I-Genics

Watson in Jeopardy

2011-03-10T12:27:00.006-05:00

From time to time a new computer, robot or piece of software comes by and impresses us so much that I think it cannot be real, must be a fake of some kind.
When Deep Blue faced Kasparov in a series of chess matches, winning 2-1, it is reported that after a particularly unexpected move, the human player stood up and accused the computer of being controlled by humans: a computer could never conceive such a creative move.
When I watched the recent Jeopardy match between the computer (robot? software?) Watson and two champions of the game, I had the same feeling. The first thing that impressed me was that the moderator of the game spoke so fast that the algorithm used to translate the speech into text had to be really great.
Second, translating speech to text is one thing, now how to place this into context? At certain moments the moderator would address Watson and ask questions while in other moments the moderator would talk to the other participants or even the audience, so how did Watson know he was being addressed? There were probably keywords that are used in this game, and the programmers that built Watson probably added these as reference, but by what I saw, in only one occasion Watson spoke out of time, when he incorrectly pronounced the detergent "Cheer" as "Cheering".
Third, the questions of this game are a challenge by itself. I noticed that the two human players took at least one attempt before they understood what the category of questions was about, while Watson didn't miss any of them. How could he "understand" something better than a human? I will reinforce the question: humans have this belief that we are better capable than anything else on Earth of understanding a situation, making sense of it. After all, we can watch tv, which is a projection of a 3D universe into a plane. We can watch a six year old drawing of car and understanding that it means a car. So how come Watson was capable catching the ideas of the questions so fast that the other players would look at each other with that "Ahan..." look?
Fourth, once the scope of the question was defined, how did Watson translate the meaning of the question to the answer? We can conceive that Watson has almost limitless storage capacity and a super-fast processing, but how do you determine that George Bush rhymes with "tush"? Does a computer know what rhyme is? Does Watson have stored somewhere the notion of rhyme, or maybe of sound?
I don't believe so, it appears to me too much, but perhaps I am wrong. What I believe, however is that perhaps if you are fast enough and have enough processing power, you can come up with solutions that were not built with logic reasoning, step by step, as we do. Maybe Watson is not a robot built to think like us, maybe he was not even built to think in first place, perhaps he's just like the room full of monkeys which eventually write down all the work from Shakespeare.
But this rises at least one question? Even if Watson is quick and powerful enough to create a huge number of different answers almost instantly, he still needs to parse those and choose only one, and this implies that he must be capable of comparing the answers and saying which ones are better than the others. Doesn't this imply that he has at least to understand the question?
This hypothetical approach would be similar to a person who cannot solve a differential equation but who can derive expressions, thus he can generate a random list of functions and test each of them as the possible solution for the problem. But again, how does Watson score his answers?
Of course other possibilities for what we saw in Jeopardy, for instance, it is possible that IBM had a thousand different Jeopardy experts playing in a network and they all submitted their answers within the 3 second limit, the answer most voted would then be chosen, but I don't believe this happened. The answer that Watson gave to a tennis term which was also used in races was so out of contest ("automobile races" instead of "rally") that it rose giggles from the participants and audience.
A second possibility is that Watson is connected to a Doomsday machine: every time Watson gave a wrong answer, the universe was destroyed (or at least Earth, or at least me and you reader). In universes where Watson got the right answer we would be left baffled by this wondrous machine. I first read this example of the ultimate computation in a book by Hans Moravek "Mind Children", and of course would only work if the theory of parallel universes is valid.

Can the knowledge of the observer alter the subject of observation?

2010-03-01T17:00:00.004-05:00

There are at least two well known novels where a character is capable of "seeing" the future, the first one is Foundation from Isaac Asimov and the second is Dune from Frank Herbert.
In Foundation, a mathematician name Hari Seldon develops a branch of Mathematics named PsychoHistory which he uses to model the universe (more specifically the interactions across a galaxy-wide humanity) and predict how it would behave. Hari discovers that the galactic empire is about to fall (within the next hundreds of years) and he uses PsychoHistory to interfere with this fall in order to minimize it and create a Foundation for the creation of a new empire.
In Dune, Paul Muad'Dib, the Kwisatz Haderach, has the power to see the future through trances induced by Spice, a mysterious drug. In Dune, many are able to see hints of the future thanks to the spice but Paul is the only one that can clearly see the future of human kind, much like Hari Seldon, as much as his own.
Both are tragic characters, like Cassandra from Greek mythology, and their gift of vision into the future eventually becomes their ruin.
These two examples along with memories from my Logic classes and Goedel Incompleteness Theorem (basically a system of rules cannot contain itself and thus cannot self-validate) made me think that any observer could be classified into at least three categories: (a) An observer with little knowledge (predictive power) of the subject being observed, (b) an observer with total knowledge of the object and (c) an observer with knowledge of the object and itself.
In the first case the object's properties are independent of the observer's existence and thus the observer may find the subject "unpredictable" or predictable but showing some "noise" or "error".
In the second case the observer knows in advance the next state of the subject of observation. Considering that this is known ahead of time only to the observer, does it imply that the object is determined by the observer? Does the observer see the future or does he create it?
The third case is the most elaborate: the observer not only knows how the subject will behave but also how he (the observer) will react to this and thus the subject is aware of an immutable future in which he is trapped.
Seldon and Muad'Dib also had another ace in their sleeves: both were leaders of men and eventually were believed as Oracles, Seldon after death, MuadDib in life. Seldon continued to guide his followers through video recordings that explained the current state of matters and how they should act. Was Seldon using these communications as a way of shaping the future? Were his predictions nothing more than tricks that made people believe that he could actually see the future and thus they would do as he said, thus creating a future foreseen by him?
Muad'Dib becomes emperor of the known universe with the goal of avoiding a great tragedy that would eradicate mankind. Eventually he becomes the cruelest tyrant in History in his desperate attempt to steer mankind into the right direction. No matter how much he tried, the universe found a way of slipping through his fingers and returning to his apocalyptic visions. Eventually he realizes that his own existence and his influence in others was the key log that kept that terrible future immutable and he decides to walk into the desert alone towards death.
So comes the final question: do we have really free will or are we only deluded because of our lack of knowledge of the universe and ourselves?

Slums in big cities and tumor invasion

2009-11-04T16:55:00.003-05:00

In this assay we compare two phenomena: tumorigenesis and the development of slums in big cities, and propose that not only the rules that control their existence are similar but also that the strategies in order to eradicate them are equivalent and that the lessons learned from one problem can be used in the other.

Slums are a grave problem in big cities in underdeveloped and in development countries. In 2007 in São Paulo, the biggest city in Brazil, there were approximately 2,000 slums with a total population of more than 400,000 families living in sub-human conditions. Besides the social problem of this population deprived of minimum sanitary conditions, slums are also safe haven for organized crime and drug dealers and gradually grow by engulfing neighborhoods of the city whose real-state is downgraded by the proximity with them.

Tumors are believed to be created by the relentless replication of genetically unstable cells that, through mutations and selection from microenvironment, acquire a set of phenotypes that allow them to invade healthy tissue, promote angiogenesis and colonize new regions of the host and create new tumors [1, 2], eventually reaching a state of tumor burden that is fatal to the host.

Both phenomena, slums and tumors, often develop in the periphery of the host (carcinomas develop from epithelial tissue separated by host by basement membrane while slums have their origin in the outskirts of towns where real state is less expensive) where resources are limited and uncontrolled growth lead to gradients of resources and harsh conditions.

Both systems invade by “trashing” their surroundings: tumors invade healthy tissue by both degradation of extracellular matrix and by causing death of healthy cells; it is known that tumors constitutively metabolize glucose anaerobically producing lactic acid [3, 4] even in presence of oxygen. It was proposed that this glycolytic phenotype would be a mechanism through which tumors would intoxicate their surroundings in order to kill healthy tissue and make room for new tumor cells [4]. A similar mechanism is found in the periphery of growing slums: a wave of devaluation of real state moves outwards of the slum propagated by criminality which imposes a “bad reputation” to the neighborhood, scaring the dwellers away and leaving room for new residents from the slum periphery or from outside of the system.

Solid tumors are often avascular during the early steps of tumorigenesis and are only able to promote angiogenesis as they achieve a critical mass. The fragile infrastructure of slums is no different from solid tumors: as one progresses into the settlement, the roads become narrower until cars cannot traffic, what considerably reduces efficiency of law enforcement. This inability of law enforcement and a minimum infrastructure for the survival of the slums is similar to what happens in solid tumors. In one side poor perfusion prevents a faster growth of tumor but on the other hand it protects the tumor by preventing the action of the immune system, chemotherapy and radiotherapy by limiting diffusion of drug, inducing quiescence in hypoxic tumor cells and by generating a heterogeneous microenvironment that confers robustness to attack [5].

We have discussed some aspects in how carcinomas and slums develop in a similar manner, notably by uncontrolled population growth in an area in the edge of the host/city with poor infrastructure but also with small or no interference from immune system/law enforcement, as is the case with carcinomas which are separate from immune system by a basement membrane.

Both systems appear to be robust to brute force attacks (toxins and antibiotics in cancer, and law enforcement and eviction in slums) not only because these approaches cause higher side effects in the “host” than in the target but also because the forces that promoted the initial development of these systems remain unchanged (genetic instability and microenvironment-imposed selection for cancer, and social inequality in slums) and thus will promote regrowth of the original system or other similar ones in other areas.

We propose that the most promising strategies for eradicating and preventing carcinomas and slums are those that target the forces that promote their emergence. For carcinomas these strategies would focus on intratumoral pH normalization, use of glucose competitors, use minimum amounts of therapy necessary to arrest tumor growth and delay patient relapse, and finally assess tumor response to therapy in a closed-loop approach. For slums, whose emergence is due to a considerable mass of poor people, the most promising approach would be to invest resources into bringing this share of the society into more equal conditions, which can be achieved by full-time public education with meals and recreational activities in order to keep the children away from one environment permeated by violence, drugs and poverty. Work laws that ensure minimum wages and social programs to provide credit to families to finance homes are also more immediate actions. Finally, the problem of slums in big cities will never be solved if the flow of migrants from poorer underdeveloped regions of the country remains. It is important thus that such an action for reduction of social disparities happens country-wide.

As a final note, we would like to stress that even though slums carry within criminality and major social and public health problems, they only exist and grow because of the initial advantage of cheap labor they offer to the richer population of the cities. An interesting point is that in carcinomas the cells that develop as tumors are exactly those that are isolated in the periphery of the host and considered as “expendable”.

Goldie JH: Drug resistance in cancer: a perspective. Cancer Metastasis Rev 2001, 20:63-68.
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.
Gatenby RA, Gillies RJ: A microenvironmental model of carcinogenesis. Nat Rev Cancer 2008, 8:56-61.
Gatenby RA, Gawlinski ET, Gmitro AF, Kaylor B, Gillies RJ: Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 2006, 66:5216-5223.
Kitano H: Cancer robustness: tumour tactics. Nature 2003, 426:125.

Mets are Vets?

2009-03-11T13:59:00.002-04:00

The other day I was talking to one of my advisers and he mentioned that a reviewer had just critiques the fact that the Acid Mediated Tumor Invasion does not consider the fact that the aggressive cells selected by tumor microenvironment (hypoxic and acidic) should lose this phenotype once they progress through healthy tumors, since the selective pressure on these cells decreases as they invade further from original tumor.
A metaphor used by that time was that tumor cells are like Navy Seals who, once far from their training environment, relaxing in a paradisaical beach would eventually get soft like other regular people.
The point here, I believe, is that the metaphor is wrong for tumor cells are not trained to be tough, they are selected, they are traumatized like 17-year old boys who are sent to war. Those who are able to adapt, to toughen up, survive and come back home, but many of them cannot adapt back to normal life.
The perfect example is John Rambo. When Rambo, and many other Vietnam war vets, returned to US, he no longer could live in society as we do. He would see threats everywhere, he would trust no one and would not accept the authority of civilians. In the movie Rambo escapes from prison and hides in the woods nearby the city. When the police and National Guard try and capture him he turns back to the Green Beret M.O. and kills them all.
At the end of the movie he destroy much of the city including the Police Station.
I believe that the cells that survived the stress created by tumor development and reached a more healthy environment to live will, in their majority, settle down. The cells that start new metastases however are like John Rambo: they cannot re-adapt to normal environment so they tend to re-create the original environment that traumatized them.
If this is true, there may be ways of acquiring an aggressive phenotype through reversible ways (most of tumor cells) but some of these ways may yield to irreversible conversion and eventually lead to cells that can generate metastases.
A microarray analysis as well as protein expression of cells recovered from metastases compared to the original tumor cells might yield to clues on how this commitment happens.

Substrate-induced starvation in cells?

2009-03-02T14:28:00.001-05:00

I was just reading an article sent to me by my PhD adviser about evolution of metabolic networks.
It is impressive how metabolism is structured in a complex network with apparent redundancies, inefficiencies and bottlenecks.
But this post is about something extremely interesting I read in one of the references: apparently some of these metabolic pathways are "boosted up" by an energy-dependent step. These are called "Turbo-designed pathways" and glycolysis is one of them.
In glycolysis, before glucose catabolism can yield 4 molecules of ATP, first it consumes 2 molecules.
When yeast is grown in culture with high glucose concentration, negative feedback mechanisms prevent the cell from wasting too much energy in accumulating substrates intracellularly and at the cost of a lot of energy. Yeast just uptakes enough glucose, phosphorilates it (2 moles of ATP consumed) and then metabolizes it to get enough energy.
However, when yeast is grown in media with high malate (analogous to glucose) concentration, these cells will deplete all their energy uptaking this substrate and before they are able to make out the ATP surplus, they are already dead.
It is like someone spending all their money in seeds and not saving anything for sowing the crops.

The funny thing is that tumor cells are known for increased glucose metabolism, not only increased glucose consumption but anaerobic glucose metabolism, which is much less efficient. So wouldn't these cells just starve to death? I guess they would, if the increase in the metabolic flux where in the ATP consuming steps, what would lead to accumulation of metabolites and energy deprivation. But if the increase is in the ATP generating steps (after glyceraldehyde-3-phosphate dehydrogenase) then it would yield to energy surplus.

This conclusion is very interesting because it suggests that any increase in expression of glycolytic enzymes pre-GAPD should come only after the ATP-surplus enzymes have already been mutated (or its expression increased) to increase its reactions fluxes.

For references:

The danger of metabolic pathways with turbo design. Teusink et al., 1998
Glycolysis, turbo design and the endocrine pancreatic β cell. Iynedjian, 1998

Humankind and cancer

2009-02-06T10:47:00.000-05:00

One Day I was talking to my postdoc mentor about how a therapy for total cancer eradication should look like. We were not arguing any specific strategy bust just were trying to imagine how a cure for cancer would look like and how we would describe it if we found a Djinn in a desert.
The dialog proceeded a bit like this:

Mentor-An average tumor should have something around 5-10 billion cells. This tumor, however, is often spreaded around the body in regions from which it cannot be extracted without causing patient death.
I-But can't we help the body fighting it? Cancer immunotherapy proposes to identify over-expressed proteins that can be targeted by immune system.
M-Do you know the success rate of these therapies?
I-5-10%?
M-You'd be surprised by what a placebo can do...
I-So how could we envisage a therapy? Any sort of cure? Maybe keeping cancer as a chronic disease, just slow down its growth?
M-Coming back to the tumor size, imagine humankind where a tumor on earth, there are around 6 billion people, spreaded all over the world. They eat differently, have different resistant to diseases, live in different weathers, humankind is pretty much as heterogeneous as tumors...and as pernicious to the planet as tumors are to human body.
I-So the problems are equivalent: how to eradicate human kind and save the planet is like eradicating a tumor?

Now how can we overcome such a challenge? The more we proliferate on Earth and the more we pollute, destroy natural ecosystems, the closer we get to our own extinction, but will life on the planet survive our extinction or shall we bring all life with us like a real cancer?

Why do tumor cells glycolyse?

2009-01-23T11:32:00.000-05:00

Since Pasteur and Warburg it is known that tissue tends to increase glucose uptake in low oxygen environments and that tumors continue metabolizing glucose anaerobically even in presence of oxygen.
Warburg originally hypothesized that this effect not only was a hallmark of cancer but also that is was its main cause. Warburg believed that all tumor cells had malfunctioning mitochondria and thus were forced to rely on anaerobic energy metabolism.
Gatenby and Gillies recently proposed the acid mediated tumor invasion hypothesis, through which, not only glycolysis was necessary for tumor proliferation and invasion, but also that this phenotype is selected by the micronenvironment were epithelial tumors are formed.
This hypothesis proposes that the use of abundant glucose in serum anaerobically would provide enough energy for tumors to develop and also produce acicity that promotes degradation of extracellular matrix and induces apoptose in normal surrounding tissue.
One interesting point, however is that tumor do not entirely abandon aerobic metabolism. Oxygen is necessary for keeping the basic functioning of TCA cycle that not only produces energy but also is linked to production of fatty acids and and many other metabolic pathways in cells. It has been shown that tumor regions in anoxic conditions become too acid for even tumor cells to survive.
I propose that the reduction of O2 consumption in tumors is an adaptation at population level. The cells that are in tumor rim, closer to oxygen-rich tissue, consume less oxygen which diffuses through them towards the cells in the inner core of tumor, preventing excessive acidosis and allowing tumor growth.
This kind of behavior is not normally proposed in tumors, that are normally considered as a heterogenous disorganized mass, but maybe these systems of cooperation between different subpopulations in a heterogeneous environment are exactly what differentiate malignant tumors from the many neoplasias that are periodically destroyed in our bodies without our knowing.

Democracy and Cancer

2009-01-23T10:33:00.000-05:00

For long time it has been known that molecular signaling in cells is done through scale-free networks, both at gene and protein levels.
Such networks possess an architecture that confers resistance to failures but fragility to attacks.
The Internet uses such architecture: every computer is connected to an "internet access provider" which is connected to other servers that are interconnected all over the world. The design of internet addresses is an example of this hierarchical architecture, where each node is directly connected to approximately the same number of nodes (or at least the same order of magnitude).
A failure in a random computer in the network is not likely to affect the network performance since the chances of this computer being in a node in the lowest levels of the network (a user computer) is a lot lower than being one of the servers. Also, the catastrophic consequences of a failure in one main node in the network, associated with the low number of computers in this level, allow spending more money in protecting these high-level nodes with backup systems.
This architecture also allows control of network flux (it is sufficient to control a few high level nodes in order to control most of network flow) but also raise the risk of attacks.
Many examples exist of hacker attacks directed to websites, corporative networks and even entire countries.
How does this links to cancer?
It is widely accepted that cancer is originated from genetic instability. Many other factors, such as population heterogeneity (also born from genetic instability) and environmental conditions (selective forces, inflammation, exposure of body to carcinogens, etc.) are also important and may harness the genetic variability and direct towards malignancy.
Genetic instability can be considered as failures in the regulatory networks of the cell. These failures are most probable to happen in nodes in the lower levels of the network, for these are the most numerous. The mutations can occur in three ways: the first would be either a silent mutation or a mutation that would cause little effect on cell state, the second being a mutation that would alter cell state in a way that it would activate cell programmed death mechanism.
The third and most dangerous way if a mutation that alters cell state but bypasses apoptosis. Such mutations, if accumulated, would allow cell to escape body's control system and start a tumor.

Another point I'd like to point out is that the scale-free architecture from cell networks are optimized for evolutionary purposes: when a node is connected to many different others, and each of these others is connected to many others, it is possible for this system to gradually evolve to selection through increase of weight of influence from one of the 2nd degree nodes but also show more dramatic evolution due to modification of weight of a 1st degree neighbor or of the node itself.

Lastly, this architecture is very similar to a democracy, where most of the people has one low value vote, while fewer have higher level votes (congressmen) and very few have rights to alter the state of entire groups (governors, president). The idea of democracy is not that the majority is smarter than individuals but rather that a great number of people are less likely to take decisions that will harm the entire group. Due to practicity, democracy had to be stratified to allow decisions to be taken more rapidly, and thus appeared the scale free network of decision making known today is most democratic nations.

Most of the efforts today in cancer treatment are focused on finding targets that can be treated by highly specific drugs. It is believed that if these targets, which are often mutated in cancer, are silenced, cancer cells would die or at least lose its advantage over normal cells.
This idea would be correct if the only mutated nodes were the ones selected by the therapy. Unfortunately cancer is not based on attack but rather to failure and thus the probability is that, if a high level node has been mutated, this event was preceded by many more other mutations in intermediate and lower levels nodes all over cell signaling network.

Instead of a corrupt governor or president, cancer is more likely to be the result of a coup d'êtat that gradually formed from the infiltration of enemies all over the hierarchy of cell network. If one leader is removed from the network, it is likely that many other still exist in a lower level and will eventually replace the lost comrade.

In such a situation, the strategies to be used would be similar to the ones that have had success in fighting corruption in poor countries: the development of education and the increase of level of life of citizens tends to reduce the chances that corrupt leaders will be elected. The same is true for cells: if the micro environment of tumors is changed to endanger the survival of cells, there will be an opportunity for these cells to suffer mutations and diverge towards cancer. Conversely, modification in micro environment may reverse this tendency by preventing new cells from turning into cancer cells and also by reducing the efficiency of the tumor phenotype which is adapted to adverse conditions.

Regulatory network of genes with known role in cancer.
From "A map of human cancer signaling."
Qinghua Cui, Yun Ma, Maria Jaramillo, Hamza Bari, Arif Awan, Song Yang, Simo Zhang, Lixue Liu, Meng Lu, Maureen O'Connor-McCourt, Enrico O Purisima & Edwin Wang doi:10.1038/msb4100200

A 3D Computer Model to Map Modifications in Cellular Metabolism into Different Tumor Phenotypes

2007-07-29T17:06:00.000-04:00

In this work we propose an approach for studying tumor
development as an iterative process that searches for the
minimum set of modifications in cell metabolism that would lead
healthy tissue to develop an invasive tumor.

There are many models in the literature describing putative
steps necessary for a homogenous population of healthy
epithelial cells to generate an invasive tumor, however these
studies do not account for the cellular metabolic modifications
that drive and support cancer development and progression
(hyperplasia, high aerobic glycolysis and acid resistance).

We propose an integrated process for discovering the minimal
sets of modifications in cellular processes that lead tumors to
become invasive (growth of tumoral tissue, invasion of normal
epithelial cells and basement membrane).

The development of tumors such as Ductal Carcinoma In Situ
(DCIS) is a complex process where a genetically heterogeneous
population of tumoral cells is submitted to selective pressure
in a dynamic environment. Here, we represent DCIS as a 3D
computer model based on a tubular structure of 40 x 40 cells
dimension (diameter x length), composed of endothelial cells,
basement membrane and a layer of normal epithelial cells
(Figure 1).

One region of this layer of healthy cells is chosen to be
mutation prone, meaning that these cells have a higher than
normal mutation rate due to environmental changes such as
chronic inflammation or a mutation in DNA repair mechanisms.
This will lead to appearance of different phenotypes - a
process that will ultimately lead to evolution of a malignant
population.

Each individual cell was built with algorithms to perform
duplication or apoptosis, and three metabolic pathways:
Glycolysis, TCA cycle, and pentose phosphate cycle. These cells
were therefore programmed to duplicate, die, metabolize glucose
and oxygen and generate ATP and excrete lactate. In order to
account for dynamics in different time scales, the model is
simulated in three levels: the first one being the
reaction-diffusion of chemical species, the second is the
metabolism of each cell and the last level is the cell
duplication.

Within this model, one simulation is performed for each set of
phenotypic modifications in tumoral cells and the set of
modified cells that have successfully achieved invasiveness are
selected. For each of these sub-populations the search moves
one step further and details the reactions composing that
pathway in search for the minimum set of enzymes that might be
responsible the modifications in the phenotype previously
observed. This drill-down process proceeds until reaching the
genes responsible for the synthesis of the proteins that
catalyze or regulate these metabolic reactions. Finally, the
candidate genes found are compared to oncogenes known in
literature and assessed experimentally for validation of the
model.

This approach may improve understanding the intricate factors
behind the development of tumors as well as test for treatments
such as modification of acidity, oxygen and other substrates in
the tumor microenvironment.

On the left, a snapshot of the simulation of a tumor developing in an epithelial duct (3D view on top right) and a 2D view of a transversal slice of the model showing the PH, oxygen and glucose concentration gradients. In the 3D view, red dots are blood vessels, gray represent the basement membrane, pink are healthy epithelial cells and the others are tumoral cells with different phenotypes. On the right, histology of DCIS shows the expansion of tumor cells within the duct (from Gatenby and Gilles, 2004).

External Simmetry versus Internal Assimetry

2006-11-13T14:13:00.000-05:00

Most mammals display a remarkable external simmetry (same number os limbs on both sides of body, same numbers of fingers on each hand/foot, eyes placed in symmetric positions, etc.) in spite of a considerable asimmetry of organs within the body.

First we can point some organs that are placed unevenly in the body such as the heart and organs whose size are different such as the two lungs. Other organs such as pancres, liver and appendix are placed in one side of the body and have a corresponding counterpart of completely different function on the respective position on the opposite position in the body.

One way of seeing the point is to state that the position of these organs does not matter so much as long as they work properly. This could be true if we found human beings with livers on either sides of the body and the same for pancreas as well as intestines winded clockwise and counterclockwise but the reality is that these organs's placements is quite conserved.

Why do we have two kidneys if one unique bigger kidney would do the same job? Many theorists state that Nature does not work with redundancy, meaning that Natural Selection would not creatures with two kidneys so they could survive a kidney failure: instead of that, natural selection would remove those that carry alleles that will lead to liver conditions. This said one could expect the second kidney to be either a mandatory step during development of a mammal or simply a 'bug' during the development program and this bug will be soon corrected.

A bug, however, shouldn´t have spreaded all over the mammalian kingdom meaning that the second kidney development must really have a mandatory presence.

Why do we grow up?

2006-11-13T13:53:00.000-05:00

We are born from a single cell that duplicates itself many times until we reach a volume and mass so many times bigger than our original self that one could very well wonder if we keep any link to that tiny part of us.

One could argue that development is needed in order to achieve a level of specialization of tissues where our organs will work properly and the inumerous tasks to be performed by our organism will be fulfilled. However, even after our organs are fully developed and in their right place, we countinue to grow up.

Let´s arbitrarily say that a 10-year-old child is completely functional - its teeth are all there, lungs, heart and intestines are all working and so is its brain and mind- then why does it keep growing, getting denser (more cells per cubic centimeter) and reach a point where many of its main functions will begin to decay (ageing)?

One hypothesis could be that a human being must grow until an optimal point for its survival and then push the envelop a little further so its offspring will be favored. A bigger mother can certainly bear more children and during more time (longer pregnancy, more developed children) but on the other hand this oversize will certainly claim its share and the life expectancy of the mother will be shortened.

Anoter reason for being born smaller than our maximum size is because an adult cannot fit inside another one, it´s mandatory that a life be born more simple than it will be at is apex. This rule can only be bent in cases such as unicelular organisms but even in this case the 'mother' cell must double its volume so when it splits into two 'daughter cells' the two newborns will be approximately the same size as an adult cell.

Development is as necessary for pluricelular organisms as the simplification of mechanisms is for life itself. Life is only possible if we are capable of breaking its functions into smaller more simple ones that will be themselves broken into more simple ones and so on.

One interesting question would be if death by ageing (and ageing-related diseases) is somehow linked to this dynamics and also if there is a correlation between the number of final cells of the organisms, its development time before birth, and the life expectancy of the indiviual.

Did sex start as DNA takeovers?

2006-08-10T15:48:00.000-04:00

I wonder what would lead a cell to exchange its DNA/RNA/or any other kind of genetic material with another cell.

The process through which unicellular organisms become more complex ones is acceptable up to a certain level if we consider the hypothesis that the somatic cells are indeed slaves of the original reproductive cells (named reproductive because they can generate other non-specialized fully functional cells and not because they´re cells specialized in reproduction as germ line cells) but how could the "modern" mechanisms of sex be created?

Bacteria are capable of exchanging genetic material through conjugation, the individuals that have a plasmid named F factor are capable of inserting this genetic material into bacteria of the same species that do not have the F factor. It is supposed that this mechanism can be a way of transmitting resistance against pathogens or drugs such as antibiotics.

Here I propose another interpretation, I believe that a good reason for a cell to be willing to insert its genetic data into another one is in fact an attempt to hijack the host cell and use its inner machinery to work for the original cell and its genome.

If this mechanism becomes widespread, these invasions could end up by happenning simultaneously and thus giving the ilusion that there´s a mutually consented sexual intercourse happenning.

In order to avoid multiple invasions (what could lead to an invasion of the original cell itself) some sort of mechanism must have been put in place and so the genome multiplicity might have reached an equilibrium : the cells split themselves before attempting an invasion and thus reduce their genetic content into half, leading to two individuals with the same genome size as the original ones but with a different set of genes.

At this point the invasion strategy no longer provides advantage to the cells capable of doing so but now a new advantage appears for the individuals that are capable of exchanging their genetic material are now more resistant to pathogens and their "evolution" can happen faster for all the reasons that are attributed to modern sex.

On pluricellular organisms.

2005-11-17T13:20:00.000-05:00

Why would one species evolve from one cell into a multicellular being?

This question can only be answered if we consider that in multicellular organisms only a small group of cells is allowed to duplicate endelessly (the germ line cells as well as the stem cells). All other cells in an organism are there just to perform a task and when they are no longer healthy they are replaced by newly specialized stem cells that promptly loose their high reproductible capability.

Two things are necessary for a cell to be useful to the organism: it must not be able to reproduce independently and it shall be specialized in a way that a specific trait (or group of traits) will be pushed to the maximum so this cell will perofrm tasks for the sake of the organism and not of itself.

Imagine for instance a single-cellular organism that creates a copy of itself but this copy due to some sort of mutation cannot reproduce. This copy will tend to grow and accumulate energy but since it cannot reproduce this process should proceed until it either dies or the nutrients flow out of its cytoplasm and be ingested by the normal reproducing cells. This is an example of "cooperation" between a germ line cell and a somatic cell. The term cooperation is quoted because in fact the copy is being enslaved by the other cell that is using it to acquire more energy and reproduce. If this cell manages to keep the capability of creating both normal daughters and "slave" copies it will have an advantage against the other cells that only create normal copies of itself.

The lack of reproducibility being the first specialization necessary for the somatic cell, let's pass to the next step: imagine that the slave cell now suffered some sort of mutation that causes it to produce an enormous amount of nutrients ( aminoacids, ATP, or any other metabolite necessary for survival) and after overproducing this payload it dies, suffers necrosis and the "master" cell captures all this energetic package. Once again we have an advantage for the master cell. This kind of specialization can be extended from energy metabolism to oxygen transport, mechanic protection, termal protection or any other kind of use; It's life using life to survive.

This makes us wonder who's really in control of our lives: our brain or our gonads?

On reduction of complexity of Central Dogma

2005-11-17T12:22:00.000-05:00

Central Dogma states that DNA is a template for synthesis of RNA (mRNA) that in turn is a template for synthesis of proteins. The point to be addressed here is that this system cannot be reduced, i.e. if part of it is removed, say the RNA Polymerase or the Ribosomes we will not have a system that performs less well it's job, we'll have a system that does nothing at all.

Irreducible systems are generally used as a proof of design however this system is not irreducible if we consider the molecular complementarity principle in which evolution of most molecules does not happen only based on selection but also on complementation: two selected entities combine to give birth to a third one that performs another task.

Let's think now about the question: Why doesn't the Rybosome encode the proteins directly from the DNA?

One might state that there might be some sort of subcellular localization issue since proteins are supposed to be used both in nucleus and cytoplasm and it's safer that they be produced out of nucleus and only imported if necessary. However in bacteria there's no separation between DNA and cytoplasm and still the Ribosomes do not read the DNA directly (even though they are quite close since the poli-Ribosomes translate proteins while the mRNA is still being transcribed).

I'd suggest three hypothesis for the birth of Central Dogma (from now on referenced as CD):

a)Direct translation of proteins from DNA was a step that preceded modern CD. This step was replaced and the mRNA where used as intermediates.The Ribosome would'nt have to be that more different in order to handle DNA than it is today (considering that there was some sort of mechanism for openning the double strand such as the helicases) but this evolutionary step should happen a lot before the divergence of the species known today and this should be such an evolutionary leap that the other species with different DNA->Protein strategies would be extinct;

b)RNA was synthesized from DNA to do the job that is done by proteins nowadays (catalysis, structure, etc.) and later RNA was replaced by proteins. Again this must have been a leap in the early days of life. However a detail not to be forgotten is that the "genes" previously used for the synthesis of tri-dimensional catalytic RNA structures would be replaced by new "genes" dedicated to the synthesis of mRNAs with no tri-dimensional meaning but with a specific linear code that was very little error-robust (the functionality migrated from the form to the content). One might say that such a transition would explain why we have som much "junk" DNA around the real encoding regions but this hypothesis would be valid only if all species had similiar amount of non-coding DNA and this is not true;

c)In early times there were two different types of life: the first was based on DNA (double strand or not) and its mebaolism was catalyzed by RNA enzymes. The second type of life would have its "genes" encoded in RNA and it would synthesize proteins for its metabolism. So in the frist case we have RNA Polymerase acting as a enzyme generator while in the second case this enzyme fuctions as a genetic information replicator. By the fusion of two of these entities a hybird was born capable of both keeping large amounts of genetic information stored and also with the flexibility of producing proteic enzymes instead of RNA catalysts.

The last hypothesis reminds me the theory of the mitochondria swallowed by an early cell and used in complementarity with the cell's metabolism.

What's a Ribosome?

2005-10-15T10:11:00.000-04:00

A Ribosome is an enzyme.In most books it's describe as a huge machinery that has a specific function o mapping mRNA into proteins and many creationists use this complicated design (much like a turing machine) as a proof of existence of a "designer".

However if we think it out differently we can see a ribosome as an enzyme that has no specificity (see previous article on enzymes and specificity) and whose function is to create peptidic bonds. This enzyme however has two mobile parts, the first one is a domain that allows for a "mobile specificity" that is provided by RNA molecules that can be of 4 types as well as a two other domains that allow for the entry of tRNAs and also peptides (the growing chain of protein).

The ribosome then catalyzes the reactions where there's a match between the "mobile specificity" and the tRNA anticodon, when this happens the aminoacid bonded to the tRNA is transferred to the poly-peptide chain and a conformational change causes the mRNA chain to be displaced and a new codon is presented to the ribosome.

This complex behavior could be simplified as an enzyme that could only catalyze peptide bond reaction formations and then allowed for some degree of specificity that later became more complex as codons were inserted as well as the mechanism of using a mRNA string that would lead to the catalyzing reaction to become irreversible.

A good way to prove this theory would be to prove that a ribosome would have catalytic capabilities even if it had only one of its parts (the top part with the tRNA input for instance) and this could be simulated using 3-D lattice grids.

On reversibility of reactions and life

2005-10-11T22:42:00.000-04:00

Irreversible reactions are those that either liberate energy as they happen or require energy in order to happen (this depends on the amount of Gibbs free energy difference of substrates and products).

An organism would try and do most of its work by using reversible reactions because these not only do not consume energy but also will not waste energy that could be used for more important tasks. In fact most of the irreversible energy freeing reactions happen in the glycolytic and cytric acid cycle where the free energy can readily be stored in the form of nucleotide triphosphates and other well known carriers of life. The reactions that are irreversible and consume energy are coupled to reactions that are irreversible and free energy (ATP dephosphorilation into ADP) and happen in situations where they are needed for the construction of polimers required for the cell's survival (DNA,RNA,etc.) or for the early steps of pathways that will later return the energy consumed (glycolysis for instance).

An important point to keep in mind however is that the control exerced by the organism in within the irreversible reactions and if all the reactions were reversible the organism would not be able to decrease its entropy and increase its environment's entropy and it could be no more complex than any thermodinamically closed system.

On the origins of Glycolysis

2005-10-11T22:37:00.000-04:00

Glycolysis requires in its first steps the consumption of 2 molecules of ATP for each molecule of Glycosis to be digested. However such a metabolic pathway could not have emerged as so since it first requires consumption of energy that would be replaced only in later steps that might no exist yet.
Thus the evolution of glycolysis must have been in the inverse order of intake of Gycosis: in the beginning the cells or any previous forms of life used the molecules that were at the most energetic side of glycolysis and as evolution and natural selection acted, ways of converting more abundant species into the ones that could provide energy were developed (as enzymes that could catalyze these reactions).

On bacteria treatment

2005-10-11T22:26:00.001-04:00

The approach used to erradicate bacteria, infections by parasytes such as T. cruzi/brucei and cancerous cells is to attack the targetted cells with radiation or drugs in order to kill them all despite thendeath also of host's cells. This approach however does not work on an heterogeneous population that will in fact loose the weakest (in relation to the drug attack) individuals and have them replaced by others more suitable to handle the drug attack. This process works exactly as natural selection and will lead to pathogens more and more resistant. However a reverse approach could be taken: A great abundance of nutrients would lead to an increase in the population where resistant pathogens would have to compete with the non-resistant ones that should have some sort of metabolic advantage since they don't have to carry the burden of the mechanisms that allow them to resist to the drugs. In this case after some generations the resistant pathogens should have lost all their resistant members and a drug attack would be more efficient. So a strategy could be to overfeed the pathogen and use a brutal drug attack as late as possible (as late as the pacient can survive the dru shock treatment).

On origin of life and need of DNA for a starter

2005-10-11T22:26:00.000-04:00

The origin of life doesn't need a system enclosed by membranes in fact it would require a system as open as possible so the probability of different chemical species meet would be greater. The origin might be of multiple different molecules being interchanged by each other in equilibrium however the presence of some of them could act as catalysts (although weak) and this process might have lead to the eventual formation of chains where the substance A catalyzed the transformation of B into C (and vice versa) and the substance C catalyzed the convertion of a substance D into A and as long as B and D are abundant there will be an increase in the amount of A and C: an autocatalytic system that can be the precursor of life itself.

The system is easier to create when there are many more susbtances in the pool so the probability of making a closed chain becomes bigger and eventually the system becomes autocatalytic. The existence of membranes might have appeared later when the control of the input and output of substances into the system became more important than the diversisty of substances available (we can imagine that there's an equilibrium between a too big number of different substances are now required to stay together and that would be scattered away without the presence of some physical limitation (after all the membranes are catalysts as well since they keep the metabolites whithin a closed region of space)).

So life might have started before the advent of DNA or RNA or any other form of information storage system as predicted by Shroedinger. An information carrier might have appeared only after a mapping code started to be used in order to better control the metabolism, in fact the advent of a mapping system in only an extension of the process of adding intermediates into a chain reaction in order to provide autocatalysis.

Enzymes: evolution of catalysis and specificity

2005-10-11T22:22:00.000-04:00

Enzymes probably didn't "appear" in nature as specific as they are today, in fact the first enzymes should be very general (break ester or peptide bonds, etc.) and then as a need of more control of the reactions, these enzymes have been duplicated and each of these copies specialized in order to account to specific metabolites (cross between substrates and products) that define a unique (or almost unique) reaction.

This process could proceed an then we would reach a situation where we will have more than one enzyme for each reaction (isoenzymes) that will have different control in different types of cells.

In order to prove this hypothesis one could create a simulator with a control system (enzyme sysnthesis and degradation) with both general and specific enzymes and show the differences between the control of metabolism in these two systems

SETI and elephant trunks

2005-07-03T22:44:00.000-04:00

When I first heard about the Search for Extra Terrestrial Intelligence program (SETI) and some years later watched the movie Contact from Carl Sagan I was really excited about the idea of a universe full of intelligent life forms such as those depicted in tv series like Star Trek and Stargate.
I wondered when and how the first contacts would happen, would it be something like the War of the Worlds or would it be something like E.T.?
The truth is that I don't care about this anymore.
The main argument of scientists that support the idea of extra terrestrial intelligence is that there are too many planets and stars out there in the galaxy and the odds of only one of them having intelligent life would be too low.
I agree with them in terms: I believe there is "life" in many other places in universe but not "intelligent" as we define.
To illustrate this I will use a metaphor I read in Steven's Pinkler book "How the mind works":

In a congress of the Elephant Search for Extra Terrestrial trunk program, a very wise senior scientist was finishing his argument about why the government should continue supporting the program:
-And as I proved mathematically, if we consider the age of the universe on around 4 billion years and if we consider that there are millions of galaxies in the universe and that in each of these galaxies there are millions of solar systems with tens of planets the odds are that there are at least some thousands of plantes harboring life at this exact moment. As everyone knows, the trunks we elephants have are extremely useful organs that can be used to drink water, take a shower, breath under water, grab apples from the trees and seveal other uses. This means that in these planets the life forms have had time enough to evolve and to create trunks -that is the paramount and goal of evolution- and thus our project will soon-at any moment- receive signs of civilizations with trunks somewhere in the universe.

The mistake of the elephant's argument is that a trunk is an organ that appeared by natural selection in one group of species and not in others and should the group of mutations that led to the trunk not happen, the concept of the organ trunk would never have existed. There are many other adaptations that can lead to a selective advantage and depending on the conditions of the planet, maybe pluricellular organisms would'nt even exist, maybe the plant would be flooded by bacteria.

The same point is to be used against intelligence, it's an adaptation that does not confer such an advantage as we may think, in fact the free will is an extremely dangerous bet since our "instincts" trained by our genes for generations are overwhelmed by our "rational" thoughts based on something we call common sense and logic. If it were not for the exctintion of the big predators on earth we human beings would surely not have reached a number big enough to survive and do some real use of our intelligence.

Green little men?

2005-06-28T22:14:00.000-04:00

In many science fiction movies and books the aliens and the men of the far future are always depicted the same way: short, slim, green or blue -often pale-skin, bald and with big head and eyes.
This image is in fact the extension of the "evolution" process that separates us from the other primates: we are slimmer than the gorillas, we have less hair and our head -brain- is supposedly more developed, thus the man of the future should follow the same path, or not?
The big question here is, are we still under selection? Are we still evolving genetically?
The answer is no.
Selection means that different phenotypes have more probability of leaving descendants than others. This process leads to stronger lions, faster cheetas, smarter monkeys but it does nothing to human beings because our society-our mind child- was projected to erase all the effects of selection and the laws in mot modern countries states clearly that every man is equal.
The truth is that in our society, being bigger, faster or stronger makes no difference since the "fitness" and status are defined by the capacity of acumulating money.
Does this should mean that the man of the future will be a yuppie?
The answer is no.
Even the wealthiest men on earth have in average 2-3 children, some only one. Most middle-class families in rich countries in Europe and USA are composed only by the husband and wife, they have no kids (double income no kids: dinks) what is a lot less compared to the families in poor and miserable countries where the number of children can't be counted on the fingers of the two hands.
This process will indeed lead to a future where most of the humans will be decendants of the poor people of the countries under development today and since poverty is not a genetic trait but a historical condition, mankind shall remain the same yet for a long time.

Shakespeare Monkeys

2005-06-12T19:28:00.000-04:00

Once I read in a book about theoretical computer science that if we had a room of infinte size with an infinite number of chairs and in front of them an infinite number of typewriters it would be enough to put an infinite number of monkeys in front of them and after some time (maybe an infinite amount of time that could be shortened by increasing the quantity of monkeys or by replacing the type writers by voice activate system adapted to monkey cries) they would end up by writing Shakespeare complete collection of books.

The other day I heard a colleague say that if we had no computing power limitations we could solve most of the genetics problems we have nowadays (philogenetic analysis, protein 3D structure prediction,etc.). This comment really reminded me of the monkeys playing with type writers and made me wonder that if we really had an infinite computational power we wouldn't even need to care about creating smart algorithms since we would just need to test all the possible solutions in a very simple program, everything would be reduced to brute-force search.

To conclude, the main reason for writing this text: the more I study genetics and gene regulatory systems the bigger my impression that evolution has a lot to do with monkeys and typewriters, however since we didn't dispose on an infinite amount of time (neither of monkeys and type writers) we are far from William's elegance. A close look into our cells would show a great crowd of molecules shouting orders to one another in an environment that would remind Wall Street's NYSE in a hot market day.

I wonder how we are still here and how far the evolution will take us based on this principle of mutation/ natural selection / genetic drift. Even more, I wonder how could this text come out of an entity organized in such a chaotic way, maybe what we believe is rational thinking is nothing but the sound of monkeys typing endlessly...

On ageing and on death

2005-06-09T23:14:00.000-04:00

Ageing and death due to ageing is a characteristic that is not mandatory in all life forms. In fact bacteria and other living entities who reproduce symmetrically do not age since the "mother" entity splits into two twin entities that can't be identified as the mother and the child. This means that these basic life forms must ensure they do not age and thus once they duplicate they are as viable as they were when they were born from a previous duplication.
Mammals and other higher forms that developed the capacity of creating multi-cellular organisms do age and this is not a problem since the degradation affects only the mother, the children are born with their "age counter" at zero.

The interesting points here is why do we have to die and what would happen if we didn't.

We must die because pluricellular organisms are immune to mutation and thus to natural selection, only our species can evolve but the individuals do not. Unlike unicellular organisms, mutations on higher organisms will happen only in one cell, one tiny piece of ourselves and this mutation will not propagate to the rest of the being. This means that once we are born our species has bet on us and counts on us to have as many descendents as possible, prove the fitness of our genes and then die, leaving behing our progeny to continue the evolution/selection process.

If you consider two species of mammals, one living indefinitely and the other with a limited life span (probably fine-tuned by natural selection) a computer simulation will show that the limited-life span species will have a faster response to evolution and thus will more quickly adapt to changes in environment as well as double cross the other species in competition.
The other species, the one with immortal individuals will face two problems: the first is that since the elders do not die and they have more experience/resources than the youngsters they will keep the monopoly of the habitat's resourses and will kill the youngsters by hunger. The second point is that their presence will delay the evolution of the species since archaic genomes will continue to mix with newer ones generated by mutation and meiosis crossing.

In the next article we'll talk about why this process created by natural selection is useless in human beings and we'll also trace a link between cancer, development and ageing.

In the beginning...

2005-06-04T12:52:00.000-04:00

My first contact with genetics came when a friend of mine lent me Nobel winner's James Watson book "The Double Helix" and I finally learned how a 22 year old guy and his colleague Francis Crick established the basis of what we now know of DNA.

My second contact with genetics was thorugh the book "Molecular Biology of the Cell" that's a great compendium of what we now understand and suppose about the cellular functioning. I first got puzzled to see a book with more than 1000 pages dedicated only to the cell's itnernals but after I started reading it I realized I was entering a totally new world I had never conceived before.

Many say the 21st century will be the beginning of the genetic revlution, that many diseases will be cured and people will live a lot longer and better, however even though we have better technology and more money for investigation than ever before, the advances of biotechnology is threatened by a new Dark Age of inquisition and ignorance.

This is the Brave New World we live in and I intend to do my part to make the difference. If you also believe you're here to do something and leave your marks on this planet then you're more than welcome.

Best regards,

Ariosto