We take a look at the trendy world of fermented foods. Are they actually good for you? And if so, why? Plus, the latest genetics news: from bacteria that live inside cancer cells, to gene sequencing the dead sea scrolls...
In this episode
The bacteria in cancer
Ravid Straussman, Weizmann Institute
Back in 2017, Chris Smith spoke with Israeli scientist Ravid Straussman. Looking at pancreatic cancer samples, he'd stumbled on the surprising observation that the majority of the cancerous cells he looked at had bacteria lurking inside them. These microbes appeared to be helping the cancer cells to survive and even defending them from chemotherapy drugs. Knocking out these bacteria might therefore be an additional way to target cancer cells, or at least sensitise them to some anti-cancer drugs. But is it just pancreatic cancer that does this? In a new study from the Weizmann Institute in Israel, published in Science, by widening the search, it looks like the answer is no, as Chris has been finding out...
Ravid - A few years ago, we found almost incidentally that inside human pancreatic cancer - so inside these tumours - one can find bacteria. We're also able to show that these bacteria can protect cancer cells from chemotherapy, we found that these bacteria can inactivate the chemotherapy. So our challenge here was, we wanted to know if this is a more general thing. Can we find bacteria in many different tumour types? So what we did was we took biopsies or tumours from 1500 cancer patients. These included breast cancer, bone cancer, pancreatic cancer, brain cancer, ovarian cancer, lung cancer, skin cancers. And we were surprised to see that in each one of these cancer types, we could find bacteria. We found that in every cancer type there seems to be different bacteria. So you kind of find the same bacteria in different patients, let's say with breast cancer; but the bacteria that are present in patients with breast cancer are very different from the one that you find in lung cancer or other cancer types.
Chris - Do you think these bacteria are viable? It's not just that the tumour cells are being like a giant sieve and the bacteria that naturally go around the bloodstream anyway, they're getting grabbed in a deactivated or dead state and just pulled into these cancer cells, 'cause they're abnormal cells. Are these live, viable bacteria?
Ravid - For sure these bacteria are viable. We were able to grow live bacteria from these tumours.
Chris - What comes first then? Does the tumour develop and then it recruits these bacteria from somewhere, or do you think the bacteria settle in tissue that's destined to become a cancer and the two co-evolve?
Ravid - We don't have good enough data to answer that for all these cancer types. My bet is that both of them can be true. It's been known for many years that some viruses, as well as some bacteria, can contribute to the transformation process - meaning transforming normal cells to cancer cells. But it can be the case, as you mentioned, that you have some tumours; and after you have these tumours, bacteria find refuge in them. So we're not sure yet which comes for us in the process of tumourigenesis.
Chris - It's not just a random process though, is it? Because you're seeing these very similar types of bacteria that crop up time and again in the same sorts of tumours, and they're quite different from other sorts of tumours; which suggests there's some kind of control going on, something is determining whether that's coming from the bacteria selecting their host tumour or the tumour selecting their bacteria they want to give a home to. Something is guiding that process.
Ravid - Absolutely. A nice glimpse that we had into this process is probably coming from lung cancer. We looked at lung tumours from smokers and patients that never smoked before. And when we compared the bacteria inside tumours coming from the lungs of smokers and nonsmokers, we saw some bacteria that are very specific only to the smokers. And then we looked into the genes that are found inside these bacteria. What we found is enrichment of genes that can degrade chemicals that are found in cigarette smoke; for example, nicotine or other chemicals. So what we reason is that patients who smoke have all these smoke-related chemicals in their lungs. And bacteria that can chew up on these chemicals are probably being selected to live in these types of tumours.
Chris - What are the implications of this finding then? Do you think that this offers us an avenue to management or therapy? Because is it possible to do something to the bacteria and exploit their presence there to destroy the cancer?
Ravid - I think this is the most exciting thing. The fact that you have bacteria in tumours probably implies that they have a lot of crosstalk with the tumour cells, with the immune cells, and they're probably affecting much of the tumor biology that we see. A good example for it is we found, for example, that tumours of the skin... we looked at patients that responded or did not respond to immunotherapy. And we found that there are specific bacteria that are more prevalent in the responders or the non-responders, suggesting that maybe the bacteria also affect the response of these patients to immunotherapy. And if we learn more about how to modulate the bacteria in the tumours we might find completely novel ways to treat cancer patients.
05:49 - Coronavirus: 7 of 27 PCR tests contain mismatches
Coronavirus: 7 of 27 PCR tests contain mismatches
Kashif Aziz Khan, York University
Since the start of the pandemic, whenever someone has been tested for coronavirus, it’s almost always been using something called a PCR. This machine looks for the genetic code of the virus itself, and compares it against a ‘gene sequence’ it uses as a template so that it can say, “yes, this is genuine SARS-CoV-2 right here”. But a recent analysis found that a number of those templates that are being widely used actually no longer match versions of the coronavirus. That is - its genes have mutated in tiny ways, and so some of the tests might be missing it - what are called ‘false negatives’. Phil Sansom heard from study author Kashif Aziz Khan…
Kashif - 7 tests out of 27 we studied have mismatches with the virus genome. Not necessarily that they are wrong because not every mismatch would lead to false negative, but they is a possibility. And especially certain tests were developed earlier in the outbreak when only few sequences are available. While in our study, we use 17,000 sequences. So there is room for improvement of the test.
Phil - That seems like a pretty big problem, no? How many cases of coronavirus do you think might have been missed thanks to this?
Kashif - It's difficult to like really give a number to these mismatches compared to other factors, but there are estimates of up to 30% false negatives. We cannot put all the false negatives due to mismatches. One of the major factors is timing off sampling, but I believe part of that might be due to these mismatches.
Phil - And these are tests that are looking for the viruses, what genetic code?
Kashif - Yeah. So these are called PCR. In PCR, DNA is amplified. In the case of coronavirus it's RNA, so we convert RNA to DNA, and then DNA is amplified using PCR.
Phil - So you're saying that those PCR tests, they're looking for little bits of the viruses genetic code, its RNA. And actually the virus now looks completely different.
Kashif - I would not say that all these tests are not detecting the virus at all or virus is completely different now, but there are small changes. These small mutations, we should not really worry because not all these mutations are bad. So these are small changes. It has not developed into a separate strain.
Phil - Why are there 27 different tests though?
Kashif - Earlier in the outbreak, different national organisations around the world developed certain tests. In addition to these 27 that I found in the literature, there are many other being developed by different commercial manufacturers.
Phil - These 7 out of the 27 that you found the mismatches in, where are they getting used right now?
Kashif - Actually, most of these are used around the world. Like one of the tests, which is widely used, it has one mismatch. So we need to improve it. That's what we have suggested. And in addition, many different countries are using commercial tests. And for those, I could not include those in my study because the information for those tests is not available.
Phil - And does that apply to tests that aren't these PCR tests as well? Cause I know people are definitely interested in looking for something that's quicker or something that's cheaper or whatever.
Kashif - So that would apply to any molecular test, even if it's not a PCR. If the test is targeting the exact region, we can go check how much that region is variable. That was the objective of this study to put this information there. And we have a pipeline which is easy to use, anybody can use on a regular computer because we use all open source free software.
Phil - And that that's the message that you're trying to get out. You're saying, come to me, check that you're looking for the right bit of the virus.
Kashif - Yeah.
10:09 - Dead sea scrolls: DNA reveals biblical secrets
Dead sea scrolls: DNA reveals biblical secrets
Noam Mizrahi & Oded Rechavi, Tel Aviv University
The dead sea scrolls are a famous historical treasure - a trove of ancient manuscripts that include the earliest copies of parts of the Hebrew Bible. They’re so old that it’s been difficult for biblical scholars to actually piece them back together. But an unlikely collaboration between at Tel Aviv University has uncovered a clue that would make Sherlock Holmes proud: ancient DNA inside the manuscripts, from the animals whose skin they’re written on. Phil Sansom heard from the duo responsible, Oded Rechavi and Noam Mizrahi…
Noam - My name is Noam Mizrahi, and I've been studying biblical literature and the dead sea scrolls for some 20 years now.
Phil - What are these dead sea scrolls?
Noam - The dead sea scrolls is the remains of ancient manuscripts that were found along the shore of the dead sea. These texts come from the last centuries BC and the first century AD, and they represent the library of religious and literary texts of ancient Jewish society. Most of them have, unfortunately, disintegrated into thousands of fragments of various sizes, 25,000 fragments. And even though a lot of progress has been made, thousands of fragments are either not located at all, or we don't know where to place them exactly.
Phil - And then how did you get involved with your now colleague?
Noam - My coauthor, Oded, and I met on actually a retreat that the university had organised for new recruits and we found ourselves sitting next to each other in the bus.
Oded - Hi, I'm Oded Rechavi, and I'm a molecular biologist.
Phil - You were trying to get ancient DNA out of these bits of manuscript. How do you actually do that?
Oded - We can't really mess with these precious samples. We can't even touch the parchments, the people from the Israel, antiquities authorities do it for us, and we have to first make sure that we're not damaging the priceless samples. So the huge challenge here was to extract DNA out of tiny amounts.
Phil - How tiny amounts?
Oded - First of all, for many fragments that we would like to sample, we couldn't get a sample because they're too fragile to even sample. For other samples that were less fragile, the conservators just cut off very, very tiny amounts. And in other cases, they just let us have dust that fell off or scraped scroll dust off the fragments, and this is what we sequenced.
Phil - And I imagine the DNA in them, being a couple thousand years old, is in pretty rotten condition, right?
Oded - Right. First of all, to know that you are looking at ancient DNA, you have to look for ancient DNA patterns. Ancient DNA degrades in a predictable way. We look for these patterns in the DNA, indeed we found them, but it's important to understand that we only get a very partial coverage of the genome. Not like when you send the sample to a 23 and me here, you only get a fraction.
Phil - What did you find in there?
Oded - Unsurprisingly, perhaps without many contaminations, in addition to the authentic animal DNA. So microbes, but also human contaminations. This could be from the humans that handled the scrolls 2000 years ago or from the humans that handled them in modern times since their discovery in the last 70 years. We think that most of the contaminations come from the modern humans because they don't show these degradation patterns that characterise ancient DNA. But there are tons of human DNA in there that we had to get rid of computationally.
Phil - Is this like a needle in a haystack to find out what the parchments are actually made of?
Oded - It's not that bad, depending what your question is. Species identification was a problem that we could attack from multiple different angles because it wasn't clear which animals were used to make the scrolls. So we try to align the DNA that we sequenced to many animals and found that in the case of the scrolls, most of them are made from sheep. A small fraction are made from cow. We also identified the specific species of sheep and cow. In one case, we found that the few pieces that were thought to be part of the same scroll are actually made out of different animals.
Phil - Noam, were you surprised by any of the stuff that came out of the DNA?
Noam - I was very surprised by some of the results. For example, we looked into several fragments that were thought originally to belong to the same scroll, which was evidently a copy of the biblical book of Jeremiah. Nowadays, the book of Jeremiah looks the same, whether you open an edition of Jeremiah in London or in Tel Aviv or in Sydney. But in the Qumran scrolls, what we really find are widely divergent editions next to each other. We discovered that some of these fragments of Jeremiah are made from cow hides. Cows cannot be grown in the desert. It seems likely that these fragments come from scrolls that were prepared and written elsewhere. So we can now show for certain, for the first time, divergent texts of a prophetic book.
17:03 - Kefir, explained
Paul Cotter, APC Microbiome Ireland
Kefir is a fermented milk drink that, over the past few years, has started to appear in UK supermarkets. But in reality it's an ancient beverage, full of live bacteria that have a range of health claims attached. Which of these are true and which are hot air? Phil Sansom heard from Paul Cotter of APC Microbiome Ireland...
Paul - Kefir is a fermented milk and it's made by virtue of adding a kefir grain into normal milk. It carries out the fermentation process; some of the good bugs that are in the grain enter into the milk and start living there and growing and producing things; and then the following morning, you remove your kefir grain from your milk, you use a sieve or some other sort of approach; and you place the grain into fresh milk and begin the process all over again.
Phil - Okay. What actually is kefir?
Paul - It's a consortium, or a group, or a gathering of lots of different microbes; thousands of different microbes all together in a cluster. And it has an appearance, it's quite like a small cauliflower, and it has kind of a slightly slimy texture. The bacteria... certain bacteria within the mix produce a polysaccharide called keferin - kind of a complex sugar - to keep all of the different bacteria and yeast together in a clump.
Phil - And is this, you said it was a grain, is it something that comes from a plant?
Paul - No, so the term grain is a misnomer, so it's not a... it doesn't accurately reflect where it comes from. It originally was developed primarily in Eastern Europe; there's some evidence of some kefir being produced in the Middle East as well. The thinking was that farmers stored some milk in pouches, and those pouches would have come from calf stomachs or goat stomachs, but by virtue of the different microbes that were present in those calf stomachs and the different nutrients that are in the milk, they formed spontaneously there. And then over time, individual kefir grains were passed through families because what happens is every time you ferment a milk, the grain gets a little bit larger, eventually to the point where it kind of breaks in two. And within families or among particular communities, people would keep one grain themselves and then pass the others onto their friends or their siblings or their kids. And that would pass on through the generations over and over.
Phil - Where does it come from today? Are there people making new ones?
Paul - For the most part, people are using grains that they've inherited or gotten from other people. We've studied kefir from lots of different locations around the world and we've gotten them through Ebay or Facebook requests. So the sharing of them has become even easier now. But because they've become so popular, there are slightly different versions of kefir grains that are available right throughout the world. And in a way Western society's just rediscovering them, but they've been there in the background the whole time. And in fact, there's a suggestion that maybe the insufficient consumption of fermented foods for quite some time now has perhaps contributed to some of the problems associated with the gut in Western society and increased levels of allergy and so on and so forth.
Phil- If so, what gap do they fill? What do the kefir grains do when you put them into milk?
Paul - I suppose from a big picture perspective, in Western society, the argument was that we weren't exposed or consuming enough healthy microbes, and just not having enough microbes in our lives in general. So as a consequence of higher levels of hygiene and overuse of antibiotics and whatnot, then our body is just not so used to dealing with microorganisms. And when it comes across harmful microorganisms, sometimes our immune system overreacts. And that's why you have lots of increases in things like inflammatory bowel diseases and allergies and so on and so forth. Coming back to the kefir in particular: what happens there is the various different microbes in the grain enter into the milk, and a subset of them really like the milk and they grow well there. So they can remove lactose, which means that lactose intolerant people can consume it. And then also by interacting or being in close proximity with the gut, they can also produce compounds and trigger different reactions. So they will be sensed by the immune system. And in some cases dampen down the immune system, where you have a case where somebody is susceptible to having a high level of inflammation. Some of the other molecules that they produce can be neurotransmitters - compounds that we normally associate with being in our brain and sending signals there, and telling us whether we should feel good or bad; but we also have lots of neurotransmitters in our gut. And so we can impact on their levels of, we think at least, that we're impacting on our levels of anxiety and stress and so on by virtue of consuming these as well. And then there's lots of other evidence to suggest that the microbes can remove cholesterol, remove cholesterol from food products. There's a multitude of other different things that fermented food microbes can do.
Phil - Good Lord. It sounds like a real cocktail of different effects. How can I be sure this isn't, whatever 'Big Wellness', just trying to promote a new product and it's really just fancy yoghurt?
Paul - Yes. That is a concern of mine in that I agree that Western society has almost gone the other extreme now, and that is overselling fermented foods. And we are one of those who are trying to insist on the requirement that good, standard science and human tests and trials are carried out in order to definitively stand over what an individual fermented foods can do.
23:13 - Fermented foods: a genetic survey
Fermented foods: a genetic survey
John Leech, APC Microbiome Ireland
The science of fermented foods like kefir isn’t quite settled. Which bacteria are in different fermented foods and drinks? And what do each of these bacteria do? The questions start to multiply. John Leech from APC Microbiome Ireland has been taken a genetic approach into expanding this search - as he told Phil Sansom…
John - Well, we've been exploring a variety of fermented foods. The first project looked at roughly 58 fermented foods from mostly Western Europe or from some other countries too. There's a huge variety of fermented foods, including beer, but we're focused mostly on the ones that will contain live microorganisms at the point of consumption. Foods like milk kefir, sauerkraut, kimchi.
Phil - Does this overlap with what you might buy in a store labeled probiotics?
John - It does a bit, yeah. This is - so a probiotic by the scientific definition is any microorganism when consumed in adequate amounts, confers a health benefit. It's widely believed that fermented foods are a good source of probiotics. Now that's something that we're hoping to explore and to investigate and to find maybe more probiotics in fermented foods.
Phil - Okay. What have you been finding?
John - So we looked at genes in these foods that could potentially give some health benefit to the consumer after eating the food. And it was quite promising across the 58 foods. We compared them to non-fermented foods and these foods had much more of these potentially health promoting genes.
Phil - How can you actually tell whether a gene gives a benefit?
John - We scanned the previous studies on probiotic bacteria - bacteria that have been shown to provide a health benefit. In a scientific sense we have a couple of criteria that will help us class a microorganism as a probiotic. And one of the first things that a bacteria or yeast needs to do in order to be considered probiotic is it needs to survive traveling through your stomach, which is quite a low pH, very acidic environment that will kill most things. Can this microorganisms survive all that? So we look for genes that will allow the microorganism to pass through this hostile environment and actually get to your big intestine. Other genes then will be genes that will allow the microorganisms to actually colonise your gut. So these will be genes that would allow the bacteria possibly to stick to your intestinal walls. And then there are other genes we found in some experiments, genes that allow that particular microorganism to influence the host immune system. This microbiome is extremely important in terms of extracting nutrients from your food. And it's also associated with all sorts of different health conditions, particularly chronic health.
Phil - And the more, the better?
John - We think so, it's early days. I mean, a lot of disease states are associated with lower diversity in your gastrointestinal tract. In general having lots of different species down there seems to be good.
Phil - Okay. What did you find? If you had to design me a menu of the best possible foods, what would it be?
John - Foods that were fermented with a high concentration of sugar. These would be foods like kombucha and water kefir and beet kvass. These foods actually showed the highest potential. And that was surprising to us because generally kefir and other dairy foods, they have a ton of research done on them, and they've shown quite good potential so far. But in our investigations, it was actually sugar foods, which they have a very different type of bacteria in them than dairy foods do. So we were a bit surprised by that, but it leads to an awful lot of interesting research down the line.
Phil - You mentioned one there that I didn't, I've never even heard of. What's that beet thing?
John - Beet kvass is a salty drink. In the case of beet kvass it's made out of beetroot juice with a lot of salt added to it. It's not great tasting, to be honest with you. Personally, I'd eat a lot of sauerkraut and kimchi too. I think variety and diversity is probably the key here, but we'd have to actually see if this potential can be translated into actual results. But from our early explorations of the potential, then yeah things like kombucha and water kefir seem to be, have the most potential so far,
Phil - What's this stuff actually going to do for me?
John - Absolutely no idea yet. There has been quite a few studies into kefir and a couple of human studies on kefir, and that can help with things like cholesterol and hypertension. But by and large, most of these fermented foods don't have human trials. Studying fermented foods is very complicated, like one kefir could be very different to another kefir in terms of its composition. So we don't really know yet is the answer.
Phil - If you've got me drinking all this kombucha, water kefir, I gotta be honest: I feel a bit Gwyneth Paltrow right now.
John - Yeah. This is what we're trying to resolve. And this is why we don't make any strong claims about it because there's an awful lot of things on the internet about kombucha and kefir. You'll often see particularly, with kombucha online, claims about it curing cancer and curing arthritis and curing all of these things and kind of information like that can be dangerous. We're trying to see how much truth is behind this. Now our studies are very early days. We're not investigating each food in such depth, but we're trying to catch up and do all these experiments to validate a lot of these health claims. However I know in the Westernised industrial world, we live in quite a sterile environment. We sterilise our foods either through adding preservatives or by cooking it. So we are exposed to an awful lot less bacteria and yeast in our environment. So there are considerations at the moment, just like you'd be given a daily recommended allowance of certain macro and micronutrients. We are trying to push for a daily allowance of bacteria and fermented foods. Obviously you're going to be a great way, and in a lot of cases, a tasty way to fulfil this kind of recommended daily allowance of microorganisms a day.
Phil - It's a lot better than licking the ground every day.
John - Well, it depends on where you live, I guess!