• WABLOG: From the desk of Matthias Wabl

How inflammation leads to multiple myeloma

In mice, mineral oil causes inflammation, which leads to a lupus-like condition and to the formation of plasma cell tumors. It has long been known that chromosomal translocations (breakage of two chromosomes and rejoining the wrong ends between them) drive tumor formation and progression. But clearly, this is not enough for full-blown tumors, and it raises the question: What do inflammatory tissues provide to promote further mutagenesis? We have shown that endogenous retroviruses and retrovirus-like particles mutate DNA in such a way as to activate cancer genes.

From the peer review of the paper:

“This is a well written paper that progresses our understanding of the transforming events that may be associated with inflammation-induced cancer. Experiments described in this manuscript will fuel further investigations to determine whether human cancers associated with chronic inflammation can be associated with reactivation, replication and mobilization of endogenous retroelements, thereby possibly contributing to tumor initiation maintenance and/or progression.”

Read the paper:

It seems that lupus and HIV avoid each other. Why is that?

There is only anecdotal and retrospective evidence for it, but it seems that HIV and lupus avoid each other. One might think, no wonder: HIV patients are immune-deficient and thus may be autoimmune-deficient, too. However, there ought to be patients who suffered from lupus before they were infected with HIV. Clinician-scientists tell me that of the thousands of HIV patients they have seen, none had lupus. While this does not rise to the cogent standards of scientific evidence, it may be worth thinking about.

Mice have many endogenous retroviruses (viruses that are part of the mouse genome), and so do human beings. The endogenous retroviruses in people are not infectious, but they still can produce some proteins. These proteins may prevent completion of the infection cycle by HIV. In mice, the so-called Fv-1 resistance gene, which stymies infection by a mouse retrovirus, encodes a protein similar to that of the core of the exogenous virus. By analogy, lupus patients may express a retroviral protein that interferes with the life cycle of HIV.

“How to Understand a Friend” — almost a decade later

The following letter was written at the height of the intense discussion about intelligent design versus Darwinism. It was in response to an editorial by Cardinal Schönborn, the lead editor of the official 1992 Catechism of the Catholic Church, in the New York Times of July 7, 2005. It was not sent for personal reasons.

“How to Understand a Friend”

Dear Christoph,

Your article in the New York Times of last Thursday has had serious percussions in Austria, and it has been noticed elsewhere in the world as well. If it were possible to create a bridge between the catholic and the scientific world in this specific matter, I think it would have to be built on your interpretation of the word “design.”

In your rebuttal of the statements you cite in your opening paragraph, you say that “the Catholic Church, while leaving to science many details about the history of life on Earth, proclaims that by the light of reason the human intellect can readily and clearly discern purpose and design in the natural world, including the world of living things.”

As I have understood Darwin, he did give many details about the history of life, but his main point seemed to be that the structures we see can be understood in terms of their natural history. This history was driven by variation and “natural” selection (as opposed to “artificial” selection by breeders, for example). Darwin did not know about mutations; the knowledge about, and the understanding of these, are among the great triumphs of biology of the twentieth century.

Yes, there clearly is “purpose and design in the natural world, including the world of living things.” No biologist would argue with that! But now, how is this purpose and design accomplished? And here your understanding of what science ought to be departs from what today’s biologists think. Yes, indeed, as you have formulated so clearly, most biologists think that “purpose and design are achieved by an unguided, unplanned process of random variation and natural selection.” Read More »

Hybridoma history, as written by the journal Nature

If journalism is “the first rough draft of history” (Philip Graham), then we might be doomed, at least in a small way. An editorial referring to—and advertising—the Nature PastCast makes the point, “If those who do not learn from the past are truly doomed to repeat the same mistakes, then Nature has done its bit over the past few months to help them avoid that fate.” It goes on to talk about the hybridoma technique, published in 1975 by Köhler and Milstein in Nature. This technique enables the easy generation of monoclonal antibodies, an over-$50 billion-industry today. Curiously, the editorial informs us that:

“The revolution was nearly stillborn: the published technique to make monoclonal antibodies could not be reproduced. ‘The crisis was such,’ says historian Lara Marks at King’s College London, ‘that the authors considered withdrawing their article from Nature’. It was years before the investigations paid off and the huge medical potential of monoclonal antibodies started to crystallize. ‘Nowadays it seems prophetic,’ says Greg Winter, who made the first monoclonal antibody for use in humans, ‘but at that point I don’t think anyone had realized the importance.’ ”

If my recollection of the events serves me right, almost everything in this account is wrong. Read More »

The Bureaucratization of Science

“Science has always been bad” – Charles Steinberg

In November of 1895, when following up on a radiation experiment “that needed further investigation,” the fifty-year old Wilhelm Röntgen saw the bones of his fingers on a fluorescent screen. Worried about his sanity, he locked himself in his lab for two weeks to understand what was wrong with his worldview, or with himself. He finally emerged and, with trepidation, led his wife to his experimental setup, for her to confirm what he had seen. Only then did he tell the world about his discovery of X-rays.

Some twenty years earlier, Friedrich Miescher recovered a precipitate that contained phosphorus and nitrogen, but not sulfur, from cell nuclei. He called the substance “nuclein” (now known as DNA) and submitted a paper describing his finding for publication. The editor of the journal, Hoppe Seyler, found the discovery hard to believe, and only published the manuscript (ref. 1) after he repeated Miescher’s experiment and convinced himself of its validity.

These are but two examples of the many conscientious laborers in the garden of truth. Today, on the side of the experimental scientists, there are still many Röntgens among us, though clearly, it would be difficult for the modern editors to do as Hoppe-Seyler did. But what can they do, and what have they done, to ensure that the experiments and the conclusions of the manuscripts they publish are basically correct? In light of the recent, disputed paper by Obokata et al. describing stimulus-triggered acquisition of pluripotency, or STAP cells (ref. 2), and the ever-increasing number of rules, experiments, and requirements thrust upon authors to avoid such scandals, it is important to consider the role of the journal in curating science: Read More »

“The opposite of a fact is falsehood, but the opposite of one profound truth may very well be another profound truth.” — Niels Bohr

As scientists, we believe in cause and effect. If this is so, then everything is predetermined, at least at the macroscopic level. This would also mean that we are just molecular machines that have no responsibilities because we have no free will. In society, we would regard a person with such a radical view as a sociopath. We argue that we are indeed responsible for our actions and thus rightly punished for our crimes. How can these two views co-exist? Obviously, the human brain has evolved to observe, interpret and react to the outside world, but this does not mean that our soul, our thoughts, and our language are in perfect sync.

“From such crooked wood as that which man is made of, nothing straight can be fashioned.” — Immanuel Kant.

Clinical trial initiated, based on an experiment performed in the Wabl lab

In May 2014, a clinical trial of reverse-transcriptase inhibitors in Aicardi-Goutières syndrome (AGS) is scheduled to start at the Necker Hospital in Paris. The orphan disease AGS is a Mendelian inflammatory disorder of the brain and skin. It is a clinical and radiological mimic of congenital infection, and it is associated with increased levels of the antiviral cytokine interferon alpha. Sadly, thirty-five percent of children with this disease die before the age of 10. A subgroup of patients carry a mutation in a gene that encodes the enzyme Trex1. Mutations in this gene are also responsible for 2% of lupus cases. The investigators of the trial write that they were “inspired by the really fantastic paper [from our lab: http://www.retrovirology.com/content/8/1/91], … which indicates that the accumulation of cytosolic DNA in Trex1-null cells can be ameliorated by inhibiting endogenous retro-element cycling.” In that paper we showed that mice with this lethal enzyme defect can be rescued by FDA-approved drugs (retroelement inhibitors) and suggested that such treatment might also ameliorate AGS in humans.

Thinking about lupus while walking

Most people with lupus have in their blood antibodies to DNA that is “native,” i.e., in the state most often found in our cells. DNA contains the information to build and maintain our bodies. Unlike a plan to build a bridge or a building, DNA is not separated from the cells that make up the body: all cells except red blood cells contain it. The DNA also instructs the cells of the immune system, which defends us against invading microorganisms and parasites. Read More »

A Miracle

Imagine you just woke up from a nightmare—all sweaty and terrified. Thank God, it was only a dream! How do you know? The systems check tells you that now you are awake: Your body and the world around you obey the natural laws, with no exceptions. Persons and things no longer metamorphose on a whim, there is familiar cause and effect again, and you cannot fly, either. Read More »

An Explanation

We are satisfied with explanations at different levels. In daily life, to explain a situation that is not important, we tell a quick story, perhaps without much structure, before moving on to the next topic. The explanation is unlikely to, and is not intended to, contribute a greater framework of understanding. Read More »