Thursday, October 08, 2020

Factcheck: Regeneron's use of embryonic stem cells

This week, Trump's opponents misunderstood a Regeneron press release to conclude that the REG-COV2 treatment (which may have saved his life) was created from stem cells. When that was proven false, his opponents nonetheless deliberately misinterpreted events to conclude there was still an ethical paradox. I've read the scientific papers and it seems like this is an issue that can be understood with basic high-school science, so I thought I'd write up a detailed discussion.

The short answer is this:

  • The drug is not manufactured in any way from human embryonic tissues.
  • The drug was tested using fetal/embryonic cells, but ones almost 50 years old, not new ones.
  • Republicans want to stop using new embryos, the ethical issue here is the continued use of old embryos, which Republican have consistently agreed to.
  • Yes, the drug is still tainted by the "embryonic stem cell" issue -- just not in any of the ways that people claim it is, and not in a way that makes Republicans inconsistent.
  • Almost all medical advances of the last few decades are similarly tainted.
Now let's do the long, complicated answer. This starts with a discussion of the science of Regeneron's REG-COV2 treatment.

A well-known treatment that goes back decades is to take blood plasma from a recently recovered patient and give it to a recently infected patient. Blood plasma is where the blood cells are removed, leaving behind water, salts, other particles, and most importantly, "antibodies". This is the technical concept behind the movie "Outbreak", though of course they completely distort the science.

Antibodies are produced by the immune system to recognize and latch onto foreign things, including viruses (the rest of this discussion assumes "viruses"). They either deactivate the virus particle, or mark it to be destroyed by other parts of the immune system, or both.

After an initial infection, it takes a while for the body to produce antibodies, allowing the disease to rage unchecked. A massive injection of antibodies during this time allows the disease to be stopped before it gets very far, letting the body's own defenses catch up. That's the premise behind Trump's treatment.

An alternative to harvesting natural antibodies from recently recovered patients is to manufacture artificial antibodies using modern science. That's what Regeneron did.


An antibody is just another "protein", the building blocks of the body. The protein is in the shape of a Y with the two upper tips formed to lock onto the corresponding parts of a virus ("antigens"). Every new virus requires a new antibody with different tips.

The SARS-COV-2 virus has these "spike" proteins on it's surface that allow it to invade the cells in our lungs. They act like a crowbar, jamming themselves into the cell wall, then opening up a hole to allow the rest of the virus inside. Since this is the important and unique protein of the virus, it's what most antibodies will want to lock onto.

Proteins are created from genes. A new protein, like an antibody with tips identifying a new virus, needs a new gene to create it. In other words, we need new DNA.

This happens in "white blood cells". Inside these cells, the gene that makes antibodies can easily mutate. When the white blood cell encounters a new object, it mutates that gene slightly, makes some new antibodies, and tests them against the foreign object. The cell then divides, and the child cells do the same thing. Each generation gets better and better and better at creating antibodies. Those tips of the antibody become better and better at locking onto the infecting virus.

Before we go down into Lamarck genetics, we should point out that these genes are not passed down to children. Only a few white blood cells change their DNA, but this doesn't affect any other cells, especially not the ones in your gonads.

The way Regeneron makes its treatment is to harvest the white blood cells, extract the gene that makes the antibody, then sticks that gene inside some hamster cells to produce copious amounts of the antibody. (Yes, hamsters, but we'll get to that).

Sometimes human subjects aren't available as a source of white blood cells. For example, let's consider a disease that hasn't infected humans yet, but which has a potential to do so. In that case, you need a factory for white blood cells that isn't human.

Regeneron has a solution for this: transgenic mice that have the important parts of the human immune system grafted in. This allows them to inject things into the mice to cause this hypermutation of the antibody gene, which they can then harvest.

In the case of their REG-COV2 treatment, Regeneron used both mice and men. They gathered about 200 candidate antibody genes from both sources.

Remember: each time white blood cells mutate to create an antibody, they'll do it differently. That means everybody's antibodies are different even though the disease is the same. Even a single patient will have multiple strains of white blood cells mutating in different directions, creating different antibodies, for the same thing.

Thus, from 32 mice and a few human patients, Regeneron got around 200 candidate antibody genes. They then reduced this number down to 4 really good candidates, and then 2 (one from a human, one from a mouse) that they decided to use for manufacturing. These were sent to the hamster factory.

It's at this point we need to talk about hamsters and immortalized cell lines.

You can keep tissues alive outside the body by bathing them in a nutrient bath, but they won't grow on their own. But in some cases, you can cause them to grow without end, in which.case, you'll have an endless supply of those cells. The cell line has then become immortal. This is especially true if the original cells came from a cancer -- that's what cancer is, when the thing that prevents cells from dividing has been broken, and they grow out of control.

Of the many immortalized cell lines used by researchers, some come from adults who consented, some from adults who were never asked (such as the famous HeLa line), some from animals, and of course, some from embryos/fetuses.

One important cell line comes from a Chinese hamster ovary (CHO) that was smuggled out of China. It's become the preferred source for producing mammal proteins that can't be produced from yeasts or bacteria. In other words, simple proteins like insulin can be produced from yeast, but complex proteins like antibodies can only be produced within mammals. They insert a human gene into the cell, then encourage it to start dividing into billions of cells containing a copy of that gene.

Note that while the CHO cell line is used for about 50% of the time in this sort of case, about 20% of the time, human cell lines are used. The two human cell lines for doing this are known as HEK293 and PER.C6. Once Regeneron decided upon which genes it wanted to manufacture, it inserted those genes into Chinese hamster ovary (CHO) cells to mass produce the drug. The fact that it was CHO and not the human cell lines is pretty important to this story.

Immortalized cell lines appear in other places in our story. When selecting which of the 200 candidate antibodies it wanted to mass produce, Regeneron tested them for efficacy. It tested against tissues in vitro (a test tube using immortalized cell lines) rather than in vivo (inside a human body). One cell line is "Calu-3", derived from a 25-year-old lung cancer patient in 1975. Another cell line is "Vero", derived from the kidney's of an African green monkey in 1962.

A third test uses proteins made from the "HEK293" cell line from the kidney of a human fetus aborted around 1972-1973 in the Netherlands. This the center of the current controversy.

This test wasn't necessary to the creation of REG-COV2. It was included with the tests because other researchers used the technique, and that's what science does, replicates the work of other researchers.

I mention this because while people have reluctantly agreed that REG-COV2 isn't manufactured from embryos (from the HEK293 or PER.C6 cell lines), they insist that because of this test, it couldn't have been made without embryonic cells. This is not true, the test wasn't necessary. In addition, the test could've been done in different way, using a different source for the proteins involved. Vaccines are tested in similar ways, some using the ethically questionable cell lines, some not.

But the results are still ethically tainted. The point here isn't to excuse this taint, but to simply point out it's different type of taint. There's a range of ethical questions here. The issue is being politicized to make this one ethical question, when it's a different ethical question.

This is a good time to talk about the ethics of embryonic stem cells. There are a lot of different technical issue here.

The major issue that upsets Republicans is the harvesting of new material from blastocysts, embryos, and aborted fetuses. This is a wholly separate question of continuing to use old material from 50 years ago.

When President George Bush was elected in 2000, he instituted rulings forbidding harvesting new material, but which allowed the continued use of old material (within the United States). The continued use of HEK293 was explicitly allowed. Likewise, Trump issued an executive order limiting stem cell research. It explicitly targeted harvesting new embryonic cells, while at the same time, explicitly allowed existing lines like HEK293.

Thus, if you are trying to show that Republicans are hypocrites, that their rules change when their own life is at stake, then the evidence doesn't support your conclusion. Even if the HEK293 cell line was used for manufacturing instead of testing, it still would be consistent with Republican positions. Their concern is to stop the use of exploitation of new embryos.

Now for Catholics, things might be different. The Vatican has repeatedly come down against using old material like HEK293 [a] [b]. They view it along the same lines as using research from Nazi medical experiments on Jews in concentration camps. People ask the ethical question whether the event was so offensive that the medical knowledge can't be used, even if it saves lives. Even here, though, Catholics have a more nuanced view, allowing just things to be used in practice when there is no alternative.

From that perspective, then all medical research is tainted. For example, our knowledge from all vaccines comes from Edward Jenner's testing on an unwitting 8 year old boy. Ethics have been continually changing throughout history, if we reject all knowledge from what we now consider to be unethical sources, then we wouldn't have any medicine. 50 years ago when the HEK293 was acquired, it was under a different understanding of ethics than we have today.

Cell lines like the 50 year old HEK293 are used to test almost every drug. Google those letters and any of the other drugs Trump took in response to his infection, and you'll find they are all tainted. Moreover, many of the upcoming vaccines will also use these such cell lines to test their efficacy. This may still be an ethically important question, but it's not the politicized question at stake here.

This piece has tried to avoid getting into the technical weeds. For example, the HEK293 line aren't "stem cells" but "kidney cells". But HEK293 still comes from an aborted fetus, and thus, has the same ethical issue as what people understand by "embryonic stem cells". Instead, I tried to look at the technical issues I feel do matter, like whether this is researchers using a 50 year old line that Republicans have consistently agreed to, versus newly harvested material which they vehemently oppose. Theoretically, somebody could have an issue with "stem cells" even when they come from bone marrow or cord blood, in which case, this article is not for you. I'm pretty sure no such people exist, except those who misunderstand the science. If you feel I've glossed over a technical issue (or gotten it wrong), please tell me https://twitter.com/ErrataRob.


Conclusion

This piece is not a defense of Trump but of science. Please vote for Biden on November 3. European countries with leaders to the left of Biden are nonetheless still prosperous. Conversely, when otherwise prosperous democracies have failed, it's because of leaders as unfit and corrupt as Trump.

This issue started when people gleefully believed they had caught Trump in a trap. When this was proven a misconception, they went searching for other ties to stem cells, and found them. This is still a gross distortion of science -- every modern medical treatment can be found to be tainted if you look hard enough. Trying to rescue your misconception by jumping through hoops like this makes you look worse, not better.

The MIT Technology Review article cited above is a particularly egregious example of the politicization of science. It cites Trump's order on embryonic stem cells while knowingly avoiding what the order actually said, that it was about new vs. old embryos. They knowingly distorted the information to make it look like the consistent position was inconsistent. They knowingly distorted the science to make political points.

There are important areas where science is entangled with politics (e.g. climate change). But it seems like everyone takes the opportunity to irresponsibly distort science to further their politics, as seen here.

Frankly, I'm freaked out by planting a human immune system into mice into order to drive hypermutation, to extract a gene that you then place into an immortal line of hamster ovary cells to produce a crafted protein. I'm sure when somebody makes a movie based on this, it won't be anything other than dystopic.

3 comments:

Unknown said...

Why is Trump unfit? Biden looks like he has Parkinson’s Disease and appears very unhealthy.

Unknown said...

"Republicans want to stop using new embryos, the ethical issue here is the continued use of old embryos, which Republican have consistently agreed to."

NOT TRUE

'The issue has become highly politicized by conservative lawmakers and advocates who have attempted to enact “personhood” laws that define embryos (including frozen embryos) as “persons.” The advent of embryonic stem cell research drew even more attention to the ethical issue of using embryos for medical research."

https://www.iflg.net/abandoned-embryos/

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