Sunday, May 18, 2014

The Cure for Cancer: Where is it?

Source: Mama Natural
One of the strongest health fears of current modern society is the potential risk of developing cancer. Even developing countries such as Colombia (where infectious diseases and perhaps violence were the main cause of dead) are reaching problematic numbers of cancer incidence. This has foster malicious people claiming to have found the cure for cancer which is usually accompanied for conspiracy theories that pharmaceutical companies are hiding the cure from us. This is total PSEUDOSCIENCE, or if you forgive me the expression "Product-of-moving-your-bowels-science".

As cancer biology student I feel the necessity to speak up about this issue and to actually propose where a potential "Cure" might be based on scientific facts.

The classical approach to eradicate cancer has tried to find new drugs that basically induce a complete damage either on the skeleton of the cancer cell, its machinery for cell division or inducing the "suicide" machinery without causing damage to the normal cells. This is exactly the same strategy that has been applied to rest of human diseases, how to specifically control what is wrong without damaging the rest. This has been successful in a tremendous amount of cases (we have pretty much a "pill" for every human morbid condition). Infectious diseases are the best example, a simple urinary infection can be treated with antibiotics that do harm the bacteria but leave the rest of the cells untouched. Off course the picture is never black and white and drugs might have side effects, (after all we share many biochemical similarities with different organisms and among our diseased cells) but for this we rely in the ability of our body to compensate those side effects, which was called homeostasis in the early years of science.

However cancer is a different story, it has been proved more challenging to treat, even harder than AIDS. In Cancer's biography book "The Emperor of All Maladies" by Siddhartha Mukherjee we can clearly see that cancer has been around from quite some time, with first evidence from the Egyptian period (and probably even before, but harder to collect evidence). So it is not as new as one would think, however cancer is not really threatening our species since usually affects elderly, which have probably generated descendants, therefore we lack of selective pressure in eradicating cancer by the sake of evolution (or maybe not?). Current cancer therapies can in principle kill cancer cells but at the same time causing serious side effects in the patient and it does not block cancer growth in advanced stages where most of the cases are diagnosed. Few cancers have an ID, like prostate cancer which release the Prostate specific antigen (PSA) which has been used in diagnosis (with current limited utility) but most of cancer types lack of this molecular ID that can help to distinguish them from normal cells. Here is where the problem arises. Additionally we know that cancer cells are favored from mutations which tend to be very frequent in some cancer types giving superpowers to cancer cells, such as "immortality", metabolic strength and migration potential to invade whatever organ they want.

So it looks like that we are running out of options of how to treat cancer. Basically the only solution until now is to live a healthy life and wait for the best. Although it's an easy and low cost solution I do really believe that there is a hope for a cure and 4 important scientific advances currently under development, which possibly combined together, can really push forward the reality of having one day a cure for cancer. Nanotechnology is the first.  Richard Feynman, Nobel prize physicist and one of my scientific super-heros, envisioned nanotechnology, long before the first nano-devices were even created (see his famous nanotechnology lecture here). Things like having nano-robots that can deliver drugs directly into the cancer cells and kill them are one of the possible applications. There are actually fascinating advances in this field, for example, scientists from Penn State have designed nano-robots that make a cell dancing like a whipping top: rotating HeLa video (check 1:47 min):

This is a fancy example of nanotechnology achievements but medical applications are currently being developed and tested, such as nanoparticles for drug delivery which are just simply more elaborated molecular transporters than currently used in pharmaceutical production. A list of clinical trials using nano-particles for different cancer types can be found here. It is pretty much like an intelligent missile, in contrast to the current drug missiles that are fired in a hope that it "hits" something. Before we get too excited, nanoparticles can only solve the problem of drug toxicity but specific delivery is still challenging, meaning a nanorobot that specifically finds all cancer cells, even the hidden ones and kills them, it is still science fiction, but let's remember that science fiction is just simply science plus time, so eventually all these dreams will come true and probably much more sooner than later.

The second finding, very encouraging, it's the fascinating properties of a molecule that I'm sure will be a star in the cancer field for some time. The funny part is that we all probably have tasted it at least once. The compound is called Curcumin, and it is the main ingredient of indian curry and asian related cusine. What is fascinating about this molecule is that induces dead in cancer cells but it DOES NOT harm normal cells, and in fact it can protect them. This turns the hope on again that there might be a difference between cancer cells and normal cells that could allow us to selectively kill them, and curcumin is rescuing this hope. It is amazing to see the exponential growth of publications about curcumin and cancer:

But it hasn't been only used in cancer, It has recognized anti-inflamatory properties and a clinical trial in advanced pancreatic cancer has shown promising results; no toxicity and tumor regression (see study here). However, curcumin does not distribute well in the body, since it is not very soluble in water, but even nano-preparations are being made to overcome this problem (1). To date, 15 clinical trials are about to start, in the hope of finding more clinical relevant effects of curcumin (full list here). But this will just be the start for developments of a new family of drugs based on the knowledge that will be acquired with curcumin. Before knowing about curcumin, what I would have probably said is that the hope resides in using many different drugs that target different parts of the cancer cell separately giving no chance to this monster to adapt and scape the treatment, but curcumin has changed the game again showing that a single molecule can have all these effects without the need of complex combinations or even complex dosing schedules, (e.g giving drugs at particular times). Nature does not stop in surprising us.

The 2 remaining advances which I think it will positively contribute to the way we look at cancer are: The study of mole rats and the understanding of spontaneous regression in cancer. There is one left which I won't mention much but it is a hot topic in cancer research and it is the use of the immune system to kill cancer cells, and the development of the so called cancer vaccines. To be honest I think it is a fascinating field as well, but the immune system is something to be careful about, an incorrect stimulation can trigger the destruction of our own normal cells and develop an autoimmune disease.

What is the interesting thing about naked mole rats? They basically can live about 30 years which translated in human years is 900!!!!!! , I found this incredibly hard to believe but it is actually true, and as you can probably immediately think those rats do not get cancer. (2).

source: National Geographic
Imagine living for 900 years, I hope we find some more interesting things to do than flirting with high school girls like the guy from Twilight in the movie. In any case, there is active research going on in figuring out how these rats avoid cancer, which mechanisms do they employ to control cell proliferation. The initial proposal is that these rats possess a molecule that avoids the cells to get directly in contact with other cells, sort of like making a room for each cell, therefore if a cells starts to become crazy it does not have close friends to help it. However I'm pretty sure more interesting anti-cancer mechanisms will be discovered in these animals. What about spontaneous regression?, there is something that probably is not well known in the community and I was very surprised myself as a biologist that I did not know about this phenomena. Cancer can actually disappears spontaneously without any help from drugs. Even though these are rare cases, from 1-2% in common cancer types, it can go up to 30% in Neuroblastoma which is a cancer that affects children from less than 1 year old (3). It also surprises me the negativism of cancer researchers around the topic of spontaneous regression, but I could understand that those cases are like watching comets in the sky, you don't see them very often but when you see them, you go desperately to find your camera and when you come back they are gone. Perhaps this problem can be solved more with the initiatives of Translational medicine which is not other thing than having medical doctors right next to experimental labs talking to scientists, maybe some patterns can be seen right before the regression starts and being able to monitor it. But for now, cancer scientists just give a very sad-face explanation of how this spontaneous regression occurs by oversimplifying the problem and trying to get your attention out of it.

So let's imagine an scenario where drugs like curcumin are developed and are delivered directly to tumor cells using nanodevices for treating advanced patients. Pretty much like in the recent movie Transcendence, with the amazing difference that we did not need artificial intelligence to come up with the idea, we can already figure it out ourselves by combining creatively different types of knowledge. And what about the knowledge coming from understanding the anti-cancer mechanisms in naked mole rats and spontaneous regression in humans?, I think this will boost as well a family of drugs (or perhaps nutritional supplements?) that can activate those mechanisms in our cells and develop a potent anti-cancer destruction response right before the tumor starts to become out of control. And off course for the scientists that enjoy curiosity, this knowledge will be a tasty apfelstrudel of information to just simply understand how human cells proliferate and how they can avoid cancer just for the sake of feeding curiosity.

This 2 last topics makes also rise evolutionary questions. Natural selection is giving us clues of how to fight cancer, with super rats and spontaneous cures of cancer in humans. And the clues are not accidental since they repeat again and probably other animals have anti-cancer mechanisms unknown for us. After listening a discussion in youtube between two amazing scientists and science communicators, Richard Dawkins and Neil deGrasse Tyson (video here 39:00 min). A question that Tyson asks which I found extremely interesting and never thought about it, is: evolution has always found the way to come up with the same solutions, how many times life has come up with eyes?, many animals do have eyes and the structure is really similar between them. Therefore it seems important to have eyes. The cancer has appeared in rats and appears in us (perhaps less frequently) so it is probably important for evolution to find out the solution for cancer, the reason, I don't know, but if you allow me to speculate, it will probably be important for our future survival.

To sum up, cancer cure might come, probably sooner than we expect, but the issue for that to happen is that the scientists need to be aware of the amazing facts that are going on in nature rather than being amazingly blind to only the molecular descriptions we made in our day by day experiments. We kind of have to lift up our heads and look to what nature is telling us. Now that I mention the gene problem, every time we affect one gene in a cell we see an effect and we claim that such a gene is important. The problem with this approach is that we have approximately 20.000 genes which are heavily connected so this actually won't tell us much of the cell behavior as we will always see an effect, because the gene is there for a reason right?. However a turn around of events, again by looking at nature is that there are some humans which lack of certain genes and they are still alive and healthy, and now that we can sequence people in a blink of an eye, it will be extremely exciting to find this human "knockouts" which can actually tell us the importance of the different genes. And this is what is going now in the Project Human Knockout which intends to characterize that. This project will actually tell us which genes are really important for our survival.

Conclusion: Long life for humans!, although I think we might need better psychological techniques to keep us motivated if we want to live 900 years! perhaps at the end we will all become scientists, something that we all were when we were babies (see article) but then we somehow lost it because of education. If you think living 900 years is funny, see the paper of the research that was done from a lady that lived 115 years!

Remember: The cure for boredom is curiosity since there is no cure for curiosity! - Dorothy Parker.

Andres Florez.

The "Executable" Dogma of Molecular Biology

The DNA is normally represented in textbooks as the "Code" that dictates cell's organization. In some aspects it can be considered as a code in the computational sense. I will show briefly the tremendous similarities between the Central dogma of Molecular Biology and The Central Dogma of computer programming. This will show clearly that maybe Francis Crick was a computer scientist in his heart.

The DNA represents the open source code that contains the instructions that dictate the cell behavior and its dynamics. This code was hidden for long time like code of google, but the new technologies of sequencing have now revealed it to us. However as the source code in every computer program, it cannot do anything by itself, as in the cell, the DNA is useless alone, and it needs to be compiled into other kind of code that can actually perform some functions, and that code is the PROTEIN code. If we take the example of a language, like C , the code (DNA) has to be taken by other program (Transcription machinery) and be explicitly expressed in the pre-compiled code RNA by a series of processes. If we look at how a computer program is generated, the code needs first to be checked  and processed in order to be compiled, and this will require for example the deletion of comments. Remarkably, the cell executes these steps and "comments" in the code or introns are deleted before the final pre-compiled code or mRNA can be generated.

Once the code is ready or pre-compiled, it can now become an executable. This final compilation is carried out by the ribosome which generates the proteins or the "executables" of the cell and generates the whole operating system of different types of cells. We know some of them in our daily life, like, windows, linux or mac windows but all of them have some logical architecture built on this pieces of software that in the cell are called proteins.

Nevertheless, as in every computer program, errors or bugs can be arised, because of lack of programming skills of the "Programmer" or simple by random errors that the programmer hasn't realized about. This can led to terrible consequences like unexpected crashes, or in cell terms, unexpected "cancer" or some other diseases that are generated by errors in the code.

According to this, we can simply say that a cell is just a a very efficient computer, but it seems necessary a better understanding not only of the source (which is already very well known)  but also the operating system and the hardware, and only by integrating the knowledge derived from software and hardware, we will be able unreveal the correct functioning of the cell computer and the recipe that will allow to built new "computers" or who knows, maybe "Cell"pads that allows to understand biology while sitting on the back part of the train.

Andres F.

Sunday, April 28, 2013

Symptoms and treatment options for Machaca's bite. A retrospective description.

(This entry was written only for entertainment, even though the organism really exist the story is a legend modified with some sciency language)

A fascinating insect called Machaca (Fulgora laternaria) has caused an increasing curiosity among the fellows outside of South America, especially by the controversial treatment once the person is bitten by this organism. However I think this interesting insect deserves to be investigated since not much is known about the molecular mechanisms involved in the pathology of the disease as well as the reasons for the tremendous effectiveness of the treatment, which was discovered by using popular wisdom. In this note I will give some information that I hope can help to fill the gaps of knowledge in the biology of Machaca. This curious organism that possibly increased the human population in Colombia around the 90s decade, has very interesting features that are worth to mention in this short note.

The Machaca is planthopper that ranges a distribution from almost entire Brazil (where pretty much all kinds of insects can be found) up to Mexico. An interesting feature of this insect is its head similar to a lizard, which makes the appearance funny and perhaps disgusting, as some people may think. But the fact is that at least in Colombia, the image of a lizard is associated to great sense of humor, with colombian comedians such us "Hombre Caiman" or the “Caiman man” or better Cai-man (anyways doesn't sound right in english), using its figure. However from the evolutionary point of view, The Machaca does not share any relationship with lizards and potential genome sequencing projects are currently developed by the cultural preservation organizations such as Rosa Melano foundation. This mythical animal, however has been the reason for un-countable amount of stories, much of them made up but unconscious people, therefore a careful study is needed to explain the true about this animal.

The description of the disease caused by Machaca started in Putumayo, a region in the south of Colombia where people knew by their own experiences the danger that constitues the Machaca. All the information we have gathered is provided by an adventurous Journalist from Cali, Henry Holguin. The machaca almost reaches 10 cm large and usually flies by extending its wings like Da Vinci initial designs and using the air currents as propulsion without so much active wing movement. In its lower part of the thorax posses a sting that injects a viscous liquid that people from Putumayo claims is the venom that causes Machaca’s disease. 

The clinical symptoms after the bite includes a very painful erection with a highly extended rash. People who has suffered from Machaca bite claim that it is worst pain they have experimented and it is only equivalent to see how Barcelona gets 4 goals from the Bayern. (Not fan of soccer so I can’t understand the comparison). Additionally and this is an important warning sign of the imminent dead, is a progressive somnolence. This somnolence is the responsible for final cardio-respiratory arrest if treatment is not provided within 24 hr of the bite. You may want to ask, Why isn’t this animal being eradicated or Why isn’t the CDC or other control organisms trying to employ strong measures for protection against this insect?. Well it turns out that the treatment is so simple and without any cost, (maybe?) that is not worth to scare people out about the Machaca. The treatment consists in having sex immediately after the bite. However first question can pop up, is it just sex or other sex-related acts can work as well?. In fact, recent studies on Machaca venom have explained that only man-woman coital contact is needed to block the venom since the woman's secretion contains endorphin-related peptides that are able to compete for Machaca’s venom receptors without inducing the sleeping-depressing mortal effects. The first documented case of dead due to Machaca's poison was documented in 1948. Jack Meoff from Barranquilla died from a cardio-respiratory arrest since he wasn’t able to get involved in sexual intercourse before 24 hr after the bite since he was working inside the jungle with no female companion (further regulations have been implemented for workers in isolated places). Another sad case was Ben Dover of 45 years old in 1996, who was defeated by Machaca since he forgot the treament only works with male-female interaction. 

One might ask, Does Machaca bite women as well?. The answer is yes and the effects and treatment are the same as for the case of man (excluding the painful erection), however the molecular mechanisms are different. In the woman’s case, man’s secretions contain high levels of IgA antibodies that work as ligands. These IgA molecules activate a certain subtype of receptors that trigger the activation of protein clusters that store some specific microRNAs which are then released into the blood. These complexes travel to the brain where they are internalized and basically downregulate the expression of endorphin receptors therefore blocking the sleeping and respiratory depression caused by the Machaca's venom. Some other authors have claimed that excitement of sexual act  (especially when a lot of screaming is involved) alters histone acetylation patterns that lead to a better response to Machaca’s venom by increasing the expression of counteracting decoy receptors. People from outside of South America has suffered this disease as well, and one documented case of a woman from the Netherlands ended well as she was able to survive when she received the treatment in her country. However as a strange case, she had a relapse after a month what made her to come back to Colombia to receive a more strong and lasting effect treatment provided by a Latino.

However all is not bad about Machaca and it turns out that german scientists are trying to isolate the machaca venom to characterize it, since it could be used as a potent sexual stimulant which may help to the birth rate crisis in that country. 

Some antibody-based treatments are being developed, and machaca activists have sarted to protest by sitting in front of the responsible pharmaceutical companies carrying “signs” saying, “WE ALREADY HAVE A GOOD TREATMENT, DO NOT TAKE THE FUN OF IT”.

I hope this gives a clearer overview of the fascinating biology of this organism, and as you my dear readers may think, Machaca has been in fact inspiration for many and even songs have been written to it. I want to thank Nikko (who will release his Machaca song soon) and Mostafa for his scientific interest in this animal that has motivated me to write this article.  I want to thank as well to Wikipedia and Espectador journal for providing the necessary information.