BSE: One Protein, Three Perspectives.

"Mad Cow Disease" emerged in the United Kingdom in 1986. Named from the symptoms seen in cattle, it was eventually renamed more appropriately to Bovine Spongiform Encephalopathy (BSE). When humans are infected, the disease seen is variant creutzfeldt-jakob disease (vCJD).  

This episode explores the story of how a prion shaped the beef and biotech industries and revealed a failure in questions and ethics.  We are joined by Dr. Fiona Houston (senior researcher and veterinarian), Anne McVey (ethics advocate and mother of a victim), and Kelly Creighton (biologics manufacturing regulatory expert).

Join us to learn how scientists tackle emerging infections, why we need to ask the hard questions, and how this prion has shaped the industry.  

Transcript

Annie McVey: 0:00

So we swing back and forwards between economics success and ethical failure. And that can't be that really can't be what we want for our world surely. Hi, I'm Aaron Harmon. And I'm Diane Cox Welcome to Insight out quality. both Dan and I build and implement quality systems in the biotech and medical device industry. But we often get asked, Is this really necessary? That we know if we are doing too much too early? Or do we even need a quality system? Our goal is to explore questions like these through real life events and experiences shared by our guests from various regulated industries. We will show you why quality is not just about compliance and how when it's done right, it can help your product and company improve lives and make a difference.

Aaron Harmon: 0:51

In 1967, the idea of a new type of infectious disease came about a prion. In the 1980s. A prion was recognized as the cause of an infectious disease and cheap called scrapey. Few years later, in 1986, another new prion disease emerged in the UK, this one infected cattle and was quickly nicknamed Mad Cow Disease. How did this news disease spread? What was the risk to human health at that time, no one knew the UK his Chief Veterinary Officer Mr. Reese commented, there is no evidence that the bovine disease is transmissible to humans. Another key government leader Dr. William Watson advise, there was no reason at all to believe there was a risk to human health. They were kind of right. There was no evidence that this new disease could be transmitted to humans. Other known prions like scrapey didn't cross species barriers. However, there also wasn't evidence. It didn't cross the species barrier and infect humans. Here's the timeline. In 1986, mad cow disease was recognized. Then in 1990, a cat got infected with Mad Cow Disease, presumably from eating contaminated meat. 1995 Stephen Churchville died from a new variant of the disease, Crutchfield Jakob disease, something that resembles mad cow disease in humans. And then in March of 1996, a decade after it was first found. It was determined that mad cow disease could and did infect humans. Currently, 232 people have died from the disease. Mad Cow disease has shaped regulations in animal feed and biologics. There's a lot to discuss about Mad Cow disease. And to help us today is Dr. Fiona Houston of the University of Edinburgh. Dr. Houston graduated from the Royal School of Veterinary studies in 1989, and then spent four years working as a veterinarian in Canada and in the UK, right in the midst of the Mad Cow epidemic. In 1997. She obtained her PhD at the Institute for Animal Health and Compton, where she led studies on the pathogenesis of prion diseases. Her work led to the discovery that mad cow disease could transmit through blood and into other animals like sheep. She is now the group leader in the Roslin Institute. Welcome to the show, Dr. Houston.

Fiona Houston: 2:54

Thank you. Good afternoon.

Aaron Harmon: 2:56

So right off, right off the bat, what does Mad Cow Disease look like in cattle? If you were to see a symptomatic cow? Well,

Fiona Houston: 3:05

I graduated from vet school in 1989. And I was working in, in practice in an area with a lot of dairy cattle during the peak of the BSE epidemic. So we would be called like, fairly regularly to see animals that farmer suspected had BSE, and they would be typically very nervous, they would react very violently to sudden noises or touch it. They could be quite aggressive. They also had very stilted movements and tended to fall over if they had to turn sharply. And sometimes they were just what we call diner cause, which can occur for a whole variety of reasons, but cattle that can't get up. And sometimes they were just present like that.

Aaron Harmon: 3:55

What tipped people on that this was something new, and it wasn't rabies, or, you know, just some kind of normal aging degeneration or something like that?

Fiona Houston: 4:05

Well, that they'd never been cases like, quite like this in cattle of the age groups that were affected. So most of the cattle, although they were adults were quite young, they were about four or five years old. The we don't have rabies in the UK. So that wasn't one of the differential diagnoses. One of the most common differentials would have been Listeriosis. So infection with listeria bacteria. The clinical signs for that are quite distinctive. So it was quite easy to tell the difference between animals that have been affected by that. So they went they went rarely a whole lot of things that looked like this, and that didn't respond to any treatments. Normally, it would be if you suspected the case, it would be confirmed by a government that and the animal will be slaughtered and tested.

Aaron Harmon: 4:54

So you were starting out your veterinary career into the midst of this epidemic crisis almost. No, what was that? like,

Fiona Houston: 5:00

Well, I suppose at the time, it was just part of our normal routine. And I don't think at that stage, the link with human disease hadn't been established yet. So it was a new disease that had just appeared. But there were ways of dealing with it, you know, we had to report the cases, but then it was very much down to the government, feds to deal with them. We didn't think too much, I suppose about the you know, I think the full impact of the disease hadn't really hadn't really come to the fore at that point.

Aaron Harmon: 5:36

It was that because there wasn't believed to be in association with the ability for it to infect humans, or was it just because it was? Yes, I frequent?

Fiona Houston: 5:44

I think so. I mean, the government line at that time was very much the risk to humans is minimal. You know, this is like scrapey, and sheep, which had been around for years, you know, didn't didn't show any signs of transmitting to humans. So it was there was a big change once the new disease in humans emerged.

Annie McVey: 6:05

In that regard, why did it take so long to believe that it could infect humans? Were there? Were there just no apparent associations? Or what else might be involved?

Fiona Houston: 6:16

I think, I think it was the, like I say, it was very much that BSE was a completely new disease. So we didn't really, we didn't really know how to view it. So very much relied upon the experience of what we knew about scrapey and sheep, to inform risk assessments associated with BSE, although there were people who took the opposite view and said, Well, this is a new disease, and we should be as cautious as possible. I think there was a tendency to think, well, it's, it's similar to scrapey. And it probably won't transmit to humans. I mean, typically, these diseases don't transmit very readily between species, it's very unusual. And BSE was very unusual in that regard, because it transmitted to several different species, not just to humans, so it also transmitted to cats, and some zoo species as well. I think the other thing is that these, all of these diseases have very long incubation period. So typically, and what I mean by that is the period between when an individual becomes infected, and when they develop the disease is usually yours. You know, for other infectious diseases, it's often days or, or weeks or months, but it's it's typically years for these diseases. That's why the association of the disease in humans didn't appear until 10 years after BSE had been discovered and tattle. And there's no way there was no way of telling or testing to find out that people were infected before they actually develop the the symptoms of disease.

Aaron Harmon: 7:53

So you transition from being a veterinarian to a researcher, you know, what made you make that career switch? And how did you end up down the path of studying the SES and Mad Cow Disease?

Fiona Houston: 8:06

Well, I wanted to, I think I wanted to do to do something to benefit, particularly farm animal health, I was most interested in livestock health and disease, I suppose I also wanted a bit more of an intellectual challenge. So I decided to do a PhD in immunology in cattle. And then when I was finishing my PhD, that was about 1997. And it was just after all the publicity about the new variant CJD, which was caused by BSc in cattle. So an opportunity came up then at the Institute I was working out to get involved with and leader, a new group that was starting to study BSE in sheep, actually, because one of the big concerns was, at that point was well, it's possible that sheep have also been exposed to BSE. BSE, in sheep, when they're experimentally infected, looks very, like scrapey. And therefore, there was a lot of concern that perhaps not only cattle, but sheep might be a source of BSE infection for humans. So there was an opportunity to get involved in a great new unit, and, you know, lots of funding for research in that field to look at the specific risks of BSE, and sheep. And that's how I got started in this particular area and continued, and then the experiments themselves, because the disease has such a long time course take quite a long time. So to see them through, could take several years. I think the longest one we had was 12 years. Wow. From start to finish. So

Aaron Harmon: 9:42

there had to be like so many potential things. A researcher could have gone down for paths, and something like this, but so many unknowns, like was there just tons of ideas being thrown around that were then being prioritized and stuff like what that looks like from a research front? Yeah,

Fiona Houston: 9:57

there were so many things that that weren't known. And I suppose we were, we were trying to understand how the disease might be transmitted, whether it would change over time if it was transmitted, you know, BSE, and sheep, for example, whether it was transmitted from sheep, sheep, and would change. There were obvious practical questions. And I think that that influenced a lot of the research, both from a public health point of view, and from an animal health point of view, a lot of the funding from government was very practically directed at, you know, understanding these fundamental questions about about transmission and control, and what the risks were,

Diane Cox: 10:35

sort of help us kind of understand how this disease presented in humans. Could you also speak to whether it was able to be transmitted between people? Or is it just from the source of the contaminated meats?

Fiona Houston: 10:50

Yes, this is a really interesting question. And it was a concern right from the beginning, that this new disease in humans would it transmit from person to person and the the roots that people were concerned about, in particular, were via surgical instruments, because the prions that cause these diseases are known to be extremely resistant to most forms of decontamination. So, the normal autoclave cycles that you would use for surgical instruments wouldn't be effective at inactivating the infectious agent. So that was a huge area of concern, surgical and dental instruments and the other one of the other major areas was blood transfusion. This was something that we, we started to research using sheep as a kind of model for humans. So we took sheep that were experimentally infected with BSE, and then did blood transfusions, and showed that actually, the disease could be quite easily transmitted by blood transfusion. And then subsequent to that, I think a total of four cases in humans were discovered that that were attributed to infected blood transfusions. So so there is some evidence that blood transfusion, it can be a route of human to human spread. But the last of those cases, I think, was, was identified in 2006. And so far, there have been no further transfusion associated cases.

Aaron Harmon: 12:16

When you when your lab discovered that be like, Whoa, this is a big deal. I gotta get this out. Like, how did that? How did you process that information? When you discover that? Yeah, it does transmit from blood transfusions?

Fiona Houston: 12:27

Well, it was a big, it was a big shock, because I remember when I was setting up those experiments, I, I just thought, this is going to be the most boring experiment ever. Because, you know, we know that the levels of infection and blood are really low. So it probably going to be a completely negative result. And then when the first animal developed the disease, I remember I had to go to my boss on the director of my institute and say, you know, this has happened. And it was, it was really was a big deal. And then that we made the decision to because it was, it was so I guess I expected we published that result, straight away. Before we got any confirmation, or we got any additional cases, not a lot of people were saying, You that You've contaminated your experiment, or this can't possibly happen, you know, there was a lot of pushback from the the scientific community saying this, you know, you can't publish a result on a single animal, and you must have made a mistake. But then we confirmed it, you know, in many other in many other animals in that experiment, and it's been subsequently, you know, repeated by a lot of other people. So, definitely, so it was, yeah, it was a big deal at the time,

Aaron Harmon: 13:41

when you said that people are thought of maybe contamination, a joke and Diane, and I kind of have is whenever something goes wrong, and there's an investigation within a, within a business, the reflex is to blame the person that they had done something wrong, they made a mistake. That's why whatever it was didn't work. It's kind of a human nature thing, I think.

Fiona Houston: 14:00

Yeah, exactly. And it was so unexpected to me that we checked everything, you know, as carefully as we could. And we knew, you know, we didn't want to put anything out there. If we if we weren't certain that it was raised. So

Diane Cox: 14:14

just from pure numbers standpoint, how, how widespread was this, back then, when it was first discovered, and then compared to now, the peak number of

Fiona Houston: 14:25

cases in the UK was reached in about 1992. And there were over 35,000 confirmed cases of BSE and cattle in that year. And since then, it's been going down and no, we're at the numbers of cases are really low and most years there are no cases reported but every so often, there'll be there'll be another, you know, isolated case. We have one in Scotland in 2018. And I think that's the latest one in the UK.

Aaron Harmon: 14:54

What stop the epidemic.

Fiona Houston: 14:57

It really is dying to the I think the country falls on feeding meat and bone meal to livestock. I think quite early in the epidemic, the epidemiologists thought that it was consistent with a foodborne source of infection. And they recommended removing animal protein from ruminant diets. And that seems to have been, fortunately, there doesn't seem to have been very much transmission from cattle to cattle. So removing the the infection source in the diet has been effective.

Aaron Harmon: 15:28

And that was Was that pretty early on that that was introduced?

Fiona Houston: 15:31

Yes, the first ban was introduced in 1988. But the first Ban said that you couldn't feed meat and bone meal to ruminant livestock to sort of sheep and cattle. But what they discovered was that there were still cases occurring. And the reason for that was cross contamination in feed mills. So the same feed mills were processing food for pigs and poultry. And for cattle and sheep, if they were using meat and bone meal in their pig and poultry rations, that was enough, there was enough contamination in the system to contaminate the the cattle feed. So in 1996, they reinforced the legislation to say that animal protein couldn't be fed to any livestock. And that actually includes fish, I think, up until fairly recently, at least. So yeah, that's pretty universal. And that's, that was extended across the EU, I think, after 2000.

Diane Cox: 16:27

So I know, just being in the medical device space, we have regulations on making sure that the whereabouts from where our components of animal origin come from need to be known and understood. And we need to make sure that there's plenty of testing done to be to confirm that there's no disease within the components and devices that we're assembling. I guess, just from that perspective, how would manufacturers be able to confirm such a thing, what kinds of testing needs to be done, in order to confirm that there's no source of contamination in the devices or even medical Medicinal Products,

Fiona Houston: 17:06

it's actually really difficult because it's not easy to detect the infectious agent, because it's composed of protein, only the tests we have that we you know, that you apply to say a cell line or a particular product are not particularly sensitive. I mean, there are there are no much more sensitive amplification techniques that you can use. But they're not really adapted for commercial use. They're kind of research tools, rather than something that you could use to routinely test products. And I think that that is the biggest challenge. So if it was a virus, for example, you would think of maybe using PCR to detect contamination or something like that, or bacterial culture, but that's just not an option with with primes.

Aaron Harmon: 17:57

Do you have a sense of like, how many prions are needed to cause an infection? In an animal or human?

Fiona Houston: 18:03

That's, that's an interesting? That's an interesting question. I can't tell you just off the top of my head, but it's the infectious doses quite low. So I think in terms of infection experiments in cattle, you know, they've they've used decreasing doses of what they used to infect them in experiments, his brain homogenate From an infected animal, and they can go down below point one of a gram, I think it's still sometimes get infection. Now what that means in terms of the number of protein molecules, I can tell you, it's I imagine

Aaron Harmon: 18:41

that's hard to calculate. But yeah, it's it's quite low. Are there recent cases of variant CJD appearing in UK? Or is this pretty much been solved with measures that we're in but again,

Fiona Houston: 18:55

it's yeah, the the numbers of cases in humans have have come down. Since two, they I think they reached their peak in the year 2000. And they've been coming down since then. And in the last six or seven years, there's only been maybe one or two cases. So the last case that I'm aware of was in 2016. But the interesting thing about that case was their genetic background was different from all of the previous cases. There's evidence that the the prion protein gene itself can affect susceptibility to disease. And all of the cases had one particular genetic variant up until that point, but this person was heterozygous at the codon that that is associated with susceptibility. So what that means is we know that these genetic variants can be associated with different incubation periods. And therefore, there was a bit of concern that actually, we might see a second wave of cases in people with the who are heterozygous just because they had longer incubation periods and took longer to do But disease, but so far, there's been no additional cases.

Aaron Harmon: 20:04

So the control measures seem to have worked pretty good. So it's, yes, like fortuitous that that was at least started. The year after that the debate didn't go on too much longer. Yes. Yeah. One thing I'm curious about, we had the Mad Cow Disease thing, it seems to be, you know, pretty much slowly working its way to being something historical. Are there other things we could see emerge that you would could predict? Could there be something in poultry, something in swine?

Fiona Houston: 20:34

One of the things we just don't really understand this is where these diseases come from. So we don't really know how BSE originated in the past few years. chronic wasting disease that affects dear has appeared in Norway. Now, it's that was thought to be a problem just in North America, previous to that, but there doesn't seem to be any connection between the cases in Norway and any introduction from North America. Again, we don't really understand where has that come from three or four years ago, a new disease, a new prion disease emerged in camels in Algeria. And again, nobody knows where that came from, you know, I think we've got to be wary that it could, it could appear again, not necessarily, as you expect, pigs seem to be, I mean, there was a lot of concern about pigs, and there's been quite a lot of experimentation done on them. And they seem more resistant to be se than a lot of other species. So they were fed quite large, you know, infected with quite large doses of BSE, and didn't really develop the disease, if it was given by the oral route. I think it's, some species are definitely more resistant. And sometimes we can infect animals experimentally by direct inoculation into the brain. But that doesn't really tell you whether they would become infected in a natural setting.

Aaron Harmon: 21:53

Sure. Like there's a balance in the world of things that occur and stay control them, we do some things we can set that balance off. And so the, the meat and bone meal, feeding that back to animals cause that imbalance. And when that happened, we had the the outbreak, and when that then was taken away, it stopped it.

Fiona Houston: 22:13

But one of the interesting things is that meat and bone meal had been included in in animal feed for quite a long time previous to the you know, the 1980s, maybe not at the same scale, that one of one of the things that was thought at the time was there was deregulation of rendering processes at the beginning of the 1980s. So the industry was quite tightly regulated up to then and then they relaxed some of the regulations. People did warn at the time, well, if you relax these regulations you might get they weren't thinking of prion diseases, but they thought other infectious diseases like salmonella, and so on might might survive in animal feed and cause disease outbreaks. Although it's never been definitively proven that that was theory that that was very prominent in the early stages that actually, the changes to rendering allied the prime agent to survive in animal feed.

Aaron Harmon: 23:09

One of the things that Dan and I really see is there's a lot of value in regulations. And when regulations done well, they can help companies or industries prevent things from going wrong. And that's probably why we do this podcast. And so it's interesting that you mentioned that, because that kind of supports what we're saying, and the fact that a regulation is kind of what helps stop this. Yeah, just goes to show the importance of them.

Diane Cox: 23:31

Yeah, there are there are obviously possibilities for outbreaks within animals. But how do we know? Or have any intuition or studies to know whether it's transmittable to humans? Is it just through these types of events happening? Or is there a way to kind of predict that?

Fiona Houston: 23:54

It's a really important question, because I think, with BSE it was, you know, it was a very special set of circumstances where you had a large outbreak of disease and cattle followed several years later by a completely new disease in humans. And then in many ways, it was easy to make the association between Okay, BSE causes this disease in humans, but for other prion diseases on a smaller scale, if someone became infected by eating say, a sheep with scrapey and 20 years later, developed a neurological disease. It's very hard to make that association just from epidemiological data alone, especially if your surveillance, your disease surveillance isn't absolutely excellent, which which is not, it's not universally, great, you know that you'll have the level of surveillance that you need to make those associations. So we really have to rely on experimental evidence, and that comes down to a lot a lot of times to experimental infection. So we'll try to infect primates as being closely related to humans, but there are also two transgenic mouse models which have been genetically altered to express the human prion protein, and therefore are more susceptible to human prions. So we can use them as a kind of surrogate of, would this particular animal prion disease transmit to humans. So there are various models like that that can be used to assess the risk. But at the end of the day, you kind of then need the epidemiological evidence to back that up, because as I said, Before, you can infect these experimental animals. And usually it's done by artificial roots by inoculating into the brain. And that doesn't necessarily show that it could happen in real life. So yes, I don't know if that answers. Yeah, yeah, it's a question. But, but yes, and no, you know, to try and get away from the use of animal models, where we're also trying to develop in vitro models, where, where you sort of, you have a simplified model for prion replication, and you can use that and it gives you answers a lot more quickly. They need these sort of models probably need a bit more validation. But in future they might be really useful for assessing those kinds of risks to humans. Sure, sure.

Aaron Harmon: 26:09

If you can remember back to when you first heard about this new disease and animals are in cattle. Did you ever have any inkling that this is going to shape your career shape the cattle industry shape regulations?

Fiona Houston: 26:21

No, not at all. You know, I remember first hearing about it and seeing my first cases when I was a vet student in Edinburgh. But yes, I had no idea of the impact on me and on the whole industry as well.

Aaron Harmon: 26:33

It's crazy how that works out. Yeah.

Diane Cox: 26:36

Fascinating.

Aaron Harmon: 26:37

Well, thank you for being on the show, Dr.Houston.

Fiona Houston: 26:39

Very welcome. It's been a pleasure.

Aaron Harmon: 26:42

Now we'll take a quick break to hear from one of our sponsors.

Joni Ekstrum: 26:45

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Aaron Harmon: 27:24

I'd like to make a transition in terms here. When this prion disease was first identified, it was referred to as mad cow disease because of the behavior of the cattle it infected. Its true name is Bovine Spongiform Encephalopathy, called BSE for short. When BSE infects the human, the disease scene is referred to his variant Creutzfeldt Jakob disease called V CJD for short. Why are these terms important? Because diseases aren't just viruses, bacteria, parasites and prions. They affect who we are, they shape our lives, they take from us physically and drain us emotionally. So it's important that we give them a proper identity, one that calls them for what they are or not taking away from who we are. The youngest victim of BSC was clear McVeigh, she died aged 15 on January 11, of 2000. Claire was born on May 29 1984. If you remember the timeline from the beginning of this episode, BSC was first identified in 1986. Claire was two years old. The government officials at the time insisted there was no risk to humans, people should continue eating beef without worry. They continued to insist it couldn't infect humans until 1996. Three years later, any McVeigh Claire's mom noticed something was wrong with her daughter. And he witnessed the tragedy of this disease in her home, she experienced loss in a way most of us haven't, and hopefully never do. The worst part was that though she trusted to protect her and our family told her and everyone else that BSE couldn't infect humans, they erred on the side of protecting an economy instead of the lives of those they were supposed to protect. This podcast covers when things go wrong, not to point fingers or to blame, but an attempt to prevent things from happening again. We've covered suppliers that lied about data, vaccine counterfeiters, managers cutting corners to save cost, poorly designed drug trials by scientist. When we fail to do our jobs, people can die as Claire did. And he has her own approach to helping prevent this tragedy from happening again. She joins us here to share.

Annie McVey: 29:23

Thank you, Aaron for having me. I've spoken a lot about Claire since she died. And often people want the story of the horror of her dying and her death. But I understand why. But there's more to the story than that. It's about all the decisions that were made out of my control before she became ill. And those are the ones that people continue to make every day because businesses run. They want to be economically viable and successful and they make decisions. And I understand that. I think all the families understand that that, you know, businesses there for profit. But it should be more than that is the ethical considerations that sometimes get left behind in this race to make a good spreadsheet at the end of each financial year that the shareholders will be happy with. Now, we could all do that we could all make money, if we never looked at the consequences of doing that. And one of the things that I've done since Claire died first in anger, because those first few years when you're bereaved, you're very angry, or at least I was. And since then, I've wanted it to be more of a positive contribution to policymaking. And that's to remind the politicians who were involved in the BSE scandal, and the ones who are making similar decisions now that every decision they make, has a human consequence, I write to the politicians, usually around Christmas, that's when our emotions are usually focused on family. I also include the Muslims in government and atheists in government. And I tried to tailor my letters that might speak to them, to remind them that every decision they make has a consequence. And sometimes that can be a fatal consequence. And not to take them purely for financial gain, because that is disastrous for any business. Because once you take away your customer, once you can be blinded to that in the search for financial benefit, then you almost lose your soul. The spreadsheet is valuable, and I understand it. But there's another one, there's another part of that balance sheet, and I just ask the politicians to remember that when they sit down for their Sunday lunch, or the Christmas lunch, remember, I'm sitting down, and there's a space across from me. And there always will be. And as times gone on, there's not just one space, there's a space for her children, because they're missing as well. And a partner, you need to know that is not enough, do think a decision is made. Pros and cons. It's not just black and white, there are gray areas. And in those gray areas, people can die. The letter goes out, some of those politicians have retired now, but new ones take their place. And if they're the same political hue, normally, they're making the same decisions. And I have to say, with Coronavirus, COVID-19, they appear not to have learned very much. And that's that. So this year, I think my letter might just be a little bit more hard hitting. And we'll see what we get from that. That's my contribution.

Aaron Harmon: 33:00

I really like the approach you take. There's all these decisions to be made in the future, right? And we want them to be made for the right reasons. And they're not easy to make. But if it's always airing towards the balance sheet, there's a cost to that. How did you transition to making this approach, you have

Annie McVey: 33:15

to become realistic after a while, initially, when Claire was ill and died. I mean, as I said previously, it was the anger to that, that I couldn't think I just wanted to punish people. And I wanted people to hear the story and to feel the grief I felt. Then I thought about well, where do I go from this because I can live my life in anger and grief. And is that really the best memorial to my daughter and all the other sons and daughters. And it seemed to be that you have to be realistic. When I looked at business, and I saw that they made decisions sometimes which I would not say were ethical. I wanted to know why they made those decisions. And the pressures they were under to do that. Because in 2000, when the BSE inquiry was published, Claire had already died. And all I could see with the retrospective nature of the inquiry was all the mistakes they had made. All the times when they they had information, which if you didn't allow yourself the imagination to see where that could go. The consequence of that you could never have ignore consciousness have continued that course of action. But they didn't allow themselves to see that they were blinded. They only wanted to see what they wanted to see. And they wanted to avoid any disruption to the feed industry any disruption to the meat industry, the livestock industry, even when it passed from one species to another. They didn't have the imagination to realize that we are basic Aliy animals, if it passes from cow to cat, why won't it pass from cat to human? Not in the sense that you, you catch it, but in the sense that it will evolve, it will mutate. And it's having that imagination and being listened to, because there were people saying those things. They were just not welcome at the table. Because they're like the specter at the feast, the person who brings you down by saying, Yeah, you can, you know, you can double your profits this year, you can really make sure this business flies, and somebody says yes, but And so the way to do that, for me was to show the, you know, if you've got a very cold hearted CEO, what you do is you tell him how it will impact on his profits, because a couple of large lawsuits are not going to help his profits. So you have to speak to the person, you have to get to them in a way that they understand. And I realized, you know, after about a year or so, after Clara died, that I wasn't reaching the people it was necessary to reach, I was reaching the other parents who hadn't lost children. And they were acknowledging the pain, and they saw the horror. But the people who made the decisions, just dismissed me as a bereaved mother, they didn't think I had anything valuable to say, or any understanding of the position they were in. So you have to bite your tongue, try not to be hypercritical, but give constructive criticism, which is Have you thought about this? Have you thought about that? I would love to see every board, have a person who is purely there to give the dark side, purely there to take down the enthusiasm and say, We need to think about this. The worst case scenario, what would happen, proper open risk management, not the sort of closed risk management you do in the business, but something which really does make everybody around that table thing. So that's what I've been trying to do. I've been trying to be a little more calm about things less emotional about things, and I try to hear what the other person is saying. And the pressures they're under, you know, shareholders want money. That's what they want. Some of them don't think about the ethical product. And you need that other person that that everyday person who doesn't have one narrow remit, but looks at the whole picture, really. And if they don't, they get a letter from me at Christmas. So

Aaron Harmon: 37:40

I really appreciate you, Annie. I feel like we're totally aligned. Oh, this should go and I'm glad you you've gone that route and do that.

Annie McVey: 37:47

I wish I could do more because I I think it's an important thing to do. Thanks for sharing with us any. That's okay. You're welcome. And thank you for inviting me.

Aaron Harmon: 37:58

One lesson often learned in quality is that's not the problem. But the questions you asked about the problem. And he mentioned the gray areas. These are the areas where it's easy to steer into a mistake, because the answers aren't obvious. Here's how it played out with BSE. There was a gray area in 1987, a new disease appeared and there was nothing known about that specific pathogen. Do you shut down the beef industry? Do you risk the lives of your public? Someone or some committee needs to make a decision? researchers like Dr. Houston spend their lives trying to bring answers to the table those trying to answer these gray area questions. I think the challenge in gray areas is asking the question correctly. Example. Can anyone prove that BSE infects humans? In 1987? The answer was no. No one can prove that. How might this question and answer impact the decisions you make? Now let's ask it a different way. Still a 1987? Can anyone prove that BSE does not infect humans? And the answer is also no, no one can show that it is safe for people. How does that impact the decisions you make? The later is the way quality assurance folks ask questions. We want to ask, do we know it safe? Is there a way to make it safe? We do this to help prevent disasters? How did BSE affect pharmaceuticals biologics and medical devices? There is still research ongoing and BSE. There are still people dealing with the impact the pathogen had in their lives, and in biotech, we think about this pathogen and others and ways to stop them from getting into our product. Joining us again to discuss the impact that BSE has had in the medical product industry is Kelly Creighton. Welcome back to Inside Out quality Kelly.

Kelly Creighton: 39:33

So it's good to be here again, Aaron.

Aaron Harmon: 39:35

So Kelly, you've been in the pharma and biologic space for many years. How did you see BSE impact this area?

Kelly Creighton: 39:42

Well, obviously it has a direct impact ultimately on the industry, as many people probably realize that a lot of animal derived products are used during the manufacturing process specifically in biologics, things such as serum or enzymes or liquid lipids. are often used in the cell culture processes and such that are used to generate biological products. So in that instance, right, FDA ultimately had to address this issue with regards to ensuring safety and quality of those products that go in and to those manufacturing processes, as well as not only direct products that go into the medical and biological processes, but other things such as like gelatin, which is a very common product that is used to make capsules, those most gelatins, at least definitely back in the 80s and early 90s, were directly derived from bovine materials. So of course, FDA had had to address this, to ensure that the drug supply and biologic supply did not put people at risk for potential BSE infection. So in 1993, FDA issued their first position and first regulations that basically required that all mammalian derived proteins, so it also included some controls around Oh, Vine, the swine regulations came a little bit later. But in 1993, they issued their first guidance and regulations with regards to where bovine derived materials could be sourced from. So this basically relied on the USDA list, which listed out all the countries for which there had been either confirmed or suspected BSE cases. And basically put those countries on the list of prohibited countries that could import any type of bovine or ruminant derived materials into the US. So that was kind of the first impact that we saw is that FDA limited where you could source those types of materials, ultimately, right? In 2000, they came back and they did a very deep review into all of the vaccine programs that are on the market in the US. Vaccines are probably one of the biggest users of animal derived products that go into the process, not ultimately ending up in the final product, but go into the process. And then 2000, they found that even though the regulation had been in place for seven years, they found several products that were still using bovine materials from basically from the USDA less countries, which are countries that were banned. And people asked hell does this happen? Like, why could that happen? Is because Right? Those materials may have been made in a country that it was not on the list. Therefore, they were imported directly from a country that could import bovine bribe materials into the US. However, they actually sourced it from countries that were on the USD less. So that is, where's that whole supply chain management and understanding and people really figuring out, okay, we've got to have better controls around this. So at that point, FDA basically asked that all vaccine manufacturers that had currently been using products from countries derived in the US the less to go back and remove those materials. And this had a rather large impact for some companies, because this included going all the way back to cell banks, which are typically the starting point for the process. And it takes a lot of work to to derive and qualify cell banks. Now, this applies only to working cell banks, not all the way back to the master. So FDA agreed that the master cell bank, even if it was used materials from USDA, less countries, that that was far enough back in the process that that presented a very low risk, but all working cell banks had to be remade and derived from with more materials from countries not on the USDA less. So all immediately had a big impact on on those companies as they had to go back and do that. Ultimately, right, that's FDA has gone back and done a deep review and dive and monitoring. And there has never been a single case of BSE anywhere in the world that has been linked to a biologic or pharmaceutical product. So overall, right? The controls that have been in place now since 93, have been adequate to prevent that type of transmission. But I can tell you working in industry and working heavily in the biologics industry, the sources and quality of raw materials that go into the process into a biologic process is always a major concern with FDA. And anytime you're you're presenting that information to FDA, you have to submit a substantial question Have you documentation around the product to verify that it is derived from areas or regions that no longer have BSE and that basically have quality statements, very specific quality statement, that the product is at very low risk of containing either BSC or TSC agents. So that is a very big, big part of the industry now. And as the industry has evolved, we're actually starting to see more and more companies pivot away from the use of animal derived products altogether in their manufacturing, and using either recombinant protein type products to replace enzymes or, or things like that, or plant derived components. So they industry continues to try to move away from animal derived products, just just to continue to address that safety risk and try to get further away from it.

Aaron Harmon: 46:00

Sure. And even on if I understand, right, so take bovine serum, if you purchase bovine serum for use manufacturing, it's a being sourced from countries that would not be having BSE outbreaks, then it is gamma radiated potentially, yep, filtered to levels that would remove any potential contaminating bacteria. So by time it makes it to the manufacturing floor, it has been cleaned up as much as possible. Well,

Kelly Creighton: 46:24

right as possible. And again, right, the prion that causes BSE is very difficult to remove sir. So even like the gamma radiation, but does not necessarily prove that. So that is why the control goes all the way back to the source of where those cattle originated, because there really is no, quote, unquote, validated clearance process to truly make sure you can get rid of the prion throughout the process. So that is why you have to control it all the way back to the source. Now now, right? So back, when talking about in 2000, all the vaccines went under review. At that time, basically all of Europe was was on the USB less, right, because it originated in UK, or at least, that's where the first cases were. But really, basically all of Europe ultimately got indicated, even though like very specific countries never had a reported case like Austria, but basically, because of open borders within Europe, and everything all of Europe got on the list. Now that we're getting 3040 years out from the original finding, there are now ways for countries that were ultimately on the list to come back in. And so the import restrictions have dropped for a lot of countries that were originally on that list. Now, again, there's there are still countries on the list. And you have to be aware of that when you're sourcing. And you know, it tends we tend to see that Australia and New Zealand tend to be still the preferred sources for at least bovine derived materials, because they were they were never implicated in the original. So they still tend to be kind of the preferred and kind of the gold standard for source when people are looking at sourcing bovine derived materials. But there are a lot more countries that are able to to import into the US. But again, it goes back to the sourcing because the lack of ability of a process to truly ensure that you would kill any type of prion if it was present, that just doesn't exist. So you have to control it back.

Aaron Harmon: 48:30

So and then, as you mentioned, to getting away from bovine products when you can, there's so much effort to get out of animal products

Kelly Creighton: 48:37

it is but you know, it's funny. One of the things we see is like I said, for a lot of specific things, but like enzymes, people are trying to go to recombinant sources. And those are derived typically in either bacterial or yeast systems. And then of course, right grown up by recombinant technology and then purified. The tricky thing is there is that a lot of recombinant processes also use animal derived components. So I have seen FDA dig into that, and I haven't I firsthand experience with FDA having a safety concern for a product because an enzyme used in the manufacturing of a certain biologic was actually derived from recombinant technology. And when they dug into that recombinant technology found that process use basically animal derived products. So you see where you can get very deep levels not having to dig and verify your entire supply chain of whether or not animal derived materials are actually ever chance because FDA always considers once you have one place where those agents be at BSE or some other type of adventitious agent. If there's ever a chance for those types of agents to enter into the supply chain, it is almost impossible for Most processes to ever remove them. And so they will have, they will make you verify that all of those materials, Mat current standards with regards to BSE, or advantageous or viral agent qualifications. So it can be a very tricky issue for people and quality to be able to control all the way back, you know, maybe three or four vendors back for raw material that you're using in your process.

Aaron Harmon: 50:30

So that's just good reason for it. And so you're right, no, yeah.

Kelly Creighton: 50:35

Right now, it's it's a legitimate concern from the FDA. And I said, the systems now are, are well enough develop that it's typically not that onerous, or burdensome now to make those links, all those chains. But I can tell you even going back to early 2000s, that wasn't necessarily an easy task. And also right, a lot of products, biologic products and getting developed late 90s, early 2000s. Those products, especially like the master cell, banks, and potential you in the working cell banks were derived prior to 1993. So before there ever was regulations, and so that is where a lot of people had gotten caught up. But again, right now we're getting far enough away, that the regulations are basically just everybody understands. And that's just part of part of the industry. And there really is less concern or risk and being able to trace your raw materials all the way back to source at this point. I hope for those that are listening to this episode that are not working in the biotech space, like we do hear this and say, Well, they do quite a bit of effort to make sure our products are safe. Because that's exactly why we do that. That's what the FDA wants. And that's what we're trying to accomplish. Exactly. Yeah. I mean, and like I said, the industry has always been fully behind these regulations. It's not like people have pushed back or companies have been pushed back and thought this was overkill, or that it was not required. Everybody has always supported them because they understand at the end of the day, patient safety is always the key and Paramount thing with regards to products. And nobody wants to put patients are under duress because of some issue like this. Yeah. Well, thank you for your insights, Kelly, for joining us. Of course, I'm happy to do

Aaron Harmon: 52:32

and stay tuned for the next episode of insight quality. We hope you enjoyed this episode. This is brought to you thanks to South Dakota biotech Association. If you have a story you'd like us to explore and share, let us know by visiting www. SD bio.org. Also, if you live in the Sioux Falls area, check out QUIBIT A local Quality Assurance Professionals Network. You can find out more about QUIBIT by clicking on the link on our website too. Thanks for listening