Dartagnan wrote a great diary about the Catholic Dioceses of New Orleans and their pronouncement that “the latest vaccine from Janssen/Johnson & Johnson is morally compromised as it uses the abortion-derived cell line in development and production of the vaccine as well as the testing.” My research laboratory is one of thousands around the world that uses the HEK293 and HEK293T cells on a nearly daily basis. Therefore, I thought it might be worth expanding on the further implications of any such pronouncement.
HEK293 cells were originally developed in the Netherlands in 1973 from a female fetus. HEK stands for “human embryonic kidney” cell, although there are several reasons to believe that the cells actually came from the adrenal gland, a small endocrine organ that sits on top of the kidney. In more technical terms, they may have come from a neural crest cell, which explains some of their properties, especially for studies of receptors, ion channels and transporters often found in neurons. This cell line was created by transfecting some embryonic cells with a human adenovirus type 5 [1]. As a result, the cells would continue to divide essentially forever, thereby establishing a cell line. Someone writing in Wikipedia has tried to trace the history of the cell line in more detail. According to that entry, Dr. Frank Graham, who carried out this initial transfection, cannot recall the origin of the human cells he used in those procedures. He stated that “they could have come from either a spontaneous miscarriage or an elective abortion. Regardless, the abortions that gave rise to the three cell lines—or in the possible case of HEK293, the miscarriage—happened decades ago." [2] In fact, it is possible that he never knew where the tissue actually came from.
HEK293 cells have many properties that make them very useful in cell biology, molecular physiology and drug discovery [3]. The first is that they grow quite easily. They divide at a very predictable rate, not too fast and not too slow, and the medium you grow them in doesn’t require any exotic ingredients (by the normal standards of cell biology). They adhere to uncoated plastic culture dishes or glass strongly enough that they do not detach due to simple fluid handling procedures, such as pipetteing stuff into our out of the medium in which they are growing. But they don’t attach so strongly that it is impossible to remove them from a dish without killing them. This makes them especially well-suited for robotic procedures, which I’ll come back too. The most important thing of all is that they will express proteins at very high levels if you put some interesting mRNA into them, and this is especially true for proteins that would normally be secreted or proteins that would normally be found on the cell surface. And that is why they have been used in vaccine research, and also for studies on membrane surface proteins, including receptors, that often make excellent drug targets.
Over the last nearly five decades, the cells have changed quite a bit, so it’s hard to recognize them as human cells. For one thing, they typically have a really strange number of chromosomes (their so-called karyotype is highly aberrant), and this has made it almost impossible to infer their origins. Another feature is that if they are propagated in different laboratories they are prone to drift in terms of genotype and phenotype, so that an HEK293 cell line in one laboratory may be somewhat different from an HEK293 cell line in another. In my own mind I think of them as almost a unique and continually evolving set of species at this point.
Pharmaceutical companies and academic researchers interested in drug discovery would like to automate as many steps as possible. One advance along the way came from chemists, who developed procedures of combinatorial chemistry that allowed for construction of so-called “compound libraries” [4]. Using those procedures, it is straightforward and relatively inexpensive to develop a library of tens of thousands of drug-like molecules. Big drug companies now have huge compound libraries (probably several of them) that are highly proprietary, and success in drug discovery often depends on the size and quality of the libraries. These libraries can be accessed by robots to allow for automated screening of tens of thousands of compounds — if one can engineer a cell line to express your desired drug target, and if there is an automated measurement system (assay) to figure out if one of the compounds in the library can alter the activity of your target in some desired way. Typically this means to activate it or to inhibit it, and the measurements often entail some sort of optical or fluorescent signal detected and quantified by microscopes and sensitive digital imaging systems. Over the years, drug companies have refined and enlarged their compound libraries. The robotic procedures and types of measurements that can be made have become increasingly sophisticated and clever, especially the use of fluorescent imaging. Collectively, these procedures are referred to as “high-throughput screening”.
The goal is to identify a small number of “lead compounds” that can then be subjected to more time-consuming procedures to accept or reject the compound, and if accepted, to refine its structure to make it more and more drug-like. With a lead compound in hand, a number of cell-based assays are carried out. Later, the most promising compounds are tested in animal disease models to see if any of them work in vivo (in an living organism). If a compound still seems interesting after that, it may be refined further to make it something that could be taken by mouth, ideally just once per day, etc. etc. Most lead compounds never get that far.
Central to a vast amount of this is the HEK293 cell line. As mentioned above, that’s because it has properties that make it ideal for high-throughput screening. It makes the target protein in large quantities, and it is ideal for robotic handling. They are used in the discovery of those ever elusive “lead compounds”. They have other uses in vaccine development as well, but here I am focusing on drug discovery as opposed to vaccine discovery. (A vaccine is a drug, but it has very specific features and for this diary it is useful to make a distinction, and indeed clinical trials for drugs and vaccines have to be designed somewhat differently).
This leads back to the Archdiocese of New Orleans. Because, if for some sort of moral reason they reject any vaccine that was developed using HEK293 cells, then they also need to reject the use of a very substantial percentage of the drugs that have been developed over the last 10-15 years. What percentage? It would be very difficult to say, I certainly can’t. But a very substantial percentage.
And of course that leads to the question of how many turtles down we need to count? Let’s say some research paper in a basic science journal suggested a protein as a potential drug target and used HEK293 cells at some point in the study. Then, years later, drug companies developed a drug targeting that protein. Does that make this drug morally unacceptable? Where do you draw the line?
At the end of the day, to be safe and philosophically consistent, to avoid being “morally compromised” these priests should advise their acolytes to not take any newly developed drugs at all, and they certainly shouldn’t take any themselves. To cite just one example, for people with type 2 diabetes, metformin would be ok, but newly developed SGLT2 inhibitors like canagliflozin, dapagliflozin, and empagliflozin would be forbidden [5].
Which is simply insane. In my view, any such position is itself morally compromised.
1. Graham FL, Smiley J, Russell WC, Nairn R (1977). Characteristics of a human cell line transformed by DNA from human adenovirus type 5. Journal of General Virology 36 (1): 59–74.
2. https://en.wikipedia.org/wiki/HEK_293_cells#cite_note-2
3. Stepanenko AA, Dmitrenko VV (2015) HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution. Gene 569(2):182-90.
4. Weber L (2000) High-diversity combinatorial libraries. Current Opinion in Chemical Biology 4(3):295-302.
5. Hediger MA, Coady MJ, Ikeda TS, Wright EM (1987). Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature 330: 379–381, 1987.