Selenium And Cancer: What the Research Shows:
An interview with Drs. Larry Clark and Lon Baugh.
Part 2: The newest research
Richard A. Passwater, Ph.D.
Last month we chatted with Dr. Larry Clark about his nutritional prevention of cancer research and with Dr. Lon Baugh about the selenium nutritional supplement used in Dr. Clark’s clinical studies. Now we will look at the latest research by Dr. Clark and some more of the considerations in selecting a nutritional supplement for clinical studies.
Passwater: Dr. Clark, in Part 1 you explained some of the advantages of using high-selenium yeast in your clinical trials. There are several advantages, but a major one is that yeast provides an array of organo-selenium compounds. Tell us some more about the advantages related to the whole cell yeast versus a single compound such as selenomethionine?
Clark: Yes, a major factor is the fact that you are getting a complex of organo-selenium compounds versus a single compound. This means that there are more compounds that can follow different pathways in the body and persist in the blood for various periods of time.
Passwater: Using a natural food, rather than a single compound also presents a problem of consistency. Natural products tend to vary considerably due to different growing conditions. Dr. Baugh, is it difficult to grow a high-selenium yeast that is consistent in the types and quantities of various selenium compounds that are present?
Baugh: Yes, it is. You must have a very complete knowledge of the yeast physiology and its growth control parameters to be able to produce a selenized yeast: The salts of selenium at high levels are also toxic to the yeast, such that the selenium must be fed to a growing fermenter at the same rates or matching rate of the yeast growth. If the selenium is fed too rapidly, the yeast will stop their growth. If the selenium is fed too slowly, you don’t get enough of it incorporated to achieve the desired potency. The control parameters of both the growth of the yeast and the feed rate of the selenium being fed must be precisely maintained. You must know the yeast, you must know the equipment, and you must have excellent control mechanisms for the dosing of the selenium.
Passwater: What are some of the other critical steps in the production of high-selenium yeast of high quality?
Baugh: One of the most important things is to grow yeast such that you achieve the highest protein synthesis during the time periods the selenium is available. In addition, selenium competes with sulfur in many of the synthetic processes of the yeast. To achieve the highest potencies and the highest incorporation efficiencies of selenium, you must provide the selenium at levels that are ten to twenty times the availability of sulfur. We were not aware of the selenium/sulfur competition in yeast biosynthetic pathways until the late 1970's. In early 1980, we discovered how to reduce sulfur’s availability while increasing selenium’s availability and these were the keys to our success in the production of high-potency organically-bound selenium yeast.
Passwater: What is the importance of protein synthesis in relationship to organically binding the selenium salts?
Baugh: The protein synthesis is the key because we know that because we know that a significant proportion of the selenium ends up being incorporated into proteins and glycoproteins. We now know that a high percentage of the selenium is incorporated into the alpha-amino acids that contain sulfur, methionine and cysteine, and their conjugates, peptides, and proteins.
Passwater: Let me interrupt you there. I think a lot of people are under the impression that a compound like selenomethionine is simply methionine with a selenium atom tacked on somewhere. They don’t visualize that selenomethionine is the same compound as methionine except that a selenium atom has replaced the sulfur atom. You can’t make selenomethionine by adding a selenium ion to a methionine molecule, or taking methionine and reacting it with selenium or selenium salts. Just as there is no butter in a butterfly, there is no methionine in selenomethionine.
Baugh: Yes, and I have found that mental error even among scientists and physicians which is surprising to me. The selenium substitutes for sulfur and competes with sulfur. The methionine does not contain both sulfur and selenium, it contains one of the two but not both. We also know that selenium competes for sulfur binding sites in all of the organic molecules normally found in yeast that incorporate sulfur, i.e., there are glycoproteins, there are lipids, specifically some phospholipids that are membrane bound structures and some smaller lipids (fats). However, we find a significant percentage of the selenium is incorporated into proteins and/or glycoproteins and most of that we believe is involving five forms of amino acids.
Passwater: This is of particular importance and Dr. Clark’s study is not necessarily a nutritional study. We are not looking at selenium as a nutrient for the body, we are looking at perhaps specific selenium compounds and perhaps specific selenium pathways. This is of particular importance to see that we have an array or spectrum of different selenium compounds that are present, because not knowing which compound is most effective or which ones are even effective anti-cancer compounds (as opposed to compounds that are utilized in nutritional pathways), the anti-cancer action may be due primarily to compounds for which we do not ordinarily monitor or even know about.
Baugh: That is exactly correct. It is also possible that combinations thereof provide the desired anti-cancer action. I think it is very important to remember that the only thing we know for sure from Dr. Clark’s study is that the SelenoPrecise™ product produced the effects of inhibition of cancer development and inhibition of cancer mortalities. This product is special in that it contains a variety of organic compounds which have substituted selenium for sulfur, and in that it is a biological hodgepodge of organo-selenium molecules. Many of these are structural components, by that I mean they have specific functions but they are found in mitochondrial enzyme systems, microsomal membranes and Golgi vacuole complexes so they have both structure and function. It is very important to remember that these sulfur-containing compounds are deeply involved in the structure or the topography of the larger globular proteins, which have enzymatic function and structural function. Therefore, I agree with Dr. Clark that it is critical that the follow-up studies be done with a product that is identical to SelenoPrecise™.
Passwater: We were talking about the critical steps and I wanted to ask you what kind of quality control is required to assure that the process goes as you described.
Baugh: The key steps in the quality control are to begin with a culture which has the capability of producing more than half of its weight as protein and to be able to force that culture to grow at the most rapid possible rates genetically defined by the culture. The control of the process is through biofeedback microprocessors which continuously report data to a computer, whose software has been created to maintain the most beneficial growth environment possible for the yeast. The computer also continually adjusts the selenium concentration to match the increase of yeast cell mass.
It is essential to provide a high oxygen environment at the end of fermentation so that all the baby buds or daughter cells become mature and develop good membranes. When growth and maturation are complete, the yeast goes through a series of washes with clean pure water. The SelenoPrecise™ product requires four washes with 2X volumes of water to remove any trace of remaining waste products or the inorganic salts. The washed liquid yeast is analyzed for the presence of selenium salts and then sterilized and spray-dried.
Passwater: Washing with water doesn’t really sound that expensive but it adds to the cost. Is this because disposal problems with the effluent of the washes or is it just the matter of time?
Baugh: It is a matter of the huge volumes of water. For instance, on a fermentation that is producing 10,000 pounds of dry product you will utilize over 200,000 gallons of water. It is a huge volume of water and then if it contains selenium you have an environmental effect that can be both a major financial strain and a criminal event if you put free selenium salts out into the environment.
Passwater: How does the primary grown strain used by Cypress differ from ordinary baker’s yeast? Are they both common Saccharomyces cerevisiae?
Baugh: There are currently at least 100 different strains of Saccharomyces cerevisiae that are utilized in baking industries around the world. They are all very similar but have distinct differences in their efficiencies or their physiologies. The baker’s yeast strain that is utilized by Cypress Systems was selected because of its very high percentages of protein and its rapid aerobic growth rate. The other yeast strains that could be utilized can be very effective as long as their percent proteins are at least 50 percent or higher. Selenized yeast should have at least a minimum of 50 percent protein and this would basically rule out most brewer’s yeast strains and many of the baker’s yeast strains as well.
Passwater: In what form is the organic selenium normally found in SelenoPrecise™ high-selenium yeast that Dr. Clark has used in all of his studies?
Baugh: I would like to answer that in two parts. Firstly, we know that approximately 60 percent of the organically bound selenium is found in structural components of the yeast, i.e., in the membranes such as the microsomal membrane fraction, the endoplasmic reticulum, the Golgi vacuole, and the ribosomal structural areas. These are both structural components and functional components; meaning they form structures we can see under the electron microscope and they are functional enzyme systems or co-enzyme systems. Approximately 60 percent of the organically bound selenium is in physical structures that are involved in synthetic processes or energy production. The mitochondrial fraction contains a large quantity of the organically bound selenium. There is also a supernatant with soluble proteins and these may simply be in transport from a vesicle to a membrane. Some of these are very large molecules that are agglomerated into structural components. They have secondary and tertiary structure, which is where the sulfur- containing amino acids can affect the topography. We find the organo-selenium molecules in the peptides, as we mentioned earlier, that substitute for sulfur, but also in the membrane-bound and non-membrane-bound lipid fractions, the glycoprotein fractions that are involved in the cell wall and the structural component of the outer surface of the yeast. So it is a complex biological system.
Passwater: Wouldn’t it be important to identify the specific protein binding sites of the selenium?
Baugh: Yes, this work is currently underway in several laboratories and is also being aggressively pursued in Europe as part of the new study. To be able to understand the specific molecular functions involved in inhibition of tumors and inhibition of tumor formation we need to know the exact biochemistry involved. It is a very complicated issue and it is going to require a great deal more work.
Passwater: Earlier you implied that some selenium yeast products display significant levels of "free" inorganic selenium salts and large batch- to- batch variations in nutrient content. In clinical studies it is very important to have a consistency from batch to batch of ingredient or compound being studies. With natural compounds this desired level of consistency is often difficult to achieve due to many variations. Dr. Clark has reported that with SelenoPrecise™ yeast the consistency from batch to batch has been very good. What have you done to achieve this consistency?
Baugh: This speaks very directly to equipment available in the fermentation process. By that I mean the SelenoPrecise™ products manufactured by Cypress Systems are grown in fermenters which contain complete computerized control over the feed rates, the oxygen that is available, the pH, the levels of temperature and respiration. All of these are controlled by computers on a very tightly controlled program. These software programs control the selenium feed at exactly matching rates to the growth rates in the yeast. This expensive equipment adds to the production costs, but it provides the rigorous quality control needed for the FDA standards of products used in clinical studies. The SelenoPrecise™ product is manufactured under a very precisely controlled, automated fermentation system which allows us to match exactly the growth rate of the yeast to avoid toxicities, excesses, or low efficiencies of incorporation.
Passwater: Dr. Clark, how important is batch-to-batch consistency in clinical trials?
Clark: It is important to be able to demonstrate the reliability of the material being tested in order to establish the validity of your results. It is crucial that there is little batch to batch variability in the product that you are using in front of a trial. We started our study in 1983; we are now in 1998. That is almost 15 years and we have monitored the blood selenium levels to look for the biologic availability of the selenium and what we find is very constant bioavailability of the selenium that we get from this yeast product.
Passwater: Dr. Baugh, you told us why you feel that SelenoPrecise™ yeast shows minimal batch-to-batch variation? How can we be sure?
Baugh: Cypress Systems provides a complete Certificate of Analysis on each batch produced. Of all the batches produced in 1997, there was a +/- five percent variation in selenium concentration. The reason we have that accuracy is due to the automated control systems during the growth of the yeast. SelenoPrecise™ yeast is certified to be at least 98% organically bound yeast with no inorganic selenium present and this leaves little room for variations in batches.
Passwater: Well, Dr. Clark, that helps explain why chose high-selenium yeast for your studies and why you have been so insistent on using this type of selenium yeast in his clinical studies. Now let’s get back to your studies. Have you been able to extract any other information from the data collected during your cancer study?
Clark: We have very interesting data that we recently published in the British Journal of Urology looking at what is the effect of selenium on prostate cancer. The article is entitled "Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial." (British Journal of Urology 81:730-734;1998) It is really the same data that we published in the JAMA article but it is more detailed looking at stage, rate of disease, whether it is local or advanced, and how selenium effected these parameters.
Passwater: How did it?
Clark: It affected them just like you would expect a compound that has cancer-preventive activities would. It affected early-stage disease more effectively than late-stage disease. It affected the well-differentiated tumors more than the poorly-differentiated tumors. The interesting effect with that was that it was almost equally effective in older versus younger people which is intriguing since that means it is never too late to start taking a selenium supplement if you are concerned about your health.
Selenium treatment was associated with a significant (63%) reduction of prostate cancer. There were 13 prostate cancer cases in the selenium-supplemented group and 35 prostate cancer cases in the placebo group (relative risk = 0.37, P=0.002). When we restricted the analysis to the 843 patients who originally presented with normal PSA levels (less than four nanograms per milliliter), only four cases were diagnosed in the selenium-supplemented group and 16 cases were diagnosed in the placebo group after a two-year treatment lag (relative risk = 0.26, P = 0.009). There were significant health benefits also in terms of significant reduced total cancer mortality, and the incidence of total, lung and colorectal cancers.
Passwater: Is the data collected for this article from the same timeframe as the original 1996 JAMA article?
Clark: Yes, it is the same timeframe.
Passwater: Have you done been able to look at data collected two years later since the publication of the Nutritional Prevention of Cancer study we published in JAMA in 1996.
Clark: We are looking at that information now and preparing a publication for the Journal of National Cancer Institute. Essentially we are seeing the same effects. It is not quite as strong but that is because we have a lot more data and we are doing what is called an "intention to treat" analysis which means that whoever is assigned to take the supplement gets counted in the analysis. We are not counting just people who actively take the supplement.
Passwater: So essentially in this study, you have looked at two years more data from the same people.
Passwater: The 1996 study was terminated early because the ethics and safety committee that oversaw your study detected that the groups had markedly different cancer rates, therefore they insisted that the study be halted, and the "code" be broken to see which group was which. If the supplement happened to increase cancer, then ethically it had to be discontinued. However, in the case, the selenium so significantly reduced cancer that it would unethical to withhold the selenium from the other volunteers. Little additional information could be obtained, and the other volunteers were owed the right to take the supplement and be protected as well.
Were you able to follow the volunteers who were on the placebo throughout the blinded part of the study and then were given the supplement after the study was stopped?
Clark: We are anxious to do that, but it is really too early to say anything about that. I think the next two years — there is about a year or a year and a half latency it looks like in the time between when you start taking the supplement and when you can see the effect. It has been about a year and a half to two years now.
Passwater: Would that latency period be the same for all types of cancer? Wouldn’t some cancers diverge from the baseline earlier than others?
Clark: It appears that it is related to how fast the cancer grows. It is shorter for the fast-growing tumors and longer for the slow-growing tumors. Again, that adds to the biologic plausibility of what we are observing.
Passwater: Are you planning any similar studies
Clark: Yes, we have just recently received word that we are getting funded from the National Cancer Institute for a five-year study on patients with early prostate cancer to see if selenium affects the progression of their disease.
Passwater: Is this the "Watchful Waiting" study?
Clark: This is the watchful waiting protocol where we will be examining the number of different doses of selenium to see how they are affected on the velocity of prostate specific antigens (PSA).
We have targeted three prostate protocols:
1. We have already received funding for the watchful waiting protocol.
2. The negative biopsy protocol which is patients who have a high PSA, have been to their urologist and have been biopsied, but in whom the biopsy was negative. These patients have a very high chance of being diagnosed with prostate cancer in the future. We figure that now is the time to intervene. Perhaps we can actually lower their incidence of prostate cancer as well as look at mechanisms that might be affected by selenium supplementation. This is a fascinating protocol.
3. The third one in the series looks at people who have been diagnosed, who are scheduled for prostatectomy and gives them selenium in the period between diagnosis and prostatectomy. We want to see if there is any change in some of the cell enzymes in the prostate that might effect their risk of progression in the future.
Passwater: When do you think you will have results from any of these studies?
Clark: The watchful waiting trial is designed as a five-year study. We may have results within a year or so after we start, depending on how fast we are able to get patients on the study..
Passwater: Thirty months from now?
Clark: Probably something like that. You have to get them enrolled, you have to see the results, and then you have to publish the results.
Passwater: When your dramatic 1996 study was published in JAMA, the skeptics tried to downplay the importance by saying that this was only one study and that more studies would be required before they would recommend that the public take selenium supplements. Your study was the first study in a well-nourished Western population using commercially available selenium supplements. But there were other studies in China that give support to your findings.
Clark: Researchers have done a couple of studies, but the problem with this second group of studies -- which I was originally involved in designing -- is the lack of quality control. There are methodological issues that limit our interpretation of the results. The results are what we would have expected but methodological issues make it difficult to accurately interpret the results.
Passwater: Even though there are supportive clinical studies, dozens of epidemiological studies, hundreds of animal studies and mechanistic studies, skeptics still insist on larger clinical trials to confirm your 1996 findings. I know that you have been working on this. Tell us about your new international study, "Prevention of Cancer with Selenium (PRECISE) in Europe and America" which you are planning.
Clark: I think it very appropriate when you have a study result like this ... with the implications that it has for the public health ... that it be repeated. So we are planning a large general population trial to replicate the MPC trial. We are designing that with colleagues in six countries. It will have a total of 52,500 subjects , and it is designed to replicate the results and provide a definitive answer. There will be enough power to detect differences as small as 10 percent in total cancer incidence.
Passwater: What countries will be involved?
Clark: The U.S., Finland, Sweden, Denmark, Holland, the UK.
Passwater: What can people do to help you get these studies under way? How can we help you?
Clark: We are looking for donations that would help us start the pilot studies in these countries. As an example, Solgar Vitamin & Herb Company, Inc. has funded our organizational meetings and Cypress Systems is providing their SelenoPrecise™ yeast and placebos for the study at no charge. We are making application to the National Cancer Institute for funding but that is a slow process and certainly by no means guaranteed. The likelihood of success there is enhanced if we are able to demonstrate that we are doing the project, so in each country we are looking for support to start pilot studies. Those cost about $150,000 a year to run in each of the countries.
Passwater: This pilot study phase is actually assists in the grant application because it shows the effectiveness of not only the mechanism of setting the test up but also the providing of the intervention agent being the selenium and the tablet and it shows the whole mechanism of the study so that as you in each of these countries begin the pilot study phases then you are more easily to go to he funding institutions and say there are some preliminary results but as importantly we are able to put together the organization that will eventually manage the population the size of 52,500 people.
Clark: We can do the studies. In fact, we have the best investigators available in each of these countries so there is really no question when you come down to the investigators credibility or their CVs. They are the best people there. In Finland we have the people who ran the large ATBC study on vitamin E and beta-carotene; in Sweden we have the chairman of the epidemiology department at the Karolinska Institute where the the Nobel prizes come from; in England, we have the Medical Research Council’s clinical trial group working with us; in Holland, we have a group from one university which has a cohort study of 150,000 people. All of these people have tremendous expertise and experience in recruiting patients, managing patients, and doing the long-term analysis that is necessary for these types of studies.
Passwater: At this time, you can’t predict when you might have these needed results because you are not fully funded yet.
Clark: That is correct. We hope that if we are successful in the fund raising, and I should say the ICARE which is International Cancer Alliance for Research and Education has set up a targeted research funding for this project so if people want to give money they can send it to us with a check made out to ICARE and we will forward it to them and this is a way to really target your cancer research money so that you know what it is going for. We hope to start the first studies in Denmark in December. That is our target.
Passwater: If you were able to get funding as needed, when would you expect to have an answer which may be the definitive answer to take care of cancer prevention for all time?
Clark: The studies planned for this five-year study in six calendar years if it goes full length. I personally think that it probably would be stopped early. So in fact, in six years, hopefully we could have an answer.
Passwater: Thank you both for sharing your knowledge and plans with us. Indeed, this study can change the world with selenium.
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