War or Police metaphor in immunology?

I am concerned about the use of the police and war metaphor in immunology; you can have a look at my previous post. I find it very difficult to think outside of this specific box. We are taught immunology with this metaphor. We told to communicate about immunology with this metaphor. I have the feeling that I face a wall when I try to think differently.

When you try to avoid the political extremism of this metaphor, it is difficult not to go into an other extreme, into a caricature of the opposite position. Indeed, we could be tempted by a peace and love metaphor (ref 1), but this would  be such a caricature.

I chose here to take a political direction to give an example of a way to rethink the metaphor. I agree that science should avoid politics. But today for the sake of thinking outside of the book, I will assume my political positions and explore new avenues.

In this case, my vision of the immune system is a system that maintains homeostasis. We can push further away Michod idea about the role of the immune system in the emergence of multicellularity (ref 2). I will propose that the immune system plays a role in the maintenance of this multicellularity.  We can draw a parallel between this maintenance and human social cohesion systems. In this case the immune system could not only be the police, but also social security? Justice? Moreover if we consider that citizenship can be achieved through local social cohesion, then several different actors can play a role depending on the local condition. Maybe this can help us understand why we have difficulties to define the actors of the immune system. They change depending on the local environment, such as epithelial cells.

Of course, this is a first idea that needs to be further developed. I hope you will be interested and I am waiting for your friendly suggestions.

References:

1. Ed Cohen. Metaphorical Immunity.  Literature and Medicine 22. 2003.

2. Richard Michod & Denis Roze, Cooperation and conflict in the evolution of multicellularity, Heredity, 2001.

For who have ever asked questions about the origin of HeLa cells

An unusual post today. It is not about modeling or immunology. I was just confused by the article published in Science this month.

Of HeLa and Human Lives by Leigh Krietsch Boerner

It is hard to imagine a scientist who hasn’t heard of HeLa cells. Rapidly reproducing and amazingly robust, these cervical cancer cells have become indispensable in modern biomedical research. Their nearly ubiquitous cell line has been used in innumerable experiments that required a human cell culture. It has served in work ranging from the creation of a polio vaccine, to the development of leukemia treatments, to discoveries in cloning and gene mapping.

Despite the vast amounts of scientific data on HeLa, most people know very little about the cells’ origin. Obviously they came from a woman, but who was she? HeLa, from the initial letters of the donor’s first and last names, provides a small clue. Commonly reported as Helen Larson or Helen Lane, her actual name was Henrietta Lacks. But just knowing her name does not tell us that she was poor, that she was black, or that she was largely uneducated. It does not tell us how she died, moaning in agony, in the free ward of Johns Hopkins Hospital in 1951, when she was barely 31 years old, leaving behind five children. Nor does it tell us how her cells were taken without her knowledge and without her consent.

Rebecca Skloot’s The Immortal Life of Henrietta Lacks does tell us all these things—and more. It gives us Henrietta’s life, laid out like a cell under a microscope. And like any good scientific research, this beautifully crafted and painstakingly researched book raises nearly as many questions as it answers: questions about ethics, racism, and, most importantly, humanity.

Skloot (who teaches creative nonfiction at the University of Memphis) twines together the strands of HeLa cells and Henrietta Lacks and of “Henrietta’s family … and their life-long struggle to make peace with the existence of those cells, and the science that made them possible.” She does that so eloquently one can’t imagine the story being told any other way. Most notably, Skloot presents people in a completely straightforward manner. She does not insert her own opinions of them, just gives us the details and lets us decide for ourselves.

Her approach is particularly important in regards to the scientists, especially Richard TeLinde (chair of the hospital’s gynecology department) and George Gey (head of tissue culture research at Hopkins). TeLinde, who was collecting biopsies from patients for a cervical cancer study, offered Gey samples from which to attempt to grow some cells. Having been trying for over 30 years to establish an “immortal” cell line, Gey jumped at the chance. He and Margaret Gey succeeded at culturing Lacks’s cells and discovered their amazing capacity for reproduction.

In a time when it’s fashionable to demonize scientists, Skloot generously does not pin any sins to the lapels of the researchers. She just lets them be human. The humanity of Gey comes out in particular relief. Instead of spending his time publishing his HeLa results, Gey flew around the country helping other labs set up the culturing techniques he had developed, and he gave away HeLa cells. Eventually, he was scooped by a lab to which he had distributed cells.

Did Gey or TeLinde really see Lacks as a person, possessing rights about what happened to her cells? Likely not: they saw her as a patient. At the time, it was generally held that physicians could use patients treated in a free ward as research subjects (with such use seen as a form of payment). But Mary Kubicek, Gey’s young lab assistant, did eventually recognize Lacks as more than a cell source. After Lacks died, Kubicek was sent to collect additional samples directly from the body. Noticing the toenails Lacks had meticulously kept painted red, she “‘started imagining her sitting in her bathroom painting those toenails, and it hit me for the first time that those cells we’d been working with all this time and sending all over the world, they came from a live woman. I’d never thought of it that way.’”

Anyone who has ever worked with HeLa cells will find it easy to relate to this revelation. Some years back, I injected a drug our lab group had synthesized into a group of HeLa cells. I watched the treated cells through a fluorescence microscope, the blue dots of drug shining out like stars from the white of Henrietta’s cells, and thought, “Who was this person?”

At 16, Skloot asked the same question after hearing about Henrietta Lacks in a biology class. She could find little information then, but curiosity kept the story in the back of her mind. Eventually, she returned to it and spent 10 years researching and writing her book, during which she got Lacks’s reticent family to talk to her.

The book’s first half intertwines the stories of Lacks and the science of HeLa. The second half binds together the author’s own desire to learn Lacks’s story with that of Lacks’s daughter, Deborah. Veering from the road usually trod by journalists, Skloot forms a close emotional bond with Deborah Lacks and becomes a character in her own book. Such a presence can be risky, but she makes it work. Skloot presents Deborah’s emotionally charged story of confusion and loss in the same unassuming style with which she told the scientists’ stories: she does not judge, just tells what happened. And by writing her story this way, Skloot draws in anyone who, like her and me, has ever wondered who was the person from which researchers obtained HeLa.

In the prologue, Skloot remarks, “The Lackses challenged everything I thought I knew about faith, science, journalism, and race.” Similarly, Skloot challenges much of what we believe of ethics, tissue ownership, and humanity. Looking back, it may seem easy to say that those cells never should have been taken from Lacks in the first place. But can you imagine a world without HeLa cells? Without the advancements that they’ve helped us make?

The HeLa cells I used in my experiment, now two years past, still sit at the back of my waste cabinet. I just can’t seem to throw them away. Likewise, the story that Skloot tells is something that will not be easily forgotten. Thanks to the author’s narrative skills, it is a tale that one experiences rather than reads. Through her cells, Henrietta Lacks was already immortal. But with this book, Skloot may make her story immortal as well.

references

Science 26 February 2010: Vol. 327. no. 5969, pp. 1081 – 1082

The Immortal Life of Henrietta Lacks by Rebecca Skloot Crown, New York, 2010. 392 pp. $26, C$32. ISBN 9781400052172.

The reviewer is at the Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. Web page: http://ljkboerner.wordpress.com

On the way to explore modeling

What I have learned up to now is that several kinds of models exist. From the point of view of a biologist these models could be classified depending on:

– the scale of modelling:

Many models are built at molecular level, considering one or several molecules. It can also be at the level of one cell, several cells, an organ (see paper from Irun cohen ou Rob de boer 07), between different organs or the whole organism.

Multiscale models have also been developed (for an example on antigen presentation see Denise Kirschner) where scales are bridged together  by input and output functions. These multiscale models are based on bottom-up effect which supposes that a hierarchy between scales exists. I have not seen yet any approaches taking into account an top-down effect.

– the model being only theoretical or also mixed with experimental data:

I really prefer (you still prefer them! If you use preterit, it means you don’t prefer them anymore) models combining an experimental and a theoretical approach as I has already explained.

– some models are about a specific technique and try to show what should be the right process to be used by an experimentalist using this technique. The idea is to use modelling approaches to improve in the end measurements or the solidity of conclusions drawn from an experience. The review by Rob de Boer on measuring proliferation of T cell is a good example (Rob de Boer 07)

In practice modeling is useful in only two cases, which depend on the knowledge about your biological question. If for your question, all the components and mechanisms are known, you can do quantification by modelling. If the components or the mechanisms are unknown and you have various competing hypothesis, modelling could help you discriminate between these hypothesis. The model should be build in way such that it gives qualitative differences that could be compared to experimental data..

When your biological question is well defined and you proceed to meet a modeller, you should be able to tell :

–      if your variables are discrete (meaning they can take discontinuous values) or continuous (meaning they are continuous within a range),

–      if you need a deterministic or stochastic model  (stochastic mean that the value are associated with a probability to appear, it is used for example when you don’t know the sequence in which states of the system occur)

–      the range of variation of your values (not the easy part for a biologist!).

When you have clarified these aspects, on the mathematical point of view several options remain available.  For a deterministic model with continuous variables you can use ordinary differential equations (their short name is ODE). For example these type of equation give you the mean behaviour of a population. They are typically used for variables such as concentration that are measured globally. Variations of the differential equation exist such as partial differential equation or Monte Carlo simulations.

In other cases you can use an agent-based model that I already presented on this blog. You have to define for each agent : parameters, the environment, rules and time.

The major problem is to define the variables that we know little or nothing about. You can estimate them by measurement, estimation or take the magnitude from other examples that are better known. This estimation is the most important point because it determines the relevancy of your model! Indeed you can obtain completely different results for two ranges of estimation.

Hope to see you soon along the way of my discovery of modelling…

Why modeling?

This is a question often asked to me. I think it is important starting point for this blog. I was quite embarrassed when writing this post and I have been thinking about it for two years now. I made several attempts that were not much conclusive in the end. As it is often the case, I found someone to write it better than me so I decided to report a few quotes for you!

It is an article that introduces an issue of the Journal of Immunological Reviews published in 2007 on “quantitative modeling of immune response” (Quantitative modeling of immune responses. Cohn M, Mata J. Immunol Rev. 2007 Apr;216:5-8). This issue is so rich and complete.  The tone sounds a bit depressed but we understand the authors because they started ten years ago and never had any feedback from experimental immunologist.

“The central role of theoretical studies in genetics and evolutionary biology is well recognized. By contrast, in immunology, we remain crassly empirical. Even the theoretician has become a victim of this view, often equating theory to a tool to store or catalogue the vast amount of complex data being generated. Simulation, the extrapolation of which is called a prediction, is viewed as understanding. As theoreticians, we must face the fact that building a mathematical web around a random collection of observations does not in and of itself increase understanding. »

« The theorist conjures up the various ways that the system might work; the experimentalist determines which of those ways is actually used. We should look to the theorist to define clearly and make transparent the competing concepts, extrapolate them to possible mechanism, apply the extrapolations to existent data, suggest where new data are needed, and design experiments distinguishing validly competing concepts, theories, and models. But above all, the theorist should be a discerning critic bluntly evaluating the pool of experiments and putting them into a larger cohesive framework. The role of the theorist is to characterize and widen our understanding, not to review it. »

Just to finish a point I feel very concerned about.

« Theoreticians in this field believe that today’s experimentalists are not sufficiently adroit in the use of mathematics and computer modeling and, therefore, are not prepared to deal with immunology as it increases in complexity. Experimentalists believe that most theoretical studies are sterile meanderings into Neverland, either because they are too general to be useful or so specific that they become another way of describing what we know already. Clearly, interactive discussion is needed. »

This has been written in 2007 and little has changed since. Once a physician (that I will not name here) clearly told me that he does not want to teach modeling to immunologist. I totally disagree with this attitude. You can also find these kind of attitudes among experimentalists and it is also unacceptable!

This citation will end my first political post about science.

Emmanuel Kant : « conduct yourself in a way that the maxim of your action can still be used as principle to universal law »