understanding the human microbiomeacademic.uprm.edu/~amassol/biol4365/forney2008.pdf · normal...

Understanding the

Human Microbiome

Larry J. Forney, Ph.D.University of Idaho

Tuesday, August 26, 2008

The microbial communities of humans are characteristic and complex mixtures of microorganisms that have co-evolved with their human hosts. The species that make up these communities vary between hosts as a result of restricted migration of microorganisms between hosts and strong ecological interactions within hosts, as well as host variability in terms of diet, genotype and colonization history. The shared evolutionary fate of humans and their symbiotic bacteria has selected for mutualistic interactions that are essential for human health, and ecological or genetic changes that uncouple this shared fate can result in disease. In this way, looking to ecological and evolutionary principles might provide new strategies for restoring and maintaining human health.

From: An ecological and evolutionary perspective on human–microbe mutualism and disease. (2007) Les Dethlefsen, Margaret McFall-Ngai & David A. Relman. Nature 449, 811-818


From: An ecological and evolutionary perspective on human–microbe mutualism and disease. (2007) Les Dethlefsen, Margaret McFall-Ngai & David A. Relman. Nature 449, 811-818


High numbers, high diversity, low recovery

Variation among individuals

Spatial variation within individuals

Three big problems faced in efforts to understand

these ecosystems


The Importance of Understanding Normal Vaginal Communities

The bacterial communities normally found in the vagina represent the first line of defense against infectious

diseases affecting the female reproductive tract.

Common wisdom:

‣ pH of the vagina is low (~4.5).

‣ Restricts growth of nonindigenous organisms, including pathogens.

‣ Lactobacillus spp. are characteristic of vaginal flora in normal healthy women.

study design


‣ Are there different kinds of communities in different healthy women?

‣ If so, are the communities functionally equivalent?

‣ Are there differences among racial groups?

‣ Do these differences have important consequences for women’s health?

ObjectiveDetermine composition and structure of microbial

communities in the human vagina.

MotivationCan not discriminate between normal and abnormal conditions

until normal conditions have been accurately defined.

Research questions

study design


Tiered Approach‣ Community profiles based on terminal

restriction fragment length polymorphisms of 16S rRNA genes ➙ Different kinds of communities

‣ Phylogenetic analysis of cloned 16S rRNA gene sequences ➙ Species composition of communities

Screen large number of samples

⬇Identify

representative samples

⬇In-depth analysis of selected samples

Statistics analyses that account for metadata.

study design

Will the need for a tiered approach be obviated by the continued development and ‘democratization’

of sequencing technologies?

Probably.


Secondary Structure: small subunit ribosomal RNA

Escherichia coli

Nov 1999

(J01695)

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Symbols Used In This Diagram:

G A

- Canonical base pair (A-U, G-C)

- G-A base pair- G-U base pair

G C

G U

U U - Non-canonical base pair

Citation and related information available at http://www.rna.ccbb.utexas.edu

Every 10th nucleotide is marked with a tick mark,and every 50th nucleotide is numbered.Tertiary interactions with strong comparative data are connected by solid lines.

1. Bacteria 2. Proteobacteria 3. gamma subdivision4. Enterobacteriaceae and related symbionts5. Enterobacteriaceae 6. Escherichia

analytical methods


T-RFLP[Terminal restriction fragment length polymorphism analysis of 16S rRNA genes]

Fragment Size (bp)

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men

t Abu

ndan

ce

(flu

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Coolen et al. Microbiology 71: 8729-8737, 2005

T-RFLP Profiles1 primer pair, 1 restriction enzymeGeneScan® 3.1 untitled Display-1 Page 1 of 1

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High Resolution T-RFLP Profiles2 primer pairs, 2 restriction enzymes

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Still another miracle happens

PCR

Another miracle happens

A miracle happens

Vaginal swabs

Extract bacterial DNA

Community 16S rRNA genes

Community fingerprints T-RFLP of 16S rRNA genes

Number of different kinds of communities

Libraries of 16 S rRNA genes

Sequence cloned genes

Composition of communitiesAnalytical Procedure

Reference: Abdo et al., Environmental Microbiology 8: 929-938, 2006; http://www.ibest.uidaho.edu/tools/hitsa/index.php


Groups

Ave. Distance B

etween C

lusters

Zhou et al. ISME J 1: 121-133, 2007

results


Twelve groups with ≥ 2 women

Eight “Supergroups”

These supergroups account for all that occur in the general populace at a frequency of >0.05 (p=.99)

There is a long ‘tail’, i.e., many women will have communities that

differ from those shown here.

Table1. Species composition of vaginal communities in healthy Caucasian and Black women.

Supergroupb (% clones)

I II III IV V VI VII VIII Phylotypea G1 S4 S7 G2 G5 G3 G10 G12 G4 G6 G7 G9 G11 Lactobacillus iners 86.1 93.3 96.8 0.6 0.0 7.0 2.4 0.0 52.1 1.0 0.0 3.6 0.0 Lactobacillus crispatus 0.6 1.1 3.2 93.3 86.8 0.2 0.0 0.0 23.8 19.0 50.5 0.0 0.0 Lactobacillus jensenii 0.5 0.0 0.0 1.5 10.0 0.0 0.0 0.0 6.3 0.3 49.5 0.0 0.0 Lactobacillus gasseri 0.5 0.0 0.0 0.0 2.4 6.4 0.0 0.0 4.5 77.4 0.0 0.0 0.0 Lactobacillus vaginas 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0 Lactobacillus coleohominis 0.2 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Lactobacillus salivarius c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Actinobaculum sp. c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Aerococcus sp. 1.1 2.3 0.0 0.0 0.0 0.5 2.4 1.1 0.3 0.0 0.0 0.0 0.0 Anaerobranca sp. 0.1 0.0 0.0 0.0 0.0 0.1 9.8 0.0 0.0 0.0 0.0 0.0 0.0 Anaerococcus sp. c 0.2 0.0 0.0 0.0 0.0 3.9 0.0 1.1 0.0 0.0 0.0 0.0 0.0 Atopobium vaginae 1.5 0.0 0.0 0.0 0.0 16.9 4.9 27.8 0.0 0.3 0.0 0.0 3.4 Clostridium sp. 0.2 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Dialister sp. 0.0 0.0 0.0 0.0 0.0 2.3 4.9 3.3 0.0 0.0 0.0 0.0 0.0 Eggerthella hongkongensis 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Enterococcus faecalis 0.0 0.0 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Finegoldia magna 0.0 1.1 0.0 0.0 0.0 0.0 0.0 2.2 0.0 0.0 0.0 0.0 0.0 Gardnerella vaginalis 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.4 0.0 0.0 0.0 Gemella palasticanis 0.3 0.0 0.0 0.0 0.0 1.1 0.0 7.8 0.0 0.0 0.0 4.8 0.0 Lachnospiraceae sp. 0.4 0.0 0.0 0.0 0.0 2.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Leptotrichia sp. 0.0 0.0 0.0 0.0 0.0 2.9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Megasphaera sp. 1.1 2.2 0.0 0.0 0.0 5.5 9.8 12.2 0.0 0.0 0.0 0.0 10.3 Micromonas sp. 0.4 0.0 0.0 0.0 0.0 7.0 0.0 6.7 0.0 0.0 0.0 0.0 4.5 Mobiluncus mulieris c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.3 Mycoplasma sp. c 0.0 0.0 0.0 0.0 0.0 0.0 2.4 0.0 0.0 0.0 0.0 0.0 0.0 Peptococcus niger c 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Peptoniphilus sp. 0.3 0.0 0.0 0.0 0.0 1.5 9.8 1.1 0.0 0.0 0.0 0.0 3.4 Peptostreptococcus sp. c 0.0 0.0 0.0 0.0 0.0 5.0 29.3 0.0 0.0 0.0 0.0 0.0 0.0 Prevotella sp. 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Pseudomonas sp. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0 0.0 Staphylococcus sp. 0.0 0.0 0.0 2.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Streptococcus sp. 0.8 0.0 0.0 1.8 0.0 0.0 0.0 0.0 11.8 0.3 0.0 91.6 0.0 Veillonella sp. 0.2 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Novel cladec, d 3.1 0.0 0.0 0.0 0.0 1.9 0.0 0.0 0.0 0.0 0.0 0.0 72.4 Miscellaneous novel phylotypese 2.3 0.0 0.0 0.1 0.6 32.5 24.3 36.7 1.0 0.8 0.0 0.0 3.7 Total number of women (per group) 50 1 1 24 9 20 2 2 10 8 4 2 2 Number of Caucasian women 24 1 1 16 7 5 0 0 9 5 4 1 0 Number of Black women 26 0 0 8 2 15 2 2 1 3 0 1 2 Number of women (per supergroup) 52 33 24 10 8 4 2 2

a The classification of clones was done by comparing their 16S rRNA gene sequences to those of known organisms. The genus and species names were used if the sequence similarity to a type species was >97%; the genus name only was used if the sequence similarity was <97% but >90%; and a clone was designated as novel if the sequence similarity to known organisms was <90%.

b Mean relative abundances of populations in clone libraries analyzed. “G” indicates cluster of > 1 sample, “S” designates a single sample (‘singleton’).

c Not found in Caucasian women. d Single clade of the family Lachnospiraceae that was unrelated to any named bacterium, but closely related (>97% 16S rRNA gene sequence

similarity) to an uncultured bacterium (GenBank AY471619). See Fig. 3b. e Includes various phylotypes within the phylum Firmicutes, including those shown in Fig. 3b.

Zhou et al. ISME J 1: 121-133, 2007


SUMMARY: Species composition of vaginal communities in healthy Caucasian and Black women.


I II III IV V VI VII VIII

Phylotypea G1 S4 S7 G2 G5 G3 G10 G12 G4 G6 G7 G9 G11

Lactobacillus iners 86.1 93.3 96.8 0.6 0.0 7.0 2.4 0.0 52.1 1.0 0.0 3.6 0.0

Lactobacillus crispatus 0.6 1.1 3.2 93.3 86.8 0.2 0.0 0.0 23.8 19.0 50.5 0.0 0.0

Lactobacillus jensenii 0.5 0.0 0.0 1.5 10.0 0.0 0.0 0.0 6.3 0.3 49.5 0.0 0.0

Lactobacillus gasseri 0.5 0.0 0.0 0.0 2.4 6.4 0.0 0.0 4.5 77.4 0.0 0.0 0.0

Lactobacillus vaginas 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0

Aerococcus sp. 1.1 2.3 0.0 0.0 0.0 0.5 2.4 1.1 0.3 0.0 0.0 0.0 0.0

Anaerobranca sp. 0.1 0.0 0.0 0.0 0.0 0.1 9.8 0.0 0.0 0.0 0.0 0.0 0.0

Anaerococcus sp. c 0.2 0.0 0.0 0.0 0.0 3.9 0.0 1.1 0.0 0.0 0.0 0.0 0.0

Atopobium vaginae 1.5 0.0 0.0 0.0 0.0 16.9 4.9 27.8 0.0 0.3 0.0 0.0 3.4

Dialister sp. 0.0 0.0 0.0 0.0 0.0 2.3 4.9 3.3 0.0 0.0 0.0 0.0 0.0

Gemella palasticanis 0.3 0.0 0.0 0.0 0.0 1.1 0.0 7.8 0.0 0.0 0.0 4.8 0.0

Lachnospiraceae sp. 0.4 0.0 0.0 0.0 0.0 2.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Leptotrichia sp. 0.0 0.0 0.0 0.0 0.0 2.9 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Megasphaera sp. 1.1 2.2 0.0 0.0 0.0 5.5 9.8 12.2 0.0 0.0 0.0 0.0 10.3

Micromonas sp. 0.4 0.0 0.0 0.0 0.0 7.0 0.0 6.7 0.0 0.0 0.0 0.0 4.5

Peptoniphilus sp. 0.3 0.0 0.0 0.0 0.0 1.5 9.8 1.1 0.0 0.0 0.0 0.0 3.4

Peptostreptococcus sp. c 0.0 0.0 0.0 0.0 0.0 5.0 29.3 0.0 0.0 0.0 0.0 0.0 0.0

Streptococcus sp. 0.8 0.0 0.0 1.8 0.0 0.0 0.0 0.0 11.8 0.3 0.0 91.6 0.0

Novel cladec, d

3.1 0.0 0.0 0.0 0.0 1.9 0.0 0.0 0.0 0.0 0.0 0.0 72.4

Miscellaneous novel phylotypese 2.3 0.0 0.0 0.1 0.6 32.5 24.3 36.7 1.0 0.8 0.0 0.0 3.7

Total number of women (per group) 50 1 1 24 9 20 2 2 10 8 4 2 2

Number of Caucasian women 24 1 1 16 7 5 0 0 9 5 4 1 0

Number of Black women 26 0 0 8 2 15 2 2 1 3 0 1 2

Number of women (per supergroup) 52 33 24 10 8 4 2 2

Zhou et al. ISME J advance online publication, May 10, 2007; doi:10.1038/ismej.2007.12


Table1. Species composition of vaginal communities in healthy Caucasian and Black women.


I II III IV V VI VII VIII Phylotypea G1 S4 S7 G2 G5 G3 G10 G12 G4 G6 G7 G9 G11 Lactobacillus iners 86.1 93.3 96.8 0.6 0.0 7.0 2.4 0.0 52.1 1.0 0.0 3.6 0.0 Lactobacillus crispatus 0.6 1.1 3.2 93.3 86.8 0.2 0.0 0.0 23.8 19.0 50.5 0.0 0.0 Lactobacillus jensenii 0.5 0.0 0.0 1.5 10.0 0.0 0.0 0.0 6.3 0.3 49.5 0.0 0.0 Lactobacillus gasseri 0.5 0.0 0.0 0.0 2.4 6.4 0.0 0.0 4.5 77.4 0.0 0.0 0.0 Lactobacillus vaginas 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0 Lactobacillus coleohominis 0.2 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Lactobacillus salivarius c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Actinobaculum sp. c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Aerococcus sp. 1.1 2.3 0.0 0.0 0.0 0.5 2.4 1.1 0.3 0.0 0.0 0.0 0.0 Anaerobranca sp. 0.1 0.0 0.0 0.0 0.0 0.1 9.8 0.0 0.0 0.0 0.0 0.0 0.0 Anaerococcus sp. c 0.2 0.0 0.0 0.0 0.0 3.9 0.0 1.1 0.0 0.0 0.0 0.0 0.0 Atopobium vaginae 1.5 0.0 0.0 0.0 0.0 16.9 4.9 27.8 0.0 0.3 0.0 0.0 3.4 Clostridium sp. 0.2 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Dialister sp. 0.0 0.0 0.0 0.0 0.0 2.3 4.9 3.3 0.0 0.0 0.0 0.0 0.0 Eggerthella hongkongensis 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Enterococcus faecalis 0.0 0.0 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Finegoldia magna 0.0 1.1 0.0 0.0 0.0 0.0 0.0 2.2 0.0 0.0 0.0 0.0 0.0 Gardnerella vaginalis 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.4 0.0 0.0 0.0 Gemella palasticanis 0.3 0.0 0.0 0.0 0.0 1.1 0.0 7.8 0.0 0.0 0.0 4.8 0.0 Lachnospiraceae sp. 0.4 0.0 0.0 0.0 0.0 2.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Leptotrichia sp. 0.0 0.0 0.0 0.0 0.0 2.9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Megasphaera sp. 1.1 2.2 0.0 0.0 0.0 5.5 9.8 12.2 0.0 0.0 0.0 0.0 10.3 Micromonas sp. 0.4 0.0 0.0 0.0 0.0 7.0 0.0 6.7 0.0 0.0 0.0 0.0 4.5 Mobiluncus mulieris c 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.3 Mycoplasma sp. c 0.0 0.0 0.0 0.0 0.0 0.0 2.4 0.0 0.0 0.0 0.0 0.0 0.0 Peptococcus niger c 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Peptoniphilus sp. 0.3 0.0 0.0 0.0 0.0 1.5 9.8 1.1 0.0 0.0 0.0 0.0 3.4 Peptostreptococcus sp. c 0.0 0.0 0.0 0.0 0.0 5.0 29.3 0.0 0.0 0.0 0.0 0.0 0.0 Prevotella sp. 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Pseudomonas sp. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0 0.0 Staphylococcus sp. 0.0 0.0 0.0 2.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Streptococcus sp. 0.8 0.0 0.0 1.8 0.0 0.0 0.0 0.0 11.8 0.3 0.0 91.6 0.0 Veillonella sp. 0.2 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Novel cladec, d 3.1 0.0 0.0 0.0 0.0 1.9 0.0 0.0 0.0 0.0 0.0 0.0 72.4 Miscellaneous novel phylotypese 2.3 0.0 0.0 0.1 0.6 32.5 24.3 36.7 1.0 0.8 0.0 0.0 3.7 Total number of women (per group) 50 1 1 24 9 20 2 2 10 8 4 2 2 Number of Caucasian women 24 1 1 16 7 5 0 0 9 5 4 1 0 Number of Black women 26 0 0 8 2 15 2 2 1 3 0 1 2 Number of women (per supergroup) 52 33 24 10 8 4 2 2

a The classification of clones was done by comparing their 16S rRNA gene sequences to those of known organisms. The genus and species names were used if the sequence similarity to a type species was >97%; the genus name only was used if the sequence similarity was <97% but >90%; and a clone was designated as novel if the sequence similarity to known organisms was <90%.

b Mean relative abundances of populations in clone libraries analyzed. “G” indicates cluster of > 1 sample, “S” designates a single sample (‘singleton’).

c Not found in Caucasian women. d Single clade of the family Lachnospiraceae that was unrelated to any named bacterium, but closely related (>97% 16S rRNA gene sequence

similarity) to an uncultured bacterium (GenBank AY471619). See Fig. 3b. e Includes various phylotypes within the phylum Firmicutes, including those shown in Fig. 3b.

95/144 women


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I II IV III V VI VII VIII

Supergroup

FrequencyBlack Caucasian

Zhou et al. ISME J advance online publication, May 10, 2007; doi:10.1038/ismej.2007.12

results


‣ Ecological function of communities – lactic acid production – is conserved.

‣ Not all vaginal communities were dominated by species of Lactobacillus.

‣ Suggests that hosts exert selective pressures that shape the composition of communities.

Observations

background

(1) There were (only) eight common kinds of vaginal communities with fundamentally different species composition.

(2) Rank-abundance of communities differs among racial groups


community ecology


An ecosystem

Community

Host

Environment

community ecology


Effect of Disturbances on Vaginal Communities

Normal[Dynamic equilibrium]

DisturbedEcosystem

Frequency or Duration

Inte

nsity

Disturbances to the vaginal environment are often imposed by human actions:

- douching

- intercourse

- birth control methods

But also include:

- menstruation

- menopause

- parturition

➙

community ecology


So what factors are key to ecosystem stability?

‣ The strong linkage between high numbers of lactic acid bacteria and a ‘healthy’ vaginal microbial community is consistent with Walker’s Driver-Passenger model of community structure and function (Walker, 1995).

‣ Under this model, species of lactic acid bacteria would be considered ‘drivers’ that strongly influence the function or structure of the ecosystem by producing lactic acid and maintaining a low pH.

‣ The environment thus created would be a strong determinant of community species composition and activity because they would all have to flourish or at least tolerate an environmental pH of 4.0-4.5.

‣ The non-lactic acid bacteria would be considered ‘passengers’ that are typically present at lower numerical abundance, have little influence on the ecology of the system, and can be lost from the community or change over time without markedly affecting community function.

community ecologyspeculation

Lactic acid bacteria (LAB) Includes, but are not limited to, species of Lactobacillus


Resilience

Resilience is the amount of disturbance that an ecosystem can withstand without changing its self-organizing processes.

‣ Not all disturbances have equal intensity, occur at the same frequency, or endure for the same length of time. Therefore, not all disturbances have the same consequences.

‣ Communities with fundamental differences in species composition and structure will differ in resilience.

community ecology

http://www.affordablehousinginstitute.org/blogs/us/Train_wreck_2_vertical_small.jpg

Ecological Disequilibrium

Disturbed communities are more readily invaded by “weedy” species (opportunistic pathogens).




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community ecology

‣Disturbances provide opportunities for invasive species to become established in a community.

‣The disturbed state itself could be a disease.

‣Not all diseases are caused by a single etiological agent.

Host

Environment Community

DISTURBED


No role proposed for normal microbiota

sickhost

isolatesuspected

causitive agent

infect healthy host

new host becomes sick

Germ Theory of Infectious Disease

Gause's Law of Competitive Exclusion A theory that states that two species competing

for the same resources cannot stably coexist

community ecology


proteins

polysaccharides,monosaccharides,

urea

Na+, K+, Cl-

Host

MicrobialCommunity

community ecology

All resources used by vaginal microbial

populations are derived from the host

Quantity and composition of resources probably

differ among hosts

Competition for resources is probably severe


Community

Host

Environment

community ecology

Mutualism: both parties benefitCommensalism


Conclusions

Forney Lab- Xia Zhou, MD- Jacob Pierson- Maria Schneider

Collaborators:

University of Idaho- Zaid Abdo, PhD- James Foster, PhD- Steve Krone, PhD- Chris Williams, PhD

University of Maryland- Jacques Ravel, PhD

Procter and Gamble- Catherine Davis, PhD

Funding:NIHP&G


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