Prime Time Replay:
Bruce Lehnert, Ph.D.
on the effects of radiation on DNA
MsgId: *breakthrough(1)
Date: Wed Oct 22 10:29:04 EDT 1997
From: moderator At: 152.163.207.39
Welcome to Breakthrough Medicine. I'm your host, Madeleine Lebwohl, and today I'll be speaking with Bruce Lehnert, Ph.D. of the Los Alamos National Laboratory. Dr. Lehnert will be discussing his research on the effects of radon on the cell. This is going to be an instudio interview right now.BL: Hello, Madeleine. Its a pleasure to talk to you and your audience.
MsgId: *breakthrough(5)
Date: Wed Oct 22 10:36:48 EDT 1997
From: bruce At: 128.165.139.51
Let's make this work
MsgId: *breakthrough(6)
Date: Wed Oct 22 10:38:52 EDT 1997
From: moderator At: 152.163.207.39
You're doing research at Los Alamos on how DNA is affected by radiation. What have you found?
MsgId: *breakthrough(7)
Date: Wed Oct 22 10:42:08 EDT 1997
From: bruce At: 128.165.139.51
Our most recent work in the area of radiation biology has been focusing on radiation effects caused by alpha particles that are emitted by radon and radon decay products. As I'm sure you know, radon exposure is thought to be a major cause of lung cancer.First, for the uninitiated, it may be worthwhile to describe what alpha particles are. Basically, they consist of doubly charged helium nuclei that are generated during radioactive decay. They are considered or classified as what is called high linear energy transfer radiation, meaning that they distribute their energies over short pathways because of their ionization potential.
A long lived dogma has been that alpha particles like those emitted by radon, as well as a variety of other materials, including plutonium, thorium, radium, and polonium that can be contained in cigarette smoke cause DNA damage as they directly traverse cell nuclei. Because of their ionization potential, the damage they induce in cellular DNA is very complex and focal. Our work indicates that direct nuclear "hit" by the alpha particles are not required to induce DNA damage, and, moreover, cells do not have to experience any hits at all for the induction of DNA alterations.
I should clarify that there is little doubt that alpha particles indeed cause direct DNA damage when they traverse cell nuclei, and, in fact, numerous microdosimetric models assume this is how radon can cause its mutagenic and carcinogenic effects. However, we have found that alpha particles can induce changes in DNA in the absence of nuclear interactions via an extracellular mechanism or mechanisms.
MsgId: *breakthrough(12)
Date: Wed Oct 22 10:51:41 EDT 1997
From: moderator At: 152.163.207.39
What is radiation doing when it causes damage? And is the radon found near homes what you're studying? Are you working on developing any protection for the cell against the effects of radiation? Or treatments once damage is done? And do you have any suggestions for lessening effects of radiation on cells?
MsgId: *breakthrough(15)
Date: Wed Oct 22 10:59:16 EDT 1997
From: bruce At: 128.165.139.51
How the DNA damage is mediated by the extracellular mechanisms is not yet clear, but it appears that intracellular reactive oxygen species may be involved. The significance of the work is that the high LET alpha particles can interact with biological fluids and cells to cause the production of factors that in turn stimulate cells to produce enhanced levels of potentially DNA damaging oxygen species, specifically superoxide anions and hydrogen peroxide.Our work was performed in vitro, but if our findings extend to the in vivo condition, it would appear as though the inhalation of radon may lead to the generation of factors that are transferrable from one anatomical location to another. Instead of any particular cell receiving a hit, cells may respond to factors in fluids like the airway lining fluid in the respiratory tract and thereby affect cells indirectly. As well, extracellular factors that are release from cells that do experience hits by alpha particles additionally can induce responses in neighboring cells.
How these results figure into risks associated with indoor radon requires further study. However, it is worth noting that our findings were obtained with very low exposures to alpha particles.
MsgId: *breakthrough(16)
Date: Wed Oct 22 11:02:16 EDT 1997
From: moderator At: 152.163.207.39
Could we talk a little about what an oxygen species is, and why it plays a part in damage? And is there any way of controlling the development of these particles after exposure to radiation?
MsgId: *breakthrough(21)
Date: Wed Oct 22 11:11:57 EDT 1997
From: bruce At: 128.165.139.51
In a recent publication we describe how the induction of reactive oxygen species by the extracellular factors that are generated in response to alpha particles can be blocked by the enzyme called superoxide dismutase, or SOD. SOD catalyzes the conversion of superoxide anions to hydrogen peroxide. By inference, this suggests the possibility that antioxidants may afford some protection against the indirect DNA damaging effects of inhaled radon, but, again, this requires further study. Incidently, I should point out that the inhalation route is not the only pathway by which we can get exposed to radon.In numerous geographical locations, including regions here in New Mexico, radon is present in drinking water. It is, after all, a gas, and accordingly, one would expect that its occurrence in water will follow Henry's Law. Conceivably, what we have uncovered may be involved mechanistically in cancers that may arise from radon-contaminated water. This is, of course, yet another area of investigation that merits further consideration.
MsgId: *breakthrough(20)
Date: Wed Oct 22 11:06:16 EDT 1997
From: moderator At: 152.163.207.39
Is there any research into medications that would inhibit the spread of these damaging particles? A buffer between them that neutralizes them? And do you get any data from conditions that people experience after to exposure to radiation? How else can damage occur from radon? Do you have any thoughts on why it seems so hard to find medications that prevent, or reverse, damage from radiation?
MsgId: *breakthrough(24)
Date: Wed Oct 22 11:18:00 EDT 1997
From: bruce At: 128.165.139.51
As to why it has been so difficult to find simple prophylactic or therapeutic approached for preventing or reversing radiation-induced DNA damage, respectively, we must consider the complexity of the problem.In all honesty, we do not know all of the mechanisms by which radiation induces genomic damage, and even though DNA damage is a known effect, the exact nature of the damage can involve a host of features, including DNA strand breaks, DNA oxidative adducts, etc., as well as other problems at the level of chromatin structure. To "fix" these types of perturbations that can occur concurrently in different places in the genome or as clustered damage in the case of alpha particles is not a trivial pharmacological problem.
Fortunately, we do have an array of DNA repair mechanisms that do the job rather nicely, as indicated by the observation that not everyone who is exposed to ionizing radiation develops cancer. At Los Alamos and elsewhere, we are busy trying to elucidate how these pathways operate. So, what I am trying to convey here is that pharmacologic repair of DNA damage will require so doing in the future. With regard to prophylactic approaches to prevent radiaition-induced DNA damage, I am a firm believer in antioxidants and free radical scavengers.
MsgId: *breakthrough(29)
Date: Wed Oct 22 11:33:26 EDT 1997
From: moderator At: 152.163.207.39
By antioxidants, do you mean broccoli? Do you think eating antioxidant foods helps, or do you need supplements? And are the scavengers medications or foods? You mentioned genomic damage -- what happens to the DNA pool when people are exposed to radiation of all different sorts?
MsgId: *breakthrough(30)
Date: Wed Oct 22 11:36:53 EDT 1997
From: bruce At: 128.165.139.51
I don't claim to be a nutritionist, but Bruce Ames, in my opinion is on tract with his advocacy of fruits and vegetables. For what ists worth, I personally utilize vitamin supplements as well, especially vitamins C and E.More objectively, we do not know what concentrations of antioxidants/free radical scavengers are required to do the job, and, at least with regard to alpha particles, it is not clear that such supplements will necessarily afford protection against the DNA damage that can be induced when cell nuclei are directly hit.
Regarding genomic damage, the question is a very important question in that human individual susceptibility to environmental stresses is an emerging forefront science. That is to say, we know that stresses such as ionizing radiation induce numerous responses, including cell cycle checkpoints, apoptosis, or programmed cell death, senescence, and of course, mutation and cancer.<
MsgId: *breakthrough(26)
Date: Wed Oct 22 11:20:11 EDT 1997
From: moderator At: 152.163.207.39
What are some of the specific research obstacles for finding treatments? Since not everyone gets the same radiation damage, what goes into the variation in people's resistance?
MsgId: *breakthrough(34)
Date: Wed Oct 22 11:55:13 EDT 1997
From: moderator At: 152.163.207.39
BL: All of these end points involve gene products. Genes that code for these products can be variable from one person to another. A polymorphism for example, in a gene that is involved in the repair of DNA damage, can render that gene product more or less efficient in the repair process. For some time now the US department of Energy has funded research to characterize such genes and the DOE is very interested in identifying individuals in terms of their susceptibility based on their polymorphisms.Most recently,the National Institute of environmental health sciences initiated a new effort called the Environmental genome project, where the goal is to identify, at the genomic level,individuals that are at increased risks for enviromentally induced disorders. Hopefully, these efforts will culminate in offering new approaches for individual risk to ionizing radiations and chemical pollutants.
MsgId: *breakthrough(36)
Date: Wed Oct 22 11:58:04 EDT 1997
From: moderator At: 152.163.207.39
Could we talk about what surprised you in your research?
MsgId: *breakthrough(37)
Date: Wed Oct 22 12:00:04 EDT 1997
From: moderator At: 152.163.207.39
BL: Our greatest surprise from our work, was the finding that alpha particles can mediate DNA damage by extracellular factors. And accordingly, the work has demonstrated that the dogma that direct nuclear traversals by alpha particles alone cause DNA damage, is erroneous. Finally I'd like to make a comment or two about some other potential aspects of the work.We are now investigating the possibility that these indirect effects of alpha particles may induce a condition of genomic instability. In this case, we hypothesize that exposure to radon and radon progeny on a more or less continuous basis may also bring about genetic change or changes that induce a condition in which the genome becomes unstable, leading to increased mutations.
BL: On the other hand, we are also investigating the possibility that low level exposure to alpha particles may induce an adaptive response that provides the cell with protection against subsequent exposure to alpha particles. Preliminary evidence suggests that this may be accomplished by an up regulation in the antioxidant status of cells that have been exposed to the alpha particles.
MsgId: *breakthrough(40)
Date: Wed Oct 22 12:07:51 EDT 1997
From: moderator At: 152.163.207.39
Where do you think your research is headed?
MsgId: *breakthrough(41)
Date: Wed Oct 22 12:11:41 EDT 1997
From: moderator At: 152.163.207.39
BL: We will continue to focus on low dose alpha particle exposure, but additionally we are initiating studies to determine whether or not our results also pertain to other forms of ionizing radiation such as gamma rays and x rays. Of significance, we will be pursuing whether or not these extracellular factors we have seen with the alpha particles can induce mutations in the genome.A longer term goal is to determine how polymorphisms in genes that figure into the oxydative processes may underlie an individuals risk to radiation induced cancer.
Thank you for the opportunity to talk to your audience, and to you.
MsgId: *breakthrough(44)
Date: Wed Oct 22 12:14:56 EDT 1997
From: moderator At: 152.163.207.39
Thanks for speaking with me on Breakthough Medicine.Please join me next week when I speak with Mary Fissell, of Princeton University's Shelby Cullom Davis Center for Historical Studies, on the evolution of the self-help book, beginning with guides for women in the seventeenth century.
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