How to ruin your credibility

The recent post at Terra Sigliata brought up memories of my first thesis project in Prague. I got involved with ‘independent cancer researchers’ and one of them became my thesis adviser. He was a very kind old man and he let me do anything in their lab I wanted to – but eventually I moved out of there because doing synthetic chemistry in a poorly equipped biology lab was difficult.  I managed to re-synthesize some of their substances – the compounds turned out to be active in antiproliferative assay done at another institute but we could not really test them extensively anymore and my adviser retired and that was the end of the project.

It was an interesting experience. The sad part of it was that our colleague who actually started the work and made most contributions before retiring used to be a reputable virologist – he pioneered interferon production method using human fibroblast cultures. Later he got interested in analysing a ‘natural cancer cure’ from a quack that seemed to have positive results. So this virologist began looking for the active principle and was doing animal testing on the extracts – a legitimate research program – but his chemistry and also the animal work done in a very limited setting was not up to the task. The lab absolutely lacked the resources needed for natural product research and synthesis. He had nobody to test it so he brough mouse cages into the lab… He tried to push forward on non-existent budget and without the necessary expertise, simply by improvising and calling favors on his friends to gain the testing and instrument access unofficially. With this strange research project going on for years, his confrontational style also won him no admiration with the management and the neighboring groups at his institute. He was never forced to stop but he got increasingly isolated in his little lab.

He did succeed in finding something interesting – a class of naturally-occurring substances related to synthetic cytotoxic ether-phospholipid analogs of PAF (that were independently developed for chemotherapy). His natural ether phospholipids seemed to work on some cancer lines and were well-tolerated by normal fibroblasts. They also showed a promise in xenograft mice tumor models. Since these phospholipid substances are naturally-occuring in humans (under conditions like ischemia), the hope was that perhaps they could be less toxic than the synthetic alkylphospholipids.

As he and his few colleagues were getting increasingly anxious about the project progress and its lack of support, they decided to campaign in the media. They were also giving out their naturally-derived quack remedy to cancer patients; they genuinely thought they were doing favor to these patients… and they antagonised the medical community. That made them even more exasperated and resentful.

I had nothing to do with this patient compassionate “treatment”, I only re-synthesized some  substances in a pure form and got them independently tested; the compounds were active in a cancer cell culture but their poor solubility was a major complication:

Here is the synthesis I did for the project – it turned out to be a fairly straightforward scheme although it took some effort to figure out. (There was a bit more to it; I was also isolating these substances from a natural phospholipid mixture and characterizing them by chemical derivatization).

This project story from 20 years ago shows that people promoting the “natural cancer remedies” may even have careful scientific approach at the beginnig but as they continue they get carried away by wishful thinking to the point of delusion. They start as researchers but derail as quacks. When you are working on biologically active natural substances and you have great hopes for the medicinal potential of your project you have to be very conservative about the way you interpret and present your results. You can’t skip the preclinical research stage even when your compounds are “natural and non-toxic”. You need to look for any artifact argument against your promising results – if there is a discrepancy in your numbers you have to understand it (could the results be possibly influenced by the purity/instability/solubility of your compounds,  the way you make the stock solution, grow the cells or inject the mice?). Claiming that your critics from the medical community are hindering you because they surely are in confederacy with pharma companies is the surest method of earning yourself a crackpot reputation.

Also, please don’t take a thesis adviser who works on a fringe project even if you are excited about the research – after finishing my thesis; my adviser and his colleague could not help me with my career even though they were well meaning. They retired and our work came to nothing.

Strange bits from Schlosser

2,5-dihalopyridines lithiate with LDA into the 4 postion quite nicely. With 5-CF3-2-halopyridines the lithiation goes all over and separating the isomers is pain; a colleague found that with LDA in Et2O he can improve the selectivity up to 3:1- which was sufficient for his purposes – so it appears the regioselectivity of lithiation and the isomerisation of the lithiated species is sensitive to the media effect. Now it turns out Schlosser group published a lithiation procedure that uses iPr2NCO2Li – “a carbonated LDA” – together with LDA and LiBr – and with these additives all of sudden the lithiation becomes almost completely 4-selective for the 5-CF3 substrates. We needed the material so the trick came handy – yet I don’t pretend to understand what is actually happening here. And those mysterious isomerisations…

Anyway, if you ever consider this carbamate as a modifier for your lithiations, I found a more practical protocol: rather than spooning out a fairly hygroscopic solid lithium salt from a flask and into the LDA solution as described in the publication, I have been preparing and evaporating the reagent into the flask used for the next lithiation step and then transfering the LDA solution to this solid – in that way I was able to run the lithiations on a 250 mmol scale. (Keeping things dry takes more effort here in Florida).