Monoclonal antibodies, the demonstration of the ability to make which won Jerne, Kohler and Milstein the Nobel Prize in Physiology, are extremely versatile tools in medicine & biological research. Before moving on, it is important to familiarise oneself with some terminology.
Antibodies are molecules that can bind to antigens, and are made by cells called B-lymphocytes in animals. They are made up of two heavy chains and two light chains, and have constant regions and variable regions. Heavy chains are just longer than light chains, and constant regions are identical in all antibodies from a species, while variable regions are, um, variable.
Structure of IgG, A typical antibody, schematic representation.
If you took the serum of an animal species, you would find that the mixture of antibodies contained therein would be polyclonal by nature, i.e, they would contain antibodies and antibody producing cells that are capable of reacting to a wide variety of antigens, even if each antibody would be specific to its own antigen.
Sometimes this is ok, as in the case of antivenom, but in some other cases, especially for antibody therapy in humans and for use in diagnostics, better quality is desirable. This is where monoclonality becomes important, a mixture of monoclonal antibodies would only react with ONE specific antigen, with the implication being that all the antibodies in the mixture belong to a single clone of antibody-producing cells (that is what monoclonal means, simple Latin & English)
A Graphical Summary of how monoclonal antibodies are produced.
Monoclonal antibodies are produced using a technology that relies on isolating a B-cell that produces a specific antibody and fusing it with cells that come from a cancerous mouse cell, with the cancer being known as multiple myeloma. To produce a monoclonal antibody of our choice, the following procedure is adopted…
[1] Inject the antigen that we need antibodies against into mice.
[2] Harvest the spleen from the mouse after a few days, which should be around two weeks if one were to assume that the time for the primary humoural response to build was the same as that in humans.
[3] Isolate multiple myeloma cells that do not produce antibodies and cannot produce HGPRT (That is a substance required for growth in a HAT medium) , media are concoctions that serve as food for growing cells.
[4] Fuse with B-Lymphocytes obtained from step [2], then put into HAT medium for culture. The clever part of this step is that only successfully fused cells can grow in HAT medium. These fused cells are called Hybridomas.
[5] Select B-Lymphocytes that produce the required antibody, start to culture them, and ta-da, you have a source of monoclonal antibodies. Lovely, innit?
So now we have a source of high quality monoclonal antibodies, but it doesn’t end here, remember that I said that constant regions are only constant in all antibodies from a particular species? This means that the constant regions of rat antibodies are different from those of human antibodies, and this can trigger an immune reaction if rat/mouse antibodies are put into humans (for purposes of therapy) , as a result, a process called humanization is carried out.
Here, genetic engineering is used to modify the amino acid sequence of antibodies such that it is identical to naturally occurring human antibodies insofar antigenicity is concerned. One way of doing this is to modify human B-lymphocytes so that they produce the antibody with the variable regions we want and then create hybridomas, and proceed with the workflow presented above.
Another approach involves the use of chimerisation, while these antibodies are just semi-humanized, they are better than completely unmodified animal-derived monoclonal antibodies, here, the antigen binding fragments of mouse antibodies are fused with the constant region peptides of human antibodies, resulting in a mouse-human hybrid antibody.
Various degrees of humanization, a graphical summary.
In my last post, which was on Gleevec, I focussed on a small-molecule drug, monoclonal antibodies belong to a different class of drug, called biologics, which are molecules of biological origin. Monoclonal antibodies can be used not only to bind to and block things like target receptors but also to provoke an immune response against those targets. This can be beneficial and not so beneficial, since there are constraints imposed by the immunogenecity of the targets we are looking at.
List of FDA-Approved Monoclonal Antibodies for Therapeutic Use. Courtesy Wikipedia.
This table was obtained from the relevant article on Wikipedia , please click on the thumbnail for a larger, clearer view.
So, please do dig around on the internet to learn more about Monoclonal antibodies, they are sure to stay because of specificity, amenability to engineering, ease of large scale production and ease of use. They are also used in things like antibody based diagnostic kits regularly.
That’s it from me, for the moment, on this topic. In the meantime, you may want to consult Basic Biotechnology, 3rd Edition, Ratledge and Kristiansen, Cambridge University Press as a reference, there is a dedicated chapter on this subject.
You may also want to hear the scientists who developed this technology explain their work at the Nobel Prize Ceremony in 1984, Dr.Jerne’s Nobel lecture is here , Dr.Kohler’s Nobel lecture is here and Dr.Milstein’s lecture is here
Right, in my previous post I wrote a bit about why treating cancer is such a bitch, given that there are so many ways in which cells can drive phenotypes that are associated with cancer. However, in some cases, the pathology of a certain kind of cancer may be very invariant (not much variation) in which case the problem of heterogeneity isn’t as big a headache.
Once an invariant target has been identified a process of rational drug design can be carried out. Rational drug design means that you use evidentially supported principles and methods to develop drugs. Once a target has been identified, its structure can be deduced and its function studied. If preventing that target from working efficiently can knock out the disease phenotype it contributes to, it can be considered as a potential target for therapy.
Example development cycle for rational drug design.
Chemists can then use computational tools and their intuition to design drugs, either small molecule drugs which are completely synthesized from chemicals, or biologics, where biological sources of molecules that can knock out our target are sought.
This post features the poster boy of targeted therapy against cancer, called Gleevec, or Imatinib mesilate. This is different from traditional, non-specific chemotherapy because it only targets proteins whose overproduction is a feature of cancer cells, whereas traditional chemotherapy tends to hit all fast growing cells, normal or cancerous.
The Chemical Structure of Imatinib.
The Pathology of Chronic Myelogenous Leukaemia & What Gleevec Targets…
Now Gleevec is a blockbuster drug that has been most successful with a particular type of Leukaemia, called Chronic Myelogenous Leukaemia (CML), in which there is rapid and uncontrolled proliferation (aka cancer) involving a class of White Blood Cells and their precursors called Granulocytes.
CML cells, notice the large number of granulated cells.
This aberrant growth happens due to a mutational event that involves the fusion of two genes with aberrant regulation, namely the BCR gene from Chromosome 22 to the ABL gene from Chromosome 9, giving rise to a fused chromosome popularly known as the Philadelphia Chromosome. (This name comes from the documentation of the disease by two scientists from Philadelphia in the American state of Pennsylvania)
This fusion gene produces a new protein that is a tyrosine kinase (it can add a phosphate group to an amino acid called tyrosine on proteins that interact with it) which is transcriptionally active (the mutant cells keep making the BCR-ABL fusion protein without needing any external signal) and this fusion protein can halt DNA repair and get cells to really hurry up while dividing. This is what drives mutant cells on the path to cancer, aided no doubt by the fact that DNA repair, once stopped, enables large scale mutations to happen as a consequence of genomic instability.
Downstream Effects of BCR-ABL fusion protein and Cancer Phenotypes, Courtesy Nature Reviews Cancer.
Now notice that the protein produced by the fused gene is capable of triggering things like proliferation, cell survival, increased motility et cetera, in other words, cancer. To sum up, this gene, Bcr-Abl is central to the pathology of CML, and as a consequence is an excellent drug target, since you can knock out all the cancer phenotypes it can trigger by knocking it out.
Now here is the smart bit involved in targeted therapy, Imatinib was selected because it is a competitive inhibitor of BCR-ABL fusion protein, that is, instead of the proteins with which this tyrosine kinase interacts Gleevec goes and binds to the active site, thereby preventing BCR-ABL from triggering the signalling pathways that lead to the formation of cancer phenotypes. It is like filling a box up with something that is harmless to prevent something harmful from getting in and being able to use the box. It is like playing a prank on someone who needs to empty their bladder desperately by occupying the bathroom without needing to urinate, and what Gleevec does is the biochemical equivalent of that.
It also helps that it binds specifically to this kinase and not a lot of kinases in general which could have otherwise had detrimental effects on normal cells.
Gleevec is the chemical equivalent of a sniper that can take out a target without hitting anybody innocent, and if evidence is to be trusted then it has done wonderfully well. Not only is it used as the first line of attack against CML but is also used against some other forms of cancer, such as Gastrointestinal Stromal tumours that act using the KIT pathway, if I recall correctly. This is because it is also capable of blocking c-KIT, which is another protein that can drive cancer.
Most importantly, it provides validation of the concept that it is possible to account for heterogeneity provided we have enough information, that it is possible to selectively take targets out, and that it is possible to develop high class chemotherapy that doesn’t suffer from the abhorrent side effects of traditional chemotherapy. In other words, it is the drug that has made it possible for oncologists and oncopharmacologists to dream, even if CML is just one of many cancers around.
Here is a video on Gleevec’s mechanism of action.
Here is a long scientific lecture/presentation on the development of Gleevec and how it went from bench to bedside.
First of all I must thank the ever so eloquent Christopher Hitchens for the phrase “The Topic of Cancer” , which I would have wished he’d have come up with without having to suffer from the disease. In this post, I hope to introduce you to what cancer is, since this is crucial to understanding it and towards the development of therapies for it. Please note that references will be inline and linked-in.
The first thing I want to mention is that cancer is not a single disease, nor does it have a single cause, nor do all cases of cancer have a similar pathology, it is a group of diseases that are extremely varied in terms of what drives them and causes them to persist in the body, eventually making them potentially lethal. At the same time, it is possible to define cancer based on similarities that exist in all cancer cells.
Before I go on to write about that, I wish to tell you about things like cellular homeostasis and the properties of normal cells, in most eukaryotes, the process of cell division is tightly regulated, genetically, and as a consequence normal cells just don’t divide out of control.
Using the above statement, it is possible to arrive at an operational definition for purposes of this post, that cancer is the phenomenon of dysregulated cell division, or to put it in another way, cell division gone haywire.
What features define Cancer Cells?
Cancer cells, while being extremely heterogenous (varied) , also have some universally present features, and here I wish to point you to the paper as far as this area is concerned. (Hahnahan & Weinberg, The Hallmarks of Cancer, Cell, Volume 100, Issue 1, 7 January 2000, Pages 57-70)
They go on to specify the acquired traits that are universally common to all known cancer cells, including
[1] Self sufficiency in growth signals – this means they can drive their own replication without external control, this can be conferred by mutations in proteins that regulate cell division. These mutations happen in ways that allow cells to activate signalling pathways that trigger growth even if an otherwise-necessary external signal is absent.
Genes which can, upon mutation, give rise to these genes are called proto-oncogenes, and the aberrant forms are called oncogenes, it is a term you can expect to come across regularly if you wish to learn more about cancer.
[2] Insensitivity to anti-growth signals – It may make sense for you to imagine cellular growth being the result of a balance between growth signals and anti-growth signals, with the two sets of entities being involved in a dynamic equilibrium. It is possible for mutations to wreck the pathways that keep growth in check, thus upsetting the balance and allowing otherwise normal levels of growth signals to drive proliferation. Genes which are normally active in preventing this kind of uncontrolled growth are called tumour suppressor genes.
[3] Ability to evade apoptosis – in case cells do go kaput due to genetic aberrations, it is quite normal for those cells to be pushed into a non-replicating state or towards cellular suicide, cancer cells have to avoid this fate to be successful (from the cancer’s point of view)
, they can do this by acquiring dysfunctional pathways of apoptosis involving defective versions of more tumour suppressors or by producing more proteins that can prevent apoptosis from happening. (Again the idea of an equilibrium would hold, here)
[4] Limitless replicative potential – this is extremely crucial to cancer cells because of their high rate of replication, you see, there are sequences at the ends of chromosomes, called telomeres, and every time a cell divides, due to a biochemical kink in the mechanisms of DNA replication, they shorten. The faster a cell divides the faster they shorten, too. Eventually, when the ends of chromosomes end up being exposed they are prone to fusing haphazardly with other cells, which sends the cell to a dysfunctional state and a lethal end.
Cancer cells, however, can reactivate pathways that prevent telomeres from becoming shorter, one pathway involves the use of an enzyme called telomerase and the other one uses a process that is called ALT (Alternative Lengthening of Telomeres). Both of these allow cancer cells to go on replicating in their merry ways, and eventually bring about the death of the host if left untreated. They can, of course, evolve resistance to therapy and kill the patient even if treated, but that is another matter.
[5] Sustained angiogenesis – now cancer cells are hungry little buggers, and that is no wonder since they grow so fast, and this requires energy and oxygen for cellular biochemistry which is needed for growth to take place, and in the body, cells get these resources from the blood.
Cancer cells have to find a source of blood, and to do this they use a process called angiogenesis, which tells blood vessels to spread capillaries to the vicinity of the tumour so that a blood supply can be established.
[6] Metastasis & Tissue invasion – ultimately, tumours that just sit in their original location aren’t as dangerous as ones that spread, it is the process of spreading that is called metastasis, and tumours that can do this are said to be malignant (as opposed to benign if they cannot), this requires cancer cells to gain the ability to move and to survive in the bloodstream. It is metastasis that is the most lethal facet of cancer, for the original tumour can spawn offshoots elsewhere in the body, clogging up organs, causing excruciating pain, and eventually, through organ failure, the death of the patient.
Acquired capabilities in cancer, visual summary.
So that is a summary of the hallmarks of cancer, we’ve only barely scratched the surface, however, in this blog post.
What causes cancer?
This is a tricky question, but if you look at what has been written above you may be able to discern the role of mutations in cancer, and mutations are, at the most fundamental level, responsible for cancer. It is a disease of genes. Now there are different kinds of mutations that act in different ways, and they are all essentially stochastic (statistically indeterminate) and as a result there can be several routes to cancer.
For example point mutations can produce a misfolded/dysfunctional growth signalling protein which can go on to trigger uncontrolled growth, or can knock out a tumour suppressor, or in cases where bits of different chromosomes get fused together they may produce a gene whose expression is not regulated properly, this happens in the case of the Bcl-Abr fusion gene in Chronic Myelogenous Leukaemia, where the aberration is known as the “Philadelphia Chromosome”. To sum up, any mutation which disturbs cellular homeostasis such that the affected cells begin to acquire some of the aforementioned characteristics can cause cancer. Viral infections such as Human Papilloma Virus can play a vital role in the development of Cervical cancer.
Now it is eminently possible for a variety of risk factors to exacerbate the risk of some of those mutations happening, it is like having better chances of winning by throwing dice more often, these can include inherited factors (for example, if you get a defective tumour suppressor gene from one of your parents, it is easier for mutation to knock out the other copy, leading to cancer), this is seen in some cases of Retinoblastoma and in some cases of Breast Cancer or other environmental influences, including ionizing radiation, ultraviolet radiation, tobacco products, pollutants and so on. These substances are called Carcinogens.
Now, there is a common misconception amongst people, at least to the extent that I’ve seen, who assert that things like smoking are ok because they know of smokers who didn’t get lung cancer. That assertion is nonsense, because tobacco smoke increases the risk of being hit by a cancer-triggering mutation by increasing the overall mutation rate in the tissues it comes into contact with. Still not convinced? Try this paper which offers a large scale review, and this too, if you would like.
Why is Cancer such a bitch to treat?
To put it simply, evolution. One of the other defining features of cancer cells is genomic instability, in other words, there is an enormous amount of mutations happening, genes jumping from here to there, chromosomes sticking up to each other in different ways, different genes undergoing different mutations in different cells of the same tumour and so on, for starters. (This was mentioned, if you recall, in the video showing cancer cells in culture posted towards the beginning)
This means that it is always likely that treatment will end up wiping out a vulnerable subset of cancer cells leaving behind others which are resistant. It also does not help that cancer cells can find ways to evolve resistance to drugs by finding genotypes (through mutation, of course) that allow them to express proteins that can pump chemotherapy out of cells. Genes like Mdr1 can do this.
It also doesn’t help us (and helps cancer cells) that there can be more than one way to obtain a necessary trait. For example, cells can bypass apoptosis by either losing functional p53 or by gaining duplicated copies of Mdm2, or by having defective caspases or by overexpressing Bcl2 which can block apoptosis. It is testament to the dodgy, convoluted nature of evolution that the pathways that govern the functioning of our cells are capable of being wrecked so easily, these pathways are prone to breakage and may have more maintenance issues than a Jaguar XK in the course of their functional lifetime.
Cells which can divide quickly have a selective advantage, too, to make things worse, and in the context of cellular homeostasis in the body the features that were described in the first part of the post the traits that cancer cells eventually acquire give them a great advantage. Cells can get f**ked up in several ways, to sum it all up.
How many ways, you ask?
Try this for a sense of perspective.
Various ways to get things wrong, various roads to cancer.
A high resolution .PDF of the poster can be found here.
So yeah, things are tough on the oncology front at the moment, but the more we learn, and the more we study the disease, it doesn’t seem unlikely that we will find things that are not heterogeneous, things that don’t vary too much, things that can be treated without cells being able to develop resistance. There is cause for optimism, which I feel is genuine, seeing reports like this
I hope to continue to post a lot more about various little things pertaining to the study and the treatment of cancer in the near future, I’m now signing off from this little introduction by pointing you to a textbook that has taught me, hopefully well, and continues to teach a great many students around the world about the biology of cancer. The book is “The Biology of Cancer” by Robert A.Weinberg.
This is a video montage of electron micrographs taken by scientists from CRUK’s (Cancer Research UK’s) London Research Institute’s Electron Microscopy Unit.
Characteristic invasive growth of a tumour.
Ovarian tumour.
Lung Tumour, courtesy National Geographic.
Eww, that says it all about the disease, doesn’t it?
This is a slightly belated announcement and welcome, seeing that she’s already made a post, but I’d like to introduce you to Juliet, who is an anthropologist and a skeptic with a penchant for sharp, incisive and lucid writing, as her first post will have already hopefully illustrated.
You can expect to see lots of very educational and informative posts in due course of time.
I have just been added as an author and going to kick off with a post which was inspired by a facebook message I received today from someone who asked me to watch the following 2 videos:
As requested I stuck with the videos and decided to write a response as it’s something that needs addressing and I’ve wanted to address for a while…so it’s a generalised response and not all aimed at the person who originally sent me the message.
Firstly, seeing as I spent 8 and a half minutes of my life watching the first video, and a further 7 minutes watching the second…and a further 20 minutes researching this stuff for myself and a further 30 minutes writing this…others can now do the same, and spend roughly an hour on my point of view, which is as follows, and on further research – ie. don’t take my word for it 😛
First thing to note is that in life I like to look at things skeptically. This doesn’t make me a cynic – it just means I want to believe as many true things and as few false things as possible.
If presented with stuff like the above (this is mostly in reference to the first video by the way), I will independently research to see if there’s any truth in the claims. This guy is quite clearly pushing an agenda – firstly, he’s using buzzwords like ‘sacred‘ and ‘divine‘ all the way through, and then in the last minute or so he makes the colossal jump to say ‘this is amazing, therefore god’, and secondly…he’s trying to sell his art which isn’t all that nice lool.
I should also note that this is a classic argument from ignorance. He can’t explain it and so leaps to God as an explanation, rather than exploring further through rigorous scientific study. It is also clear that he has started with a presupposition (God), which is obvious, as he was using the buzzwords I picked out above throughout, and is only exhibiting evidence to support his presupposition.
He fails to note that actually, many claims of sightings of the so called ‘Golden Ratio’ in nature have been discredited, because much variation in proportions has been observed in these cases (see wiki: ‘Disputed observations’ section).
To posit a god here when one isn’t needed is intellectually dishonest; these patterns apply to some individuals, not all, and therefore any assertion that ‘the golden ratio is Universal and indicates design’ is automatically falsified by even one example that doesn’t meet that criterion.
It’s also worth noting here that the human brain is excellent at recognising patterns, even when there aren’t any there (ie. something may at first appear to be a pattern but on further investigation is not) (hence why people see Jesus in a slice of toast.)
My next problem with this is that labelling this phenomenon the work of God hasn’t actually increased our actual understanding of why it occurs; in fact it immediately limits any possible further understanding or investigation, because so many people are happy to accept God as an ‘explanation’. This frustrates me no end, as it is complete and utter ignorance – for the reason I just noted, and also because there are people who spend their lives researching this stuff, and people like this guy jump in and make the blind assertion that ‘God did it’, without any credentials behind them. (I don’t know about the video guy’s credentials, but I’m saying this as something I’ve generally noticed about people who cry ‘God’. However seeing as he has done just that I’m willing to bet he’s just as ignorant on the topic as everyone else who says God did it..)
Furthermore, if you think about it, it’s not all that impressive that you can put a square inside a rectangle and come out with a rectangle with the same ratio as the original rectangle.
To use Douglas Adams’ analogy:
‘Imagine a puddle waking up one morning and thinking, “This is an interesting world I find myself in — an interesting hole I find myself in — fits me rather neatly, doesn’t it? In fact it fits me staggeringly well, must have been made to have me in it!” This is such a powerful idea that as the sun rises in the sky and the air heats up and as, gradually, the puddle gets smaller and smaller, it’s still frantically hanging on to the notion that everything’s going to be alright, because this world was meant to have him in it, was built to have him in it; so the moment he disappears catches him rather by surprise. I think this may be something we need to be on the watch out for.’
Basically, this ‘golden ratio’ is given way more significance than it deserves and has been made out to be way more complex than it actually is.
This ratio does not point to design. By definition the posited designer must be even more complex than everything in existence, so nothing has been explained and a bigger problem has been created. We also know from the observable Universe that things naturally start simple and get more complex. So to put forward a god that is more complex than the Universe itself simply doesn’t make sense.
Intelligent design is not helpful in understanding how the Universe came to be. What people should really strive for is the proper practice of science, as through the pursuit of science and reason we can discover the true beauty of the Universe and how everything actually came about.
The Universe operates under certain physical laws; laws that allow this pattern to reoccur in nature. If there was a God, surely he should sign his work with something slightly more obvious than a spiral pattern?
With regards to evolution, many animals share a body plan. This is because evolution can only work with what it already has, and if something works and is advantageous in an environment it will be propagated. In fact, here’s a link to some research which seems to show that when the golden ratio appears in living things, it does so because it is extremely efficient and something selection would favour.
Last bit (had a little help from Ankur on this part):
1. The assertion is that everything that shows the golden ratio is designed.
2. It follows from 1. that if the golden ratio is a universal indicator of design, then all objects that are designed must show the golden ratio
3. It follows from 2. that anything that does not show the golden ratio is not designed.
4. It is possible to show examples in nature that don’t show this ratio.
5. Therefore it follows that all those examples aren’t designed, and because they are extremely similar to other examples of a similar type which do show the golden ratio, it follows that extremely similar objects would be designed and not designed, this is absurd.
6. It is also true that I can draw things that don’t show the golden ratio, and these drawings would be designed, thus showing the initial assertion (2.) to be flawed and invalid.
To conclude, presence of the golden ratio is not a viable indicator of design.
So yeah, I was told to look a little deeper and as it turns out, the argument was exposed to be severely flawed. A little critical thinking goes a long way 😉
Being passionate about science, I wonder a lot about the way I was taught science throughout school (and at college) and the way the people I know are being taught science in educational institutes. I think there is something fundamentally wrong with any approach that seeks to impose a linguistic corset on the processes involved in the understanding of science. You don’t make people good at science by making them learn answers to questions and then evaluating how well they reproduce those answers in an exam, not more than you can produce Olympic medallists by teaching them the history of their discipline as in who won what in the past!
That approach only tends to work as long as what is being evaluated is the state of knowledge about what is known about the world. Science, however, happens to be much more than a mere compendium of facts that is supposed to be assimilated. It is a process, a set of tools, a systematic approach that enables one to discern relationships between different things and examine the nature of those relationships.
It is also about being fundamentally rebellious in a strange sort of way, it is an attempt to try and be a paradigm shifter in matters of human knowledge. It involves not being satisfied with the nature of explanations but to probe further, to see if there are chinks in the proverbial armour of our knowledge of observational reality, or if there are gaps that need patching up. Science may, as far as one is inclined to treat it as an enterprise, eventually turn out to be unending. There’s so much to learn, so much to ask, and so much to find out.
It is in light of this that I find the almost authoritarian “You shall accept what I tell thee, and don’t ask me questions!” attitude that is so much a feature of science educators (this would appear to be a feature of educators here in general, too) here a bit bizarre, for science class, in my opinion, is a place that should not only entail knowing what is known to be true, but why, and how we arrived at that state of knowledge.
I know that anecdotes do not count for much, but it was rather surprising that I ended up explaining causality, controls and experiment design to a 13-year old, despite the scientific method being treated in the curriculum at the age of 11, obviously not very well.
So, having got that preliminary rant out of the way, I think it is time to focus on the key question. How should science be taught? What skills should we be focussing on? While I will not claim to having the definitive answer, I will still put forth my opinions, in the hope that it will foster discussion that will eventually give rise to a new consensus.
Firstly, I think that the scientific method ought to be taught, as in the experimental discernment of causes and effects. The idea of variables and causes and effects are perhaps the easiest to convey, and can be demonstrated with things like food. It is possible to demonstrate that the cause of the lemony taste of lemonade is due to the presence of lemon extract in it. Show that if you take two glasses of ingredients other than the lemon , add lemon to one and not the other (this is the concept of a control and a test), the variation in taste will be down to the presence of lemon extract in the preparation.
Another example would be sweets prepared with and without sugar, or food with and without spice. The core idea here is simple, the introduction of the principle of determinism. Stochastic processes is something they’ll have to be introduced to later, and a plausible method of demonstrating stochasticity using everyday examples evades me at the moment.
It is not difficult to see how one may, with knowledge of the aforementioned basics, go on to be in a position to understand and test hypotheses, and also to properly design experiments to do so. Concepts such as scientific theories can be introduced later, and by the time one enters late middle school, with well-developed skills in mathematics, at around the age of 12-13, much more advanced concepts can be introduced, culminating with the establishment of solid scientific foundations for further study if one so desired.
The other issue I want to write about in this essay pertains to the way science is presented. As I already said, I was really put off at school by the way science was taught. It used to be people reading the textbook out loud, more or less, and this already compounded the problems posed by a badly devised curriculum. Those people would really do well to learn from someone like Walter Levin at MIT, with a high degree of experimentation involved. If you are teaching Newton’s laws of motion, for instance, it isn’t difficult to illustrate them at all! , something like a duster on a table would do for the first two and then you could perhaps make a little rocket to illustrate the third…
The lack of connection with what is being studied is a special problem with biology, in my opinion. There is just so much natural beauty out there, and there are excellent books such as National Geographic’s “Exploring the Human Body” which are eminently suited in the conveyance of said natural beauty.
There also could be great benefits to getting a microscope, just to highlight all the diversity there is, and to show students the tissues in plants and animals they read about in the curriculum, which they tend to do so without any sense of connection. It is also not difficult to take fruits to the classroom and illustrate the concepts of radial and bilateral symmetry, or to introduce the myriad of resources available on the web that bring the concepts they’re being taught to life (pun intended).
More could be conveyed about ideas such as mitosis and meiosis and photosynthesis and so on just through the judicious use of animations and videos. There is no substitute to a good time-lapse video of cells dividing if one were to be studying that, or bacteria growing.Finally, I would like to chime in for the introduction of practical science earlier in education, including at school level, I would like to substantiate the fact that children can do good science at a very young age by pointing to the peer-reviewed study that a group of 8-11 year olds in Blackawton Primary School in the UK was able to produce.The full paper is here http://rsbl.royalsocietypublishing.org/content/7/2/168
I hope that more educators will turn their attention to what is a very important area of education, and that it will bring forth ideas that can utilize the full breadth of analogy, technology and good old science to impart the tools required for scientific reasoning and the knowledge required to enable that reasoning to be solid in a way that is no longer coma-inducing.
Most importantly, I hope that those ideas are tested experimentally so that the science curriculum becomes an example of the principles it is supposed to teach. That is all from me this time round.
The ability to grow organs for replacement in the lab would have been considered as part of science fiction just one or two decades ago. However, as our knowledge of organ development has been steadily increasing, and this has led to the emergence of a new field, called Regenerative Medicine.
Before going on to discuss a few aspects of the field, I wish to give you a short summary of what happens during development. All multicellular, sexually reproducing organisms start from one cell, which divides and divides and divides to produce more and more cells, and these cells, in the early stages of embryonic development are capable of forming many kinds of tissues, they are described as being undifferentiated and are known as stem cells.
The eventual differentiation of a cell, and the type of organ it forms, and the types of tissues it does this through are all determined by the external environment which can supply cues that regulate gene expression. Being aware of this can be used to turn stem cells growing in the lab to the desired kind of tissue, by means of conditioning the environment to supply the apposite cues.
I wish to introduce you to two videos at this point, both from EuroStemCell.
This one is called A Stem Cell Story and gives you an idea of what Stem Cells can do.
This one, about Cell Culture, introduces you to some of the laboratory work that goes into the culture of stem cells and some of the basic principles that can be used to turn stem cells into the desired tissue type.
Now the problem, you see, isn’t just the production of the requisite cell types, although it may not be difficult to envisage the limited use of the cell types you want to replace damaged sections of already extant organs. The real challenges in the field are in the production of organs in the laboratory.
Organ formation introduces the concept of spatial specification, the cells you have must be put into specific configurations such that they form organs…
There are two ways this can be done.
1) Using sheets of biodegradable polymer, print stem cells or organ precursor cells layer by layer and then stack all the layers together. Once the cells have fused you can melt the polymer, leaving the organ in place.
This can be done using, among other things, a modified inkjet printer that spits out cells.
This is an introduction to an organ printer.
This one enables you to see more of the technology.
2) Using cadaver organs.
Cells are stripped away using a detergent from cadaver organs, and the collagen framework that results is then used as the scaffold.
An example of that approach in action is this
In both cases the seeded scaffold has to be put in a bio-reactor where the necessary environmental factors to ensure differentiation into a particular organ are present.
You can find more videos about the field below.
How about a couple of textbooks?
Fundamentals of Tissue Engineering and Regenerative Medicine, Ulrich Meyer et al , Springer, ISBN: 978-3-540-77754-0
Tissue Engineering, van Blitterswijk et al, ISBN 9780123708694, 2008.
I hope you can start to see how science can change, improve and extend life, and if it interests you I think you may want to start looking at careers in this field.
That is all from me as far as this introduction goes, but I may deal with some areas of this field in-depth in future posts.
Now before we get started, I cannot tell you enough how cool this field is! I hope to substantiate that claim with some extraordinary demonstrations of the concept to go with a simple description.
The term Optogenetics is a fusion of the prefix Opto (related to light) and Genetics (study and manipulation of genes). This should tell you that the field involves the coupling of the study and manipulation of genes to an external control source using light.
Perhaps the most prominent example of optogenetics involves the use of genes and light to control the function of neurons or nerve cells. Basically, neurons conduct electrical impulses through gradients of ions like chloride and potassium and sodium and so on…in other words, if you alter the gradients of these ions you can get a neuron to “fire” (or propagate an electrical impulse)
This process of conduction has been illustrated here
Now, here is where optogenetics comes in, there needs to be a mechanism of getting ions in and out of cells in response to light. The thing with genes and the fact of a nigh on universally conserved genetic code is that a straight port of genes is possible from organisms of different species and they will always produce the same product.
In the application I’m talking about, they used proteins that pumped ions in and out in response to blue and yellow light, taken from a green alga called Chlamydomonas reinhardtii and an egyptian archaebacterium.
They managed to express those genes and consequently those proteins in specific cells using tissue specific promoters…wondering what those are?
Well, every gene has a region that tells the cell that there is a gene that follows, and tells the cell to make mRNA from the DNA of the gene, while also regulating the process. It is also a fact that some genes are specifically expressed in some tissues and some cells, if you take a promoter of such a gene, and fuse it to a gene of your interest, you can get it to form protein only in those tissues/cells.
This enables light to be introduced through fibre optic cables with a bit of a scattergun approach, and also enables the response to be accurately controlled. In other words, we can switch neurons on and off, mind control here we come mwahahaha 😉
Well, we really do.
The following lecture discusses what I’ve described above and has lovely illustrations, too.
These experiments were carried out in the lab using cell cultures in Petri dishes and in model organisms in the laboratory, including rats and mice, it wouldn’t surprise me if technologies such as this eventually found applications in humans, given the potential it has.
A small sampling of the peer reviewed literature on the subject follows.
This post will be an introduction to the phenomenon of Bioluminescence. Bioluminescence is the emission of light by living organisms utilizing chemical reactions.
The components of a bioluminescent pathway include a luciferin and a luciferase.Luciferin reacts with oxygen to form oxyluciferin, which emits light as a byproduct, luciferase is an enzyme that catalyzes this reaction, with molecules like ATP serving as co-factors.
Having got the nitty gritties of bioluminescence aside, I think it is time for visual appreciation…
The photograph above is by Phil Hart and can be found here , it shows Noctiluca scintillans bioluminescence in action.
This is a photograph of the Bioluminescent copepod Metridia longa
Original image here.
The aforementioned image, copyright Y.Kito, is a Japanese Firefly Squid (Watasenia scintillans) , truly scintillating, ey?
Bioluminescent Jellyfish!
One more.
If you are looking for more bioluminescent eye candy, you may try the gallery here
Academic rigour is often expected in matters of scientific and rational discourse, but this isn’t always guaranteed,and this is why peer-reviewed papers constitute the minimum standard of acceptability in the communication of science, with the consensus view that indicates the acceptability of results and implications of research being a better indicator of the validity of whatever does get through peer review, in this short essay, I hope to illustrate why something like this is the case.
Sometimes, however, standards are simply not met, and while the following examples are not strict examples of kooky stuff getting through peer review journals they are close enough.
The first one is the Sokal affair, Alan Sokal, a physicist, in 1996 managed to get an essay titled “Transgressing the Boundaries: Towards a Transformative Hermeneutics of Quantum Gravity” published in a journal called Social Text(at this point you may want to take the detour and enjoy Sokal’s brilliant hoax essay here)
There had been this trend amongst quite a few postmodernist academics to make blind assertions about the nature of objectivity in science , and Sokal provides ample evidence of this by citing them in the paper, I quote the apposite section below
But deep conceptual shifts within twentieth-century science have undermined this Cartesian-Newtonian metaphysics1; revisionist studies in the history and philosophy of science have cast further doubt on its credibility2; and, most recently, feminist and poststructuralist critiques have demystified the substantive content of mainstream Western scientific practice, revealing the ideology of domination concealed behind the façade of “objectivity”.3 It has thus become increasingly apparent that physical “reality”, no less than social “reality”, is at bottom a social and linguistic construct; that scientific “knowledge”, far from being objective, reflects and encodes the dominant ideologies and power relations of the culture that produced it; that the truth claims of science are inherently theory-laden and self-referential; and consequently, that the discourse of the scientific community, for all its undeniable value, cannot assert a privileged epistemological status with respect to counter-hegemonic narratives emanating from dissident or marginalized communities. These themes can be traced, despite some differences of emphasis, in Aronowitz’s analysis of the cultural fabric that produced quantum mechanics4; in Ross’ discussion of oppositional discourses in post-quantum science5; in Irigaray’s and Hayles’ exegeses of gender encoding in fluid mechanics6; and in Harding’s comprehensive critique of the gender ideology underlying the natural sciences in general and physics in particular.7
So aforementioned wibble that he cited from the writings of postmodern philosophers all seem to portray a world where the scientific consensus is not grounded in objectivity but in the ideological biases of the researchers doing the work (which is manifest nonsense and exposes the droolingly anencephalitic thinking of the postmodernist ignoramuses who comment on science despite knowing sweet bugger all about it) , this opinion of course extremely prevalent in elements of society like the media, a brilliant counter to this attitude by Dara O’Briain can be found here
So now, back to the Sokal affair, to get to the bottomline, he wrote a load of tosh and Social Text published it without requisite fact checking just because of his credentials as a phycisist and they wished to include an article by a Phycisist, not least in an issue that was dedicated to arguing that science was shorn of objectivity, and it bloody worked in the end because it was accepted and published by Social Text even though Sokal refused to make editions, just because he was a phycisist, which is a logically fallacious appeal to authority.
It was only exposed as a hoax after Alan Sokal himself let everybody know in a magazine called Lingua Franca, and that document can be found here http://www.physics.nyu.edu/sokal/lingua_franca_v4/lingua_franca_v4.html , he also wrote another piece as a follow up explaining why he executed the hoax, and that can be found here
He explains his primary motivation thus, by invoking a quote by someone else
I did not write this work merely with the aim of setting the exegetical record straight. My larger target is those contemporaries who — in repeated acts of wish-fulfillment — have appropriated conclusions from the philosophy of science and put them to work in aid of a variety of social cum political causes for which those conclusions are ill adapted. Feminists, religious apologists (including “creation scientists”), counterculturalists, neoconservatives, and a host of other curious fellow-travelers have claimed to find crucial grist for their mills in, for instance, the avowed incommensurability and underdetermination of scientific theories. The displacement of the idea that facts and evidence matter by the idea that everything boils down to subjective interests and perspectives is — second only to American political campaigns — the most prominent and pernicious manifestation of anti-intellectualism in our time.
— Larry Laudan, Science and Relativism (1990, p. x)
And anybody involved with the utterly nonsensical “chalega” or “everything goes” attitude , not least the rationalists I have had the pleasure of knowing, will immediately recognise that the subversion of truths about observational reality is at the heart of every doctrine driven nutter in the world who, to summarise, would assert that if doctrine and reality differ, the former is right and the latter is wrong and also be able to appreciate how pernicious an influence it can have on important issues like policy-making, ranging from climate change to proper scientific education (look no further than the right wing in the US of A)
The problem amongst some sections of the postmodernist academia at least was an endorsement of such obviously misinformed thinking, exacerbated in some other cases by the complete lack of understanding of what constitutes the scientific picture of observational reality, and to expose this in an effort to promote better academic standards was one of Sokal’s motivations, and I suppose he pulled it off brilliantly.
This brings us to the second part of the Scientific Sting Ops special, the Lachlan affair.
Like the people endorsing postmodern anti-intellectualism people in the alternative medicine community often hold similar viewpoints, where people often attempt to pass off kooky stuff that can claim lives as scientifically rigorous not by ensuring that high standards of EBM (Evidence Based Medicine) are met, but by attempting to bypass standards of evidence altogether, including a over-reliance on case histories and confirmation bias that are characteristic of anecdotes pertaining to those case histories.
In other words, if they had to pass an exam, they wouldn’t do it through scoring high marks, but by lowering how much they need to score to pass, in effect sacrificing empirical rigour for purposes of kooky medical viewpoints (I would again argue that these are doctrines, things like the Galenic concept of humour or “like cures like” or “less is more” are held to be axiomatic by the systems of “medicine” that utilize them with no effort made to verify them, which automatically converts them to unquestionable dogmas)
Other features include arguments from authority, allegations of conspiracy theories against big pharma, and as anybody who has spent time on RatSkep in the same thread as a certain annoying homeopath will tell you, asinine arguments suggesting that some conventional meds don’t work, ergo CAM must, all the while completely being unable to provide evidence.
John Lachlan decided to investigate if an argument made with the inclusion of the aforementioned features would manage to gain acceptability at a CAM or “Integrative Medicine” conference, he cooked up a fabricated CV to confer a sense of authority and came up with an utterly ridiculous concept, reflexology of the arse (lol)
He was asked to submit an abstract, which he duly made up and submitted, and this led to acceptance for presentation at a conference in Jerusalem, at an international level convention no less. Lachlan’s expose of this issue can be found in the British Medical Journal (please see the link here)
His abstract makes all the claims characteristically seen from opponents of scientific rigour wherein measures to ensure rigour are challenged using ad hominems against proponents of such standards “close minded” and arguing that alternative therapies are not amenable to testing by rigorous, high quality DB-RCT (Double Blind – Randomized Controlled Trials) while disguising a bleedingly obvious hoax that would require a full frontal lobotomy or its cognitive equivalent to be held as valid (homonculi in the bum, really?!) while simultaneously making an appeal to authority.
Guess what, it got accepted, and the rest they say is history.
People might still insist that this was just a conference, and just one conference, but the core principle underlying Lachlan’s scientific sting op is still essentially valid, that lowered standards of evidence must never be used as a tool for sneaking nonsense into medicine, lives could be saved or lost, it is that bloody serious.
He of course echoes this sentiment in the BMJ paper when he says, and I quote
“So called integrative medicine should not be used as a way of smuggling alternative practices into rational medicine by way of lowered standards of critical thinking. Failure to detectan obvious hoax is not an encouraging sign”
Talking of appeal to authority, I think it is often used all too much, and for some reason people are really vulnerable to it, and it is not a surprise that people in positions of authority often use it as if it proves any bloody thing (“I have X years of experience, ergo I am omniscient” would be a very apposite praraphrase when describing the reactions of teachers who were challenged with evidence through my academic career until now) and I know that is a case history and I am obliged to present empirical evidence about the effects that appeals to authority can have, so, as a final exhibit in this short essay, I would like to introduce you to the Michael Fox experiment, a popular account of which may be found here
and the actual paper can be found here
To put it simply, if you make your qualifications look impressive and spout nonsense in dulcet tones you can expect to be taken seriously.It also strikes me as funny that the actor in the Dr.Fox experiment was a Mr.Fox, and we all know that people who solicit your votes are , erm, Foxy.
Exploreable 
