Modifying plants for human consumption

– the story of a CRISPR salad

Modifying plants to feed the world

How are we going to feed the 7.45 billion people in the world? Many people including scientists believe that genetically modified plants are one route to food security (1).  However, we as a species and society remain largely afraid of genetically modified organisms, perhaps, because of the seeming “unnaturalness” of it all.

A new technology now allows scientists to modify plants and other organism in a more “nature-identical” way. In fact, plants produced by this method are so indistinguishable(genetically) from naturally occurring varieties that no one an tell the difference. Therefore, the Swedish agricultural board and the United States Department of Agriculture (for mushrooms, fungi not ”technically” plants) have set the precedent by clearing seeds and mushrooms produced by this method for production and consumption.

The method used to produce these is called the CRIPR-Cas9 system (Watch Carl ZImmer’s  video on CRISPR here). It can be used to remove bits of DNA from an organism’s genome in a targeted manner.  Think of it like what the invention of the engine was for transportation. Scientists all over the world are using this metaphorical scissor to snip out pieces of DNA exploring function and consequences, in an effort to understand ourselves, the living world around us, and curing mice of rare mice diseases (a favourite among us lab rats!) (2-5). Why not make varieties of plants that are better suited for human consumption using this method?

Undoubtedly, there are serious and complex socio-economic issues around the use and misuse of plant genetic engineering, but the discussion has often focussed on and suggested that the “science” is not good enough, which in the personal opinion of those of us writing this piece is a problem. We think that this blanket idea of “imprecise science” actually detracts from the actual concerns -mostly social and economic (monopolization, unexpected risks of cultivation of new cultivars, proprietary seeds etc.). How well-founded or rational is our fear of modified crops? What do we know and not know? We thought we would ask the scientist who recently publicly (broadcast on Swedish Public Radio by host Gutaf Klarin) ate a plate of CRISPR generated cabbage and broccoli and has been actively reaching out to people about the use of this technology in agriculture.

Further Reading and References

1. Original Broadcast of the CRISPR dinner from Sverige Radio by Gustaf Klarin (In Swedish, amenable to translation using Google Translate or similar other tools), September 5th, 2016

2. What was on the plate?

References

  1. http://time.com/4521582/2016-election-food/?iid=sr-link1
  2. RNA-guided genome editing in plants using a CRISPR-Cas system. (review)
  3. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy
  4. In vivo gene editing in dystrophic mouse muscle and muscle stem cells.
  5. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy.

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An interview with Stefan Jansson

Q. You may be remembered as the first man to eat a CRISPR modified plant, how do you feel about that?

Well, I would of course prefer to be remembered because of my contributions to science, not just because I made some cooking once upon a time. But these two things are closely connected, if I have´t had the scientific credibility that I actually have, I would just have been regarded a ”mad scientist” doing a stunt and the meal would not have got the same positive attention.

Q. As a plant biologist, do you have concerns about genetically modified crops – for example, what if the gene modified leads to increased requirement for water etc.? What measures are in place to assess this?

As with all plant breeding techniques, one can of course create varieties that are better or worse for the environment. I do like those that are likely to have a positive impact but not those that are likely to have a negative impact, regardless of they are made with techniques that fall under the GMO legislation or not

Q. If CRISPR becomes a patented/proprietary technology it may restrict the adoption to richer countries and not actually benefit or ensure food security. What are your thoughts?

It would of course be better for the world with no restriction of access, but I also realize that we cannot change the patent legislation, and as companies are there to make money, we simply have to live with any restrictions that may come. I do hope that they will not restrict the use of those that need it most, but that is beyond yours and my control.

Q. Within the current norms of GMO versus non GMOs, is insertion of genes from the same plant (not-foreign) allowed?

It is considered a GMO, at least under the EU legislation.

Q. Do seed companies make new varieties using random mutagenesis using chemicals and radiation? Is this permitted?

Many breeders are still busy exploiting the variation created by mutagenesis programs conducted many decades ago, but I assume that also run new mutagenesis programs for some species. These are not considered GMO

Q. Plants have been selected by humans since the time we began agriculture. Would comparison of ancient plant genomes to current plant genomes be a good starting point to identify or make an inventory of desirable changes?

Indeed, and I have understood that some breeders do this

Q. Given that most genes in a plant that make protein are useful in some circumstance or other, how many genes do you think can we knock-off and ensure ‘improvement’?

It is of course only few genes that we can knock out and increase the fitness of the plant, if so evolution would probably have already selected those changes. But all genetic changes that we have made so for during the domestication have probably lead to a reduced fitness of the plant, but made them more useful to us in the agricultural system, so there is indeed a huge room for improvement also with new techniques.

Emulsifiers bring gut bacteria too close for comfort

Feeding mice with artifical emulsifiers impacts their metabolism

Snap-shot of the study

Emulsifiers are used extensively in the food we eat (ice creams, biscuits etc.). This study examines the effect of feeding mice emulsifiers both in their food and drink (5).

Mice fed on emulsifiers (Carboxymethylycellulose CMC and Polysorbate P-80) showed increased appetite. They also showed signs of low-grade inflammation in the gut and increased fat deposition. The authors attribute these effects to changes in the gut microbiota. While the number of microorganisms in the gut was not altered by diet containing emulsifiers, the kinds of microbiota were completely different. The mucus lining was also depleted and the microbes were closer to the cells in the gut, possibly causing the inflammation. While this study has been done on mice, perhaps the quality and quantity of our microbiota and their response to emulsifiers has some bearing for us too.

What did they do?

 

They added widely used  emulsifiers- Carboxymethyl cellulose (E466) and Polysorbate-80 (E433) to the food and drinking water of young mice at equivalent concentrations commonly used in human food.

They measured the abundance and diversity of the gut microbiota, inflammation of the gut (colitis) and also metabolic disorders (fat accumulation, increase in food intake and fasting blood sugar levels) in the emulsifier-fed mice and compared to control mice (no emulsifier in food or drink)

 

What did they find?

These mice (treated) had same number of bacteria (in their gut) compared to mice that were not fed emulsifier (control mice). The types of microbes however was quite different. The microbes were also found closer to the gut that in control mice. The treated mice showed increased appetite, followed by  fat deposition and low grade inflammation of the gut. Interestingly, transplantation of the microorganisms of the gut from emulsifier fed animals into germ-free mice also resulted in increased fat deposition and inflammation of the gut. Suggesting that changes in the microbiota caused by the emulsifiers may be sufficient to cause the metabolic dysfunction and observed inflammation.

Erosion of the protective mucosal layer around gut epithelium in emulsifier-fed mice resulting in reducing the separation between the microbiota and the gut epithelium. Emulsifiers caused a marked change in gut microbiota composition – Higher pro-inflammatory microbiota including the bacterial species that are the leading cause of colitis like Bilophila and Helicobacter. Changed gut microbiota in emulsifier-fed mice increased gut inflammation and colitis. Emulsifier-fed mice also show – dysregulation of blood sugar levels (mild diabetes), increased food consumption correlated with increased adiposity(fat deposition) and weight gain. In older mice (4 months old) the changes persisted for more that 6 weeks even after emulsifiers were stopped. The observed effects of emulsifiers are exclusively due to the change in gut microbiota as the emulsifiers did not show any effect in mice having no gut microbiota (germ free mice). Interestingly such germ free mice become labile to the effects of the emulsifiers if the regular gut microbiome is reintroduced in them.

 

Background to the study

An undisturbed gut flora is emerging as an important factor in health versus disease (1). Multiple different physiological conditions including obesity and type 2 Diabetes are now associated with changes in the gut microflora (2-3). Recent studies have found that artificial sweeteners can cause blood sugar related disorders in humans (4).

 

Take-home and implications

This necessitates a reevaluation of what goes into our food, how it affects our gut microbiota and our health. Standard food safety tests include toxicity and carcinogenicity (ability to cause cancer), however, the importance not perturbing the natural flora of the intestine is becoming clear only now. These findings suggest the following in mice- intake of food/drink containing emulsifiers leads to weight gain and disorders such as diabetes, by directly increasing food intake. These findings need to be verified in humans.The intriguing  realization that dawns on someone after looking at this study is that not just the quantity, but also the quality of the microorganisms in the mouse gut matters. In humans the importance of gut microbial diversity has been documented in other contexts (1-3, video below – courtesy MinuteEarth)

Limitations and Open Questions

Only 2 synthetic emulsifiers have been tested. We feel that this work makes a strong argument for the development of assay systems that monitor microbial health (especially gut microbes) for compounds added to food, medicines etc. Given that the findings have such strong implications, we hope to see in the future a wider spectrum of compounds (including  the more natural products like lecithin) examined similarly by the authors and others.

The authors have only discussed in brief the possible mechanism underlying the change in the microbial population or how these changes result in increased inflammation. This remains a major open question.

Germ free mice already have a really bad situation in their gut, they are somewhat prone to inflammation. It is important to bear this in mind while interpreting the results of the fecal transplantation into germ free mice.

The study is a mouse study, it remains to be extended to humans.

An interview with Dr. Andrew Gewirtz

Q. From your work, it is clear that altered microbiota could lead to weight gain, fat deposition and the loss of the ability to control blood sugar levels, can this be reversed by altering the microbiota?

Our studies in mice indicate it is reversible but it takes some time.

Q. How do you think the emulsifiers are changing the gut microbiota? Can you elaborate on some potential mechanisms?

They seem to promote bacteria breaching the mucus, which promotes inflammation, which changes bacterial populations, possibly by favoring detrimental bacteria.

Q. Are you suggesting that the normal gut flora under different conditions (presence absence of emulsifiers) could turn pro-inflammatory? Are the other missing microbiota (in the presence of emulsifiers) keeping them in check under normal circumstances?

Yes

Q. What according to you are the major caveats of your study?

It is a mouse study.

Q. Did you face challenges in publishing this work, given that it has such strong implications?

Some reviewers suggested a dialog with food industry prior to publication but we argued our tax payer funded research did not require such approval. Nature editors agreed with us.

Q. Do you plan to take this study forward in humans? What would be a suitable cohort for such study?

Yes. Probably start with healthy college students.

Q. Your work clearly has implications for how we decide what to put in our foods.. What Changes would you suggest to the current process by which such compounds are screened, approved and used?

I think major overhaul is needed. Both more tests are needed and more information made readily available to consumers.

Q. Has your study affected your life and food choices?

Yes, my family has cut our consumption of processed foods in general and emulsifiers in particular.

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