Emiliano Ponzi

Science of the Sexes (continued)

Not just any old flu, but the H1N1 pandemic of 2009. The fact that it hit in the midst of a panic about vaccine shortages proved fortuitous for Klein. Steeped in sex-based biology à la influenza, she was ready with a kill shot. She leveraged interest in the pathogen, finessing a low-grade professional buzz about sex differences into a very public debate. Flu, once and for all, confirmed the legitimacy of her convictions.

“Sabra was the prepared mind in the right place at the right time,” says Florence Haseltine, MD, PhD, director of the Center for Population Research at the National Institutes of Health and a founding member of the Organization for the Study of Sex Differences. “H1N1 threw her—and sex-based biology—into the limelight.”

Klein, a mother of two girls, promptly coauthored an op-ed (“Do Women Need Such Big Flu Shots?”) published in The New York Times in October 2009. She wrote, “In all likelihood, we’d have a better H1N1 vaccine—and more of it—if in our preparations we had accounted for the biological differences between men and women.” That article sparked the WHO to enlist Klein’s help in preparing “Sex, Gender and Influenza,” a report issued in July 2010 that examines the 2009 H1N1 pandemic through the prism of sex differences in immunology.

“In biomedical science, the dogma is that there are no differences between men and women. People like myself who design studies looking at both sexes are left with that uphill battle of challenging the dogma.” —Sabra Klein

Meanwhile, Klein also co-authored a review that appeared in the May 2010 edition of The Lancet Infectious Diseases (“The Xs and Ys of Immune Responses to Viral Vaccines”) that re-examined published data from a high-profile paper by analyzing it according to sex. The review revealed conclusions strikingly different from those of the original authors who had ignored sex. When Klein re-analyzed the genomic data by sex, she found that the transcriptional activity along immunological pathways—pathways that supposedly predict long-term protection following, in this case, yellow fever virus vaccination—was 10-fold higher in samples collected from female than from male volunteers, suggesting that females may be better protected than males.

About that same time, a landmark reference book Klein co-edited was published: Sex Hormones and Immunity to Infection.

Amid her publishing flurry, Klein accepted invitations to speak locally and abroad. She described how her female mice were mounting inflammatory responses up to a hundred-fold higher than males in the first week after flu infection. She cautioned audiences against assuming that a bigger immune response is better. Take the 1918 flu or the avian flu, for example: They caused profound sickness and death, she explained, not because of out-of-control viral replication but because the human hosts—and hostesses—initiated excessive immune responses to those pathogens.

Despite her persuasive preaching about a pervasive lack of consideration for sex differences in the design of scientific studies, and therefore in the analyses of data, Klein never expected people to suddenly fixate on sex differences. She just wanted them to pause and question the assumption that males and females weren’t going to be different.

And then, out of the blue, a Hopkins physician investigating Lyme disease contacted Klein about analyzing his patient data according to sex. On the heels of that request, a scientist from New York University conducting malaria research in Peru sought her out, wanting to discuss intriguing sex-based trends. Most recently, a Harvard researcher offered to share unpublished epidemiological data and asked to pick her brain about sex differences in flu immune response.

“Flu is of such great public health importance,” Klein says, “that it puts all of this sex-based biology business in a context people suddenly care about.”