A few months ago I received (2015) an e-mail from the NCFS (Nederlandse Cystic Fibrosis Stichting or Dutch CF Foundation), asking me if I would be willing to speak at their upcoming annual conference on February 12th, 2015. I nearly fell of my chair! What an honour and how super exciting!
Last week the day came. I had been working on my speech (see below) for weeks and was very nervous but excited at the same time.
I had 10 minutes to tell my story. I could have spoken the entire day about our experience, but I had to do it in 10 minutes. The audience was CF professionals only. Pulmonologists, gastro enterologist, nurses, physical therapists, dieticians etc.
My goals were to motivate them to always keep an open-mind towards natural supplements, because you never know if they may work. Also to point out why there is not a lot of clinical evidence (clinical trials) for natural supplements. So even though it's not proven in a large clinical, that doesn't mean it doesn't work.
Here is the text of the speech:
"Today it is almost a year ago to the date that we learned J's sweat test had dropped from 118mmol/L to 59mmol/L as a result of the food supplements Curcumin and Genistein. I have been asked to tell you how that came about and how it lead to a clinical trial.
Six years ago J was diagnosed with CF. He was 2 years old at the time and it was mainly oily stools that had lead to his diagnosis.
As soon as we heard that J had CF, I remembered a time before his diagnosis when, after struggling to gain weight for six months, he had suddenly gained 2 kilo's in one month, from 8 to 10 kilo's. This coincided with the time I started giving him soy formula.
I wondered which ingredient in the soy formula could have been responsible. After searching the internet for months, and I really had to search a long time, because I have no medical background. I graduated as a Speech Pathologist and Therapist over 20 years ago, but that doesn't get you very far once you start studying medical research papers about CF. But 'where there is a will, there is a way' and after a lengthly search I found the connection between soy and CF. The compound Genistein. A compound from soy beans, which had been used for years in lab studies to potentiate the G551D mutation.
J doesn't have G551D, but S1251N and delF508. After more searching and puzzling, there wasn't much known at the time about S1251N, I found out that the defect in S1251N is very similar to that of G551D. Both are so-called 'gating mutations'. A short explanation for the people that don't know how it works: CF is caused by a defect in CFTR. CFTR is a protein that is made in the nucleus of the cell. It then has to travel from the nucleus to the cell membrane (the outer layer of the cell), where it is supposed to create a channel or a 'gate'. In CF this process can go wrong at different stages, depending on which mutations someone has. For example the CFTR protein is produced by the nucleus, but never makes it to the cell's surface. Or it does make it to the cell surface but doesn't make a 'gate'. With S1251N and G551D the CFTR protein makes it to the cell surface and even makes a 'gate' or channel, but that gate doesn't function properly. These types of mtuations are called 'gating mutations' and their function can be partly restored with the help of Genistein or for example the new medication Kalydeco. Compounds like these are called 'potentiators'. They potentiate the gating mutations and the CF cells start functioning more like non-CF cells.
Let's go back to what we did at home for a minute.
By that time I was convinced it had to have been Genistein that had kept J so healthy before his diagnosis. I continued giving him soy milk, but Genistein is also available as a food supplement and as he got bigger, I started giving it as a supplement as well.
Quite soon after his diagnosis I also found lots of information about Curcumin. Curcumin or Curcuma is a compound from Turmeric a spice used often used in the kitchen, in Curry for example. It's well known for its anti-inflammatory, anti-bacterial and anti-viral properties and it has an excellent safety profile, so I thought: "if it doesn't help, at least it won't hurt".
For the last 6 years I've made a jar of 'supersauce' every morning. A small container with applesauce with all kinds of food supplements mixed into it. Not just Curcumin and Genistein, but also Selenium, Magnesium, Taurine and Glutathion for example.
The supersauce is bright orange, because Curcumin turns everything bright orange, including your fingers and your kitchen. With that supersauce we give him his enzymes during the day.
J grew like crazy. A really big kid! Above average in height and especially above average in weight, maybe a bit too heavy even. His lungs stayed clear, he never coughed and the CT scans showed no signs of CF. We didn't use a nebuliser, barely ever antibiotics. Actually only enzymes and of course the supersauce. The older he got, the more his health started to stand out. Something we did seemed to work, although we didn't yet know what it was.
In 2012 something strange happened. The Curcumin manufacturer had changed its packaging and without realising it I accidently ordered the wrong bottles. Curcumin is badly absorbed from the intestine and to increase that absorption a black pepper extract is often added. Unknowingly I had ordered Curcumin without black pepper. J's stools turned bad. Lots of oily stools and diarrhoea. We didn't understand what was going on. One day I decided to give 2 capsules Curcumin in stead of one and his stools improved, but things weren't back to 'normal' yet. A few weeks later I suddenly (finally!) noticed the text on the bottle and realised we had been using the wrong bottles. As soon as I started him back on the right ones, everything normalised within a day. At that moment I was sure Curcumin was clearly having a positive effect for J, at least for his intestinal function.
Fast forward to 2013. Kalydeco, the medication by Vertex, a potentiator, for gating mutations, had become available for G551D patients and had been shown in lab studies to be effective for J's S1251N mutation as well. I'm not one to sit and wait and I thought: "it's here, why not try to get it covered by insurance now?". Our doctor was willing to help, on the condition that we would first prove efficacy of Kalydeco on J's intestinal cells from a rectal biopsy.
And that's how I met Dr. Hugo de Jonge. Biochemist and head of the CF research group of the Erasmus University Medical Centre in Rotterdam, The Netherlands, specialised in intestinal CFTR. During a meeting we had before the biopsy, J's remarkable health and our supersauce were also discussed and on the day that Dr. de Jonge had J's cells under his microscope, not only did he test efficacy of Kalydeco at our request, but also, out of his own curiosity, the effect of Curcumin and Genistein, because he suspected that those were the two most likely candidates to explain why the supersauce seemed to work so well.
He was right! It worked! It worked very well actually. Better than we could have ever expected. The effect was close to that of Kalydeco. A few days later, when we discussed the results of the test in Dr. de Jonge's office, I remembered reading an article about an in vitro study into the binding sites of Curcumin and Genistein on CFTR. We were doing a Google search for that article, when another article popped up by the same author, about the synergistic potentiating effect of Curcumin and Genistein on the gating function of G551D. Synergistic means that they enhance each other. Let's say Genistein gives and effect of +2 and Curcumin +1. You would think that giving them together you would see an effect of +3. But the effect of the combination is much higher. Somewhere between +15 and +30. A 5- to 10 fold effect.
At that moment we realised what we were looking at and how we could explain the unexpected large effect of Curcumin and Genistein on J's intestinal cells.
I forgot all about Kalydeco and started raising the doses of Curcumin and Genistein at home. To check progress we did our 'do-it-yourself-sweat test'. We licked J's forehead to find out if he started tasting less salty. We called it a 'Kojak' (remember the lollipop?). We noticed other improvements as well, his mouth was less dry, he had more energy, better endurance and he looked better. His sinuses opened up further. There were many clues. J is really bad at doing PFT's (Pulmonary Function Tests) and unfortunately we couldn't draw reliable conclusions from those.
After a few months we were at 6 capsules Curcumin (3600mg) and 3 capsules Genistein (150mg) total per day. To be sure we were still on the right track, I wanted to do a sweat test.
And that's how in February 2014, we ended up with a sweat test of 59mmol/L At diagnosis it was 118mmol/L. A drop of 59! For the people that don't have the sweat test numbers fresh in their memory: below 30 is usually no CF, between 30 and 60 is inconclusive, above 60 is usually CF. We were at 59! Just below 60! To compare, the average drop in sweat test in G551D patients in the Kalydeco trial was 55, we had dropped even a little further with 59.
As far as I know, this had never happened before in the world. Lowering a sweat test like that with food supplements. I knew Curcumin and Genistein worked, but never expected this to happen.
While I was doing a 'happy dance' at home, Dr. de Jonge started working on an outline for a clinical trial and with ZonMW, a government agency, to try to get a budget to do the trial. And he succeeded! Thanks to financial support of ZonMW and the Dutch CF Foundation, the TicTac study started in september 2014 at the University Medical Centre in Utrecht with the pimary endpoint being sweat chloride concentrations and secondary endpoints: pulmonary function and BMI a.o. With Erasmus Medical Centre Rotterdam, Academic Medical Centre Amsterdam and Haga Hospital The Hague also participating in the trial. At this moment the trial is still ongoing and the results are not known yet. It's very hard for me to await the results, I don't know anything yet (this was in 2015, Now, Nov 2016, we know that the trial showed a small but statistically significant drop in sweat chloride concentration and a statistically significant decrease in airway resistance. So we can conclude that Curcumin and Genistein actually work on the underlying CFTR defect. The combination increases CFTR chloride current in the sweat gland in people with CF with the S1251N mutation.)
The trial will be continued this year with a second part: as soon as all S1251N patients are taking Kalydeco, it will be evaluated if the addition of Genistein can enhance CFTR function even further. (note 2016) The inital idea was to use all three, but it's a randomized, double blind, placebo controlled trial and it turned out that making a placebo for Curcumin would be too costly, mostly because of it's color)
It is an extraordinary story.
First of all because it turned out to be possible to lower a sweat test from 118 to 59 with food supplements.
Second because it originated from a bowl of supersauce in our kitchen and not from a lab.
Third it is special because we received funding to perform a clinical trial.
Fourth because Kalydeco costs about 240,000 euro's per year, 'supersauce' about 3,000 a year.
What do I hope for?
That CF professionals, after hearing our story, will keep an even more open mind. Who could have ever thought that this would be possible? Getting defective CFTR proteins to function again using a piece of Turmeric root and soy beans? But it's true! It really works!
I also hope that everyone will realise even more that even if efficacy isn't clinically proven, that doesn't mean it doesn't work. Maybe it works, it's just not clinically proven.
But why are there so few clinical trials with natural supplements? I think the biggest problem is in the funding of these trials. Clinical trials are hugely expensive. Who will pay for it?
Pharmaceutical companies see these costs as an investment that they can earn back and start making profits on, because they can patent their (synthetic) compounds for years. Only they can sell the medication and only they will make a profit on them.
But food supplements can't be patented. Beside that, laws and regulations make it difficult to do clinical trials with food supplements, because of e.g. purity of the supplements. All in all, it's difficult to work with and no one is going to make profit on it.
At the same time a lot of laboratory studies have been done with natural compounds on CFTR function. I personally think that there may be many more natural compounds that could have a positive influence on CFTR function in patients.
My fear is that this research will remain on the bookshelves somewhere, simply because there is no money to test efficacy in patients and because no one will ever make a profit from it.
To realise that the efficacy of Genistein has been known for at least 15 years and has never been tried in patients.... Could it have saved lives over the last 15 years? Who knows...
For now we have been able to do the trial with Curcumin and Genistein. How clinical trials with other natural compounds should be financed in the future is something to seriously think about.
I would like to express my gratitude of course to Dr. de Jonge; to the Dutch CF Foundation for their invitation to speak here today and their financial support for the trial; to ZonM for their financial support and to everyone that has contributed to the trial so far. It's fantastic! Thank you."
Link to Dutch CF Foundation website page on the 2015 conference
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