Just why is ‘pioneering’ cancer treatment so expensive?

A heartstring-tugging appeal in the NZ Herald doesn’t tell the full story.

Jesse Bessant is a little boy from Auckland with a very rare brain tumour. He has a ganglioglioma, a tumour that arises from ganglion cells in the central nervous system. As these tumours are very slow-growing, and with the location of his tumour (close to his brain stem) making surgery very risky, Jesse’s doctors have advised a ‘wait and see’ approach. However, the Bessant family have opted instead to try the Burzynski clinic in Houston, Texas, where Dr Stanislaw Burzynski offers his ‘pioneering’ antineoplastin treatment.

The catch? It’s going to cost the Bessants $375,000 to join one of Dr Burzynski’s clinical trials. The family’s fundraising appeal was covered by the NZ Herald in early March under the headline: “Hope for toddler with rare tumour”.

So what are antineoplastins and why is a clinical trial at the Burzynski clinic so expensive? Let’s start with those ‘pioneering’ antineoplastins. Might they be the next big thing in the treatment of cancer? I’m afraid to say that this is unlikely, as it turns out that Dr Burzynski has been trialling antineoplastins for over 35 years and has never produced strong evidence that his approach actually cures patients or increases their chances of long-term survival.

In fact the results of his trials don’t seem to have been published in the peer-reviewed medical literature and the American Cancer Society has gone so far as to recommend that people don’t spend their money on antineoplastin therapy. Dr Burzynski coined the phrase to describe a group of peptides that he identified first in human blood and then in urine and which he claimed to be “natural, non-toxic compounds that cure cancer”.

It turns out that the peptides can also be made by the body metabolising the drug sodium phenylbutyrate, which is how Dr Burzynski has been administering them for several decades now. Rather alarmingly, each 500 mg tablet of sodium phenylbutyrate contains approximately 62 mg sodium, meaning there is considerable risk of side effects including lethargy, weakness, irritability, seizures, coma and even death.

So if antineoplastins are just the by-product of sodium phenylbutyrate, why are Dr Burzynski’s clinical trials so expensive? After all, patients don’t usually have to pay hundreds of thousands of dollars to join a clinical trial. Sometimes they might even be reimbursed for taking part! It turns out that Dr Burzynski doesn’t just treat patients with his ‘antineoplastins’ anymore. Instead, he seems to be exploiting a very legitimate trend in real cancer therapy, often referred to as personalised medicine. Here patients are tested for particular disease markers which have been shown to respond to specific therapies. Orac, of the Respectful Insolence blog, has described Dr Burzynski’s “Personalized Gene Targeted Cancer Therapy” approach as “throwing everything but the kitchen sink” at the tumours. In fact, Dr Burzynski’s personalised therapy is part of a complaint against him by the Texas Medical Board, which is currently awaiting a hearing date. The complaint describes Dr Burzynski’s treatment of a patient with metastasised breast cancer, which included prescribing sodium phenylbutyrate with another four very expensive immunotherapy agents, none of which are approved for the treatment of breast cancer, and in combination with a chemotherapy agent.

In fact, it also transpires that Dr Burzynski owns the pharmacy that supplies the drugs he prescribes. His pharmacy is also accused of overcharging for drugs. A former patient, Lola Quinlan, has filed a lawsuit, claiming Dr Burzynski swindled her out of nearly $100,000 by using false and misleading tactics, including charging $500 per pill for drugs that could be bought elsewhere for a fraction of that price. And as well as the cost of drugs, there are his consultation fees, listed on one potential patient’s blog as:

  • Review of medical records prior to commencing treatment – $500
  • Initial consultation appointment – $1,000
  • “Genetic Tumor Markers” test – $4,000
  • Monthly treatment fee (with treatment suggested to last 4 to 12 months) – $4,500 – $6,000

All of which might explain why Dr Burzynski lives in a mansion with his initials in gold on the gates! But none of this was covered in the NZ Herald article. Don’t those being asked to donate deserve to know where their money is going? Instead, my emails to the journalist remain unanswered and Letter to the Editor unpublished. And the Bessant family continue to raise funds to send their child to be treated by a man who is accused by the Texas Medical Board of “unprofessional or dishonorable conduct that is likely to deceive or defraud the public or injure the public”. Pioneering? More like profiteering, if you ask me.

Bioresonance therapy for smoking – miracle cure or con?

A therapy marketed as a guaranteed way to stop smoking appears to lack a sound theoretical basis and to have little experimental support.

As health researchers in the field of tobacco smoking cessation our aim is to find effective ways to help people quit smoking, and to improve access to effective smoking cessation treatments. The New Zealand government is currently investing heavily in policies that support such actions.

Proven therapies for helping people to quit smoking

When people decide to quit smoking without any assistance (ie by going ‘cold turkey’), they have to cope with the loss of all the dependency-forming aspects of smoking at once. Consequently, approximately 90 percent of people who try and quit without any assistance fail1.

Most smoking cessation support strategies involve the use of nicotine replacement therapy (NRT). With NRT, people stop smoking and replace the ‘dirty’ nicotine they would normally get from smoking a cigarette with ‘clean’ nicotine delivered in a lower concentration (such as via patches, gum, inhaler, and lozenges) and in a safer way (that is, without the harmful constituents present in tobacco smoke). In this manner smokers can deal with cravings and other unpleasant nicotine withdrawal symptoms, thus making it easier for them to quit.

Research evidence for the use of NRT has shown it to approximately double the chances of long-term quitting(2-3). When combined with behavioural support, pharmacological support is even more effective. Good quality evidence from placebo-controlled randomised trials indicates that behavioural support can improve the chances of successfully quitting by two to seven percent(1,4-6). Behavioural support (eg counselling people about dealing with cravings and urges, encouraging them to persist, helping them to consider the benefits and possibilities of being an ex-smoker) can be delivered face-to-face, by telephone or through the internet.

In New Zealand, the cost of NRT patches, gum and lozenge is subsidised ($5 for four weeks’ supply). Subsidised NRT is available to smokers coming into contact with cessation support services (such as the national telephone- based Quitline services and the Maori cessation service Aukati Kai Paipa), which also offer behavioural support. The Government has plans to further improve access by promotion of low cost NRT through primary care (ie through a general practitioner).

Unproven therapies

Despite good access to inexpensive, effective treatment to assist in quitting smoking, unproven and costly therapies are still actively promoted in the media in New Zealand. A recent review of the scientific evidence for the effectiveness of alternative smoking cessation interventions reported that acupuncture, St. John’s Wort and NicoBloc are probably not effective(7). There was insufficient evidence to determine the effectiveness of Allen Carr’s Easyway Programme and Nicobrevin, and hypnosis did not appear to be any more effective than simple advice to quit.

Bioresonance therapy

Another therapy being marketed in New Zealand as a “guaranteed way to stop smoking” is bioresonance therapy. This therapy appears to have originated from Europe and according to its proponents has been in use since the 1970s. Claims made on a website (www.stopsmokingclinic.co.nz) state that “Bioresonance therapy works through the body’s energetic system” or more specifically, “the technique uses biophysics – the physics of the body”. According to the above website it works by eliminating nicotine from the body and thus takes away the cravings for cigarettes.

“All living cells give off energy as weak electromagnetic waves similar to brain waves used in orthodox medicine (EEG scans). Bioresonance therapy, using the Bicom machine, uses these and those of substances (cigarettes) for therapy. The Bicom separates these waves into harmonious (healthy) and disharmonious (unhealthy) components. The healthy signals can be boosted and sent back to the patient to strengthen normal functions, while the unhealthy signals are ‘inverted’ or turned upside down by an electronic mirror circuit before returning them to the patient through electromagnetic mats. What actually happens is more complicated but the ‘inverted’ wave cancels the harmful wave that was stressing the body’s energetic system. You can see this effect at the beach where a wave reflected from a rock flattens the next incoming wave.”

Furthermore, it is claimed that:

“…nicotine has an electromagnetic charge over your body giving you the craving to smoke. Bioresonance therapy inverts the energy patterns of nicotine which are then passed to the body via electrodes. This process produces phase cancellation which means that the electromagnetic charge of nicotine is reduced. Therefore, it becomes easier for the body to eliminate nicotine over the next 24 hours and your cravings dramatically reduce as your body detoxifies. Additionally, the phase cancellation removes the energetic pattern of nicotine from the body, erasing the ‘memory’ of nicotine which also reduces the cravings.”

To simplify this process even more, according to the Auckland proprietor of a bioresonance clinic, the patient smokes their last cigarette and places it into the bioresonance machine, which then measures the “frequency” of the cigarette. This frequency is then “reversed” and fed back to the patient via two brass electrodes which the patient holds.

The appointment takes about an hour and it appears some behavioural support is offered, as the website correctly mentions the need to avoid second-hand smoke exposure and smoky environments, known triggers for relapse. Patients are advised not to use NRT during treatment nor use any other pharmacological treatments for smoking cessation. “Detoxification” apparently takes a couple of days (patients are advised to drink water to help with this process) and can include the following symptoms: “headaches, fatigue, upset stomach, metallic taste in the mouth, sweaty palms or a sluggish feeling”. Most of these are classic symptoms of nicotine withdrawal.

Perhaps most bizarrely, patients are also:

“…provided with a Bicom chip that contains the memory of the stop smoking treatment provided. This information lasts for up to 4 weeks and is placed on the body, two finger widths below the navel. This chip will support the detoxification process and help if any cravings are experienced. Drops are also available to support you in times of stress in the following weeks.”

Does bioresonance therapy work?

The New Zealand Stop Smoking Clinic website states that Bicom Bioresonance therapy is “the most successful stop smoking therapy in New Zealand.” Even the authoritative BBC and New Zealand’s very own Close Up TV programme have extolled the virtues of this intervention – see www.stopsmokingclinic.co.nz for video links. However we were unable to locate any randomised controlled clinical trial evidence to support this treatment, despite an extensive search for the term “bioresonance” in a number of medical databases, specifically Medline (1948 to May 22 2009), Embase (1980 – week 21, 2009), AMED (Allied and Complementary Medicine) database (1985 – May 2009), Cochrane Central Register of Controlled Trials (2nd Quarter 2009), ACP Journal Club (1991 to April 2009), Cochrane Database of Abstracts of Reviews of Effects (2nd Quarter 2009), the Cochrane Database of Systematic Reviews (1st Quarter 2009) and the Conference Papers Index (1985 – present).

In total, only 13 articles were located that even mentioned the term, of which eight were non-English publications. The articles with English abstracts were commentaries, non-randomised rat studies, case-series studies or physiology studies. The papers were predominantly published in journals that focused on alternative therapies and no reference to smoking was made in any of the publication titles or English abstracts provided by the database searches. One paper discussed treating 12 athletes with “strain syndrome” with Bicom therapy and 12 with more traditional methods (eg ultrasound, stimulating current, etc)(8). This study reported less therapy time and treatment time in the Bicom group, but we were unable to determine if the study was truly randomised nor the validity of the rest of the study design. However, given the small sample size (24 people only), any positive findings could well be due to chance alone. Interestingly, one paper discussed the use of pseudo-scientific language to cloud important issues (how to present nonsense as science), using bioresonance therapy as an example.

The evidence is not there

Overall, no studies that stand up to the standard level of scrutiny used for orthodox treatments could be identified. The weight of evidence to support the use of this therapy (for any condition and not just smoking cessation) seems to consist of material in non-peer-reviewed publications, such as case studies provided on websites and in books(10-12) and promotional literature provided by those marketing the therapy. A number of Bicom websites (e.g. www.bioresonance.net.au/bicom_therapy.htm) mention the existence of three studies on allergic conditions supposedly published in Chinese medical journals(13-15). These studies were not identified by our search above, but translations for the papers are provided on the above website (although there are no details provided about the source journals so it is not possible to verify their authenticity), along with two additional studies (one on chronic inflammatory bowel disease16 and one on central nervous disorders in children)(17) – once again with no details provided about their source. Four of the five studies are case studies or case-series(14-17). One of the Chinese studies claims to have randomised 300 children, but no details were provided on how the randomisation was undertaken(13). Furthermore, if the randomisation had been done it seems not to have worked given 213 children were in one group and 87 were in the other. Our suspicions are that the study was not randomised and therefore the findings are likely to be biased and meaningless.

It is possible that our search may have missed identifying some papers. It remains odd, however, that so little research appears to have been published given that:

  • In May 2009 bioresonance therapists meet in Germany to celebrate the 49th (ie they have had 48 previous meetings) International Congress for Bicom Therapists. Most congresses and conferences (even those in the complementary and alternative medicine field) publish posters or presentations from their meetings and these are referenced on international databases – yet none of these conference proceedings were located.
  • The therapy is claimed to be so effective.
  • The therapy is claimed to be in widespread use. One website (www.bicom.co.nz) states that “the technique is almost mainstream in Germany, and the German-speaking countries, Austria and Switzerland”, and that the instrument is “widely used in Poland for helping smokers to quit and has over 70 percent success (over 100,000 people have been treated over six years).” And that in China, the therapy is “used exclusively in children’s hospitals mainly to treat eczema and asthma.”

If it truly worked surely you would be doing everything to show the world that it did … and there have been at least 35 years to show the world.

Accepted international criteria for what is regarded as an effective smoking cessation method use the benchmark of six months of continuously not smoking (not even a puff) after quitting. The New Zealand Stop Smoking Clinic website claims that Bicom Bioresonance therapy has “70-90 percent success after one hour” for stopping smoking. Anyone can stop smoking after an hour … it’s a bit like asking you to stop eating for an hour. The issue is when you start smoking again. The Auckland proprietor was unable to provide us with this information.

In conclusion

There is no evidence to support the therapeutic claims made by those promoting bioresonance therapy other than uncontrolled case studies. Any benefits are likely to be due to the placebo effect. A systematic review of 105 NRT trials (involving a total of 39,503 smokers) found that when the quit rates for all the trials were pooled using the longest duration of follow-up available from each trial (6-12 months), 17 percent of smokers allocated to NRT had quit compared to 10 percent in the placebo control/no NRT group2. Clearly the placebo effect plays a significant role in smoking cessation.

Is it therefore wrong to make a claim about a product when simply believing that the product will work makes it effective for some individuals? Does it matter how you try to give up smoking as long as you make an attempt to give up?

In 2002/3, 24.5 percent of New Zealand adults smoked (47.2 percent of Maori), with this figure dropping to 19.7 percent in 2006/7 (38 percent in Maori)18. Despite this recent evidence of change, based on the current rate of progress it is estimated that it will take 100 years before the New Zealand adult smoking rates reach five percent, the level of smoking in New Zealand doctors19. New approaches to assist smokers to quit are still urgently needed, ideally ones with proven efficacy and that are cheap, easily accessible, and acceptable to Maori and people from the lowest socio-economic group (who have a three times higher rate of smoking than people from the highest socio-economic group18). At $450 per treatment (second treatment free if taken within the first month), Bicom Bioresonance therapy is far from accessible to the people that need it most. One could argue that it is designed to generate revenue as quickly as possible, by using pseudoscience to bamboozle the innocent. Are we too cynical? One company (www.bicom2000.com) will gladly send you a detailed profitability calculation form.

For a rather interesting conversation of how another member of the skeptic community views this treatment, see www.sciencepunk.com/2007/03/monadith-bioresonance-smoking-cure/

References

  1. Stead L, Lancaster T, & Perera R. Cochrane Database of Systematic Reviews, The Cochrane Library 2003;1:CD002850.

  2. Silagy C, Lancaster T, Stead L, Mant D, & Fowler G. The Cochrane Database of Systematic Reviews, The Cochrane Library 2008;1.

  3. Hughes J, Stead L, & Lancaster T. The Cochrane Database of Systematic Reviews, The Cochrane Library 2008.

  4. Stead L, & Lancaster T. The Cochrane Database of Systematic Reviews, The Cochrane Library 2008.

  5. Lancaster T, Stead L. The Cochrane Database of Systematic Reviews, The Cochrane Library 2007(3).

  6. Strecher V, Shiffman S, & West R. Addiction 2005;100(5):682 – 688.

  7. McRobbie H, Hakej P, Bullen C, & Feigin V. . 2006; www.nice.org.uk/nicemedia/pdf/SmokingCessationNon-NHSFullReview.pdf

  8. Papcz, B & Barpvic J. Erfahrungsheilkunde 1999: 48(7): 449 – 450.

  9. Ernst E. Forschende Komplementarmedizin und Klassische Naturheilkunde 2004 Jun;11(3):171 – 173.

  10. Will, RD. Bioresonanz Therapie. Publisher: Jopp Verlag, 2001.

  11. Schumacher, P. Test Sets According to Dr. P. Schumacher. Publisher: dtp Tyrol – Klaus Leitner, Innsbruck, 2000

  12. Schumacher, P. Biophysical Therapy of Allergies. Publisher Thieme Medical Publishers 2005

  13. Jinzhi, Y & Li Z. www.bioresonance.net.au/bicom_therapy.htm#CL Accessed 25 May 2009.

  14. Ze, Y, Jiali, H, Haiyan W & Chunyan Y. www.bioresonance.net.au/bicom_therapy.htm#CL Accessed 25 May 2009.

  15. Jinzhi, Y. www.bioresonance.net.au/bicom_therapy.htm#CL Accessed 25 May 2009.

  16. Oesterle, R. www.bioresonance.net.au/bicom_therapy.htm#CL Accessed 25 May 2009.

  17. Barrie, A & Barrie A. www.bioresonance.net.au/bicom_therapy.htm#CL Accessed 25 May 2009.

  18. Ministry of Health. A portrait of health – Key results of the 2006/7 New Zealand Health Survey. Wellington: Ministry of Health, 2008.

  19. Laugesen M. New Zealand Smokefree enews. Auckland: Health New Zealand, 2004.

The physiology of the placebo effect

Placebos may contain no active ingredients, but they have real effects on the human brain. This article is based on a presentation to the NZ Skeptics 2008 conference in Hamilton, September 26-28.

Earlier this year, Dr Tipu Aamir of the Auckland Pain Management Service drew my attention to something peculiar. In a double-blind, randomised, placebo-controlled trial of morphine after a standard knee operation, 30 percent of those receiving a placebo get pain relief. When those people are given a specific morphine antagonist (‘antidote’), their pain comes back! In the words of a former contributor at an annual conference of this society, this was an epiphany. I needed to know more.

After all, how could something that was ‘all in the mind’ be changed predictably by a substance with a known pharmacological action?

Any study of homeopathy raises the issue of the placebo effect. As a result of a meta-analysis in 2005 of a number of studies comparing homeopathic remedies with orthodox treatment, Shang et al stated in their conclusion that the effect of homeopathic remedies was no greater than that of a placebo. Not that they had no effect, but it was no greater than that of a placebo.

We skeptics are often happy to accept the explanation that if a response to some arcane practice is a placebo response, that settles the issue.

Over the last 30 years there has been a large amount of research into the undoubted effects of placebos. I thought it might be of interest to review this work in the context of our frequent use of ‘placebo effect’ to explain the unscientific.

Placebo is a Latin word for “I shall be pleasing, or acceptable”. It is the first word of the first antiphon of the Roman Rite of the Vespers for the Dead (!), Placebo Domino, dating from the seventh to ninth centuries. Chaucer called one of his characters Placebo in the Merchant’s Tale, because the word had come to mean a flatterer, a sycophant, or a parasite, by the 14th century.

“Placebo seyde: Ful little need had ye, my lord so deare, Council to ask, of any that are here But that ye be so ful of sapience.”

He also uses it in the Parson’s tale: “Flatterers be the Devil’s chaplains, which sing ever ‘Placebo’.”

In the 1811 edition of Hooper’s Medical Dictionary, placebo was defined as “an epithet for any medicine adopted more to please than benefit the patient”. In a recent edition of Collins’ Concise Dictionary of the English Language it is defined as “an inactive substance administered to a patient to compare its effects with those of a real drug, but sometimes for the psychological benefit of the patient through his believing he is receiving treatment”.

However, placebos do benefit patients, and they are certainly not inactive in the context in which they are given.

The most dramatic example of this that I saw in clinical practice involved a young man on artificial kidney treatment. When erythropoietin became available for the treatment of the severe anaemia seen so often in this situation, he was the first patient in our unit to receive it. Erythropoietin is a hormone made in the healthy kidney, which increases the number of red cells in the blood and the amount of the oxygen-carrying haemoglobin. The synthetic version has achieved notoriety as a performance enhancer in sport, for example in the Tour de France. We were all very enthusiastic about this improvement in management for our patient, and he was given his first dose with much interest from all of us. That night he went home, recovered his bicycle from the shed where it had been undisturbed for many months, and rode all around his town with great energy and pleasure. He hadn’t heard the information that the drug took three weeks to act on the anaemia.

We are left with some questions. What was the physiology of his sudden ability to exercise at a ‘normal’ rate, long before there was any change in his blood count? What does ‘it’s all in the mind’ mean? Was he somehow at fault, or was it me and the staff who were lacking in understanding?

I would like to consider:

  • The psychological processes involved in the placebo effect
  • The physiological mechanisms in the brain
  • The site of this activity in the brain
  • Why there is variation in the placebo effect from individual to individual
  • What are the implications for the classical drug trial format?

Psychological mechanisms

Those who study the psychological processes of the placebo effect cite two major mechanisms.

Conditioning. Pavlov (1849-1936) showed that dogs given meals as a bell rang would subsequently salivate when the bell rang despite not being given food. This process has been explored in humans, who will experience pain relief when a placebo is substituted for a pain reliever when a sequence of active analgesia has been associated with an environmental cue. It is an unconscious process. At the nerve cell level, conditioning leads to a stronger and more sustained response.

Expectancy. This effect is seen when the patient has ‘great expectations’ of the substance being given. These are raised by the conscious or unconscious attitude of the therapist. It is a conscious process on the part of the patient.

It is currently suggested that both conditioning and expectancy are active in the placebo effect, and that in fact, as an inert placebo can have no effect per se, what we see is the effect of the context in which the treatment is given.

Neurophysiology of placebo pain relief

Over the last 30 years, there has been much interest in the neuro-physiological mechanisms of the placebo response.

In 1975, Hughes et al identified in the brain two related pentapeptides (a chain of five amino acids linked together) with potent opium-like action. There are many more now identified. These compounds act on specific receptors on the membranes of neurones, and via intracellular metabolic changes increase synaptic transmission. They are made in the pituitary and hypothalamus, and are called endorphins.

A digression

In pharmacology the term agonist denotes a drug with an effect, and antagonist, a drug which specifically blocks the effect of the first substance.

When I spent a year in the pharmacology lab in Dunedin (1959) it was becoming recognised that drugs exerted their effects by way of a specific receptor molecule at the cell surface. The actions of adrenaline, for example, were explained by the presence of two different molecules to which it could attach, which mediated different effects. Noradrenaline would latch on to only one, explaining its more limited range of action. With their usual desire for learned coherency, pharmacologists called them alpha and beta receptors. Antagonist molecules attach to the receptor molecule and block access by the agonist. Hence the term ‘beta-blockers’. These are substances which block the action of adrenaline on its beta receptor. They are widely known for their action in the control of blood pressure, and recently for their unwanted effects when given to protect patients at risk of heart trouble when undergoing operations.

Agonists and antagonists are related by similarities in molecular size, shape, and charge.

Morphine antagonists have been available for some time. In 1961 as a house surgeon in casualty, I was asked to manage an opium addict, brought in because he was deeply unconscious, and breathing perhaps once a minute. He had been without the drug for some weeks, due to market fluctuations. When access was resumed, he used a dose which was the same as his habituated dose. This was much more than he could now tolerate. I had access to nalorphine, a specific morphine antagonist, and 30 seconds after an IV injection, the patient took several deep breaths, sat up, expressed considerable surprise at his surroundings, and then lapsed back into his former state. I was able to repeat this dramatic procedure several times until he recovered!

In 1978 a group of dental surgeons working in California (Levine et al) carried out the following experiment. Patients who had had an impacted wisdom tooth extracted were treated routinely with nitrous oxide, diazepam and a local anaesthetic. At three hours after the procedure they were given either a placebo or naloxone, a specific morphine antagonist. At four hours they were given a placebo or naloxone. Those who had initial pain relief with the first dose of placebo (39 percent), when given naloxone had an increase in pain.

The authors concluded that “this was consistent with the hypothesis that endorphin release mediates placebo analgesia in dental postoperative pain.”

The elegance of this study lies in the unequivocal evidence that a supposedly psychological state (placebo analgesia) was reversed by a specific opioid antagonist. Note that none of the patients was given morphine. There must be a physiological cause for placebo analgesia.

This sort of study has been repeated many times, and always naloxone reverses placebo analgesia.

The site of action of opioids in the brain

The site of this process has been determined. The sites for opioid receptors in the brain can be found by specific cell staining methods and histology on brain tissue. But more exact, ‘real-time’ evidence comes from positron emission tomography (PET) scans.

Another digression

PET utilises short half-life radioactive elements which undergo spontaneous beta decay. In the process, they emit a positron, which collides with an adjacent electron resulting in mutual annihilation, and the generation of two high-energy photons at a near-180 degree angle. These can be detected, and with many, many such events, used to build up a tomographic picture of the source in relation to surrounding tissue. In the studies of the brain, radioactively-labelled glucose is injected, and congregates where activity (utilisation) is greatest. PET scans are used to monitor metabolic activity in specific organs. For example, the extent of heart muscle damage after a heart attack.

In 2002, Petrovic et al were able to show that both opioid and placebo analgesia are associated with increased brain activity in specific regions: the anterior cingulate cortex and the brain stem. There was no increase of activity in these regions with pain only.

Similar localised brain activity has been shown in placebo responses in Parkinsonism (dopamine) and some depressive states (serotonin).

I find these studies exciting and provocative.

Genetic predilection

A further question can be asked in the light of the evidence for a physiological mechanism for the placebo effect. Why does it occur in only 30-40 percent of us for a given situation? It may occur in a greater proportion of a population sample if the context is made more convincing. But why don’t we all have the benefits? Variation in a physiological function begs the question of a genetic predilection.

De Pascalis et al (2002) have shown that individual differences in suggestibility contribute significantly to the magnitude of placebo analgesia. The higher the suggestibility score (there are several tests available) the greater the placebo analgesic effect.

As early as 1970, Morgan et al showed that there was a correlation of suggestibility between monozygotic twins but not dizygotic (fraternal) twins. (Monozygotic twins are the result of the fertilisation of one ovum by one sperm. The resulting zygote splits into two cells which each develop into an individual. These individuals have exactly the same genes.)

Wallace and Persanyi (1989) looked at hypnotic susceptibility and familial handedness. Subjects with close left-handed relatives scored lower in a test for hypnotic susceptibility.

At the 2008 conference, I carried out an experiment with a group of clearly non-suggestible Skeptics. I asked those in the audience to raise their hands if they, or a close relative, were left-handed. If the hypothesis was correct, more than 10 percent of our attendees should have been left-handed. In the event, 22 of 84 attendees indicated they or a close relative were left-handed.

The control study should be done with a church congregation, Protestant or Catholic. In fact, we could do this on both and answer the question as to which is the less suggestible! I haven’t had the nerve to ask. Thomas Bouchard, beginning in 1979, has carried out a number of studies on twins who for a variety of reasons were reared apart. He compared correlations between identical twins and between fraternal twins. The studies from his group (in Minnesota) have shown a large group of correlations in identical twins reared apart, which do not occur in fraternal twins reared apart. The correlations differ very significantly. Table 1 has some examples in twins reared apart:

Similar studies have given similar results in Australia and Western Europe.

Because the nurture of these twins is different, and identical twins have identical genes, the similarities must be genetic. This approach to behaviour has lead to the science of behaviour genetics. (Physical attributes are of course also correlated more between identical twins reared apart, than fraternal twins reared apart.)

Amir Raz (2005, 2008) and his group in New York State have shown that a genetic polymorphism (more than one version of a specific gene) exists for a gene on chromosome 22, which codes for an enzyme active in the breakdown of dopamine, a neurotransmitter. One amino acid substitution (valine for methionine) in the gene alters the enzyme activity by a factor of four times. Since we have a copy of this gene from each parent, we may have val/val, or val/meth, or meth/meth genotypes.

Val/meth heterozygote confers the greater suggestibility. The enzyme is called COMT or catechol-o-methyl transferase.

Brain pathways in which opioid receptors are active are linked to those in which dopamine is the transmitter (nerve to nerve). If there is genetically conferred variation in dopamine activity it is likely that this will influence the result of changes in activity in the opioid pathways.

We must remember that we are talking of a genetic predisposition to be suggestible, and not a gene for suggestibility. It is not that 69 percent of identical twins vote Republican, but that if one does there is a 69 percent probability that the other one does too.

The implications for drug trials

In 2003, Benedetti and his colleagues in Turin examined pain relief in patients after thoracotomy. Patients were allocated to either open infusions of morphine, with information about the efficacy of the drug, or to receive hidden doses of morphine by infusion without any information and without any doctor or nurse present (the open / hidden model for drug trials).

With the same dose, same infusion rate, same timing and same drug, pain relief was less in the ‘hidden’ group.

In the ‘open’ group, the ‘meaning-induced’ expectations had enhanced the drug effect.

This research group has gone on to postulate that in all drug treatment the effect is the sum of actual physiological effect and the effect of expectations. This means that the placebo effect will always cause part of the usual ‘physiological’ response to active drugs. They say that the classical double blind randomised placebo-controlled trial does not allow for expectation effects, and may suggest that a drug has a specific effect gre’open/hidden paradigm’ will give more meaningful results.

Conclusions

  • The analgesic placebo effect is accompanied by a distinct, observable, and locatable physiological event in the brain.
  • Susceptibility to the placebo effect varies in the population at large.
  • This susceptibility is at least in part genetically determined.
  • It may be possible to harness this facet of human behaviour for the benefit of individuals, and to prevent its on-going exploitation by charlatans.
  • Although placebos are inert and cannot have any effect on the healing processes, their meaning and the context in which they are given can.
  • All drug effects include some placebo effect, except when the drug is given surreptitiously. This should alter the classic clinical trial structure.

We have come a long way from the Vespers for the Dead!

Placebos are inert substances but the context in which they are given can alter neurophysiology in such a way as to cause subjective and objective effects.

This is not due to the ‘molecular memory’ of water, nor to strange force-fields as yet unknown to physicists. It is due to our human nature, how we react to our environment, and the relationship, between our minds and our bodies.

Full references available from the editor.

Natural products chemistry – the road from nature to pharmaceutical

Many pharmaceuticals originate from nature, but their development is very different from that of so-called natural health products. This article was originally presented at the 2005 Skeptics Conference.

The field of natural products chemistry deals with the scientific study of chemicals isolated from living organisms. This can be anything from isolating indigo dye from woad, distilling lavender oil from the lavender plant, working with plant oils and animal fats to make soap, to trying to find the active ingredient in a plant extract that reduces fever.

Interest in compounds from living organisms dates back to the beginnings of civilisation. More recently it also gave birth to what we now call ‘organic chemistry’. Initially, organic chemistry was natural products chemistry, when people thought that carbon containing molecules were imbued with a ‘vital force’ and could only be made by living organisms — hence the name ‘organic’. Friedrich Wöhler shattered that idea in 1828 when he became the first to make urea (an organic molecule) from inorganic precursors. Now we define organic chemistry simply as the chemistry of carbon containing compounds.

Unfortunately this mystical feeling that “natural” things are somehow better, or special, has survived till today, and many people are still convinced that “it’s natural, so it’s got to be good!” When dealing with natural substances that have biological activity, one must ask why they have any physiological effect. The answer is chemical defense: plants that do not have thorns, for example, have evolved chemical substances to poison animals that would otherwise eat them. The ‘natural’ effect of any herbal product then, is to make the user sick! We should not be talking about ‘natural is good’, but about chemical warfare.

Chemical warfare

The mould Penicillium notatum produces and secretes an antibiotic, a compound that inhibits bacteria that could compete with it for food or resources. This is chemical warfare on the microscale, a life and death battle for survival between the mould and its enemy. The mould certainly does not make the antibiotic for the benefit of mankind — any beneficial effect to us is an accidental advantage. But we can certainly make good use of that! The antibiotic in question is of course penicillin, the first discovered antibiotic. It has revolutionised medical treatment of bacterial infections and earned its discoverers Sir Alexander Fleming, Ernst Chain and Sir Howard Florey the 1945 Nobel Prize in Medicine.

We certainly exploit this type of biological activity to our great advantage. Natural products, or compounds derived from natural products, comprise the majority of pharmaceuticals in use today. So what is the difference between them and ‘herbal remedies’ that are sold in health shops and supermarkets?

The big difference is that herbal remedies are not tested. Not tested for efficacy (we don’t know whether or how they work), they are not tested for safety (we don’t know whether they are toxic or have side effects). They are not regulated in any way, so you don’t know what you are buying at all!

Drug development process

Before a natural product can be approved for use as a human pharmaceutical, it must go through a rigorous process of testing during clinical trials. And before it even enters those, it must be fully identified and characterised. This precise analysis is what makes the known and well understood pharmaceuticals stand apart from herbal remedies. For the most part, we know very little, if anything, about their chemical composition and effects.

Once the initial discovery process is complete, the natural product is subjected to a barrage of tests in vitro (in the test tube) and in vivo (in lab animals). Once biological activity and initial safety is demonstrated, the potential pharmaceutical can be admitted to the Phase I clinical trial. This involves a small group of healthy volunteers who are given the compound to determine its safety (that is, evaluate any toxicity and side effects) and tolerated dosage. Phase II trial follows, where the effectiveness of the compound at curing a disease is finally tested on a small number of human patients.

Finally, Phase III is a large scale trial on 1000 to 3000 patients, verifying effectiveness and monitoring any adverse effects from long term use. At the end, all the data are submitted to the monitoring agency (in the US this is the Food and Drug Administration) for evaluation. Once approval is given, the drug can be launched onto the market, where it still undergoes long-term safety monitoring and additional tests during the so-called Phase IV trial.

On average, out of 5000 compounds that undergo pre-clinical testing, only five are deemed promising enough to enter clinical trials. Out of those five, only one is approved — others fail because they do not show effectiveness once trialled in humans, or exhibit unacceptable levels of toxicity or side effects. From discovery to prescription, the whole process takes on average 12 years, with costs estimated to be in the hundreds of millions of US dollars.

While the process may not be perfect, it does attempt to ensure that the medication we are prescribed is first of all safe, and that it works. Herbal remedies cannot claim the same.

The Story of Taxol

In the 1960s the National Cancer Institute (NCI) launched a screening programme to test various plants for potential anti-cancer activity. Over the next two decades they screened more than 114,000 plant extracts. This included, in 1962, a collection of bark from the Pacific Yew, Taxus brevifolia. Immediately, this shrub generated great excitement as it showed interesting activity in biological assays. A research project was launched to investigate these properties, and in 1967 the active ingredient was isolated and named paclitaxel. The structure was not solved until four years later in 1971, a reflection of its high degree of complexity. Paclitaxel exhibited a broad spectrum of activity against cancer cells in vitro, and in 1979 scientists discovered its mode of action in the cell — a completely novel way of stopping and killing cancerous cells. In vivo testing showed phenomenal successes — paclitaxel stopped the growth and even shriveled breast cancer tumours in mice. All of these results made paclitaxel the hottest natural product around. Everyone wanted to get their hands on some, but paclitaxel had many hurdles yet to overcome.

Researchers rushed the compound into clinical trials, but immediately faced a problem. Paclitaxel was not soluble in anything. As one researcher put it, “it had the solubility of a brick.” How were they going to administer it to patients? Finally a concoction consisting mainly of castor oil was found to be effective, but was almost the drug’s undoing. Paclitaxel proceeded to clinical trials, and was almost rejected right then and there, as it showed unacceptable levels of side-effects. Fortunately, someone figured out that most of these were due to the castor oil, and after the formulation was changed somewhat, the drug continued to Phase II clinical trials.

The results were astonishing: against the most virulent forms of ovarian cancer, paclitaxel showed unheard of levels of response. Doctors and researchers were suddenly clamouring for more and more of the drug. But Taxol faced its greatest challenge yet: that of supply.

The compound paclitaxel is present in only minute amounts in the bark of Taxus brevifolia. Fifteen kilograms of the bark yield barely half a gram of the active compound, which means it would take six 100-year-old trees to treat one patient. Quite aside from the ecological impact of the large scale logging operation required, there simply are not enough Pacific Yew trees in the world to treat all the cancer patients.

Making the compound in the lab was not an option. Though a successful synthesis of paclitaxel was reported in the literature, the molecule was too complex for this to be a viable route to obtaining large quantities. Fortunately however, researchers discovered that the much more common English Yew (Taxus baccata) contained relatively large quantities of a compound that is related to paclitaxel. Eventually in 1989 they succeeded in transforming this 10-deacetylbaccatin into paclitaxel. This semi-synthetic pathway is how Taxol is made even today.

The billion dollar wonder molecule

Having successfully completed clinical trials, paclitaxel was launched onto the market in 1993 under the trade name Taxol as a drug to treat ovarian cancer. Sales of Taxol grew exponentially, rapidly reaching and passing the US$1 billion mark. Today, Taxol remains the leading treatment against ovarian, breast and lung cancers, and Karposi’s sarcoma. Yet it had not been an easy journey: from bark to drug it took 31 years, and with an estimated cost in excess of US $300 million.

Victoria University Marine Chemistry Lab

Most of the natural products that have “made it” as pharmaceuticals come from the terrestrial environment, not surprisingly, as terrestrial plants, animals and fungi are most easily accessible to researchers. In the last few decades however, with the advent of scuba diving, a whole new world has opened up: the marine environment. The Marine Chemistry Lab at Victoria University studies chemical compounds found in marine plants and animals. We examine a wide variety of organisms, including sponges, seaweeds, sea-slugs and others. Our ultimate goal is to discover new, biologically active chemicals from marine organisms and develop them into pharmaceuticals.
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Discovery of peloruside

In 1998, Lyndon West (who was at that time doing his PhD in our lab), discovered a new compound from the sponge Mycale hetsheli. He named it peloruside, after Pelorus Sound where the sponge came from. The compound looked very interesting right from the start, so patents were filed right away, and biological testing initiated. Indeed, exhaustive in vitro tests revealed that peloruside had the same mode of action as Taxol! This news generated a lot of interest, and in 2004 a deal was signed with Reata, a US Pharmaceutical company. Their tests in mice showed very promising results: injections of peloruside into grafted tumours radically reduced their growth. With exciting results like that, everyone is now keen to start clinical trials.

Unfortunately, we face a supply problem even worse than the Taxol people did: the compound is once again present in only small amounts in the sponge. In addition, sponge populations are scarce in the wild, and difficult to reach. They also show a large variability in the amounts of peloruside they produce, depending on depth, season, geographical location and even individual animal.

Aquaculture

But, we have a solution: aquaculture! Fortunately for the project, the sponge can be propagated from small cuttings. We have taken bits of wild sponges and tied them to ropes that have been suspended off the anchor lines of a mussel farm in the Marlborough Sounds. The sponge has grown well — our sponge farm yielded almost 100 kilograms of the sponge in 2005. Some of this mass was returned to the ropes to grow again for this year, the rest has been harvested and is now being processed in our lab. We hope to get gram amounts of peloruside and hopefully start clinical trials with Reata Pharmaceuticals in the US this year.

Could peloruside be the next wonder drug against cancer? Well, it has a long way to go yet. But it certainly shows promise, so watch this space.