What a nice surprise (insert sarcasm). Naveen Jain, the CEO of Viome and Moon Express, with over 100k followers on Twitter, sent me such a flattering tweet tonight. What else can I do than to make sure the Internet never forgets…. 🙂
What a nice surprise (insert sarcasm). Naveen Jain, the CEO of Viome and Moon Express, with over 100k followers on Twitter, sent me such a flattering tweet tonight. What else can I do than to make sure the Internet never forgets…. 🙂
My second (and last) day of reporting from the 4th Annual North American Microbiome Congress in Washington DC, organized by Kisaco Research. Here is a roll-out of my tweet storm from today.
Good morning! In 15 minutes I will start live tweeting Day 2 from the 4th Annual Microbiome Congress, in Washington DC, organized by @KisacoRes #MBCongress2019
I am all ready to go in the front row at the plenary session, with Larry Weiss, Amanda Kay, and Ken Blount.
Larry Weiss @LWeissMD, CEO and founder of Persona Biome opens this morning’s session. In this field, we have undergone a transformation. We start thinking more like a microbial community, how everything is connected.
Larry Weiss: As scientists we gather data, and build models. But models are not truth. There is so much we don’t know that we don’t know. This field is still very early.
Larry Weiss: We are intimately connected to our microbiome, but have cut connections with our environment. We are a complex process of processes.
Larry Weiss: Finally, I want to talk about “shit”. We need to treat feces with much more respect. It is not only a waste product, but the product of a bioreactor.
Larry Weiss: This science is going to transform everything. We need to develop partnerships and work together.
The opening presentation of today is by Amanda Kay, VP at Synlogic @synlogic_tx, and Bradford McRae, AbbVie Discovery Immunology @abbvie about “Collaborating with AbbVie to develop a novel class of living medicines”
Bradford McRae starts off: There are several key questions for microbiome-based drug development. Most importantly: Are changes in the microbiome the cause of disease or a secondary consequence of the disease state?
Bradford McRae: Will altering the composition/function of the microbiome change the natural history of disease? Can the composition/function of the microbiome be used to stratify patient populations and/or define future disease course?
Bradford McRae: There are many factors that influence microbiome composition and function, such as diet, exercise, stress, medications, metabolism, immunity.
Bradford McRae: Some challenges for understanding the therapeutic potential of the microbiome: Intra-individual disease and microbiome heterogeneity make it hard to understand patterns of disease.
Bradford McRae: It is also still difficult to link sequence data to function, and to understand what happens in the different compartments of the gut by just looking at what comes out at the far end.
Bradford McRae: Excellent work on altering the function of the microbiome is being done in metabolic disease, such as FMT from lean donors to patients with metabolic syndrome, which improved glucose sensitivity.
Bradford McRae: Evidence that diet may alter the course of IBD through modifying microbiome function from Schwerd et al.
Bradford McRae: Future developments:
1. Moving beyond descriptive analysis to molecular pathways
2. Future deliverables for patients: diagnostics, mechanisms
3. Potential for engineered bacteria to deliver specific therapies
Amanda Kay: At @synlogic_tx, we are designing for life. We do rational design for bacterial based therapy, and collaborate with partners. We do synthetic biotic(TM).
Amanda Kay: Synthetics: genetic circuits, degradation of disease causing metabolites, production of therapeutic molecules
Biotics: bacterial chassis, non-pathogenic, amenable to genetic manipulation
Amanda Kay: In the context of IBD, we @synlogic_tx started a collaboration with AbbVie @abbvie We both brought in our key expertise, in drug development and translation into drug candidates.
Amanda Kay: Goal of our collaboration was to leverage known homeostatic functions to resolve disease and maintain health in patients
The next speaker is Ken Blount, CSO, Rebiotix @Rebiotix, with: “Discovering the potential of Microbiota Restoration Therapy (MRT) drug platforms for the treatment of intestinal diseases”
Ken Blount: Fecal transplant has a long history of working well, in particular in Clostridium difficile infections, but how do you perform it in a controlled and reproducible way?
Ken Blount: In a healthy gut, non-spore forming class Bacteroidia constitutes ~30% of bacteria. In our platform, the Microbiome Restoration Therapy (MRT), we want to restore a healthy gut microbiome in a patient.
Ken Blount: In C. diff infections (CDI), it is challenging to restore the foundation of a healthy microbiome. Our MRT is not a fecal transplant, but a standardized consortium of live spore forming and non-spore forming microbes.
Ken Blount: We designed several trials, phase 2 trials already done, phase 3 enrolling. We got 87% of treatment success in our initial phase 2 trial.
Ken Blount: In our second phase 2 trial, we learned that 2 doses worked as well as 1, but success rate was only around 60%. Placebo had 47% success rate (because of pretreatment with Abx?)
Ken Blount: After treatment, the patients’ microbiomes shifted towards that of a healthy population (HMP dataset). It restores Bacteroidia and Clostridia, decreasing Gammaproteobacteria.
Ken Blount: We developed the Microbiome Health Index (MHI, TM). High MHI means healthy, lower MHI is a deviation from healthy. This single number allows to better differentiate healthy and unhealthy.
Ken Blount: We are now in the middle of a phase 3 trial. We are working on a new stable formulation, in an oral capsule, RBX7455, which had a 90% success rate in a phase 1 trial.
Ken Blount: We are working on many other applications as well (for the enema formulation): ongoing trials in VRE, pediatric UC, UTI, hepatic encephalopathy.
We will now have two talks in the session “Regulation of biotech: Are we Prepared? “
Jim Weston, senior VP at Seres Therapeutics @SeresTX will talk about: “How we navigated the evolving guidelines”
Jim Weston: I will tell you about the process we did to get our products to market and collaborate with the regulatory offices such as the FDA.
Jim Weston: Our strategy at @SeresTX is a focused R&D, (e.g. C. diff infection), and to have a great clinical manufacturing operation. How do you meet the needs of patients as well as regulators?
Jim Weston: Therapeutic Microbiome Products are regulated in US as both biological products (drugs) as well as live biotherapeutic products. The best strategy is to have case-by-case collaborations with the regulators.
Jim Weston: TMPs can vary from stool (FMT), communities of strains, single strains, or genetically modified strains. These all require different regulatory processes.
Jim Weston: In the US, we have one agency for approval, the @US_FDA. It is best to start work with the FDA in an early stage. In Europe there is the EMA @EMA_News and national level agencies.
Jim Weston: It would be great to have some guidance for (fecal) donor screening and safety. Trial design needs guidance too, but end points are well defined.
Jim Weston: How do we ensure good manufacturing, and measurement of results? Regular interaction between industry and regulatory agencies is key.
The second talk in the session about regulatory agencies, will be by Larry Weiss @LWeissMD, CEO of Persona Biome, with “Re-writing the rules for microbiome therapeutics”
Larry Weiss: We are trying to get really solid data, but not by hacking the system or evading the rules. There are existing rules that we can follow, but solid science is important.
Larry Weiss: “The @US_FDA regulates two things: substances and words” – Peter Barton Hutt.
Larry Weiss: We are changing the states of pharmaceutical development, moving from pharmacology (chemistry) towards systems biology (microbiology). This is challenging a lot of our structures, including regulatory.
Larry Weiss: Shows the definitions of “drug”, “cosmetic”, “dietary supplement” by the FDA. There are several situations where it is difficult to distinguish between these categories.
Larry Weiss: The definition of GRAS: Generally Recognized as Safe states “no genuine dispute among qualified experts” – ha! When does that happen?? You can define your own product as GRAS (food ingredient).
Larry Weiss: There are many overlapping categories.
* Drug, cosmetic, medical food, probiotic?
* Bugs as drugs (probiotics, known commensals), drugs from bugs (purified extracts), microbiome manipulation (FMT, phages, prebiotics).
Larry Weiss: Each product that you might develop might have to follow a different path. It is not about evading rules, you have to make ethical decisions.
We will have a coffee break and then I will go to one of the three parallel sessions. Hard to choose! But I will probably go to the “Food and the Microbiome” session with Kristen Beck @theladybeck and Cindy Davis @NIH
Back from coffee, at the “Food and the Microbiome” session with Kristen Beck @theladybeck (we finally meet!) @IBMresearch , and Cindy Davis @NIH
Kristen Beck: I get asked a lot if IBM is involved in life sciences, and the answer is Yes! We have several collaborations in the microbial space, including in the microbiome. 20/3000 researchers at our division are involved in the microbiome.
Kristen Beck: We have partnerships with e.g. UCSD Center for Microbiome Innovation, and with Mars, to look at microbes in the food chain.
Kristen Beck: Food poisoning is very frequent, and companies invest a lot in processes to limit food safety hazards. There are known (e.g. Salmonella) and unknown (never anticipated before) hazards.
Kristen Beck: The microbiome will respond to its environment, much like a canary in a coal mine. In food samples, there can be microbes, which can be detected by sequencing.
Kristen Beck: We analyzed 312 terabytes of data, generating >270,000 data files, building up datasets from food microbiomes. We also build a bioinformatics tool that could work for a wide range of people, including those who cannot run from the command line.
Kristen Beck: Kiwi, an advanced prototype of food microbiome analysis – an easy to use interface for analyzing food microbiomes.
Kristen Beck *shows some Kiwi dashboard screenshots *. On the left, you see a good sample, with no microbial hazards detected (in blue and green) – on the right, hazards detected (in red and orange). These are easy to interpret.
Kristen Beck: For the more advanced users, we offer advanced analysis tools of these samples.
Kristen Beck: We work with deep sequencing of the metatranscriptome (mRNA), around 350 million reads per sample. Samples all retrieved from same factory and sample type.
Kristen Beck: With food, it is not always clear what the matrix (host) is: is it chicken or some other type of meat? This provides unique computational challenges to the bioinformatics analysis.
Kristen Beck: We search for a reference set of 6,000 plant and animals genomes, then use Kraken to filter out these matrix reads. This filtering should only remove the matrix, not the microbial reads.
Kristen Beck: We can also use this process to see the composition of host DNA in a sausage sample (55% sheep, 35% cattle, 7.5% pig and 1% horse!).
Kristen Beck: In screening chicken samples, we found most of them to be >99% chicken, but some had pig and cow DNA in them.
Kristen Beck: The microbiome analysis is then done on the non-matrix nucleic acids. We show the high abundance microbes to signal if something is wrong.
Kristen Beck: Unclassified reads are a missed opportunity, caused by lack of homology. Reference databases are biased towards cultured organisms. We are building better reference sets that include many more genomes to better capture the diversity of strains.
Kristen Beck: Introducing OMXWare: We @IBMResearch assembled 166,000 high quality genomes, annotated genes, proteins, and domains. It has lots of data in a structured and optimized DB2 database.
Kristen Beck: OMXWare can be used e.g. to extract novel CRISPR/Cas sequences and to find higher % of functional annotations.
The next speaker is Cindy Davis, Office of Dietary Supplements, National Institutes of Health @NIH with “Diet, microbiome and health: the influence of diet on the intestinal microbiome”
Cindy Davis: Diet shapes the microbiome in humans: globally distinct populations, food pattern consumption vs enterotypes. High fat vs high fiber diets are associated with different microbiomes.
Cindy Davis: Prevotella is associated with diets with lots of fibers, while Bacteroides is more prevalent in Western diets with more animal fats. Diet can influence the microbiome composition, even in short term experiments.
Cindy Davis: Shows data from the Daphna Rothschild Nature paper.
Environment dominates over host genetics in shaping human gut microbiota
Cindy Davis: Shows WHO definition of probiotics, which now form a >2 billion dollar sales market in the US. They are the 3rd most common dietary supplement. But what do they do on humans?
Cindy Davis: Stool samples do not reflect the whole microbiome in the gut. Some people’s microbiota resists colonization with probiotics.
Shows data from Zmora et al.
Cindy Davis: There have been several studies using the effect of probiotics on BMI. Most of these are short duration, small sample size (underpowered), used variable strains, not preregistered, and not clinically significant.
They don’t prove anything.
Cindy Davis: So where is the science? The FDA has not approved any probiotics for preventing any health problem. There is some preliminary evidence for some effect of probiotics in certain situations.
Cindy Davis: Dietary fiber is associated with a decreased risk of colon cancer. They are fermented in the colon into short chain fatty acids (SCFA), such as butyrate.
Cindy Davis: Butyrate can affect proliferation of cancer cells (which prefer glucose) and increase apoptosis, thus plays role in cancer prevention.
Cindy Davis: Dietary fiber can protect the mucus barrier. In the absence of fiber, the gut bacteria start to eat the mucus layer.
* shows data from Desai et al. 2016
Cindy Davis: Dietary allicin (in garlic) reduces metabolism of L-carnitine into TMAO. See Wu 2015 (link: https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.199)
We need to think about food interactions!
Cindy Davis: *shows tiny graphs from many more papers by other groups*
Cindy Davis: There is a dynamic relation between microbes, food components, and microbial metabolites. Can your microbiome tell you what to eat?
Zeevi et al. : high interpersonal variability in glucose response in 800 person cohort.
(link: https://www.cell.com/cell/fulltext/S0092-8674(15)01481-6) cell.com/cell/fulltext/
Cindy Davis: When you are going to have lunch now, remember that you are also feeding your microbes. And they might want something different to eat than you. 🙂
This talk gave a good overview of the current state of microbiome research in the setting of diet, but did not present anything new. Would have been a better talk as a keynote/opening lecture, not in a specialized conference track.
We start after lunch with a talk by Scott Jackson from the National Institute of Standards and Technology @usnistgov, with “Standards for Microbiome and Metagenomic Measurements”
Scott Jackson: We are a non-regulatory agency, but often work together with the FDA to develop standards that can be used by industry.
Scott Jackson: The microbiome industry is rapidly growing, and standards are needed for diagnostics and methods. Many biases in metagenomic measurements, e.g. DNA extractions, primer choice, library prep, sequencing technologies, and bioinformatics analyses.
Scott Jackson: 5 years ago, it was “cowboy country” – different methods will give different microbiome community outcomes. We make references and standards to try to guide this.
Scott Jackson: The Mosaic Standards Challenge was launched in May 2018, made possible by Janssen, Biocollective, DNAnexus, and NIST. You can sign up for free. You process samples through your favorite method and upload your data.
(link: http://mosaicbiome.com/) MOSAIC: A Cloud-Based Microbiome Informatics Platform
Scott Jackson: Here are some results from submitted datasets on a set of 10 bacterial standards. Results vary widely between labs, and we are looking at which factors make the most impact.
Scott Jackson: High number of reads often corresponded to more false positives (detection of strains that were not in the tube we sent).
Scott Jackson: None of the companies that do microbial diagnostics do have FDA approval, but the FDA calls on NIST for microbial standards. We have made a mix of 19 different pathogens in human DNA, which can be used to validate tests.
Scott Jackson: We made different serial dilution mixtures and tested expected vs observed abundance using 3 metagenomics analysis tools to infer specificity and sensitivity.
Scott Jackson: International microbiome and metagenomics standards alliance IMMSA provides lots of tools, workshops, videos. We also have a pathogens workshop group. Our next NIST/FDA/NIH workshop is Sept 9-10 in Gaithersburg, MD.
(link: https://microbialstandards.org/) microbialstandards.org
Moved to parallel session 1, where I caught the summary slide of Peter Karp @SRI_Intl talk, in which he presented:
* Multi organism Metabolic Route Search
* BioCyc Databases Combine
* Pathway Tools software
The next talk will be by Curtis Huttenhower @chuttenh from Harvard University @harvard, with “Integrating molecule measurements of the microbiome for translation in population health”
Curtis Huttenhower: Our group works on methods development to analyze the microbiome on different levels, including very large-scale studies.
Curtis Huttenhower: BIOM-Mass: Biobank for Microbiome Research in Massachusetts. Developing a room temp-ship-able kit for stool and oral samples suitable for metagenomics, metatranscriptomics, metabolomics, and culture.
Curtis Huttenhower: Phase 2 of the Human Microbiome Project, HMP2, or integrative HMP (iHMP). Our lab is studying the microbiome of inflammatory bowel disease (IBD) patients over time, including CD, UC. Roughly every 2 weeks + blood draws and biopsies.
Curtis Huttenhower: This allows us to connect host response to microbiome profiles, at roughly the same timepoints. Database and raw data available here: (link: https://www.ibdmdb.org/) ibdmdb.org
Curtis Huttenhower: We can see which microbial metabolites (as measured biochemically) are enriched or depleted in IBD patients vs healthy controls and connect these to variations in microbial taxa.
Curtis Huttenhower: We can also link microbial function to strain specific phenotypes in IBD. *shows heatmap of Ruminococcus gnavus genes and their abundance in patients/controls*. Most gut microbial genes are unfortunately still of unknown function.
Curtis Huttenhower: Type 1 diabetes infant cohorts in Finland, Estonia, Russia / TEDDY study: functional shifts in genes at birth, at year 1, at year 2. Some are linked to specific functions, e.g. HMO utilization in infants in Bifidobacterium longum strains.
Curtis Huttenhower: Nicola Segata: assembled 150,000 genomes from 10,000 metagenomies, 5,000 species-level genomic bins (SGBs). Many of these genome bins are novel, many from uncharacterized, international populations.
Curtis Huttenhower: Even among well characterized clades, such as Bacteroides, we found genomes that were separate from characterized strains, so novel taxa without reference genomes.
Curtis Huttenhower: ASCA and ANCA antibody levels in blood corresponded significantly with microbial dysbiosis. We also found that each patient, and even some of the controls have a very dynamic microbiome, with different stable states, and periodic blooms.
Curtis Huttenhower: Our computational tools are available from the bioBakery website. (link: https://bitbucket.org/biobakery/biobakery/wiki/Home) bitbucket.org/biobakery/biob…
We also teach courses – and we are hiring computational and wet-lab postdocs, so please come and join our lab.
The next speaker is David Zeevi, @DaveZeevi from Rockefeller University @RockefellerUniv with his talk entitled “Sub-genomic variation in the gut microbiome associates with host metabolic health”.
David Zeevi: What are we looking for in microbiome data? Observation? Association? Mechanism? We are moving from the first towards the last, but each step brings bigger challenges.
David Zeevi: Metabolic diseases are on the rise, in particular obesity. We collected blood glucose data and correlated that with microbiome and dietary data. Each person responds differently. See: (link: https://www.cell.com/cell/fulltext/S0092-8674(15)01481-6) cell.com/cell/fulltext/…
David Zeevi: Even small differences, in a few microbial genes, can have a significant phenotypic effect. Think about the presence/absence of a toxin gene. What are the variable regions in microbiome bacteria?
David Zeevi: About 20% of metagenomics read gets assigned to more than one reference microbial genome. Errors caused by differential coverage in reference genomes.
David Zeevi: We have a paper in press for an iterative coverage based algorithm for read-assignment correction. This creates more accurate assignments.
David Zeevi: Sub-genomic variability (SGVs). These regions are very abundant across different datasets (Elies: not sure how they are defined)
David Zeevi: SGVs are person-specific and are shared with habitat. SGVs also correlate with disease risk factors. E.g. Anaerostipes hadrus region: if present, people are leaner and more healthy. It encodes butyrate production and inositol degradation.
David Zeevi: Thus, variable gene clusters facilitate mechanistic insights. This would be not be discovered if you just look at presence of specific strains or species.
After the break, we will have Kara Bortone @kara_bortone, head at jLABS @JLABS, Johnson & Johnson @JNJInnovation with “Catalyzing and supporting the translation of preventative research in the microbiome space”
Kara Bortone: Clinical research is still reactive: we wait until a person has a disease and then try to cure them. Can we study underlying mechanisms and better predict and prevent?
Kara Bortone: Future models of care: a holistic approach to eliminate diseases. Prevent, intercept, and cure disease. We are shifting our effort to a much earlier in the process, before the onset of observable symptoms.
Kara Bortone: The microbiome is a promising target for drug development. @JNJInnovation
has a recognized leading partnership role in the microbiome space. @JLABS
is an incubator space to grow and foster startup companies.
Kara Bortone: Jlabs are life-science incubators. There are now13 JLabs sites all across the globe, 480 portfolio companies in sectors ranging from health tech, medical devices, and pharmaceutical.
Kara Bortone: Small companies get big company benefits at JLabs. It is hard to buy equipment for early stage companies. So we have shared equipment and shared space, with support staff, education, and connections to VCs and other investors.
Kara Bortone: We organize events with investors and foundations to facilitate connections and QuickFire Challenges, with currently over 60 winning companies. And @AstarteMedical is one of them, yay!
Kara Bortone: Of the companies we hosted, 88% are still in business or acquired (that is more than the average restaurant in DC!). 12 companies have gone public, 12 were acquired.
That completes my tweeting from the Kisaco Microbiome Congress in Washington DC. I hope you all enjoyed this report!
Today, I live tweeted from the 4th Annual North American Microbiome Congress, in Washington DC. Here are my tweets, nicely bundled for you, per talk.
In about 30 min, I will start live tweeting from the 4th Kisaco North American Microbiome Congress in Washington DC. @MBCongress @KisacoRes
Get your coffee ready and hear about the latest in Microbiome Research!
While I am going to grab a coffee, get ready for the morning session at the DC Microbiome Congress @KisacoRes with Jo Handelsman @Jo_Microbe and Jeff Leach.
David Kyle of @EvolveBio will be the chair of this morning, and welcomes us all. He reminds us about all the great research that came out in the last decade.
David Kyle: The gut microbiome is sort of a complex organ that needs to be fed well. We sometimes damage it by antibiotics – which we should not eliminate, because they save lives! How can we return it to its original state after the use of antibiotics?
David Kyle: The first 100 days of life are fascinating. Immune system is learning what is self or not, microbiome is forming – infant nutrition is important.
David Kyle: In this congress we will hear about the impact of the microbiome on many aspects of physiology, skin, gut, brain. The microbiome has in impact on our whole body, this is a multidisciplinary field.
David Kyle: Let’s recognize that we are all students. We are all here to learn about this rapidly changing field. Please engage in questions! And make sure to network, and challenge each other. Let’s make this a melting pot of thoughts.
Next up is Jo Handelsman @Jo_Microbe @jo44atWID @WIDiscovery who starts off with some remarkable words: “The most valuable citizen of the Earth was the microbe” – written by Mark Twain in “My 3000 Years with the Microbes”
Jo Handelsman: Catching up with Mark Twain: The number of microbiome publications and investment has increased incredibly. The White House Microbiome Initiative from 2016 played a big role.
Jo Handelsman: Microbes are connected to many different diseases, either being protective or associated. For example, work from the Jeff Gordon lab doing microbiome transfers from obese humans to germ-free mice.
Jo Handelsman: The microbiome plays roles in most chronic diseases. Most stunningly and un-anticipated, there are associations between the microbiome and the brain. Depression, autism, Alzheimers, have all been linked to microbiome composition.
Jo Handelsman: These diseases can e.g. be transferred by fecal transplants to mice. Extensive research going on in all these fields.
Jo Handelsman: One of the challenges is that the microbiome is very hard to change. It is resilient. Metchnikoff consumed liters of yogurt and found Lactobacillus, but it disappeared after he stopped eating yogurt.
Jo Handelsman: There are of course ways to change the microbiome, such as fecal transplants, phages, probiotics, prebiotics. But we don’t yet understand the basis for community robustness, the resistance to change, or resilience (change but then snap back).
Jo Handelsman: We launched the White House National MIcrobiome Initiative in 2016 under the Obama administration, to fund basic research on the microbiome.
Jo Handelsman: The White House Microbiome Initiative evolved around two basic questions:
1. What is a healthy microbiome? Is a change after a perturbation good or bad? Parallels with changes in water microbes in Gulf of Mexico after Deepwater Horizon oil spill.
Jo Handelsman: 2. How do we change a microbiome? Can we restore a microbiome after a perturbation? Can we change it in a directional and predictable way?
Jo Handelsman: National Microbiome Initiative goals: interdisciplinary research on fundamental questions about diverse microbiomes, different environments, but we all have the same questions. Also, to develop new platforms and tools to probe microbiomes.
Jo Handelsman: Of course, we hoped for practical outcomes to improve the health of humans, animals, agriculture and environmental habitats.
Jo Handelsman: We need to understand how to alter microbiome predictably and reliably, understand robustness, and develop predictive models for microbiome behavior.
Jo Handelsman: Do not only look at human microbiome studies, we need to broaden our view to other fields (plant, animal, environmental) to learn about the principles that govern microbiome composition and robustness.
Next up: Jeff Leach, founder of the Human Food Project. @humanfoodproj with “Re-becoming Human”.
Jeff Leach: I got interested in the microbiome, and asked the question: why is no one working in Africa? We started a project on hunter gatherers. We are going to talk about poop today (shows image of elephant pooping).
Jeff Leach: The Hadza in Tanzania are hunter gatherers. Women gather tubers, men hunt for zebras etc. They are connected to nature in a way no one else is anymore. They live like humans lived for millions of years.
Jeff Leach: The Hadza eat a lot of birds, honey, baobab, berry and tubers. Depending on the season, they might eat honey for days in a row, and fiberfull berries.
Jeff Leach: They might eat 10-15 pounds of meat in a sitting, or 1000s of calories of honey. It can be very monotonous, and not what your nutritionist would recommend.
Jeff Leach: The women dig up tubers all day, every day. They taste like a sweet potato. (shows lots of pictures of Hadza and their food).
Jeff Leach: The vast majority of their calories comes from one type of food, lots of fiber. The kids’ bellies are swollen because of fermentation; they eat >100 gram of fiber (age matched kids in the US eat 10 grams).
Jeff Leach: We wanted to see what the Hadza microbiomes looked like. So we took lots of samples: 14,000 samples from skin and gut, but also of their food/environment. We freeze in the field in liquid nitrogen. Very difficult.
Jeff Leach: I spent many months there, not showering, drinking water from puddles, eating with the Hadza, but I never got sick. I sampled myself before/after these trips.
Jeff Leach: Our original question was to find out how seasonal changes affect the Hadza microbiomes. During wet season, their microbiome diversity drops, because they eat less meat (less contact with animal droppings).
Jeff Leach: Certain bacteria are coming and going, seasonably, but they are missing from western microbiomes.
Jeff Leach: Treponema, Akkermansia, Prevotella are much more common in non-industrialized communities.
Jeff Leach: The Hadza are connected to nature. They kill an animal, take out the colon, squeeze out the poop, and eat it. They don’t wash their hands, and then touch their children.
Jeff Leach: Their skin microbiome changes all the time because they touch and butcher and don’t wash their hands.
Jeff Leach: The average life expectancy of the Hadza is 36 years, mainly because of child mortality, but also of falling out of trees, shooting each other with poison arrows, and infections. But not because of obesity or poor nutrition.
Jeff Leach: The Hadza stand at the microbial highway of Africa. They come into contact with all microbes in their environment. Where do you stand, here in DC? Most of us spend >80% of our lives indoors.
Jeff Leach: Hadza men eat a lot more honey and meat than the women, but their microbiomes largely overlap. Most of their BMIs are around 20.
Jeff Leach showing the many differences between Hadza lifestyle and Western lifestyle.
Jeff Leach: The Hadza have twice the microbial diversity as most of us (except me). Their microbiome bounces back within 48h after antibiotic treatment. Very resistant and resilient microbiomes.
Jeff Leach goes way over time, but seems unstoppable.
Jeff Leach: We need new nutrition and health advice that does not focus on our food input but on our filters – our environment. We need more connections with nature.
Next up: Panel discussion: Pharmaceutical investment in microbiome therapeutics and strategizing ways to overcome the valley of death.
Daniel Couto @VedantaBio – moderator
James Brown @GSK
Dirk Gevers @dirk_gevers @JanssenGlobal
Arpita Maiti @pfizer
Arpita Maiti: At @Pfizer we look at the microbiome in a broad context – the data is not yet robust enough for us to make big investments. But this could quickly change in the next 12 months.
Dirk Gevers: @JanssenGlobal At the Janssen Human Microbiome Institute we invested in lots of research and partnerships – we have a very broad portfolio.
James Brown @gsk It is great to be looking at one particular small molecule but we probably need to focus more on consortia.
Question from the audience: Why aren’t there more physicians at these conferences? Or on panels?
Arpita Maiti @pfizer – we might still be very compartmentalized – the microbiome spans many disciplines.
Dirk Gevers @JanssenGlobal – many physicians are very involved. Scientists and physicians are including the microbiome in increasing number of clinical trials.
James Brown @GSK Most of our work is on clinical populations, not on animals. We need more interventional studies.
David Kyle: Breast milk is an important source of nutrition for babies. 85% of the nutrients in milk go into infant growth, 15% of the nutrients are HMO’s – this is the food for their microbiome.
David Kyle: Bifidobacterium infantis is the sole consumer of these HMOs (Human Milk Oligosaccharides). It converts indigestible HMOs into usable fuels: lactate and acetate. These reduce the fecal pH.
David Kyle: HMO + B. infantis provides pathogen colonization resistance to baby. In those first 100 days, the immune system is educated, so does not work properly. Breastmilk helps protect the baby, it is full of protective factors (IgA etc).
David Kyle: Most babies nowadays have highly variable microbiotas. Disrupted by c-section, antibiotics, formula feeding. How did baby poop look like 100 years ago?
David Kyle: There is a 1913 publication (W.R. Logan, J Path Bacteriol) that described almost pure culture of Gram-positive bacilli – which we believe were Bifidobacteria.
David Kyle: Several studies have described high amounts of Bifidobacteria in Bangladesh, Gambia, etc (80%). Much lower in western countries, and often not B. infantis.
David Kyle: Gut pH of infant stool in 1920s was 5.0. Now the pH is 6.1. Steady increase of pH in stools might be associated with the loss of B. infantis in baby stool.
David Kyle: The vaginal microbiome does not contain B. infantis, but mom’s stool might contain low amounts. This symbiosis is disrupted by formula feeding (no HMOs), C-section, antibiotics (B infantis is very sensitive to that).
David Kyle: IMPRINT trial (Smilowitz, Frese): B. infantis for 21 days in first weeks after birth. These babies got high levels of B. infantis, even after stopping the probiotics.
Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 in Breastfed Infants
David Kyle: Significant different in stool composition (high Bifido, lower Klebsiella / Escherichia/ Clostridium/ Streptococcus) and HMO utilization between infants who did or did not receive the B. infantis.
David Kyle: Escherichia/Klebsiella/Clostridia break down mucin glycans (they eat it). B. infantis EVC001 binds to the mucin glycans, but don’t break it down, protecting the breakdown of the gut barrier.
David Kyle: Control babies (no B. infantis) showed higher inflammatory markers, such as calprotectin (high calprotectin can predict atopy/asthma at later age).
David Kyle: Are we remodeling the gut? Or “unremodeling”? Just restoring it to where it was 100 years ago?
Next up is Maxim Daniel Seferovic @MaximSeferovic, Baylor College of Medicine, with “Our earliest microbial encounters and the developmental origins of disease”.
Maxim Seferovic: What are the long term consequences of early exposures to microbes? Genomic variation and epigenomics only partially explain diversity of human phenotypes.
Maxim Seferovic: Do microbial metagenomes contribute to our phenotypic diversity? Which factors, including maternal factors, determine microbial exposure early in life?
Maxim Seferovic: The vaginal microbiome is different during pregnancy – diversity is temporarily diminished during pregnancy (Pace, revised submission).
Maxim Seferovic: There is a mismatch of microbial taxa between the gut of newborns (first days of life) and vaginal bacteria. Are babies exposed to bacteria before birth?
Maxim Seferovic: The uterus (womb) is not sterile; it is open to the vagina. There might be microbial exposure to the developing fetus. Placenta functions as a conduit for microbial communication between mother and fetus.
Maxim Seferovic: We did in situ hybridization (amplified FISH) labeling of placental tissue. We found bacteria in roughly half of the placentas in cesarean, term, healthy pregnancies. Not in all tissues, though.
Maxim Seferovic: Meconium is different, while mouth/gut/nose of newborns look very similar. At 6 weeks old, microbiomes of newborns are diversified / differentiated.
Maxim Seferovic: We did not find any effect of cesarean delivery on community. See Chu 2017:
Maturation of the infant microbiome community structure and function https://www.nature.com/articles/nm.4272
Maxim Seferovic: Directly after delivery, neonates are seeded with maternal strains. These are gone after 6 weeks.
Maxim Seferovic: We confirmed in animal studies that placental sequences were different than those found in kit reagents. These are not contaminants.
Maxim Seferovic: Animal experiments: maternal high-fat diet alters the offspring gut microbiome from fetal life, onto adult life (in monkeys). Maternal factors (diet, breastfeeding) influence early exposures.
I switched to Track 2 but the talk started too early so I missed half of it 😦
Amir Bein – Human intestine chip colonized with complex gut microbiome for in vitro disease modeling and drug testing
Actually, his talk is already finished. I only saw the last 2 slides. That is too bad – I had hoped to see more of it. 😦
OK, all of us from the other rooms complained, and Amir Bein is kind enough to give his talk again – Yay!
Amir Bein: Challenges in drug development: it costs a lot of money to do studies, and animal studies are difficult and not always good models for human disease.
Amir Bein: We built a microfluidic device with a membrane, that mimics a human lung, with different cells and media on different sides of the membrane. We can use this to study e.g. adherence of certain immune cells, and measure this with a microscope.
Amir Bein: shows videos of cells flowing over the chip, or adhering to it.
Amir Bein: We took this technique further to develop “organ on a chip” modules, such as the “gut on a chip”. Epithelial cells are seeded on a membrane, and fed with liquid flow. These develop vili-like structures.
Amir Bein: Mechanical cues are important. But we can also co-culture with microbes. We see that bacterial exposure increases the barrier functions. They change the morphology as well: higher villi.
Amir Bein: Inflammatory bowel disease model (Kim 2015, PNAS). We can also study protective effect of probiotic therapy. We can grow anaerobic bacterial communities on these chips too.
Amir Bein: We also developed a primary human small intestine chip, with beautiful villi. Transcriptomic analysis: it really resembles the duodenum much better than older models.
Amir Bein: We use this chip to study Environmental enteric dysfunction: stunted growth because of recurrent infections and poor nutrition.
Amir Bein: Doing all these complex studies would be very hard in most in vitro models, but this chip allows to study and measure many variants.
Amir Bein: It takes about 3-4 weeks to grow the complete organ/chip model. Thanks to the amazing team at the @wyssinstitute and the @gatesfoundation.
There are three parallel sessions to choose from but I will be live tweeting the talk by Nur Hasan, CSO of @CosmosID with “Unlocking the microbiome with bias-free, affordable, metagenomic sequencing and best-in-class cloud bioinformatics”
Nur Hasan: The microbiome is broadly implicated with health and disease. Therefore, it is a target for many diagnostic and therapeutic approaches. Interpretation of cause and effect, and understanding pathways all are still not well established.
Nur Hasan: You need to have high resolution strain-level data for better functional insight. A strain is the clinically informative and actionable unit, not a species.
Nur Hasan: Different Lactobacillus casei strains are used for making Wisconsin cheese, chardonnay wine, or yogurt. Same species, very different strains.
Nur Hasan: We offer end-to-end sequencing and analysis services, as well as bioinformatics analysis and visualization, even for people with little bioinformatics background.
Nur Hasan: There are several different next-generation sequencing methods – which method for which purpose?
Amplicon sequencing has served us well, but has limitations. Shotgun sequencing adds to specificity. Need good reference databases.
Nur Hasan: Within shotgun metagenomics, choice of sequencing depth depends on e.g. % host DNA, diversity in your sample, desired information, and purpose.
Nur Hasan: We have done lots of probiotics studies, which are very strain-specific.
Nur Hasan: We have developed large curated strain-level databases @CosmosID , and I invite everyone to try our tools online at app.cosmosid.com
The second talk of this session will be by Johan van Hylckama Vlieg, @vanHylckama, VP of Microbiome & Human Health Innovation, @Chr_Hansen with “The microbiome as a source of next-generation probiotics and therapeutic microbes”
Johan van Hylckama Vlieg: I changed my title to “Microbes Matter – More than Ever”. I work for @Chr_Hansen, a company in Denmark, the largest producer of live bacterial cultures – for over 140 years!
Johan van Hylckama Vlieg: Food cultures and enzymes (mainly dairy cultures), health & nutrition, and therapeutics. We ship trillions of bacteria every day!
Johan van Hylckama Vlieg: Industrial production of bacterial cultures involves huge fermentors! Everything gets big at this scale. We also know a lot about dosage forms and stability e.g. at room temperature.
Johan van Hylckama Vlieg: More than 100y ago, Elie Metchnikoff postulated that supplementation of diet with lactic acid bacteria has health benefits, even if you cannot consume dairy products.
Johan van Hylckama Vlieg: Lactobacillus rhamnosus LGG was isolated from human gut in 1983, used worldwide for more than 20 years. Tested eg. in preterm infants, pregnant women, elderly. Prevents infections in children, and promising results in other fields.
Johan van Hylckama Vlieg: LGG produces pili important for mucus adhesion. However, genomic locus for these pili is absent in some strains – see:
Genome Instability in Lactobacillus rhamnosus GG
Luckily, in our production chain, the pili locus is present throughout. 🙂
Johan van Hylckama Vlieg: Given homology of LGG pili to Vancomycin-Resistant Enterococci (VRE) pili, it might be helpful in eradication of VRE infection. aem.asm.org/cgi/pmidlookup…
Johan van Hylckama Vlieg: The small intestine is a highly attractive target for probiotic interventions – much lower bacterial density.
Johan van Hylckama Vlieg: Much interest for the role of gut barrier function in maintaining health – and many in vitro models to study this. We are currently studying the effect of probiotics on aspirin-induced damage (ulcers).
Johan van Hylckama Vlieg: New probiotics (other than Lactobacillus and Bifidobacterium spp) are being investigated: Clostridium, Eubacterium, Faecalibacterium, Akkermansia, Christensenella spp.
Johan van Hylckama Vlieg: After the hype: more realism and managing expectations.
The Zmora 2019 paper gives an excellent overview on food as a modulator of the human gut microbiome.
Johan van Hylckama Vlieg: Dobzhansky 1973 said: “Nothing in biology makes sense except in the light of evolution”
Let me end by giving you a variant of that statement:
“Nothing in probiotics makes sense except in the light of the microbiome”
Christopher Mason @WeillCornell with “Modern methods for deliniating metagenomic complexity: defining clinical quality genome measurements and editing for the microbiome space”
Christopher Mason: We work on standardization of 16S and metagenomic analysis: Genome in a bottle (GIAB): extensive, public and un-embargoed data.
Ratios of 16S derived taxa vary a lot with primer choice.
Zymo has a good set of standards to monitor extraction.
Christopher Mason: IMMSA-Home – IMMSA http://MicrobialStandards.org
lists many approaches, and our 2017 paper has suggestions for methods to use:
Comprehensive benchmarking and ensemble approaches for metagenomic classifiers
Christopher Mason: How many species do I have? Each metagenomic tool gives a completely different number.
Christopher Mason: We have an ongoing project in our lab to sample the public environment, e.g. the subways of major cities #MetaSUB
Homepage – MetaSUB: http://metasub.org/
Christopher Mason: This way we are building genetic maps of public transportation systems and expanding the number of microbial taxa that are known. Which city has the most mystery taxa? Tokyo has the most novel peptides, Santiago has many novelty as well.
Christopher Mason: We are also mapping the antibiotic resistance gene abundance per city. Highly correlated with use of over-the-counter antibiotic use.
Christopher Mason: What can be learned from a surface? Skin bacterial communities (“microbial fingerprints”) were some of the earliest application. Small molecules on your phones and shoes reveal differences between people.
Christopher Mason: We swabbed phones at JPMorgan, metagenomics sequencing, and used MetaGenScope, a basic pipeline for taxonomy and functional profiles.
Christopher Mason: We mapped DNA from phones to corn, apple, salads, orange, leather purse, often what people ate just before swabbing. But also skin microbes. Engineers had urogenital bacteria on their phones. We can predict who has cats or dogs.
Christopher Mason: Twin astronauts study – Firmicutes/Bacteroidetes ratio switched while in space. Can we sequence in space? Nanopore was tested by Kate Rubins and it worked well.
The next speaker is @KnightsDan with “New methods for affordable and high-resolution shotgun sequencing”
Dan Knights: There is a big need for cheap tools (like 16S) that have a high level of information content (like WGS). We started to develop affordable methods of the whole workflow.
Dan Knights: How can we automate the lab work? How can we do shallower sequencing to save some money? See our publication here:
Evaluating the Information Content of Shallow Shotgun Metagenomics
Dan Knights: With moderate depth shotgun sequencing, you get much better information than 16S. Even with 5000 reads (shotgun) you can almost get the same signal (betadiv ordination plot) as with 50 million reads.
Dan Knights: 10K gives alpha/beta diversity, 500k gives strains, 2M ($99) gives strains at 0.01%, 20-50M ($500) reads allows assembly of new genomes. Big step between these last 2. You can start by 2M reads, then follow up by deep shotgun sequencing on subset.
Dan Knights: Using this approach we sequenced gut microbiome of 34 people over time, correlated that with diet. Most folks have stable gut communities, despite super variable dietary intake.
Dan Knights: In two people who followed a (super stable) soylent diet, there was as much variation in gut microbiome as in regular, variable diets.
Dan Knights: We found that microbiome pairs with food groups (e.g. vegetables, eggs), not with nutrients (kale vs spinach). But every person responds differently to each food group.
I hopped rooms again, for Kiran Krishnan, CSO of Microbiome Labs, with “Intelligent microbiota modulation”
Kiran Krishnan: We can define dysbiosis associated with disease as low amounts of keystone strains. E.g. amounts of Akkermansia, Faecalibacterium, and Bifidobacterium sp. are negatively associated with several health conditions.
Kiran Krishnan: Low amounts of these keystone species: disrupted mucosa, higher immune response, dysfunctional gut barrier, leaky gut.
Kiran Krishnan: Bacillus subtilis HU58 results in higher amounts of butyrate production and less ammonium. Synbiotic increased butyrate production even more.
Kiran Krishnan: We published a paper last year about effect of a probiotic on post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers.
Oral spore-based probiotic supplementation was associated with reduced incidence of post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers
That concludes all the talks of today. There were 3 parallel sessions, so I could not report on all the talks, but I hope you enjoyed my reporting.
Today and tomorrow, the Biotweeps conference is happening!
@Biotweeps is a Twitter account that features a different biologist each week. Last year, they organized the first Biotweeps conference, where 60 scientists were tweeting about their work. You can read their tweets by looking for #BTCon17 on Twitter.
Today and tomorrow, the second installment of this conference is taking place, with – you guessed right! – the hashtag #BTCon18. I could not find how many presenters there were this year, but I was one of the invited “speakers”. Each speaker gave their talk entirely through tweets, and we all were given a time slot, just like at a regular conference. Regular speakers had a 15-min timeslot in which they could tweet 4-5 slides. Invited speakers could tweet as many tweets as they liked in a 30-min timeslot. You can read all the abstracts here.
My talk was about the vaginal microbiome. Here is my abstract:
2100 Invited presenter – Elisabeth Bik (@MicrobiomDigest)- uBiome San Francisco
The vaginal microbiome: Women and their microbial BFFs
The human body is home to complex communities of microbes: the human microbiome. Most of these microbes are bacteria, and most of these live in our gut. But vaginas contain microbes as well. Which microbes “down there” are our friends, and which are the ones that cause bacterial vaginosis, yeast infections, infertility, or cervical cancer? How can we keep vaginas healthy and happy, and what do we need to do in case of a microbial imbalance? If you are interested in science, have a vagina, or love vaginas owned by others, you do not want to miss this #BTCon18 thread.
If you want to read my “talk” (“tweepinar”?), you can start here.
The Verge had a fun article by Rachel Becker on Thursday about funny science stock photos called “Stock photos of scientists reveal that science is mostly about staring –
Sometimes at chickens“.
In case you did not know, I made a whole collection of these on this blog – brought together on this page: Lab Stock Photo Fails.
And it made me realize that it was time for a new installment of this series. Today, let’s focus on some great ways to pipet sideways. Because gravity is so over-rated.
Happy New Year again!
Last week, I asked you all to vote for the best microbiome papers of 2017. And just like the previous year, we have a very clear winner. A paper that had some obvious help from the author’s Facebook friends, who all wrote in to vote 🙂
Full disclosure: I was the handling editor of this paper.
The winner is…. (drumroll)….
Second place was won by:
- Cesarean Section, Formula Feeding, and Infant Antibiotic Exposure: Separate and Combined Impacts on Gut Microbial Changes in Later Infancy – Farzana Yasmin – Frontiers in Pediatrics
And in shared third/fourth place:
- Systematic Characterization and Analysis of the Taxonomic Drivers of Functional Shifts in the Human Microbiome – Ohad Manor – Cell Host & Microbe
- Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut Microbiome – Weston R. Whitaker – Cell
Other nominees were:
I wish you all the best for the new year! Hopefully, 2018 will bring even more great microbiome science papers.
It’s that time again, where we look back on what happened in the past year. Like last year, I thought it would be nice to choose the best microbiome papers of the year. Here is a form where you can fill out your top 3 (#1 being the best, and – optional – your second and third choice). I will post the results on January 1, so you can vote until December 31, midnight, Pacific Time. Below the poll are a ton of ideas for papers that I thought were news-worthy. I probably forgot a lot, so feel free to add your own choice. Happy voting and all the best wishes for the New Year.
Update December 28: I have added Kiran Gurung’s favorite papers, so there are even more to choose from!