Lutter contre la propagation de la tuberculose
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CORDIScovery podcast- Episode #17 - Fighting the spread of TB
This is an AI transcription.
00:00:00:00 - 00:00:16:03
Abigail Acton
This is CORDIScovery.
00:00:16:05 - 00:00:41:05
Abigail Acton
Hello and welcome to this episode of CORDIScovery With me, Abigail Acton. 9,900,000 people fell ill with TB in 2020, according to the World Health Organization, and a million and a half died. Global efforts to combat the disease have saved an estimated 66 million lives since 2000. But the COVID 19 pandemic hit the fight against TB hard. For the first time in over a decade, TB deaths increased in 2020.
00:00:41:07 - 00:01:06:01
Abigail Acton
The work being done by today's three guests, supported by the EU's Horizon 2020 program, is more vital than ever. Welcome to Hossam Haick, a dean at the Israel Institute of Technology. The Technion. Hossam leads activities, developing noninvasive smart sensors and wearable devices to enable the early detection of diseases such as TB and lifelong monitoring of health disorders. Hello, Hossam.
00:01:06:03 - 00:01:07:05
Hossam Haick
Hello, Abigail.
00:01:07:07 - 00:01:21:21
Abigail Acton
Teresa Cortes is based at the Institute of Biomedicine at Valencia, part of the Spanish National Research Council. She is interested in understanding how the bacteria that causes tuberculosis and humans, in fact, survive cause disease and develop antibiotic resistance. Hi, Teresa.
00:01:22:02 - 00:01:24:03
Teresa Cortes
Hello. Hello, everyone.
00:01:24:05 - 00:01:43:07
Abigail Acton
Iñaki Comas is part of the Tuberculosis Genomics Institute at the Institute of Biomedicine in Valencia in Spain as well. He unravels the intricacies of pathogen genomics to understand the evolution and epidemiology of infectious diseases. His lab is particularly focused on tuberculosis, but also works on other diseases like COVID 19. Hi Iñaki.
00:01:43:09 - 00:01:44:20
Iñaki Comas
Hello, everyone.
00:01:44:22 - 00:02:01:08
Abigail Acton
I'll start with Hossam, if I may. Hossam, your project, A-patch supported by the EU and the Gates Foundation, is demonstrating a novel means of diagnosing tuberculosis using a stick on patch. Can you tell us what the problems are currently with the way that we diagnose tuberculosis?
00:02:01:10 - 00:02:28:16
Hossam Haick
In order to understand the main issue with the tuberculosis. We have to understand that the early symptoms of the disease are not specific, and this is by itself complicates the diagnosis. And therefore most of the existing bio diagnostic tests are usually slow, have low sensitivity and specificity and or if you like, accuracy and many times are too expensive or complex for resource limited settings.
00:02:28:18 - 00:02:56:01
Hossam Haick
For example, if we take a look on the sputum culture, which costs around 2 to €8 per test and that depends on the country. This technique is insensitive and takes around 4 to 8 weeks and at least three visits by the patient to finalize the diagnosis before it starts the treatment per say. The only technology which can provide us a diagnosis within 2 hours is called Genexpert.
00:02:56:03 - 00:03:29:16
Hossam Haick
But nevertheless it has relatively limited accuracy or sensitivity. It's around 88% in some cases. In other cases it's 67%. And in addition, this technology has a complicated ways in order to collect the sample and also requires some installation and complicated infrastructure. And therefore, in many times it's not accessible to a settings that has limitations in terms of resources.
00:03:29:18 - 00:03:47:20
Hossam Haick
We have also many other technologies which used for diagnosis of TB, but nevertheless most of them are complicated and have advantages in terms of the way they are collecting sputum or process. The body fluids are in many times they have some risks in terms of the biosafety.
00:03:47:22 - 00:04:03:24
Abigail Acton
Okay, I see. So they're either slow or else not as accurate as needed in order to pinpoint a potential outbreak. Exactly right. And so can you then tell us a little bit more about A-patch? So the how does A-patch differ from these methods that you've just been describing?
00:04:03:24 - 00:04:38:02
Hossam Haick
The A-patch concept actually promotes the uptake of personalized tuberculosis, 3 hours and diagnosis for use in clinics and community, and that includes also areas where we have no mobile or internet connectivity. The approach itself relies on a low cost wearable sensor space that can be attached to the arm or to the chest to analyze some array of chemical compounds that are associated with the tuberculosis and that exist in the guest space above the skin itself.
00:04:38:04 - 00:05:04:13
Hossam Haick
The patch itself costs around €1 per patch. It's fast, simple and really easy to use. There is no need for a special training in order to use this patch. And the nice thing about this technology that it can be activated by the smartphone throughout the future, which call it RFID, which found in every smartphone today and need no battery, which is also important for green technology as well.
00:05:04:15 - 00:05:20:14
Abigail Acton
Okay. The benefit from what you're describing, and especially as you've mentioned, the fact that it's it's cheap. I mean, for what it is, it's very cheap. It sounds like obviously then the benefit is that it can be used in environments where people are living on $1 a day and that maybe there's no real infrastructure for them. But then you also mentioned smartphones.
00:05:20:14 - 00:05:25:06
Abigail Acton
So I'm wondering, all those communities carrying smartphones.
00:05:25:08 - 00:05:47:15
Hossam Haick
Yes, it seems very weird. But according to the recent statistics, more than 77% of the people in the developing countries have mobile phones or smartphones. And of course, when I talk about RFID technology, which read the data from our patch, even regular mobile, which is not a smartphone, one can work as well.
00:05:47:20 - 00:06:01:15
Abigail Acton
Okay, fantastic. So it's accessible to communities who are in the middle of nowhere and living on very, very little. How how does the data then get back to the health care professional concerns? Supposing the health care professional can't make it across to that particular village or whatever?
00:06:01:17 - 00:06:19:06
Hossam Haick
These smartphones, of course, are connected with the mobile network and throughout the mobile network, we can provide all of the data directly to the cloud or big data resource from where they a resource can be accessed to the health care systems or for the clinicians.
00:06:19:08 - 00:06:29:00
Abigail Acton
Okay, great. And of course, that must be happening almost in real time. How long does it take for the patch to recognize the volatile chemicals and for the health care professional to know that there might be an outbreak or an issue?
00:06:29:02 - 00:06:59:15
Hossam Haick
As I have said, that the patch will need only 1 to 2 minutes. Are that to give us the result whether the patient has TB or is healthy. And of course the nice thing about the paths that it's a hardware that we can train it by machine learning or by artificial intelligence. So if we have other pandemics or other types of disease, we can remotely threaten the device by feeding the new algorithm into the device so we can train it in different ways.
00:06:59:18 - 00:07:11:10
Hossam Haick
You just need to think about it in the in as a smartphone device where we have the app where every time we use the device, which is the smartphone in different way according to the app, which is different algorithm now.
00:07:11:13 - 00:07:25:09
Abigail Acton
It's absolutely brilliant. It sounds wonderful. I'm not surprised the Gates Foundation have embraced it as well. It does sound like a tool that the clinicians have been waiting for, but it must have been incredibly challenging to develop. Can you tell us a little bit more about how you actually develop this? How long is it taken.
00:07:25:11 - 00:07:55:12
Hossam Haick
Of course, to develop this approach? We have, first of all, to prove the science behind it, namely that there is a profile of unique chemical compounds that are emitted because of the TB or as a result of the TB into the headspace of the skin. And for this space we were supported by the Bill and Melinda Gates Foundation to carry in-depth analysis for thousands of real skin samples of TB and health subjects in a wide variety of hospitals worldwide.
00:07:55:14 - 00:08:21:22
Hossam Haick
And the results have shown that indeed, the TB has unique molecular fingerprint of volatile organic compounds that appear in the skin, and that can be distinguished from other types of disease. Nevertheless, this discovery has been achieved by a lab instrument, which we call it mass spectrometry, which is really very big, heavy instrument, expensive and also slow. It takes sometimes two or 3 hours in order to obtain one result.
00:08:21:24 - 00:08:49:12
Hossam Haick
And therefore, to translate this results from the basic science to the point of care reality. The EU has supported our efforts throughout the Horizon 2020 A-Patch program, where we have developed and characterized these smart patches that can capture and detect the profiles of the chemicals of the TB from the skin and really affordable way cheap manner. It's around €1 per patch and very fast way.
00:08:49:13 - 00:09:09:24
Hossam Haick
And this pasture actually has been achieved throughout the development of an array of ultra thin sensors and artificial intelligence in a way that imitate the way our skin works. Of course, this journey was not simple as it might sounds.
00:09:09:24 - 00:09:14:15
Abigail Acton
It doesn't sound simple at all. It sounds very, very stimulating and exciting.
00:09:14:17 - 00:09:50:02
Hossam Haick
We have to develop all the parts of the technology from A to Z, from the material design called the device architecture, and to the development of, you know, the way how we outreach the information itself. And of course we have many challenges appropriate this ability replicability issues and the most important which way we have to use in order really to make this technology affordable and accessible to every person, disregarding of where he or she lives and how many fund they do have.
00:09:50:04 - 00:09:51:03
Abigail Acton
Brilliant.
00:09:51:05 - 00:09:58:22
Hossam Haick
Of course, of overcoming all of these challenges. We do have this technology right now in reality, and we have started to use it.
00:09:58:24 - 00:10:07:19
Abigail Acton
Okay. That was going to be my question. Actually, I was about to ask you, I mean, where are you up to with regards to clinical validation? Is it already being used in the field? How's that going?
00:10:07:21 - 00:10:38:01
Hossam Haick
This batch is actually has been validated in three independent studies on right now on 1000 subjects in India, South Africa and also Latvia. And we are still working on further examinations. The results so far has shown based on double blind analysis that we can distinguish active tuberculosis from healthy controls with over 90% sensitivity and over 80% specificity also.
00:10:38:01 - 00:11:06:09
Hossam Haick
And the nice thing about it that the patches have shown excellent discrimination between the so-called latent tuberculosis and activity clauses with over 90% accuracy, which is very important as well. And this promising results actually today has been used as a launchpad for other infectious diseases such as malaria, hepatitis C and also non-communicable diseases such as diabetes and metabolic syndrome.
00:11:06:09 - 00:11:11:14
Hossam Haick
All of these are already being validated and examined in our research group. In the technical.
00:11:11:16 - 00:11:15:18
Abigail Acton
You must be very proud of your work and the work of your team. How do you feel about the work that you've done?
00:11:15:20 - 00:11:44:23
Hossam Haick
I'm very proud about my team. They are the real people who is doing the real job, very hard job, which includes also basic science, translational science and engineering in one lab and the nice thing about it and really what makes me happy, that it's really very multidisciplinary research and development and every team member speaks many scientific languages to communicate this multidisciplinary project with each other.
00:11:45:03 - 00:11:52:10
Abigail Acton
Now that sounds brilliant. What about the other guests here today? Iñaki ? Teresa? Do you have any questions that you'd like to put to Hossam? Yes, Teresa.
00:11:52:10 - 00:12:17:04
Teresa Cortes
So Hossam I think it's a very interesting work and it's amazing that we can have just two parts from this game that can help us to identify who was active today and later, tuberculosis. I was just wondering, what about truck sensitivity and drug side of the bacteria? Can your parts in Farah, if you are dealing with drug resistant bacteria or can sensitivity bacteria can for treatment?
00:12:17:06 - 00:12:47:22
Hossam Haick
Of course, we have started to tailor our device in order to make follow up of the treatment process for two ways. But first of all, because of the multi-resistant and bacteria, this is one side. And on the other side we have started to train our system and to examine it. In Latvia today in order to follow up the treatment process with the hope that we can personalize the treatment according to the right treatment and also the timeline that is needed for the treatment.
00:12:48:03 - 00:13:04:17
Hossam Haick
For example, today there is very well defined period for the treatment and we hope sometimes we might shorten or elongate that period. But for that we need something to follow up the treatment in real time, every hour or every day or every week, not every few months as well.
00:13:04:19 - 00:13:15:13
Abigail Acton
Because of course, each individual I'm sure, would be responding to the treatment slightly differently. We're not one size fits all. So this way you'd actually be able to see where how far the treatment has actually progressed in controlling the bacteria.
00:13:15:15 - 00:13:35:23
Hossam Haick
Exactly. And this is what I mentioned with personalized TB treatment. So we will personalize it. Namely, we will have the patch on the skin of the person and that will be the baseline. And then we will start the process of the follow up based on that baseline. And from that we can just tailor the treatment accordingly.
00:13:36:00 - 00:13:42:11
Abigail Acton
Excellent, wonderful. And also saves a lot of drugs being used unnecessarily and so on. Inaki, would you have a question? Yes, please.
00:13:42:12 - 00:14:12:19
Iñaki Comas
Just so very nice question. I just have a question because now we know that latent tuberculosis is not anymore the definition of one single scene, but is really on a spectrum of a states. No. So it's people that we saw before, they where they have a latent individuals. Also, they may be very different in physical status. And and this includes these what is called incipient crosses to clinical tuberculosis when people that has been able to clear tuberculosis know.
00:14:12:21 - 00:14:27:00
Iñaki Comas
So you had something that probably your patch can distinguish a latent enough to do a cross and do you have any plan to try to adapt it to these different stages? So because this becoming a really important topic in the.
00:14:27:01 - 00:14:35:14
Hossam Haick
Process, actually we haven't thought about it, but glad you raised this comment and will be glad to find a way to collaborate with you guys.
00:14:35:16 - 00:14:36:12
Iñaki Comas
Perfect.
00:14:36:14 - 00:14:57:01
Abigail Acton
Yes. I should put you all in contact with each other at the end of this now. Thank you very much indeed. Details. And that was fascinating. I'm going to move over to Teresa now. Teresa of the MtbTransReg Project focused on understanding how TB adapts to stress and drug resistance at the molecular and cellular level. So what was the characteristic of TB infection that most interested you do?
00:14:57:03 - 00:15:24:03
Teresa Cortes
To me, the most interesting aspect of TB infection is, as we were just talking about, the spectrum of TB disease, we know that some cases develop active disease, but most of the cases go into developing an asymptomatic infection that we just talked about it. That is not just a single stay. This obliterates different status. And we know here the vector and remain dormant for decades in the host.
00:15:24:05 - 00:15:48:13
Teresa Cortes
And if we take into account that the current estimates are that a quarter of the global population is late infected, that represents over 2 billion people. So these people have the potential to reactivate, to resist and become infectious during their lifetime. So we have a huge reservoir of potential reactivation of the disease and you can start to realize of the magnitude of the problem we face with latent.
00:15:48:15 - 00:16:18:22
Teresa Cortes
It is. So for me, it's important to understand that during this process of infection, the bacteria must adapt to a diverse variety of environments on soil. Today, we don't know the molecular mechanisms that the bacteria uses to switch, for example, between active replication and latent or dormant inside the host. And in this respect, our previous research has shown that regulatory control at the level of protein synthesis may be important for this process.
00:16:19:02 - 00:16:27:13
Abigail Acton
Now, can I break you down slightly? Regulatory control at the level of protein synthesis? Could you could you break that down for me a little bit? What are what are the what is the bacteria actually doing with the protein that changes?
00:16:27:15 - 00:16:58:02
Teresa Cortes
Well, I mean, protein synthesis, at such is a very important process that all cells make proteins. It's very concerned among proteins. But we have started to realize that a that a process that we have thought that it was very conserved and we thought it was very well known has different levels where it can be regulated that the virus now and that can alter how the bacteria is making the protein, if that makes sense.
00:16:58:04 - 00:17:15:06
Abigail Acton
Now, that does, That does. Thank you. That's a good explanation. Okay. So tell us more about the production of the protein in the cells and why it matters. I know it's a technical concept and it might be quite difficult to break it down, but you've done really well so far. So tell us a little bit more about why is the way that the protein is produced and used you important?
00:17:15:08 - 00:17:44:20
Teresa Cortes
So as I say, I mean, protein production is it's a requirement for all cells for by viral replication and involves many cellular components with about half of the energy expenditure of growing cells being used to wash protein synthesis. And protein synthesis is basically the way that messenger RNA or genes are read by the ribosome, which is the machinery that makes protein production possible in order to synthesize proteins.
00:17:44:20 - 00:18:15:04
Teresa Cortes
And in bacteria, genes carry canonical signals that are known as the sequences. And those signals tell the ribosome where to start producing proteins from those genes. And they are like a genetic signposts if you want that an organism DNA harbors in order to tell a ribosome where to start making proteins. And this kind of sequences are found in genomes from many types of bacteria.
00:18:15:06 - 00:18:25:22
Teresa Cortes
However, in the TB bacterium, approximately half of the genes in the genome engage with ribosomes without using these conditional signposts.
00:18:25:22 - 00:18:29:03
Abigail Acton
And is that something that's relatively recently, recently been understood?
00:18:29:08 - 00:18:58:06
Teresa Cortes
Well, it's true that there are many bacteria and, for example, many archaea that do not rely on those canonical signals to start translation. And that's something we have just started to to realize. Thanks to the use of whole or next generation sequencing techniques where we kind of screen the whole transcriptome And we do know that it's not something that it's just common to to the closest.
00:18:58:06 - 00:19:19:04
Teresa Cortes
I mean many other bacteria from the same. If one family also has this characteristic, what is important in the context of tuberculosis that there are several of these genes that rely on noncanonical signals to produce proteins. They are important in the persistent estate of bacteria.
00:19:19:07 - 00:19:35:03
Abigail Acton
Okay, so break that down for me then. So so some of them are not using the signals that that are typically used. And what does that tell us with regards to to the TB bacteria? What does that tell us? Does it does it warn us that it's going to go from latent to active or is there some indication that it it changes depending on the status of the condition?
00:19:35:07 - 00:20:03:03
Teresa Cortes
Well, it's telling us a lot of interesting things from the, let's say, fundamental point of biology. I mean, we know that now TB bacteria, tuberculosis by the fact of not having a lot of genes with a conventional shine, the cardinal sequence of the ribosome is going to recognize relies possibly on alternative mechanisms that haven't been described at all in order to be able to intercept translation.
00:20:03:03 - 00:20:12:05
Abigail Acton
And is that what you're looking at, what the alternative mechanisms are? And if you discover what those alternative mechanisms are, might it be possible to disrupt them and to find that for a new, new way of treating?
00:20:12:11 - 00:20:30:11
Teresa Cortes
Yeah, absolutely. I mean, by knowing how the molecular ribosome or machinery of the translation machinery regulates new novel mechanisms for protein production, It has because a lot of potential to to be able to target this process.
00:20:30:15 - 00:20:35:06
Abigail Acton
So if you can work out the machinery, you can throw a spanner in the works of that machinery and stop it from working.
00:20:35:08 - 00:21:05:20
Teresa Cortes
Yeah, exactly. And also bear in mind that most of the antibiotics that we currently use to target tuberculosis target the ribosome, they target the ribosome and they associate or they are interacting with parts of the ribosome that are key in the process of translation initiation, for example. So if we to understand how this mechanisms operate, we are going to be able to infer new potential targets for antibiotic treatment.
00:21:05:20 - 00:21:22:00
Abigail Acton
It's fantastic. It sounds wonderful. And I can I can totally see that by this deconstructing you can you can almost yeah, you can work out what to target. You can work out what to disable, what to get in the way of, what to interrupt rate super. Does anyone have any questions for Teresa? So this is very interesting research.
00:21:22:02 - 00:21:23:01
Abigail Acton
Yes. Hossam.
00:21:23:03 - 00:21:45:03
Hossam Haick
There is a big debate among the specialists and the field of cancer whether there is a need to treat precancerous lesions or not. I would say it's 50 50% and I wouldn't bring the same question to the TB field. There is a need to make a treatment at the very early stages of the TB at the latent stage, for example.
00:21:45:06 - 00:21:51:21
Hossam Haick
Do you think it's immediate or efficient or helpful or it's quite risky ?
00:21:51:21 - 00:22:16:07
Teresa Cortes
To treat at this late in the state? I think it's it's needed. I mean, I guess in an ideal world, I think a treatment for target in the late in a state it will be needed because as I mentioned at the beginning, the potential of people with latent tuberculosis that at some point are going to develop active tuberculosis and the infectious and actively transmit it's very high. Iñaki?
00:22:16:09 - 00:22:16:20
Iñaki Comas
I just.
00:22:16:20 - 00:22:42:04
Iñaki Comas
Wanted to say is something that this has been going on for a while, treating latent TB but also in particular risk groups. So you give a kind of isoniazid preventive therapy to these groups. Okay. But the reality is that because we we have this spread through until now, we have treated all people that we consider relatedness as one single thing.
00:22:42:06 - 00:23:04:09
Iñaki Comas
It doesn't work that well because we don't know really who we have to treat or not for in risk of developing TB because we don't know how to classify them in the spectrum. And because obviously, as I say, I don't think we can treat one quarter of the world population, which by the way, is healthy. So you need to ask these people, okay, you are healthy.
00:23:04:09 - 00:23:11:23
Iñaki Comas
But anyway, I am going to give you a break. So so I probably would need more, more evidence for that.
00:23:12:00 - 00:23:37:23
Hossam Haick
Yeah. And this is what I'm trying to say, that, you know, latent is like a healthy person at high risk to get or at medium risk to get TB in the future. And therefore the issue of whether to treat or not, that's really know a big issue to think about. But anyways, if there will be a treatment, of course I think the regulation system will find a way how to use it.
00:23:38:01 - 00:23:58:09
Abigail Acton
Well, the regulation system and the regulatory system and also Iñaki, because I'm going to turn to Iñaki right now, this is actually really sort of where your your project comes in through your project Iñaki, TB-ACCELERATE, you wanted to get a better understanding of the TB genome to develop innovative methodologies, to transcribe transmission at an on precedented resolution.
00:23:58:11 - 00:24:07:20
Abigail Acton
So you were looking at the stages of transmission and I guess also considering the various stages of latency, what were you hoping that whole genome sequencing would reveal?
00:24:07:23 - 00:24:31:21
Iñaki Comas
So we are genome sequencing before podia. So the pathogen that this infected people to be, to be cases sorry, and we use this information from the genome of the bacteria because it's like us that there is they are not to genome. So the same so we can use the genetic differences between bacteria and 15 different people to trace transmission, which is another way of trying to understand transmission or to a process.
00:24:31:21 - 00:25:01:23
Iñaki Comas
Instead of asking people, instead of doing contact tracing, we go for the genome and from the bacteria we ask the bacterial genome how transmission is happening. And and then we have these possibilities very similar to what we have been witnessing almost in real time for COVID, for SARS-CoV-2, in which we have this possibility because we have the sequencing capacities necessary, sequences that allow us to sequence hundreds or thousands of cases or isolates of the bacteria.
00:25:02:03 - 00:25:27:19
Iñaki Comas
We can now compare that because we have computer protocols for that and we can trust for genetic distances in transmission factors. So we can understand now transmission at the level that was not possible before. We can understand transmission between continents, between countries within a country, within a city, within between two persons. And that was not possible before because before we have a how to say a lens that was very low resolution.
00:25:27:21 - 00:25:48:19
Iñaki Comas
So we have to put everything in one pot but now we can start to desegregate that pot. And this is allowing us to understand TB transmission as a pattern. First of all, also mass scale. That was not even possible before. And now we are starting to understand since that that we had no answer in how to say five, ten years ago now.
00:25:48:21 - 00:26:10:01
Abigail Acton
It's amazing. I mean, again and again in this podcast, what I'm coming across is, is that just the speed at which technology is moving and how that really opens up so many new horizons. Also cheaper, faster, all of it. So how does this actually benefit health care providers? Iñaki, are you at the stage already where you're communicating information to health care providers regarding an outbreak rather like we were doing with PCR tests during the coronavirus crisis?
00:26:10:02 - 00:26:12:06
Abigail Acton
Or or how is this working for you in practice?
00:26:12:10 - 00:26:35:23
Iñaki Comas
Yes. So we are genome sequencing. This is more than a PCR and that's why it's a little bit difficult. You had seen that in March 2020 was not obvious, that sequencing, the whole genome of hundreds of millions of genomes for SARS-CoV-2 will help in any way. I know it's very clear that these hopes and it has been integrated in health systems, something I be country that tried to control a data epidemic.
00:26:35:23 - 00:27:12:12
Iñaki Comas
They have some kind of genomic surveillance system. I mean, testing footwear crosses. So now we go it's more complicated and this is and that's why it's more difficult to integrate in the whole system because these are not routine processes. PCR was already there in some way or another in the hospitals, but the whole genome sequences and all taken that in some countries like UK and now so just one of our to get this into place it will work and particularly here in Valencia for example is that we can integrate the genomic information we get in the health system in different ways, both for the diagnosis of the bacteria and resistance.
00:27:12:14 - 00:27:37:09
Iñaki Comas
This is for the hospitals but also for the public health offices. We are helping two different ways. One is ongoing investigation of outbreaks. So it's something that is going on. So we try to help there and to try to clarify or complement what they are doing. And then the other way, the other part is evaluating the program, the tuberculosis control program, how much transmission, educating as you able to halt transmission is going on.
00:27:37:14 - 00:27:46:17
Iñaki Comas
And is it whether this transmission dynamics is the same here in Valencia, is the same in Mozambique, or is this in this kind of since we can now do that so.
00:27:46:17 - 00:28:03:14
Abigail Acton
You can actually see the impact of best practices. So if somebody is doing something and you can see clearly that the transmission is really, really greatly reducing, then you can apply whatever they're doing elsewhere and hope that the the same thing will have the same result. Yeah. Fascinating. So are you finding that health care professionals are embracing this?
00:28:03:14 - 00:28:17:18
Abigail Acton
And another thing, actually, I also wanted to ask you about antibiotic resistance. So two questions about is this something that's being embraced? You mentioned it's a bit tricky to do because it's not standard procedure, but are people trying to do it and doesn't reveal anything about antibiotic resistant strains?
00:28:17:20 - 00:28:44:13
Iñaki Comas
So simple? Is there is there one single answer to both questions that this study clearly, clearly convinced this is the way to move forward? Of course, the health care systems, public health care system, most a little slower than other health systems and other stakeholders, because it's not that easy to integrate this new process. But they really see which which the advantages.
00:28:44:18 - 00:29:09:06
Iñaki Comas
And now we have now this about as as the coronavirus pandemic, one of the few good things we have after the coronavirus pandemic or after two years of pandemic is that it has been integrated for coronavirus in the health system. Finally, and this has opened the door to many other infectious diseases they were waiting behind. They waited. There was no funding or no priority list to integrate.
00:29:09:12 - 00:29:30:01
Iñaki Comas
So now it's been embraced much more. And also because we have sown during the last five years, it proved that they can help a lot. So we have hub here to diagnose multi-drug resistant cases in Valencia and we have health here to complement the testing in the hospital with our best with genomic information. And this has allowed personal treatments.
00:29:30:03 - 00:29:50:16
Iñaki Comas
So again, unrelated with what has been explained here, there is a lot of room into a closeness in different aspects of tuberculosis for personalized treatment, for personalized identification of TB cases, etc., etc., that will allow hopefully to implement much better ways to to control the disease.
00:29:50:18 - 00:29:57:19
Abigail Acton
Okay, fantastic. And what's the one finding from your project that you think actually will have the biggest impact in our outbreaks are controlled.
00:29:57:21 - 00:30:22:17
Iñaki Comas
So I think I think because we are looking at transmission, as I said before, with with our solution was not available before we can ask questions that we were not able to do like five years ago. And one of these questions is there is this dogma that tuberculosis always transmits with symptoms and we come back to latency again, which is a because as you have seen, that is very a hot topic farts necrosis and destroyed masses.
00:30:22:17 - 00:30:47:02
Iñaki Comas
Okay. It's kind of do you go to the hospitals you have symptoms, they screen and they say, okay, you have necrosis, you are isolated. But it turns out that by genomic sequencing we can now tell when one person has infected to another person and in retrospective. So when we started to do that, we realized that there were people in the community that were transmitting tuberculosis before having symptoms.
00:30:47:04 - 00:31:10:20
Iñaki Comas
So this kind of asymptomatic, probably subclinical tuberculosis or incipient tuberculosis that's not is 100% clear, but it clearly has to multiple people much in the way a courageous transmit so also so the major problem which to coronavirus control is really asymptomatic transmission or person automatic transmission so in this way so difficult to control and that's why we had to go to lockdowns.
00:31:10:22 - 00:31:32:19
Iñaki Comas
So it's the same for TB. This looks like there is some percentage of cases of transmission that that due to asymptomatic people, which well, we don't know right now is which is the contribution to the global body, which is the contribution to the number of cases we see every year. And this is something we are investigating. We are not this, of course, investigating right now.
00:31:32:24 - 00:31:50:12
Iñaki Comas
So how important is to incorporate asymptomatic transmission in our TB control programs? Because our TB control programs, are they still based on the dogma TB symptoms transmission and this domain as you see started to have links. So we are trying to understand yeah.
00:31:50:12 - 00:32:05:01
Abigail Acton
To be undermined. Yeah. Yeah. I mean it's fantastic that you can obviously it's absolute fantastic that you can identify that and that perhaps system all systems will have to adapt accordingly. But at the same time it must have been bad news when you discovered it. I mean.
00:32:05:03 - 00:32:29:13
Iñaki Comas
I mean just but that also if you find something new or you understand something that was not known before and you know that TB epidemic, it's been evolving very slowly the way we control we are. And that number of cases have been reduced to only 2% incidence per year, not even with COVID. Then you really now you need to implement new ways of controlling TB.
00:32:29:13 - 00:32:35:14
Iñaki Comas
So it's not back to now is what we need now is to implement ways to tackle this.
00:32:35:14 - 00:32:42:07
Abigail Acton
Yeah. And to actually use this new information. So indeed, thank you very much. Then you got any questions for Iñaki? Yes. Hossam.
00:32:43:01 - 00:32:50:17
Hossam Haick
Please tell us about the relation on the transmission of the TB for people with HIV or people with COVID 19 as well.
00:32:50:19 - 00:33:20:16
Iñaki Comas
So for we have a lot more information for HIV than for COVID and that suspected because more recently then TB also has this latency periods that takes more time to evaluate everything and transmission on many other aspects. And for TB originally it was thought or it was 2000 or it was proven that the people with HIV tend to trust less tuberculosis because they tend to have a supplement with losses.
00:33:20:17 - 00:33:44:04
Iñaki Comas
They tend they don't tend to generate that typical lesson in the lung called capitation. And capitation, we know, is very tightly associated to transmission and but now, because we have all these improvements in HIV treatment, many people, many HIV many patients living with HIV are now looking like health. So they are kind of catching up in this time.
00:33:44:05 - 00:34:08:01
Iñaki Comas
So they are starting to look like much more like a person, a person without HIV and therefore we can see a lot of transmission. Of course, in countries where there is a high about the known for TB, like South Africa, like Mozambique, where the HIV TB is seen limited. There we see a lot of transmission irrespective of HIV, but also in part because treatments are kind of catching up with that.
00:34:08:01 - 00:34:08:16
Iñaki Comas
Yeah.
00:34:08:18 - 00:34:15:16
Abigail Acton
Thank you, Inaki. Any other questions? Teresa would you like to ask a question? Yeah, it's more of an observation.
00:34:15:17 - 00:35:01:10
Teresa Cortes
Yeah, an observation or a thought that I have to know your opinion. So obviously we know that next generation sequencing has been a key in order to, to know more about transmission and epidemiology of tuberculosis and of the bacteria. So do you think we have reached the point where we have, let's say, for as much information as we come from this technique or just with further developments of next generation sequencing, we can still go farther in understanding on tackling tuberculosis or we are at the point where we need to, for example, to combine with artificial intelligence for some studying, or we have just reached the top off how much we can get from next generation
00:35:01:10 - 00:35:01:22
Teresa Cortes
sequencing.
00:35:01:23 - 00:35:06:09
Abigail Acton
That's a lovely question. Thank you. So that's a Inaki. Have we got as far as we can get?
00:35:06:13 - 00:35:06:24
Iñaki Comas
I don't know.
00:35:07:00 - 00:35:11:14
Abigail Acton
You need your crystal ball.
00:35:11:16 - 00:35:36:04
Iñaki Comas
But the first thing is that we are putting in we talk almost a lot about whole genome sequencing. And the reality is that that right now, that typical technique we use for genome sequencing only allows to screen around 90, 90% of the tuberculosis. You know, that means that is a 5% of black matter, which we are not screening and may host secrets to say.
00:35:36:04 - 00:36:02:11
Iñaki Comas
So both for transmission and for proper system, which we don't know, this can be solved. There are there are now sequencing technologies that allow us to cover the whole genome. Now this and an angle for the 100% or 99%. And this will be developments in the future for sure to understand what is in this part of the genome that may help to increase resolution even more than we have right now.
00:36:02:13 - 00:36:27:08
Iñaki Comas
Of course, there are many other developments in parallel that are important in genomics, like artificial intelligence, particularly for grammar system has been a play a lot or so we try or people, the people that is working in genomics and estrogen in terms of drug assistance is to identify all the mutations in the genome. On my questions about growth is to make it resistant to an antibiotic.
00:36:27:10 - 00:36:55:04
Iñaki Comas
And this looks like simple because or you do to what is you talk about with people that is not going to sort of make it into it will say yes, because tuberculosis kind of a low diversity pathogen is should be simple is not it turn out that we are still missing a few percent of mutations that we don't know where they fly and they we can not use for diagnosis because we don't know which mutations are.
00:36:55:06 - 00:37:12:24
Iñaki Comas
And artificial intelligence is being used in that direction. Also to try to to to predict where in the genome of the data, we need to look at it to produce resistance. So genes that are many developments in terms of a knowledge that can still be applied.
00:37:13:01 - 00:37:15:19
Abigail Acton
Or anywhere near out of work yet.
00:37:15:21 - 00:37:16:24
Iñaki Comas
Not yet, no.
00:37:17:01 - 00:37:18:09
Abigail Acton
Not yet. Not for a while.
00:37:18:09 - 00:37:36:17
Iñaki Comas
I mean that your work on TB probably the only thing that can shorten or or task is protected vaccine. And this is something which we are not expecting in the near future, probably in ten years, 15 years, not even with messenger RNA vaccines. They are because TB is more complicated than SARS-CoV-2.
00:37:36:20 - 00:37:51:03
Abigail Acton
Yeah, fascinating. Yeah, that's a pity. I'm glad you mentioned vaccines. I hadn't thought of that at all. So that's a really good place to end on and I really appreciate that. I want to thank you so much for your time. I've really enjoyed this conversation and I particularly enjoyed the way that you chatted amongst each other as well.
00:37:51:03 - 00:37:58:24
Abigail Acton
Thank you for that. It was always interesting listening to you guys talking together with stories up more interesting points. Superb. Thanks very much to all of you.
00:37:59:01 - 00:38:02:04
ALL
Thanks a lot. Thank you. Bye bye bye.
00:38:02:04 - 00:38:20:17
Abigail Acton
That was a very bye bye. Bye bye. Are you interested in what other EU funded projects are doing to understand how TB infects US Resistance drugs and switches from one state to another? The Cordis website will give you an insight into the results of projects funded by the Horizon 2020 program that are working in this area.
00:38:20:19 - 00:38:42:15
Abigail Acton
The website has articles and interviews that explore the results of research being conducted in a very broad range of domains and subjects from giant fossilized dormice to giant planets. There's something there for you. maybe you are involved in a project or would like to apply for funding. Take a look at what others are doing in your domain, so come and check out the research that's revealing what makes our world tick.
00:38:42:17 - 00:38:49:16
Abigail Acton
We're always happy to hear from you. Drop us a line editorial at Cordis dot Europa dot EU. Until next time.
This is an AI transcription.
00:00:00:00 - 00:00:16:03
Abigail Acton
This is CORDIScovery.
00:00:16:05 - 00:00:41:05
Abigail Acton
Hello and welcome to this episode of CORDIScovery With me, Abigail Acton. 9,900,000 people fell ill with TB in 2020, according to the World Health Organization, and a million and a half died. Global efforts to combat the disease have saved an estimated 66 million lives since 2000. But the COVID 19 pandemic hit the fight against TB hard. For the first time in over a decade, TB deaths increased in 2020.
00:00:41:07 - 00:01:06:01
Abigail Acton
The work being done by today's three guests, supported by the EU's Horizon 2020 program, is more vital than ever. Welcome to Hossam Haick, a dean at the Israel Institute of Technology. The Technion. Hossam leads activities, developing noninvasive smart sensors and wearable devices to enable the early detection of diseases such as TB and lifelong monitoring of health disorders. Hello, Hossam.
00:01:06:03 - 00:01:07:05
Hossam Haick
Hello, Abigail.
00:01:07:07 - 00:01:21:21
Abigail Acton
Teresa Cortes is based at the Institute of Biomedicine at Valencia, part of the Spanish National Research Council. She is interested in understanding how the bacteria that causes tuberculosis and humans, in fact, survive cause disease and develop antibiotic resistance. Hi, Teresa.
00:01:22:02 - 00:01:24:03
Teresa Cortes
Hello. Hello, everyone.
00:01:24:05 - 00:01:43:07
Abigail Acton
Iñaki Comas is part of the Tuberculosis Genomics Institute at the Institute of Biomedicine in Valencia in Spain as well. He unravels the intricacies of pathogen genomics to understand the evolution and epidemiology of infectious diseases. His lab is particularly focused on tuberculosis, but also works on other diseases like COVID 19. Hi Iñaki.
00:01:43:09 - 00:01:44:20
Iñaki Comas
Hello, everyone.
00:01:44:22 - 00:02:01:08
Abigail Acton
I'll start with Hossam, if I may. Hossam, your project, A-patch supported by the EU and the Gates Foundation, is demonstrating a novel means of diagnosing tuberculosis using a stick on patch. Can you tell us what the problems are currently with the way that we diagnose tuberculosis?
00:02:01:10 - 00:02:28:16
Hossam Haick
In order to understand the main issue with the tuberculosis. We have to understand that the early symptoms of the disease are not specific, and this is by itself complicates the diagnosis. And therefore most of the existing bio diagnostic tests are usually slow, have low sensitivity and specificity and or if you like, accuracy and many times are too expensive or complex for resource limited settings.
00:02:28:18 - 00:02:56:01
Hossam Haick
For example, if we take a look on the sputum culture, which costs around 2 to €8 per test and that depends on the country. This technique is insensitive and takes around 4 to 8 weeks and at least three visits by the patient to finalize the diagnosis before it starts the treatment per say. The only technology which can provide us a diagnosis within 2 hours is called Genexpert.
00:02:56:03 - 00:03:29:16
Hossam Haick
But nevertheless it has relatively limited accuracy or sensitivity. It's around 88% in some cases. In other cases it's 67%. And in addition, this technology has a complicated ways in order to collect the sample and also requires some installation and complicated infrastructure. And therefore, in many times it's not accessible to a settings that has limitations in terms of resources.
00:03:29:18 - 00:03:47:20
Hossam Haick
We have also many other technologies which used for diagnosis of TB, but nevertheless most of them are complicated and have advantages in terms of the way they are collecting sputum or process. The body fluids are in many times they have some risks in terms of the biosafety.
00:03:47:22 - 00:04:03:24
Abigail Acton
Okay, I see. So they're either slow or else not as accurate as needed in order to pinpoint a potential outbreak. Exactly right. And so can you then tell us a little bit more about A-patch? So the how does A-patch differ from these methods that you've just been describing?
00:04:03:24 - 00:04:38:02
Hossam Haick
The A-patch concept actually promotes the uptake of personalized tuberculosis, 3 hours and diagnosis for use in clinics and community, and that includes also areas where we have no mobile or internet connectivity. The approach itself relies on a low cost wearable sensor space that can be attached to the arm or to the chest to analyze some array of chemical compounds that are associated with the tuberculosis and that exist in the guest space above the skin itself.
00:04:38:04 - 00:05:04:13
Hossam Haick
The patch itself costs around €1 per patch. It's fast, simple and really easy to use. There is no need for a special training in order to use this patch. And the nice thing about this technology that it can be activated by the smartphone throughout the future, which call it RFID, which found in every smartphone today and need no battery, which is also important for green technology as well.
00:05:04:15 - 00:05:20:14
Abigail Acton
Okay. The benefit from what you're describing, and especially as you've mentioned, the fact that it's it's cheap. I mean, for what it is, it's very cheap. It sounds like obviously then the benefit is that it can be used in environments where people are living on $1 a day and that maybe there's no real infrastructure for them. But then you also mentioned smartphones.
00:05:20:14 - 00:05:25:06
Abigail Acton
So I'm wondering, all those communities carrying smartphones.
00:05:25:08 - 00:05:47:15
Hossam Haick
Yes, it seems very weird. But according to the recent statistics, more than 77% of the people in the developing countries have mobile phones or smartphones. And of course, when I talk about RFID technology, which read the data from our patch, even regular mobile, which is not a smartphone, one can work as well.
00:05:47:20 - 00:06:01:15
Abigail Acton
Okay, fantastic. So it's accessible to communities who are in the middle of nowhere and living on very, very little. How how does the data then get back to the health care professional concerns? Supposing the health care professional can't make it across to that particular village or whatever?
00:06:01:17 - 00:06:19:06
Hossam Haick
These smartphones, of course, are connected with the mobile network and throughout the mobile network, we can provide all of the data directly to the cloud or big data resource from where they a resource can be accessed to the health care systems or for the clinicians.
00:06:19:08 - 00:06:29:00
Abigail Acton
Okay, great. And of course, that must be happening almost in real time. How long does it take for the patch to recognize the volatile chemicals and for the health care professional to know that there might be an outbreak or an issue?
00:06:29:02 - 00:06:59:15
Hossam Haick
As I have said, that the patch will need only 1 to 2 minutes. Are that to give us the result whether the patient has TB or is healthy. And of course the nice thing about the paths that it's a hardware that we can train it by machine learning or by artificial intelligence. So if we have other pandemics or other types of disease, we can remotely threaten the device by feeding the new algorithm into the device so we can train it in different ways.
00:06:59:18 - 00:07:11:10
Hossam Haick
You just need to think about it in the in as a smartphone device where we have the app where every time we use the device, which is the smartphone in different way according to the app, which is different algorithm now.
00:07:11:13 - 00:07:25:09
Abigail Acton
It's absolutely brilliant. It sounds wonderful. I'm not surprised the Gates Foundation have embraced it as well. It does sound like a tool that the clinicians have been waiting for, but it must have been incredibly challenging to develop. Can you tell us a little bit more about how you actually develop this? How long is it taken.
00:07:25:11 - 00:07:55:12
Hossam Haick
Of course, to develop this approach? We have, first of all, to prove the science behind it, namely that there is a profile of unique chemical compounds that are emitted because of the TB or as a result of the TB into the headspace of the skin. And for this space we were supported by the Bill and Melinda Gates Foundation to carry in-depth analysis for thousands of real skin samples of TB and health subjects in a wide variety of hospitals worldwide.
00:07:55:14 - 00:08:21:22
Hossam Haick
And the results have shown that indeed, the TB has unique molecular fingerprint of volatile organic compounds that appear in the skin, and that can be distinguished from other types of disease. Nevertheless, this discovery has been achieved by a lab instrument, which we call it mass spectrometry, which is really very big, heavy instrument, expensive and also slow. It takes sometimes two or 3 hours in order to obtain one result.
00:08:21:24 - 00:08:49:12
Hossam Haick
And therefore, to translate this results from the basic science to the point of care reality. The EU has supported our efforts throughout the Horizon 2020 A-Patch program, where we have developed and characterized these smart patches that can capture and detect the profiles of the chemicals of the TB from the skin and really affordable way cheap manner. It's around €1 per patch and very fast way.
00:08:49:13 - 00:09:09:24
Hossam Haick
And this pasture actually has been achieved throughout the development of an array of ultra thin sensors and artificial intelligence in a way that imitate the way our skin works. Of course, this journey was not simple as it might sounds.
00:09:09:24 - 00:09:14:15
Abigail Acton
It doesn't sound simple at all. It sounds very, very stimulating and exciting.
00:09:14:17 - 00:09:50:02
Hossam Haick
We have to develop all the parts of the technology from A to Z, from the material design called the device architecture, and to the development of, you know, the way how we outreach the information itself. And of course we have many challenges appropriate this ability replicability issues and the most important which way we have to use in order really to make this technology affordable and accessible to every person, disregarding of where he or she lives and how many fund they do have.
00:09:50:04 - 00:09:51:03
Abigail Acton
Brilliant.
00:09:51:05 - 00:09:58:22
Hossam Haick
Of course, of overcoming all of these challenges. We do have this technology right now in reality, and we have started to use it.
00:09:58:24 - 00:10:07:19
Abigail Acton
Okay. That was going to be my question. Actually, I was about to ask you, I mean, where are you up to with regards to clinical validation? Is it already being used in the field? How's that going?
00:10:07:21 - 00:10:38:01
Hossam Haick
This batch is actually has been validated in three independent studies on right now on 1000 subjects in India, South Africa and also Latvia. And we are still working on further examinations. The results so far has shown based on double blind analysis that we can distinguish active tuberculosis from healthy controls with over 90% sensitivity and over 80% specificity also.
00:10:38:01 - 00:11:06:09
Hossam Haick
And the nice thing about it that the patches have shown excellent discrimination between the so-called latent tuberculosis and activity clauses with over 90% accuracy, which is very important as well. And this promising results actually today has been used as a launchpad for other infectious diseases such as malaria, hepatitis C and also non-communicable diseases such as diabetes and metabolic syndrome.
00:11:06:09 - 00:11:11:14
Hossam Haick
All of these are already being validated and examined in our research group. In the technical.
00:11:11:16 - 00:11:15:18
Abigail Acton
You must be very proud of your work and the work of your team. How do you feel about the work that you've done?
00:11:15:20 - 00:11:44:23
Hossam Haick
I'm very proud about my team. They are the real people who is doing the real job, very hard job, which includes also basic science, translational science and engineering in one lab and the nice thing about it and really what makes me happy, that it's really very multidisciplinary research and development and every team member speaks many scientific languages to communicate this multidisciplinary project with each other.
00:11:45:03 - 00:11:52:10
Abigail Acton
Now that sounds brilliant. What about the other guests here today? Iñaki ? Teresa? Do you have any questions that you'd like to put to Hossam? Yes, Teresa.
00:11:52:10 - 00:12:17:04
Teresa Cortes
So Hossam I think it's a very interesting work and it's amazing that we can have just two parts from this game that can help us to identify who was active today and later, tuberculosis. I was just wondering, what about truck sensitivity and drug side of the bacteria? Can your parts in Farah, if you are dealing with drug resistant bacteria or can sensitivity bacteria can for treatment?
00:12:17:06 - 00:12:47:22
Hossam Haick
Of course, we have started to tailor our device in order to make follow up of the treatment process for two ways. But first of all, because of the multi-resistant and bacteria, this is one side. And on the other side we have started to train our system and to examine it. In Latvia today in order to follow up the treatment process with the hope that we can personalize the treatment according to the right treatment and also the timeline that is needed for the treatment.
00:12:48:03 - 00:13:04:17
Hossam Haick
For example, today there is very well defined period for the treatment and we hope sometimes we might shorten or elongate that period. But for that we need something to follow up the treatment in real time, every hour or every day or every week, not every few months as well.
00:13:04:19 - 00:13:15:13
Abigail Acton
Because of course, each individual I'm sure, would be responding to the treatment slightly differently. We're not one size fits all. So this way you'd actually be able to see where how far the treatment has actually progressed in controlling the bacteria.
00:13:15:15 - 00:13:35:23
Hossam Haick
Exactly. And this is what I mentioned with personalized TB treatment. So we will personalize it. Namely, we will have the patch on the skin of the person and that will be the baseline. And then we will start the process of the follow up based on that baseline. And from that we can just tailor the treatment accordingly.
00:13:36:00 - 00:13:42:11
Abigail Acton
Excellent, wonderful. And also saves a lot of drugs being used unnecessarily and so on. Inaki, would you have a question? Yes, please.
00:13:42:12 - 00:14:12:19
Iñaki Comas
Just so very nice question. I just have a question because now we know that latent tuberculosis is not anymore the definition of one single scene, but is really on a spectrum of a states. No. So it's people that we saw before, they where they have a latent individuals. Also, they may be very different in physical status. And and this includes these what is called incipient crosses to clinical tuberculosis when people that has been able to clear tuberculosis know.
00:14:12:21 - 00:14:27:00
Iñaki Comas
So you had something that probably your patch can distinguish a latent enough to do a cross and do you have any plan to try to adapt it to these different stages? So because this becoming a really important topic in the.
00:14:27:01 - 00:14:35:14
Hossam Haick
Process, actually we haven't thought about it, but glad you raised this comment and will be glad to find a way to collaborate with you guys.
00:14:35:16 - 00:14:36:12
Iñaki Comas
Perfect.
00:14:36:14 - 00:14:57:01
Abigail Acton
Yes. I should put you all in contact with each other at the end of this now. Thank you very much indeed. Details. And that was fascinating. I'm going to move over to Teresa now. Teresa of the MtbTransReg Project focused on understanding how TB adapts to stress and drug resistance at the molecular and cellular level. So what was the characteristic of TB infection that most interested you do?
00:14:57:03 - 00:15:24:03
Teresa Cortes
To me, the most interesting aspect of TB infection is, as we were just talking about, the spectrum of TB disease, we know that some cases develop active disease, but most of the cases go into developing an asymptomatic infection that we just talked about it. That is not just a single stay. This obliterates different status. And we know here the vector and remain dormant for decades in the host.
00:15:24:05 - 00:15:48:13
Teresa Cortes
And if we take into account that the current estimates are that a quarter of the global population is late infected, that represents over 2 billion people. So these people have the potential to reactivate, to resist and become infectious during their lifetime. So we have a huge reservoir of potential reactivation of the disease and you can start to realize of the magnitude of the problem we face with latent.
00:15:48:15 - 00:16:18:22
Teresa Cortes
It is. So for me, it's important to understand that during this process of infection, the bacteria must adapt to a diverse variety of environments on soil. Today, we don't know the molecular mechanisms that the bacteria uses to switch, for example, between active replication and latent or dormant inside the host. And in this respect, our previous research has shown that regulatory control at the level of protein synthesis may be important for this process.
00:16:19:02 - 00:16:27:13
Abigail Acton
Now, can I break you down slightly? Regulatory control at the level of protein synthesis? Could you could you break that down for me a little bit? What are what are the what is the bacteria actually doing with the protein that changes?
00:16:27:15 - 00:16:58:02
Teresa Cortes
Well, I mean, protein synthesis, at such is a very important process that all cells make proteins. It's very concerned among proteins. But we have started to realize that a that a process that we have thought that it was very conserved and we thought it was very well known has different levels where it can be regulated that the virus now and that can alter how the bacteria is making the protein, if that makes sense.
00:16:58:04 - 00:17:15:06
Abigail Acton
Now, that does, That does. Thank you. That's a good explanation. Okay. So tell us more about the production of the protein in the cells and why it matters. I know it's a technical concept and it might be quite difficult to break it down, but you've done really well so far. So tell us a little bit more about why is the way that the protein is produced and used you important?
00:17:15:08 - 00:17:44:20
Teresa Cortes
So as I say, I mean, protein production is it's a requirement for all cells for by viral replication and involves many cellular components with about half of the energy expenditure of growing cells being used to wash protein synthesis. And protein synthesis is basically the way that messenger RNA or genes are read by the ribosome, which is the machinery that makes protein production possible in order to synthesize proteins.
00:17:44:20 - 00:18:15:04
Teresa Cortes
And in bacteria, genes carry canonical signals that are known as the sequences. And those signals tell the ribosome where to start producing proteins from those genes. And they are like a genetic signposts if you want that an organism DNA harbors in order to tell a ribosome where to start making proteins. And this kind of sequences are found in genomes from many types of bacteria.
00:18:15:06 - 00:18:25:22
Teresa Cortes
However, in the TB bacterium, approximately half of the genes in the genome engage with ribosomes without using these conditional signposts.
00:18:25:22 - 00:18:29:03
Abigail Acton
And is that something that's relatively recently, recently been understood?
00:18:29:08 - 00:18:58:06
Teresa Cortes
Well, it's true that there are many bacteria and, for example, many archaea that do not rely on those canonical signals to start translation. And that's something we have just started to to realize. Thanks to the use of whole or next generation sequencing techniques where we kind of screen the whole transcriptome And we do know that it's not something that it's just common to to the closest.
00:18:58:06 - 00:19:19:04
Teresa Cortes
I mean many other bacteria from the same. If one family also has this characteristic, what is important in the context of tuberculosis that there are several of these genes that rely on noncanonical signals to produce proteins. They are important in the persistent estate of bacteria.
00:19:19:07 - 00:19:35:03
Abigail Acton
Okay, so break that down for me then. So so some of them are not using the signals that that are typically used. And what does that tell us with regards to to the TB bacteria? What does that tell us? Does it does it warn us that it's going to go from latent to active or is there some indication that it it changes depending on the status of the condition?
00:19:35:07 - 00:20:03:03
Teresa Cortes
Well, it's telling us a lot of interesting things from the, let's say, fundamental point of biology. I mean, we know that now TB bacteria, tuberculosis by the fact of not having a lot of genes with a conventional shine, the cardinal sequence of the ribosome is going to recognize relies possibly on alternative mechanisms that haven't been described at all in order to be able to intercept translation.
00:20:03:03 - 00:20:12:05
Abigail Acton
And is that what you're looking at, what the alternative mechanisms are? And if you discover what those alternative mechanisms are, might it be possible to disrupt them and to find that for a new, new way of treating?
00:20:12:11 - 00:20:30:11
Teresa Cortes
Yeah, absolutely. I mean, by knowing how the molecular ribosome or machinery of the translation machinery regulates new novel mechanisms for protein production, It has because a lot of potential to to be able to target this process.
00:20:30:15 - 00:20:35:06
Abigail Acton
So if you can work out the machinery, you can throw a spanner in the works of that machinery and stop it from working.
00:20:35:08 - 00:21:05:20
Teresa Cortes
Yeah, exactly. And also bear in mind that most of the antibiotics that we currently use to target tuberculosis target the ribosome, they target the ribosome and they associate or they are interacting with parts of the ribosome that are key in the process of translation initiation, for example. So if we to understand how this mechanisms operate, we are going to be able to infer new potential targets for antibiotic treatment.
00:21:05:20 - 00:21:22:00
Abigail Acton
It's fantastic. It sounds wonderful. And I can I can totally see that by this deconstructing you can you can almost yeah, you can work out what to target. You can work out what to disable, what to get in the way of, what to interrupt rate super. Does anyone have any questions for Teresa? So this is very interesting research.
00:21:22:02 - 00:21:23:01
Abigail Acton
Yes. Hossam.
00:21:23:03 - 00:21:45:03
Hossam Haick
There is a big debate among the specialists and the field of cancer whether there is a need to treat precancerous lesions or not. I would say it's 50 50% and I wouldn't bring the same question to the TB field. There is a need to make a treatment at the very early stages of the TB at the latent stage, for example.
00:21:45:06 - 00:21:51:21
Hossam Haick
Do you think it's immediate or efficient or helpful or it's quite risky ?
00:21:51:21 - 00:22:16:07
Teresa Cortes
To treat at this late in the state? I think it's it's needed. I mean, I guess in an ideal world, I think a treatment for target in the late in a state it will be needed because as I mentioned at the beginning, the potential of people with latent tuberculosis that at some point are going to develop active tuberculosis and the infectious and actively transmit it's very high. Iñaki?
00:22:16:09 - 00:22:16:20
Iñaki Comas
I just.
00:22:16:20 - 00:22:42:04
Iñaki Comas
Wanted to say is something that this has been going on for a while, treating latent TB but also in particular risk groups. So you give a kind of isoniazid preventive therapy to these groups. Okay. But the reality is that because we we have this spread through until now, we have treated all people that we consider relatedness as one single thing.
00:22:42:06 - 00:23:04:09
Iñaki Comas
It doesn't work that well because we don't know really who we have to treat or not for in risk of developing TB because we don't know how to classify them in the spectrum. And because obviously, as I say, I don't think we can treat one quarter of the world population, which by the way, is healthy. So you need to ask these people, okay, you are healthy.
00:23:04:09 - 00:23:11:23
Iñaki Comas
But anyway, I am going to give you a break. So so I probably would need more, more evidence for that.
00:23:12:00 - 00:23:37:23
Hossam Haick
Yeah. And this is what I'm trying to say, that, you know, latent is like a healthy person at high risk to get or at medium risk to get TB in the future. And therefore the issue of whether to treat or not, that's really know a big issue to think about. But anyways, if there will be a treatment, of course I think the regulation system will find a way how to use it.
00:23:38:01 - 00:23:58:09
Abigail Acton
Well, the regulation system and the regulatory system and also Iñaki, because I'm going to turn to Iñaki right now, this is actually really sort of where your your project comes in through your project Iñaki, TB-ACCELERATE, you wanted to get a better understanding of the TB genome to develop innovative methodologies, to transcribe transmission at an on precedented resolution.
00:23:58:11 - 00:24:07:20
Abigail Acton
So you were looking at the stages of transmission and I guess also considering the various stages of latency, what were you hoping that whole genome sequencing would reveal?
00:24:07:23 - 00:24:31:21
Iñaki Comas
So we are genome sequencing before podia. So the pathogen that this infected people to be, to be cases sorry, and we use this information from the genome of the bacteria because it's like us that there is they are not to genome. So the same so we can use the genetic differences between bacteria and 15 different people to trace transmission, which is another way of trying to understand transmission or to a process.
00:24:31:21 - 00:25:01:23
Iñaki Comas
Instead of asking people, instead of doing contact tracing, we go for the genome and from the bacteria we ask the bacterial genome how transmission is happening. And and then we have these possibilities very similar to what we have been witnessing almost in real time for COVID, for SARS-CoV-2, in which we have this possibility because we have the sequencing capacities necessary, sequences that allow us to sequence hundreds or thousands of cases or isolates of the bacteria.
00:25:02:03 - 00:25:27:19
Iñaki Comas
We can now compare that because we have computer protocols for that and we can trust for genetic distances in transmission factors. So we can understand now transmission at the level that was not possible before. We can understand transmission between continents, between countries within a country, within a city, within between two persons. And that was not possible before because before we have a how to say a lens that was very low resolution.
00:25:27:21 - 00:25:48:19
Iñaki Comas
So we have to put everything in one pot but now we can start to desegregate that pot. And this is allowing us to understand TB transmission as a pattern. First of all, also mass scale. That was not even possible before. And now we are starting to understand since that that we had no answer in how to say five, ten years ago now.
00:25:48:21 - 00:26:10:01
Abigail Acton
It's amazing. I mean, again and again in this podcast, what I'm coming across is, is that just the speed at which technology is moving and how that really opens up so many new horizons. Also cheaper, faster, all of it. So how does this actually benefit health care providers? Iñaki, are you at the stage already where you're communicating information to health care providers regarding an outbreak rather like we were doing with PCR tests during the coronavirus crisis?
00:26:10:02 - 00:26:12:06
Abigail Acton
Or or how is this working for you in practice?
00:26:12:10 - 00:26:35:23
Iñaki Comas
Yes. So we are genome sequencing. This is more than a PCR and that's why it's a little bit difficult. You had seen that in March 2020 was not obvious, that sequencing, the whole genome of hundreds of millions of genomes for SARS-CoV-2 will help in any way. I know it's very clear that these hopes and it has been integrated in health systems, something I be country that tried to control a data epidemic.
00:26:35:23 - 00:27:12:12
Iñaki Comas
They have some kind of genomic surveillance system. I mean, testing footwear crosses. So now we go it's more complicated and this is and that's why it's more difficult to integrate in the whole system because these are not routine processes. PCR was already there in some way or another in the hospitals, but the whole genome sequences and all taken that in some countries like UK and now so just one of our to get this into place it will work and particularly here in Valencia for example is that we can integrate the genomic information we get in the health system in different ways, both for the diagnosis of the bacteria and resistance.
00:27:12:14 - 00:27:37:09
Iñaki Comas
This is for the hospitals but also for the public health offices. We are helping two different ways. One is ongoing investigation of outbreaks. So it's something that is going on. So we try to help there and to try to clarify or complement what they are doing. And then the other way, the other part is evaluating the program, the tuberculosis control program, how much transmission, educating as you able to halt transmission is going on.
00:27:37:14 - 00:27:46:17
Iñaki Comas
And is it whether this transmission dynamics is the same here in Valencia, is the same in Mozambique, or is this in this kind of since we can now do that so.
00:27:46:17 - 00:28:03:14
Abigail Acton
You can actually see the impact of best practices. So if somebody is doing something and you can see clearly that the transmission is really, really greatly reducing, then you can apply whatever they're doing elsewhere and hope that the the same thing will have the same result. Yeah. Fascinating. So are you finding that health care professionals are embracing this?
00:28:03:14 - 00:28:17:18
Abigail Acton
And another thing, actually, I also wanted to ask you about antibiotic resistance. So two questions about is this something that's being embraced? You mentioned it's a bit tricky to do because it's not standard procedure, but are people trying to do it and doesn't reveal anything about antibiotic resistant strains?
00:28:17:20 - 00:28:44:13
Iñaki Comas
So simple? Is there is there one single answer to both questions that this study clearly, clearly convinced this is the way to move forward? Of course, the health care systems, public health care system, most a little slower than other health systems and other stakeholders, because it's not that easy to integrate this new process. But they really see which which the advantages.
00:28:44:18 - 00:29:09:06
Iñaki Comas
And now we have now this about as as the coronavirus pandemic, one of the few good things we have after the coronavirus pandemic or after two years of pandemic is that it has been integrated for coronavirus in the health system. Finally, and this has opened the door to many other infectious diseases they were waiting behind. They waited. There was no funding or no priority list to integrate.
00:29:09:12 - 00:29:30:01
Iñaki Comas
So now it's been embraced much more. And also because we have sown during the last five years, it proved that they can help a lot. So we have hub here to diagnose multi-drug resistant cases in Valencia and we have health here to complement the testing in the hospital with our best with genomic information. And this has allowed personal treatments.
00:29:30:03 - 00:29:50:16
Iñaki Comas
So again, unrelated with what has been explained here, there is a lot of room into a closeness in different aspects of tuberculosis for personalized treatment, for personalized identification of TB cases, etc., etc., that will allow hopefully to implement much better ways to to control the disease.
00:29:50:18 - 00:29:57:19
Abigail Acton
Okay, fantastic. And what's the one finding from your project that you think actually will have the biggest impact in our outbreaks are controlled.
00:29:57:21 - 00:30:22:17
Iñaki Comas
So I think I think because we are looking at transmission, as I said before, with with our solution was not available before we can ask questions that we were not able to do like five years ago. And one of these questions is there is this dogma that tuberculosis always transmits with symptoms and we come back to latency again, which is a because as you have seen, that is very a hot topic farts necrosis and destroyed masses.
00:30:22:17 - 00:30:47:02
Iñaki Comas
Okay. It's kind of do you go to the hospitals you have symptoms, they screen and they say, okay, you have necrosis, you are isolated. But it turns out that by genomic sequencing we can now tell when one person has infected to another person and in retrospective. So when we started to do that, we realized that there were people in the community that were transmitting tuberculosis before having symptoms.
00:30:47:04 - 00:31:10:20
Iñaki Comas
So this kind of asymptomatic, probably subclinical tuberculosis or incipient tuberculosis that's not is 100% clear, but it clearly has to multiple people much in the way a courageous transmit so also so the major problem which to coronavirus control is really asymptomatic transmission or person automatic transmission so in this way so difficult to control and that's why we had to go to lockdowns.
00:31:10:22 - 00:31:32:19
Iñaki Comas
So it's the same for TB. This looks like there is some percentage of cases of transmission that that due to asymptomatic people, which well, we don't know right now is which is the contribution to the global body, which is the contribution to the number of cases we see every year. And this is something we are investigating. We are not this, of course, investigating right now.
00:31:32:24 - 00:31:50:12
Iñaki Comas
So how important is to incorporate asymptomatic transmission in our TB control programs? Because our TB control programs, are they still based on the dogma TB symptoms transmission and this domain as you see started to have links. So we are trying to understand yeah.
00:31:50:12 - 00:32:05:01
Abigail Acton
To be undermined. Yeah. Yeah. I mean it's fantastic that you can obviously it's absolute fantastic that you can identify that and that perhaps system all systems will have to adapt accordingly. But at the same time it must have been bad news when you discovered it. I mean.
00:32:05:03 - 00:32:29:13
Iñaki Comas
I mean just but that also if you find something new or you understand something that was not known before and you know that TB epidemic, it's been evolving very slowly the way we control we are. And that number of cases have been reduced to only 2% incidence per year, not even with COVID. Then you really now you need to implement new ways of controlling TB.
00:32:29:13 - 00:32:35:14
Iñaki Comas
So it's not back to now is what we need now is to implement ways to tackle this.
00:32:35:14 - 00:32:42:07
Abigail Acton
Yeah. And to actually use this new information. So indeed, thank you very much. Then you got any questions for Iñaki? Yes. Hossam.
00:32:43:01 - 00:32:50:17
Hossam Haick
Please tell us about the relation on the transmission of the TB for people with HIV or people with COVID 19 as well.
00:32:50:19 - 00:33:20:16
Iñaki Comas
So for we have a lot more information for HIV than for COVID and that suspected because more recently then TB also has this latency periods that takes more time to evaluate everything and transmission on many other aspects. And for TB originally it was thought or it was 2000 or it was proven that the people with HIV tend to trust less tuberculosis because they tend to have a supplement with losses.
00:33:20:17 - 00:33:44:04
Iñaki Comas
They tend they don't tend to generate that typical lesson in the lung called capitation. And capitation, we know, is very tightly associated to transmission and but now, because we have all these improvements in HIV treatment, many people, many HIV many patients living with HIV are now looking like health. So they are kind of catching up in this time.
00:33:44:05 - 00:34:08:01
Iñaki Comas
So they are starting to look like much more like a person, a person without HIV and therefore we can see a lot of transmission. Of course, in countries where there is a high about the known for TB, like South Africa, like Mozambique, where the HIV TB is seen limited. There we see a lot of transmission irrespective of HIV, but also in part because treatments are kind of catching up with that.
00:34:08:01 - 00:34:08:16
Iñaki Comas
Yeah.
00:34:08:18 - 00:34:15:16
Abigail Acton
Thank you, Inaki. Any other questions? Teresa would you like to ask a question? Yeah, it's more of an observation.
00:34:15:17 - 00:35:01:10
Teresa Cortes
Yeah, an observation or a thought that I have to know your opinion. So obviously we know that next generation sequencing has been a key in order to, to know more about transmission and epidemiology of tuberculosis and of the bacteria. So do you think we have reached the point where we have, let's say, for as much information as we come from this technique or just with further developments of next generation sequencing, we can still go farther in understanding on tackling tuberculosis or we are at the point where we need to, for example, to combine with artificial intelligence for some studying, or we have just reached the top off how much we can get from next generation
00:35:01:10 - 00:35:01:22
Teresa Cortes
sequencing.
00:35:01:23 - 00:35:06:09
Abigail Acton
That's a lovely question. Thank you. So that's a Inaki. Have we got as far as we can get?
00:35:06:13 - 00:35:06:24
Iñaki Comas
I don't know.
00:35:07:00 - 00:35:11:14
Abigail Acton
You need your crystal ball.
00:35:11:16 - 00:35:36:04
Iñaki Comas
But the first thing is that we are putting in we talk almost a lot about whole genome sequencing. And the reality is that that right now, that typical technique we use for genome sequencing only allows to screen around 90, 90% of the tuberculosis. You know, that means that is a 5% of black matter, which we are not screening and may host secrets to say.
00:35:36:04 - 00:36:02:11
Iñaki Comas
So both for transmission and for proper system, which we don't know, this can be solved. There are there are now sequencing technologies that allow us to cover the whole genome. Now this and an angle for the 100% or 99%. And this will be developments in the future for sure to understand what is in this part of the genome that may help to increase resolution even more than we have right now.
00:36:02:13 - 00:36:27:08
Iñaki Comas
Of course, there are many other developments in parallel that are important in genomics, like artificial intelligence, particularly for grammar system has been a play a lot or so we try or people, the people that is working in genomics and estrogen in terms of drug assistance is to identify all the mutations in the genome. On my questions about growth is to make it resistant to an antibiotic.
00:36:27:10 - 00:36:55:04
Iñaki Comas
And this looks like simple because or you do to what is you talk about with people that is not going to sort of make it into it will say yes, because tuberculosis kind of a low diversity pathogen is should be simple is not it turn out that we are still missing a few percent of mutations that we don't know where they fly and they we can not use for diagnosis because we don't know which mutations are.
00:36:55:06 - 00:37:12:24
Iñaki Comas
And artificial intelligence is being used in that direction. Also to try to to to predict where in the genome of the data, we need to look at it to produce resistance. So genes that are many developments in terms of a knowledge that can still be applied.
00:37:13:01 - 00:37:15:19
Abigail Acton
Or anywhere near out of work yet.
00:37:15:21 - 00:37:16:24
Iñaki Comas
Not yet, no.
00:37:17:01 - 00:37:18:09
Abigail Acton
Not yet. Not for a while.
00:37:18:09 - 00:37:36:17
Iñaki Comas
I mean that your work on TB probably the only thing that can shorten or or task is protected vaccine. And this is something which we are not expecting in the near future, probably in ten years, 15 years, not even with messenger RNA vaccines. They are because TB is more complicated than SARS-CoV-2.
00:37:36:20 - 00:37:51:03
Abigail Acton
Yeah, fascinating. Yeah, that's a pity. I'm glad you mentioned vaccines. I hadn't thought of that at all. So that's a really good place to end on and I really appreciate that. I want to thank you so much for your time. I've really enjoyed this conversation and I particularly enjoyed the way that you chatted amongst each other as well.
00:37:51:03 - 00:37:58:24
Abigail Acton
Thank you for that. It was always interesting listening to you guys talking together with stories up more interesting points. Superb. Thanks very much to all of you.
00:37:59:01 - 00:38:02:04
ALL
Thanks a lot. Thank you. Bye bye bye.
00:38:02:04 - 00:38:20:17
Abigail Acton
That was a very bye bye. Bye bye. Are you interested in what other EU funded projects are doing to understand how TB infects US Resistance drugs and switches from one state to another? The Cordis website will give you an insight into the results of projects funded by the Horizon 2020 program that are working in this area.
00:38:20:19 - 00:38:42:15
Abigail Acton
The website has articles and interviews that explore the results of research being conducted in a very broad range of domains and subjects from giant fossilized dormice to giant planets. There's something there for you. maybe you are involved in a project or would like to apply for funding. Take a look at what others are doing in your domain, so come and check out the research that's revealing what makes our world tick.
00:38:42:17 - 00:38:49:16
Abigail Acton
We're always happy to hear from you. Drop us a line editorial at Cordis dot Europa dot EU. Until next time.
Perspectives et idées
Les efforts mondiaux de lutte contre cette maladie ont permis de sauver environ 66 millions de vies depuis 2000. Mais la pandémie de COVID-19 a durement affecté la lutte contre la tuberculose (TB). Pour la première fois depuis plus de dix ans, les décès dus à la tuberculose ont augmenté en 2020, selon l’Organisation mondiale de la santé(s’ouvre dans une nouvelle fenêtre). Cet épisode de CORDIScovery donne la parole à trois chercheurs qui ont tous été à l’avant-garde du contrôle de la propagation de la maladie. De nouveaux tests peu coûteux et non invasifs, l’étude du génome de l’agent pathogène pour mieux comprendre son mode de propagation, le travail effectué au niveau moléculaire pour déterminer comment la bactérie passe de l’infection latente à l’infection active: tout cela est vital si nous voulons maîtriser et prévenir les épidémies. Hossam Haick(s’ouvre dans une nouvelle fenêtre) est doyen de l’Institut de technologie d’Israël(s’ouvre dans une nouvelle fenêtre), le Technion. Son travail de développement du dispositif A-Patch a été soutenu à la fois par l’UE et par la Fondation Bill et Melinda Gates(s’ouvre dans une nouvelle fenêtre). Hossam Haick dirige les activités de développement de capteurs intelligents non invasifs et de dispositifs portables pour permettre la détection précoce de maladies telles que la tuberculose, et le suivi à vie des troubles de la santé. Teresa Cortes(s’ouvre dans une nouvelle fenêtre) est basée à l’Institut de biomédecine de Valence(s’ouvre dans une nouvelle fenêtre), qui fait partie du Conseil national de la recherche espagnol. Elle cherche à comprendre comment les bactéries responsables de la tuberculose chez l’homme déclenchent l’infection, survivent, provoquent des maladies et développent une résistance aux antibiotiques. Teresa Cortes a participé au projet MtbTransReg. Iñaki Comas(s’ouvre dans une nouvelle fenêtre), qui explique les résultats de son projet TB-ACCELERATE, est également basé à l’Institut de biomédecine de Valence. Il s’efforce de démêler la complexité de la génomique de la tuberculose pour comprendre l’évolution et l’épidémiologie des maladies infectieuses. Son laboratoire est particulièrement axé sur la tuberculose, mais travaille également sur d’autres maladies, comme la COVID-19.
Vos retours sont les bienvenus!
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