The Race To Break The Carbon Barrier
The fusion of nano- and biotechnology means that in the near future there will be no difference between living and nonliving materials.
WHAT IS NANOBIOTECHNOLOGY?
Within a generation, biology will face its ultimate identity crisis as researchers in the field of nanobiotechnology race to achieve the complete molecular integration of living and nonliving materials.
That bears repeating: The mission of nanobiotechnology is the molecular integration of living and nonliving materials.
We will hack into the CPU of life in order to insert new molecular hardware and software designed by human engineers. Initially, most molecular bioengineering will operate under the umbrella of biomedical research. The goals will be congruent with the missions of agencies such as the NIH and the NSF, i.e. treatment or elimination of human diseases and disorders coupled with the need to retain a leadership role in basic research. Other agencies will couple molecular engineering to their various mission statements: the DoE will have energy applications while the DoD will require nanoscale technologies to defend us from threats such as bioterrorism.
But before long it will become obvious that most of the techniques and devices that emerge from the molecular engineering revolution will have multiple applications including the extension of our ‘biological’ capabilities (e.g. our physical senses) far beyond the limits imposed by evolution. Molecular engineers will expand and extend the limits of living systems by integrating the amazing biochemistry of life with the equally spectacular chemistry that has emerged from basic research on molecular and atomic properties of nonliving materials: e.g. semiconductors, fiber optics, quantum dots etc. The idea is to hardwire biological and nonbiological (a.k.a. living and nonliving) materials together by building hybrid molecular structures. Initially research into such hybrid materials will be rationalized as the logical ‘next step’ in a technology revolution designed for our benefit. Optoelectronic splices for the vision impaired, micromechanical valves to restore heart function. But the moment we close that nano-switch and allow electrons, photons, or any other type of physicochemical phenomenon to move with molecular precision between living and nonliving matter, we are opening the nano-door to new forms of living chemistry. Simply put, nanobiotechnology will shatter the Carbon BarrierTM* of life.
This is, without doubt, the most extreme application of science since the development of nuclear weapons. Nanotechnology – more correctly called Molecular Engineering - is so powerful that – in creating the National nanotechnology Initiative (NNI) - the federal government has concluded it is “likely to change the way almost everything is designed and made.” “Everything” includes ‘living things’, and when we change the way living things are designed and made, we must be prepared to change the very definition of life. Yet no coherent strategy exists to identify the moment when nanoengineered smart materials cross over into the realm of living materials. Why? Because the significance of the Carbon Barrier is not understood, even by those working the hardest to break it.
J. Robert Oppenheimer once said, “It is a profound and necessary truth that the deep things in science are not found because they are useful; they are found because it was possible to find them.” It is exactly because of the unlimited possibilities inherent in the exploration of the new scientific frontier of nanotechnology that we continue racing to break through the Carbon Barrier… even though most of us cannot begin to imagine what’s on the other side.
NANO- AND BIOTECHNOLOGY ARE BOTH FORMS OF MOLECULAR ENGINEERING.
Nanotechnology is simply a convenient shorthand for the emerging ability of humans to conduct Molecular Engineering the way biological systems such as the human cell have done for billions of years. Molecular Engineering, in turn, may be defined as the ability to fabricate molecular devices with atomic precision under external control. This definition separates Molecular Engineering from the thousands of industrial chemical reactions in use today. Chemical Engineers can produce tons of a specific molecular compound that differs from its closest chemical relative by a single atom. But what they can’t do is build up one molecule of that compound starting with individual atoms. In other words, modern chemistry takes a ‘top down’ approach that results in a primitive form of molecular engineering. But the future of this field belongs to the ‘bottom up’ approach whereby individual molecules are assembled in a controlled manner much as one would assemble any other device or machine one piece at a time. It is this ability to manufacture a single molecule as a stand-alone device the way we currently manufacture larger components such as integrated circuits that makes nanotechnology (including biotechnology) different from anything that has preceding it. Biological systems – such as the human cell - evolved their Molecular Engineering capability through billions of years of random variation followed by natural selection. For human beings, Molecular Engineering is the culmination of centuries of reductionist scientific exploration… taking the world apart piece by piece to learn how it works.
In the near future, these two fields will fuse to create the mature field of Nanobiotechnology. Workers in the area of Nanobiotechnology will be able to engineer both living and nonliving molecules with atomic precision which, in turn, will allow nonliving molecules to communicate directly with biomolecules. The degree and complexity of this ‘molecular communication’ will define whether the nonliving molecule is simply a high-tech prosthesis or whether it has crossed over to become an integral component of the biosystem into which it has been introduced.
WHAT IS THE CARBON BARRIER?
To date, we have inhabited a world where materials could be easily categorized as living or nonliving. But what if a molecule composed of nonliving materials (e.g. metals, Carbon nanotubes, or nanostructured silica) was engineered so that is could be fully integrated into a biosystem such as a bacterial or human cell? By fully integrated, we mean that Molecular Engineering has been used to fabricate a nonliving molecule that is recognized and accepted by the living cell. This is not hard to imagine because – after all – atoms are atoms and molecules are molecules. In the end, what the cell ‘sees’ is a molecule with a certain size and shape; perhaps carrying a distribution of charged groups in specific regions while electrostatically neutral elsewhere. If this nonliving molecule has been engineered according to the structural and functional rules recognized by the cell, then the cell will have no reason to question its presence.
Taking this scenario one step further; if the nonliving molecule has been engineered to carry out a specific function within that cell, and that function is recognized as biochemically legitimate by the cell’s own internal chemical logic, then this ‘nonliving’ molecule will be able to masquerade as a living molecule (biomolecule). The design of such molecules is already a subfield of Molecular Engineering called biomimetics… literally the design and fabrication of nonliving molecules to ‘mimic’ biomolecules. But if a molecule designed and fabricated from nonliving materials can function as a biomolecule than why isn’t it a biomolecule?
The answer to this question is complex. So complex that before the field of Nanobiotechnology gets much older scientists and engineers may be required to create one or more additional categories of matter. Within the next decade or two the old binary litmus test of living vs. nonliving matter may no longer apply… at least not for matter organized at the complexity level of molecules.
Is it biological or inert material, i.e. is this molecular piece of stuff biological or nonbiological?! The answer to this question is also the key to defining the Carbon Barrier. Biotechnology has already created a new category of biomolecule: one that is synthesized entirely in the test tube from nonliving precursor molecules. This field is known as Synthetic Biology and synthetic biologists can already build their own atomically perfect versions of Nature’s most important structures. Molecules such as DNA, RNA, and proteins. But Synthetic Biology and Natural Biology (i.e. biological phenomena arising entirely without human intervention) share the same fundamental chemistry. All biochemistry to date is based on and dominated by the chemical reactions and physicochemical characteristics of the element Carbon. The mathematician and philosopher Bertrand Russell even went so far as to call life on Earth the product of “chemical imperialism” with the implicit designation of Carbon as the chemical whose imperialist drive has created all living creatures great and small.
It is this dominance of Carbon chemistry over the world of biology that is the essence of the Carbon Barrier. Conversely, it is the rise of biomimetic Molecular Engineering that threatens the dominance of Carbon and creates the vehicle that will drive humanity through the Carbon Barrier.
INTERMOLECULAR COMMUNICATION BETWEEN LIVING AND NONLIVING MATERIALS WILL BE THE FIRST MILESTONE BY WHICH HUMANITY MAY CHART ITS PROGRESS THROUGH THE CARBON BARRIER.
This web page and its associated sites and blog has been created to chart our progress in designing a true Biomolecule-To-Materials (BTM) Switch… a molecular device that provides specific and direct communication between living and nonliving materials. On pages we will chronicle a classic Gedankenexperiment (German for thought experiment). A Gedankenexperiment provides the means to test a hypothesis or theory that (currently) cannot be performed due to practical limitations. It is important to emphasize that we are using the Gedankenexperiment approach for two reasons:
1. We do not have the laboratories or funds to design and fabricate a true Biomolecule-To-Materials (BTM) Switch in the real world. But it is crucial to keep in mind that such devices are currently being designed and built by others… many others under a wide range of rationales from biomedical engineering to the creation of bioweapons (although the official designation will more likely be biodefense). The Molecular Engineers engaged in this sort of work in the real world are, in general, not concerned with the Carbon Barrier or the global implications that breaking the Carbon Barrier will have for biology in general and humanity in particular.
2. A Gedankenexperiment carried out on the worldwide web offers the opportunity for both the S&T (science and technology) community and other interested folks to participate in both the actual design work and the accompanying discussion of the issues raised by the creation of a BTM switch.
Unlike the sound barrier, or the first nuclear chain reaction the Carbon Barrier does not lend itself to a simple Boolean yes or no type of analysis (Are we through it yet… Yes or No). Many of the researchers closest to breaking through the Carbon Barrier have never considered that it exists while others will never acknowledge its existence… even after we are through it. For those of us outside the S&T community the arguments around the Carbon Barrier will be even more difficult to follow.
The best place to begin is with a discussion of what is meant by ‘chemical communication’. We can see the results of chemical communication all around us but living organisms offer the most dramatic example. Consider the sequence of events by which you came into being. The fusion of sperm and egg kicked off a series of complex and highly coordinated biochemical reactions. Each biochemical reaction was designed by evolution to accomplish a specific task. The completion of each task usually resulted in the creation of a part of your body and acted as a signal to induce the next stage of your development. At some point these developmental processes became large enough to see with the naked eye. But no matter the size each process was ultimately the result of an orchestrated set of thousands of chemical reactions. Each of these reactions, in turn, was the result of a process whereby individual specific molecules recognized and targeted other individual specific molecules: their cognates if you will. This highly specific molecular recognition is the ultimate language of life… but how does it happen?
Biosystems operate via the unique physical chemistry of molecules selected over evolutionary time to perform specific functions: DNA to store and transmit a particular organism’s global schematic (everything from the number of fingers and toes to hair color and blood type). RNA to carry the schematic from its storage vault to the workshop of the cell. Enzymes to carry out the much of the work to build new cells and maintain those already in existence. At this point it is necessary to repeat the mantra that all living creatures are more than just the sum of their genetic code. It is the unique interaction of any individual with its environment that creates an individual life form. But this is just another way of saying that some of our biomolecules have been designed by evolution to accept and process input from the outside world. At the end of the day, molecular communication is still the basis for all that we are. So how do molecules communicate?
Communication occurs via the ability of a specific biomolecule to ‘see’ and ‘talk to’ another biomolecule. Not just any other biomolecule, but its unique target or cognate. Just as you or I can sort through a crowded auditorium to find our spouse or child, subcellular information is transmitted via a series of specific molecular recognition events. Enzyme catalysis is a classic example of molecular recognition. The specificity of an enzyme for its substrate - the target molecule with which it will react - is often so precise that the enzyme can discriminate between chiral versions of the same substrate compound. Chirality is – literally – a molecule’s mirror image. Consider your left and right hands. Barring any major accidents, these hands will appear identical yet they cannot be superimposed, i.e. the left and right hands cannot be arranged such that every part of one is in the exact same position as the other. The catalytic specificity of enzymes allows them to literally sort through the hundreds of thousands of small molecules inside a normal human cell until the target substrate is encountered. Even chiral versions of the substrate molecule are ignored! Only when the exact target chemistry is encountered does recognition and reaction occur.
The easiest way to visualize molecular recognition is to expand the classic ‘lock and key’ model developed many years ago to explain enzyme catalysis. In this model, the enzyme is the key and the substrate the lock. In our macroscopic world, if the a key does not have the exact sequence of peaks and valleys that complement the lock cylinder then it will not turn in the cylinder and the lock does not open. In that same manner – but amplified a million-fold - two biomolecules react only when their unique topographies produce an exact fit on the atomic scale! When the shape of a key and the cylinder it must turn are determined both by the types of atoms in the molecules and the position of those atoms relative to one another… the number of possible shapes and sizes for this lock-and-key system becomes astronomically large very quickly. As a result, the chance of a molecule reacting with anything but its cognate becomes astronomically small. This is how tens of thousands of different molecules in the living cell can carry out their programmed functions.
One simple example is the number of ways to build a DNA molecule. Consider a trivially small strand of DNA just 20 bases long (a ‘typical’ bacterial gene might be a few thousand bases long). The first position in our 20 base strand can be any 1 of the 4 bases: A, G, T, or C. Likewise the same 4 possibilities exist for position 2, position 3 and so on. The single-stranded DNA molecule is like a string of pearls; each base is fixed into its position along a linear sequence. The base in position three cannot be moved without physically breaking the strand. So a molecule with the sequence CAT is physically different in topography from a molecule with the sequence TAC. In addition, your cell always ‘reads’ the information contained in a strand of DNA from left to right so that the molecule that reads as CAT is chemically different from the molecule that reads TAC. One needs to feed a CAT whereas one might hold down a carpet with a TAC (phonetically speaking).
When both the number of things are important (A, G, T, or C) are so is the order in which they appear (TAC vs. CAT) then we can calculate the number of permutations using a standard mathematical formula. Without going into the details, there are 116,280 ways to build a 20 base strand of DNA! Since each of these strands differs from all 116,279 others by at least one chemical subunit none of these strands is exactly like any other either in structure or function.
Now consider protein molecules. While there are only 4 bases in DNA, there are 20 unique amino acids used by biosystems to make protein molecules. The way a protein molecule folds up into its final shape is a function of the linear sequence of amino acids on the strand and, as we have already seen, even a very small biomolecule made up of a string of unique subunits has an enormous number of possible sequences. As a result, no two protein molecules will present exactly the same atomic structure and topography to the outside world. By analogy, two protein molecules designed by evolution to work together will beat these enormous odds and have the exact, complementary topography necessary for molecular recognition and communication.
WHEN MOLECULAR ENGINEERS CAN BUILD THE REQUISITE RECOGNITION STRUCTURES INTO NONLIVING MOLECULES THEN WE WILL HAVE THE COMPONENTS FOR A BTM SWITCH.
We now have a picture why the rise of Nanobiotechnology means the fall of the Carbon Barrier. Molecular communication is based on molecular recognition which, ultimately, is based on the specific physical positions and chemical identities of individual atoms that make up the communicating molecules. The goal of Molecular Engineering is fabricate molecules with atomic precision under external control. If we know the structure of a molecule, which of these structural components are involved in molecule-to-molecule communication, and the chemical role each of these components plays in that communication then it will be possible for Molecular Engineers to reverse-engineer that molecule’s cognate, substrate, receptor, etc.
It is important to realize that many of these recognition processes are quite generic in terms of their chemistry. For example, the hydrogen bond plays a crucial role in many biological reactions. But a Hydrogen bond is nothing more than the attraction of two clusters of atoms for one another based on the willingness of Hydrogen to share its bonding electron in an asymmetric manner with a second atom. The Hydrogen nucleus contains only one proton. So when it is in a chemical bond with an atom such as Oxygen, the electrons in that bond (one provided by H and one provided by O) are pulled closer to the Oxygen creating a slight separation of positive and negative charge. The Hydrogen has the positive charge because its electron is spending more time orbiting Oxygen. Conversely, the Oxygen atom has a slightly negative charge precisely because that same electron is spending more time its orbit. This state is known as a permanent dipole. One molecule (call it X) would have a cognate (call it Y) with the exact geometry so that the negative end of one Y’s dipoles aligns precisely with the positive end of one of X’s dipoles. This H bond helps hold the two molecules together long enough for communication. Of course one H bond would not be enough. Molecular recognition and communication results from structural precision that allows for literally hundreds or thousands of such bonds to be formed.
The point is that electrostatic attraction created by complementary atomic precision is the real method of molecular communication. Going back to our lock and key analogy, the key could be made of metal or it could be made of high impact plastic… so long as it is grooved correctly and will not break under the pressure necessary to turn the lock cylinder. Not all forms of molecular communication are this generic. For example, reactions that create entirely new types of molecules from chemical precursors (enzyme catalysis) will not easily accept an engineered precursor with different chemistry.
But many of the important molecular functions of the living cell involve the transmission of information based on the mutual recognition of two cognate molecules. These functions are excellent candidates for nonbiological analogs fabricated by Molecular Engineering. An example of this type of system is the binding of a hormone on the outer surface of a cell. Hormones, by definition, are signal compounds made by cells in one part of the body that act on cells elsewhere. The target cells have a receptor on the outside that often binds its cognate hormone via exactly the mechanism we have previously described. In fact, the biopharmaceutical industry is largely made up of chemical compounds that look enough like their biological counterparts to either enhance or inhibit some essential cellular function. Many of the early pharmaceuticals were discovered by accident or through a serendipitous observation. As we learned more about the biochemistry of humans and their pathogens molecules were designed and synthesized to intentionally transmit information either to the cell or the pathogen. Antibiotics are often designed to irreversibly bind to their cognate molecules within the pathogen thereby interfering with the pathogen’s metabolism. Another example is Genentech’s Herceptin® (Trastuzumab) which is an Anti-HER2 antibody used in treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer < http://www.gene.com/gene/products/information/ >. By using an antibody, the genetic engineers at Genentech were able to take advantage of nature’s molecular engineering systems. The antibody was not made by human Molecular Engineering but buy biotechnology, i.e. we let cells that know how to engineer antibody molecules do the exact design and production work. But the result was a cognate molecule designed and produced by humans to recognized and bind to the hormone receptor HER2. This Biomolecule-To-Biomolecule switch helps turn of the uncontrolled growth of the target cancer cell.
Now let’s take it to the next level. Once human beings can design and fabricate molecules from nonliving material that can transmit information directly to a target biomolecule we have created a hybrid system that speaks a common molecular language. The specificity of such intermolecular communication creates the possibility of a bidirectional switching device fabricated from a nonbiological component on one side and a biological component on the other. This is the essence of a BTM Switch… a nonbiological key to fit a biological lock!
Once molecular recognition can be achieved between living and nonliving systems it will be possible to hardwire directly into the CPU of life. It is the engineering destiny of Nanobiotechnology to create the first such interface between the living and nonliving worlds. Or, more correctly, the first interface that does not discriminate between the living and nonliving states of matter. Fabrication of the world’s first true Biomolecule-To-Material (BTM) switch will be infinitely more than a landmark in the evolution of human technology. Like the separate days of Genesis, the first nanofabricated BTM switch will be its own monumental act of creation and a crucial step on the path to bona fide living materials outside the realm of Carbon imperialism.
In the history of science, the conduction of signals between living and nonliving materials will be divided into the pre-nanotech and nanotech eras. We are still pre-nanotech, which means that a direct BTM switch has yet to be fabricated. Bioengineering has created synthetic devices that communicate indirectly with living materials. For example, the artificial pacemaker transmits an electrical voltage to the biological pacemaker cells of the heart. In a healthy human, these pacemaker cells generate their own action potential, an electrical waveform of about one hundred millivolts. This may not sound like much energy until we remember that this electrical potential is sustained across an insulating membrane only five nanometers thick. That is five billionths of a meter. So the energy of an action potential is almost 20,000,000 volts per meter. Compare this to the 12,000 volts per meter at a standard wall plug. Healthy pacemaker cells spark the electrical wave that drives heart muscle contraction. When these cells malfunction, an artificial pacemaker may be implanted to take over. Waves of electrical voltage generated at the metal lead of the artificial device cross over to living tissue and initiate normal muscle contraction.
While the pacemaker is a magnificent feat of bioengineering, it does not operate via a true BTM switch. The metal lead of the artificial pacemaker, a small wire, is physically embedded in cardiac tissue and the wave of voltage spreads from the charged tip into the surrounding region. Only pacemaker cells will respond to the artificial voltage wave by initiating a further action potential. So the living system must identify the artificial signal and act upon it. The voltage produced by an implanted pacemaker, like a radio signal, will pass through space unnoticed unless there is an antenna to pick it up. In this case the receiving antennas are individual protein molecules embedded in the membrane of the living cardiac pacemaker cell. Other heart cells feel the electrical signal, but do not respond to it. They may be considered as nonspecific noise in the system. We must flood the local tissue with electricity in order to obtain the desired response. This strategy is extremely effective but does not constitute a direct interface between living and nonliving materials. In the end, the pacemaker electrode does not ‘know’ that the target cells are out there. It will send its signal regardless of whether it is received or not. Likewise, the cardiac pacemaker cells do not know that the charged metal lead is out there, they simply respond to an electrical shock.
A nanofabricated pacemaker with a true BTM switch will feed electrons from an implanted nanoscale device directly into electron-conducting biomolecules embedded in the membrane of the pacemaker cells. There will be no noise across this type of interface. Electrons will only flow if molecular recognition occurs between the living and nonliving materials that are hardwired together. In this sense, the system gains functional self-awareness. Each side of the BTM interface has an operational knowledge of the other.
THE FIRST MILESTONE IN THE ELIMINATION OF THE CARBON BARRIER MAY BE DATED FROM THE FABRICATION OF THE FIRST TRUE BTM SWITCH.
The creation by Molecular Engineering of a synthetic molecular device capable of targeting and changing the state of a biological system via specific molecular information transfer will change the rules of the game forever. Creation of such a device – which we have termed a BTM Switch – will be the first demonstration of human manipulation of biological function via a biorationally designed but nonbiological molecule. An operational BTM switch provides ‘proof of concept’. The concept being that life need no longer be limited to the chemistry selected by natural evolution.
The purpose of this project is to work out the design parameters for the first BTM Switch. We invite the scientific community to join with us in this effort. The design itself will be developed in a transparent, open-source manner at this website. Our model biosystem is the axon of the nerve cell. The purpose of the project is to use the tools of Nanobiotechnology to construct a switch that is capable of sensing and responding to an action potential. The preliminary technical specifications of the switch require:
1. That it be self-contained, i.e. be implanted into the body and become fully operational with no further external intervention.
2. That it sense and respond to the voltage change produced by a single axon’s action potential.
3. That the response be to induce 10 additional action potentials within the target axon then reset and wait for the next transmission of a biologically-produced action potential to repeat the process.
In other words, this BTM Switch will act as a single-axon amplifier. The utility of such a device in the study of neural networks is obvious. Preliminary designs and subsequent modifications will be posted along with reference materials and a blog that will document this effort. We welcome feedback from interested colleagues who recognize the significance of this Gedankenexperiment. We also welcome information about other nanobiotechnology systems under development that would qualify as a true BTM Switch since development of such a switch is a crucial milestone in the race to break the Carbon Barrier.
Best regards, Alan H Goldstein, Ph.D.
*The term Carbon Barrier is the trademark of Dr. Alan H Goldstein and his consulting firm Industrial Nanobiotechnology.