Men sent to Mars and women sent to Venus: A thought experiment in honor of the NIH’s upcoming policies on incorporating sex in basic research

Imagine if you will…

Editor's note: this is my favorite drawing ever.

Editor’s note: this is my favorite drawing ever.

It’s the year 2075. After a worldwide search for the hardiest human beings, one man and one woman are selected to colonize other planets: Bob (a chemist from Finland) is sent to Mars, and Flo (a rice farmer from Thailand) is sent to Venus.

Editor's note: I like the one eyebrow cocked in these clones. They're like clones, but skeptical ones.

Editor’s note: These are skeptical clones (see the eyebrow??).

Each of them is placed in a large spacecraft provisioned with a laboratory for human cloning, 6 months’ worth of basic food and water rations along with oxygen, and space to house 5000 people; the World Space Organization will send additional rations for the populations every 6 months, and once the colonies are at maximum capacity, the WSO will conduct scientific tests of a variety of parameters on the colony.

After a lengthy journey, Bob and Flo arrive on their respective planets, set up their laboratories, and begin producing clones of themselves. They are very successful: by 2125 they are at maximum capacity, and the WSO sends scientists to study the populations.

In the first battery of tests, the scientists make the following measurements:

  • Editor's note: WHO IS THIS GUY?! I definitely don't trust his results.

    Editor’s note: WHO IS THIS GUY?! I definitely don’t trust his results.

    Assay serum levels of LDL cholesterol

  • Administer the “Verbal Reasoning” section of the MCAT
  • Determine the ED50 (effective dose in 50% of the population) for the anaesthetic drug propofol
  • Evaluate leg strength by determining the maximum amount of weight the subjects can leg press
  • Measure height

Their findings are as follows:

Editor's note: bar graphs!!

Editor’s note: bar graphs!!

 Excited by these data, the WSO scientists send the following report back to earth:

MAJOR GENDER* DIFFERENCES FOUND IN MOST EARLY MEASURES

Our initial testing of the inhabitants of Mars and Venus revealed stark differences between men and women for a variety of parameters. Men had significantly higher serum LDL cholesterol than women, which may explain the higher prevalence of cardiovascular disease in men. As expected, women had a much stronger aptitude for verbal reasoning than men, which is in line with the body of literature documenting that women have stronger communication skills than men. Women also required a 44% lower dose of propofol to achieve anaesthesia; anaesthesiologists should adjust their dosages of propofol accordingly for male and female patients. Just like on Earth, men were taller than women, but surprisingly there were no significant differences in lower body strength.

It is probably instantly obvious to most people that this experiment has a whole whack of problems that invalidate the scientists’ conclusions. Given the way this was set up, it is OBVIOUSLY completely unreasonable to ascribe the differences observed in these tests to the sex of the populations. The results could reflect any number of other differences between the two populations that have nothing to do with their sex, for example:

  • Genetically-inherited tendencies:
    • Turns out that Bob has a family history of genetic hypercholesterolemia and tall stature, and his allele for CYP2B6 is a variant that is very efficient in breaking down propofol. On the other hand, Flo comes from a somewhat short family with normal cholesterol, and her allele for CYP2B6 is a variant that has moderate efficiency in metabolizing propofol.
  •  Socio-cultural factors:
    • The MCAT verbal reasoning test was administered in English. Flo speaks fluent English and Thai, and so the clones on Venus learned both languages from her and are fluently bilingual. Bob speaks Finnish and broken English, and so the clones on Mars are not very proficient in English.
  • Environmental influences:
    • The specific gravity is 0.376g on Mars, and 0.904g on Venus. Thus, gravity exerted less downward force on the bodies of the inhabitants of Mars, which would tend to allow them to grow taller than those living on Venus.
  •  Interactions between genetics and environment:
    • The genetic tendency to tallness of the Bob clones that was magnified by the lower gravity on Mars; although their bodies were larger, the lower gravity on Mars meant that their leg muscles did not have to be as well developed in order to support their (higher) body weight. In contrast, the genetic tendency to shortness of the Flo clones was magnified by the higher gravity; although their bodies were smaller, the higher gravity on Venus meant that their leg muscles had to be relatively more developed to support their (lower) body weight. Thus the net effect of these genetic and environmental influences resulted in similar lower body strength between the groups.
    • Radiation exposure on the space journey to Venus caused a mutation in the CYP2B6 allele in the cell that Flo happened to use in her cloning; the mutation caused a 50% decrease in the activity of the enzyme, so propofol was metabolized more slowly in the clones than in Flo herself.
  •  Researcher bias and over-extrapolation:
    • The findings on verbal reasoning fit with the researchers’ pre-existing perception that women are better communicators, so they didn’t consider whether there might be other factors that confounded their findings (ie. language).
    • The researchers are stretching their conclusions pretty far to argue that the difference seen in LDL cholesterol in a genetically homogeneous population under tightly controlled conditions explains a difference in the prevalence of a complex disease in a genetically heterogeneous population with little control over conditions.

You might be saying “well this is OBVIOUSLY a TOTALLY RIDICULOUS scenario and scientists would NEVER make these kinds of mistakes in interpretation.” Well, actually, what I’m suggesting is that people make these kinds of mistakes all the time when interpreting data from cell and animal studies (and also from human studies) that make crude comparisons of male vs. female.

Let me unpack my tortured analogy a bit to make the parallels more explicit:

THOUGHT EXPERIMENT CELLS EXPERIMENTAL ANIMALS
The hardiest humans are chosen to colonize another planet. Normal people aren’t chosen because they probably wouldn’t survive. Most cells grown in vitro for laboratory use are ‘cell lines’: cells of the type we’re interested in that have a nearly limitless ability to proliferate. These are usually cancer cells, or cells that have been genetically modified to permit ongoing proliferation. They are NOT normal. Most animals used in experiments are inbred, and have been adapted to laboratory conditions over many generations. They are NOT human and differ from humans in substantial ways.
The colonizers live in an atypical environment with the bare essentials they need to survive.   This does not reflect the conditions in which humans live. Cells are grown in a plastic flask, fed by culture media. This does not reflect the conditions in which normal cells live. Experimental animals live in cages under highly controlled conditions. This does not reflect the conditions in which humans live.
Instead of living in a complex, dynamic human society made up of many different people, the colonizers live in a relatively static environment surrounded by others exactly like them. This does not reflect the conditions in which humans normally live. Instead of living in a complex, dynamic body made up of many kinds of cells, the cells live in a relatively static culture environment surrounded by other cells exactly like them. This does not reflect the conditions in which cells normally live. Instead of living in natural social groups and engaging in natural behaviour, animals are segregated into groups based on the convenience of the scientist, and live only with other animals of the same sex. This does not reflect the conditions in which mice or humans normally live.
The living conditions of the residents of Mars are different from those of the residents of Venus. The culture medium and conditions used for different cell lines are often different. In mice (the most commonly used experimental mammal), males are usually housed at lower density than females because of the males’ tendency to aggression against one another.
Differences observed between the inhabitants of Mars and Venus may be ascribable to a variety of factors, so making crude “male vs female” comparisons between the inhabitants of Mars and Venus is not very useful for understanding the influence of sex on the outcomes of interest. Differences observed between male and female cell lines may be ascribable to a variety of factors, so making crude “male vs female” comparisons between male cell lines and female cell lines is not very useful for understanding the influence of sex on the outcomes of interest. Differences observed between male and female animals may be ascribable to a variety of factors, so making crude “male vs female” comparisons between male cell lines and female cell lines is not very useful for understanding the influence of sex on the outcomes of interest.
More nuanced approaches are required to discern the influences of sex. More nuanced approaches are required to discern the influences of sex. More nuanced approaches are required to discern the influences of sex.

In the 14 May 2014 edition of Nature, the NIH announced that it intends to roll out policies beginning in October 2014 that will “require applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions.” Although I applaud the motivation underlying these changes, I am far from convinced that simply requiring scientists to include male and female cells or animals in their work will be a significant advance in addressing sex and gender in medical research – in fact, I fear that a crude approach of this sort will not only fail to address concerns around equity, but it may in fact exacerbate them and serve to affirm our cultural bias that men are from Mars and women are from Venus.

So what do you think? Is my tortured analogy off-base? Will this policy and others like it help or hinder equity in biomedical research?

 

 

*Let’s ignore for the moment the ways that scientists tend to conflate sex and gender….that’s a whole other kettle of fish.

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