24 Jun When it comes to the secrets of life, proteins are where the action is
Editor’s note: This is Part II of this column on the study of proteins in medical research. Part I can be found here.
Chicago, Ill. – If one can fix the CFTR protein, one has fixed cystic fibrosis even without addressing the fundamental mutation at the genetic level. Moreover, this therapy would not simply be a palliative treatment but would in fact be truly curative. One does not need to completely fix the DNA to cure the disease. It is like making concrete.
One does not have to apply nanotechnology techniques in moving about the constituents of concrete molecule by molecule in order to attain the desired strength and weight. The Romans did it in ways that match (in terms of the result) the sophistication of modern methods. The Pantheon, which is still standing in Rome after nearly 2,000 years, is simple evidence of that.
While not perhaps as fundamental as DNA, nor as glamorously simple, aiming at proteins is likely to be the most fruitful approach to winning the war on disease. After all, this has been the case for thousands of years as medicines using salicylic acid (the core ingredient of aspirin) have been used since antiquity. In the long run, the heyday of genetics will likely be a sideshow to where the real action lies.
Ironically, the study of DNA will be but a supplement to the main feature (an important one to be sure). This will provide further insight into proteins and a richer and deeper list of the products of these genes (namely the proteins that have for the longest time been the targets of our Promethean desire to manipulate life and death).
Proteins also are the target for more sinister applications.
Other than applying massive physical destruction (e.g. overwhelming flames, a large explosion, or a bullet through the head), there are limited ways in which a life can be rapidly extinguished. It is virtually impossible to do this through DNA. After all, DNA is just sitting there waiting for its information to be decoded and translated into proteins.
The victims of Hiroshima and Nagasaki who survived the initial blast (e.g. the massive physical destruction noted above) died after days and weeks even after the gamma radiation flowing about them caused catastrophic damage to their DNA. Many died, but it was not at all quick. Weight for weight, plutonium is considered the most toxic substance known. Its effects, however, take days and weeks to exert.
Apart from physical destruction, other methods of rapid killing involve the pharmacological manipulation of proteins (specifically those involved in critical functions such as breathing, circulation, and the neurological circuits that support these functions). Curare, for example, relaxes muscle and therefore makes breathing impossible by binding to and blocking the nicotinic acetylcholine receptor.
This protein transmits the signal for muscle cells to contract. With no signal, there’s no contraction. The rapidity of paralysis depends on the mode of administration. Intravenous injection (as used by anesthesiologists) results in paralysis within half a minute. If breathing is not artificially supported, death will occur a few minutes afterward.
Of course, medical anesthesia combines muscle paralysis with artificial ventilation along with agents that induce sedation and unconsciousness. Whether one saves a life or kills one, the target is the same: the nicotinic acetylcholine receptor. The end result all depends (in a technical sense) on how that target is attacked and (in a moral sense) on the intentions of the attacker.
Botulinum toxin is another example and a protein itself. It is one of the most toxic naturally occurring substances. It is well known with Botox and is used in near-homeopathic concentrations for wrinkle effacing and cosmetic treatments. The botulinum toxin (of which there are several subtypes) is a multi-chain protein that binds to a protein at the neuromuscular junction.
The neuromuscular junction is the nexus between nerve and muscle in which the signal for the muscle to contract is transmitted via acetylcholine molecules that flow from one side (the nerve side) to the other (the muscle side of the junction). The botulinum toxin binds to a fusion protein: a protein that would otherwise allow acetylcholine containing vesicles on the nerve side to fuse with the membrane and release their contents into the cleft between nerve and muscle.
With botulinum toxin in the mix, there is no fusion of these vesicles. With no fusion, there’s no acetylcholine released. With no acetylcholine, there’s no signal and hence no contraction. The end result is similar to that of curare (though somewhat slower in effect).
One might think that interfering directly with the muscle proteins (for example, the myosin-binding protein in cardiac muscle) might be a good target. In terms of conventional pharmaceutical approaches, there are two problems with this strategy. First, the intracellular location of such proteins limits the possibilities for drugs to reach these targets quickly and efficiently.
Among other functions, the cell membrane is protective and allows foreign elements to enter only sparingly. Second, interfering with only a fraction of muscle proteins is likely to have only an attenuated effect.
An absolute flood of drugs needs to wash over nearly all the muscle constituents and this is neither practical nor quick. Neuromuscular junction elements, therefore, represent effective drug targets. They are extra cellular and the binding to just a few targets amplifies the effect by virtue of the signaling function at such junctions.
Electromagnetic radiation, however, is not constrained by the same limits as pharmaceutical methods. Many forms of radiation pass through the body (and into cells) fairly easily. Certainly ionizing radiation such as gamma rays and X-rays do. Even much lower-energy electromagnetic radiation (such as radio waves) likewise traverses easily into cells.
A ray of electromagnetic energy can easily wash over all the constituents of a cell and an organ. If such radiation could incapacitate critical protein functions, then potent medical and military applications could easily be conceived. Whether the technology is used for life or death depends on the mode of application as well as the intentions and moral constitution of the operator.
Previous articles by Ogan Gurel
• Ogan Gurel: Where are the secrets of everyday life, in proteins or DNA?
• Ogan Gurel: Italian view on invention and innovation
• Ogan Gurel: Socialized risk not confined to subprime mess; healthcare impacted
• Ogan Gurel: Innovation versus invention: Why accelerating development makes sense
• Ogan Gurel: Fostering innovation doesn’t occur in a vacuum
He is also an adjunct associate professor of bioengineering at the University of Illinois at Chicago. Dr. Gurel has a Bachelor’s degree in biochemical sciences from Harvard, earned his M.D. degree from the Columbia University College of Physicians & Surgeons and completed surgical internship at the Massachusetts General Hospital. As a health care technology expert and futurist, Gurel has been a frequent conference speaker worldwide. His particular focus has been on convergent medical technologies, including medical nanotechnology.
In addition to Wisconsin Technology Network, his commentaries have been published in the Wall Street Journal and other print and online venues. His regular blog on life sciences, business and investment can be found here.
This article previously appeared in MidwestBusiness.com, and was reprinted with its permission.
The opinions expressed herein or statements made in the above column are solely those of the author, and do not necessarily reflect the views of Wisconsin Technology Network, LLC. WTN accepts no legal liability or responsibility for any claims made or opinions expressed herein.