Speaking of Radicals Part I: Back to the Basics
by Richard A. Passwater, Ph.D.
It has been exciting to see the large number of books and articles written for the general public grow in recent years. However, it is somewhat disturbing to see even our fine weekly news magazine sometimes butcher their simplified explanations of free radicals and antioxidant nutrients. In case you have found some of these distortions confusing, I thought that it would help if I called upon an old friend to help explain free radicals and antioxidant nutrients. Although we corresponded in the early 1970's, we did not actually meet until many years later.
Dr. William Pryor has been the leading expert on free radicals in biology since the 1960s and has been explaining these subject to scientists and writers alike for these many years. In 1966, when I first had a need to study free radicals beyond that taught as "Advanced Organic Chemistry" and what could be gleaned from the meager existing scientific literature, I turned to Dr. Pryor's new book.
Since both Dr. Pryor and I have very busy schedules, it was no easy task to find enough time to obtain these special explanations for you. It took more than two years. Part of the following interview was conducted while horseback riding and hiking up Big Mountain, near Whitefish, Montana, part while panning for gold in the Sonora Desert, part while cruising to Bahamas, and in between sessions at various scientific symposia. Yes, in order to expand our understanding of the travels of electrons through our bodies as part of the life process, it helps to have a mind not encumbered with routine thoughts. Getting out into nature can be hard work, but you deserve the most thoughtful answers to your questions.
Dr. William A. Pryor is the Director and Boyd Professor of the Biodynamics Institute of Louisiana State University in Baton Rouge. He has published over 500 scientific reports and 25 books. He has served as editor of the leading journal in the field, Free Radical Biology % Medicine and the book series Free Radicals in Biology.
Passwater: Dr. Pryor, you became "THE" free radical expert in the 1960s. At that time, I had become interested in free radicals in biochemistry as a result of my experience and publications in fluorescence spectroscopy and my laboratory studies on cross-linking agents and the aging process. I had been investigating the aging process since 1959 by doing in vitro experiments on UV-induced cross-linking of proteins in gelatin gels. After I included fats in my experiments, I became very interested in free radicals and lipid peroxidation. By the mid-1960s, I began in vivo studies with small laboratory animals. At that time, there was little organized in-depth knowledge of free radicals and there were no computerized compilations of the scientific literature. Research areas were more fragmented and it took years longer to come across related publications from other fields.
That's how I became interested in free radicals and I am grateful to you for your book and other discussions through the years. What caught your interest in free radicals? Why weren't you focusing on something else?
Pryor: When I became a faculty member, I wanted to work in a field that wasn't overrun. When I became an academician there were two very well known English chemists, Professors Hughes and Ingold (Ingold was knighted, so now it's Sir Christopher Ingold.), and several American chemists (one of them was a UCLA professor named Saul Winstein) who were studying ionic reactions. That was probably the most popular field for faculty members to study when I became an academician. So I decided that was exactly what I didn't want to do -- I didn't want to be a member of that herd. I wanted to do something different that would be in a more unique area.
Passwater: Are you saying you were a radical?
Pryor: I wanted to go up the down staircase and I was fortunate enough to start my career for a chemical company that gave me a great deal of freedom. They were interested in sulfur as an oxidant -- sulfur is right below oxygen in the periodic table and behaves a lot like oxygen. It turned out that sulfur oxidation very often involved free radical reactions, so I became interested in free radicals. I realized that there was no book that introduced free radicals to beginning students. There was an excellent 1957 monograph written by a Columbia professor named Cheves Walling called "Free Radicals in Solution," but it was about 700 pages long and was very difficult reading for students. So I wrote a book which was published by McGraw-Hill Book Co. in 1966. It reduced radical chemistry down to its skeleton and provided students with a way to understand how free radicals worked. In other words, whenever they would hear about a new free radical reaction, they would have a framework into which they could put that fact, and to understand how radical chemistry worked.
That book (Free Radicals; McGraw Hill Book Co., 1966) was used in a lot of universities to teach free radical chemistry to young students.
Passwater: Now in those days there was very little research with free radicals in biological systems. Dr. Denham Harman developed the free radical theory of aging in the mid 1950s but very few other scientists were studying radicals. Drs. Al Tappel and Lester Packer come to mind, but there were very few. Now there are thousands.
Pryor: After my book "Free Radicals" was published, I thought I would be an organic free radical chemist for the rest of my life. That book was published in 1966 but in 1968 I was invited to speak at a conference on free radicals in biology organized by the American Institute of Pathology at the Federation meeting in Atlantic City. When I got the phone call to speak I said you have the wrong guy because I don't know anything about free radicals in biology -- I am an expert on organic free radicals. They said that was just what they wanted. They wanted someone to teach them about free radicals. Now free radical biologists are very well educated about free radical reactions, but 1968 was essentially the beginning of that field.
I went to that meeting and gave an introductory lecture on how free radicals worked, but I rapidly realized that what everybody else was saying was a heck of a lot more interesting that I was saying and I had better find out something about free radicals in biological systems. So I expanded my reading of the scientific literature on the subject and wrote a review article for Chemical and Engineering News which they made into a feature article, called "Free Radical Pathology."
Then I started a book series called "Free Radical Biology." In 1974, when I was organizing the first book for that series, the only scientists I could find were those doing radiation biology -- the effects of radiation on biological systems. But by the sixth volume of that series, I was inundated with scientists doing all kinds of interesting free radical biology. In fact, if you look at the six volumes of that series you can see the evolution of free radical biology from rather esoteric things that aren't really of concern to the practicing physician to interesting disease processes like arteriosclerosis, heart disease, and cancer. You can see why the explosion in interest in free radical biology has occurred.
For example, it was thought for many years that the most potent effect vitamin E would have would be as a anti-cancer agent. However, it appears that vitamin E is going to have a more important effect in reducing heart disease, than in protecting us against cancer. Coronary artery disease appears to begin by oxidation of the LDL particles to a fat-rich cell called a foam cell that builds up in arterial walls and produces the occlusion of the artery.
Similarly, nitric oxide is interesting. It was always though of as merely as a toxic component of smog. It's a free radical, but not a very reactive one. My group had been studying nitrogen dioxide, which is the more reactive nitrogen oxide in smog. Then it was discovered that nitric oxide is produced in many types of cells in our body and controls all manner of reactions. It controls smooth muscle cell contraction, for example. When heart victims take nitroglycerin, it is because it releases nitric oxide which causes the muscles in the artery bed to relax and reduces blood pressure.
Nitric oxide control also is involved in penile erection, and this is the first new lead in some time in the treatment of impotency. Nitric oxide is a key component in one nerve cell transmitting an electrical impulse to the next. So, here in just a few short years we have gone from nitric oxide being a relatively uninteresting toxic component of smog to being a key component in biology.
Drug companies are actively involved in synthesizing new compounds that will release nitric oxide, compounds better than nitroglycerine for example.
Passwater: The field of free radical pathology is rapidly expanding into new fields of study. You must have some measure of this by the frequency of which free radical research is quoted since you are the editor of the journal Free Radical Biology in Medicine.
Pryor: Yes, I edit a journal called Free Radical Biology in Medicine. I am a co-editor with Dr. Kelvin Davies who is head of biochemistry and molecular biology at the Albany Medical School in New York. Dr. Davies and I started this journal -- I started the review portion of it and Dr. Davies started the fundamental scientific portion of it -- about ten years ago.
The Institute for Scientific Information, which does computer ranking of the importance of scientific journals based on the frequency with which other scientists cite articles in those journals, now finds that we are in the top twenty journals in the field of biochemistry and molecular biology -- there are almost 200 journals in that field. Three years ago we were in the top 50 and we have come up to the top twenty very fast. That's because we've been careful to only publish high-quality articles in our journal, but also it is because of the enormous interest in the field of free radical biology.
I used to tell my students that they could very easily do a literature search by coming to my office and I would tell them the most important person in that field and I had a file on that person. I filed everything by author and we could do a complete literature search in the five file cabinets I used for this. Soon, however, my students then began doing computer searches and turning up names I had never heard of doing things that were vitally important. I rapidly began to realize this field had outgrown my knowledge of the people in it.
The field has mushroomed to the extent there are so many bright young people flooding into the field, M.D.'s and Ph.D.'s doing research on all manner of conditions and diseases, that it is now beyond any one person's ability to know and understand the entire field.
Passwater: It just goes to show how little science actually does know about the chemistry of life. We have known about nitric oxide for over a hundred years, but we had no idea that it was a neurotransmitter or hormone until a few years ago. It was just two years ago that Science magazine called it the "Molecule of the Year." It is increasingly appreciated as a physiologic messenger and a major regulator in the nervous, immune and cardiovascular systems. We are constantly learning of the effects of free radicals and now we have a free-radical hormone.
Let's get to the basics. What are free radicals?
Pryor: All that a non-chemist interested in this subject has to understand is that a free radical is an active part of a molecule. Readers who wish a basic, but more technical description, can define a free radical as merely a chemical species with an odd number of electrons.
Readers who have had basic science or chemistry courses probably are familiar with drawings of atoms with various "shells" or layers of electrons. These electronic shells consist of one or more electron orbitals. An electronic orbital is merely a region in which there is a high probability of finding an electron. These orbitals (or regions) are determined by the structure of the species, but a common feature of all electronic orbitals is that they hold a maximum of two electrons.
Passwater: Those definitions of a free radical are certainly adequate for the lay person to understand what free radicals are and how they may damage the body. However, since we also have quite a few readers who are biochemists can you elaborate a little more? I am sure that our non-chemists friends will bear with us for just a moment.
Pryor: Chemists use even a more technical definition of a free radical. The lay person doesn't have to understand "how" free radicals interact with other chemical species, nor do they have to predict the energy used or released in such interactions. This is the job of chemists, and we need more precise definitions and understandings.
It is helpful for chemists to consider a free radical as any chemical species having one or more "lone" or "unpaired" electrons. When an electron is by itself in an orbital, there is "extra" energy available due to the magnetic field resulting from its spin. Normally, two electrons are coupled or paired in an orbital and since their spins are in the opposite direction, their magnetic vectors cancel each other.
The reason that the more basic definition is accurate is that all atoms and molecules that have an odd number of electrons must have at least one electron that is in an orbital by itself. However, this basic definition doesn't take into account such things as di-radicals, which are chemical species having two, one or unpaired electrons, and atoms of the many elements, which are free radicals because they contain lone electrons in orbitals even though the total number of electrons may be even. All chemical species with an odd number of electrons are free radicals, but there are some free radicals that have an even number of electrons, but generally speaking those exceptions are not the free radicals we generally deal with in biochemistry.
A few free radicals are stable molecules; nitric oxide, which we were just discussing, is an example of a stable molecule being a free radical. The nitric oxide molecule has an odd number of electrons so it is a free radical.
I hope that all of these technicalities don't confuse your non-chemist readers.
Passwater: If it does, all they have to do is remember your basic definition that a free radical is the reactive part of a molecule. Since you have given us a non-technical definition of a free radical, would you also give us a non-technical explanation of how free radicals can be so destructive in the body and be involved diseases?
Pryor: When you have a free radical produced in a chemical system you generally get a propagation of damage. Envision a situation at a dance hall where you have all couples dancing and then you admit a lone bachelor -- what used to be called a "stag." Now this lone male is "reactive" -- he really wants to dance -- so he reacts with "i. e., cuts in on" a dancing couple. So now he has a partner to dance with but another odd man is produced. Whenever you have an odd species and you throw it into a collection of even species, there will always be odd species. In the case with a free radical, which has an odd number of electrons, you will always have some chemical species with an odd electron present until another free radical comes along and couples with that first free radical to make a stable species with an even number of paired electrons. So in the dance hall analogy, it would take another woman, who would then partner with the odd man, and then you would have all pairs again, and the dance would be uninterrupted by this propagation of "cutting in."
Free radical damage propagation and "dancing uninterrupted" propagation are similar because electrons also have a property analogous to the "sex" factor of our dancers. AS we discussed earlier, electrons spin about their axes, like the Earth spins on its axis to give us day and night. Electrons also travel about the nuclei of atoms or travel in orbitals in molecules much like the Earth travels around the Sun to give us yearly seasons. So electrons in chemical species have spin and travel in orbitals. We describe their spin vector property in Quantum Mechanics as being either "down" or "up." It is much like the concept of being either "positive" or "negative," and somewhat akin to our dancer analogy of being either "male" or "female."
In order to pair up, free radicals must have opposed spins. In our dancers analogy we used opposed sexes to represent this capacity to pair up. In some circumstances, free radicals can keep track of their spin so that two free radicals with an "up" spin cannot pair. It would take a free radical having its extra electron with an "up" spin and another free radical having its non-paired electron with a "down" spin to form new stable species. So in the sense having ladies and men dancing and having a spare man propagating "damage" and then taking a woman coming in to even things out in a way makes chemical sense.
Passwater: In quantum mechanics, we describe the electrons within a molecule or atom in terms of four quantum numbers. Each electron differs from the other electrons in the atom or molecule by a given amount of energy. The smallest difference in energy between electrons is due to their spin. As you said electron spins can be described loosely as being "up" or "down." Earlier you mentioned that when electrons in an orbital are paired and thus spinning in opposite directions, the forces of the magnetic fields generated are neutralized. When there is a lone electron, the molecule or atom will have a magnetic vector and is said to be "paramagnetic."
People sometimes confuse radicals with ions. Ions are electrically charged due to either an excess of electrons or protons. Radicals have magnetism due to the lone electron's spin.
I have enjoyed your analogies for almost forty years now. Chemists have the extensive background to understand orbital theory and quantum mechanics, but it is indeed an art to be able to quickly explain complicated concepts to those who haven't had the opportunity to study the appropriate background. This is why the press used to come to you for background explanations -- it wasn't only because you were an "authority," it was because you were the great communicator.
Dr. Pryor, let's pause here and resume the discussion of various types of free radicals in Part II, and we'll save antioxidant nutrients for part III. I am going to have fun and see if you can come up with even more analogies to explain more about biologically important free radicals.