BodyLab with Grant Ramm



Claire Blake (00:00):

The liver is an incredible organ. It puts up with a lot, a lot of diseases impact the liver. It gets stuck with cancers that started somewhere else. It gets no thanks for doing all the cleaning. It does have a superpower to help, but fight back, but first it needs to overcome a PR problem. I’m Claire Blake, you’re listening to body lab. This is a QIMR Berghofer medical research Institute podcast. Professor Grant Ramm has been on the leading edge of liver disease research, especially in cystic fibrosis for nearly two decades. He’s group leader of the hepatic fibrosis laboratory and deputy director of the Institute. Thanks for joining us grant.

Professor Grant Ramm (00:40):

Thanks Claire.

Claire Blake (00:41):

I’ve said it’s an extraordinary organ and you’d have to agree wouldn’t you?

Professor Grant Ramm (00:44):

Absolutely. It’s a remarkable organ. It is vital for normal functioning of the body. It cleans the body of all the toxins and it can completely regenerate itself if it’s damaged. Most of the organs in the body can repair themselves, but if you’re remove up to 75% of the liver, it will regenerate that lost mass.

Claire Blake (01:05):

That’s extraordinary. I guess we’ve learnt that from accidents and disease in the past.

Professor Grant Ramm (01:08):

That’s right. And also from resections of liver tumours or resections of damaged liver that can grow back,

Claire Blake (01:14):

It can take a fair bit of abuse or insult.

Professor Grant Ramm (01:18):

Yes, it can. It has to deal with an awful lot of insults that we, um, inflict upon it. For instance, diet that we choose the lifestyle. We choose how much alcohol we consume. It can handle all those insults and it can still function normally. But if done in excess, it does start to damage the liver.

Claire Blake (01:35):

If you keep on abusing it, first of all, you get fatty liver disease.

Professor Grant Ramm (01:40):

Yeah. When the liver’s damaged, you can get fat deposited within the cells of the liver. And that fat can be derived from excess alcohol consumption, but remarkably one in four Australians live with some form of fatty liver disease. That’s generally caused by a poor dietary choices over a prolonged period of time or a sedentary lifestyle. And that leads to a condition called non-alcoholic fatty liver disease, which has recently been named metabolic associated liver disease. As it has links to the metabolic syndrome.

Claire Blake (02:10):

Now that’s distinct from alcoholic fatty disease brought on by excess alcohol.

Professor Grant Ramm (02:16):

Yeah. Excess alcohol can damage the liver and cause, uh, what’s called a hepatitis, not a viral condition, but a hepatitis meaning that the cells of the liver, the hepatocytes are damaged and they burst open, but it also leads to fat deposition in the liver. Whereas non-alcoholic fat liver disease doesn’t necessarily cause the cells to burst open, but it still results in a deposition of fat in the liver. Now non-alcoholic fat liver disease can eventually progress to a more serious conditions where you do get hepatitis again, not a viral condition, but the cells of the, the liver burst open damages, the liver and causes the liver to try and protect itself or heal itself in a wound healing process, whereby collagen is deposited. And if left untreated that can progress to scarring of the liver, which is excess deposition of collagen, basically rivers of scar tissue running through the liver. And that’s called fibrosis fibrosis can progress to even more significant disease, which is cirrhosis and ultimately liver cancer.

Claire Blake (03:17):

And even at that stage of fibrosis and scarring, it’s completely reversible by changing your habits.

Professor Grant Ramm (03:22):

Yeah. Early stages of fibrosis, um, or early stages of collagen deposition can be completely reversed if you stop the insult. So if you stop the excessive alcohol consumption, if you change your lifestyle, become more active, it healthier foods. If the insult is removed, then the liver can completely repair itself.

Claire Blake (03:39):

You don’t have to appear to be carrying a lot of weight to have fatty liver do you? 

Professor Grant Ramm (03:42):

No, not at all. Everyone’s different. Everyone’s an individual. So the body reacts in different ways. Apparently fit. People can also have fat deposited in their liver as well.

Claire Blake (03:53):

So at this stage it’s fully reversible, but once it gets to the stage of cirrhosis, then it’s more serious.

Professor Grant Ramm (03:58):

Yeah. It’s more serious. The jury is out. Whether cirrhosis can be reversed, some experimental model studies have shown cirrhosis can be reversed yet. Other clinical conditions. The evidence is not as clear, but you don’t want to develop cirrhosis. If the injurious insult is removed and you have cirrhosis, the cirrhosis will lessen in severity and you can still live quite normally, the liver can still function, but that’s the kick. You’ve really gotta remove those end injurious agents, the alcohol fatty foods, poor diet and other causes of liver disease. Anything that may damage the liver,

Claire Blake (04:32):

It can take that much abuse and still bounce back.

Professor Grant Ramm (04:34):

Oh, it’s a remarkable organ. It’s a remarkable organ to study and to investigate, to understand how it works and what mechanisms cause disease and how you can reverse those. It’s given me a lifetime of interest in research and, um, I’m passionate about continuing that work.

Claire Blake (04:48):

It’s got a bad rap.

Professor Grant Ramm (04:50):

It does have a bad rap. Um, the perception in the public is that it’s an acquired condition. You’ve somehow done this to yourself. And in some cases that’s true with excess alcohol consumption. If you are on a prolonged period of prescription drug medication, drugs can also cause damage to the liver, but there’s a significant number of liver diseases that are, are not acquired or self-inflicted, they are the inherited or congenital diseases. The diseases that we study at QIMR Berghofer,

Claire Blake (05:19):

It’s so vital that this research is funded. But for some reason it attracts very little funding.

Professor Grant Ramm (05:24):

Yeah. I guess it’s the public perception. It’s not a sexy organ.

Claire Blake (05:28):

It doesn’t garner a lot of support

Professor Grant Ramm (05:29):

We need to change that perception with a public, with government, with private sector and raise the profile of liver diseases that have been neglected when it comes to the public attention and, uh, the consequent funding that comes from various different revenue sources.

Claire Blake (05:44):

And when it gets really serious, it leads us into your passion. Now, cystic fibrosis, an organ that doesn’t attract a lot of funding, but young babies that are born with something that they have no control over.

Professor Grant Ramm (05:56):

That’s right. Yeah. Cystic fibrosis occurs in about one and two and a half thousand people in Australia. It’s the most common lethally inherited disease in Australia. And if couples have one copy of the, uh, mutated gene and decide to have children, then one in four kids born to parents who carry an affected copy will end up with cystic fibrosis. And that’s diagnosed with a hill prick test around about the time of birth.

Claire Blake (06:21):

Now people see it as a lung disease and that’s true, but the liver plays a really crucial role.

Professor Grant Ramm (06:26):

Yeah. It’s especially important in paediatric years. Significant liver disease occurs in about 10 to 15% of children in the second decade of life. When you combine that with the more well known effects of cystic fibrosis on lung congestion and lung infection, it provides a survival disadvantage to that percentage of population of those kids. If you’re able to manage getting through those paediatric years into early adulthood, the incidence of liver disease isn’t as, as obvious, there are some adults that do continue to have some liver function problems, but it’s more evident in those children in the second decade of life. It’s a significant additional health burden on those kids who have to deal with so many different tests and treatment options to improve their, their lung function to have to put up with ongoing liver disease is, uh, is a pretty tough road to travel.

Claire Blake (07:16):

This is the one instance that the liver actually can’t repair itself because it can’t stop the insults.

Professor Grant Ramm (07:24):

Is that right? No, that’s right. With acquired conditions, you can stop drinking alcohol. You can change your lifestyle with inherited diseases or congenital diseases. And then you’re born with those generally due to our mutation in a gene that’s vital for survival. And so you have no recourse people with cystic fibrosis over the last 20 or 30 years have had a dramatic increase in their life expectancy. Albeit life expectancy is still about 50 years of age with the, um, introduction of enzymes to improve pancreatic sufficiency increase absorption from the gut. Those have really had a great impact on increasing life expectancy. And more recently, the introduction of modulators of the defective protein have really helped a percentage of people with cystic fibrosis. The gene that’s affected is called the CFTR, the CFTR protein aids in hydrating lung passages and bio ducts. And you need to have a more fluid environment in those ducts so that you can remove mucus.

Claire Blake (08:24):

Sounds counterintuitive, doesn’t it?

Professor Grant Ramm (08:26):

Yeah, it does. Yeah. Without having some fluid in your lung, the mucus builds up in your lung causes congestion and infection, and that’s generally leads to pneumonia. Something similar happens in the, in the liver when the liver detoxifies the blood removes all the, the dangerous chemicals, it excretes it through the bile duct, into the intestine, in those kids with a defective CFTR protein, the bile duct isn’t hydrated, and the bowel becomes thick and sludgy and the removal of those toxins from the body stops. And those toxins then build up in the liver, damage the liver and cause collagen expression deposition of collagen fibrosis or scarring. And then ultimately cirrhosis.

Claire Blake (09:06):

I know you’re passionate about this disease and it’s really brutal. We talked about the lifespan. They’re the one group of people who can’t be in a support group and support each other because it’s just dangerous to be around one another.

Professor Grant Ramm (09:17):

Well, particularly these days with COVID people who have, uh, chronic lung conditions really can’t be associating too many other people because of the concern about catching COVID as well.

Claire Blake (09:27):

Now let’s get back to the modulators because this is where you think the answer might come from and you desperately would like funding to take this further. It’s been very promising.

Professor Grant Ramm (09:36):

Yeah. The CFTR modulators, uh, work in a percentage of people with cystic fibrosis, but not all. Unfortunately it’s believed through anecdotal evidence that they are not really appropriate for people who have concurrent liver disease and may actually worsen liver disease. So what we’ve been working on for quite some period of time is to try and identify children earlier that may have liver disease or may be predisposed to liver disease so that they can be better managed. But more importantly, we’ve been working on a molecule that we’ve identified that may play a role in inhibiting that collagen deposition and inhibiting scarring of the liver and therefore stopping fibrosis progression. If we can develop an agent that can treat the liver disease, then those children may be more able to access the CFTR modulators to improve both their liver and their lung function and have a better quality of life.

Our current research focus is to follow up on an observation we made in children with cystic fibrosis that have modified levels of a particular type of molecule in the liver called a micro RNA and micro RNAs regulate how many proteins or, or what volume of proteins are produced in the liver and this particular micro RNA we are very excited about as it actually regulates the level of collagen in the liver. What we have demonstrated is that we can put a modified version of this micro RNA into liver cells, and we can stop the production of collagen. And as I mentioned before, it’s collagen that causes scarring of the liver and fibrosis. So we believe we may have a potential antifibrotic agent that can treat liver disease. And this is not just applicable to cystic fibrosis. This could be applicable to scarring or fibrotic injuries in other organs, such as the lung in cystic fibrosis or indeed in the heart or the pancreas that may be affected by other conditions that cause fibrotic scarring in those organs.

All of our work so far has been in discovery in the laboratory using tissue culture methods. What we next plan to do is to scale this work up into pre-clinical models, to show that we can actually reverse or inhibit the fibrosis or the liver scarring in models of chronic liver disease. Ultimately, if those are successful, then that would progress to clinical trials, but that’s a few years away, but this is really exciting work that we’re doing. And we are really encouraged by the results we’re generating. A lot of funding obviously goes into those areas where the public and the government have observed. There’s a significant need in the community. That funding has gone into other diseases where the, the government can see where the cost benefit is. I think the, the lack of understanding by the public and the government about the seriousness of liver disease and the impact on the community is only just becoming apparent now. So we’re playing catch up. We need to do a better job in selling the problems associated with chronic liver disease in Australia. And I believe we are doing that, but we are a long way behind where the funding should be for these studies

Claire Blake (12:34):

To understand the implications of this for all the other diseases.

Professor Grant Ramm (12:38):

That’s right. It’s not just about cystic fibrosis. All those, that is my passion. I work in other inherited diseases like the iron overload disease hemochromatosis, which affects one in 200 Australians. It’s an imminently treatable condition because it’s simply requires a blood donation to remove excess iron from the blood. There are a considerable number of other chronic liver diseases that are underfunded. There was a study published by Deloitte access economics about 10 years ago that showed the economic cost of chronic liver disease to the Australian economy was 50 billion. That was 10 years ago. That’s a significant cost to the economy of Australia. And yet the investment in research in discovery research in translation and in the clinical trials that may happen through the discoveries from basic research is chronically underfunded in this country.

Claire Blake (13:29):

And when you consider, is it one in four people have fatty liver disease.

Professor Grant Ramm (13:32):

One in four people have a fatty liver disease

Claire Blake (13:35):

In Australia?

Professor Grant Ramm (13:36):

In Australia. Most people will live quite normally not knowing that, but if they do have a second insult such as if they are consuming excess alcohol, that compounds the existence of the fatty liver disease and can lead to fibrosis.

Claire Blake (13:48):

When I walk down the pharmacy ISS and see liver detoxes in supermarkets online, tell us how that sits with the liver. And do you have an opinion on whether they might work?

Professor Grant Ramm (13:59):

Oh, my opinion is save your money. Don’t buy them. They don’t work. Uh, the liver can heal and repair itself if you give it time. And that requires consideration of your lifestyle of a sedentary lifestyle, doesn’t help poor dietary choices over a long period of time. Don’t help alcohol in moderation. If at all, and your liver will be fine. Some of those liver diets or liver juices, particularly the herbal remedies, you dunno, what’s in them. And they can actually be quite serious for the liver and can damage the liver in itself. So I would say don’t

Claire Blake (14:34):

Thank you so much, Grant. I think hemochromatosis deserves its own podcast. What’s this space. If you’d like to know more about professor Grant Ram and his team and their work, or if you’d like to donate Thank you Grant. 

Professor Grant Ramm (14:53):

Pleasure, Claire. Thank you.