value to many of their existing materials--not to mention a medium for crafting materials yet unimagined.
There are several catches. “Because we don’t yet understand how biopolymers fold, this is not yet a predictive science,” says Caltech’s Peter Dervan. “We don’t really understand the relationship between structure and function.”
Indeed, DeGrado notes that “there’s a huge gap here--chemists really need to get into the act here” both in terms of theoretical contributions and the actual synthesis of new organics.
But the payoff would be enormous. Watson and Crick got their Nobel for the double helix and laid the cornerstone for the biotechnology revolution that’s now redefining life. Sometime, somewhere, some researchers will make comparable breakthroughs into protein folding. They’re going to come away with a Nobel and, most probably, an equity stake in what is sure to be the most lucrative new era in commercial biotechnology.
