Four of my favorite things are development, evolution, and breasts, and now I have an article that ties them all together in one pretty package. It’s a speculative story at this point, but the weight of the evidence marshaled in support of the premise is impressive: the mammalian breast first evolved as an immunoprotective gland that produced bacteriocidal secretions to protect the skin and secondarily eggs and infants, and that lactation is a highly derived kind of inflammation response. That mammary glands may have had their origin as inflamed glands suppurating mucus may not be the most romantic image to arise in a scientific study, but really—they got better and better over the years.
Vorbach et al. have carried out a descriptive analysis of the elements of breast milk and lactation and come to this conclusion on the basis of three general lines of evidence.
- Immunoprotective proteins are a significant component of breast milk.
- The nutritional components of milk are synthesized by enzymes that are derived from immunoprotective proteins.
- Many of the molecular regulators of lactation are shared with inflammation pathways.
My previous article on mother’s milk gave a highly abbreviated list of the components found in milk, but there’s more detail in the list below. Milk is much, much more than baby food—it’s an incredible cocktail of interesting proteins, and 1) many of them are shared with mucus secretions produced by other secretory epithelia, and 2) many of them are elements of the innate immune system. Milk is actually a kind of anti-microbial snot mixed in with a lot of fat and sugar.
(click for larger image)
Molecules that play a dual role in immunity and nutrition. Proposed origin of milk as an antimicrobial mucus secretion containing many evolutionarily conserved, protective molecules, which today comprise part of the whey proteins of milk (blue). Two of these molecules,
xanthine oxidoreductase and lysozyme, evolved due to gene sharing and gene duplication additional functions in the ancient mammary
epithelium such as milk fat droplet secretion and the unique synthesis and secretion of a-lactalbumin as well as the milk sugar lactose. The
secretion of these calorie-rich components markedly increased the nutritional value to milk (green). The nutritional and protective
importance of milk was further expanded by serum-derived proteins that comprise part of the whey proteins of milk (red). In particular,
lactose and its derivatives are osmotically active and draw water into milk. Caseins are the major protein source of milk in higher mammals.
While the calcium-sensitive α1 α2, β, γ, δ-caseins presumably originated de novo, the calcium-insensitive κ-casein shows structural and sequence similarities to fibrinogen (purple). Abbreviation: Ab, antibody; Ig, Immunoglobulin; PRM, Pattern Recognition Molecule; PRR,
Pattern Recognition Receptor; XOR, Xanthine oxidoreductase.
The innate immune system is a primitive defense system that uses peptides that recognize various common microbial surface molecules, and also uses enzymes that produce chemical agents lethal to bacteria. It’s a first line of defense that differs from the more specific immune system in that it doesn’t require specialized immune system cells and also doesn’t acquire the kind of highly refined specificity we see in antibodies (note, too, that antibodies are also secreted in milk—they are the IgG, IgE, and IgM molecules listed above.)
One key element in milk is XOR, xanthine oxidoreductase. This enzyme mediates purine catabolism and, for instance, the synthesis of uric acid, but also generates reactive oxygen species and reactive nitrogen species, compounds that can be voraciously reactive and interact destructively with bacteria. You may have heard of one reactive nitrogen species, the nitrites that hot dogs are loaded with as preservatives. Reactive oxygen species are chemicals like hydrogen peroxide, which is often used as a disinfectant, and superoxide anions and hydroxyl radicals.
Another is lysozyme, a protein that hydrolyzes the polysaccharides (sugars) that make up bacterial cell walls. This is a very common component of the innate immune system of many animals: you ooze this protein out of your skin, your mucus is loaded with it, and it’s also found in high concentrations in other places, such as egg whites. It’s simply generally useful protection to be able to chemically strip bacteria of their protective coats.
Other proteins also have bacteriocidal functions, and are found in other glandular secretions: lactoferrin and transferrin, lactoperoxidase (which as you might guess from the name, synthesizes reactive oxygen species), defensins (which disrupt bacterial membranes), and pattern recognition molecules (PRMs), which bind to certain common molecular motifs on bacterial surfaces. It’s so sweet and tasty, yet so deadly to microbes!
Now wait, you may be wondering…how is this evidence that milk’s original function was immunoprotective? If you’re secreting a sweet and fatty nutritious substance for your young, it would definitely be advantageous to load it up with antimicrobials to keep the nasty beasties from growing in it. XOR and lysozyme and all those others could have been added secondarily.
One reason to think otherwise is that those protective molecules are universal to vertebrates—lizards and birds have them, too. These enzymes and other proteins came first.
Those of you wise in the ways of evolution are saying to yourselves, “So what? It’s another example of cooption, taking a protein used for one function and adapting it to another.” And you’d be right: that’s only suggestive. Another good reason, though, is to look at the enzymes responsible for generating the nutritive components of milk, the lactose sugars and the fat droplets.
Breaking up fat into droplets and enveloping them with some kind of coat to promote suspension in water is an essential function in the production of milk. The protein that is responsible for this structural function, and which if knocked out prevents lactation and actually leads to collapse of the mammary gland, is…XOR! This is a wonderful example of a protein doing double duty, as an enzyme responsible for bacteriocidal action and as a structural protein involved in solubilizing fats. It almost certainly had the enzymatic function first, and if any cooption was going on, it was to recruit an immunoprotective protein to secondarily assist in a nutritive function.
The other essential nutritive component of milk is lactose, the milk sugar. Lactose is an odd and unusual sugar—that’s actually it’s advantage, that it is a sugar that many bacteria have difficulty digesting (it’s not just people that can be lactose intolerant!)—and it requires a specific synthetic complex consisting of β-1,4 galactosyltransferase and α-lactalbumin for its production. Where did α-lactalbumin come from? It’s sequence makes the homologies clear: the α-lactalbumin gene is a modified copy of…lysozyme!
I think that’s remarkable. The two primary nutritive components of milk, the sugars and fats, are the product of novel activity by proteins that are clearly primitively associated with innate immunity.
To further the similarities, the authors give a long list of components of signaling pathways that are typically associated with inflammatory and immune system responses and are also essential in lactation. For instance, the transcription factor NF-kB, which is also a hot candidate molecule in cancer research, is involved in regulating the expression of various cytokines and antimicrobial agents; transgenic mice that knock out this pathway also exhibit developmental failures in the differentiation of the mammary gland. They’ve modified other elements of this pathway (RANKL, C/EBPβ, TNF-α) which act in inflammation responses, and they all also induce developmental problems in mammary gland tissue and reduce or shut down lactation.
I’ve just finished teaching a human physiology course in which we learned the basics of endocrinology, and I gave my students the usual story on the pituitary hormone prolactin: it regulates milk production. It’s too bad I hadn’t read this paper earlier, because it makes the story much, much more complicated (my students are probably relieved, though—the class was complicated enough as it was).
Prolactin is known as a key lactogenic hormone but,
depending on the cellular context, prolactin can also act as an
anti-inflammatory or proinflammatory cytokine. Interestingly, it has been demonstrated that prolactin is involved in the
protective as well as the nutritional role of milk. Prolactin
participates in regulating the secretion of immunoglobin A
(IgA), the prominent Ig in mucus and milk that inhibits the
colonization of pathogenic bacteria on mucosal surfaces.
Changes in the secretion of IgA are associated with the anti-
inflammatory potential of epithelial tissues. In addition,
prolactin stimulates the uptake of some amino acids and
glucose, as well as the synthesis of casein, α-lactalbumin,
lactose and milk fat droplets in the lactating mammary
epithelium. Finally, prolactin and IFN-γ also stimulate the
expression of XOR in mammary epithelial cells via the Jak/Stat
signaling pathway. Thus, multiple small molecules and
ligand-receptor systems that have critical roles in inflammatory responses exert dual and, in many cases, essential functions in immunity and mammary gland biology.
Gee, I’m going to have to revise and add some stuff in that class next time I teach it. Very cool.
Their model for the evolution of the mammary gland is illustrated below. It’s reasonable, and the molecular evidence is persuasive. Basically, the process began as the secretion of antimicrobials agents from the skin of the early mammal (something we still do) as a protective function. This function was elaborated by infoldings of epithelia to increase surface area and generate reservoirs of mucus and the antimicrobials. Eggs and infants would have benefitted from more copious secretions from the mother, coating them as well with this immunoprotective substance. The young would have also lapped up the tasty rich goo, and infant survival would have been promoted by changes that caused the secretion of ever-richer substances.
(click for larger image)
Proposed evolution of the mammary gland from a mucus-secreting epithelial gland. Mammary glands presumably evolved as
mucus-secreting skin glands that similar to many mucus surface epithelia secreted antimicrobial enzymes such as XOR and lysozyme. The
evolution of additional functions of XOR and lysozyme in the ancient mammary epithelium resulted in the secretion of fat droplets, α-
lactalbumin and lactose. Consequently, the mammary gland evolved from a protective immune organ into a reproductive organ unique to the
class mammalia.
One question not addressed by the paper is why only females lactate—you’d think the young would have benefitted if Papa Proto-mammal was also slathering them with immunoprotective slime. I’d guess that this supports the idea that those ancient males weren’t particularly involved in caring for their progeny, so it made little difference in infant survival if the father turned these secretions down to a level sufficient to selfishly protect just himself. These secretions are also expensive—I’ve seen figures that suggest that a third to half of the energy budget of nursing small mammals may be leaking out their lactating teats—so it would have been advantageous for those slacking males to shut down the production so necessary for female reproductive success.
Vorbach C, Capecchi MR, Penninger JM (2006) Evolution of the mammary gland from the innate immune system? BioEssays 28:606-616.
Now that explains why I ended up with an interest in digital logic and working in software development. I was breastfed on XOR!
Has anyone looked at marsupial or monotreme milk, for comparison?
Classically, mammary glands have been described as modified apocrine glands, which have migrated just a teensy bit medially from the axillary regions to form a milk line. I wonder if there are any papers on antimicrobial components in the apocrine secretions?
James 2:24
PZ said: “Four of my favorite things are development, evolution, and breasts”
So you’re counting each breast individually? Random silly question: if intelligence had evolved in the feline lineage instead of the Hominoid, would you be discussing your favourite 8 things?
I was going to suggest looking at monotremes and marsupials as well. I recall that the platypus produces milk, but has no nipple – the milk simply comes out onto a patch of skin.
Thanks for the mammaries.
There, I said it.
And more stuff for Biochem next semester. I’ve taught XOR in purine catabolism for a long time, but this is new to me.
I had thought there were a few cases of male lactation.
Dear good strong fusilier at 12:39,
What does James 2:24 have to do with anything? I looked it up: it’s “[y]e see then how that by works a man is justified, and not by faith only,” right?
Why are you trying to get into my head? GET OUT! GET OUT OF THERE!
. . .
Hmm…Does anyone happen to know if lactation produces a chronic inflammation-like picture? For example, do lactating women have higher CRP and ESR levels than when they aren’t lactating?
What does this do for the hypothesis I learned in school, namely that milk is modified sweat, whence breasts are modified sweat glands?
There are.
PS: is there a consensus yet on the reason for the development in humans of prominent, pendulous, and rather unwieldly mammary organs?
Redstripe,
James 2:24 is part of my sig, it just doesn’t work properly with the TypeKey set-up. Yes, that’s exactly what it means. Among other things, it bugs the living daylights out of fundamentalists – of all stripes.
PS: is there a consensus yet on the reason for the development in humans of prominent, pendulous, and rather unwieldly mammary organs?
Apparently guys like them.
Many species (like dogs, cats, and bears) have distinct periods of estrus, which is when they are receptive to mating. Other species (like humans) menstruate, and can mate anytime during their cycle.
Animals with estrus usually have distinct behavioral or anatomical changes that indicate that they are receptive (like baboons’ and mandrills’ red asses, or cats’ yowling and rubbing)*. While menstrual animals also have changes, they are much more subtle than estrus, and judging where they are in their cycle is correspondingly more difficult.
It may well be that there is a differential advantage in concealing what reproductive stage you’re in as a menstrual animal, and having breasts that remain (relatively) the same size,, rather than disappearing except when you’re lactating (cf. rodents**), helps in concealing reproductive stage.
* estrus is from the Greek word for “gadfly”, a reference to the erratic behavior the animal in estrus exhibits.
** I say “mice breasts” as shorthand sometimes, but it’s really bad form on my part. Mice have lactiferous duct trees and mammary glands (even peri-anal ones!), but no breasts.
PZ, have you ever read Natalie Angier’s chapter on breasts and breastmilk from her book “a href=”http://www.amazon.com/gp/product/0385498411/sr=8-1/qid=1148090228/ref=pd_bbs_1/103-9061185-0673430?%5Fencoding=UTF8″>Woman”? A highly recommended read and I’d love to hear what you think of it.
Crap. I messed up the link.
PS: is there a consensus yet on the reason for the
development in humans of prominent, pendulous, and
rather unwieldly mammary organs?
Apparently guys like them.
I had always AssUMed that it was indeed a classic (the classic) case of a sexual selection positive feedback loop.
Yes? No?
-Steve
Raven T,
Some new and interesting work is coming out of primatology on estrus in anthropoids. The famous catarrhine (Old World Monkey) sexual swellings don’t necessarily indicate ovulation and the females are sexually receptive throughout the reproductive cycle. Cristina Campbell, who studies spider monkeys, has made the argument that anthropoids do not exhibit estrus (characterized by lordosis in females, inability to have intercourse outside of estrus etc.)
Bonobos (pygmy chimps) are particularly known for their sexual activity. They’re similar to humans in many ways, but don’t have breasts.
Based on comparative primate data, I don’t buy the concealed estrus arguments. Sexual selection may or may not play a role. Remember, females are a limiting resource for males. Males are not (as a general rule) a limiting resource for females. If you look at primates, it’s always the male that is elaborated, not the female. That’s how sexual selection in primates works, the males get bigger/prettier, while the females remain quite plain. A good non-primate example of this phenomenon is the peacock. Modern cultural preoccupation with breasts as sexual organs with the sole purpose of attracting males is a rather limited perspective.
Personally, I think breast development is related to broadcasting sexual maturity in relatively hairless apes.
Thanks, this was an interesting article, and you gave an answer at the end to what would have been my question (why not males?).
“Four of my favorite things are development, evolution, and breasts…”
One of the best lines I’ve ever heard from a scientist.
Thanks, Pygmy Loris–as you can tell, it’s been a while since I studied primate reproduction (and at that, it was only to compare it to bears, which is my focus). I’ll follow up on those references you provided.
I have a question that has bugging me ever since Tara at Aetiology posted about wallaby milk in a Saturday roundup.
You wrote “The innate immune system is a primitive defense system that uses peptides that recognize various common microbial surface molecules, and also uses enzymes that produce chemical agents lethal to bacteria. It’s a first line of defense that differs from the more specific immune system in that it doesn’t require specialized immune system cells and also doesn’t acquire the kind of highly refined specificity we see in antibodies (note, too, that antibodies are also secreted in milk–they are the IgG, IgE, and IgM molecules listed above.)”
THis is obviously a small part of your explanation. But if breast milk has immunoprotective properties for babies, what has been the consequence of bottlefeeding? Is this a partial explanation for the rise in childhood allergies?
In regards to formula formulations, I was appalled to find out that baby formula traditionally was made from trans fats until just recently when EFA’s were added. How can this impact a developing immune system, AND hurt neurological development?
Having nursed and bottlefed, I am no La Leche league advocate. Much of why I bottlefed was because it was offered as a superior choice. Convenience and father bonding was also touted. I think this was a wrong view now. Especailly after reading this and a link Tara put on her site that listed all the properties that breastmilk has inherently. But it was 17 years ago, and soon after the “norm” changed back to nursing.
So SHOULD women breastfeed? This is why I said that I am no LLL advocate. I think that they can be extremely over the top to women who JUST CANNOT nurse. That can be detrimental to mom’s who are just starting out who are told that they are not doing best for baby. But if you are a run of the mill, no problem gal, should you make the attempt? How long should you do it in order to get optimum immunological protection?
Any thoughts?
Or perhaps we should concentrate on giving new mothers the most accurate and complete information available, instead of tailoring the facts so that no one feels bad.
impatientpatient,
Very few women “just cannot” nurse. Millions of years of evolution has enabled mammal females to nurse, and resulted in breast milk that is the right blend of nutrients to feed a baby of a particular species. The LLL are quite obnoxious about it, but the truth is that the vast majority of women can nurse. Those who truly can’t shouldn’t be made to feel guilty or bad about it though.
The information I’ve read (cannot remember where) says breastfeeding until 6 months will give the baby nearly all the immunological protection breastmilk can offer to a baby. Approximations based on ape and hunter/gatherer lactation periods suggest that the “natural” period for breastfeeding was until 3-5 yrs old, before the advent of agriculture (which enabled people to create mush to feed babies and young children and freed women up for hard labor in the fields).
I think breastfeeding is the best choice for infants, but for some women it really isn’t feasible after maternity leave runs out. When people try to make you feel bad about that it really makes me angry
Read the AAP recommendations. With some specific reservations, they strongly recommend breast feeding.
Thanks for the link PZ. Most of my info comes from anthropological approaches. It’s good to see the AAP agrees.
That’s pretty interesting. I also was surprised by this
And, for some people the greatest benefit of breastfeeding?
NO BOTTLES TO WASH!!!
Issues around breastfeeding are amazingly contentious, though–a few years ago, here in Seattle, there was a controversy over the recommendation for Vitamin D supplements for exclusively breast-fed infants of African and Southeast Asian refugees, as described in this patient information handout. The Somali, Oromo, Amharic, Tigrinya, and Khmer versions are available at the EthnoMed site, as well.
The basic problem is that at this latitude, producing Vitamin D endogenously is hard enough for pale-skinned people, due to the amount of sunlight we get. Refugees from Africa and Asia can actually fail to produce enough Vitamin D to prevent rickets in their babies, so the Refugee Clinic began prescribing Vitamin D supplements for infants of color who were exclusively breast-fed.
The intersection of the history of interference with breast-feeding, race, and immigration was volatile enough to produce a controversy about that recommendation, although I have to say I never saw how prescribing a supplement was interfering with breastfeeding itself. Anyway, the controversy seems to have died down; I haven’t heard anything about it in a while. But these issues are quite contentious–understandably so, if you look at how breastfeeding has been discouraged and displaced in the US and in the developing world (cf. the Nestlé boycott)
Vitamin D is a big issue for immigrants. Moving from the latitude your skin color is adapted to can have tremendous effects. However, even light-skinned people can have problems in our modern, indoor-oriented society. Even pale-skinned adults are coming up with vitamin D deficiency. Seattle is actually not that far north (approximately same latitude as southern France), vitamin D deficiency among people of European descent is probably the result of cultural phenomena like spending most time indoors, using sunscreen/block, wearing lots of clothing etc.
For infants: that AAP report PZ linked to recommends vitamin D supplements for infants instead of sun exposure because of the risk of sunburns and skin cancer.
I personally don’t think the half an hour a day it’s supposed to take to synthesize vitamin D is going to do that much damage though.
If vitamin D is so desperately necessary for infant health, and exposure to sunlight is the only way infants could normally get enough of it, I can’t help but think that there’s something wrong with medical advice instructing parents not to expose their kids to sunlight.
I just had this VItamin D discussion with my creationist relative after my Mothers Day supper. Funny thing how he passed of science as hookum crookum kind of stuff and dnied that there was any difference in how people who lived in different parts of the world were able to synthesize it.
Vitamin D is my pet thing to know about. Another question. If Vitamin D is so important immunologically, could this be why there are still certain kinds of skin cancers developing? Could it be, like the tale of Goldilocks, that we need to get the “just Right” amount of Vitamin D for optimum all over health, and that by blocking all sunlight we are creating conditions for other cancers and diseases to marinate in. MS is a disease with a huge amount of “lack of Vitamin D” evidence. It happens in northern latitudes in certain populations more than others.
I just had this VItamin D discussion with my creationist relative after my Mothers Day supper. Funny thing how he passed of science as hookum crookum kind of stuff and dnied that there was any difference in how people who lived in different parts of the world were able to synthesize it.
Vitamin D is my pet thing to know about. Another question. If Vitamin D is so important immunologically, could this be why there are still certain kinds of skin cancers developing? Could it be, like the tale of Goldilocks, that we need to get the “just Right” amount of Vitamin D for optimum all over health, and that by blocking all sunlight we are creating conditions for other cancers and diseases to marinate in. MS is a disease with a huge amount of “lack of Vitamin D” evidence. It happens in northern latitudes in certain populations more than others.
I just had this VItamin D discussion with my creationist relative after my Mothers Day supper. Funny thing how he passed of science as hookum crookum kind of stuff and dnied that there was any difference in how people who lived in different parts of the world were able to synthesize it.
Vitamin D is my pet thing to know about. Another question. If Vitamin D is so important immunologically, could this be why there are still certain kinds of skin cancers developing? Could it be, like the tale of Goldilocks, that we need to get the “just Right” amount of Vitamin D for optimum all over health, and that by blocking all sunlight we are creating conditions for other cancers and diseases to marinate in. MS is a disease with a huge amount of “lack of Vitamin D” evidence. It happens in northern latitudes in certain populations more than others.
impatientpatient,
I’m not sure about the link between vitamin D deficiency and all these other cancers, but there is a delicate balance of skin pigmentation. Light enough to allow vitamin D synthesis, but dark enough to prevent folic acid break down and skin cancer. Usually we talk about cancer being the major selective factor for darker skin, but it looks like folic acid may be more important in terms of evolution. After all, malignant melanoma doesn’t usually kill people until after the childbearing years when they pass on their genes, but folate problems could kill much younger individuals i.e. before they reproduce. I just taught a unit on skin color in humans a couple of weeks ago and my students were surprised at how important skin color is to survival, but totally irrelevant in classification.
Repeat after me: skin color variation is clinal not racial!
Folic Acid Breakdown- very intrigued now. How is this related to Vitamin D, what else can I learn and where can I go to find more. I know much about spina bifida having two (non related but lived with) siblings with it. Nasty ass stupid disease. But what ELSE does lack of folic acid do if you are NOT pregnant?
Skin color and survival? So- is Australia having a problem with skin cancer mostly because light skinned people are living where it is not optimal that they live? Could that hypothesis even be a proper hypothesis? Or is that just dumb?
More on MS and Vitamin D anyone? If we are keeping babies out of the sun and slathering them with sun screen are we setting them up for future problems with immune system screw ups?
Even better: Everybody sleeps all night, every night. Baby wakes up… roll over, stick a boob in baby’s mouth, go back to sleep.
(Plus sleeping with a snuggly baby is just all-around good for you.)
I’m late to this discussion… but as a scientist who studies diarrheal disease I had to put my two cents in. Breast milk also contains oligosaccharides, which provide protection against specific diarrheal diseases. These disease-specific oligosaccharides are secreted into milk and are associated with protection from specific pathogens, such as campylobacter or norovirus; breastfed infants are significantly protected from disease by these oligosaccharides. Some mothers may code for production of anti-norovirus glycans, others for anti-ETEC glycans, some for both… totally fascinating stuff! No one has studied whether these protective oligosaccharide vary by place of geographic origin– perhaps people from southern Asia, the natural home of cholera, produce milk that is more likely to protect infants from cholera infection?
That fits with what I’d also learned about lactation being a “modification” of the sweat glands.
Re comment by TheBrummel (close to the top): Actually if PZ were interested in cat mammaries it would have been ten of his favorite things, not eight. Next time you see a lactating cat, count ’em.
Yay spam
Connecting breasts and evolution gives an interesting line of thought for the future:
1) We (as a culture) tend to value size when it comes to breasts.
2) Plastic surgery is becoming safer, and more affordable, allowing small-breasted women to overcome their “shortcomings”
3) Sice women who are naturally small-breasted are becoming augmented, they are finding husbands more readily, and reproducing with greater success than “average” sized women
Ergo: we are selecting for smaller breasts as a culture – albiet accidentally.
#46:
For that selection to have any value, it would have to continue for many generations. It’s highly unlikely that our current preference for larger breasts will remain for that long. More likely, it will, as it has in the past, go through cycles. There will be phases of preferring smaller breasts, and phases of preferring larger breasts. In addition, as plastic surgery continues to become cheaper and safer, it’s likely that it will become increasingly common for all types of individuals, who will reshape themselves into whatever the culture’s current ideal is, thereby negating any sexual selection advantage.
I just wanna thank the spammer for bringing this to the list of recently commented upon posts. It’s from before I started reading.
Thank you too, PeeZed. Fascinating.
Many of the molecular regulators of lactation are shared with inflammation pathways.