From so simple a beginning…

Curcuminised Chicken

There are two articles in the journal Cell this week, which talk about the value of traditional medicine, especially Ayurveda, in modern drug discovery and medicine. The articles are encouraging, and they essentially say that modern pharma is now actively pursuing the development of some of the medicines. There are five molecules cited which can be considered semi-success stories.

One of them is a molecule named curcumin, the dominant molecule in turmeric which gives it its familiar yellow colour. In fact the second article in the journal talks almost exclusively about curcumin. Since we as Indians are so familiar with it, and since it is such an interesting molecule, I thought I would say a few words about it. But doing so also entails saying a few words about modern drug discovery. At some point in the future, I am planning to pen a series of articles describing drug discovery, or at least what I know of it. But for now only a short account.

Basically drug discovery started when the first human beings discovered the benefits of chewing grasses, roots, bark, and berries to alleviate their misery. Some Cherokee Indian discovered the pain mitigating effects of chewing willow bark, and thus began the road leading to aspirin. Some other Peruvian Indian chewed Cinchona bark, and fired off the story of quinine. Chinese and Indian monks and sages through their prescriptions gave us azadirachtin (from neem) and artemisinin (antimalarial). In fact, even today, with all the advances in producing artificial and synthetic drugs through the power of chemistry, about 50% of all best selling drugs are derived from natural sources. Some of them come straight from a tree or fungus. Many are not the natural molecules themselves, but they are modified analogs of those molecules and could not have been made without them. This argument alone should make preserving the environment an urgent task. The sources of these molecules are exotic and novel; a soil bacterium in Japan for an anticancer drug, a marine sponge in the Maldives for another one, the Pacific yew tree for the bestselling anticancer drug Taxol®, a fungus collected on a Canadian mountain for an anti-inflammatory drug, and the skin of a frog from the Amazon for an analgesic. Researchers have combed forests, swamps, and the ocean for these molecules, and it would seem that there is a wealth of untapped sources for new drugs for all our ailments out there.

One such molecule is curcumin from turmeric, largely neglected by Western civilization for a long time. We in India know about it for millenia through Ayurveda. But as we also know, turmeric is an integral part of that amorphous entity we see in our mind when we hear or see the word “India”. Through our festivals, celebrations, medicine, and most importantly food, the ubiquitous presence of turmeric and its striking yellow colour has indeed become engraved in the collective Indian consciousness. From our grandmother telling us to apply it on burns and cuts, to Vicco and Santoor telling young women how it can make their skin glow, turmeric has been everywhere in our country.

Turmeric’s beneficial effects as recorded in Ayurveda are impressive. It is a multitalented molecule, and in its particular case, many of its effects have stood up to the hype. It shows among other things, potential antiinflammatory, anticancer, digestive, respiratory, pro immune system, and cardio and neuroprotective (anti-Alzheimer’s) effects. With such a profile, curcumin would be extremely alluring as a drug, almost seeming like a magic cure.

However, the very varied tricks that curcumin can perform also makes it a somewhat problematic molecule as a drug. A drug usually needs to be very potent, and selective for one particular disease that you are trying to cure. Almost all drugs exert their beneficial effects by either speeding up, or more commonly, inhibiting the activity of a protein that’s involved in a disease. For example, many proteins are perpetually “turned on” in cancer cells leading the cells to incessantly proliferate, and many anticancer drugs work by blocking the activity of these proteins and therefore bringing rampant cell division under control. What we, and pharmaceutical companies are looking for, is a molecule that is potent, selective, and safe. All these qualities are of paramount importance. Potency is important for the very action of the drug, and also so that doses can be small; a weakly potent drug may have to be administered in intolerably large amounts to work. Selectivity is perhaps even more important, because if the drug hits other proteins or targets, it is going to cause unwanted side effects. As we all realise when we take a pill, no drug is completely selective, and there are always side effects, but an effort has to be made to keep them mild and to a minimum. Which naturally brings us to the last point; safety, without which you cannot convince any patient to take a drug, no matter how effective it may be.

In case of curcumin, it shows beneficial effects, but it is not particularly potent for one specific disease. To make it potent for one disease, first of all it would have to be known which protein(s) it blocks or interacts with in the body. Then, knowing the structure of the drug and the protein, chemists can make efforts to modify the structure and increase the potency, and also to reduce the above quoted off-target effects. In case of curcumin therefore, much work needs to be done, before if it can be turned into, say, an effective anticancer drug. In addition, there will need to be extensive animal and finally clinical testing of the modified molecule before it can be approved and marketed. Not surprisingly, the effort required for this whole process has been compared to that expended in putting a man or woman on the moon and getting him or her back. The current estimates are staggering; upto a billion dollars, and 10-12 years, from conception of an idea for a drug (say, curcumin) to finished marketed product, with a success rate of about 5%! No wonder that making drugs is an extremely risky business in all its aspects. This is also the reason why companies are obssesed with patents, because that is the only way for them to recover all this money that has been spent and make a profit to fuel further research.

That’s why it is sometimes hard to take the claim seriously, that because traditional Indian medicine has “discovered” curcumin years ago, no company can file a patent based on it. Because as noted above, it is a long and tortuous route to start from a molecule in nature, and turn it into a safe, potent, selective, and cheap drug. The difference is somewhat like finished product and raw material, no matter how promising it is.

On the other hand, filing a patent on curcumin itself would cause a problem, because it would preclude further development of the molecule into a viable drug. However, this is what a US university did in 1995, thus essentially making it very difficult for especially non-profit organisations to investigate the benefits of the molecule. It is to the credit of the CSIR in India that it fought a hard battle and in 1997, made the patent null and void.
After that incident, while research on curcumin has flourished, no US company has been interested in filing a patent on it, because until now, data that promises turning curcumin into a profitable drug has been wanting. Plus, there is no incentive to make curcumin artificially, because it can be abundantly harvested from turmeric.

However, the late 90s changed that. Bharat Aggarwal at the University of Texas’s M.D. Anderson Cancer Center found that curcumin blocks the activity of a protein called Nf-kB, which is responsible for turning genes on and producing other proteins during times of stress, or when certain signals activate it. It was found that overactivation of Nf-kB plays an important role in many diseases, including inflammation and cancer to name two, so blocking its activity could be a viable therapy for these diseases. My own advisor has been one of those working on curcumin. He and his coworkers discovered a modified version of curcumin called EF24, which shows even better activity against Nf-kB and some other proteins, and filed a few patents on this molecule.

There is a still a long way to go for curcumin. As mentioned above, it needs to surpass many hurdles before it can become a bonafide drug. In case of Nf-kB, one of the most common and easily discerned objections is that it is a universal substance, present everywhere in the body. Blocking it would almost certainly lead to many side effects. However, it is usually overexpressed and continuously activated in cancer cells. One hopes that advantage can be taken of this difference in its behaviour to block it in cancer cells, while minimising “casualties” in normal cells. The other big problem is that curcumin is not soluble in water, an important requirement for an oral drug or one which needs to dissolve in the bloodstream. To resolve this issue, the new science of nanotechnology is working on methods to combine curcumin with nanoparticles that can dissolve in the blood and release it.

But at least now, with so many tantalizing hints, including observed anti-Alzheimer’s activity, pharmaceutical companies have started to show serious interest in it. Aggarwal himself has started a company colourfully named “Curry Pharmaceuticals”, and my advisor has also been associated with it. The data that is most lacking about curcumin is detailed information about its effects through controlled, rigorous, large scale clinical trials. Now such trials are underway in many countries, including India. If these clinical trials produce truly promising results, we can almost bet that pharmaceutical companies would jump at the chance to develop curcumin as a drug, and it could potentially rake in billions while saving or extending people’s lives. Promises certainly loom over the horizon.

From the snehlep (medicinal paste) prescribed by ancient sages, to Nf-kB modulating anticancer agent, curcumin has come a long way. It has already become one of the most impressive success stories of what modern medicine can get from the wisdom of traditional medicines. While it has a long way to go before getting converted into an actual drug, we can only hope that India, where its presence has lingered in so many guises for millenia, is the country which also takes advantages of its properties, and any monetary and humanistic benefits that can be accrued from it.