Developmental origins of disease

screen-shot-2016-11-18-at-8-24-16-pmDevelopmental programming is thought to be a source of many adult diseases, including obesity, diabetes, and cardiovascular disease. The notion that early life experiences, including nutrient transfer from the mother in utero, can shape the risk of later adult diseases is known as the Developmental Origins of Disease.

This relationship first came to light when Barker documented a curious association between birth weight and adult cardiac events in British men. Babies born small had a higher risk of chronic inflammatory diseases as adults. These small babies have been described as adopting a “thrifty phenotype.” That is, nutrient deprivation as a fetus is thought to have shaped the developmental trajectory in these individuals. This shift results in reduced expenditure on muscle and increased energy storage as fat. These developmental adjustments would be “thrifty” because muscle has much greater metabolic fuel demands than does fat. In addition, these small babies are also known to differ in the composition of their adipose tissues: they store fat primarily as visceral fat.  Visceral fat is the “unhealthy” abdominal fat which predisposes to diabetes and atherosclerosis. However, visceral fat has the advantage of being readily mobilized in the setting of stress or infection. The combination of metabolic thriftiness, reduced outlays devoted to costly muscle tissue, and increased ability to mobilize energy during times of stress is posited to promote survival. In terms of human development, the thrifty phenotype also preserves priority energy access for key organs, such as the brain.  For an expanded treatment of these concepts, see Kuzawa et al: Developmental Origins of Adult Function and Health: Evolutionary Hypotheses (below).

As a corollary to these arguments, it has been suggested that fetal nutrient provisioning provides a signal to the developing organism about the future state of the environment it will be born into. If conditions are good, reflected by increased maternal transfer of resources to the developing fetus, the baby will be born large. If these cues are an accurate signal of plentiful nutrition in childhood and later life, babies born large may develop as more muscular, larger, and with less stored fat, even though this strategy may be riskier in times of famine or epidemic disease.  By contrast, small babies, reflecting poor maternal nutrient provisioning in utero, may portend a resource-scarce environment during childhood and early adulthood. These infants might have an advantage if they develop a thrify phenotype that promotes a robust response to environmental stress.   The key is whether in utero conditions can predict a future state. If so, these fetal physiological adjustments, favoring a thrifty phenotype, will be adaptive in later life.

Recently, the Predictive Adaptive Response (PAR), which provides the underpinnings of the adaptive nature of the thrifty phenotype, has come under criticism. The main argument against the PAR is that fetal nutrient scarcity is a poor predictor of later scarcity. Even if a mother is pregnant in a time of famine, it does not mean that 20 years later, their adult offspring will be more likely to experience famine than a baby born to a mother who did not experience food shortage. As a result the thrifty phenotype is as likely to be maladaptive in adulthood than adaptive.

However, the fetus does have access to other cues which might be better predictors of a future state.

These are microbial cues, because infants inherit their microbiota from their mothers. Because microbiota transfer is a key determinant of the composition of the gut microbiota, with durable effects, it follows that microbiota transfer constitutes an intergenerational transfer of signals that can affect development.

Readings:

1) Kuzawa et al: Developmental Origins of Adult Function and Health: Evolutionary Hypotheses Annu Rev Anthropol 2009 

2) Gluckman Effect of in Utero and Early Life Conditions on Adult Health and Disease

3) Saben Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations Cell Reports 2016

Extra 1): Muller birth mode and the neonatal intestinal microbiome

Extra 2) Of the bugs that shape us: maternal obesity, the gut microbiome, and long-term disease risk

The Evolution of Virulence

Why do some infections kill us, while others are hardly noticed? Rapper Baba Brinkman may have the answer:

“For the pathogens, that’s why some are deadly serious
And others are mild: it’s the evolution of virulence…We got the pattern figured out. Some can only spread if they keep you walkin’ around
Others spread better if you’re stuck in bed in agony.”

Baba Brinkman’s “Parasite Wars”:

Read:

Evolution of virulence. Ewald PW. 2004. Infect Dis Clin N Am (18)

Virulence in malaria: an evolutionary viewpoint MacKinnon and Read AF 2004 Proc Royal Soc B

Beyond mortality: sterility as a neglected component of parasite virulence Abbate et al. 2015 Plos Pathogens

The adaptive evolution of virulence: a review of theoretical predictions and empirical tests Cressler et al. 2015 Parasitology

Writing: If bednet deployment is successful and permanently widely adopted in countries plagued by Falciparum malaria, how would you expect the parasite to evolve over time.

Also enjoy Baba Brinkman’s “So Infectious”:

 

Baba’s full lyrics below. Continue reading

Evolution of cancer

screen-shot-2016-10-24-at-5-59-39-am

Multi-cellular organisms have solved a special problem that single celled organisms don’t have: how to make cells cooperate together and restrain themselves from reproduction. In single cell organisms, there is no (little) cost to replication. Every division and  replication = higher fitness. Not so for multi cell organisms. Multi-cell organisms benefit because cells can differentiate and perform different jobs. This division of labor allows increased flexibility and potential for adaptation. But, flexibility comes with a cost: specialized cells must cease or slow their own cell division. This reduction in cell division is altruistic but potentially evolutionarily unstable. How?  Rogue cells that prioritize replication are favored by short term selection. These traits benefit the cell, but not the organism as a whole. This conflict is inherent in multicellularity.  When cooperation breaks down, cancer happens.

In cancer, clonal cells evolve ways to escape restraints on growth and motility. These evolved traits favor the fitness of the clones (in the short term anyway) usually to the detriment of the organism that gave rise to the cancer. However, cancer lineages are usually dead ends, so that adaptations that allow cancer are not passed on from generation to generation. New cancers have to start from scratch, evolving de novo mechanisms to evade controls on growth and reproduction in each lineage. At the same time, anti-cancer adaptations have evolved in multicellular organisms that control and remove proto-cancerous cells. Multi-generational selection thus permits ongoing evolution of adaptations against outlaw cells, keeping cancer at bay, at least most of the time.

What happens when cancer lineages don’t die with their host? Those cancers would not require de novo mutations to escape control. One might suppose that a cancer that can jump from host to host would evolve to be a formidable parasite with efficient means of evading host control. A transmissible leukemia found in clams seems to support this view. Transmissible cancer in clams joins only two other contagious cancers, the facial tumors of Tasmanian devils and a venereal cancer of dogs.  In these unfortunate cases, the cancers is apparently passed from generation to generation. These cancers do not have the handicap of starting from scratch in carcinogenic evolution. They behave more like pathogens, in a never ending evolutionary arms race with the host organism.

Figure 1 from Aktipis and Nesse 2012

  1. Aktipis and Nesse Evolutionary foundations for cancer biology
  2. A second transmissible cancer in Tasmanian Devils
  3. Cancer across the tree of life.

Writing project (pick one)

  1. If cancer is an inevitable part of life, and starts with a single cell, it makes sense that early detection should allow doctors to start treatment early, and save lives. However, aggressive widespread early screening and treatment of many cancers can be counterproductive: Screening for breast cancer in young women and widespread melanoma screening have each failed to reduce death rates. If screening really does not save lives, why do you suppose this is so?
  2. Doctors often biopsy tumors to figure out how dangerous a cancer is. High genetic diversity of the tumor predicts a bad outcome, carrying an increased rate of death. From an evolutionary perspective, why is high genetic diversity in cancers bad for mortality?

Malaria in Uganda – Roland Cooper November 1st

Roland Cooper PhD of Dominican University has spent the last several summers in Kampala Uganda studying resistance patterns to the malaria parasite Plasmodium falciparum. He will be visiting UNM on November 1st to discuss his work on Artemisinin Resistance in Plasmodium falciparum.

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Read his recent article  Lack of Artemisinin resistance in Plasmodium falciparum in Uganda

For review:

  1. Malaria Infection Increases Attractiveness of Humans to Mosquitoes. Lacroix R, Mukabana WR, Gouagna LC, Koella JC (2005) PloS Biol 3(9):e298.
  2. NPR Mosquitoes are more likely to seek out human blood after infection with Plasmodium. Another example of hijacking of host neural machinery?
  3. Malaria Chapter
  4. Read Curious Orthodoxy Antibiotic Prescribing

Writing Assignment: Artemisinin is modern drug derived from wormwood, an ancient remedy for malaria. Artemisinin in combination with other drugs is the last effective treatment for Falciparum malaria in many places in Asia, and especially in Africa. If you were in charge of the World Health Organization, what are two things you would recommend to ensure that we can still use artemisinin for malaria in Africa 20 years from now.

Make up extra credit (only do this if you have missed a writing assignment, or missed a class because of illness, or previously turned in an assignment late). Some research supports the idea that malaria parasites manipulate their hosts. How and why might the malaria parasites affect  mosquitoes and their human hosts?

Tuesday, November 1st 2016, 5:30PM; 107 Castetter Hall, guest lecture for the Evolutionary Medicine Class:

Campus map – (Castetter is #21):screen-shot-2016-10-25-at-11-09-29-am

Special CETI Lecture – Elies Bik PhD

This Friday, October 28th, don’t miss Elies Bik’s special invited lecture for the University of New Mexico Center for Evolutionary and Theoretical Immunology and for Evolutionary Medicine students. She will be discussing her recent work on marine mammal microbiomes. How do you sample marine mammal microbiomes anyway? Find out on Friday!

Title: “A world full of wonder, under the sea: Marine mammal microbiomes”

Oct 28, 2016 – 12:00pm – 01:00pm,  lunch is available at 11:30am.

 107 Castetter Hall

eliesbik

Elisabeth Bik is a Research Associate at the Department of Medicine, Division Infectious Diseases, at Stanford University School of Medicine. In addition to her amazing work focused on the human and animal microbiomes, she is editor of MicrobiomeDigest, a daily compendium of microbiome research. Dr. Bik She received her PhD at Utrecht University in The Netherlands and worked at the Dutch National Institute for Health and the St. Antonius Hospital in Nieuwegein. In 2001, she moved to the San Francisco Bay Area to join the laboratory of David Relman at Stanford. In the past 15 years she worked on the characterization of the human microbiome in thousands of oral, gastric, and intestinal samples. She currently works on the microbiota analysis of marine mammals and children with inflammatory bowel diseases.

Bik et al. 2016 Nature – Marine mammals harbor unique microbiotas shaped by and yet distinct from the sea

 

Microchimerism and maternal health

Special Lecture – Amy Boddy PhD

Amy Boddy PhD will be giving a special invited lecture for Joe Alcock’s evolutionary medicine class and the UNM community. Dr. Boddy studies evolutionary applications of human health and disease, using genomics, computational biology and evolutionary theory. Her recent work has focused on cooperation and conflict in pregnancy and cancer.  She will share her work on fetal microchimerism – the invasion of fetal cells into the maternal body – next Tuesday.

Date: Tuesday October 25th, Time: 5:30pm

Location: Main Campus, Castetter (Biology) room 107.

Title: Fetal microchimerism in pregnancy and maternal health

screen-shot-2016-10-18-at-10-23-53-am fetal_cell_mother_baby_anb8wo-1.png

Amy Boddy PhD is an Assistant Research Professor at the Biodesign Institute, Arizona State University. Dr. Boddy received a Ph.D in Molecular Biology & Genetics from Wayne State University, School of Medicine in 2013.

Dr. Boddy’s work on fetal microchimerism was covered by Carl Zimmer in the New York Times in September 2015. Zimmer writes of pregnant women:

“But male cells were present in every organ that the scientists studied: brains, hearts, kidneys and others.”

A Pregnancy Souvenir: Cells That Are Not Your Own. A video abstract describing her recent Bioessays review on fetal microchimerism and maternal health is here: Super Chimera.

Read:

  1. Boddy, Amy M., et al. “Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb.” Bioessays 37.10 (2015): 1106-1118.
  2. Haig D. Genetic Conflicts in Pregnancy. Quarterly Review of biology. Volume 68(4). Dec 1993, 495‐532.

The evolution of sleep

Why do we sleep? How much is enough? What happens when we don’t get enough. These questions will be the topic of next Tuesday’s October 18th Evolutionary Medicine class.

Sleep is one of the last frontiers in the study of lifestyle-related risk factors for chronic diseases. For instance, it has been well established that smoking reduces lifespan and increases the risk of chronic inflammatory diseases and cancer. Same goes for certain diets. The opposite is true for exercise. Now we can add disrupted sleep to the list of risk factors for chronic disease and shortened lifespan. Read Disruption of Circadian Clock Linked to Obesity, Diabetes and Heart Attacks. The question is, why?

Sleep via Jawbone

The sleep and activity tracker Jawbone (I have no financial interest in this company) released some data showing the ideal amount of sleep for a happy mood (above). This result, from a large sample makes it appear that sleep duration has a prominent effect on mood.

More about the Jawbone data here.

Work done here at the University of New Mexico by Gandhi Yetish PhD tried to answer the question: how much sleep are we evolved to need? He compared sleep in  modern industrialized populations in comparison to diverse hunter gatherer populations.

Read Yetish et al Current Biology 2015 here.

Other evolutionary work has centered on the uniquely human habit of nesting on comfortable beds, unlike other primates. We seem to prioritize sleep more than our closest relatives? Why?

Nunn, C. et al. 2016 Shining evolutionary light on human sleep and sleep disorders.

The discussion of sleep would be incomplete without the microbiome, of course. A landmark study showed that sleep deprivation, if long enough, is fatal. Death happens because microbes escape from the gut, causing abscesses and sepsis. Sleep seems to be important in preventing microbes gone amok.

Everson and Toth  Am J Physiol Regul Integr Comp Physiol 2000

screen-shot-2016-10-13-at-3-43-42-pm

Bacterial overgrowth after sleep deprivation (solid bars) in rats

Until recently, little evidence has linked sleep with gut microbiota in humans. One major finding was that gut microbiota have a circadian rhythm, with gene expression and population numbers that cycle in circadian fashion:. For example Lactobacillus populations expand and contract in the gut microbiome, depending on the time of day:

Thaiss et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 2014. 159 (3) 514-529

This group showed that the gut microbiota follows a circadian rhythm, just like host cells. Moreover, they showed that healthy cycling microbiotas require a host that follows a normal circadian pattern of eating and sleep. When the mouse sleep and eating pattern is disrupted, their microbes lose their rhythm. When this “jet-lagged” microbiota is transplanted into germ free mice, the inoculated mice become fat and lose glucose control, that is, they exhibit a pre-diabetic state

The investigators also studied humans who suffered jet lag. Two subjects with 10-12 hour time change gave fecal samples before, during, and after resolution of jet lag. The samples were inoculated into germ free mice. Lo and behold, the mice receiving jet-lagged poop became obese and pre-diabetic, exhibiting glucose intolerance:

Jet lagged human microbiota causes metabolic changes

These findings mean that all our body’s activities, and those of our microbiota, have evolved to be on a timer. Mistimed sleep and eating has real consequences, increasing the risk of obesity, diabetes and many other diseases.

Thaiss-et-al-2014-transkingdom-control-of-microbiota

Sleep is a thread that is tightly woven in the fabric of metabolism, diet, activity level, inflammation, and obesity. Teasing out the cause and effect relationships between these features is a fascinating challenge for science and for evolutionary medicine.

Writing assignment for Tuesday: Why do we sleep? Use the readings to defend your answer.