By Juan Miguel Pedraza

Boy or girl? Male or female? Is there something in between?

These questions rankle cultures across the globe and fuel passionate debates about who does what and who should be “boss.” But before any of that debate rolls across dinner tables and legislative agendas, there’s the scientific question at the heart of it all: how does life choose gender?

Commonly, we figure the birds do it, the bees do it. And, for that matter, so do roses and sycamore trees. Gender — the genetically determined difference that distinguishes, in our culture, what garb we don in the morning and whether we apply the lipstick and mascara — is still a wondrous mystery to scientists like UND biologist Turk Rhen.

“I have long been fascinated by the evolution of gender differences,” said Rhen, whose Ph.D. in physiology took him into research that closely probes the theoretical and empirical aspects of sex determination, sexual differentiation, and reproductive biology.

“I’m looking at several levels and hope to put everything back together to understand how organisms adapt to their environment, from the molecular level to how the organism behaves,” Rhen said. “A major component of that is sex: whether an individual becomes male, female, or both.”

Rhen has looked at the critical process of gender “creation” at the molecular level, mostly in vertebrates (animals with spinal cords), with a view to producing comparative models that will help understand much more clearly what exactly gender is, how it happens, and how it can go wrong.

Rhen, in other words, is practicing his science in the field of comparative genomics, which sets him and his coworkers at the forefront of bioscience research.

Rhen and his research team of graduate and undergraduate students recently received a National Institute of Child Health and Human Development grant to study the sex determining mechanisms in snapping turtles and mice.

“Essentially, we’re working to identify the genes that are turned on or off in the development of testes (male) or ovaries (female) in both species,” Rhen explained. “We’ll compare those genes in these two very different species, ova in both species, and identify the common set as the basic blueprint across species — including humans — for producing male or female sex organs.”

OK, we know something about how we get to boy or girl. And we’re getting closer to figuring out how this selection process works at the primary molecular level. Why is that important beyond the labs of researchers such Rhen?

"Because, ultimately, this knowledge of gonad development and function will help us to prevent birth defects,” said Rhen. About 150,000 children annually in the United States are born with birth defects, according to the March of Dimes. The American College of Obstetricians and Gynecologists says that out of every 100 babies born in the United States, three have some kind of major birth defect.

“We define birth defects — which can be caused by genetic or environmental factors, or, in many cases, by things we don’t know — as structural abnormalities of function or metabolism,” Rhen said.

Birth defects can, but do not always, lead to health consequences later in life, including physical and/or mental disabilities. A few defects are fatal. There are more than 4,000 different known birth defects ranging from minor to serious, and although many of them can be treated or cured, they are the leading cause of death in the first year of life, according KidsHealth.org.

“So my research specifically harnesses the power of comparative and functional genomics to identify an evolutionarily conserved set of sex-determining genes in amniotic vertebrates, including humans,” Rhen said.

It boils down to finding out which genetic structures — which specific genetic molecules — work their gender determination miracle and when in the growth process and how they do it. “I’m basically looking at sex differentiation mechanisms to determine their implication for human health, specifically reproductive health,” he said.

Rhen is pursuing a line of inquiry that will define common links in this process that will tell us how much of this process is shared across species. In other words, what are the common traits of gender selection in most animals that can help us define what exactly should be happening after conception in humans?

Rhen’s studies represent a major pioneering effort that’s fusing comparative genomics — looking at differences among species — with functional genomics, where you’re studying the specifics of one species or of a single process.

“What we’re looking for is patterns in genetic mechanisms that have the same function in sex determination in all vertebrates, including humans,” he said. And, with about 60 percent of birth defects in humans having so-far undetermined causes, research initiatives such as Rhen’s are major steps toward providing sorely needed answers.

“This approach promises to speed the rate of discovery of sex-determining genes in humans, which to date has been slow and haphazard.”

It’s not always one or the other

Sex is a key part of the tree of life — at least one side of it.

There are two types of organisms,” says UND biologist and genomics explorer Turk Rhen. “First there are the prokaryotes, such as bacteria, which have no nucleus, and there are eukaryotes, including humans, that possess a nucleus. Either group can be single or multicelled.”

Among eukaryotes there are two fundamentally different groups, plants and animals. In these two basic groups, gender differentiation evolved separately and very distinctly, Rhen explains.

However, even though plants differ from animals in how the gender mechanism works, both plants and animals can be either male or female, or they can be both, depending on a number of factors, including genetics and environment.

“In other words, within each of these two groups, you can have males and females,” Rhen said.

“This evolution of sex differentiation — and the variations of sex in animals — and how and why that evolved are the fascinating questions,” Rhen said.

For example, in some species individuals can express true hermaphroditism, that is, they possess both male and female reproductive organs, and depending on who their sex partner is, they can play either role. Hermaphroditism is common among fish, crocodilians (alligators, crocodiles, and their relatives), lizards, and even some birds.

There are no true hermaphrodites among human beings that we know of, Rhen says. However, a person can be born with both characteristics of a male and female, though they can’t reproduce as both (and in many cases, such an individual can’t reproduce at all).

“Some animals even produce offspring without any contribution from males — essentially no males in the species,” Rhen said. “That’s called parthenogenesis. For example, my Ph.D. advisor worked with a species of lizard that has no males. Somewhere back in time, a set of parents produced offspring who mated with those parents and produced a species that was only female.”

The curious thing, though, is that even though there are no males among them, the females during the reproduction cycle can be receptive to other females that are behaving like males — let’s call it lizard pseudo-sex — where one female will mount another, stimulating the reproductive response in the other female, Rhen notes.

Essentially, this species produces offspring that are identical to the mother. The group is cloning itself, Rhen observed.

And that’s why, Rhen says, the study of gender differentiation is so compelling.

“I’ve developed some population genetic models to find the gene that’s present in both sexes,” he said. “I want precisely to define why that gene is turned on in one but not the other, and what sort of evolutionary selective pressure has determined how males and females differ in expression of that gene.”