“About 10,000 years ago, humans began to domesticate plants and animals. Now it’s time to domesticate molecules“. – Susan Lindquist, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology.
By Shuguang Zhang *
By imitating nature, scientists are designing completely new molecular patterns that can serve as a blueprint of new materials and sophisticated molecular machines. In the emerging field of nanotechnology, basic natural building blocks such as amino acids are used to create structures such as peptides and proteins for applications in medicine and energy. Nanobiotechnologists have begun to exploit molecular self-assembly as a fabrication tool for building new nanobiostructures such as nanotubes for metal casting, nanovesicles for drug encapsulations, and nanofiber scaffolds for growing new tissues. They also have constructed an extremely high-density nanoscale photosystem and ultra-lightweight solar-energy-harvesting molecular machines. With better understanding of this seemingly intractable phenomena, one day mankind may be able to use nano devices to repair body parts or to rejuvenate the skin, enhance human capabilities, harness the unlimited solar energy, and achieve other feats that seem impossible today.
Biotechnology, which is known primarily by its medical and agricultural applications, is increasingly being focused on the building of new biological materials and machines in an astonishing diversity of structures, functions, and uses. The advent of nanotechnology has accelerated this trend. Learning from nature, which over billions of years has honed and fashioned molecular architectural motifs to perform a myriad of specific tasks, nanobiotechnologists are now designing completely new molecular patterns – bit by bit, from the bottom up – to build novel materials and sophisticated molecular machines. Over the next generation, advances such as new materials to repair damaged tissues and molecular machines to harness solar energy from the smallest molecular amino acids and lipids will likely have an enormous impact on our society and the world’s economy.
Modern biotechnology has already produced a wide array of useful products, such as humanized insulin and new vaccines. But what lies ahead can be even more revolutionary. That is why governments small and large, and industries local and global, are increasingly seeking to attract biotechnology talent and investment. There is no doubt that biotechnology, helped by the tools of nanotechnology, is expanding at an accelerating rate, and that the best is yet to come.
Nature itself is the grandmaster when it comes to building extraordinary materials and molecular machines atom by atom and molecule by molecule. Shells, pearls, corals, bones, teeth, wood, silk, horn, collagen, muscle fibers, and extra-cellular matrices are just a few examples of natural materials. Multifunctional macromolecular assemblies, such as hemoglobin, polymerases, and membrane channels, are all essentially exquisitely designed molecular machines.
Through billions of years of molecular selection and evolution, nature has produced a basic set of molecular building blocks that includes 20 amino acids, a few nucleotides – the structural units of nucleic acids such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) – a dozen or so lipid molecules, and two dozen sugars. From these seemingly simple building blocks, natural processes are capable of fashioning an enormously diverse range of fabrication units that can further self-organize into refined structures, materials, and molecular machines that not only have high precision, flexibility, and error-correction capacity, but also are self-sustaining and evolving. For example, the photosynthesis systems in some bacteria and all green plants take sunlight and convert it into chemical energy. When there is less sunlight, as, for example, in deep water, the photosystems must evolve to become more efficient to collect the sunlight.
In the early 1990s, biotechnologists began to learn how to manipulate natural building blocks with at least one relevant dimension being between one nanometer (one billionth of a meter) and 100 nanometers to fabricate new molecular structures, thus ushering science and technology into the age of designed molecular materials. Much like clay and water can be combined to make bricks with multiple uses that, in turn, can be used to build walls such as the Great Wall of China, houses, or roads, basic natural building blocks such as amino acids can be used to create structures such as peptides and proteins that can be used for a variety of purposes. For example, animals grow hair or wool to keep themselves warm, shellfish grow shells to protect their tissue from harm, spiders spin silk to capture insects, and our cells make a lot of collagens to keep cells together to form tissues and organs.
If we shrink the construction units one billion times to the nanoscale, we can construct molecular materials and machines from prefabricated units in a way similar to that in which a house is assembled from prefabricated parts.
Peptides formed from amino acids are molecular architectural units that are proving very useful in the development of new nanobiological materials. In water and in the body fluids, these peptides form well-ordered nanofiber scaffolds useful for growing three-dimensional (3-D) tissue and for regenerative medicine. For example, scientists have fabricated artificial cartilage and bones to replace damaged tissue using the biological scaffolds and cells. Furthermore, scientists have also shown that the designer self-assembling peptide nanofibers can stop bleeding instantly, a characteristic useful in surgeries. New peptides are proving to be remarkably useful in drug, protein, and gene deliveries, because they can encapsulate some water-insoluble drugs and ferry them into cells and other areas of the body. They also are essential to fabricating bio-solar, energy-harvesting molecular machines that use the photosystem from spinach and tree leaves.
All biomolecules, including peptides and proteins, naturally interact and self-organize to form well-defined structures with specific functions. By observing the processes by which these biological molecular structures are assembled in nature, nanobiotechnologists have begun to exploit self-assembly as a fabrication tool for building new nanobiostructures such as nanotubes for metal casting, nanovesicles for drug encapsulations, and nanofiber scaffolds for growing new tissues.
Molecular self-assembly involves mostly weak bonds – as does human handholding – that can be joined and disjoined quickly. This is in sharp contrast to the very strong bonds that join our arms to our body. Individually, weak molecular forces are quite insignificant. Collectively, weak interactions such as the hydrogen bond and the ionic bond play an indispensable role in all biological structures and their interactions. The water-mediated hydrogen bond, in which numerous water molecules work as a bridge to connect two separate parts, is especially important for biological systems, since all biological materials interact with water. The bond, found in all collagens, works to increase the moisture for an extended time.
As to molecular building blocks, the designed peptides resemble the toy Lego bricks that have both pegs and holes arranged in a precisely determined manner and can be assembled into well-formed structures. Often referred to as “peptide Legos,” these new molecular bricks under certain environmental conditions spontaneously assemble into well-formed nanostructures.
In water, peptide Lego molecules self-assemble to form well-ordered nanofibers that further associate to form scaffolds. One such nanofiber scaffolding material that has been commercially realized is PuraMatrix, so called because of its purity as a biotechnologically designed biological scaffold. Biomedical researchers currently use it worldwide to study cancer and stem cells, as well as to repair bone tissue.
Since these nanofiber scaffolds contain 5 to 200 nanometer pores and have extremely high water content, they are of potential utility in the preparation of 3-D cell and tissue growth and in regenerative medicine. In addition, the small pore size of these scaffolds may allow drugs to be released slowly so people do not have to take their medicine several times a day but rather once over a longer period. A slow-release nanoscaffold device can be implanted on the skin with medicine supplies sufficient for months or years.
Creating more building blocks
Using nature’s lipids as a guide, a new class of lipid-like peptide detergents has been designed. These peptides have seven to eight amino acids, giving them a length similar to naturally occurring lipids, which make up cell walls 20,000 times thinner than the diameter of a piece of human hair.
Simple lipid-like peptide detergents produce remarkably complex and dynamic structures in the same way that the assembly of numerous simple bricks can make many different and distinctive architectural structures.
Some peptide detergents have been found to be excellent materials for stabilizing notoriously hard-to-stabilize membrane proteins – protein molecules attached to or associated with the membrane of a cell – thus opening a new avenue for overcoming one of the biggest challenges in biology: obtaining clear pictures of the ubiquitous and vital membrane proteins.
Numerous drugs exert their effect through membrane proteins. But how these drugs interact with vital membrane proteins at the finest molecular level remains largely unknown. The designed peptide detergents promise to change this. If we can fully understand the interactions of these proteins, we may be able to produce more effective and efficient drugs with few or no side effects.
Harnessing solar energy
Detailed molecular study of how membrane proteins function is just an exercise in understanding them. By deepening our knowledge of how cells communicate with their surroundings, we learn how all living systems respond to their environments. With this know-how, modern nanobiologists have begun to fabricate advanced molecular machines able to develop extremely sensitive sensors for medical detection or to harness bio-solar energy. For example, ancient Chinese doctors smelled a patient to diagnose a medical problem because they believed that an illness can change a patient’s body odor or secretion. In modern medical science, a number of instruments are used to make an accurate diagnosis. In the future, a smell sensor as sophisticated as a dog’s nose could help distinguish people with medical problems from healthy ones. In the United Kingdom, dogs have already demonstrated their ability to identify people suffering from cancer by sniffing their odors.
No one would argue that affordable, sustainable, and environmentally sound energy is requisite for the welfare of modern civilization. With environmental damages caused by fossil fuel pollution and the demand for energy burgeoning worldwide, the world’s energy problems are now more urgent than ever. Alternative solutions, long debated but rarely seriously pursued, are now being pursued with a sense of urgency.
Further, the increasingly mobile nature of computing and communication, and the nanonization of materials and molecular machines, demand that smaller, lightweight, self-sustaining energy sources be developed. An obvious source of infinite energy is the sun. Nature has produced an efficient system to directly convert photons into electrons and further into chemical energy; green plants and other biological organisms have been using this system for billions of years.
Most energy on earth is obtained from photosynthesis through photosystems, the most efficient energy-harvesting system. If a way to harness the energy produced by natural photosystems can be developed, we will have a clean and nearly inexhaustible energy source.
Borrowing from the bacterial and green plant energy-harvesting photosystem, nanobiotechnologists have demonstrated that photons can be converted directly into electrons by newly designed bio-solar molecular machines. Through a combination of precision engineering and biological engineering of the photosystem, they have constructed an extremely high-density nanoscale photosystem and ultra-lightweight solar-energy-harvesting molecular machines.
Two key components are required to fabricate a bio-solar energy-harvesting molecular machine – a bio-solar energy production system (photosystem) from leaves of green plants, and the designed peptide detergents. For bio-solar energy production, a simpler photosystem was used. Scientists originally purified the photosynthesis system from spinach, and they have recently reported successfully purifying photosynthetic systems from maple, pine, and oak trees and from bamboo leaves. The entire photosystem complex – only about 20 nanometers in height – was anchored onto a gold surface with an upright orientation.
Experimentation is continuing to devise ways to increase the amount and duration of energy produced by this exciting new molecular-energy-harvesting machine.
What lies ahead?
The continued development of nanobiotechnology materials and molecular machines will deepen our understanding of seemingly intractable phenomena. Nanoscale engineering through molecular design of self-assembling peptides is an enabling technology that will likely play an increasingly important role in the future of biotechnology and will change our lives in the coming decades. For example, aging and damaged tissues can be replaced with the scaffolds that stimulate cells to repair body parts or to rejuvenate the skin. We also might be able to swim and dive like dolphins or to climb mountains with a nanoscaffold lung device that can carry an extra supply of oxygen. It is not impossible to anticipate painting cars and houses with photosynthesis molecular machines that can harness the unlimited solar energy for all populations on every corner of the planet, not just for the wealthy few.
We are just at the beginning of a great journey and will make many unexpected discoveries. Although nanotechnologists face many challenges, they will actively pursue many issues related to the molecular fabrication of composite materials and molecular machines. Biotech self-assembling peptides can be considered the building blocks for emerging materials and for fabricating future man-made molecular machines. These peptides can also be designed in combination to incorporate other building blocks such as sugars, lipids, nucleic acids, and a large number of metal crystals. Nature has inspired us and opened the door to its secrets. It is up to our imagination to expand upon its materials and molecular machines.
* Shuguang Zhang is associate director of the Center for Biomedical Engineering at the Massachusetts Institute of Technology.
1. Article puclished originaly in the eJournalUSA